DE2337581A1 - DERIVATIVES OF 9-HYDROXY-13-TRANS-PROSTIC ACID - Google Patents

Description

24 009

American Cyanamid Company, Wayne, Mew Jersey, V.St.A.

Derivatives of g-hydroxy-1β-tra ns-prostenic acid

The invention relates to new hydroxy-substituted 15-deoxyprostanoic acids and derivatives of these acids as well on starting materials and intermediate compounds for their production and processes for their production. the new compounds according to the invention can be represented by the following general formula:

ZCR ₃

1 ... ι

where mean:

R _{1 is} hydrogen, a hydroxy group, a lower alkoxy group, a tetrahydropyranyloxy group, a lower alkanoyloxy group, a lower alkoxy group which is hydroxy-substituted in the omega position or a lower alkoxy group which is tetrahydropyranyloxy-substituted in the omega position,

409811/1203 \

a group of the formula

CH "P. CH ₀ P

, 2, 2

-CH = CH-CH-R ¹ , -CH ₀ -CH ₀ -CH-R'-,

C-C. , -J

CH = CH-CH ₂ -R "or

in which P is a hydroxy or triphenylmethoxy group, R 'is a straight chain alkyl group having 2 to 10 carbon atoms or a straight-chain alkyl group having 2 to 6 carbon atoms, which is replaced by a branching Alkyl group is substituted with 1 to 3 carbon atoms, and R "is a straight chain alkyl group with 2 to IO Carbon atoms represented by a hydroxy and triphenylmethoxy group is substituted, or a straight-chain alkyl group having 2 to 6 carbon atoms, the .by a branching alkyl group having 1 to 3 carbon atoms with a hydroxy or triphenyl methoxy substituent is substituted, mean

R _{3 is} a hydroxyl group, an alkoxy group with 1 to 12 carbon atoms or a tetrahydropyranyloxy group,

Y is a divalent group of the formula

0 'HO _x , HH "OH

%•' or \-,'

811/12

Z is a divalent group of the formula

- (CH ₂ ) _n -0-CH ₂ - or

in which η is an integer from 3 to 8, R is an alkyl group with up to 3 carbon atoms and R _{5 is} an alkyl group up to 3 carbon atoms, a fluoratoia or a

Mean phenyl group.

where the group of the formula

I »

the divalent group of the formula

ti

H-C

11

may mean, when R ₃ represents a hydroxy or an alkoxy group having 1 to 12 carbon atoms. In the context of the invention, considered to be well suited lower
Alkoxy and lower alkanoyl groups are those with
up to 4 carbon atoms such as methoxy,

^ 09811/1203

BATH

- Λ -

. "Vchoxy, isoprcpoxy, sec-butoxy, formyl, acetyl, propionyl and isobutyryl.

Also within the scope of the invention are the toxic, pharmaceutically acceptable salts of the new compounds according to the invention, for which R_ is a hydroxy group. The cations present in these salsa include, for example, the non-toxic levels of synthesis such as those of sodium, potassium, calcium and agnesia, as well as the cations of organic amines such as the vcv, tri (lower alkyl) anines (e.g. of triethylamine) and procaine .

The new compounds of the invention are usually obtained as yellow oils which have characteristic absorption spectra. They are relative in water insoluble; however, they are in common organic solvents such as ethanol, ethyl acetate, dimethylformamide and others are relatively soluble. The cationic salts of compounds where R-, is hydrogen, are in general colorless to yellow crystalline solids that have characteristic melting points and / absorption spectra own. They are relatively soluble in water, methanol and ethanol, but relatively insoluble in benzene, Diethyl ether and petroleum ether.

The prostaglandins are a family of closely related compounds obtained from various animal tissues vrden and which stimulate the smooth muscles and the lower arterial blood pressure, antagonize the mobilization of free fatty acids induced by epinephrine and also other pharmaceutical and autopharnacological Cause effects in mammals (verci. Bergstrom, et. Al, J. Biol. Chein. 238, 3555 (1963) and Horton, Sxperientia 21, 113, 1965) and

409811/12 03 BAD ORiQlNAt "

sources cited therein. All so-called natural Prostaglandins are derivatives of prostanoic acid:

The hydrogen atoms attached to the C-8 and C-12 atoms are bound are in the trans configuration. The natural ones Prostaglandins are only one type of the possible optical isomers. Those according to the invention Compounds include all possible optical isomers.

The new compounds according to the invention can be readily prepared from certain cyclopentenones substituted in the 4-position, which are generally pure by the following Formula can be reproduced:

■; ... II

where mean:

R 'water, a lower alkoxy group, a tetrahydropyranyl oxy group, a lower alkanoyloxy group or one substituted with tetrahydropyranyloxy in the omega position lower alkoxy group and

409811/12 0 3

a - C.

R 'is a tetrahydropyranyloxy group or an alkoxy group rait 1 to 12 carbon atoms.

Leave the 4-oxycyclopentenone intermediates easily from 2-carbomethoxycyclopentanone Prepare the Reaction Schemes shown in Reaction Schemes A through D. In detail can so the necessary 2- (oraega-carbethoxyalkyl) -cyclopent-2-en-l-one intermediates (VIII) are prepared according to the following reaction scheme;

Reaction scheme A

X- (CHa) _n -COaC ₂ H ₃

• (χι) "

(IV)

(CHa) _n -CO ₂ K ₃ C _{3 5} CO C ₂ H ₃

40981 171203

BATH

r 7 Reaction scheme A (cont

£ 337581

IV

(Y)

(CH ₂ ) _n -CO _e C ₂ H _s (VIII)

(CHa) _n -CO ₂ C ₂ H ₃

O-C-CH ₃
0

(VI)

.Br

(CHa) _n -CO ₈ CaK ₉

In the formulas given above, η has the meaning given above, and X denotes iodine or bromine. As in dies-ir. Reaction scheme shown, v / ground the Cyclopent -2-en-l-one (VIII) formed by first adding 2-Carbäthoxyeyelopentanone (I) with sodium hydride in dirrethoxyethane transferred into their sodium enolates and this then with an · ethyl omega halide canoate (II) treated, whereby the corresponding 2-carbethoxy-2- (oir.ega-carbäthoxyalkyl) -cyclopentanone (III) which is then hydrolyzed to form 2- (omega-carboxyaikyl) -cyclopentanone (IV) and is decarboxylated. This acid is then converted into 2- (onega-carbethoxyalkyl) cyclopentanone with ethanol

(V) esterified. The reaction conditions for carrying out the above reaction sequence are well known. The conversion of the cyclopentanone (V) into the Snol acetate

(VI) is made by heating with acetic anhydride in the presence ven p-toluenesulfonic acid causes. The production

4 0 9.8 1.1 / 12 0-3 BATH

the enol acetate (VI) usually requires heating for about 8 to 36 hours. During this time it is advantageous to allow acetic acid formed as a by-product to distill off in order to force the reaction to be complete. The chlorination of the enol acetates (VI) to give the 2-bromocyclopentanones (VII) is preferably carried out in a two-phase system, as described below. A solution of bromine in chloroform is added with rapid stirring to a mixture of a solution of the enol acetate (VI) in chloroform and an aqueous solution of an acid acceptor such as calcium carbonate or sodium carbonate. This addition takes place at 0 to -5 ° C. for about 90 minutes, the stirring being continued for a further time of about half an hour to a few hours, and the product (VII) is then prepared according to procedures known per se isolated. The dehydrobromination of the 2-bromo-cyclopentanones (VII) is preferably carried out in dimethylformamide with a mixture of lithium bromide and lithium carbonate at the reflux temperature for about 30 minutes to one hour. The cyclopent-2-en-1-ones (VIII) thus formed are likewise isolated by generally customary procedures which are known per se. If nan uses the compound X- (CH ₂ J _n -C (R ₄ ) 2-CH ₃ C ₂ K ₅ instead of the compounds (II) in reaction scheme A and then carries out the further illustrated reaction sequence, then those in the following formula indicated cyclopent-2-en-l-one (Villa).

(CHa) _n -C-CH ₂ -CO ₂ C ₂ H ₃

(Villa)

0 9 811/1203 BAD ORKSiNAL

In the above formula, X, η and R. are as above given meanings.

The necessary cyclopent "2-en-l-ori-intermediate" products of the general formula (XVI), the side chain of which "a lower alkyl group, a fluorine atom or a phenyl group in alpha position to the carbethoxy function can be prepared according to the following reaction scheme:

409811/1203 ORIGINAL BATHROOM

1 »■ 'Λ Λι <«

V,,; AM

Reaction scheme B

(IX)

S ^ (CK

If

"OCH ₃

(ΧΕΙ)

-CO ₂ CaH ₅

OCH

if.

(CHa) _n -OH

'OCH ₃ . (XI)

(CHa) _n -O-SO ₃ -Y

(XII)

CO ₂ C ₂ H ₃ I · § · Na-C -R ₃

CO ₂ C ₂ Hg

(XIII)

ι I. ^ (CHa) _n -CH-CO ₂ H j ^ (CH CO ₂ C ₂ Ii ₃ Sr (XV) OCH ₃ i
₂ ) _n -CR ₅ O CO ₂ C ₂ Hs (XIV) V il · R ₅

(CHs) _n -CH-CO ₂ CaHs

0 _t 409 811/12 0 3.

(XVI)

BATH

233758Ί

In the above reaction scheme, η and R_ have the .! meanings given above, and Y denotes a methyl group or a p-ToIyIgruppe. As shown in this reaction sequence, the 2- (oir.ega-Carbethoxyalkyl) -cyclopent-2-en-l-ones (IX), which have been prepared as in Reaction Scheme A for the preparation of (VIII), wherein 2 to 7 means converted into the corresponding l-methoximino-2- (omega-carbethoxyalkyl) -2-cyclopentene (X) by treatment with methoxyamine. With the ring carbon function blocked in this way, it is possible to bring about a preferred reduction of the ester group by treatment with diisobutyl aluminum hydride. The alcohol (XI) formed in the process is converted into a mesylate or tosylate (XII), which is reacted with the sodium compound of a di'ithyl malonate (XIII) to give the disubstituted malonate derivative (XIV). The desired 2- (omega-carboxy-omega-substituted- (, alkyl) -cyclopent-2-en-l-ones (KV), which are obtained according to the usual Let the Fischer procedure be converted into the corresponding compounds (XVI) without difficulty.

The required 2- (omega-carbethoxy-S-oxy-alkyl) -cyclopent-2-en-l-ones (XXII) can according to the reaction sequence in reaction scheme C, in which η has the meaning given above has, is shown, produced v / earth.

409811/1203 EAD

Reaction scheme C

(XVII)

(CH ₅ J) _n -O-CH ₂ CO ₂ C ₂ H ₃ (XX)

(XVIII)

Supreme Court ₁

(CH ₂ ) _η -

\ · (XIX)

OCH ₃

(CHa) _n -O-CHaCO ₂ H (XXI)

(CHg) _n -O-CH ₂ -CO ₂ C ₂ H ₃ (XXII)

409811/1203

Like in that. for the preparation of Reaction Scheme C above of the oxa derivatives (XXII), the corresponding ■ 2- (omaga-Carbäthoxyalkyl) -cyclopent-2-en-l-one (XVII) is in the corresponding methoxime (XVIII) converted, its ester function then preferably with diisobutylaluminum hydride is reduced, whereby the methoxy alcohol (XIX) is formed will.' The alcohol (XIX) becomes with n-Butyllithiura in the Lithiumalkoholat transferred, which is then 0-alkylated by reaction with Sromessigsäureäthy! ester to (XX). hydrolysis Acetone / aqueous hydrochloric acid delivers the end-blocked Keto acid (XXI), then in the presence of p-toluene sulfonic acid again to the required 2- (omega-carbethoxy-3-oxaalkyl) -cyciopent-2-en-l-one (XXII) is esterified. The O-alkylation can also be achieved by treating the lithium alcoholate of

(XIX) iro.t sodium or other metal salt of bromoacetic acid in which case the free carboxylic acid corresponding to the ester (XX) is obtained. The like for

(XX) carried out hydrolysis gives the keto acid (XXI).

Some of the reactions that go into making 4-0xocyclopentenone intermediates play a role are shown in the following reaction scheme:

4 0 9 811/12 0 3

Reaction scheme D

, η - ■ 1-COR ₈

(XXIII)

B, r

Z-C-0-R3 (XXIV)

(XXX)

0
ZC-OH

1 Z-C-O-R

0- _(CH2) 4-OH

(XXXI)

409811/1203

Z-C-O-R

8 (XXVI)

8 (XXVII)

In the above reaction scheme, R "denotes hydrogen or a lower alkyl group and R" denotes a lower alkyl group, and Z ¹ has the meaning given above for Z with the exception that it is the group - (CH ₂ ) · -S-CH ₂ - does not include, and m is an integer from 2 to 5. ' The introduction of the oxy function into the 4-position unsubstituted cyclopentenones (XXIII) is achieved by first halogenating the 4-position with an allyl halogenating agent, preferably with n-bromosuccinimide. The 4-brcmcyclopentenone (XXIV) thus formed is solvolysed for the introduction of the oxyfunction. This step is preferably carried out in the presence of a silver salt, which facilitates the replacement of the halide ion. The 4-oxide derivative formed in each case depends on the type of solvent system. By treating the • 1-bromocyanoentenone with silver fluoroborate in water / acetone (to make it soluble), the 4-kydroxycyclopentenone (XXV) is formed. If the cyclopentenone is a carboxylic acid (ie R "=. Hydrogen), then this procedure gives (XXXI). If the solvent system is water / tetrahydrofuran, in addition to the 4-hyaroxy derivative, the 4 '-hydroxybutyloxy derivative (XXVI), which is formed by solvolysis with tetrahytirofuran, is also obtained. If the solvent is only tetrahydrofuran, then only the latter compound is formed. The 4-alkoxycyclopentenones (XXVII) are formed by replacing the tetrahydrofuran with an alcohol, for example methanol, ethanol, isopropyl alcohol or butanol. With ethylene glycol or propylene glycol and the like - the corresponding 4- (omega-substituted hydroxy-alkoxy) -cyclopentenones (XXVIII) are obtained. In the three working methods described last, it is advantageous to add a proton acceptor which does not react with (XXIV), for example symmetrical collidine. If the soivolysis is carried out with a silver salt of a lower alkanoic acid in the corresponding alkanoic acid, for example the silver acetate / acetic acid system, then this is the case

08811/120 3

Obtaining 4-acetoxy derivative (XXIX) - Careful alkaline hydrolysis of this product with potassium carbonate in aqueous Methanol provides the free 4-II-hydroxy derivative (XXX). Further Hydrolysis with barium hydroxide yields the free carboxylic acid (XXXI).

In general, these working methods can be combined with the free ones Carboxylic acids or with the alkyl carboxylates. A particular alkyl carboxylate that is not represented by formula (XXIII) can be supplied by hydrolysis to the acid and esterification in a book manner, for example with the appropriate Alcohol or for a tert-butyl ester with isobutylene will. For the subsequent alanate conjugate addition procedure However, it is necessary to use a cyclopentenone in which both the carboxy! acid and all free Hydroxyl groups are blocked. A particularly suitable blocking group for both functions is the tetrahydro-

pyrany! group (see for example XXXI> XXXII), there

this group with weak acid under conditions' easy can be split off, which then produced the relatively unstable ll-oxo-9-keto system (ß-hydroxy-ketone) do not destroy. So it is not possible to achieve a satisfactory chemical hydrolysis of an alkyl ester or an 11-0-alkanoyl group of a II-oxo-9-ketoprostanoic acid derivative to be carried out under conditions to which this system is stable (enzymatic hydrolysis is possible). Of course, these stability considerations do not apply to the "F" - (9-hydroxy) series.

The 9-keto-15-deoxy-13-trans-prostanoic acids and esters according to of the invention, as they were defined in the first general formula given at the outset, can be made from cyclopentenone (XXXVII) and the triphenylmethoxy-substituted alkynes (XXXIII) prepared v / ground, as in the reaction scheme E is shown. In this Reaction Scheme E have

R ', R' and Z have the meanings given above, and R ^. be-Ij b

indicates a group of the formula

409811/1203

CIi ₂ OC (C ₆ H _{5 I 3}

■■ -CH-R '°. ^ ^d -CH ₂ -R '",

where R ^{f has} the meaning given above and R- '' ^{l is} a straight-chain alkyl group with 2 to 10 carbon atoms which is substituted by a triphanylmethoxy group, cds.r -sine straight-chain alkyl group with 2 to 6 carbon atoms and a branching alkyl group with I to 3 Carbon atoms substituted by a tri-phenylmethoxy group. Furthermore, R denotes a lower alkyl group having up to 4 carbon atoms; R "has the meaning given above for R with the exception that it does not mean a tetrahydropyranyloxy group or pmega-fetrahydropyranyloxy-substituted lower alkoxy group, and R" has the meaning given above for R- with the exception that it does not mean tetrahydropyranyloxy.

40981

Reaction scheme E.

(XXXIII)

CH ₃ -CH-CH ₃

■

+ CH ₂ -Al-H

I.
CH ₂

CH

A \

CH3 CH3 CH ₃

CHCH ₂ -Al ^ - \ / ■ ( *

CH ₃ CH ₂ '

i
CH

CH ₃ CH ₃

ZCB ₃

- 0

(XXXVII)

(XXXIV) (XXXV)

RLI

(XXXVIII)

(XXXIX)

11/12

As shown in Reaction Schana E, the phanylmethoxy-substituted 1-alkyne (XXXIII) is reacted with diisobutylaluminum hydride (XXXIV). This reaction of the 1-alkyne (XXXIII) with diisobutylaluminum hydride (XXXIV) gives the alan (XXXV), which contains the trans double bond and is in an inert solvent, for example benzene or toluene, at temperatures in the range from 40 to 60.degree carried out for a few hours. It can also be carried out in a solvent such as tetrahydrofuran, usually in about a 2: 1 mixture with benzene or hexane. In this case the reaction requires somewhat more severe conditions, usually a temperature of about 70 to 75 ° C for about 1 hour. The subsequent reaction with methyl or n-butyl lithium (R-Li) is preferably carried out in a mixture of the above-mentioned solvents with an ethereal solvent such as diethyl ether, dibutyl ether or tetrahydrofuran. This reaction proceeds rapidly and is preferably carried out at C to 10 C with cooling. The conjugate-1,4-addition of the alanate salt formed (XXXVI) to give the cyclopent-2-en-1-ys (XXXVII) is preferably carried out at ambient temperature for 12 to 24 hours. This reaction is also best carried out in an ethereal solvent such as diethyl ether, dibutyl ether or tetrahydrofuran. The alanate-ITnolat adduct formed as an intermediate product is then carefully hydrolyzed in situ with dilute hydrochloric acid under cooling, and the products (XXXVIII) can be isolated in a well known conventional manner .. Dia ¹ 3ntfernung the tetrahydropyranyl and the Triphcnylmethyl blocking groups can then c .done by treatment with weak acid. With a preferred one. The procedure is heated to 45 ° C. for 3.5 hours in a solution system consisting of acetic acid / tetrahydrofuran / water in a ratio of 4: 2: 1. If (XXXVIII) is a tetrahydrofuranyl ester, the prosthetic acid (XXXIX, E ¹ "= i-hydroxy) is obtained.

'4 098 1 1/120 3

original

All available evidence leads to the assumption that the -CH = CK-R, - ~ function introduced by the alanate method (cf.XXXVIII) is in the trans position to the II-O :: o function ( when R 'is not hydrogen). In a corresponding manner, the conclusion that the two side chains which are bonded to C ₀ and C 1 in product (XXXIX) are trans to one another. However, this configuration relationship is not yet secure for the product (XXXVIII), as it is taken directly from the :. Alenate method is obtained. These products may have the side chains in a trans or cis relationship / or they may be a mixture containing both the trans and the cis isomers. This is Id. Of the nomenclature of the relevant compounds indicated by the indication 3. ". To ensure a trans relationship both in (XXXVIII) and in (XXXIX), these products can be subjected to conditions known from the literature in order to equilibrate the CiS-S- IsO-PGE ₁ to a mixture containing about 90% of the trans product. Such conditions include, for example, treatment with potassium acetate in aqueous methanol for 95 hours at room temperature.

The triphenylmethoxy-substituted 1-alkynes (A), the alanes (B) derived from them, and the alanates (C) are new and valuable intermediates for the synthesis of the compounds of the invention and are to be regarded as part of this invention. In Forraaln (A), (B) and (C), R ₆ and R have the meanings given above.

0981 1 ^ 1203

BATH ORIGINAL

HC = CR ₀ HR ₆

\ * ΧΏΩ3 /

^ HC-CH ₂ -A ^ · \ R - GH ₂

R-C-H i R.

(B)

If the 11-oxy derivatives (XXXVIII) or (XXXIX), preferably the 11-hydroxy derivatives, treated with dilute acid, it is possible to eliminate and the formation of the corresponding Delta derivatives (prostaglandins of type A). A preferred mode of operation involves treatment in tetrahydrofuran / water (2: 1) solvent that 0.5 η with respect to hydrochloric acid, for about 70 hours at ambient temperature, as shown in the following reaction scheme- Under these conditions a tetrahydropyranyl ester experiences a hydrolysis.

Reaction Scheitia F

409811/1203

In these formulas, R ₃₇ R-, R "and Z have the meanings given above. Those compounds according to the invention which, in the case of -C ₁ -, - have C ₁ .

13th

speaking delta derivatives (produced by the alanate process) by catalytic reduction, preferably at low pressure with a noble metal catalyst in one inert solvents can be prepared at ambient temperatures.

The 11-oxy-9-keto derivatives according to the invention can be converted into the corresponding 9-hydroxy derivatives.

If this conversion is effected with sodium bromohydride, then the product is a mixture of 9alpha- and 9ß-hydroxy derivative (XLIII) and (XLIV) as in the following reaction scheme

shown.

Reaction scheme G

'Ri

ZCR ₃
0

J ZCR ₃

OH

OH

ZCR ₃

(XLII)

(XLIII)

(XLIV)

If the reaction with lithium perhydro-9ß-boraphenyl hydride _ / H.C. Brown. And W.C. Dickason, Journ. Amer. Chem. Soc, Vol. 92, P. 709 (197O] _ / carried out, then the product at least passes predominantly from the 9alpha-hydroxy derivative (XLIII), in which the 9-hydroxy group is in the cis position to the side chain, bonded to C ", and to the 11-oxy function is present. In accordance with recognized convention

409811/1203

there is an alpha substituent in the 8-, 9-, 11-ocler 12-position behind the plane of the paper, while a ß-substituent in these positions in front of the plane of the paper

is present. This is usually indicated by a tie ^

for an alpha substituent a bond for one

ß-substituents and a λλλ bond for the indication of both Ties shown. Thus, the 9-hydroxy derivatives, which differ accordingly, are shown as follows will.

V V v;

η \ _H H ' ⁿ oh. ■ / oh

For the preparation of the thia intermediate compounds (XLVIII) and (IL) one starts from the intermediate compound (XLV) (XIX in Renktionsschema C) that after conversion into the tosylate intermediate product (XLVI) and reaction with the sodium salt of iithylniercaptoacetat the intermediate compound ( XLVII) delivers. Deblocking (XLVII) with acetone / aqueous hydrochloric acid yields the ketonic acid (XLVIII), which, when re-esterified with itthanol, produces the 2- (oriega-carbethoxy-B-thia-alkyl) -cyclopent-2-en-1 -one (IL) results.

811/12

BAO ORIGINAL

Reaction scheme K

(JL

-0-SO ₂ -

(XLVI)

- (CHa) _n -S-CH ₂ -CO ₂ -C ₂ H ₅

OCH

3.

(XLVII)

N.

OCH ₃ (XLV)

(CHa) _n -S-CH ₂ -CO ₂ H

(XLVIII)

(CH ₂ ) -S-CH ₂ -CO ₂ -C ₂ H ₃

(IL)

09 8.1 1/1203

The invention also relates to new organic Compounds that are close to the natural prostaglandins. More precisely, the new connections are according to the invention 11-0xy-9-keto- (or 9-hydroxy -) - · 13-trans-prostenic acids, their homologues, analogues ^ derivatives and relatives arising at the same time. The scope of the invention also includes certain 4-oxycyclopentenone sviselen compounds, which are suitable for the synthesis of these new compounds. The prostate acids of the provisional Invention can be represented by the following general formula be shown:

RiO

where mean:

R _{1 is} a hydrogen atom, a lower alkyl group, a lower alkanoyl group, an omega-hydroxy-substituted lower alkyl group, an omega-tetrahydropyranyloxy-substituted lower alkyl group, an omega-tetrahydropyranyloxy-substituted lower alkyl group or a tetrahydropyranyl group.

R ₂ (a) a straight chain alkyl group having 2 to 10 carbon atoms, (b) a straight chain alkyl group having 2 to 6 carbon atoms with a branching alkyl group having 1 to 3 carbon atoms, (c) a straight chain alkenyl group having 3 to 7 carbon atoms, and d a straight chain omega-haloalkyl group with 3 to 7 carbon atoms,

R _{3 is} a hydrogen atom, an alkyl group having 1 to 12 carbon atoms, or a tetrahydropyranyl group;

Ä Q 9 8 1 1/1203

Y is a divalent group of the formula

HO.

or*

Z is a divalent group of the formula

"(CH ₂ ) _n -CH- or .;

where m is an integer from 3 to 9, η an integer from 3 to 6, R. a lower alkyl group with up to three carbon atoms and R _n . a lower alkyl group with up to three carbon atoms, fluorine or a phenyl group and the group

H. H '

409811/1203

or the divalent group

/ ^c \

HC
HC

mean.

Likewise, in the context of the invention, the non-toxic pharmaceutically acceptable salts of the novel compounds of the invention are in accordance _t when R "Xfasserstoff means. The cations contained in these salts include, for example, the non-toxic metal cations -, for example of sodium, potassium, calcium and Kagnesiura as well as oxo cations of organic amines, such as the tri (lower alkyl) amines (for example of triethylamine) and procaine .

The new compounds according to the invention must readily be derived from certain 4-substituted cyclopentenone-Z -.- 7Xschenverbindungen which can be represented by the following general formula:

R ₇ O,

or

0 it

(CH ₂ J _1n -C-OR ₃

^f m

4098 11/1203

where m and R _{3 have} the meanings given above, Rg is a halogen atom, a hydroxy group, a lower alkoxy group, an omega-hydroxy-substituted lower alkoxy group, a lower alkanoyloxy group, a / tetrahydropyranyloxy group or an omega-tetrahydropyranyloxy-substituted lower alkoxy group / V is a divalent lower alkoxy group Remainder of the formula

R,. R =.

- (CHs) _n -C-CH ₂ -, - (CH ₂ J _n -CH. / Or! - R ₄

in which n, R ₄ and R _{g have} the meanings given above; and R _{7 represents} a lower alkyl group, an omega-hydroxy-substituted lower alkyl group, an omega-tetrahydropyranyloxy-substituted lower alkyl group or a tetrahydropyrany group.

The 4-oxycyclopentenone intermediates can be without another from 2-Carbäthoxycyclopentanonen according to the reactions shown above in the reaction schemes A to D. produce.

Some of the new compounds according to the invention can by the conjugate 1,4-addition of an alanate salt .an Preparing 2-substituted 4-oxy-substituted cyclopent-2-en-1-one; this method is also part of the present one Invention. This new way of working is shown in the following reaction scheme:

40981 1/1203

Reaction scheme L

R'iO.

R "ία

i »

ZC-OR ¹ 3,

(XXXIII)

^S F

H
.Z-CO ₂ H

(XXXVI)

T " CH ₃ -CH-CH ₃

R '^ Al-C = CC ^ H ₂ H "CH ₃ -CH-CH ₃

(XXXIV)

ZC-OR » ₃

V 'O (XXXV),

409811/1203

where Z and R_ have the meanings given above, R ^{1 is} a lower alkyl group, preferably methyl or η-butyl, R ¹ - has the meaning _{given above for R 1} with the exception that not hydrogen or 'a onega- hydroxy-substituted lower alkyl group, R "has the _{meaning given above for R 1} , with the exception that it does not mean a tetrahydropyrany! group or omega-tetrahydropyranyloxy-substituted alkyl group, and R 'has the _{meaning given above for R 3} , with the exception that it does not mean a hydrogen atom.

The yields of egg production of compounds (XXXV) by the conjugated 1,4-addition of an alanate salt "(XXXIV) a 4-oxycyclopent-2-en-1-one substituted in the 2-position (XXXIII) are usually good, and a product which is not 1,2-addition product is usually obtained is contaminated. There is also the transfer of the alkyne group while maintaining the trans configuration of the hydrogen atoms bound to the double bond, and no reaction is found at the ester function or the ester functions of (XXXIII). A Another notable aspect of this reaction is the fact that it does not require a catalyst. the Alanate salts (XXXIV) can be easily obtained by reacting a 1-alkyne (R-C = CH) with diisobutylaluminum hydride, to which the reaction with a lower alkyllithium derivative, preferably methyllithium or n-butyllithiuia, connects, produce. Suitable 1-alkynes that can be used in this reaction are for example 1-butyne, 1-pentyne, 1-hexyne, 1-decyne, 1-hendecine, 1-dodecine, 3-methyl-1-butyne, 1-heptyne, 1-octyne, 1-nonyne, 5-methyl-1-hexyne, 7-methyl-1-octyne, 7-methyl-1-nonyne, 3-methyl-1-octyne, 4-: ethy 1-1-octyne, oct-5-en-1-yne, Hept-5-en-1-yne, hex-4-en-1-yne, 5-chloro-1-pentyne,

409811/1203

6-chloro-hexyne, 7-chloro-i-hGptin and S-chloro-T-octin. The reaction of the 1-alkyne with diisobutylaluminum hydride gives exclusively the trans double bond and is preferably carried out in an inert solvent such as benzene or toluene at temperatures in the range from 40 to 60 ° C. for several hours. The subsequent reaction with methyl or n-butyllithium is preferably carried out in a mixture of the above solvents with an ethereal solvent such as diethyl ether, dibutyl ether or tetrahydrofuran. This reaction proceeds rapidly and is preferably carried out at 0 to 10 ° C. with cooling. The conjugate 1,4-addition of the alanate salt formed (XXXIV) and the 4-oxycyclopent-2-en-1-one (XXXIII) is preferably carried out at ambient temperature for 12 to 24 hours. This reaction is also best carried out in an ethereal solvent such as diethyl ether, dibutyl ether or tetrahydrofuran. The intermediate alanate-enolate adduct is then carefully hydrolyzed in situ with dilute hydrochloric acid with cooling, and the products (XXX10 are isolated in a conventional manner. If desired, the tetrahydrofuranyl blocking group can then be removed by treatment with weak acid be effected one preferred procedure consists in heating at 45 ⁰ C for 3.5 hours in a solvent system of acetic acid / tetrahydrofuran / -water in the ratio of 4:.. 2: 1 (XXXV) a tetrahydropyranyl, then yields the 11- Oxyprostenic acid (XXXVI).

All available evidence leads to the belief that the -CH = CII-R ₂ function introduced by the alanate method (see XXXV) is trans to the 11-oxy function. In a corresponding manner, the conclusion that the two side chains which _{are bonded to Cg and Cj 2} in the product (XXXVI) are in the trans position to one another. The configuration relationship

40981 1/1203

in product (XXXV) as it is straight from the alanate process is obtained but is not secured. These products can have the side chains in a trans or cis relationship wear, or they can represent a mixture, * iri die contain both the trans and cis isomers. This is indicated in the nomenclature of the compounds concerned by the indication 8 ξ. To ensure a trans relationship in (XXXV) and (XXXVI) these products can conditions known from the literature for the equilibration of eis-3-iso-PGE.j to a mixture that contains about 90% of the trans product contains, are subject to. Conditions of this type include treatment with potassium acetate in aqueous Methanol for 96 hours at room temperature.

If the 11-oxy derivative (XXXV or XXXVI) is used, preferably the 11-hydroxy derivatives, treated with dilute acid, it is possible to cause elimination and formation of the corresponding delta derivative (prostaglandins of type A). A preferred procedure comprises treatment in tetrahydrofuran / water (2: 1) as solvent, the 0.5 η with respect to hydrochloric acid for about 70 hours at room temperature; under these conditions one experiences Tetrahydröpyrany! Ester a hydrolysis. This implementation is shown in Reaktonsschema M below.

Reaction scheme M

H C

^ ZC-OR ₃

⁰ (XXXVII) ° ^U (XXXVIII)

0961 1/1203

In these formulas, Z, R ₂ and R _{3 have} the meanings given above and R ₃ denotes hydrogen or an alkyl group having 1 to 12 carbon atoms. The compounds (KXXVIII) are also to be regarded as such according to the invention.

The 1i-oxy-9-keto derivatives according to the invention can corresponding 9-hydroxy derivatives are converted. If this conversion is carried out with sodium borohydride, then the product is a mixture of 9alpha- and 9ß-hydroxy derivatives (XL) and XLI) as shown in the following reaction scheme.

Reaction scheme

(XXXIX)

RiO

OH

0
(XL) '

(XLI)

If the reaction with lithium perhydro-9b-boraphenylyl hydride / U. C. Brown and WC Dickason, Journ. Amer. Chem., Vol. 92, 709 (1o70j_ / carried out, then the product consists at least predominantly of the 9alpha-hydroxy derivative (XL),
wherein the 9-hydroxy group cis to the side chain is a Cg and to the 11-oxy function. According to recognized agreement, there is an alpha-substituent in the 9-position behind the plane of the paper, while a ß-substituent

409811/1203

is in the 9 position in front of the plane of the paper. this will

usually through a bond for an alpha-substitute

tuenten, a bond for a ß-substituent and

an ^rJX A bond if both are given. The different 9-hydroxy derivatives can be represented as follows:

^C x C ■ _ ^ ^C %

H, ΌΗ H '' OH H OH

The invention also relates to new hydroxy-substituted 15-deoxy-5-cis-prostanoic acids and "esters thereof" as well on intermediates and processes for their manufacture. The new compounds according to the invention include all also the possible optical isomers, diastereomers and enantiomers, racemates and racemic mixtures, which by the following general formula can be represented:

• R 0

II) ^ £ ll CH- (CH ₂ ) -CR ₃

CH - CH '" ⁿ

CH ⁼⁼ CH-R2
trans

where mean:

η is an integer from 1 to 5,

R is hydrogen or a lower alkyl group with up to 3 carbon atoms,

409811/1201

R _{1 is} hydrogen, a hydroxyl group, a tetrahydropyranyloxy group or a tri- (nieäeralkyl) -siIyloxygruppe,

- a group of the following formula

CH ₀ P

j ^d or "-CH _? -R" -CH-R '.

where P is a hydroxy or triphenylmethoxy group, R ^{1 is} a straight-chain alkyl or alkenyl group with 3 to 10 carbon atoms or a straight-chain alkyl or alkenyl group with 3 to 7 carbon atoms and one or two branching alkyl groups with 1 to 3 carbon atoms and R " a straight-chain alkyl or alkenyl group with 3 to 10 carbon atoms, which is optionally substituted with a hydroxy or triphenylmethoxy group or triphenylmethoxy group, or a straight-chain alkyl or alkenyl group with 3 to 7 carbon atoms and one or two branching alkyl groups with 1 to 3 carbon atoms and optionally a hydroxyl or triphenylnethoxy group as a substituent or a straight-chain onega-haloalkyl group with 2 to 7 _t carbon atoms,

R ₃ is a hydroxy group, an alkoxy group having 1 to 12 carbon atoms ,, a tetrahydropyranyloxy group or a lower TrialkylsiIyloxygruppe _r

Y is a divalent group of the formula

0, HO _x , * H _ H _x , -Jl c * ·: ioäer_ C ^

409811/1203

and wherein the group of the formula

the divalent group of the formula

(B)

H-

can be, with the proviso that one of the radicals R and R "contains an oxygen function when (A) is not (B).

The non-toxic ones are also within the scope of the invention pharmaceutically acceptable salts of the new compounds according to the invention, when R_ denotes a hydroxyl group. The cations contained in the salts include, for example, the non-toxic metal cations, for example those of sodium, potassium, calcium and magnesium as well as cations of organic amines, for example of tri (lower alkyl) amines (for example triethylamine), procaine and the like.

The new compounds according to the invention can be readily used as starting materials from certain cyclopentenones Manufacture substances that can be represented by the following general formula:

R 0 I - II

£ i £ (CH) - (CH ₂ ) -CR ¹ S

n * Jl

C = C

4 09811/1203

wherein R and η have the meanings given above, R ¹ .. all above for R ,. can have given meanings with the exception of a hydroxyl group, and R'-can have all the meanings given above for R- with the exception of a hydroxyl group. The preparation of the 4-oxycyclopentenone intermediates is shown in Reaction Scheme I below.

409811/12 03

Reaction Scheme I.

(D

• + (C ₆ H ₅ ) 3P = CH (CH) (CH ₂ J _n COO,

¹ (Π) '

ice cream

CH- (CH ₂ ) -CO ₂ H

I. ⁿ

(HI)

ice cream

'CH- (CH ₂ ) -CO ₂ H
R.

(IV)

ice cream

CH- (CH ₂ ) -CO ₂ H

(V)

409811/120

Reaction scheme I (continued)

0 R

^ iL / ν S ^ CH- (CHa) _n -CO ₂ H .. " j HH

(VI)

CH- (CHs) _n -Cp ₂ H (VII)

ice cream

CH- (CH ₂ ) -CO ₂ H

H H (VIII)

ice CSH- (CHa) _n -CO ₂ H

H, H

(IX)

• Η

(χ)

ice cream

R 0

I B

CH - (CH ₂ ) -CR ^f ₃

1/1203

(XI)

As shown in the reaction scheme above, the 3,4-epoxy lactol (I) / E. J. Corey and R. Noyori, Tetrahedron Letters, 311 (19702 / reacted with the ylid (II) to the 3,4-epoxycyclopentanol (III). Oxidation (for example with H ₃ CrO ₄ .H ₃ SO ₄ ether or Jones reagent) of (III) provides the epoxy ketone (IV), treatment of which with a mild base first leads to the formation of the 4-hydroxycyclopent-2-en-1-one (VII) and the isomer 3-hydroxycyclopent-4-ene -1-ons (VI) as a mixture. Further treatment of this mixture with dilute base under mild conditions leads to the isomerization of the 3-hydroxy isomer (VI) to the desired (VII). Conversion of the epoxy ketone (IV) to the hydroxycyclopentenones ( VI) and (VII) and the isomerization of (VI) to (VII) can proceed via the formation of the 3,4-diol (V). It is also conceivable that the isomerization of (VI) to (VII) via the epoxy derivative (IV) or the corresponding alpha-epoxide (IX) proceeds. It is also conceivable that (IV) passes directly into (VI) and (VII) without the intermediate stage from (V) ere possible intermediate compound for the isomerization of (VI) to (VII) is the corresponding diene (VIII). The production of (VII) is also conceivable "via r""" the alpha-epoxide series ^ äus _.__ (IX), which is produced via the alpha-epoxide, which corresponds to (I) and (II), for example (X) or most expediently via a mixture of the alpha and beta epoxides. The hydroxy and acid products of the 4-hydroxycyclopentenones (VII) are then blocked in a suitable manner, whereby (XI, R ^1. ^ Hydrogen) are formed. Suitable blocking groups are the tetrahydropyranyl group, the trimethylsilyl group, the dimethylsiopropoxysilyl group, the dimethyl-t-butylsilyl group and the like.

The preparation of the necessary 4-unsubstituted cyclopentenone intermediates can be done according to the reaction sequences which are described below in reaction schemes J and K, wherein R and η have the meanings given above, are illustrated.

A09811 / 1203

Reaction scheme J

(XII)

Cl-CH ₈ CH ₂ -OCH ₃

(XIII)

Sri

CH ₂ CH _Ä 0CK _3,

CO ₂ C ₂ Hs

O
(XIV)

Br

CHaCH ₈ OCH ₃ "

(XVI) :

' I.

CH ₂ CH ₂ OH

(XVIII)

CH ₃ -CO ⁰

CHsCH ₂ OCH ₃ (XVII)

(XIX>

409811/1203

Reaction Scheme J (continued).

(XIX) + (CeH ₅ JbP-CHa _- (CH) (CHa) _n COO

(XX).

'J ₁₃ N (CH) (CHa) _n -COOH - ^

(XXI)

H H

° f ■■■?

cis ^ (CH) (CH ₂ J _n -C

(XXII)

9-8 1 1/1203

In reaction scheme J above, the reaction sequence of converting 2-carbethoxycyclopentenone (XII) into 2- (β-hydroxyethyl) cyclopent-2-en-1-one (XVIII) is carried out in the manner described in Belgian patent 7 86 215 . Methyl ether cleavage of the corresponding '' 2- (ß-methoxymethyl) -cyclopentenone is achieved by treatment with boron tribromide. Oxidation of alcohol (XVIII) with Collins reagent: chromium oxide-pyridine complex in methylene chloride under anhydrous conditions / β.C. Collins χχμά WW Hess and FJ Frank, Tetrahedron Letters, 3363 (1968JI / provides the aldehyde (XIX), which is then reacted with anhydrous dimethyl sulfoxide with the ylide, which is made from an (omega-carboxyalkyl) triphenylphosphonium betaine (XX) and sodium hydride in The use of dimethyl sulfoxide as solvent for this reaction leads to the predominant formation of the desired derivative with a cis double bond (XXI). The acid function in (XXI) can be esterified in the usual way - with diazomethane the methyl ester (XXII) is obtained.

An alternative working method is in the following reaction scheme K illustrates where R and π have the meanings given above.

/, 09811/1203

Reaction scheme K

(XXIII)

ice cream

-HO

(XXV)

COO.

(XXIV)

:) _n COOH-

ice cream
CH ₂ -CH = CH- (CH) (CH ₂ ) _n COOH. . ·

• ·. R.
- (XXVI) '

CiS

CH ₂ - CH = CH- (CH) (CH ₂ ) _n COOH R
(XXVII)

/, 09811/1203

As shown in Reaction Scheme K above, the bicyclic hemiacetal (XXIII) /, P.A. Grieco, Journ. Org. Chem., Vol. 37, p. 2363, (1972) / in dimethyl sulfoxide with implemented the ylide, which from the triphenylphosphonium-j betaine (XXIV) and sodium hydride in dimethyl sulfoxide (dimsyl sodium) has been produced, whereby the · i-Hydroxy-3-cyclopentene (XXV) is formed. Oxidation with Jones reagent gives the corresponding ketone (XXVI) which, after treatment with a base, gives the required cyclopentenone (XXVII) returns. The latter can then be esterified in the usual way, for example to give (XXII).

The trans-1-alkeny! Side chain is introduced into the molecule by the new 1,4-conjugate addition reaction, with the ester-ether blocked 4-oxycyclopentenone (XI) in Reaction Scheme I or the 4-unsubstituted cyclopentenone ester (XXII) in Reaction Scheme J. with a lithio-alanate reagent, for example (XXXI) or (XXXIV), prepared as illustrated in Reaction Scheme L below. In this reaction scheme L, R, R ¹ .., R 'and m have the meanings given above; R ".. denotes hydrogen or a hydroxyl group, R ₅ denotes a lower alkyl group (in (R ₅ J ₃ Al not all of the groups R ₅ are necessarily the same); R 'denotes a group of the formula

CH ₂ -OC (C ₆ H ₅ )

or CH ₂ -R ¹ ''

-CH-R ¹

wherein R * has the meaning given above and R ¹ "is a straight-chain alkyl or alkenyl group with 3 to 10 carbon atoms, which is optionally substituted by a triphenylmethoxy group or a straight-chain alkyl or alkenyl group with 3 to 7 carbon atoms

40981 1/1203

and an alternate alkyl group with 1 to 3 carbon atoms and optionally a triphenylmethoxy group as a substituent or a straight-chain omega- Represents haloalkyl group having 2 to 7 carbon atoms;

R "_ denotes a hydroxyl or an alkoxy group having 1 to 12 carbon atoms and R" ₂ can have all the _{meanings given for R 2} with the exception of a triphenylmethoxy group.

409811/1203

(XXVIII)

Reaction scheme L

CH ₃ -CH-CH ₃ I.

CH ₂ -Al-H j
CH ₂

CH

^ CH _n

CH ₃

(XXIX)

'H trans ¹ * ¹

CH

C-C

CHCH ₂ -Al

CH ₂

- 5.H / V

CH ₃ 'CH ₃

(XXX) '

H trans R '>>

I ^ ■ * · \ f

(XXXII)

R ₅ Li

R ₅ Li

E trans R ^f ₂ } ^>. C = C **

CH

CHj

CH-CH ₂ -Al-R ₅ CH ₂

CH _n

c »c

(XXXIII)

(XXXI) H _n

_i © e ^ F

R ₅ -Al-R ₅

11/12 (XXXIV)

Reaction scheme L (continued)

R · 0 ι II (CH) - (CHa) -C-R'3

(XXXIV)

ROI II (CH) - (CH ₂ ) -C-R'3

(XXXVIII)

40981 1/1203

As illustrated in Reaction Scheme L, the required intermediate lithioalanate, for example (XXXI) or (XXXIV) on the 1-alkyne (XXVIII), are prepared by one of two procedures. In one procedure, the 1-alkyne (XXVIII) is reacted with diisobutylaluminum hydride (XXIX). This reaction of the 1-alkyne (XXVIII) with diisobutylaluminum hydride (XXIV) gives the alan (XXX), which contains the trans double bond, and is used in an inert solvent such as benzene, toluene and the like at temperatures in the range from 40 to 60 ⁰ C carried out for several hours. It can also be carried out in a solvent such as tetrahydrofuran, usually in about a 2: 1 mixture with benzene or hexane; in this case the reaction requires somewhat more vigorous conditions, usually temperatures of about 70 to 75 ^° C. and about 18 hours. The subsequent reaction with methyl or n-butyl-lithium (R ₅ -Li) to give the lithio-alanate (XXXI) is preferably carried out in a mixture of the above solvents with an ethereal solvent such as diethyl ether, dibutyl ether or tetrahydrofuran. The reaction proceeds rapidly and is preferably carried out at from 0 to 10 ^° C. with cooling.

In an alternative procedure, the acetylene (XXVIII) is reacted without isolation of intermediate compounds with one equivalent of disiamylborane (prepared in situ from diborane and 2-Methy1-2-butene) and then with excess anhydrous trimethylamine oxide, followed by a treatment with an aqueous solution of Sodium hydroxide and a tetrahydrofuran solution of excess iodine followed, which leads to the trans-1-alkenyl-1-iodide (XXXII). Treatment of (XXXII) at low temperatures, preferably at about -30 ⁰ C to -78 ⁰ C in an inert solvent, for example hexane or toluene,

U 0 9 8 '1T / 1 2 0 3

with an alkyllithium (R _g -Li), for example butyllithium, provides the trans-1-alkenyl-lithium reagent (XXXIII). Reaction of this lithium derivative with a trialkylaluminium, preferably trimethylaluminum, results in the ethiotrans-alkenyl-trialkylalanate (XXXIV). Reaction of a dialkylaluminum chloride with two molar equivalents of the lithioreagent (XXXIII) gives the corresponding lithio-bis (trans-1-alkenyl) dialkylalanate and the reaction of an alkylaluminum dichloride with three molar equivalents of the lithioreagent (XXXIII) gives the lithio-tris (trans-1- alkenyl) alkyl alanate. Any of the three types of alanates can be used for conjugated 1,4-addition, but reagents of the type represented by (XXXIV) are more economical and preferred.

The conjugate 1,4-addition of the lithioalanate (XXXIV) or (XXXI) to the blocked cyclopent-2-en-i-one (XXXV) is preferably carried out at ordinary temperatures for 12 to 24 hours. This reaction is best carried out in an ethereal solvent such as diethyl ether, dibutyl ether or tetrahydrofuran. But you can also use a solvent system such as benzene / hexane / diethyl ether. The alanate-enolate adduct formed as an intermediate is then carefully hydrolyzed in situ with dilute hydrochloric acid with cooling, and the products (XXXVI) are isolated in the customary, well-known manner. The removal of tetrahydropyranyl or trialkylsilyl protective groups and - if present - the triphenylmethyl protective group can then be effected by treatment with a weak acid. In a preferred operation of 3.5 hours, in a solvent system of acetic acid / tetrahydrofuran / -water in the ratio 4: 2: 1 is heated to 45 ⁰ C. If (XXXVI) is a tetrahydrofuranyl or trialkylsilyl ester, the prostate acid (XXXVII, R " ₃ -hydroxy) is obtained. Alkyl esters are usually not obtained with this procedure

40981 1/1203

hydrolyzed. In the 1i-oxy-9-oxo series, saponification cannot be effected chemically, but it can be achieved in the usual way by enzymatic means, for example with baker's yeast. In the 11-deoxy series (R ₁ = hydrogen) or in the 9-hydroxy series, chemical saponification can easily be effected.

All available evidence leads to the conviction that the -CH-CH-R ¹ - function introduced by the alanate process (cf. XXXVI) is in the position trans to the 11-oxy function. In the same way, the conclusion is permissible that in the product (XXXVII) the two _{side chains bound to Cg and C 2} are in transposition to one another. With regard to this configuration relationship in product (XXXVI). however, there is no certainty as it is obtained indirectly from the alanate processes. These products can have the side chain arranged in a trans or cis relationship, or the products can be a mixture containing both the trans and cis isomers. This is indicated by the designation 8 in the nomenclature of the compounds concerned. To ensure a trans relationship in (XXXVI), these products can be subjected to conditions which are known from the literature to be the cis-8-iso-PGE ,. equilibrate to a mixture containing about 90% of the trans product. These conditions are a treatment with potassium acetate in aqueous methanol for 96 hours at room temperature.

The triphenylmethoxy substituted lithioalanate reagent of type (XXXIV) and its precursors are new and valuable Compounds which are also encompassed by the invention. You can go through the following general Formulas A and B are defined:

£ 0981 1/1203

H trans

R ₇ -Ai ^e

trans C »C

Ll-

In the above formulas, A and D are

a group of the following formula

CH ₉ -OC

I.
-CH-R ^f

wherein R ^{1 is} a straight-chain alkyl or alkenyl group with 3 to 10 carbon atoms or a straight-chain alkyl or alkenyl group with 3 to 7 carbon atoms and a branching alkyl group with 1 to 3 carbon atoms and Ro is a straight-chain alkyl or alkenyl group with 3 to 10 carbon atoms and a triphenylmethoxy group as substituents or a straight-chain alkyl or alkenyl group with 3 to 7 carbon atoms and one or two branching alkyl groups with 1 to 3 carbon atoms and a triphenylmethoxy group as substituents,

R- a straight chain lower alkyl group which is not necessarily the same in every use,

W iodine or lithium atoms.

4 0 981 ■ 1/1 20.3

Triphenylmethyl (or substituted triphenyl! Methyl) is in favor of the eventual introduction of a hydroxy-substituted R ~ group via lithioalanates, which is carried out by

the sequence (XXVIII) + (XXIX)> (XXX);> (XXXI) "'*

are essential, but are different Protecting groups, for example tetrahydropyranyl, trialkylsilyl, alpha-ethoxy-lower-alkyl and t-butyl for

the sequence (XXVIII) ^ (XXXII)> (XXXIII) ^ (XXXIV)

also well suited.

If the 11-hydroxy derivatives (XXXVII, R ¹ ^ - - hydroxy) or the 11-oxy derivatives that come under (XXXVI) are treated with dilute acid, it is possible to eliminate and form the corresponding delta derivatives (XXXVIII), prostaglandins of type A. In a preferred procedure, the treatment is carried out in tetrahydrofuran / water (2: 1) as solvent, which is 0.5 η with respect to hydrochloric acid, for about 70 hours at ambient temperatures. Under these conditions, a tetrahydropyranyl or trialkylsxlyl ester undergoes hydrolysis (cf. Reaction scheme L above).

The H-oxy-9-keto derivatives, for example (XXXIX) according to the invention can be converted into the corresponding 9-hydroxy derivatives. If this conversion is effected with sodium borohydride, then the product is a mixture of the 9alpha- and 9ß-hydroxy derivatives (XL) and (XLI), as shown in the following reaction scheme, in which R, R "« * R " 21 ^R " ₃ and η have the meanings given above.

40981 1/1203

OH

O R Cr

JL > \ SiS. JCH) - (CHa) _n -CR "3. H

f ^ H-,

XXXIX)

(XXXX)

_φ ^ CH) - (CHa) _n -CR " ₃

. T ^ CH = CH ■ ⁿ

OH

'CH = CH H

R 0

/ (CH) - (CH ₂ ) _n -CR " ₃

R ^M i

(XXXXI)

4098 11/1203

If the reaction with lithium perhydro-9b-boraphenylyl hydride / HC Brown and WC Dickason, Journ. Amer. Chem. Soc. 92, 709 (197O) / then the product consists at least predominantly of the 9alpha-hydroxy derivative (XXXX), in which the 9-hydroxy group is in the cis position to the _{side chain bonded to C g} and to the 11-oxy function, if present , stands. Ent-. According to a recognized agreement, there is an alpha-substituent in the 8, 9, 11 or 12-position behind the plane of the paper, whereas a ß-substituent in these positions is in front of the plane of the paper. This becomes common

by a bond for an alpha substituent, a

Bond for a β-substituent and a / vw bond displayed for both.

The carboxylic acids according to the invention can readily by conventional treatment with the corresponding diazoalkane be converted into the various alkyl esters according to the invention.

The new compounds according to the invention are useful as hypotensive agents, anti-ulcer agents, agents for Treatment of gastric hypersecretion and gastric erosion, means of protection against the ulcerative and other gastric disorders or effects due to the use of various non-steroidal anti-inflammatory or anti-inflammatory agents Agents (for example indomethacin, acetylsalicylic acid and phenylbutasoneTals' "bronchodilators, anti-microbial Means, anticonvulsants or anticonvulsants, abortion drugs, means for diarrhea, means for the Labor induction, menstrual induction, fertility control - agents, Central nervous system regulators, salt and water retention regulators, diuretics, Agents for controlling lipid metabolism, agents for lowering serum cholesterol and as agents for treatment VQn__pejciääQnJtellen- diseases. Certain of the new ones

4 0 9 8 11/12 0

Compounds according to the invention are useful as intermediates for the preparation of other of the new compounds according to of the invention useful and valuable.

Anti-ulcerogenic effect 1 against.JIndp.me_thacJ.n, _

The compounds according to the invention require protection against the ulcerogenic properties of indomethacin. These Testing was carried out in the following manner.

Rats were starved for 48 hours (water was given ad libitum). Indomethacin (20 mg / kg Body weight) was administered subcutaneously, and "one-half the dose of test compound was administered at the same time Gavage administered. After 3 hours, the second half of the test compound was also gavaged through a gavage administered. 5 hours after the administration of indomethacin, the animals were decapitated and the stomachs became removed.'The stomachs were washed with distilled water, drained on cheesecloth, along the larger Cut open curve and drained by rinsing with distilled water. The stomachs were spread out on one Cork attached and visually inspected for ulcers under a magnifying glass. The criteria for evaluating ülcera were those already reported earlier.

valuation

0 - normal stomach

1 - petechial hemorrhage or

Needle tip ulcer

2 - one or two small ülcera

3 - many ulcers, some large

4 - many ülcera, many great

11/12

Treated with indomethacin but not with any test compound Control animals gave consistent ratings

from about 3.0 to 3.7, control animals with neither

Indomethacin still treated with a test compound

gave ratings of about 0.5-0.8. the Results obtained in this test with exemplary compounds according to the invention are as follows Table I listed. Compounds that give a rating of 2.2 or below are to be considered effective.

409811/1203

■ P a b e 1 1 e I

Total oral * "*

Dose mg / kg evaluation

Compound body weight treats comparison

11alpha-hydroxy-9-oxo-

13-trans-prostenic acid 50 1.0

9-oxo-10,13-transprostic acid 50 1.7.

11alpha- (ß-hydroxyethoxy) -9-oxo-13-trans-prostenic acid 100 1.8

9-Oxo-11alpha, 16-dihy-0.78 "1.0 3.0

hydroxy-5-ice, 13-trans-

prostadic acid 0.39 2.0 3.0

9-0xo-16-hydroxy-13-

trans-prostenic acid 50 1, 2 2.3

9-oxo-16-hydroxy

prostenic acid 50 1.3 2.3

40981 1/1203

The new compounds of the invention are also and thus are effective inhibitors of gastric acid secretion and ulceration in experimental animals potentially valuable as a means to inhibit gastric acid secretion and the formation of gastric ulcers, and as Antiulcer agents. The effect of inhibiting the

Gastric acid secretion is usually associated with the "Shay-

f 1 2)

Rats' experiment determined that with some modifications is carried out as follows.

The rats (males, CFE strain) had to starve for 48 hours (water was given ad libitum) in order for them to become the stomach contents could empty. On the morning of the experiment, the abdominal area was subjected to ether anesthesia shaved and a middle cut (2.5 to 3.8 == 1 to 1 1/2 ") was applied with a scalpel. The duodenum was picked out with the help of a closed, curved clamp. After seeing the duodenum, fingers were used to pull the stomach through the opening. Of the Stomach was then gently tapped with fingers to remove air and remaining material, which was removed through the gastric exit. Two 12.7 cm (5 inch) sutures were made under the porter's duodenal Puncture laid. A ligature was formed with one of the sutures at the junction or suture. The second Ligature was also formed but not tightened.

Shay et al., Gastroenterology Vol. 5, p. 43 (Ϊ945) Shay et al., Gastroenterology Vol. 26, p. 906 (1945)

■ -. 0 9 S- ί '/ ~ 2 P 3-4098 11/1203

The test compound or vehicle, usually 1 ml / mg Body weight,. was as close as possible to the duodenum injected at the first ligature. After the injection, the second ligature was tightened under the injection site, to keep leakage as low as possible. The stomach was pulled back through the opening into the abdominal cavity given, the areas of the incision were washed with saline, and the incision was closed with auto clips (Occasionally the animals were given the drugs by oral injection rather than intraduodenal injection or administered subcutaneously. In the latter case, the administration took place 30 to 60 minutes before the operation.)

Three hours later, the rats were sacrificed and bleeded out, being careful not to let the blood flow into the esophagus or stomach mouth. The abdominal cavity was exposed by cutting open with scissors and the stomach mouth, which was close to the stomach, was clamped with a clamp, the stomach was removed by cutting over the clamp (the stomach mouth was cut) and between the two sutures. External tissue was removed, the stomach was washed with saline and spread on gauze. A slit was carefully made in the stomach which was held over a funnel and the stomach contents were collected in a centrifuge tube. The stomach was cut further along the outer edge and then the inside was turned out. 2 ml of H ₂ O were used to rinse the stomach contents into the appropriate centrifuge tube.

The combined stomach contents and wash solutions were then centrifuged in an International centrifuge for 10 minutes Size 2 (setting at 30). centrifuged. The protruding

409811/1203

Liquid was collected, the volume was determined and written down. 2 drops of phenolphthalein indicator (1% in 95 percent ethanol) were added and the Solution was with 0.02 'n NaOH (or with 0.04 η NaOH', if larger volumes of stomach contents were present) titrated to a pH value of 8.4 (since the stomach contents usually is colored, the phenolphthalein was only used to an indication that the end point was near) then the amount of acid present was calculated.

The compounds which inhibit gastric acid secretion by 20% or more were considered to be active. In the following Table II shows the results of an experiment that can be carried out with a typical compound according to the invention is obtained.

409811 / 120.2

Tabel

link Intraduodenal
Dose mg / kg
body weight 50 f * J
Inhibition,% 11-alpha-hydroxy-9-oxo-
13-trans-prostenic acid 50 50 45 11alpha- ⁱ (4-hydroxybutoxy) -9-
oxo-13-trans-prostenic acid 50 50 42 9-oxo-10.13-trans-prosta-
dienic acid 100 31 9-oxo-16-hydroxy-13-trans-
prostenic acid 100 67 9-0x0-16-hydroxy-prostane
acid 50 58 9-oxo-20-hydroxy-13-trans-
prostenic acid '100 56 9-0XO-18/19-hydroxy-13-
trans-prostenic acid Subcutaneous
Dose mg / kg
body weight 28 9-oxo-18-hydroxy-19.20-
dinor-13-trans-prosten
acid 1.6
0.8
0.4 21 Ethyl-9-oxo-18-hydroxy-
19.20-dinor-13-trans-
prostennoat 49 9-oxo-11alpha, 16-
dihydroxy-5-cis-13-trans-
prostadic acid 48
44
35

409811/1203

The bronchodilator activity was observed in guinea pigs against bronchospasm determined by intravenous Injection of 5-hydroxytryptamine, histamine or acetyl-choline according to the Konzett method £ (see J. Lulling, P. Lievens, E. El Sayed and J. Prignot, Drug Research, 18, 955 (1968] _ /.

The following table shows the bronchodilator activity for exemplary compounds according to the invention against one or more of the three spasmogenic agents, expressed as ED _go, this value being determined from the results obtained with three logarithmic, cumulative intravenous doses.

Table III

Bronchodilator activity (Konzett experiments)

ED ₅₀ , mg / kg)

Antispasmodic agent

Link . 5-hydroxy

tryptamine histamine acetylcholine

11 -alpha-hydroxy-9-

oxo-13-trans-prosten-,,

acid 1.87 χ 10 250 χ 1θ " ⁴ 1.19

11 alpha- (4-hydroxybutoxy) -9-OXO-13-

trans-prostenic acid 4.1 4.5 5.5

The following Table IHa lists the doses, not necessarily the minimum doses, that result in a significant decrease of the diastolic blood pressure, indicated for typical compounds according to the invention.

/, 09811/1203

- οι -

Table IHa.

Hypotensive dose compound - (mg / kg body weight )

9-Oxo-11 alpha, 16-dihydroxy-5-cis, 13-trans-prostadic acid 0.5 ' ^J

9-oxo-11 alpha, 16-dihydroxy-20-

methyl-5-cis, 13-trans-prosta-

dienoic acid 0.5

9-0XO-11alpha, 16-dihydroxy-20-

ethyl-5-cis, 13-trans-prostadiene-

acid> 0.5

9-0XO-11 alpha, 16-dihydroxy-20-nor-5-cis, 13-trans-prostadic acid 1.0

9-oxo-11alpha-hydroxy-15-hydroxymethyl-5-cis, 13-trans-prostadic acid 2.0

9-Oxo-11alpha, 17-dihydroxy-5-cis, 13-trans-prostadic acid 2.0 ·

9-Oxo-11 alpha, 16-dihydroxy-4 (R) -

inethyl-5-cis, 13-trans-prostadiene-

acid "2.0

9-oxo-11alpha, 16-dihydroxy-20-

methyl-5-cis, 13-trans, 18-cis-

prostadic acid 2.0

9-oxo-16-hydroxy-5-cis, 13-trans-prostadienoic acid 2.0

9-0XO-11alpha-hydroxy-5-cis,

13-trans-prostadic acid 2.0

9-oxo-11alpha-hydroxy- 5-cis, 13-

trans, 17-cis, prostatrienic acid 2.0

9-oxo-16-hydroxy-5-cis, 10,
13-trans-prostatrienoic acid 1.0

9-oxo-5-cis, 10.13, trans-

prostatric acid 2.0

40981 1/1203

Table IV

Bronchodilator activity (Konzett attempt)

ED ₅₀ , mg / kg

Spasraogenes Middle

link

5-hydroxy tryptamine histamine

Choline

9-oxo-20-hydroxy-13-trans-117 χ 10 prostenic acid

9-Oxo * 18-hydroxy-19, 20-dino-13-trans-prostenic acid

2.85

9-Οχο-16-hydroxy-13-transprostic acid 277 χ 10

30 χ 10

mm "Ϊ

2.22

2.16

10.0

34.6 χ 10 ~ ³ 455 χ 10 ~ ³

9 ~ Oxo-16-hydroxy-prostanoic acid 92.7 χ 10 .477 χ 10 "

1.13

9-oxo-18/19-hydroxy-13-trans-prostenic acid

1.19 1, 04.

Basic exit and interconnections are general known as well as process for their production; See for example BE-PS 786 215.

The invention is illustrated in more detail by means of the following examples.

example

Production of all-cis-2- (6-carboxy-2-cis-hexenyl) -3,4- -oxidocyclopentanol

A solution of 1.4 g (10.0 moles) of all-cis-5-hydroxy-2,3-oxidocyclopentylacetaldehyde-V-lactol . (E. J. Corey and in 5 ml of sulfoxide (DMSO) becomes a solution with stirring from Wittig reagent / E. J. Corey et al. JACS, Vol. 91,

P. 5675 {19691 /, obtained from 13.3 g (0.30 moles) of 4-carboxybutyl triphenylphosphonium bromide (Example 8), 2.52 g (0.60 mol)

57 percent sodium hydride dispersion and 70 ml DMSO

16 ⁰ C has been produced for one minute.

The solution is stirred for 20 hours at ordinary temperature and, while stirring, is poured into a mixture of methylene chloride, Poured ice and hydrochloric acid. The organic phase is separated and the aqueous phase is with Extracted methylene chloride, saturated with sodium chloride and extracted with ether. The united organic Sodium bicarbonate is added to the extracts. The aqueous alkaline extract is acidified with dilute HCl, saturated with sodium chloride and extracted with ethyl acetate. The extract is washed with brine, dried over magnesium sulfate and concentrated, whereby the above crude compound is obtained as an orange oil.

409811/1203

Example 2

Production of all-cis-2- (6-Carboxy ~ 2-cis-hexenyl) -3 , A- -oxidocyclopentanone

To a solution of about 1.6 moles of crude all-ciss-2 * · (6-carboxy-2-cis-hexenyl) -3,4-oxidocyclopentanol (Example 1) 1.6 ml of 4On chromic acid are added to 1.6 ml of ether with stirring in 4N sulfuric acid at 0 C for 9 minutes. After stirring for 5 minutes at 0 C, the solution is treated with salt solution, Ether and ethyl acetate diluted * The organic phase is treated with isopropanol, washed with brine and dried over magnesium sulfate. By evaporation of the Solvent, the above-mentioned compound is obtained as an oil.

Example 3

Preparation of 2- (6-carboxy-2-cis-hexenyl) -4.-hydroxycyclopent-2-en-l-one

A solution of 1.0 mmol of all-cis- (6-carboxy-2-cis-hexenyl) -3,4-oxidocyclopentanone (Example 2) and 3.0 mmol of sodium carbonate in 15 ml of water is 3 hours at room temperature ditched. The solution is acidified with HCl, saturated with sodium chloride and extracted with ether. Of the The extract is washed with brine, dried over magnesium sulfate and concentrated. This creates a mixture from the above-mentioned compound and the isomeric compound 2- (6-carboxy-2-cis-hexenyl) -S-hydroxycyclopent ^ -en-1-one. Further treatment of this mixture with 1/10 η sodium hydroxide at room temperature for 30 minutes leads to the rearrangement of the last-mentioned isomer into the compound given in the title, which as described above from the basic solution is isolated.

409811/1203

Example 4

Preparation of 2- (6-carboxy-2-cis-hexenyl) -4-hydroxycyclopent-2-en-l-one

Implementation of cis-anti-cis-5-hydroxy-2, S-öxidöcy'clopentenylacetaldehyd-V-lactol (E. J. Corey and R. Noyori, Tetrahedron Letters, 1970, 311) prepared from the corresponding lactone and diisobutyl aluminum hydride, as described for the preparation of the corresponding cis-syn-cis-Lactpl / with 4-carboxybutyltriphenylphosphonium bromide, as described in Example 1, gives 2ß- (6-carboxy-2-cis-hexenyl) -3alpha, 4alpha-oxidocyclopentan-1ß-ol, the 2ß- (6-carboxy-2-cis-hexenyl) -3alpha, 4alphaoxidocyclopentanone in the oxidation according to the procedure described in Example 2 supplies, which in turn in the treatment with aqueous base according to that described in Example 3 Working method results in the above-mentioned connection.

Example 5

Preparation of 2- (6-carboxy-2-cis-hexenyl) -3,4-oxidocyclopentanol

A solution of 5.0 g (35 mmol) of 5-hydroxy-2,3-oxidocyclopentylacetaldehyd-γ-lactol (mixture of isomers; EJ Corey and R. Noyri, Tetrahedron Letters, 1970, 311) in 25 ml of DMSO is during 0.5 minutes at 20 ^° C. with stirring to a solution of the Wittig reagent / E. J. Corey et al., JACS, Vol. 91, p. 5675 (1969); also Example 6 / and dimsy sodium, which has been prepared from 23.5 g (53 mmol) of 4-carboxybutyltriphenylphosphonium bromide, 6.1 g (140 mmol) of 57 percent sodium hydride dispersion and 230 ml of DMSO (dimethyl sulfoxide).

40981 1/1203

The solution is stirred for 2 hours at ordinary temperature and poured into a mixture of methylene chloride, ice and hydrochloric acid with stirring. The reaction mixture is worked up as described in Example 1 and the crude product is purified by dry column chromatography on silica gel, whereby the compound given in the title (mixture of two stereoisomers) is obtained as an oil; IR (film) 340, 1710 and 832 cm " ¹ .

Example 6

Preparation of 2- (6-carboxy-2-cis-hexenyl) -3,4-oxidocyclopentanone

A solution of 2.98 g (13.2 mmol) of 2- (6-carboxy-2-cishexenyl) -3,4-oxidocyclopentanol (Example 5) in 66 ml of acetone is added dropwise with 3.30 ml of 8N chromic acid in 8N H ₃ SO _{4 added} at -10 to -5 ° C for 20 minutes. The solution is stirred for a further 10 minutes at -5 ° C. and then a few drops of isopropanol and 12 ml of water are added one after the other. The mixture is filtered and the filtrate is concentrated, saturated with sodium chloride and extracted with ethyl acetate. The extract is washed with brine, dried over magnesium sulfate and evaporated. An oil is obtained in this way; IR (film) 1740, 1710 and 840 cm

Example 7

Preparation of 2- (6-carboxy-2-cis-hexenyl) -4-hydroxycyclopent-2-en-l-one

A solution (pH 10.2 to 10.5) of 2.42 g (10.8 mmol) of 2- (6-carboxy-2-cis-hexenyl) -3,4-oxidocyclopentanone (Example 6), 4.58 g (43.2 mmol) of sodium carbonate and 216 ml of water are left to stand for 24 hours at room temperature under nitrogen. The solution is at 15 ⁰ C with

60981 1/1203

Acidified hydrochloric acid and extracted with ethyl acetate. The extract is washed with brine over magnesium sulfate dried and evaporated. An oil is obtained; IR (film) 1700 (carbony groups) and 1630 cm '(conjugated Olefin); NMR 7.11 (Dr 5.54 (2) and 495 (1) delta.

Example 8

Preparation of 4-carboxybutyl triphenylphosphonium bromide

A mixture of 103 g of 5-bromovaleric acid and 152 g of triphenylphosphine in 400 ml of acetonitrile is refluxed for 48 hours, cooled, diluted with 100 ml of benzene and allowed to crystallize. The crystals are filtered off, washed with benzene and ether and a colorless material with a ^{temperature of 207 to 209 °} C. is obtained.

Examples 9-15

Implementation of the omega-bromoalkanoic acids given in Table 1 with triphenylphosphine according to the procedure described in Example 8 also results in the Table indicated phosphonium bromide.

40981 1/1203

Tabel

If used W bromine game alkanoic acid

phosphonium bromide obtained as product

4-bromo-n-butyric acid 3-carboxypropy1triphe nylphosphoni umbromide

6-bromo-n-hexanoic acid 5-carboxypentyl triphenylphosphonium bromide

7-bromo-n-heptanoic acid 6-carboxyhexyl triphenylphosphonium bromide

5-bromo-4-methyln-pentanoic acid (2-methyl-4-carboxybutyl) triphenylphosphonium bromide

5-Bromo-4 (R) -methyl-n-pentanoic acid (2 / R / -Methyl-4-carboxybutyl) triphenyl-phosphonium bromide

5-Bromo-4-ethyln-pentanoic acid (2-ethyl-4-carboxybutyl) triphenylphosphoni umbromid

5-bromo-4-propy1-n-pe ηtanic acid (2-propyl-4-carboxybutyl) triphenylphosphonic umbromid

J.S. Dalby, G.W.Kenner and R.C. Sheppard, J. Chem. Soc, p. 4387 (1962).

/ »09811/1203

Examples 16-22

By reacting 5-Hydroxy-2, S-oxidocyclopentylacetalde-

_m *,

hyd- / y-lactol (mixture of isomers) with the Wittig reagent, which is obtained from the phosphonium bromides given in Table 2
has been prepared, according to the procedure of Example 1 and 5, the compounds also given in the table are produced.

£ 098 1 1/1203

Table 2

Phos used as a product

phonium bromide of 3 ^ -oxidocyclopentanol

Example Example (mixture of isomers)

9 2- (5-carboxy-2-cis-

pentenyl) -3 _f 4 -oxido -... cyclopentan-1-ol

, "10 *" 2- (7-carboxy-2-cis-

heptenyl) 3,4-oxidocyclopentan- ¹ ^ 1 * -ol "

11 2- (8-carboxy-2-cis-

octenyl) -3,4-oxidocyclopentane-1-oil *

12 2- {6-carboxy-4-methyl-

2-cis-hexenyl) -3,4-oxidocyclopentane-1-oil

20 '13 2- {6-carboxy-4 (R) -

methyl-2-cis-hexenyl) -3,4-oxidocyclopentane-1- 0I

14 2- (6-carboxy-4-ethyl-

2-cis-hexenyl) -3,4-oxidocyclopentane-1-oil

15 2- {6-carboxy-4-propyl-

2-cls-hexenyl) -3,4-oxidocyclopentane-1-oil

40981 1/1203

Examples 23-29

By oxidation as indicated in Table 3 below Cyclopentanols according to the procedure described in Example 6 are also the corresponding ones in the table named 3,4-Oxidocyclopentanone produced.

811/1203

Table 3

example

Cyclopentan-1-oil used from Example contains 3, 4-oxidocyclopentan · -1 -one as a product

16

17th

18th

19th

20th

21

22 2- (5-carboxy-2-cispentenyl) -3,4-oxidocyclopentane-1 -on

2- (7-Carboxy-2-egg sheptenyl} -3,4-oxidocyclopentane-1 -on

2- (8-Carboxy-2-cisoctenyl) -3,4-oxidocyclopentane-1 -on

2- (6-Carboxy-4-methy1-2-cis-hexenyl) -3,4-oxidocyclopentan-1-one

2- (6-Carboxy-4 (R) raethyl-2-cis-hexenyl) -3,4-oxidocyclopentan-1-one

2- (6-Carboxy-4-ethyl-2-cis-hexenyl) -3,4-oxidocyclopentan-1-one

2- (6-Carboxy-4-propyl-2-cis-hexenyl) -3,4-oxidocyclopentan-1-one

409811/1203

Examples 30-36

By alkaline treatment of the 3 ^ -oxidocyclopentanones mentioned in the following table according to the method in Example 7 The 4-hydroxycyclopentenones also mentioned in the table are produced.

409811/1203

T a b e lie

3,4-Oxidocyclopentanone used from Example Example 4-Hydroxycyclopent-2-en-1-one obtained as product

23

24

25th

26th

27

28

29 2- (5-carboxy-2-cispentenyl) -4-hydroxy-cyclopent-2-en-1-one

2- (7-Carboxy-2-cisheptenyl) -4-hydroxyeyclopent-2-en-T-one

2- (8-Carboxy-2-cisoctenyl) -4-hydroxy-cyclopent-2-en-one

2- (6-carboxy-4-methyl-2-cis-hexenyl) 4-hydroxy cyclopent-2-en-1-one

2- (6-carboxy-4 (R) -methyl-2-cis-hexenyl) -4-hydroxycyclopent-2-en-1-one

2- (6-Carboxy-4-ethyl-2-cis-hexenyl) -4-hydroxycyclopent-2-en-1-one

2- (6-Carboxy-4-propyl-2-cis-hexenyl) -4-hydroxycyclopent-2-en-1-one

409811/1203

Example 37

Preparation of A-Tetrahydropyranyloxy - ^ - (6-carbotetrahydropyranyloxy-2-cis-hexenyl) -cyclopent-2-en-1-one

"■ ■> *

An ice-cold solution of 9.45 g (42.5 mmol) 2- (6-carboxy-cis-2-hexenyl) -4-hydroxycyclopent-2-en-1-one (Example 7) and 14.3 g (170 mmol) of dihydropyran in 212 ml of methylene chloride 81 mg (0.425 mmol) of p-toluenesulfonic acid monohydrate are added with vigorous stirring. After 5 minutes stirring at 0 ° C. for 60 minutes and stirring at 25 ° C. for 60 minutes, the solution turns into a mixture with stirring Poured 40 ml of saturated saline, 40 ml of saturated sodium bicarbonate solution and 80 ml of water. The organic Phase is washed with brine, dried over magnesium sulfate and concentrated to an oil; ny max (movie) 1730 (Ester carbonyl), 1710 (ketone carbonyl) and 1030 cm ~ (tetrahydropyranyloxy groups).

Examples 38-44

By treating the 4-hydroxycyclopent-2-en-l-ones listed in Table 5 below with dihydropyran In the procedure described in Example 37, the corresponding ones are also mentioned in the table generated bis-tetrahydropyranyl ether ester.

40981 1/1203

Tabel

Ex. 38

4-Hydroxycyclopent-2-en-1-one used from Example

30th

31 ·

32

33

34 bis tetrahydropyranyl ether ester obtained as product

4-tetrahydropyranyloxy-2- (5-carbotetrahydropyr any loxy-2-cis-pentenyl) cyclopent-2-en-1-one

4-tetrahydropyranyloxy-2- (7-carbotetrahydropyr any loxy-2-cis-heptenyl) -cyclopent-2-en-1-ox

4-Te trahydropyranyloxy-2- (8-carbotetrahydropyranyloxy-2-cis-octenyl) cyclopent-2-en-1-one

4-Tetrahydropyranyloxy-2- (6-carbotetrahydropyranyloxy-4-methyl-2-cis-hexenyl) -cyclopent-2-2n-1-one

4-Tetrahydropyranyloxy-2- (6-carbotetrahydropyranyloxy-4 (R) -4-methyl) -2-cis-hexenylcyclopent-2-en-1-one

35 4-Tetrahydropyranyloxy-3- (6-carbotetrahydropyr any loxy-4-ethy1-2-cis-hexenyl) -cyclopent-2-en-1-one

36 4-Tetrahydropyranyloxy-2- (6-carbotetrahydropyr any loxy-4-oripy1-2-cis-hexenyl) cyclopenten-2-en-1-one

0981 1/1203

Example 45

Preparation of 4- (trimethylsiloxy) -2- (6-carbotrimethylsiloxy ^ -cis-hexenylcyclopent ^ -en-l-one

A solution of 5 g of 2- (6-carboxy-2-cis-hexenyl-4-hydroxycyclopent-2-en-1-one (Example 7) in 10 ml of dry N, N-dimthylformamide is added under a nitrogen atmosphere with 5.4 g trimethylsilyl chloride was added. The resulting solution is cooled in a tap water bath and treated with 5.05 g of triethylamine in 10 ml of N, N-dimethylformamide dropwise. The resulting mixture is stirred for 2 hours in an oil bath at 60 ⁰ C and then for 13 hours at ambient temperature. Triethylamine hydrochloride is removed by filtration, the filtrate is evaporated to dryness and the remaining oil is further purified by distillation in a high vacuum.

Examples 46-63

By reacting the 4-hydroxycyclopent-2-en-l-ones listed in Table 6 below with the trialkylsilyl chloride indicated following the procedure described in Example 45, these are also given in the table bis-Trialkylsilyläther-ester produced.

40981 1/1 2Q3

Tabel example

4-Hydroxycyclopentenone used by

example

Trialkylsi.lyl chloride

bis-trialkylsilyl ether ester obtained as product

46
47
48

-e-49
ο

30th

31

32

52

33

34

35

(CH ₃ J ₃ SiCl

(CH ₃ J ₃ SiCl

SiCl

Dimethylisopropylsilyl chloride

(CH ₃ ) ₃ SiCl

(CH ₃ J ₃ SiCl

(CH ₃ J ₃ SiCl

4-Trimethylsiloxy-2- (5-carbotrimethylsiloxy-2-cis-pentyl) cyclopent-2-en-1-one

4-Trimethylsiloxy-2- (7-carbotrimethylsiloxy-2-cis-heptenyl) cyclopent-2-en-i-one

4-Trimethylsiloxy-2- (8-carbotrimethylsiloxy-2-cis-octenyl) cyclopent-2-en-1-one

4-diraethylisopropylsiloxy-2- (6-carbodimethyl-isopropylsiloxy-2-cis-hexenyl) -cyclopent * -2-en-1 -on

4-Triraethylsiloxy-2- (6-carbotrimethylsilyloxy-4-methyl-2-cis-hexenyl) cyclopent-2-en-1-one

4-trimethyl-silyloxy-2- (6-carbotrimethylsilyloxy-4 (R) -methyl-2-cis-hexenyl) - cyclopent-2-en-i-one

4-tri-ethylsilyloxy-2- (6-carbotrimethylsilyloxy-4-ethyl-2-cis-hexenyl) cyclopent-2-en-1-one

53

36

(CH ₃ J ₃ SiCl

4-Trimethylsilyloxy-2- (6-carbotrimethylsilyloxy-4-propyl-2-cis-hexenyl) cyclOEe ^ t-2-en-1-one * · -

E.J. Corey, R.K. Varma, J. Araer. Chem. Soc., Vol. 93, p. 7320 (197OJ

Example 54 Preparation of l-oxa-2-hydroxy-bicyclo / 3.3.O / oct-4-en

A solution of 6.2 g (50 mmol) of the lactone of cis-2-hydroxycyclopent-4-en-1-acetic acid / pA, Grieco, J. Org. Chem., Vol. 37, p. 2363 (1972) _ / in 350 ml of toluene (dried over molecular sieves) is ^{cooled to -75 0} C and added dropwise under nitrogen with 84 ml of 0.89 M diisobutyl, aluminum hydride (10.55 g, 74 mmol) within one hour ", whereby the temperature the mixture is maintained at -74 + 2 ⁰ C. the clear solution formed is stirred for 2 hours at -75 ⁰ C and poured into a stirred, mixture of 15 ml concentrated hydrochloric acid and 300 ml of ice water. During heating to room temperature is further After separating the layers, the aqueous layer is treated with salt and extracted with three small portions of ether. The combined organic extracts are dried over sodium sulfate and evaporated under reduced pressure (75 ° C. water bath) Thin-layer chromatography homogeneous) as pale yellow mobile in liquid.

Example 55

Preparation of l-hydroxy-2- (6-carboxy-2-cis-hexenyl) -cyclopent-3-ene

A solution of the sodium salt of dimethyl sulfoxide is made by stirring a mixture of 160 ml of dry dimethyl sulfoxide (dried over molecular sieves and a few flakes of calcium hydroxide) with 6.0 g (0.25 mol) of sodium hydride (made by washing 10.5 g of 57 percent sodium hydride dispersion in mineral oil with two portions of

4 09811/1203

30 ml each of hexane) under nitrogen. The mixture

is heated below.

with stirring in an oil bath for 2.5 hours 75 ⁰ C.

This solution becomes "under" for about 5 minutes A solution of 44 g (0.1 mol) of 4-carboxybutyltriphenylphosphonium bromide (Example 8) in a nitrogen atmosphere Added 180 ml of dry dimethyl sulfoxide. The received dark red-brown solution is stirred for 10 minutes, cooled to room temperature and treated with a solution of crude l-Oxa-2-hydroxy-bicyclo ^ / 3.3.0 / oct-4-en (6.2 g, 50 mmol) (Example 54) added in 20 ml of anhydrous dimethyl sulfoxide. The resulting solution is stirred for 16 hours and then mixed with 250 ml of ice water.

The brown solution is extracted twice with portions of ether to remove neutral substances and then made strongly acidic with hydrochloric acid. The solution is then extracted four times with 100 ml of methylene chloride each time. the combined methylene chloride extracts are washed with water and then with 4 portions of 100 ml of 5 percent Sodium bicarbonate extracted. The combined aqueous extracts are washed with methylene chloride and washed with concentrated hydrochloric acid acidified against Congo red. The mixture is extracted three times with 100 ml of methylene chloride each time. The organic extracts are combined, dried over sodium sulfate and under reduced pressure freed from solvent. The residue (an oily solid) is extracted several times with ether, and the essential extracts are combined and under reduced Evaporated under pressure to give the crude product as a dark oil. The product is chromatographed Purified on silica gel, eluting with ether. The product is a colorless liquid.

/.09811/1203

Example 56

Production of 2- (6-carboxy-2-cis-hexenyl) -cyclopent-3-en- -1-on

A solution of 3.2 g of 1-hydroxy-2- (6-carboxy-2-cis-hexenyl) -cyclopent-3-ene {Example 55) in 60 ml of reagent acetone is added dropwise with a total of 6 ml of 8N chromic acid in sulfuric acid offset at 0 ° C. The oxidation is rather slow. The mixture formed is poured into 200 ml of water dissolves, and the solution is extracted with 6 portions of 50 ml of ether each. The combined ether extracts are over Sodium sulfate dried and the solvent is evaporated under reduced pressure. This is how the product is obtained as a yellow oil.

Example 57

Production of 2- (6-carboxy-2-cis-hexenyl) -cyclopent-2-en- -1-on

A solution of 3 g of crude 2- (6-carboxy-2-cis-hexenyl) -cyclopent-3-en-l-one (Example 56) in 1OO ml of aqueous sodium carbonate (pH 10 to 11) · is taken at ambient temperature below Stirred nitrogen for 4 hours. The solution is acidified against Congo red and extracted with ether. The essential ones Extracts are dried over sodium sulfate and evaporated under reduced pressure. This is how the product is obtained.

Examples 58-64

By treating l-oxa-2-hydroxy-bicyclo / 3.3.O / oct-4-en (Example 54) according to the procedure described in Example 55 with those listed in Table 7 from the The products obtained from phosphonium bromides are the l-hydroxy-cyclopent-3-enes also shown in the table generated.

409811/1203

Tabel example

phosphonium bromide used from Example 1-hydroxy-2- ( ^s- carboxy-2-cis-alkenyl) -cyclopent-3-ene obtained as product

10 11 12 13

14 15 1-Hydroxy-2- (5-carboxy-2-cis-pentenyl) -cyclopent-3-ene

1-Hydroxy-2- (7-carboxy-2-cis-heptenyl) cyclopent-3-enes

1-Hydroxy-2- {8-carboxy-2-cis-octenyl) cyclopent 3-en

1-hydroxy-2- (6-carboxy-4-methyl " 2-cis-kexenyl) cycopent-3-ene

1-Hydroxy-2- (6-carboxy-4 (R) methyl-2-cis-oxenyl) cyclopent-3-ene

1-Hydroxy-2- (6-carboxy-4-ethyl-2-cis-hexenyl) cyclopent-3-ene

1-Hydroxy-2- {6-carboxy-4-propyl-2-cis-hexenyl) cyclo- -3-en

0 9 8 1 1/1203

Examples 65-71

By oxidation of the l-hydroxycyclopent-3-enes listed in Table 8 below according to the method described in Example 5 * 6 The same procedure as shown in the table cyclopent-3-en-l-ones are produced.

409811/1203

Table 8

example

1-Hydroxycyclopent- 3-ene used from Example 2- (& /) - Carboxy-2- disalkenyl) cyclopent-3-en-1-one obtained as product

58 59 60

61 62

63 64 2- (S-

pentenyl) cyclopent-3-en-1-one

2- (7-Carboxy-2-cisheptenyl) cyclopent-3-en-1-one

2- (8-Carboxy-2-cisoctenyl) cyclopent-3-en-1-one

2- (6-carboxy-4-methyl-2-cis-hexenyl) cyclo-

2- (6-carboxy-4 (R-methyl-2-cis-he> ceinyl) -cyclopent-3-en-1-one

2- (6-Carboxy-4-ethyl-2-cis-hexenyl) cyclopent-3-en-1-one

2- (6-carboxy-4-propyl 2-cis-hexenyl) cyclopent-3-en-1-one

11/12

Examples 72-78

By treating the cyclopent-3-en-l-ones listed in Table 9 below with base according to that described in Example 57 The cyclopent-2-en-l-ones are also produced.

4098 11/1203

Table 9

2- ( Ij) - carboxy-2-cis-alkenyl Deisp used. cyclopent-3-en-1-one

from example 72 65

73 66

74 67

75 ^; 68

76 69

2 ~ (CO) -carboxy-2-cis alkenyl) cyclopent-2-en-1-one obtained as product

2- (5-Carboxy-2- cispentenyl) cyclopent-2-en-1-one

2- (7-Carboxy-2-cisheptenyl) cyclopent-2-en-1-one

2- (8-Carboxy-2-cisoctenyl) cyclopent-2-en-1-one

2- (6-Carboxy-4-methyl-2-cis-hexenyl) cyclopent-2-en-1-one

2- {6-Carboxy-4 (R) -methyl-2-cis-hexenyl) cyclopent-2-en-1-one

70

71 2- (6-Carboxy-4-ethyl-2-cis-hexenyl) cyclopent-2-en-1-one

2- (6-Carboxy-4-propyl-2-cis-hexenyl) -cyclopent-2-en-1-one

/.09811/1203

Examples 79-86

By handling the IO listed in the following table 2- (omega-carboxy-2-cis-alkenyl) -cyclopenta-en-1-ones with diazomethane in a customary manner (cf. the procedure for Examples 560 to 586) are the same Generated methyl ester indicated in the table.

40981 1/1203

from e 1 1 e

Eeisniel

carboxy acid used from Example 2- (CJ ) -Carbonethoxy-2-cis-alkenyl) cyclopent-2-en-1-one obtained as product

72 2- (5-Carboxnethoxy-2-cis-pentenyl) cyclopent-2-en-1-one

-73

74

75

77

78 2- {7-carbonethoxy-2-cis-heptenyl) cyclopent-2-en-1-one

2- {8-Carbone thoxy-2-cis-octenyl) cyclopent-2-en-1-one

2- (6-Garboiu3thoxy-2-cis-hexenyl) cyclopent-2-en-1-one

2- {6-Carboineth'oxy-4-methyl-2-cis-hexenyl) -cyclopent-2-en-1-one

2- (6-carbomethoxy-4 (R) raethyl-2-cis-aexenyl) cyclopent-2-en-i-one

2- (6-carbonethoxy-4-ethyl-2-cis-hexenyl) cyclopent-2-en-i-one

2- (G -CarboHie thoxy-4 propyl-2-cis-hexenyl) -cyclopent-2-en-1-one

40981 1/1203

BATH ORIGINAL Beis pie l 87_

Production of l-octyn-4-ol

A suspension of 24.3 σ (1.0 mol) magnesium. In 90 ml dry zither is at room temperature under nitrogen stirred with 100 mg of mercuric chloride. The reaction will go through Addition of 2 ml of propargyl bromide initiated and through Add dropwise a solution of 119.5 g (1.0 mole propargyl bromide and 107.7 g (1.25 mole) valeraldehyde) Maintained in 300 nl of dry zither. While the The initial reaction is quite vigorous and can only be kept at 30 by cooling in an ice bath, it may be necessary will be to heat the mixture to reflux temperature when about one third of the ether solution is added is to keep the implementation going. After complete In addition, the reaction mixture is heated to the boil under reflux until most of the magnesium has dissolved (several hours). Then the reaction mixture of the excess magnesium in 1500 ml of ice-cold ammonium chloride solution poured off with stirring. The ether layer is separated and the aqueous layer is added three times extracted with 300 ml of ether each time. The combined ether extracts are washed with saturated sodium chloride solution, dried over magnesium sulfate and filtered. After evaporation of the ether in a vacuum remain about 115 g of a yellow oil grown at 13 mm on a 15 cm Vigreus column is distilled. The fraction boiling at 81 to 82 ° is collected (36 g), and the fraction higher Boiling and lower boiling distillates can be distilled again, whereby further product is obtained will. The infrared absorption spectrum shows at most a trace of Allen (5.1, u) and the gas-liquid partition chromatography shows a purity of about 98% for the main fraction.

409611/1203

Examples 83-91

The 1-alkyne-4 oils listed in Table 11 are by reaction of the aldehydes also listed in Table 11: with propargylmagnasium bromide with according to "the" ira above Example 87 of the procedure described.

Table 11

At- '
game used
aldehyde obtained as a product
l-alkyn-4-one 33 n-Ilexaldehyde l-nonyn-4-ol 89 η-heptaidehyde l-D.acin-4-ol 90 n-butyraldehyde 1-IIeptin 91 3-cis-hexenaldeh vd 4-Hvdroxv-6-cis-en - l-n <

M. behind, HeIv. Chim. Acta, Vol. 46, p. 1792 (1963).

Example 92

Production of l-triphenylmethoxy-5-hexyne

Line mixture of 9.81 g (0.10 mol) 5-hexyn-l-ol, 33.5 g (0.12 mol) of triphenylmethyl chloride and 200 ml of dry pyridine are brought to the boil for 60 minutes while stirring heated to reflux. The cooled mixture is poured into water poured and extracted with> \ ther. The extract will successively with water, ice-cold η-hydrochloric acid, water, saturated sodium bicarbonate solution and saturated sodium chloride solution washed. Then the extract is dried with magnesium sulfate and the solvent becomes

40981 1/1203

evaporates. The product thus obtained is subjected to chromatography Purified on magnesium silicate (Florisil), whereby an oil is obtained. lanbda max 3290 (acetyl hydrogen), 1600, 1072 and 705 cn (triphenylmethoxy group).

Example 93

Preparation of 4-triphenylmethoxy-1-octyne

A 'mixture of 10 g (0.08 mol) 4-hydroxy-1-octyne / L. Crombie and AG Jacklin, J. Chem. Soc., 1632 (1957) and Example 8] _ / and 30 _f 75 g (0.09 mol) of triphenylmethyl bromide in 85 ml of dry pyridine is heated on the steam bath for 2 hours. The cooled mixture is mixed with water and extracted with ether. The extract is washed successively with ice-cold 2 percent hydrochloric acid and saturated sodium chloride solution, dried with magnesium sulfate and evaporated to dryness. Column chromatography of the residue on magnesium silicate (Florisil) gives an oil; lambda max 3, oil, 4.72 (acetylene hydrogen), 6.28, 9.65 and 14.25, u (triphenylmethoxy group.

Example 94

Preparation of 4-triphenylmethoxy-1-hexyne

A solution of 9.81 g (0.10 mol) of 4-hydroxy-1-hexyne and 33.5 g (0.12 mol) of dry triphenylmethyl chloride in 100 ml of dry pyridine is stirred for two hours heated to reflux. The cooled mixture is mixed with water and with a mixture of hexane and £ ther extracted. The extract is washed successively with water and saturated sodium chloride solution, dried over magnesium sulfate and concentrated. By

400811/1203

Column chromatography of the residue on magnesium silicate (Florisil) gives an oil; lambda max 3290 (acetylene hydrogen) 1600 , 1030 and 705 cm (triphenylmethoxy group). -

Examples 95-112

The triphenylmethoxy-substituted ones listed in the table below 1-Alkynes are prepared by the method of Example 93 from triphenylmethylbroinide and the corresponding hydroxy-substituted 1-alkynes, for each of which references are given in the table, manufactured.

409811/1203

a b e 1 1 e 12

hydroxy-substituted 1-alkyne used Example of

triphenylnethoxy-substituted product obtained as product 1-alkyne

Reference No. 1

Reference No. 1 (Example 90)

Reference No. 1

Reference No. 2 (Example 88)

Reference No. 3 (Example 89)

Reference No. 4

Literature No. 5

Reference No. 6

Reference No. 7

Reference No. 8

Reference No. 9

Reference no.

Reference no.

Reference No. 11 4-triphenylmethoxy-1-panrine

4-triphenylnethoxy-1-hcptine

4-triphenylmethoxy-5-methyl-1-he xi η

4-triphenylmsthoxy-1-nonyne

4-triphenylraethoxy-1-decyne

5-triphenylraethoxy-1-pentyne

7-triphenylmethoxy-1-heptyne

9-triphenyl methoxy-1-nonyne

1O-triphenylmethoxy-1-decyne

11-triphenylnethoxy-1-undecine

5-triphenylmethoxy-1-hexyne

4-Triphenylirtethoxy-7-ir.ethyl-1 -octine

4-triphenylnethoxy-5-ethyl-1-heptyne

5-triphenyl methoxy-4-methy1-1-pentyne

409811/12

Table 12 (cont.).

used hydroxy substituted 1-alkyne obtained as a product triphenylrr.ethoxy-substituted IcA game of tuierter 1-alkyne

109 Reference No. 11 5-Triphenyliaethoxy-

4-ethyl-1-pentyne

110 Literaturatelie No. 11 5-triphenylmethoxy-

4-ine thy 1-1 -hexine

111 Reference No. 11. 5-triphenylmethoxy

4-ethyl-1-hexyne

112 Example 91 4-triphenylinethoxy-6-cis-

en-1-nonine

References:

1. G. Fontaine et al., Bull. Sog. Chim. France, p. 1447

(1963)

2. S. Abe and K. Sato, Bull. Soc. Chem. Japan _t Vol. 29, p. 33 (1956); Chem. Abstr. Vol. 50, p. 13737 (1956).

3. L. Crombie and A.G. Jacklin, J. Chen. Soc, p. 1622

(1957); P. 174Ο (1955).

4. R. Paul and S. Tehelitchef f, Compt. χ-end. , Vol. 232, P. 2230 (1951).

5. C. Crisan, Ann. Chin. (Paris) _f vol / 13/1, p. 436 (1956).

6. R. Ricnschneider, G. Kasang, and C, Boehme, Montashefte Chen. Vol. 96, p. 1766 (1965).

7. Ames, J. Chem. Soc. (C), p. 1556 (1967).

8. LD mountains! ¹ son et al., Zh. Obschie Khirn. , Vol. 32, G. 53 (1962); Chen. Abstr., Vol. 57, p. 1493Oa (1962).

3, Vi. V. Egorov and AS Atavin, Chera. Abstr. Vol. 71, p. 61473U (1969)

10. riobuharra Akio, Agr. Biol. Chem. (Tokyo), Vol. 32,

S. 10G (19Ga); Chcn. Abstr., Ud. 70, p. 3219J (1969).

11. J. Cologne and P. Gclin, Bull. Goc. Chim., France, P. 79'3 (1954).

A09811 / 1203

- 93 -

At game 1 13 the preparation of S-tripheriylmethoxy-1-octyne

iinc; Suspension of 63.1 g (0.18 mol) of l-chloro-6-triphenylmethoxyhsxyn, which is prepared from l-chloro-6-hydroxyhexart and 'Triphanyimethylchlorid by the procedure described in Example 92 and 60 ml of dimethyl sulfoxide is stirred with a Solution of 19.9 (0.0216 mol) lithium acetylide-i-lthyleridiamin-Kompiex in 120 ml dimethyl sulfoxide were added for 20 minutes. During the addition, the temperature is kept at 25 ° C with an ice bath, after which the mixture is stirred at ambient temperature for 3.5 hours and then at 30 ° C for 15 minutes. The mixture is diluted with 100 ml of ether and 150 ml of water are added dropwise while cooling with an ice bath. The mixture is ^r with 400 nl hater and 0 2 ml of ether / petroleum ether? (2: 1) and acidified with 120 ml of 4N hydrochloric acid in an ice bath. The phases are separated and the aqueous phase is extracted with a mixture of i'.ther and petroleum ether (3: 1). The combined extracts are washed successively with water and saturated sodium chloride solution , dried over magnesium sulfate and concentrated. Column chromatography of the residue of magnesium silicate (Florisil ^u ) gives the abovementioned compound in the form of white crystals with a temperature of 43 to 45 ° C according to uflikris ^ a.! i "jxeren from P ^ trolather; lambda max 330

(Hydrogen acetylene), 2360 (triple bond), 1600, 1068 and 706 er.;. (Triphenylriethoxy group).

Example 114 Preparation of 3-bromo-1-octyne

A suspension of 600 g of triphenylphosphine in 20OO ml of acetonitrile is stirred and under a nitrogen atmosphere

40981 1/1203

BATH ORIGINAL

113 ml of bromine are added to drop wines at a temperature which does not exceed 35 ° C. After stirring for an additional hour, the supernatant liquid becomes decanted and evaporated to dryness. The solid residue becomes rr.with the previous solid with 150 ml Combined dimethylformamide. The suspension is taking Stirring at -20 ° C with a solution of 2OO g of 1-octyn-3-ol added in 300 ml of dimethylformamide in three portions. The temperature is allowed to rise slowly to 20.degree. After three hours, the solution is extracted with three portions of 1600 ml each of petroleum ether (boiling point 30 ° to 60 °). The combined extracts are washed with saturated sodium chloride solution, saturated sodium bicarbonate solution and finally washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate and dried to dryness evaporated (bath 30 to 35 C) · By distilling the remaining oil, 117 g (39%) of the product are obtained Bp. 66 to 68 ° C / 9 mm.

Example 11 5

Production of 3-hydroxymethyl-l-octyne

A suspension of 2.54 magnesium in 15 ml of ether, which contains some crystals of mercuric chloride, is taken under Nitrogen atmosphere with a small amount of 3-bromo-1-octyne added to 20 ml of ether. Once the reaction has started, the flask is placed in a water bath of Chilled to 15 C, and the remaining portion of the halide in i'.ther is added troufc.nwoise over about an hour, After all of the halide has been added, stirring is continued for a further 15 minutes. The piston will then equipped with a glass tube that extends almost to the but does not reach below the surface of the liquid. This tube is directly connected to a round bottom flask which Contains about 20 g of p-formaldehyde, or before 2 days in one

40981 1/1203

BAD ORfGiNAL

- ICO -

Vacuum exsiator contains eggs two days beforehand in one Vactar desiccator has been dried over phosphorus pentoxide v ^ r. This flask is an inlet tube for nitrogen on. The reaction flask is immersed in a Lis bath and the flask containing the p-formaldehyde is in heated in an oil bath to 130 to 200 ° C. The one by depolymerization Formaldehyde is formed by a slow stream of dry nitrogen in the Grignard reagent done. After 30 to 40 minutes, the addition of Forir.-aldehyde stopped and the reaction mixture will stirred at zipper temperature for 18 hours.

The reaction mixture is then cooled in an ice bath and first with saturated ammonium chloride and then mixed with water and finally ether. The mixture is then acidified with 2N sulfuric acid. The organic phase is separated off with saturated sodium chloride solution washed and dried with anhydrous magnesium sulfate. The solvent is removed in vacuo. The residue is distilled and 4.4 g are obtained Product with a bp 91 to 93 ° C / 9 mm.

At s p le 11 6-118

By reacting the 3-hydroxymethyl-1-alkynes listed in Table XIII below with triphenyl ethyl bromide using the procedure described in Example 93, they are also shown in the table indicated 3-triplienylmethoxymethyl-l-alkynes generated.

'♦ 09811/1203

BATH ORIGINAL

T a b c- 1 1 e 13

3-II-hydroxymethyl-1-alkyne used

triphenymethoxymethyl-1-alkyne obtained as product

3-Hydroxyme thy11- -hexin ¹ *

3-triphenyl methoxyraethyl-1-hexyne

3-hydroxyethyl-1- -heptine

3-triphenyimethoxyinethy 1-1 -hept in

3 -hydroxyme thy 1-1 octin ¹ '(Example 115)

3-triphenyimethoxyme thy 1-1 -octine

Λ. Schaap, L. Brandsma and J- F. Ärens, Rec. Trav. chim., Vol. 86, 393 (1967)

example

119

Production of l-chloro-3-triphenylir.ethoxyhexane

A solution of 27.3 g (0.20 mol) of l-chloro-3-hexanol, 77.6 g (0.24 moles) triphenylnothyl bromide, 30.0 g (0.28 Mol) 2,6-lutidine and 200 μl chlorobenzene are heated to 95 ° C. for one hour while stirring. The cooled mixture is mixed with water, and the organic phase is one after the other with Viasser and saturated sodium chloride solution washed. The solution is made over magnesium sulfate. dried and concentrated. By column chromatography of the Residue of magnesium silicate (Florisil) is obtained above compound as an oil; lambda raax 1600, 1030 and 705 cm (triphenylate ethoxy group).

409811/1203

Example 120 Preparation of 5-Triphsnylmethoxy-1-Octyne

A solution of 32.2 g (85 ml) of 1-chloro-3-triphenylmethoxyhexane (Example 119) in 25 ml of dimethyl sulfoxide (DMSO) is added with stirring to a solution of 9.4 g (102 μmol) of lithium acetylide-ethylenediamine complex added in 60 ml DIiSO for 10 minutes, the temperature being kept at 25 to 30.degree After 3 1/2 hours the mixture is diluted with ether and successively with water and 4N hydrochloric acid offset, cooling in an ice bath. The phases are separated and the aqueous Phasa is with Ether / petroleum ether extracted. The combined extracts are - Successively with water and saturated sodium chloride solution washed, dried over magnesium sulfate and concentrated. The product is then subjected to column chromatography the residue of magnesium silicate (Florisil) purified.

Example 121 Production of cis-5-octene-l-yne

A 57 percent dispersion of sodium hydride (9.56 g), O, 23 mol) is in a nitrogen atmosphere with hexane Washed free of mineral oil. The hydride is mixed with 2 20 ml of dimethyl sulfoxide Heated to 75 ° C. for 45 minutes. The educated The green solution is cooled to 18 C and treated with a solution of 4-pentynyl-triphenylphosphonium iodide (100 g, 0.22 mol) added in 220 ml of dimethyl sulfoxide in about 25 minutes. the The red solution formed is stirred at ambient temperature for 45 minutes and then with a solution of thoroughly distilled Propionanedehyde (14.0 g., 0.24 mol) in 10 ml of dimethyl sulfoxide decomposed within 10 minutes at 25 ° C. After standing at room temperature the reaction is started by adding

40981 1/1203

canceled by half saturated Salzösung, and the pH ^T \ ^T ert v; ill be adjusted with 4N HCl to fourth The product is extracted with an ether-r-hexane mixture, and the extract is washed successively with Tiassar and brine, dried over magnesium sulphate and concentrated. The crude product is fractionated with a spinning band column, and a colorless distillate of boiling point 121 to 122 ° C. is obtained; IR 3270, 2110 and 1645 era " ¹ .

Example "122 ■
Manufacture of 8-chloro-1-octyne

Said compound is made according to the method of W.J. Gansler and G.R. Thoraas, JACS Vol. 73, p. 4601 (1951) manufactured.

Beis piel 123

Production of l-JoG-4-triphenylmethoxy-trans-l-octene

A suspension of 1.73 g (0.074 mol) of sodium borohydride in 200 ml of dry glycol methyl ether - (Glyine) ^T - / ird under nitrogen and with stirring at -5 C with 15.8 g (0.21 liol) of 2-methyl-2 -butene and 16.2 g (0.11 mol) of boron trifluoride etherate are added, and the mixture is stirred ^{at -5 to 0 ° C. for 2 hours.} A solution of 37.5 g (0.10 mol) of 4-trityloxy-1-octyne- (Example 93) in 50 ml of glyme is added to the cold solution in 5 to 10 minutes, before the solution is Allowed to warm to 20 ° for 5 hours. The reaction mixture is cooled to 0 ° C. and 30 g (0.4 mol) of dry trinethylamine K-oxide are added over the course of 5 minutes. Removing the leg Kahlbads the Temoeratur rises to 40 ⁰ C, and the mixture is held for 1.5 hours between 30 and 40 ° C. The suspension is rapidly poured into 1 liter of ice-cold 15 percent

40981 1/1203

BATH

Sodium hydroxide solution is poured with thorough stirring and a solution of 20 g of iodine in 200 ml of tetrahydrofuran is added immediately afterwards. Stirring is continued after 30 minutes without further cooling, and the organic layer is separated. The aqueous layer is extracted three times with 200 ml of ether each time, and the combined organic layers are successively washed with 5% water Washed sodium thiosulphate solution and saturated lithium chloride solution, dried over magnesium sulphate, filtered off and evaporated. Thereby 50 g of a yellow pulse was obtained. The I-Iauptteil of the oil is in; .ie, - dissolved and nacii casting of a rubbery Foatsubstanz is passed through a 5.1 cn the liexanlösunrr diameter column of 1500 g of aluminum oxide with zusätulichsrc Ktxan. The fractions containing the desired product are concentrated to a pale yellow oil (33 g) which has the NMR and infrared spectrum characteristics of the desired product.

In games 124-146

By implementing those listed in Table 14 below triphenylnethoxy-substituted as alkynes nit Disianylborane, which is produced in situ from 2-methyl-2-butene, eortrifluoride and T-Tatriunborohydrid has been produced, then with trimethylamine-li-oxide and finally with ;; atriu: p.hyäroxid und iodine - all reactions after the Procedure described in Example 12 3 - the triphenylrr.ethoxy-substituted also listed in the table are 1-Joel-1-trans-alkenes produced.

409811/1203 SAD ORIGINAL

Table 14

used triphenyl-. 1-iodo-triphenyl-methoxy-substituted-methoxy-substituted- 1-alkyne obtained from Example 1 -trans-alkene

124 92 i-iodine-6-triphenyl-

methoxy-1-trans-hexene

1-iodo-4-tripheny1-methoxy-1-trans-hexene

1-iodo-4-triphenylraethoxy-1-trans-pentene

1-iodo-4-triphenylmethoxy-1-trans-heptene

1-iodo-4-tripheny1-methoxy-5-diethyl-1 -trans-witches

1-iodo-4-tripheny1-methoxy-1-trans-nonene

1-iodo-4-tx'iphenyl-methoxy-1-trans-decene

i-iodo-5-triphenyl-inethoxy-1-trans-pentene

1-iodo-7-triphsnyl-methoxy-1-trans-heptene

1-iodine-9-triphonyI ~ rnethoxy ~ 1-trans-nones

1-iodo-10-triphany I-r; ethc'r / -1-trans-decoa

1-iodine-11 -tripher-yl-matnoxy-1-trans-undecene

125 94 126 95 127 96 128 97 129 98 130 99 131 100 132 101 133 102 134 103 135 104

409811/1203

- 106 table (Cont.)

triphenylmethoxy-substituted-1- / ilkin used 1-iodo-triphenylnethoxy-substituted-1-trans-alkene obtained from Example

1O5

106

107

108

109

11O

111

113

116

117

118

120 1 -Joa-5-triphen_ylmethoxy-1-trans-hexene

1-iodo-4-triphenylmethoxy-7-methyl-trans-oetene

1-iodo-4-triphenylmathoxy-5-ethyl-1 trans-hepten

1-iodo-5-triphenylmethoxy-4-me thyI-1-t.tans-penten

1 - iodine - 5-triphenylnethoyy ~ 4-ethyl-1-Lr-Hnp-pentene

1-iodo-5-triphenylnethoxy ~ 4-methy1-1-trans-hexene

1-iodo-5-triphenyliriethoxy-4-ethyl-1 trans-witches

1-iodo-4-triphenylnethoxy * 1-trans, 6-cis-nonadiene

1-iodo-8-triphenylme thoxy-1-transoctene

1-iodine ~ 3-triphenylnethoxyinethyl-1 trans-witches

1-iodine-3-triphenyline thoxyme thy I -1 trans-hepten

1-iodo-3-triphenyliae thoxy methyl-1 trans-octene

1-uod-5-triphenylnethoxy-1-transoctene

4098 1 1/1203

Example 149

Production of 9-oxo-llalpha, 16-dihydroxy-5-cis; 13-transprostadienoic acid

Hin's solution of 25.8 g (51 r.iMol) of l-iodo-4-triphenylrethoxytrans-i-octene (Example 123) in 50 ml of toluene is rvifc 26.3 ml of 1.9 η n-butyllithiura in hexane at 70 under tubes offset. After the addition, the solution is stirred at -40 ° C. for 60 minutes. This solution, the 4-1riphenylmethqxytrans-1-octeny! Lithium contains, advises 26.8 ml 1.45 πι Trirethylalumirtiurn in Kexan of -40, and the The resulting solution is stirred at 0 for 20 minutes.

Discrete lithium tri-ethyl- (4-triphenylnethoxy-trans-locter.y-dalanate containing solution is pit a solution of 16.7 g (42.5 nmol) of 4-tetrahydropyranyloxy-2- (6-carbotetrahydropyranyloxv-2-cis ~ hexenyl) Cyclopent-2-en-l-one (Example 37) was added from 0 to 8 ° in 60 ml of zither. The mixture is stirred for one hour at 0 ° and 20 hours at 25, diluted with ether and poured into a Poured mixture of ice and 20 ml of 37 percent hydrochloric acid. The. aqueous phase is separated off; and with ether extracted. The combined organic phases are washed successively with water and brine, over Dried magnesium sulfate and concentrated to an oil.

The crude product is dissolved in 425 ml of acetic acid / tetrahydrofuran / ',' as3cr (4: 2: 1) dissolved, and the resulting solution is heated to 45 ° for 4 hours. The solvents v / ereate removed at 20 in vacuum, and one obtains Mixture of oil and crystals.

811/1 203 ORlQINAU

- 103 -

Da's crude product is subjected to vertex lung chromatography al acid washed silica gel using the conjugate phases of benzene / methanol / water (15: 15: 2) cleaned. This creates the prostate acid obtained as an oil; lambda max (film) 33OO (hydroxy), " 1735 (cyclopentanone), 1705 (carboxylic acid) and 967 cm (trans-olefin).

Examples 150-2O3H

The products indicated in Table 15 below i ^ -Oxo-llalpha-hydroxy-S-cis, 13-trans-prostadic acid are obtained according to the procedure described in Example 149. As described therein, the in Table 15 listed triphenylmethoxy-substituted 1-iodine-trans-l-alkene treated with eutyllithium, whereby the corresponding triphenylmethoxy-substituted trans-1-alkenyllithiura derivatives are formed which, when treated with methyl aluminum, form the corresponding lithium trimethyl (triphenylmethoxy-substituted trans-1-alkenyl) Deliver alanates, which in turn are reacted with the 4 oxicyclopent-2-en-l-ones listed in the table. The triphexylmethoxy-substituted 9-oxyolalpha-tetrahydropyranyloxy formed (or 1lalpha-trialkylsiIyI-oxy) -5-cis, 13-trans-prostadienoic acid-tetrahydropyranyl- (or Trialkylsilyl) esters become those listed on treatment with acetic acid / tetrahydrofuran / water Hydrolyzed products.

409811/1203

tab

lie

15th

4-oxocyclopent-2-en-1-one used

Example by example

triphenylmethoxy-1-iodo-trans-1-alkene used of example

preserved »9 ~ Oxo-1 ialpha-hyuroxy-5-cis, 13-trans-pro5tadien3uure

150

152
3 '

JO

37 37 37 37 37 45 37

37

129 130 127 125 137 138 143

126

9-Oxo-11 alpha, 16-dihydroxy-20 ~ i-nethy 1-5-cis , 1 3-tranr> -pros tadienciiiura

D-Oxo-11 alpha, 16 ~ dihydro; iy-20-ethyl-5-cis , 1 3-trans-pro; tadicic acid

9-OXO-11 alpha, 1 δ-dihydroxy-2O-nor-5-ciG, 13-trana-pro3tadienoic acid

9-0x0-11 alpha, 16-dihydroxy-19,20-dinor-5-cis, 13-trans-prontadienoic acid

9-0x0-11 alpha, 16-dihydroxy-19-mothy1- * 5-cis, 13-trans-proGtadienic acid

9-Oxo-11 alpha, 16-dihydroxy-17-ethy1-20-nor-5-cis, 13-trans-prostadic acid

9-0x0-11 alpha, 16-dihydroxy ~ 20 ~ methyl-5-cis, 13-trans, 18-cis, prostatrienic acid

■ 9-0x0-11 alpha, 16-dihydroxy-18,19,20-trinor-5-cis, 13-trans-prostadic acid '' bo

Ca)

CO

T from ο 1 1 e 15 (cont.)

inserted 4 »Q * .zo ~ eyelopent-2-an-I-on

iel of example

-triphenylmethoxy-1 used -iodine-trcins-1-alcohol of example

ir, 6

37 147 37 146 37 148 45 124 37 132 37 144 37 133 49 141

9-0xo-11alpha-hydroxy-5-cis, 13- tran s-prootadi ons only obtained

9-0XO-11-alnha-hydroxy-15-hydro-: ymethyl-5-cis , 13-trans ~ prostadienic acid

9-0XO-1 ialpha-hydroxy-1 5-hyclroxymo, thyl-20-nor-5-cis, 13-trans, prostatic acid

9-0XO-11 alpha, 17-dihydroxy-5-cis, 13-trans-prostatic acid

9-OXO-11 alpha, 18-dihydroxy-19,20-dinor-5-cis, 13-trans-prostadic acid

9-Οχο-11 alpha, 19-dihydroxy ~ 20-nor-5 ~ cis, 13-trans-prostadic acid

9-0XO-11 alpha, 20-clihydroxy-5-cis, 13-trans-prostadic acid

9-0x0-11alpha-hydroxy-20-hydroxyraethyl-5-cis , 1 3-trahs, prost-adienoic acid.

9-Oxo-11 alpha, 17-dihydroxy-16-methyl-19,2O-dinor-5-cis, 13-trans-prostadic acid ^w

9-0x0-11 alpha, 16-dihydroxy-4-methyl-5-cis , 13-trans-prostadic acid

- 110 -

Table 115, (cont.).

inserted 4-0xo-

cyclopent-2-en-i-one

Example by example

triphenylmethoxy ~ 1-iodo-trans- 1 ~ alkene used from Example

obtained D-üxo-11alpha-hydroxy-5 ~ cis, 13 "tear prostadic acid

167

168

S.
D. JN
O
ta 169 OO —V 170 I. ->
K> 171 O I. «■> 172 173 174 175

41 50

41 41 42

42 42 51 42

9-0XO-11 alpha, 16-dihydroxy-4,20-dimethyl-5-CLS, 13-trans, prostadic acid

9-0XO-11 alpha, 17-dihydroxy-4-methyl-16-ethy.l-1 8, 19,20-trinor-5-cis, 13-trans-prostadic acid

9-0XO-11 alpha, 16-dihydroxy-4,20-dinethyl-5-ice , 13-trans, 18-cis, prostatrienic acid

9-0XO-11alpha-hydroxy-15-hydroxymethyl-

4-methyl-5-cls, 13-trans-prostadionic acid /

9-0x0-11alpha-hydroxy-15-hydroxymethy1-> 4i 4 (R) -methyl-5-cis, 13-trans-prostadiene- # acid

9-0XO-11 alpha, 16-dihydroxy-4 (R) -methif. 1-5-cis, 13-trana-prostadic acid

9-0x0-11alpha, 16-dihydroxy-4 (R) -methy1-2O-ethyl-5-cis, 13-trans-prostadic acid

9-Oxo-i1alpha, 20-dihydroxy-4 (R) -methy1-5-cis, 13-trans-prostadienoic acid

9-0XO-11 alpha, i'7-dihydroxy-4 (R) -methyl-19,20-dinor-5-cis, 13-trans-prostadic acid

a b ο 1 1 e 15 (cont.)

4-oxocyclopent-2-en-1-one used

example

einyeaetztos-triphenylmothoxy-1 -iodine-trans-

1-alkene by example

obtained 'J-Oxo-1 1 alpha-hydt: oxy - 5-cin, 1 3-trans -pros tad ionn'lure

176

177
173

179
130
181

182

183
184

42

52 43

52 43 43

44 53 44

143

123 128

134 147 143

123 142 137

9-0XO-11alpha, 16-dihydroxy-4 (R), 20-dirttu thyl ~ 5-ice, 13-truns, 18 ~ cis, prostatrienoic acid

9-0XO-11alpha, 16 ~ dihyclroxY-4 ~ ethyl ~ 5-cis, 13-trans-prostatic acid G.

9-0XO-11alpha, 16-dihydroxy ~ 4-ethyl ~ 17-methyl-19 ^ O-dinor-S-cis, 13-transprostadionic acid

9-0XO-11alpha-hydroxy ~ 4-ethyl-20- (β-hydroxyethyl) -5-cis, 13-trans-prostadic acid

9-Oxo-i1alpha-hydroxy-4-ethyl-15-hydroxyethyl-5-cis, 13-trans-prostadic acid

9-0XO-11 alpha, 16-dihydroxy-4 ~ ethy1-20-diethyl-5-cis , 1 3-trans, 1 S-cis-prostatic acid

'9-0x0-11 alpha, 16-dihydroxy-4-pfopyl-5-cis, 13-trans-prostadienic acid

9-0XO-11 alpha, 17-dihydroxy-4-propyl-16-η thy1-19,20-dinor-5-cii, 13-transprostadic acid
9-0XO-11 alpha, 16-dihydroxy-4-propy 1-1 ^:) -methy1-5-cis, 13-trans-prostadic acid

AJ-L ^f ; Λ ΛQ1?

DoiEoi used s 4-oxo- 185 cyclcpont-2 -crt-1-οη 186 el from Beis P_i_e_l 187 44 44 44 O to co

ei η (j ο. set vs 1tί s -'Γ χ. "i. ρ 11 e η y 1 -

methoxy ~ 1-joJ-trans- obtained 9 ~ 0xo-11alpha ~ hydroxy-5-cis,

-a 1 k ο η ..by JJaJj ₁ spj ^ l LlziL ¹ 12iI ^! lZßK °, ^s tadienoic acid ^

9-0XO-11alpha, 20-dihydroxy-4-propyl-

5-ci.s, 1 3 ~ trans-prostadienoic acid

9-0x0-1ialpha-hydroxy-15-hydroxymethyl-

4-proOyl ~ 5-cis, 13-trans-prostadienoic acid

'9-Oxo-1lalpha-hydroxy-15-hydroxymethy1-

4-propyl ~ 1 ~ 9, 20-dinor-5 ^L cis, 13-transprostadienoic acid

- ^ 188 44 143 9-Oxo-11 alpha, 16-dihydroxy-4-propyl- ,

"- * 2O-ethyl-5-cis, 13-trans, 18-cis- ^

_ ^ prostatric acid «β *

ο 189 44 148 9-Oxo-11 alpha, 17-dihydroxy-4-propyl- '

u> 5-cis, 13-trans-prostadic acid

190 38 123 9-Oxo-11 alpha, 16-dihydroxy-4-nor-5-

cis, 1 3-trans-prostadienstiure

191 38 127 9-0XO-11 alpha, 16-dihydroxy-4,20-dinor-5-

cis, 13-trans-prostadic acid

192 46 141. 9-oxo-11alpha, 17-dihydroxy-4,19,20-

trinor-16-raGthyl-5-cis', 13-trans- ^ * prostadic acid ■ * ■ TT

193 38 132 9-Oxo-11 alpha, 19-dihydroxy-4,20-dinor- J ^

5-cis, 13-trans-prostadic acid qq

a b e 1 1 η

15th

. • i (cont.)

4-Qxocyclopunt-2-en-1-one is used

Example by example

fiincfosot ?. tes-trinhenyl-

mothoxy-1-god-trans- obtained 9-0xo-1ialpha-hydroxy-5-cis,

1-alkene of Example 13-trans-prostadic acid

194
195
196
197
193

199 *

200
201
202

38 38 39 39 47

39 47 39 39 147 46 123 129 139

147 145 143 132

9-Oxo-ΐ1alpha-hydroxy-15-hydroxymethy1-4-nor-5-cis, 13-trans-prostadic acid

9-oxo-11alpha-hydroxy-15-hydroxyme thy1-4 , 20-dinor-5-cis, 13-trans-prostadic acid

9-Oxo-11 alpha, 16-dihydroxy-4a-homo-5 ~ cis, 13-trans-prostadic acid

9-0XO-11 alpha, 16-dihydroxy-4a-homo-20- methyl-5-cis, 13-trans-prostadic acid

9-0XO-11 alpha, 17-dihydroxy-4a ~ homo ~ 16-methyl-18,19,20-trinor-5-cis, 13-trans-prostadic acid

9-0XO-11alpha-hydroxy-4a-homo-15-hydroxymethyl-5-cis, 13-trans-prostadic acid

9-Oxo-i1alpha-hydroxy-4a-homo-15-hydroxymethyl-19,20-dinor-5-cis, 13-transprostadienoic acid

9-0x0-11 alpha, 16-dihydroxy-4a-homo-20-nothy1-5-cis, 13-trans / 1 8-cis-prostatric acid · "· ·

9-ÜXO-11alphn, 19-dihydroxy-4a-homo-20-nor-5-cis-13-trans-prostadic acid

ϊ a b olio

JJL (cont.)

elugoisot-itoa 4 ~ 0xo-

cyc Lopent-2-en-1-one

Ut? I game . _r . _r .von, JIi ¹ UJiGAAi ...——

CD
OCr

.03

2Ο3Λ

2O3B

2O3C

2O3D

2O3E

2O3F

2O3G

2O3II

40 40 40

40 48 48 40 40 48

methoxy-1-iodine-trana _r 1 -aIko n, from BeIo pie 1

, 123

148 130

131 137 135 143 147 146

he hoi tenor »y-Oxo-1

9-0x0-1 1 alpha, 16-dihydroxy-4a, 4b-blshovno-5-cis, 1 3-trans-pro3tadionic acid G.

9 ~ Cxo ~ t1alpha, 17-dihydroxy ~ 4a, 4b ~ bishomo-5-cis, 13-trans-prostadienoic acid

9-0XO-11 alpha, 16-dihydroxy-4a, 4b-bis ~ hoino-20-ethyl-5-cis, 1 3-trans-prostatic acid

9-0x0-11 alpha, 17-dihydroxy-4a, 4b-bishono-18,19,20-trinor-5-cis, 13-trans- prostadic acid

9-0XO-11 alpha, 16-dihydroxy-4a, 4bbishomo-19-methyl-5-cis, 13-transprostadienic acid

9-0x0-11alpha-hydroxy-4a, 4b-bis-homo-20- (γ- hydroxypropyl) ~ 5-cis, 13-trans -prostadium avers

9-0x0-11 alpha, 16-dihydroxy-4a, 4b-bishono-20-methyl-5-cis , 13-trans, 18-cisprostatrienoic acid

9-0XO-11alpha-hydroxy-15-hydroxyraethyl 4a, 4b ~ bishorao-5-cis, .1 S ^ trans-prostatic acid

9-0XO-1 ialpha-hydroxy-Ί 5-hydroxyine thyi-4a, 4b-bishomo-20-nor-5-cis, 13-transprostadienoic acid

Example 204

Production of methyl-g-oxo-lö-hydroxy-S-cis, 13-transprostadienoate

By treating 2- (6-carbomethoxy-2-cis-hexenyl) -cyclopent-2-en-1-one {Example 82) according to the procedure described in Example 149 with lithium trimethyl (4-triphenylmethoxy-trans-1-octenyl) alanate, made from l-iodo-4-triphenylmethoxy-trans-1-octene (Example 123), likewise following the procedure described in Example-149, methylg-oxo-ie-triphenylmethoxy-S-cis-IS-trans-prostadienoate is obtained generated. Treatment of this product with acetic acid / tetrahydrofuran / water, as described in Example 149, the aforesaid Prostadienoate provides that by chromatography Purified on silica gel and through. Liquid-liquid partition chromatography is further cleaned.

Example 205

Production of 9-oxo-16-hydroxy-5-ice, 13-trans-prostadienoic acid

A solution of 2 g of methyl 9-oxo-16-hydroxy-5-cis-13-transprostadienoate (Example 204) in 32 ml of methanol / water (1: 1) containing 850 mg of potassium hydroxide is used for 18 hours stirred at ambient temperature. After acidification with 10 percent hydrochloric acid, the solution is washed several times with ether extracted. The combined ether extracts are washed with saturated sodium chloride solution, with anhydrous Magnesium sulfate dried and evaporated to dryness. An oil is obtained in this way, which can be chromatographed on silica gel is cleaned.

■ '. 0 9 8 1 ί · ■ '1 2 0 3

Examples 206-254

Those listed in the following Table 16 as products 9-OxO-S-CiS, 13-trans-prostadienoic acids are like. in, example 204 described by treating the cyclopentenone methyl esters listed in Table XVI with the respective Lithium trimethyl {triphenylmethoxy-substituted-l-trans- -alkenyD-alanate {prepared according to that described in Example 204 Procedure from the corresponding I-iodine-1-trans-alkeria listed in Table 16). Subsequent di-0 tritiation of the triphenylmethoxy-substituted formed as an intermediate Methyl 9-oxo-5-cis, 13-trans-prostadienoate and subsequent saponification according to the procedure of Example 205 of the hydroxy-substituted methyl 9-oxo-5-cis, 13-trans-prostadienoate formed manufactured.

A0 9 81 1/12 0 3

Tabel

example used cyclo-
pentenone methyl ester
of example used triphenyl
methoxy substituted
1-iodo-1-trans-alkene
of example 206 82 129 207 82 148 CD
ID 208 82 144 CO 209 82 128 • ν.
ro
ο 210 82 141 ν> 211 82 147 212 82 146 213 82 143 214 83 123

obtained 9-oxo-5-cis , 13-trans-prostadienoic acid

9-0x0-16-hydroxy-20-methy1-5-cis, 13-trans-prostadienoic acid

9-Oxo-17 ~ hydroxy-5-cis, 13-transprostadienoic acid

9-oxo ~ 20-hydroxy ~ 5-cis, 13-trans-prostadienoic acid

9-0XO-16-hydroxy-17-methyl-19,20-dinor-5-cis, 13-trans-prostadic acid

9-0XO-17-hydroxy-16-methyl-19,20-dinor-5-cis, 13-trans-prostadic acid

9-0XO-15-hydroxymethyl-5-cis, 13-transprostadienoic acid

9-Oxo-15-hydroxymethyl ~ 20-nor-5-cls, 13-trans-prostadlenic acid

9-0x0-16-hydroxy-20-methyl-5-cls , 13-trans, 18-cis-prostatrienoic acid

9-0XO-16-hydroxy-4-methy1-5-cis, 13-trans-prostadic acid.

- 118 -

Tabel

16 (cont.)

example

Cyclopentenone methyl ester used from Example

triphenyl · methoxy-substituted 1-iodo-1-trans-alkene used from Example

obtained 9-oxo-5-cis, 13-trans-prostadienoic acid

215
216
217
218
219
220

221
222
223

83 83 83 84 84 84

84 84 84

132

1 39 1 47 1 23 1 37 1 38 • 1 29 1 47 1 43

9-0XO-19-hydroxy-4-methy 1-20-nor- 5-cis, 13-trans-prostadic acid

9-0x0-17-hydroxy-4,16-dimethyl-18,19, 20-trinor-5-cis, 13-trans-prostadic acid

9-Oxo-15-hydroxymethyl-4-methyl-5-cis, -13-trans-prostadic acid

9-0x0-16-hydroxy-4 (R) -methyl-5-cis, ■ 13-trans-prostadic acid

9-0x0-16-hydroxy-4 (R), 19-dimethy1-5-cis, 13-trans-prostadic acid

9-0x0-16-hydroxy-4 (R) -methyl-17-ethyl-20-nor-5-cis, 13-trans-prostadic acid

9-Oxo-16-hydroxy-4 (R), 20-dimethy1-5-cis, 13-trans-prostadienoic acid

9-0x0-15-hydroxymethyl-4 (R) -methyl-5-cis , 13-trans-prostatic acid

9-0x0-16-hydroxy-4 (R), 20-dimethyl-5-cis, 13-trans, 18-cis-prostatrienoic acid

Table 16 (cont.)

example

used cyclo-

pentenone methyl ester

of example

triphenylmethoxy-substituted 1-iodine-1-trans-alkene used from Example

obtained 9-oxo-5-cis, 13-trans-prostadienoic acid

224

225 226 O
to 227 * y 228 ro
O
u> 229 230 231

232

85 85 85 85 85 85 85 86 86

143 123 130 127 147 134 142 123 130

9-0x0-16-hydroxy-4-ethyl-20-methy1-5-cis, 13-trans, 18-cis-prostatrienoic acid

9-oxo-16-hydroxy-4-ethyl-5-cis _r 13-trans-prostadic acid

9-Oxo-16-hydroxy-4-ethyl-2O-ethyl-5-cis, 13-trans-prostadic acid

9-0XO-16-hydroxy-4-ethyl-20-nor-5-cis , -13-trans-prostadic acid

9-0XO-15-hydroxyraethyl-4-ethyl-5-cis , -13-trans-prostadic acid

9-OXO-20- (β-hydroxyethyl) -4-ethyl-5-cis, 13-trans-prostadic acid

9-oxo-17-hydroxy-4,16-diethyl-19,20-dinor-5-cis, 13-trans-prostadic acid

9-0XO-16-hydroxy-4-propyl-5-cis, 13-trans-prostadic acid

9-0XO-16 -hydroxy ^ -propyl ^ O-ethyl-5-cis, 13-trans-prostadic acid

Tabel

16 (cont.)

Example

used cyclo-

pentenone methyl ester of example

used triphenylmethoxy-substituted 1-iodo-1-trans-alkene

of example

obtained 9-oxo-5-cis, 13-trans-pro stage acid

233

234

CD
to
OD 235 '. -Λ
- ^, 236 -Λ
ro
ο
WiS 237 238 239 240 241

86 86

86 86

79 79 79 79 79

125 140

147 143

143 123 127 136 146

9-oxo-16-hydroxy-4-propyl-19,20-dinor-5-cis, 13-trans-prostadic acid

9-0XO-17-hydroxy-4-propyl-16-ethyl-18,19,20-trinor-5-cis, 13 ~ transprostadienoic acid

9-oxo-15-hydroxymethyl-4-propyl-5-cis, 13-trans-prostadic acid

9-0x0-16-hydroxy-4-propyl-20-prostatrienoic acid %

9-0XO-16-hydroxy-4-nor-20-methyl-5-cis, 13-trans, 18-cis-prostatrienoic acid

9-0x0-16-hydroxy-4-nor, 5-cis , 13-tranaprostadienoic acid

9-0XO-16-hydroxy-4,20-dinor-5-cis, 13-, trans-prostadic acid

9-0x0-17-hydroxy-4,19 ^ 20-trinor-5-cis, 13-trans-prostedic acid

9-oxo-15-hydroxymethyl-4,20-dinor-5-cis, 13-trans-prostadic acid

Tabel

JJL (cont.)

example used cyclo-
pentenone methyl ester
of example 242 80 243 80 244 80. O
to 245 80 co 246 80 1. O 247 80 u> 248 81 249 81 250, 81

triphenylmethoxy-substituted 1-iodine-1-trans-alkene used from Example

123

129 126

138 147

143

123 130 148

9-oxo-5-cis, 13-trans-pro stage acid obtained

9-0XO-16 ~ hydroxy-4a-homo-5-c ± s, 13-trans-prostadic acid

9-0x0-16 ~ hydroxy-20-methyl-4a-homo-5-cis, 13-trans-prostadic acid

9-Oxo-16 ~ hydroxy-4a-homo-18,19,20-trinor-5-cis, 13-trans-prostadic acid

9-0x0-16 ~ hydroxy ~ 4a-homo-17 ~ ethyl-20-nor-5-cis, 13-trans-prostadic acid

9-0x0-15-hydroxymethyl-4a-homo-5-cis, 13-trans-prostadic acid

9-0XO-1 e-hydroxy ^ a-homo ^ O-methyl-5-cis , 13-trans, 18-cis, prostatrienoic acid

9-0XO-16-hydroxy-4a, 4b-bishomo-5-cls, 13-trans-prostadic acid

9-0XO-16-hydroxy-4a / 4b-bishoino-20-ethyl-5-cis, 13-trans-prostadlenic acid

9-Oxo-17 ~ hydroxy-4a, '4 & -bishomo-5-cls, 1S-di

- 122 -

Table 16 (Ports.)

example

used cyclo-

pentenone methyl ester of Example

triphenylmethoxy-substituted 1-iodine-1-trans-alkene used from Example

obtained 9-oxo-5-cis, 13-trans-pro stadlenic acid

ί-Ο (D CO

251

252 253

254

81

81 81

81

137

147 124

143

9-0XO-16-hydroxy-4a, 4b-blshomo-19-methyl-5-cis, 13-trans-prostadic acid

9-oxo-15-hydroxymethyl-4a, 4b-bishomo-5-cis , 13-trans-prostadienoic acid

9-0XO-18-hydroxy-4a, 4b-bishomo-19,20-dinor-5-cis, 13-transprostadienoic acid

9-0XO-16-hydroxy-4a _r 4b-bishomo-20-methyl-5-cis, 13-trans, 18-cisprostatrienoic acid

Example 255

Preparation of 9-oxo-llalpha-hydroxy-5-cis, 13-trans-prostadienoic acid

A solution of 7.16 g (65 mmol) of 1-octyne in 12 ml of benzene is mixed with 52 ml of 1.2 M diisobutylaluminum hydride in hexane, and the solution is heated to 50 ° C. for 2 hours. The solution is ^{cooled to 2 °} C. and treated with 28.5 ml of 2.1 M methyllithium in ether for 10 minutes. The solution "obtained is stirred for 20 · minutes at ambient temperature, cooled to 5 ⁰ C and for 10 minutes with a solution of 20.1 g (50 mmol) of crude 4-tetrahydropyranyloxy-2- (6-carbotetrahydropyranyl-2-cis- hexenyl) cyclopent-2-en-1-one (Example 37) in 30 ml of ether are added, the mixture is then stirred for 20 hours at ambient temperature, diluted with ether to 450 ml and, with stirring, poured into a mixture of 400 ml of ice and 90 ml of 4N The organic phase is separated off and the aqueous phase is extracted with further ether. The organic extract is washed successively with ice-cold hydrochloric acid, water and saturated sodium chloride solution, dried over magnesium sulphate and concentrated to an oil under reduced pressure; _ ^{max = 1735} (carbonyl groups), 1035 (tetrahydropyranyl

oxy groups) and 965 cm "(trans-vinyl group). One solution this crude oil, crude tetrahydropyran-2-yl-llalpha-tetrahydropyranyloxy-g-oxo-S-cis-IS-trans-prostadienoate, in one liter of glacial acetic acid / tetrahydrofuran / water (4: 2: 1) is 3.5 hours stirred at 45 ° C. The cooled solution is mixed with a solution consisting of 1 liter of water and 500 ml of saturated Sodium chloride solution has been prepared and extracted with ether. The extract is mixed with water and successively saturated sodium chloride solution and dried over magnesium sulfate. The crude product that after evaporation of the solvent is obtained, is purified by chromatography on silica gel. An oil is obtained; ^ max = 1740

■ '»0981! / 1 2 Q 3

(Ketone carbonyl group), 1710 (acid carbonyl group) and 965 cm "(trans-vinyl group.

Examples 256-295- '

By treating the 4-oxocyclopentenones listed in Table 17 below with the lithium methyldiisobutyl (l- -trans-alkenyl) alanants (prepared from the 1-alkynes, diisobutylaluminum hydride and methyllithium listed in Table 17) and subsequent deblocking of the llalpha-IIydroxy- and carboxylate groups according to those described in Example 255 The 9-oxo-llalphahydroxy-5-cis-13-trans-prostadienoic acids mentioned in the table are used generated.

^ 09811/1203

Tabel

4-oxycyclopentenone used from Example Example

256
257

258
259

260
261
262

263

45 37

37 37

37 37 37

37

1-alkyne used

1-octyne 1-nonyne

1-hexyne

8 ~ chloro-1-octyne (Ex. 122)

5-chloro-1-pentyne

1-heptine

cis-5-octen-1-yn (Example 121)

5 ~ methyl-1-hexyne obtained
9-0x0-11alpha-hydroxy-5-cls, 13-trans-prostadlenic acid

9-0XO-11-alpha-hydroxy-5-cis , 13-trans-prostadic acid

9-0x0-11alpha-hydroxy-20-methyl-5-cis, 13-transprostadienoic acid

9-Oxo-11 alpha-hydroxy-19, 20-dinor-5-cis, 13- ^ transprostadienoic acid

9-Oxo-i 1alpha-hydroxy-20j-chloro-52cis, prostadic acid - - -

9-oxo-11alpha-hydroxy-17-chloro-18,19 / 20-trinor-5-cis , 13-trans-prostadienoic acid

9-0XO-11alpha ~ hydroxy-20-nor-5 ~ cis, 13-transprostadienoic acid

9-0XO-11alpha-hydroxy-5-cis / 13-trans , 17-cis-prostatrienoic acid

9-oxo-11 alpha-hydroxy-17-methyl-19,20-din.or-5-cis' ~, 13-trans-prostadic acid

ro

CO

- ¹²⁶ pp

4-oxycyclopentenone used by
Example example

Table 17 (cont.)

1-alkyne used obtained
9-Oxo-i ialpha-hydroxy-5-cls , 13-trans-prostadlenic acid

264

38

265 38 ^ 266 38 ο (O co 267 39 ^ 268 39 ο
^ 269 39 270 39 271 39

1-heptyne 1-octyne

8-chloro-1-octyne

1-octyne 1-nonyne

4-x-methyl-1 ~ pentin '

8-chloro-ioctine

cis-5-octene-1-in

9-0x0-11alpha-hydroxy-4,20-bisnor-5-cis, 13-transprostadienoic acid

9-oxo-i1alpha-hydroxy-4-nor-5-cis, 13-transprostadienoic acid

9-0XO-11alpha-hydroxy-4-nor-20-chloro-5-cis, 13-trans-prostadic acid

9-oxo-11alpha-hydroxy-4a-homo-5-cis, 13-transprostadlenic acid ; '

9-0XO-1 lalpha-hydroxy ^ a-homo- ^ O-methyl-S-cis, ^ - trans-prostadic acid

9-0XO-11alpha-hydroxy-4a-homo-16-methyl-18,19, 20-trinor-5-cis, 13-trans-prostadlenic acid

9-0XO-11alpha-hydroxy-4a-homo ~ 20-chloro-5-cis, 13-trans-prostadic acid

9-0XO-11alpha-hydroxy-4a-homo-5-cis, 13-trans, -17-cis-prostatrienoic acid

Tabel

17 (cont.)

4-oxycyclopentenone used from example example

272

273

40

40

274 40 O 275 40 to
OC
L. 276 40 ^.
k 277 40 O
approx 278 41 279 41

1-alkyne used

1-decin

1-octyne

1-pentin

5-methyl-1-hexyne

8-chloro-1-octyne

cis-5-octene-1-in

1-octyne

5-chloro-1-pentyne

received
9-oxo-1ialpha-hydroxy-5-cis, 13-trans-prostadienoic acid

9-0XO-11alpha-hydroxy-4a, 4b-bishomo-20-ethyl-5-cis, 13-trans-prostadic acid

9-oxo-11alpha-hydroxy-4a, 4b-bishomo-5-cis, 13-trans-prostadic acid

9-Oxo-11alpha-hydroxy-4a, 4b-bishomo-18,19,20-trinor-5-cis, 13-trans-prostadic acid

9-Oxo-i1alpha-hydroxy-4a, 4b-bishomo-17-methyl-19,20-dinor-5-cis, 13-trans-prostadic acid

9-0XO-11alpha-hydroxy-4a, 4b-bishomo-20-chloro-5-cis, 13-trans-prostadienoic acid '

9-Oxo-i lalpha-hydroxy ^ a ^ b-bishomo-S-cis, l * * 13-trans, 17-cis-prostatrienoic acid * ^

9-Oxo-i1alpha-hydroxy-4-methyl-5-cis, 13-transprostadienoic acid

9-0x0-11alpha-hydroxy-4-methyl-17-chloro-18.19, 2O-trinor-5-cis, 13-trans-prostadic acid

- 128 -

¹ JTi CO

Table 17 (cont.)

example used 4-oxy-
cyclopentenone of
example inserted
1-alkyne 280 41 1-dodecine 281 42 1-octyne 282 42 1-nonine CD to
OO 283 42 1-pentin λ
ro 284 42 cis-5-octene
1-in O 285 43 1-0ctin 286 43 8-chloro-1r-
octine 287 43 1-decin

received
9-oxo-iialpha-hydroxy-5-cis, 13-trans-prostadienoic acid

9-Oxo-11alpha ~ hydroxy-4-methyl ~ 2Q-n-butyl-5-cis, 13-trans-prostadic acid

9-0XO-11alpha-hydroxy-4 (R) -methyl-5-cis, 13-trans-prostadic acid

9-0XO-11alpha-hydroxy-4 (R) ^ O-13-trans-prostadic acid

9-Oxo-11alpha-hydroxy-4 (R) -methy1-18,29,20-trinor-5-cis, 13-trans-prostadic acid

9-0XO-11alpha-4 (R) -methyl-5-cis, 13-trans, 17-cis-prostatrienoic acid

9-0XO-11alpha-hydroxy-4-ethyl-5-ice, 13-trans-prostadic acid

9-0XO-11 alpha-hydroxy-4-ethyl-2O-chloro-5.-cis , 13-trans-prostadic acid

9-0x0-11alpha-hydroxy-4-ethyl-_20-ethyl-5-cis, 13-trans-prostadic acid

4-Oxy cyclopentenone used from Example Example

Table 17 (cont.)

1-alkyne used

received
9-oxo-i1alpha-hydroxy-S-cis, 13-trans-prostadienoic acid

288
289
290
291
292
293
294
295

43 43 44 44 44 44 44 44

1-heptine

cis-5-octene-1-in

cis-5-octene-1-in

5-chloro-1-pentyne

1-octyne

5-methyl-1-hexyne

1-heptine 1-nonine

9-0x0-11alpha-hyüroxy-4 ~ ethyl-20-nor-5 ~ cis, 13-trans-prostadic acid

9-0x0-1lalpha-hydroxy ^ -ethyl-S-ciSjiS-trans-17-cis ~ prostatrienoic acid

9-Oxo-i1alpha-hydroxy-4-propyl-5-cis, 13-trans, 17-cis-prostatrienoic acid

9-0x0-11alpha-hydroxy-4-propyl-17 ~ chloro-18,19,2O-trinor-5-cis , 13-trans-prostadic acid

9-0XO-11alpha ~ hydroxy-4-propyl-5-cis, 13-transprostadienoic acid

9-0x0-11alpha-hydroxy-4-propyl-17-methy1-19,20-dinor-5-cis, 13-trans-prostadlenic acid

9-Oxo-i1alpha-hydroxy-4-propyl-20-nor-5-cis, 13-trans-prostadic acid

9-Oxo-11alpha-hydroxy-4-propyl-20-methyl-5-cis, 13; -trans-prostadic acid ^:

- 130 -

Example 296

Production of 9alpha, ll, le-trihydroxy-S-cis-lS-transprostadienoic acid

To a solution of 459 mg of 9-oxo-llalpha, le-d trans-prostadienoic {Example 149) in 4.0 ml tetrahydrofuran is added under nitrogen and with stirring at -78 ⁰ C 5.2 ml of a O, 6 M solution of lithium perhydro-9b-boraphenyl hydride in tetrahydrofuran. The solution is stirred at -78 ⁰ C for 45 minutes and at ordinary temprature for 15 minutes then diluted with 10 ml water and extracted with ether. The extract is in turn back-extracted with 1/4 η sodium bicarbonate solution. The combined aqueous phases are acidified with 4N hydrochloric acid, saturated with sodium chloride and extracted with ether. The extract is washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated. The residue is purified by thin layer chromatography on silica gel, whereby a colorless oil is obtained; Vmax == 3310 (hydroxyl groups), 1705 (acid carbonyl groups) and 970 cm (trans-vinyl group).

Example 297-447

Reduction of the 9-oxo derivatives listed in Table 18 below with lithium perhydro-ß-boraphenalyl hydride according to the The procedure described in Example 296 gives the 9alpha-hydroxy-5-cis, 13-trans-prostadienoic acids which are also listed as products in the table.

09811/1203

2 3 3 7 F .. 8

Tabel

18th

9-oxo-5-cis, 13-transprostadienoic acid used example from example

297 150

298 151

299 152

300 153

301 154

302 155

303 156

304 157

305 158

306 151

307 160

received

-S-cis ^, 1 3-trans prostadic acid

9alpha, 1ialpha-16-trihydroxy-2O-methyl-5-cis, 13-transprostadienoic acid

9alpha, 11 alpha, 16-trihydroxy-2O-ethyl-5-cis, 13-transprostadienoic acid

9alpha, 11 alpha, 16-trihydroxy-20-nor, 5-cis, 13-transprostadienoic acid

9alpha, 11 alpha, 16-trihydroxy-19,20-dinor-S-cis, 13-transprostadienoic acid

9alpha, 11 alpha, 16-trihydroxy-19-methyl-5-cis, 13-transprostadienoic acid

9alpha, 11 alpha, 16-trihydroxy-17-ethyl-20-nor-5-cis, 13-trans prostadic acid

9alpha, 11 alpha, 16-trihydroxy-2O-methy1-5-cis, 13-trans, 18-cis-prostatic acid

9alpha, 11 alpha-16-trihydroxy-18,19,20-trinor-5-cis, 13-trans-prostadic acid

9alpha, 11alpha-dihydroxy-15-hydroxymethyl-5-cis, 13-transprostadienoic acid

9alpha, 11alpha, dihydroxy-15-hydroxyraethyl-20-nor-5-cis-13-trans-prostadic acid

9alpha, 11alpha, 17-trihydroxy-5-cis, 13-trans-prostadic acid

0 9 8 1 1/1 2 Q 3

a b e 1 1 e

18 (cont.)

example
308

309
310
311
312
313
314
315

9-oxo-5-cis, 13-transprostadienoic acid used from Example

161

162

163

164

165

166

167

168

169

170

171 received

9alpha-hydroxy-5-cis, 13-trans prostadienoic acid -

9alpha, 11 alpha, 18-trihydroxy-19,20-dinor-5-cis , 13-transprostadienoic acid

9alpha, 11 alpha, 19-trihydroxy-20-nor-5-cis, 13-trans-prostadic acid

9alpha, 11alpha, 20-trihydroxy-5-cis, 13-trans-prostadic acid

9 alpha, 1lalpha-dihydroxy-20-hydroxymethyl-5-cis, 13-transprostadienoic acid

9alpha-11alpha, 17-trihydroxy-16-methyl-19,20-dinor-5-cis, 13-trans-prostadic acid

9alpha, 11alpha, 16-tri-hydroxy-4-methyl-5-ci3 , 13-transprostadienoic acid

9alpha , 11 alpha , 16-trihydroxy-4 ^ O-dimethyl-S-cis, 13-transprostadienoic acid

9alpha, 11 alpha, 17-trihydroxy-4-methyl-16-ethyx-18,19,2O-trinor-5-cis , 13-trans-prostadic acid

9 alpha, 11alpha, 16-trihydroxy-4 ^ O-dimethyl-o-ds, 1 3-trans-18-cis, prostatric acid

9alpha, 11alpha-dihydroxy-15-hy diro xy me t hy 1 - 4-me t hy 1-5-cis, 13-trans-prostadic acid

9 alpha, 11alpha-dihydroxy-15-hydroxymethyl-4 (R) -methy1-5-cis, 13-trans-prostadienoic acid

- '. 09811/1203

Table 18 (cont.)

example
319

320

321
322
323
324
325

9-0xo-5-cis, 13-transprostadienoic acid used of example

172

173

174

175

176

177

178

179

180

181

182 received

9alpha-hydroxy-5-cis, .1 3-trans prostadienoic acid

9alpha , 11 alpha, 16-trihydroxy-4 (R) -methyl-5-cis, 13-transpros tadienoic acid

9alpha, 11 alpha, 16-trihydroxy-4 (R) -methyl- ^ O-ethyl-S-cis, -13-trans-prostadic acid

9alpha, 11 alpha, 20-trihydroxy-4 (R) -methyl-5-cis, 13-transprostac ". ienic acid

9 alpha, 11 alpha, 17-trihydroxy-4 (R) -methyl-19,20-dinor-5-cis, · 13 ™ trans-prostadic acid

9alpha, 11 alpha, 16-trihydroxy-4 (R) ^ O-dinethyl-S-cis, ^ - trans , 18-cis-prostatrienoic acid

9alpha, 11 alpha, 16-trihydroxy-4-ethyl-5-cis, 13-trans-pro-. Stage acid

9alpha, 11 alpha, 16-trihydroxy-4-nthyl-17- methyl-1-19, 20-dinor-5-cis, 13-trans-prostadic acid

9alpha, 11alpha-dihydroxy-4-ethy1-20- (ß-hydroxyethyl) -5-cis , 13-trans-prostadic acid

9alpha, 11alpha-dihydroxy-4-ethyl-15-hydroxymethyl-5-cis, 13-trans-prostadic acid

9alpha, 11 alpha, 16-trihydroxy-4-ethyl-2O-methyl-5-cis, 13-trans, 18-cis-prostatrienoic acid

9alpha, 11 alpha-16-trihydroxy-4-propyl-5-cis, 13-trans-prostadic acid

4 0 9 8 11/12 0 3

Tabel

18 (cont.)

Example 330

used 9-0xo-5-cis, 13-transpro-stadienoic acid from Example

183

184

185

186

187

188

189

190

191

192

193 received

9alpha-hydroxy-5-cis, 13-trans prostadiensävire -

9alpha, 11 alpha, 17-trihydroxy-4-propy1-16-ethy1-19,20-dinor-5-cis, 13-trans-prostadic acid

9alpha, 11 alpha, 16-trihydroxy-4-propyl-19-methyl-5- -cis, 13-trans-prostadic acid

9alpha, 11 alpha, 20-trihydroxy-4-propyl-5-cis, 13-transprostadienoic acid

9alpha, 11alpha-dihydroxy-15-hydroxymethyl-4-propyl-5-cis-13-trans-prostadienoic acid

9alpha, 11alpha-dihydroxy-15-hydroxymethyl-4-propyl-19 , 2O-dinor-5-cis, 13-trans-prostadic acid

9alpha, 11 alpha-16-trihydroxy-4-propyl-20-methyl-5-cis, 13-trans, 18-cis, prostatrienic acid

9alpha, 11alpha, 17-trihydroxy- ■ 4-propyl-5-cis, 13-transprostadienoic acid

9 alpha, .11 alpha, 16-Tr! Hydroxy-4-nor-5-cis, 13-trans ^ prostadic acid

9alpha, 11 alpha, 16-trihydroxy-4, 20-dinor-5-cis, 13-transprostadienoic acid

9alpha, 11alpha, 17-trihydroxy-4,19,20-trinor-16-methyl-5-cis, 13-trans-prostadic acid

9alpha, 11 alpha, 19-Tr! Hydroxy-4 , 20-dinor-S-cj.s, 1 3-transnrostadienoic acids

- '. 09811/1203

Tabel

18 (cont.)

example

9-oxo-5-cis, 13-transprostadienoic acid used from Example

received

9alpha-hydroxy-5-cis, 13-trans prostadlenic acid

345

194

195

196

197

198

199

200

201 9 alpha, 11alpha-dihydroxy-15-hydroxymethyl-4-nor-5-cis, -13-trans-prostadic acid

9 alpha, 11alpha-dihydroxy-15-hydroxymethyl-4,20-dinor-5-cis , 13-trans-prostadic acid

9alpha, 11 alpha, 16-trihydroxy-4-homo-5-cis, 13-trans-prostadic acid

9alpha, 11 alpha, 16-Tr! Hydroxy-4a-homo-20-methyl-5-cis, 13-trans-prostadic acid

9alpha, 11 alpha-17-trihydroxy-4a-homo-16-methyl-18,19,20-trinor-5-cis, 13-trans-prostadic acid

9alpha, 11alpha-dihydroxy-4ahomo-15-hydroxymethyl-5-cis, 13-trans-prostadic acid

9alpha, 11alpha-dihydroxy-4ahorao-15-hydroxymethyl-19,20-dinor-5-cis, 13-trans-prostadic acid

9 alpha, 11 alpha-16-trihydroxy-4a-homo-20-methyl-5-cis, 13-trans, 18-cis-prostatrienoic acid

350

202

203

2O3A 9alpha, 11 alpha-19-trihydroxy-4a-homo-20-nor-5-cis, 1 3-trans prostadic acid

9alpha, 11 alpha, 16-trihydroxy-4alpha, 4b-bishomo-5-cis, 13-trans-prostadic acid

9alpha, 11 alpha, 17-trihydroxy-4a, 4b-bishoino-5-cis-13-transprostadienoic acid

4098 1 1/1203

Tabel

18 (cont.)

example

9-0xo-5-cis, 13-transprostadienoic acid used from Example

received

9alpha-hydroxy-5-cis, 13-trans prostatic acid *

352

353

2O3B

2O3C

354

355

20 3 D

2O3E

356

2O3F

357

358

2O3G

2O3H

359 206 360 207 361 2O8 362 209

9 alpha, 11alpha, 16-trihydroxy-4a, 4b-bishomo-20-ethyi-5-cis, 13-trans-prostadic acid

9alpha, 11 alpha, 17-trihydroxy-4a, 4b-bishomo-18,19,20-trinor-5-cis, 13-trans-prostadic acid

9alpha, 11alpha, 16-trihydroxy-4a, 4b-bishorao-19-methyl-5-cis, 13-trans-prostadic acid

9 alpha, 11 a.lpha-dihydroxy-4a, 4b-bishoiao-20 -. (V ^v -hydroxypropyl) -5-cis, 13-trans-prostadic acid

9alpha, 11alpha, 16-trihydroxy-4a, 4b-bishomo-20-methyl-5-cis, 13-trans-18-cis-prostadic acid

9alpha, 1ialpha-dihydroxy-15-hydroxyraethy l-4a, 4b-bishomo-5-cis, 13-trans-prostadic acid

9alpha, 1ialpha-dihydroxy-15-hydroxymethyl-4a, 4b-bishomo-20-nor-5-cis, 13-trans-prostadic acid

9alpha, 16-dihydroxy-20-methyl-5-cis, 13-trans-prostadic acid

9alpha, 17-dihydroxy-5-cis, 13-trans-prostadienoic acid

13-trans-prostadic acid

9alpha, 16-dihydroxy-17-methyl-19,20-dinor-5-cis, 13-transprostadienoic acid

40981 1/1203

Tabel

18 (cont.)

example
363

364
365
366
367 ■
368

369

370

9-0xo-5-cis, 13-transpro3tadienoic acid used from Example

210

211

212

213

214

215

216

217

218

219

220

221 received

9alpha-hydroxy-5-cis, 13-trans prostadienoic acid -

9alpha, 17-dihydroxy-16-methyl I-19,20-dinor-5-cis, trans-prostadic acid

9alpha-hydroxy-15-hydroxyinethyl-5-cis, 13-trans-prostadic acid

9alpha-Hydroxy-15-hydroxymethyl-20-nor-5-cis, 13-transprostadienoic acid

9alpha, 16-dihydroxy-20-methyl-5-cis, 13-trans, 18-cis-prostatrienoic acid

9alpha, 16-dihydroxy-4-methyl-5-cis, 1 3-trans-prostadienoic acid

9alpha, 19-dihydroxy-4-ethyl-20-nor-5-cis, 13-trans-prostadic acid

9alpha-17-dihydroxy-4,16-dimethyl-18,19,20-trinor-5-cis, 13-trans-prostadic acid

9alpha-hydroxy-15-hydroxymethyl-4rinethyl-5-cis , 13-trans-prostadic acid

9alpha-16-dihydroxy-4 (R) methyl-5-cis, 13-trans-pros tadic acid

9alpha, 16-dihydroxy-4 (R), 19-dimethyl-5-cis, 13-transprostadienoic acid

9alpha, 16-dihydroxy-4 (R) methyl-17-ethyl-20-nor-5-cis, 13-trans-prostadic acid

9alpha., 16-dihydroxy-4 (R), 20-dimethyl-5-cis, 13-transprostadienoic acid

409811/1203

Tabel

18 (cont.)

example

9-0xo-5-cisv13-transprostadienoic acid used from Example

received

9alpha-hydroxy-5-cis, 13-trans prostadienoic acid '

380
381
382
383

222 223 224

225 226

227 228 229 230

231

232 9alpha-Hydroxy-15-hydroxymethy1-4 (R) -methyl-5- cis, 13-trans-prostadic acid

9alpha, 16-dihydroxy-4 (R), 20-dimethyl-5-cis, 13-trans-18-cis-prostatrienoic acid

9alpha, 16-dihydroxy-4-Mthy1-2O-methyl-5-cis, 13-trans-18-cis, prostatric acid

9alpha-16-dihydroxy-4-ethyl-5-cis, 13-trans-prostadic acid

9alpha, 16-dihydroxy-4,20-diethyl-5-cis , 13-trans-prostadic acid

9alpha, 16-dihydroxy-4-ethyl-20-nor-5-cis, 13-trans-prostadic acid

9alpha-Hydroxy-15-hydroxyraethyl-4-ethyI-5-cis, 13-trans-prostadic acid

9alpha-Hydroxy-20- (β-hydroxyethyl) -4-ethyl-5-cis, 13-trans-prostadic acid

9alpha, 17-dihydroxy-4,16-diethyl-19,20-dinor-5-cis, 13-trans-prostadic acid

9alpha, 16-dihydroxy-4-propyl-5-cis, 13-trans-prostadic acid

9alpha, 16-dihydroxy-4-propyl-2O-ethyl-5-cis, 13-transprostadienoic acid

09811/1203

Tabel

18 (cont.)

example

9-oxo-5-cis , 13-transprostadienoic acid used from Example

received

S-cis', T3-trans prostadlenic acid

387

233

2.34

235

236

237

391 ' 238 392 239 393 240

241

242 243 9alpha-16-dihydroxy-4-propyl-19,20-dinor-5-cis, 13-trahsprostadienoic acid

9alpha-17-dihydroxy-4-propyl-16-ethyl-18,19,20-trinor-5-cis, 13-trans-prostadic acid

9alpha-hydroxy-15-hydroxymethyl-4-propyl-5-cis, 13-trans-prostadic acid

9alpha-16-dihydroxy-4-propyl-20-methyl-5-cis / 13-trans-18-cis-prostatrienoic acid

9alpha, 16-dihydroxy-4-nor-20-ynethy 1-5-cis, 1 3-trans, 1 8-cisprostatrienoic acid

9alpha, 16-dihydroxy-4-nor-5-cis, 13-trans-prostadic acid

9alpha-16-dihydroxy-4,20-dinor-5-cis, 13-trans-prostadic acid

9alpha, 17-dihydroxy-4,19,20-trinor-5-cis, 13-trans-prostadic acid

9 alpha-hydroxy-15-hydroxymethyl-4,20-dinor-5-cis, 13-transprostadienoic acid

9alpha, 16-dihydroxy-4a-homo-5-cis, 13-trans-prostadic acid

9alpha, 16-dihydroxy-20-methyl-4a-homo-15-cis, 13-transprostadienoic acid

09811/1203

Tabel

18 (cont.)

9-0xo-5-cis, 13-transprostadienoic acid used example from example

obtained 9 alpha-hydroxy-5-Qi s., 13-trans-

prostadic acid e

397 244

398 245

399 246

400 247

40t 248

402 249

403 250.

404 251

405 252

406 253

4O7 254

9alpha, 16-dihydroxy-4a-homo-18 , 19,20-trinor-S-cis-13-trans-prostadic acid

9alpha, 16-dihydroxy-4a-homo-17-ethyl-20-nor-5-cis, 13-trans-prostadic acid

9alpha-Hydroxy-15-hydroxymethyl-4a-hoino-5-cis , 1 3-transprostadienoic acid

9alpha, 16-dihydroxy-4a-homo-2O-methyl-5-cis, 13-trans , 18-cis-prostatrienoic acid

9alpha, 16-dihydroxy-4a / 4bbishomo-5-cis, 13-transprostadienoic acid

9alpha, 16-dihydroxy-4a , 4bbishomo-20-ethyl-5-cis, 13-trans-prostadic acid

9alpha, 17-dihydroxy-4a, 4bbishomo-5-cis, 13-trans-prostadic acid

9alpha, 16-dihydroxy-4a, 4bbishomo-19-methyl-5-Gis, 13-trans-prostatic acid

9alpha-hydroxy-15-hydroxymethyl-4a, 4b-bishomo-5-cis, 13-trans-prostadic acid

9alpha , 18-dihydroxy-4a, 4bbishomo-19 ^ O-dinor-S-cis, 13-trans-prostadic acid

9 alpha , 16-dihydroxy-4a, 4bbishomo-20-methyl-5-cis-13-trans, 18-cis-prostatrienoic acid

/ ♦ 09811/1203

Tabel

18 (cont.)

9-0xo-5-cis, 13-transprostadienoic acid used example from example

408 256

409 257

410 258

411 259

412 26O

413 261

414 262

415 263

416 264

417 265

418 266

419 267

420 268

40981 1/1 received

9alpha-hydroxy-5-qis., 1 3-trans prostadienoic acid

9alpha-11alpha-dihydroxy-5-cis-13-trans-prostadienoic acid

9 alpha, 11alpha-dihydroxy-2 0-methy1-5-cis, 13-transprostadienoic acid

9 alpha, 11alpha-dihydroxy-19,20-dinor-5-cis, 13-transprostadienoic acid

9alpha, 11alpha-dihydroxy-20-chloro-5-cis, 13-trans-prostadic acid

9 alpha, 11alpha-dihydroxy-17-chloro-18,19,20-trinor- 5-cis, 13-trans-prostadic acid

9alpha, 11alpha-dihydroxy-20-nor-5-cis, 13-trans-prostadic acid

9alpha, 11alpha _t dihydroxy-5-cis, 13-trans, 17-cis-prostatrienoic acid

9 alpha, 11alpha-dihydroxy-17-raethyl-19,20-dinor-5-cis, 13-trans-prostadic acid

9 alpha, 11alpha-dihydroxy-4,20-bisnor-5-cis, 13-trans-prostadic acid

9 alpha, 11alpha-dihydroxy-4-nor-5-cis, 13-trans-prostadic acid

9alpha, 11alpha-dihydroxy-4-nor-20-chloro-5-cis, 13-transprostadienoic acid

9alpha, 11alpha-dihydroxy-4ahomo-5-cis, 13-transprostadienoic acid

9alpha, 11alpha-dihydroxy-4ahomo-20-methyl-5-cis # 13-> -prostadienoic acid

Tabel

18 (cont.)

employed 9-Oxo-5-cis, 13-transprostadiensäure example of Example

received

9alpha-hydroxy-5-cis, 13-trans prostadienoic acid -

422

423

269

270

271

272

273

274

430

275

276

277

278

279 9alpha, 11alpha-dihydroxy-4ahomo-16-methyl-18,29,20-trinor-5-cis, 13-trans-prostadic acid

9alpha, 11alpha-dihydroxy-4ahomo-20-chloro-5-cis, 13-transprostadienoic acid

9alpha, 11alpha-dihydroxy-4a homo-5-cis, 13-trans, 17-cisprostatrienoic acid

9alpha-11alpha-dihydroxy-4a, 4bbishomo-20-ethyl-5-cis, 13-trans-prostadic acid

9alpha, 11alpha-dihydroxy-4a, 4bbishomo-5-cis, 13 "trans-prostadic acid

9 alpha, 11alpha, dihydroxy-4 a , 4b , bishomo-18,19,20-trinor-5-cis, 13-trans-prostadic acid

9alpha, 11alpha-dihydroxy-4a, 4bbishomo-17-methyl-19,20-dinor-5-cis, 13-trans-prostadic acid

9 alpha, 11alpha-dihydroxy-4 a, 4bbishomo-20-chloro-5-cis, 13-trans-prostadienoic acid

9alpha, 11alpha-dihydroxy-4a, 4bbishorno-5-cis, 13-trans-17-cisprostatrienoic acid

9alpha, 11alpha-dihydroxy-4-methyl-5-cis, 13-transprostadienoic acid

9alpha, 11alpha-dihydroxy-4-methy1-17-chloro-18,19,20-trinor-5-cis, 13-trans-prostadic acid

40981 1/1203

Table 18 (cont.)

9-0xo-5-cis, 13-transprostadienoic acid used example from example

432 280

433 281

434 282

435 283

436 284

437 285 438 286 439 287

288

289

290 received

9alpha-hydroxy-5-cis, 13-trans prostadlenic acid '

9alpha-11alpha-dihydroxy-4-methyl-2O-n-butyl-5-cis, 13-trans-prostadic acid

9alpha, 11alpha-dihydroxy-4 (R) -methyl-5-cis, 13-trans-prostadic acid

9-alpha-11-dihyroxy-4 (R), · 2O-dimethyl-5-cis, 13-transprostenarboxylic acid

9alpha, 11 alpha-'Dffiydroxy ^ (R) methy1-18,19,20-trinor-5-cis, 13-trans-prostadic acid

9alpha, 11alpha-Hydroxy-4 (R) methyl-5-cis, 13-trans, 17-cis-prostadic acid

9alpha, 11alpha-dihydroxy-4-ethyl-5-cis, 13-trans-prostadic acid

9alpha, 11 alpha, dihydroxy-4-ethyl-20-chloro-5-cis, 13-transprostadienoic acid

9alpha> ΐ laJLphä-Öihydroxy-4-ethyl-2O-ethyl-5 ~ -cis, 13-transprostadienoic acid

9alpha, 11alpha-dihydroxy-4-ethyl-20-nor-5-cis, 13-transprostadienoic acid

9alpha, 11alpha-dihydroxy-4-ethyl-5-cis, 13-trans, 17-cisprostatrienoic acid

9alpha, 11alpha-dihydroxy-4-propyl-5-cis, 13-trans-17-cis-prostaric acid

0 9 81 1/12 0 3

Table 18 (cont.)

example
443

9-Qxo-5-cis, 13-transprostadienoic acid used from Example

291

444

445

292

293

294

295 received

9alpha-hydroxy-5-cis, 13-trans prostadienoic acid -

9alpha-11alpha-dihydroxy-4-propy1-17-chloro-18,19,20-trinor-5-cis, 13-trans-prostadic acid

9alpha, 1lalpha-dihydroxy-4-propyl-5-cis, 13-transprostadienoic acid

9alpha, 1ialpha-dihydroxy-4-propyl-17-methyl-19,20-dinor-5-cls, 13-trans-prostadic acid

9alpha, 11alpha-dihydroxy-4-propyl-20-nor-5-cis, 13-transprostadienoic acid

9alpha-11alpha-dihydroxy-4-propyl-20-methyl-5-cis, 13-trans-prostadic acid

09811/1203

Example 448

Production of g-Oxo-Lö-hydroxy-S-cis-10, 13-trans-prostatrienoic acid

A solution of 1.52 g (4.3 mmol) of 9-oxo-11alpha, 16-dihydroxy-5-cis, 13-trans-prostadienoic acid (Example 149) in 80 ml of Q, 5N HCl in tetrahydrofuran / water (1: 1) is left to stand under nitrogen at room temperature for 67 hours. Salt solution is added to the solution and the mixture is extracted with ether. The extract is washed with brine and dried over magnesium sulfate. The residue that remains after the solvent has evaporated is purified by partition chromatography on Celite. An oil is obtained; V ~ ^max (film) 1700 (ketone and acid carbonyl groups), 1580 (conjugated olefin) and 967 cm (trans-olefin)

Examples 449-550

By treating the 9-oxo-llalpha-hydroxy-5-cis, 13-trans-prostadienoic acids listed in Table 19 below with dilute acid according to the procedure described in Example 448, the 9-oxo-5-cis also listed in the table are obtained , 10,13-trans-prostatrienoic acids generated.

40981 1/1203

T a b e lie

Example 449 45O

9-0xo- -11alpha-hydroxy-5-cis, 13-transprostadienoic acid used of example

452 453 454 455 456 457

458

j 459.

j 46o

151

* 152

153

15 *

155 156 157

158 159

ιβο

161 obtained 9-oxo-5-cis, -10,13-trans-prostatrienoic acid or tetraenoic acid

9-oxo-16-hydroxy-20 _{% J.} -methy1-5- CiS jIOa15-. , - trans -prostatrien * -

acid 9-oxo-16-hydroxy-20- -äfehyl-5- cis , IQ, 13- trans ■

-prostatrienic acid "*

9-CKo-lö-hydrpxy-SO-nor- -5-cis, 10.13-trans- prostatric acid

9- oxo-16-hydroxy-19.20- -dinor-5-cis, 10.13- -trans-prostatrlenr. ■ acid

9-oxo-16-hydroxy-19- -methyl-5- cis , 10.13r- trans- pros'tatriene-. acid

9-0x0-16-hydroxy-17- - ethyl-20-nor-5-cis_> - '10,13- trans- prostatrienic acid

9-Oxo-l6-hydroxy-20-methyl-5-cis, 10,13- trans, 18-cis- prostatetraensäure - - *

9-oxo-16-hydroxy-18, Ι9, -20-trinor-5-cis_, 10,13- · -trans- prostatrien ", acid

9-CKo-15-hydroxymethyl- -5- cis , 10,13- trans- -prostatrien acid- '■

40981 -20-nor-10, 13-trans- -p rο s t at r i en ö äoureT "'*'

9-Qxo-17-hydroxy-5-ci 10,13-t trans- prostatric acid

9-Oxo-18-hydroxy-19,20- -dinor-S- cis ^ lOj ^ -t -prostatrTen.acid

1/1203

Table 10 (continued)

example

461

462

9-0xo- -11alpha-hydroxy-5-cis, 13-transprostadienoic acid used of example

'

464 465 466 467

468 469 470 471

165 "

164

165

166

167

168

169

170

.171

172 obtained 9-oxo-5-cis, -10,13-trans-prostatrienoic acid and tetraenoic acid, respectively

9-Oxo-19-hydroxy-20- ~ nor-5-cis, 10, l ^ - tran5 - -prostatrlenic acid "" J

9-oxo-20-hydroxy-5-is _> , 10,13- trans -prostatrienoic acid

9- Qjco-20-hydroxymethyl- -5- £ is , 10,13-trans- -prostatrien ^acid ""

9-Oxo-17-hydroxy-16- -methyl-19,20-dinor- -5- cis , 10, I ^ «- trans- -prostatriensaure_ ^

9-Oxo-16-hydroxy-4-methyl-5-cis, 10,13- trans -prostatriene ^. acid

9-Oxo-16-hydroxy-4,20- dimethyl-5- cis , 10,15- - trans- progtatrien '"_, ^ acid

9-Oxo-17-hydroxy-4-methyl-16-ethyl-18,19 * 20-trinor-5-cis, 10, 1> - trans -prostatriene- __ "__ esaure.

9-oxo-16-hydroxy-4,20- -dlmethyl-5- cis , 10,1? - - trans , 18- cis -prds tatetraenoic acid

9-jd xo-lS-hydroxjnnethyl- -4-methyl-5-cis_, 10, 13 _ - trans- prostatrle'n- "acid

gSyyy -4 (R) -methyl-5- cis , 10, -15- trans- prostatric acid

9-OXo-16-hydroxy-4 (R) - -methyl-5-cis_, 10, I ^ - - trans -prostatrienoic acid

409811/1203

Tabel

19 (continued) ^ q ~ <7 C ₁ Q

Example 472 475 474, 475 476 477

9-oxo-11alpha-hydroxy-5-cis , 13-transprostadienoic acid used from Example

•

174

175

176

177

178

478 479 480 481 482

179

180

181

182

185

40981 1/1203 obtained 9-oxo-5-cis, -10,13-trans-prostatrienoic acid or tetraenoic acid

9-Oxo-16-hydroxy-4 (R) - -methyl-20-ethyl-Sr cis ; 10.15 - trans_-p ros taibri: - enoic acid

9-0 "Ko-20-hydroxy-4 (R) - -methyl-5- els , 10.15- -trans- prostatrien ^""acid

9-oxo-17-hydroxy-4 (R) - -raethyl-19,20-dinor-5- " CiS ₁ , 10,15 -trans- prostatrien« acid

9-Oxo-16-hydroxy-4 (R), - 20-dimethyl-5- cis , 10, -15- trans , 18 -cis- prostatetraenoic acid "i

9-oxo-16-hydroxy-4-ethyl-5-cis, 10.15.- _

- trans- prostatrlen-

acid 9- oxo-l6-hydroxy-4- - ethyl-17-methy1-19,20-

-dinor-5 -cis , 10.15-

-trans- prostatria-

acid 9-OXO-4-sthy1-20- (ß- -hydroxy ethyl) -5- cis , -10,15- trans -prostatri-

humid ""

9-oxo-4-ethyl-l5-hydroxymethyl-5 -cis, 10,15- - trans- prostatrien- ¹ 'acid

9-oxo-16-hydroxy-4-ethyl-20-methyl-5- cis , -10 , 15- trans , 18- cis , -prostatetraeric acid

9-oxo-16-hydroxy-4-propyl-5-ci £, 10.15-

-tr ans- pros'tatrietv-

acid 9-0 xo-17-hydroxy-4- -propyl-l6-ethyl-19.20- -dinor-5- cls _f 10.15- - trans- prostatrien-

acid

- 150 Table 19

example

483 484 4Ö5 486 487

488 "

489 490 491 492 495

9-0xo- -1lalpha-hydroxy-5-cis, 13-transprostadienoic acid used of example

184

.185 ·

186

I87

188

I89

190 191

192

193

194

40981 1 / obtained 9-oxo-5-cis, -10,13-trans-prostatrienoic acid or tetraenoic acid

9-oxo-16-hydroxy-4-.

- ice , 10.13 - t £ ahs _ * - prbs t'atrienoic acid. .

9-Oxo-20-hydroxy »-4- -propyl-5 -cis , 10.13- - trans- pro's tatriene"

acid

9-oxo-15-hydroxymethyl · -4-propyl-5-ci £, 10,13- -t rans - prost'atrlens acid

9-0'Xo-15-hydroxymethyl- ^ -propyl - ^^ O-dinor-

5 £ i ^ .i ¹⁰ , l. ^ Tran -prostatic acid

9-Oxo-16-hydroxy-4-tl

-is, 10.13- trans , 18- -is-prostatetraensäure -

9-oxo-17-hydroxy-4-propyl-5-cis, 10,13- -t rans- prostatrien- ■ acid

9_Oxo-l6-hydroxy-4-nor- -5-ice, 10,13 -trans- -ρ ros t'atr I ensaure

9-Oxo-16-hydroxy-4,20- -dinor-5- cis , 10,13- -trans- prostatric acid

9-Oxo-17-hydroxy-4,19, -20-trinor-16-raethyl--5-cis, 10,13- trans- prostatric acid

9-oxo-19-hydroxy-4,20- -dinor-5- cls , 10,13- - trans- prostatric acid

9-Oxo-15-hydroxymethyl- -4- ^ 0 ^ 5-013,10,13- -1 r ans -p r'osfc'atrien-

2ffJ ^re

- 151 Table 19 (continued)

Example 494 495-

496 497

9-oxo-11 alpha-hydroxy-5-cis, 13-transprostadienoic acid used of example

195

•

I98

498 499 500 501 502 505 504

199

200

201

202

203

205A

203B

40981 obtained 9-oxo-5-cis, -10,13-trans-prostatrienoic acid or tetraenoic acid

9-oxo-l5-hydroxymethyl-

-4,20-dinor-5 -is , 10? - "* l ^ - trans- prostatrien- ^J acid

9-oxo-16-hyclroxy-4a- -homo-5-cis, 10,13- trans- -prostatrienoic acid

9-oxo-16-hydroxy-4a-homo-20-methyl-5-cis, -10,13- trans- prostatric acid

9-oxo-17-hydroxy-4a-

20-trinor-5- cis , 10, l; -trans- prostatria, - "" ~ acid

9-oxo-4a-homo-15-hydroxymethyl-5- cis , 10 _} 13-tr ans- prostatrienoic acid

- - 1

9-Oxo-4a-hoIno-15-hydroxymethyl-19,20-dinor- · "5 ~ cis, 10,13- trans- | -proTEatrienaure ~ ^T ~ 7.;

9- ° xo-16-hydroxy-4a- -homo-20-methyl- »5 -cis , -

10.13-trans, 18- G sharp- "

-prostatetraenoic acid ~ _3 \ Z

9-Oxo-19-hydroxy-4a- -homo-2Q-nor-5 -cis ₁ 10, ^ _

13- trans- prostatria ^ -

acid

9- ° xo-16-hydroxy-4a, 4b- -bishomo-5-cis, 10.13- - trans- prostatrien-

• acid " ¹

9-0x0-17-hydroxy-4a, 4b- -bishomo-5- cis , 10,13- ' -trans- prostatrien- "■ acid

9-Oxo-16-hydroxy-4a, 4b- '-bishomo-20-ethyl-5-cis, · 10.13- trans- prostatrienoic acid

/ 1203

- IbZ -

Tab 1 (continued)

example

505 506 ' 50? ' 508 509 510

511 512 513 514

9-oxo- -11alpha-hydroxy-5-cis, 13-transprostadienoic acid used of example

203c

202D

203E

2O5P

516

203H

256 257

258

259 2β0

261 obtained 9-oxo-5-cis, -10,13-trans-prostatri- enoic acid or tetraenoic acid

9-Oxo-17-hydroxy-4a, 4b- -bishomo-18,19 \, 20-tr ± - "nor-5- ci s, 10, 13- trän s ^ - · -p rosta't'ri ens acid,

9- Qjco-lö-hydroxy-ila, 4b-

-cis, 10.13- trans- prostairic acid

9-Oxo-4a, 4b-bishomo-20- - ((ί-hydroxypropyl) -5- - cls , 10,13 -trans- prosta «trienoic acid_

9-Oxo-16-hydroxy-4a, 4b- -bIshomo-2.0-ynethyl-5- - cis , 10,13-trans, 18 -cis -prostatetraen salure '.

9-oxo-15-hydroxymethyl- -4a, 4b-bishomo-5- £ ls _, -10,13- trans- prostatri-

9-oxo-l5-hydroxymethyl-

-5-cis, 10,13- trans- -prostatrienoic acid "

. " 10.13-trans_. -prostatrienic acid '"* ~'

9-Oxo-20-methyl-5- £ is_, -10,15-trans-prostrienoic acid

9-0x0-19,20-dinor-5- ■ ^ cis , 10.15 -jirans -pr ο s tat rl en acid "

90S, 10.15 -trans- prostatrienic acid '

9-oxo-17-chloro-l8,19, 20-trinor-5-cis_, 10.15- - trans -ρ rost at rl en ^. acid

9-Oxo-20-nor-5-cis, 10, 13-tr ans- prostat'ri'ens acid

40981 1/1203

abelle (continued)

Example 517

518 519

52O 521 522 523, 524

9-oxo- -1lalpha-hydroxy-5-cis, 13-transpro-stadienoic acid used of example

262

265

264

266

267

268

269

270

271

272

273

274 obtained 9-oxo-5-cis, -10,13-trans-prostatrienoic acid or tetraenoic acid

9-OXO-5-C1S, 10.13- -trans, IT- cis -prosta-. .. tri-acid,. . j .,

9-OXO-I7-methyl-19,20- -dinor-5 ~ cis, 10,13- - trans -prostatrien - _ '_ acid

9- ° xo-4.20-bisnor-5- - cis « -10.13" * trans -prosta trienoic acid _ '·

9- ° xo-4-nor-5 " Cls , 10, -13 -trans- prostatrien""• acid

9 «oxo-4-nor-20-chloro- -5-ice, 10,13- trans- -prbstatrienoic acid

9-Oxo-4a-homo-5- cig- ₅ 10, 13- trans- prostatric acid

9-Oxo-4a-homo-20-methyl.5- cis , 10,13- trans -prbs't'atrienic acid

9-Oxo-4a-homo-16-methyl · -18,19,20-trinor-5-c ^ s_, · 10,13- trans- prostatrienoic acid

9-Qxo-4a-homo-20-chloro -5 -cis , 10,13-transprostatrienic acid J _

9-gxo-4a-homo-5 ~ cis , -

10.13- trans , 17-cis-

-pros tat etraen's acid

9-Oxo-4a, 4b-bishomo-20- -Sthyl-5-cis, 10,13- - trans- prost'atrien · -

"acid 9-oxo-4a, 4b-bishomo-5- - cis , 10,13- trans- prostatrienoic acid

9-Oxo-4a, 4b-bishomo- -18,19,20-trinor-5-ci £, · 10.13-trans-prostatripni acid "*

40981 1/1203

Tabel

19 (continued)

example

530

551

532

533

9-0xo- -1lalpha-hydroxy-5-cis, 13-transprostadienoic acid used of example

275 ^%

535.

536
537
538

539
540
541

276

277

278

279

280

281

282

283

-284

285

286 obtained 9-oxo-5-cis, -10,13-trans-prostatrienoic acid or tetraenoic acid

9-Oxo-4a, 4b-bishomo-17- -methyl-19.20- <iinor-.5- _rf - eis , 10.13- trans- prοstatrien acid

9-0xo-4a, 4b-bishomo-20-

'Trans -pro'statrien acid

9-4a, 4b-bishomo-5- - cis , 10,13- trans ,: L7- -cis- prostatetraen ~ '_l

Acid.

9-oxo-4-methyl-5-cis, -10 ₁ 13 -transr prostatrien-

acid

9-QXo-4-methyl-17- -chloro-18,19,20-trinor- -5-cis, 10.13-trans; - -p rost at r i en acid

9y

-butyl-5- cls , 10.13-

- trans -p rostatri en -_-...__. acid

9-Oxo-4 (K) -methyl-5- -CiS ₁ , 10,13- trans -prostatrienic acid " ¹ ""

9.0x0-4 (R), 20-dimethyl- -5-cis, 10,13- trans- -prostatriene ·, acid * "'y

9-Qxo-4 (R) -methyl-18, -19,20-trinor-5-cis, 10, -13- trans- prostatric acid

9- ° xo-4 (R5-methyl-5- cis , 10,13- trans , 17- -prostatetraenoic acid

9xoäy5 ££ _"A 13- trans prostatrien" acid

9- Qso-4-ethyl-20-chloro- - 5- cis , 10, 13 -1 r ans -. -prostatrienic acid

409811/1203

Tabel

19 (continued)

9-0xo- -1lalpha-hydroxy-5-cis, 13-trans-beiprostadienoic acid used game of example

542 287 "

543. "288 '

544, '289

545 290

546 291

547 292

548 295

549 294

550 295

obtained 9-oxo-5-cis, -10,13-trans-prostatrienoic acid or tetraenoic acid

9-Oxo-4- <ithyl-20-i thyl- . -5- £ is, 10.15-trans_-. ■> ^ -prostatrienic acid

9-0x0-4- ^ 3 ^ 1-20 ^ 0 ^ "· -5- ice , 10.13 -trans-
-prostatrienic acid .1

9-Qxo-4-Uthy 1-5-CIs ₁ IO 15-trans, 17 -cis- prostatetraenic acid

9-Oxo-4-propyl-5-cis_, 10 , 13- trans , lJ- Q.is -pr ο s tat et raen ^ acid

9-oxo-4-prppyl-17-
-chlor — 18,19,20-trinor · - 5-ice, 10.13 - trans _-_
-prostatri en ^r acid "" __ "

9-Oxo-4-propyl-5-cis, -10,13- trans- prostatrienoic acid

9-oxo-4-propyl-17-
-methyl-19., 20-dinor-5-

9-oxo-4-propyl-20-nor- -5- cis , 10,13- trans- _ -prostatrienic acid "

9-oxo-4-propyl-20-

-methy1-5-cis, 10.13-

- trans- prostatria '"'

acid

409811/1203

Production of 9alpha / ß, ll, 16-trihydroxy-S-cis, 13-transprostadienoic acid

An ice cold solution of 355 mg of 9-oxo-llalpha, 16-rdihydroxy-9-oxo-5-cis, 13-trans-prostadic acid. (Example 149) in 50 ml of ethanol is mixed with 409 mg of sodium borohydride in small portions over the course of one minute while stirring. The mixture is stirred for 5 minutes at 0 ° C and 1.5 hours at ordinary temperature. Most of the ethanol is evaporated at room temperature and the residue is treated with ether and then with dilute hydrochloric acid, cooling in an ice bath. The organic phase is separated off and washed with water and saturated sodium chloride solution. The solution is dried over magnesium sulfate and concentrated. The residue is purified by thin layer chromatography on silica gel, whereby an oil is obtained which consists of a mixture of 9alpha and 9ß-Hy droxy derivative; ") f max 3 3IO (hydroxyl groups), 1705 (acid carbon group) and 970 cm (trans-vinyl group).

Examples 552-559

By treating the 9-oxo derivatives listed in the following table with sodium borohydride according to the example The 9alpha / ß-hydroxy derivatives given in the table are produced. Each of these Products is a mixture of the 9alpha and 9ß-hydroxy compounds.

/, 09811/1203

- 157 table

20th

example

552 555 55 ¹ *

555

556 557 558 559

used 9-oxo derivatives of Example

160

165

199

205 208

255,262 9-alpha / ß-hydroxy mixture obtained

9ct / ß, Ha, 17-Trlhydroxy- -5- CiS ₁ 13- trans -prostadienäure ~ ■

9a / β, Ha, 2 0-Tr ihydroxy- -5- cis , lj- trans -prostadiensaufen

9a / ß, lla-dihydroxy-15- -hydroxymethyl-4 (R) meth yl-5- cis , 15-Jbrans-prostadienic acid

9α / β, lla-dihydroxy-15- -hydroxymethyl- ^ a-homo- -5-ci £, 15-tr ans -prostadienoic acid

9a / β, 16-dihydroxy-5- cis , 13- trans -prosta-. dienic acid

9a / ß, 20-Qthydroxy-5- -cls, 13 -trans -prostadien acid · _

9α / β, 11α-dihydroxy-5- - cis , 13 -tran s-prostadTen acid

9α / β, ila-dihydroxy-5- - cls , 13- trans , 17- cis - · -pros tat rienoic acid__

h 0 9 8 1 1/1203

Examples 560-586

By treating the prostate acids listed in Table XXI below with the one indicated in each case Diazoalkane in the manner described below are the prostate oate esters mentioned as products in the table generated.

An ethereal solution containing a molar excess of diazoalkane is added to a solution of prostate acid in ether (or acetone). After two to four hours, the solution is carefully evaporated in vacuo, and the prostadienoate ester remaining as a residue is purified in the usual way by chromatography on silica gel.

/, 09811/1203

Tabel

example

5βθ
561
562

564

565
566

567
568

569
570

used prostatic acid from example

Alkylprostadienoate obtained from diazoalkane

149 149

149 l6o 165 158

172 156 206

253

Diazomethane

Diazopentane

Diazoheptane

Diazodecane

Diazodecane

Diazoheptane "

Diazopentane

ϋ iazoheptan Diazodecan tfiazodecane Diazodecan methyl-9-BXO-lla, l6-dihydroxy-5-cis, 13- trans -prostadienoat pentyl-9-oxo-lla, l6-dihydroxy-5-_cis_, 13 -trans -prostadienoat ■ heptyl 9-οχο-ΙΙα, l6-dihydroxy-5-cis, 13 trans -prostadienoat ρ ecyl-g-oxo-llot »l6-dihydroxy-5- c Is, 13- trans pros choose tadienoat D acyl 9- oxo- 11α, 17-dihydrox'y-5- ^ is, 13 -trans pros choose tadienoat H'eptyl-9-οχο-ΙΙα, 20-dlhydroxy-5- cis, 13 trans pros choose tadienoat '

Pentyl 9-oxo-llα-hydroxy-15-hydroxymethyl-5-ls, 13- trans - -prostadienoate.

H epty1-9-OXo-IIa, 16-dihydroxy-4 (R) -methyl-5- cls , 13 -trans - -prostadienoate <.

Decyl-9-oxo-lla, 16-dihydroxy-20-methyl-5- _pi: s, 13- trans , 18- - cis -prostatrlenoate "...;

D ecyl ~ 9-oxo-16-hydroxy-20-ynethyl-5- cis , 13- trans -prostadlenoatc ·.,. · .. ·

D ecyl-9-oxo-18-hydroxy-4a, 4b-bishomo-19,20-dino "r-5-is, 13- - trans -prostadienoate

-J 'Jl

Tabel

21 (continued)

example

571 572 573

575

576 577 578 579 580

581

used prostatic acid from example

Diazoalkane

255 255 266

272 289

296 296 296 296 298

Diazodecane

Dlazopentane

Dlazoheptane

Dlazoheptane diazodecane

Diazodecane

Diazoheptane

Dlazopentane.

Diazomethane

Diazodecane

Diazodecane obtained alkylprostadienoate decyl ~ 9-oxp-lla-hydroxy-5- £ is _J 13- trans -prostadlenoate pentyl-g-oxo-lla-hydroxy-Sc ^ s, 13-jtrans-prostadienoate

5 -cls , 13-trans-

H eptyl-g-
-prostadienoat ~

Heptyl-g-
-trans-prostadienoate

, ^I lb-bishomo-20- ^/ thyl-5 -cls , 15-

Dacyl-.9-oxo-llα-hydroxy-4-ethyl-5-cls, 13- trans , 17- cls - -prostatrienoate

D'ecyl-9a, Ha, 16a-trihydroxy-5- ^ ls, 13-trans-prostadienoate heptyl-9a, lla, 16a-trihydroxy-5- cis , 13- trans -prostadienoate ρ entyl ~ 9a, lla, 16a trihydroxy-5-cis, 13 - trans -prostadlenoat methyl-9a, lla, l6a- tr hydroxy-5 - ice, 13- trans -prostadlenoat.

ßecyl-9a, lla, L6A-trihydroxy-20- thy1-5- ice, 13 -trans -prostadlenoat- - .-

Decyl-9a, lla, 16a- trihydroxy- ^, 20-dimethyl-5-cjLs ^ l3- ^ rans- -prostadienoat

Tabel

21 (continued)

example

582
583

535
586

Prostadienoate used Prostadienoate obtained from example diazoalkane

408 448 448 448 511

Diazodecane

Dlazodecane

Diazoheptane

Oil azopentane

Dlazodecane Decyl ~ 9a, Ha-dihydroxy-5-cjLs, 13- trans -prostadlenoate D.ecyl-9-oxo-16-hydroxy-5-£, 10,13-J-trans-prostatrienoate heptyl-9-oxo-16 -hydroxy-5- £ i £, 10,13-_trans-prostatrienoat pentyl-g-oxo-l ^ -hydroxy-S- cis , 10,13- trans -prostatrlenoat decyl-9-oxo-5-cis, 10, 13-trans-prostatrienoate.

Example 587 Preparation of 3-bromo-1-octyne

118 ml of bromine at a temperature not exceeding 35 ° C. are added dropwise to a suspension of 600 g of triphenylphosphine in 200 ml of acetonitrile under a nitrogen atmosphere and with stirring. After stirring for a further hour, the supernatant liquid is poured off and evaporated to dryness. The solid residue is combined with the previously obtained solid with 1500 ml of dimethylformamide. The suspension is stirred at -20 ° C. and a solution of 200 g of 1-octyn-3-ol in 300 ml of dimethylformamide is added in three compartments. The temperature is slowly to -20 ⁰ C allowed to rise. After 3 hours, the solution with three portions of 1600 ml of petroleum ether (bp. 30 to 60 ⁰ C) was extracted. The combined extracts are washed with saturated sodium chloride solution, saturated sodium bicarbonate solution and finally with saturated sodium chloride solution, dried with anhydrous magnesium sulfate and evaporated to dryness (bath temperature 30 to 35 ^° C.). By distilling the remaining oil, 117 g (39%) of product with a boiling point of 66-68 ° / 9mra are obtained.

Example 588

Production of 3-hydroxymethyl-l-octyne

A suspension of 2.54 g of magnesium in 15 ml of ether, which contains a few crystals of mercuric chloride, is mixed with a small portion of 3-bromo-1-octyne in 20 ml of ether under a nitrogen atmosphere. As soon as the reaction has begun, the flask is ^{cooled in a water bath at 15 °} C. and the remaining portion of the halide in ether is added dropwise over the course of about an hour. After all of the halide has been added, stirring is continued

409811/1203

15 minutes' continued. The flask is then fitted with a glass tube that extends close to but not below the surface of the liquid. This tube is connected directly to a round bottom flask containing about 20 g of p-formaldehyde which has previously been dried in a vacuum desiccator over phosphorus pentoxide for two days. This piston includes a Stickstoffeinlaßrohr- The reaction flask is immersed in an ice bath, and the flask containing the paraformaldehyde is heated in an oil bath at 180 to 200 ⁰ C, by formed by depolymerization formaldehyde by a slow stream of dry nitrogen transferred to the Grignard reagent. After 30 to 40 minutes, the addition of formaldehyde is ended and the reaction mixture is stirred for 18 hours at room temperature.

The reaction mixture is then cooled in an ice bath and saturated ammonium chloride is added, followed by water and Ether to be added. Then the mixture is acidified with 2m sulfuric acid. The organic phase is separated washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate and in vacuo freed from solvent. Distillation of the residue gives 4.4 g of product with a boiling point of 91 to 93 ° C./9 mm.

Example 589

Production of l-methoximino-2- (6-fluoro-6,6-dicarbethoxyhexyl) -2-cyclopentene

A solution of sodium fluoromalonic acid diethyl ester is prepared from 2.062 g (0.0491 mol) of sodium hydride in mineral oil (57.2 percent), 40 ml of dry Ν, Ν-dimethylformamide and 8.174 g (0.458 mol) of diethyl fluoromalonate is added dropwise with 11.3 g (0.0413 mol) of 1-methoximino-2- (5-methy1-sulfonyloxypentyl) -2-cyclopentene in 60 ml of N, N-dimethylformamide offset. The mixture is 2 hours under a

409811/1203

Heated nitrogen atmosphere to boiling under reflux, concentrated and partitioned between cold dilute hydrochloric acid and diethyl ether. The organic phase is washed with saturated brine, dried (MgSO ₄ ) and evaporated. 13.631 g (92%) of a yellow oil are obtained in this way. ... ^

Example 590

Preparation of l-methoximino-2- (6-fluoro-6,6-dicarboxyhexyl) -2-cyclopentene

A mixture of 13.631 g of the diester from Example 589 and 16 g of potassium hydroxide in 363 ml of aqueous methanol (1: 1) is refluxed for 5 hours, cooled, concentrated and partitioned between water and dietary ether. The aqueous phase is acidified with hydrochloric acid and extracted with ether, and the organic phase is washed with saturated brine, dried (MgSO ₄ ) and evaporated to a solid. Recrystallization of this solid from diethyl ether / petroleum ether (30 to 60 ⁰ C) to white obtained 10 g (90%) of crystals, mp = 143 to 145 ⁰ C.

Example 591

Production of l-methoximino-2- (6-fluoro-6-carboxyhexyl) - -2-cyclopenten

A solution of 10 g of the dicarboxylic acid from Example 590 in 60 ml of 2-methoxyethyl ether is refluxed for 7 hours, cooled and evaporated. This gives 8.5 g (95%) of a brownish solid substance. Recrystallization of a sample from diethyl ether / petroleum ether (30 to 60 ⁰ C) to obtain white crystals, mp = 98 to 100 ⁰ C).

40981 1/1203

Example 592

Production of 2- (6-fluoro-6-carboxyhexyl) -cyclopent-2- -en-l-on

8.5 g of the acid methoxime from Example 591 are refluxed for 5 " ¹ hours with 180 ml of acetone and 64 ml of 2N hydrochloric acid. The mixture is cooled, the solvent is evaporated and the residue is partitioned between water and diethyl ether layer is evaporated, washed with saturated brine _r dried (MgSO.) and. thus obtained 7.4 g (98%) of a light yellow oil.

Example 593

Production of 2- (6-fluoro-6-carbäthoxyhexyl) -cyclopent- -2-en-l-on

7.4 g of the acid ketone according to Example 592 are esterified according to Fischer with 300 ml of absolute ethanol and 400 mg of p-toluenesulfonic acid for 18 hours and cooled. The solvent is evaporated. The remaining oil is dissolved in ether, washed with dilute sodium bicarbonate solution and brine, dried (MgSO ₄ ) and evaporated. 7.306 g (86%) of a light yellow oil are obtained in this way,

Example 594

Preparation of 2- (6,6-dicarbethoxy-6-phenylhexyl) -1-methoximino-2-cyclopentene

By treating l-methoximino-2- (5-methanesulfonyloxypentylI-2-cyclopentene with sodium diethylphenylmalonate according to the procedure described in Example 589 creates the above-mentioned connection.

/.09811/1203

Example 595

Preparation of 2- (6, e-dicarboxy-o-phenylhexyl) -1-methoximino-2-cyclopentene

By alkaline hydrolysis of 2- (6, e-dicarbethoxy-ephenylhexyl) -l-methoximino ^ -cyclopentene (Example 594) following the procedure described in Example 20, the above-mentioned dicarboxylic acid is produced.

B e 1 s- ρ 1 e 1 '596

Preparation of 2- (6,6-dicarboxy-6-phenylhexyl) -1-methoximino-2-eyelopentenes

By decarboxylating 2- (6,6-dicarboxy-6-phenylhexyl) -l-methoximino-2-cyclopentene (Example 595) following the procedure described in Example 63 becomes the above Connection created.

Example 597

Preparation of 2- (6-carboxy-6-phenylhexyl) -2-cyclopenten-l-one

By methoxime cleavage of 2- (6-carboxy-6-phenylhexyl) -1-methoximino-2-cyclopentene (Example 596) in the method described in Example 592
the above-mentioned ketone is produced.

Example 598

Production of 2- (6-carbethoxy-6-phenylhexyl) -2-cyclopentenl-one

Fisher esterification of the carboxylic acid of Example 597 following the procedure described in Example 593 makes the above
called ketoesters produced.

40981 1/1203

Example 599

Production of 2- <6-fluoro-6,6-dicarbethoxyhexyl) -1-methoximino-2-cyclopentene

■ - »

An ethanolic solution of sodium ethoxide, which has been prepared from 0.389 g of sodium and 40 ml of absolute ethanol, is admixed with 5.05 g at ambient temperature. The resulting solution is cooled to -20 ° C. and then treated with a stream of perchloryl fluoride until the mixture is neutral. The excess perchloryl fluoride is removed with a stream of nitrogen, and the mixture is again mixed with 10 ml of an ethanolic solution of sodium ethoxide (from 0.350 g of sodium) and treated with perchloryl fluoride until neutral. The excess perchloryl fluoride is removed with a stream of nitrogen and the mixture is filtered and evaporated to an oil. The latter is partitioned between ether and water and the organic phase is washed with saturated brine, dried (Na ₃ SO ₄ ) and evaporated thus receives the connection given above.

Example 600

Preparation of 2- (6-Carbo-n-butoxyhexyl) cyclopent-2-en-l-one

A solution of 50 g of 2- (6-carboxyhexyl) cyclopent-2-en-1-one / Bagli et al., Tetrahedron Letters, No. "5, 456 (1966] _ / in 1400 ml of n-butanol, the 2 , 7 g of p-toluenesulfonic acid monohydrate is left to stand in a sealed flask for about 24 hours at room temperature. The solution is evaporated to dryness. The residue is taken up in ether and the ethereal solution is washed several times with brine, dried with anhydrous magnesium sulfate and evaporated to dryness, giving the abovementioned butyl ester.

409811/1203

Examples 601-602

By treating 2- (6-carboxyhexyl) cyclopent-2-en-l-one according to the procedure described in Example 600 with the respective alcohol, those are given in the table below Ester produced.

Table 22

Example alcohol " obtained ester

601 isopropanol 2- (6-carbo-isopropoxyhexyl) -

cyclopent-2-en-l-one

602 methanol 2- {6-carbomethoxyhexyl} -

cyclopent-2-en-1-one

603 1-hydroxy- 2- (6-carbo-n-decyloxyhexyl) cyclo- -n-decane -en-1-one

Example 604 . ..

Preparation of 4-bromo-2 (6-carboxyhexyl) cyclopent-2-en-l-one

A mixture of 35.9 g (0.171 mol) 2- (6-carboxyhexyl) -cyclopent-2-en-1-one / Bagli et al, Tetrahedron Letters, No. 5, 465 (1966) / 35.0 g (0.197 mol) of N-bromosuccinimide and 600 ml of carbon tetrachloride are heated to reflux for 35 minutes while stirring. The mixture is then ^{cooled to 5 °} C. and filtered. The filtrate is washed with cold water, dried over magnesium sulfate and evaporated to dryness. An oil is obtained; .A. ^MeOH = 225 m, u

ΣΠ3Χ _ j

(8850); y "max = 1705 (carbonyl groups) and 1625 cm (olefin group).

4 09811/1203

Examples 605-621

Following the procedure described in Example 604 above, the various are set forth in Table 23 Cyclopentenones into the corresponding 4-bromo derivatives convicted.

40981 1/1203

Tabel

The example used is cyclopentanone

2- (6-carbethoxyocty1) cyclopent- -2-en-l-one 2- {6-carboxy-5,5- -dimethylhe xy1) -jyclopent-2-en-1-o ι 2- (6-carbethoxy- -5,5-dimethyIhpxl) cyelopent-2-en-

2- (6-carboxy-5- -oxahexyl) cyelopent-2-en-l-one 2- (6- carb ethoxy- -5-Oxahexy1) cyc 1 pent-2-en-l-on

from " 592

Ex.

605
606
607
608

609
610
611
6Ϊ2 " ^:

*

615
616
617
618
619
620

621

the end
Ex.

593

2- (5-carboxypentyl) cyclopent-2-en-1-one
2- (5-carboxyheptyl) cyclopent-2--1-one

2- (7 ~ g ar b ät ho xy heptyl) cyclopent -2-en-l-one from - 597
Ex.

598

600

601

603

2- (6-Carboxyhep jtyl) -cyclopenter obtained 4-bromocyclopentenone

4- bromine. -2- (6-carbethoxyoetyl) cyclopent-2-en-1-one * ' y

4-Bromo -2- (6-carboxy-5,5-dimethylhexyl) cyclopent-2-en-1-one

-2- (6-carbethoxy-5,5-di-

methylhexyl) eyelopent-2-en-l-one .-on.

4-Bromo -2 -. (6-carboxy-5-oxahexyl) -cyclopent-2-en-1-ones

4-Bromo-2- (6-earbethoxy-5-oxahexyl5. ■ cyclopent-2-en-1-one

4-Bromo -2- (6-carboxy-6-fluoro-hexyl). Cyclopent-2-en-1-one

4-bromo -2- (6-earbethoxy-6-fluoro hexyl) eyelopent-2-en-1-one

4-Bromo -2- (5-carboxypentyl) cyclopent-2-en-1-one

4-Srom -2- (5-carbethoxypentyl) cyclopent-2-en-1-one

4a rom -2- (7-carboxyhcptyl) cyclopent-2-en-1-one

4-Brrom -2- (7-carb ethoxyheptyl) -cyclopent-2-en-1-one

4-Bromo -2- {6-carboxy-6-phenylhexyl) cyclopent-2-one-1-one

4-Bromo -2- (6-earb-thoxy-6-phenylhexyl) cyclopent-2-en-1-one

4- prom -2- (S-carbo-n-butoxyhexyl) - ;. cyclopent-2-en-l-one ξ

4-bromo -2- (6-carbo-isopropoxyhexyl) -cyclopent-2-en-l-one \

4-bromo -2- (6-carbo-ri-decyloxyhexyl) cyclopent-2-en-l-one

4-bromo-P-fe
pent-S'-en-i-on

1/1 2Q3

Tabel

23 (cont.) 2337

Supplied. preserved game cyclopentanone 4-bromocyclopentenone

621A 2- (6-carbethoxy-4-bromine -2- (6-carbethoxyhexyl) -

hexyl) cyclopent- cyclopent-2-en-1-one

-2-en-l-one 621B 2- (6-carbomethoxy- ⁱ l-bromo -2- (6-carbomethoxyhexyl)

hexyU-cyelopent- -cyclopent-2-en-1-6n

-2-en-l-one 621C 2- (M-carbethoxy- 4-bromo -2- (i | -carbethoxybutyl) -

butyl) -cyclopent- -cyclopent-2-en-l-ori '

-2-en-l-one 621D 2- (3-carbethoxy- ^ -Bromo2- (3-carbathoxypropyl) -

propylj-cyclopent-cyclopent-2-en-1-one

-2-en-l-one 631E 2- (A-carboxy- - 4-bromo. -2- (4-carboxybutyl) -

butyl) -cyclopent- -cyclopent-2-en-l-one · -. '

-2-en-l-one 621P 2- (3-carboxy- ^ -Bromo -2- (3-carboxypropyl) -

propyD-cyclopent-cyclopent-2-en-1-one . . -2-en-l-on

6210 2- (8-carbtethoxy- ^ -Bromo -2- (8-carbathoxyoctyl) -octyl) -cyclopent- -cyclopent-2-en-l-one -2-en-l-one

621H 2- (6-carboxy- Ί-bromo -2- (6-carboxyoctyl) -

octyD-cyclopent- -cyclopent-2-en-l-one -2-en-l-one:

6211 2- (8-carboxyoctyl) -4-bromo -2- (8-carboxyoctyl) - -cyclopent-2-en- -cyclopent-2-en-1-one · -1-one

4098 Ί 1/1203

B is ρ ie 1 622

Preparation of 4-hydroxy-2- {7-carboxyoctyl} -cyclopent-2-en -1-one

A solution of 57.2 g of crude 4-bromo-2- (8-carboxyoctyl) -cyclopento-2-en-l-one in 500 ml of acetone and 325 ml of water at 3 ° G is stirred with 44.1 g of ( 0.226 mol) of silver fluorate were added over the course of 15 minutes. The mixture is stirred for 2 hours at 0 to 3 ^° C. and filtered. The filtrate is diluted with water, saturated with sodium chloride and extracted with ether. The extract is washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated. Partition chromatography of the residue on Celite gives white crystals from F. = 58 to

66 ° C, ^MeOH = 223 m, u (7300); max (KBr) = 3340 (hydroxylmax / .j

groups), 1705 (carbonyl groups) and 1625 cm (olefin group).

Example 623

Production of 4-acetoxy-2- (6-carbäthoxyhexyl) cyclopent-2- -en-l-on

A mixture of 51.6 g (0.137 mol) of crude 4-bromo-2- (6-carbethoxyhexyl) cyclopent-2-en-l-one, 27 g (0.162 mol) of silver acetate and 20 ml of glacial acetic acid is 4.5 hours at Stirred at reflux temperature. The mixture is cooled and the solids are removed by filtration. The filtrate is concentrated and extracted with warm hexane. The extract is washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over magnesium sulfate and concentrated. An oil is obtained. The crude product is distilled under reduced pressure and a liquid with a boiling point of 152 to 163 ° C. (0.01 mm) is obtained; ^Me0H = 223 m, u

ITIcIX j

(10700); max = 1745 = 1745 (Estercarbony! group), 1725 (Ketone carbon groups) and 1235 cm "(acetoxy group).

/.0981 1/1203

Example 624

Preparation of 4-hydroxy-2- (6-carboxyhexyl) -cyclopent-2-en-l-one

A solution of 6,, 91 g (50 mmol) of potassium carbonate lh 1400 ml of methanol and 1400 ml of water, which contains 100 mg of hydroquinone, is mixed with 14.8 g (50 mmol) of 4- Acetoxy-2- (6-carbäthoxyhexyl) -cyclopent-2-en-l-one (Example 623) was added. The solution is stirred for 90 minutes. At this stage it contains 4-hydroxy-2- (6-carbethoxyhexyl) cyclopent-2-en-1-one. It is then admixed with 23.6 g (75 mmol) of barium hydroxide octahydrate in one minute. The mixture is stirred for 60 minutes and then concentrated under reduced pressure to a volume of 1800 ml in one hour. The solution is diluted with 300 ml of water, saturated with sodium chloride and stirred with 400 ml of ether, while 70 ml of 4N hydrochloric acid are added. The aqueous phase is extracted with further ether, and the combined organic phases are washed with saturated sodium chloride solution. The extract is dried over magnesium sulfate. The crude product obtained after evaporation of the solvent is purified by chromatography on silica gel. This gives an oil; XJ ^ ° ^H = 223 m, u (7360); if max = 3380 (hydroxyl groups), 1710 (carbonyl groups) and 16 32 cm (olefin group).

Example 625

Production of 2- (6-carboxyhexyl) ^ -hydroxy-cyclopent ^ - en-l-on

A solution of 10.6 g (approx. 34 mmol) of crude 4-bromo-2- (6-carboxyhexyl) cyclopent-2-en-l-one (Example 604) in 100 ml of acetone and 65 ml of water is stirred in two minutes 8.80 g (45.2 mmol) of silver fluorate were added. The temperature is kept at 25 to 30 ° C by external coals.

/.0981 i / 1 2 0 3

The mixture is stirred for 90 minutes, filtered off, with Saturated sodium chloride and extracted with ether. The extract is made with half-saturated sodium bicarbonate solutions extracted. The alkaline solutions are acidified again with dilute hydrochloric acid and saturated with sodium chloride and extracted with ether. The extract is washed with water and saturated sodium chloride solution over magnesium sulfate dried and concentrated. The crude product is purified by partition chromatography on Celite, and you receives an oil with the properties specified in Example 624.

Examples 626-650

Following the procedure given in the above example, the 4-bromocyclopentenones given in Table 24 below are obtained in the presence of silver fluorate in acetone / water solvolyzed, as a result of which the 4-hydroxycyclopentenones indicated in the table are formed.

40981 1/1203

Tabel

example

626 627 628 629, 630 631 632 633 63 ** 635 636

637 638 639 eno 641 6 * 12 643

used cyclopentenone of example

621A -

621B 621C 62-1D 621E 621P 621G 621H

605 606 607

608

609 610 611 612 613 6lU obtained 4-hydroxycyclopent-2-en-one

4-Hydroxy-2- {6-carb.thoxyhexyl} cyclopent-2-en-.l-one ι ''

4-Hydroxy-2 (6-carbomethoxyhexy) cyclopent-2-en-1-one

4-Hydroxy-2- (4-carbethoxybutyl) cyclopent-2-en-1-one

4-hydroxy-2- (3-carbethoxypropyl) cyclopent-2-en-l-one

4-Hydroxy-2- (4-carboxybutyl) -cyclopent-2-en-l _r on-

4-Hydroxy-2- (5-carboxypropyl) -cyclopent-2-en-1-one

4-Hydroxy-2- (8-carb ^ -thoxyoctyl) -cyclopent-2-en-1-one>

4-% -droxy-2- (6-carboxyoctyl) cyclopent-2-en-1-one

4-B5-hydroxy-2- (6-carbethpxyoctyl) -cyclopent-2-en-1-one

4-Hydroxy-2- (6-carboxy-5,5-dimethylhexyl) cyclopent-2-en-1-one

4-hydroxy-2- (6-carbethoxy-5,5-

-dimethylhexyl-cyclopent-S-en-l- -on-

4-Hydroxy-2- (6-carboxy-5-oxahexyl) cyclopent-2-en-1-oni

4-Hydroxy-2- (6-carbethoxy-5-oxahexyl) cyclopent-2-en-1-one

4- ^H ydroxy-2- (6-carboxy-6-fluoro hexyl) cyclopent-2-en-l-pn:

4-Hydroxy-2- (6-carbethoxy-6-fluorohexyl) cyclopent-2-en-1-one

4-Hydroxy-2- (5-carboxypentyl) cyclopent-2-en-1 on

4-Hydroxy-2- (5-carbethoxypentyl). Cyclopcnt-2-en-i-one

4-Hydroxy-2- (7-carboxyheptyl) -cyolopont-2-one-1-one

9 8 1 1/1 2 0 3

- 176 -

Tabel

24 (cont.)

example

used cyclopentenone of example

615

616 617

618 619

620 621 obtained 4-hydroxycyclopent-2-en-one

4-Hydroxy-2 - (7-earb ethoxyheptyl) cyclopent-2-en-1-one

4-hydroxy-2- (6-carboxy ~ 6-phenylhexyl ) cyclopent-2-eri-l-one

■ -j

4-hydroxy-2- (6-carbethoxy-6- -phenylhexyl) cyclopent-2-en-1-one

4-Bydroxy-2- (6-carbo-n-butoxyh6xyl) cyclopent-2-en-.l-one '

4-Hydroxy-2- (6-carbo-isopropoxyhexyl) cyclopent-2-en-1-one

4-Hydroxy-2- (6-carborn-decyloxyhexyl) cyclopent-2-en-T-one 4-Hydroxy-2- (6-carboxyhe ptyl) -cyclopent-2-en-1-one ■

0 9 8 1 1/12 0

Example 651

Preparation of 4-tetrahydropyranyloxy-2- (6-tetrahydropyranylcarboxyhexyl) -cyclopenta-en-1-one

A solution of 5.59 g (24.6 mmol) of 4-hydroxy- (6-carboxyhexyl) -cyclopent-2-en-l-one (Example 625) and 20.7 g (246 mmol) of dihydropyran in 100 ml methylene chloride at 20 ⁰ C is added with stirring in one portion with 47 mg (O, 246 mmol) p-toluenesulfonic acid monohydrate. The temperature is kept at 20 to 25 ^° C. by cooling, and stirring is continued at this temperature for a further hour. The solution is diluted with 200 ml of ether and poured into a mixture of 40 ml of saturated sodium bicarbonate solution, 40 ml of saturated sodium chloride solution and 80 ml of water. The phases are separated and the aqueous phase is extracted with more ether. The total extract is washed successively with water and saturated sodium chloride solution, dried over potassium carbonate and freed from volatile constituents by concentration under reduced pressure. An oil is obtained; ^MeOH> 223 m, u (9500);

ΙΏ3Χ /

max 1730 (Estercarbony! group), 1705 (Ketone carbonyl group) and 1030 cm (tetrahydropyranyloxy groups).

Examples 652-662

Following the procedure described in Example 651, the various 4-hydroxycyclopentenones mentioned in Table 25 are obtained into the tetrahydropyrany1-4-tetrahydropyranyloxyeyelopentenone esters also listed in the table convicted.

81 1/12 0 3

t /

- 178 table 25th

example

4-Hydroxycyclopentenone used from Example

653

655

656

657 -. *

658

659

660

661

662

626

"627

622

633

635

636

638

640

642

650 obtained tetrahydropyran-2'-yl-4-tetrahydropyran-

2'-yl-oxycyclopent-z-en-i-one

4-tetrahydropyran-2'-yloxy- -2- (4-carbotetYahydropyran- -2 · -yloxybutyl) cyclopent-2- -en-l-on

^ -Tetrahydropyrans'-yloxy -2- (5-carbotetrahydropyran- -2 '-yloxypropyl) cyclopent--2-en-l-one

^J f -retrahydropyran-2 '-yloxy--2- (8-carbotctrahydropyran--2'-yloxyocty1) cyclopent-2-en-1-one

4-Tetrahydropyran-2 ^f -yloxy- -2- (6-carbotetrahydropyran- -2'-y.loxyoctyl) eyelopent-2-en-1-one

4-tetrahydropyran-2'-yloxy- -2- (6-carbotetrahydropyran--2'-yloxy-5,5-dimethylhexyl) -cyclopent-2-en-1-one

^ -Tetrahydropyrans' -yloxy- -2- (6-carbotetrahydropyran--2 · -yloxy-5-oxahexyl) cyclopent-2-en-1-one.

4-Tetrahydropyran-2 ¹ -yloxy--2- (6-carbotetrahydropyran--2'-yloxy-6-fluorohexyl) cyclopent -2-en-1-one

4-tetrahydropyran-2'-yloxy- -2- (5-carbotetrahydropyran- -2'-yloxypcntyl) cyclopent--2-en-l-one

4-T et rahyd ropy ran-2 -yloxy- -2- (7-carbotet rahyd ropy ran- -2'-yloxyheptyljoyclopcnt- -2-cn-l-on

4-Tetrahydropyran-2'-yloxy-j -2- (6-carbotet rahyd ropyran-) -2 ^f -yloxy-6-phenyl hexyl) -cyclopent-2-en-1-one

4-tetrahydropyran-2 -yloxy- -2- (6-earbotetrahydropyran- -2 · -yloxyheptyl) -cyclOpent- -2-en-l-one

/, 0981 1/1 2 Q 3

Example 663

Preparation of 4-tetrahydropyranyloxy-2- {6-carbethoxyhexyl) -cyclopent-2-en-1-one

A solution of 674 mg (2.64 mmol) of 4-hydroxy-2- {6-carbethoxyhexyl) -cyclopent-2-en-l-one (Example 626} and 2.22 g (26.4 mmol) of dihydropyran in 2.6 ml of methylene chloride are mixed with 5.0 mg (0.026 mmol) of p-toluenesulfonic acid monohydrate while stirring offset. After stirring for 20 minutes at room temperature, the solution is diluted with ether and poured into a saturated sodium chloride solution containing a little sodium bicarbonate. The organic phase is separated off and washed with saturated sodium chloride solution. The extract is dried over magnesium sulfate and volatile Ingredients are reduced by evaporation under

Pressure removed. An oil is obtained; λ ** ^e0H = 224 "mu (7950);

Max /

V max «1735 (ester carbonyl group), 1710 (ketone carbonyl) and 1030 cm "* (tetrahydropyranyloxy group).

Examples 664-677

Following the procedure described in Example 663 are the alkyl 4-hydroxycyclopentenone esters listed in Table 26 converted into the corresponding 4-tetrahydropyranyloxyalkyl esters also given in the table.

409811/1203

Tabel

26th

example

664
665

S6S

667

668

.669 '

670

671
672

673
674
675

676
677

4-Hydroxycyclopentenone ester used from Example

627 628

629

632 634 636 638 640 642 644 646 647

648 649 received

4-Tetrahydropyran-2'-ylox cyclopent-2-en-1-one ester

4-tetrahydropyran-2'-yloxy-2- - (6-carbomethoxyhexyl) cyclopent- -2-en-l-on. ·. '·' ■ '

4-Tetrahydropyran-2 ¹ -yloxy-2- (4-earbethoxybutyl) cyiopent--2-en-1-one

. 4-Tetrahydropyran-2'-yloxy-2- - (3-carbethoxypropyl) cyclopent-2-en-1-one

4-tetrahydropyran-2'-yloxy-2- - (B-earbgthoxyoctylJeyelopenL-2-en-l-one. . .

4-tetrahydropyran-2'-yloxy-2- - (6-carbethoxyoctyl) cyclopent-

-2-en-l-on

4-Tetrahydropyran-2'-yloxy-2- - (6-carbathoxy-5/5-dimethylhexyl) eyelopent-2-en-l-one

4-tetrahydropyran-2'-yloxy-2- - (6-earbä thoxy-5-oxahexy1) - -cyclopent-2-en-l-one

4-Tetrahydropyran-2'-yloxy-2- - (6-carbethoxy-6-fluoro hexyl) -cyclopent-2-en-1-one

4-tetrahydropyran-2'-yloxy-2- - (ij-carbäthoxypentyl) cyclo-

pent-2-en-l-on

4-letrahydropyran-2 ^f -yloxy-2- - (7-carbathoxyheptyl) eyelopent- -2-en-l-one

4-tetrahydropyran-2'-yloxy-2- - (6-carbathoxy-6-phenylhexyl) -eyelopent-2-en-1-one

4 -fliefrahyd ropyran-2'-yloxy-2- - (G-carbo-n-butoxyhexyl) cyclo-

pent-2-en-T-one

4-toti'ohydropyran-2'-yloxy-2- - (6-carbo-i sopropxyhexy1) eyelopent.-2-on-l-on

4 - ^ - etrahyrJropyran-2 '-yloxy-2-

- (6-curbo-n-decyloxyhcxyijeyclo-

pont-2-οη-Τ-οη

A09811 / 1203

Example 678

Preparation of 4-methoxy-2- (6-carboxyhexyl) -cyclopent-2--en-l-one

A solution of 5.30 g of crude 4-bromo-2- (6-carboxyhexyl) -cyclopent-2-en-l-one in 85 ml of methanol is mixed with 4.40 g of {22, 6 mmol) of silver fluorate added in one portion. After 2 minutes, 2.66 g (24.8 mmol) of 2,6-lutidine are added to the mixture. After stirring for 30 minutes at 0 to 3 ° C., the mixture is stirred for 45 minutes at ambient temperature. After filtering off the silver bromide, the filtrate is concentrated to a volume of 40 ml. The solution is mixed with saturated sodium chloride solution and extracted with ether. The extract is washed successively with 0.5 η hydrochloric acid solution, water and saturated sodium chloride solution, dried over magnesium sulfate and concentrated. Partition chromatography of the residue on Celite yields an oil; λ ^Me0H = 220 m, u (7450); V 1715 (carbony group and 1095 cm (methoxy group).

Examples 679-707

By alcoholysis of the 4-bromocyclopentenones listed in Table XXVII below with the respective alcohol the procedure of Example 678 gives the 4-alkoxycyclopentenones also shown in the table.

4098 11/1203

Tabel

example

679 680 681 682 683 684

685 686

"692

used broracyclopentenone of example

obtained α-alkoxycyclopent-2-en-one

621A

. 621B

621C

621D 621E 621P 6211 621G 621H

605 606 607 608 609 610 611 612 613

409 4-Sthoxy-2- (6-carbäthdxyhexyl) -cyclopent-2-en-1-one

4-methoxy-2- (6-carbomethoxyhexyl) - · cyclopent-2-en-l-one,

4- £ propoxy-2- (4-carbethoxybutyl) cyclopent-2-en-1-one

4-isopropoxy-2- (3-carbethoxypropy1) eyelop ent-2-en-1-one

4-methoxy-2- (4-carboxybutyl) cyclopent-2-en-1-one

4-sthoxy-2- (5-carboxypropyl) cyclopent-2-en-l-oh

4-.Methoxy-2- (8-carboxyoctyl) cyclopent-2-en-1-one

4-Isopropoxy-2- (8-carb ethoxyoctyl) -cyclopent-2-en-1-one

4-methoxy-2- (6-carboxyocty: L) cyclop ent-2-en-1-one · ,;

4 -n- Putoxy-2- (6-carb Sthoxyoctyl) cyclopent-2-en-l-one.

4-methoxy-2- (6-carboxy-5,5-diraethylhexyl) cyclopent-2-en-1-one.

4-methoxy-2- (6-carb thoxy-5,5-dimethylhexyl) cyclopent-2-en-1-one

4-methoxy-2- (6-carboxy-5-ox & hexyl) -cyclopent-2-en-1-one

4-1thoxy-2- (6-carbethoxy-5-oxahexyl) cyclopent-2-en-1-one.

4-methoxy-2- (6-carboxy-6-fluoro-hexyl) cyclopent-2-en-1-one

4-propoxy-2- (6-carbethoxy-6-fluoro- hexyl) cyclopent-2-en-1-one

4-M2thoxy-2- (5-carboxypcntyl) cyclopcnt-2-en-1-one

4-sec_-butoxy-2- (5-carbethoxypcntyl) -

cyclopont-2-en-l-on-

1 1/1203

Tabel

27 (cont.)

example

697
698

699
700
701
702 '

703
704

"705
706

"707 V.

inserted

Bromcyclopentenone

a-Alkoxycyclopent-2-en-one obtained from Example

614 615

ice cream"

. 617 618 '619 620 604 604

604 4-methoxy-2- (7-carboxyhepty cyclopent-2-en-l-ones

4-M.ethoxy-2 - (7-carbathoxyhep ty 1) cyclopent-2-en-1-one;

4-M ethoxy-2- (B-rxyp hexyl) cyclopent-2-en-1-one

4 -χ thoxy-2 - (6-earbät hoxy- 6-pheny 1 hexyl) cyclopent-2-en-1-one>

4-? Lethoxy-2- (6-carbo-n-butoxyhexyl) cyclopent-2-en-T-one <

4-M.ethoxy-2- (6-carbo-isopropoxyhexyl) cyclopent-2-en-1-one

4-methoxy-2- (6-carbo-n-decyloxyhexyl) cyclopent-2-en-T-one

4-Ethoxy-2- (e-carboxyhexylcyclopent-2-en-l'-one ". -

4-propoxy-2- (6-carboxyhexyl) cyclopent-2-en-l-one '

4-1sopropoxy-2- (6-carboxyhexyl) -cyclopent-2-en-i-one

4-η-butoxy-2- (6-carboxyhexyl) -cyclopent-2-en-1-one '

40981 1/1203

2 3 3 ⁷ δ 8 Ί

Example 708

Production of 4-tert-butoxy-2- (6-carbethoxyhexyl) cyclo pent-2-en-l-one "- *"

A mixture of 6.35 g (20 nmol) of 4-bromo-2- (carbethoxyhexyl) cyclopent-2-en-l-one (Example 94), 3.01 g (11 mol) of silver carbonate and 40 ml of tert-butanol ^{is heated to 70 °} C. for 17 hours with stirring. The mixture is cooled and filtered, after evaporation of the tert-butanol, aqueous sodium chloride is added to the residue and the mixture is extracted with ether / hexane (3: 1). The extract is washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated. The crude product is purified by chromatography on silica gel, whereby in the order of elution one obtains: the above compound as an δ1; A! JJ ° ^H »219 m, u (8860); y ^ max = 1735

Iu el JC /

Ester carbonyl group), 1725 (ketone carbonyl group) and

1365 cm " ¹ (tert-buty! Group) and 4-hydroxy-2- (6-carbethoxy-

hexyl) cyclopent-2-en-l-one also as an oil.

Example 709 .

Production of 4- (2-hydroxyethoxy) -2- (6-carboxyhexyl) -cyclopent-2-en-l-one

A solution of 19.1 g of crude 4-bromo-2- (6-carboxyhexyl) -cyclopent-2-en-l-one (Example 93 in 310 ml of ethylene glycol is stirred with 15.6 g (80 mmol The exothermic reaction is controlled in such a way that a temperature of 29 ^° C. is obtained, and after one minute, 8.6 g (80 mmol) of 2,6-lutidine are added to the mixture for one minute Stirred for 2 hours at ambient temperature, diluted with water and filtered.

'i Π 9 8 1 1/12 0 3

The filtrate is diluted with saturated sodium chloride solution and extracted with ether. The extract is mixed with half-saturated sodium chloride solution, which contains a little hydrochloric acid, and saturated sodium chloride solution washed over Magnesium sulfate dried and concentrated. Column chromatography the residue on silica gel gives an oil.

^{= 216 ra} / ^u < ^835O) '* Vmax = 3340 (hydroxyl groups), 1700 (carbonyl groups) and 1620 cm (olefin group).

Examples 710-733

Following the procedure described in Example 2O4 the 4-bromocyclopentenones listed in Table 28 below converted into the corresponding 4- (omega-hydroxyalkyl) -cyclopentenones also mentioned in the table.

A 0 9 8 1 ι / 1 2 0 1

- 186 tabs 28

example

711 712

used 4-bromocyclopentenone obtained from Example

4- (/ ^ / - Hydroxyalkoxy) cyclopent-2-en-1-one

621A

621B

621C

621D

621E

621F

6211

621G

621Η

605

606

607

608

609 4-ß-hydroxyethoxy ^s -2 - {'6-ear-

ethoxyhexyl) cyclop "'en" tr-2-en-

-1-one yyi thoxy-2- (6-carbomethoxyhexyl) cyclopent-2-en- -1-on

4- y'-! ¹ hydroxyproDoyy-2- (4-carbethoxybutyl) cyclopent-2-en-1-one

ßyyy (3 bethoxypropy1) eyelopent-2-en- -1-on

yy ^ y (boxybutyl) cyclopent-2-en-l-

-ΟΠΛ (boxypropyl) cyclopent-2-en-l-one

4-ß-Hydroxyethoxy-2- (8-carboxyoctyl) cyclopent-2-en-1-one

4-ß-hydroxyethoxy-2- (8-carbcthoxyocty1) eyelopent-2-en- -1-on

4-β_Hycj _roX yethoxy-2- (6-carboxyoetyl) eyclopent-2-en-1-one

4-V'-hydroxypropoxy-2- (6-carb thoxyoctyl) cyclopent-2-en-1-one

^4-.beta.-K ydroxy ^ä thoxy-2- (6-ear

boxy-5,5-dimethylhexyl) cyelopent-2-en-l-one

4-ß-hydroxyethoxy-2- (6-carbethoxy-5,5-d imethylhexyl) -eyelopent-2-en-1-one

4-ß-Hydroxyethoxy-2- (6-carboxy-13 -oxahexyl) eye lopent -? .- -en-1-one

l \ -V-Kydroxy ρ rcpoxy -2 - (G- cn rb thoxy-i3-oxahexyl) eye lopent- -2-on - l-on

187 table

28 (cont.)

example

727,

used 4-bromocyclopentenone obtained from Example

4 - (^ / - Hydroxyalkoxy) cyclopent-2-en-1-one

610

611

"612

614

616

617

618

619

620

604 4-β-hydroxyethoxy-2- { 6-carboxy-6-fluoro hexyljeyclopent-2-en-1-one,

4-ß-hydroxyethoxy-2- (6-carbethoxy-6-fiuo rohexy1) cyclo pent-2-en-l-on '

4-ß-hydroxyethoxy-2- (5-car-

boxypentyl) cyclopentT-2-en-

-1-one 4-ßHydroxyethoxy-2- (7-carboxyheptyl) cyclopent-2-en-1

-on.

--2- (6-car-

boxy-6-phenylhexyl. pent-2-en-l-on ■

4-ß-Bydroxyethoxy-2- (6-carb thoxy-6-phenylhexyl) cyclopent-2-en-1-one

4 -ß ^ yd roxy ethoxy-2- {6-carbo-

-n-butoxyhexyl) cyclopent-2-

-en-l-one 4-ß-hydroxy ethoxy-2- (carbo-

-isopropoxyhexyl) cyclopent-2-

-en-l-one 4-ß4i hydroxyethoxy-2- (6-carbo- -η-ά ecyloxyhexy1) cyclopent-2- -en-l-one

4-ß-Rydroxypropoxy-2- (6-carboxyhexyl) cyclopent-2-en-1- -on

A 0 9 8 1 1/12 0

Examples 734-748

Following the procedure described in Example 651, the 4-alkoxycyclopentenone carboxylic acids listed in Table 29 are obtained converted into the corresponding tetrahydropyran-2'-yl esters also mentioned in the table.

40981 1/1203

Tabel

29

example

735

736

737

738

739

742

745

746

4-Alkoxycyclopentenone-carboxylic acid used from Example obtained

Tetrahydropyran-2'yl-ester 4-alkoxycyclopent-i-one

683 684 685 687 689

691 693 695 697 699 704 705

706 4-Methoxy-2 - '(4-carotetrahydropyran-2' -yloxybutyl) -cyclopent-2-en-1-one ^J.

4-jithoxy-2- (5-carbotetrahydropyran-2 ' -yloxypropyl) cyclopent-2-en-l-one ;.

4-methoxy-2- (8-carbotetrahydropyran-2'-yloxyoctyl) -cyclopent-2-en-1-one

4 - Msthoxy-2- (6-carbotetrahydropyran-2'-yloxyoctyl) -cyclopent-2-en-1-one

4-methoxy-2- (6-carbotetrahydropyran-2 ^f -yloxy-5,5-d-imethylhexy 1) cy.c-lopent -2- -en-1-one

4-methoxy-2- (6-carbotetrahydroxypyran-2 -yloxy-5-oxahexyl) cyclopent-2 ~ en-1-one '

^ ety ^ f

hydropyran-2 ^! -yloxy-6-fluorohexyl) -cyclopent-2-en-1-one

i | _M _s thoxy-2- (5-carbotetra-

hydropyran-2 * -yloxy-pentyl) -cyclopent-2-en-1-one

4- ^M ethoxy-2- (7-carbotetrahydropyran-2'-yloxyheptyl) -cyclopent-2-en-1-one

fHsthoxyaCecarboetyo pyran-2 ^! -yloxy-6-phenylhexyl) »cyclopent-2-en-1-one

4-Kthoxy-2- (6-carbotetrahydropyran-2'-yloxyhexyl) cyclopent- -2-en-1-one

4-piropoxy-2- (6-carbotetrahydropyian-2 ^{ -vloxyhexyijcyclopent ~ -2-en-1-one

^ -Isopropoxy ^ -fS-carbotctrahydropyran-2'-yioxyhexyl) cyclo

409811/1203

Tabel

29 (cont.)

example
7 * 8

4-Alkoxycyclopentenone-carboxylic acid used from Example obtained

Tetrahydropyran-2'yl-ester 4-alkoxycyclopenta-one

4-n-Butoxy-2- (G-oarbotctrahyd ropy rnn -2'-yloxyhexy1) eyelopent-2-en-l-one

4-methoxy-2- (G-ca rbotet rahydropyran-2'-yloxyhexyl) cyclopent- -2-en-l-on ι

40981 1/1203

Examples 749-773

By reacting the 4- (omega-hydroxyalkoxy) -cyclopentenones listed in Table 30 below with Ulhydropyran according to the procedure described in Example 651, the 4- {omega · TetrahydropyranyloxyalkOKy) -cyclopentenone ester produced.

409811/1203

example Tabel

4- (CJ- hydroxyalkoxy-cyclopentenone used from Example 30

preserved

4- (C \ / - tetrahydropyran-2 '-yloxy alkoxy) -cyclopent-2-en-1-one-

ester

749 '

750 751 752 753

710

711

712

713

709

755

756 757

758

715

717

716

718 if -β -T et rahyd ropy r any -2 '--y loxy -ä thoxy-2- (6-carb. ifchoxyhexyl) -cyclopent-2-en-1-one

if-ß-Tetrahydropyrany-2'-yloxyethoxy-2- (6-carbomethoxyhexyl) ■ cyclopent-2-en-l-one

4- 'K-Tetrahydropyran-2' -yloxypropoxy-2- (4-carbethoxybutyl) -cyclopent-2-en-1-one.

4-ß-aetrahydropyran-2'-yloxyethoxy-2- ( 3> -c8 - ** ethoxypropyl) cyclopent-2-en-1-one

4-β-tetrahydropyran-2'-yloxyethoxy-2- (6-carbotetrahydro-pyran-2'-yloxyhexyl) cyclopent- -2-en-l-on

4-ß-Tetrahydropyran-2'-yloxyethoxy-2 - (^ - carbotetrahydropyran -2'-yloxybutyl) cyclopent--2-en-l-one

4-ß-Tetrahydropyran-2'-yloxyethoxy-2- (3-carbotetrahydropyran-2 ^f -yloxypropyl) cyclopenta -2-en-1-or?

4-ß-Tetrahydropyran-2'-yloxythoxy-2- (8-carbethoxyoctyl) -cyclopent-2-en-1-one

4-ß-tetrahydropyran-2'-yloxy- Thoxy-2- {8-carbotetrahydropyran-2'-yloxyoctyljcyclopcnt- -2-en-l-on

4-ß Sßüt rahydropyran-2'-yloxy ^ä thoxy-2- (G-carbotetrahydropyran-2 -yloxyoetyl ¹⁾ cyelopont- -2-en-l-on

409811/1203

- 193 tabs 1 1 e 30 (cont. )

example
759

760

761
762

763
764

765
766 '

767
768

769
770

4- <- obtained hydroxyalkoxy-cyclo- 4- {-Tetrahydropyran-2'-yloxypentenone of example alkoxy? -cyclopent-2-en-1-one-

719

720

721

722

723

725

726

727

728

729

• 730

771; 731

^ 098-1 1/1203 if- / -Tetrahydropyrans' -yloxy- propoxy-2- (6-carbethoxyoctyl) -cyelopent-2-en-1-one

4-β -τ, et rahydropy ran-2 ^f -yloxy-ethoxy-2- (6-carbotetrahydropyran-2 ^f -yloxy-5,5-dimethylhexyl) eyclopent-2-en-1-one

4-ß-r.etrahydropyran-2 · -yloxyä thoxy-2- (6-carbethoxy-5j5-dimethylhexyl) cyclopent-2-en-1-one

4-β-ίΡ at rahydropy ran-2 ^! yloxy ^ä thoxy-2- (6-carbotetrahydropyran-2'-yloxy-5-oxahexyl) cyclopent-2-en-l-one

et rahydropy ran-2 '-yloxy-

propoxy-2 - (- 6-carb ^ä thoxy-5- -oxahexyl) cyelopent-2-en-l-on

4-β-tetrahydropyran-2'-yloxyethoxy-2- (6-carbotetrahydropyran-2'-yloxy-6-fluorohexyl) -cyclopent-2-en-1-one

4-β-tetrahydropyran-2'-yloxy-sthoxy-2- (6-carbethoxy-6-fluoro hexyl) cyelopent-2-en-l-one

4-β-tetrahydropyran-2'-yloxyethoxy-2- (5-carbotetrahydropyran-2'-yloxypentyl) cyclopent- -2-en-l-on

ßypy2 '-yloxyethoxy-2- (7-carbotetrahydropyran-2 ^f -yloxyhepty1} cyclop ent- -2-en-l-ron "

^4-.beta.-T .etrahydropyran-2 '-yloxyä thoxy-2- (6-carbotetrahydropyran-2 "yloxy-6-phenylhexyl) cyclopent-2-en-l-on

^4-.beta.-T etrahydropyran-2'-yloxy ^s thoxy-2- (6-carbethoxy-6-phenyl hexyl.) Cyclopent-2-en-l-on

4_ß_T, ethrahydropyranr2'-yloxyethoxy-2- (6-carbo-ri-butoxyhexyl) cyclopent-2-en-1-one

k ^{-β-tetrahydropyran-2-yloxy-r} 9thoxy-2- (6-carbo-lsopropoxyhexyl) cyelopent-2-en-l-on

- 194 table

(Cont.)

example

4- (hydroxyalkoxy-cyclopentenone received from example

4- {-Tetrahydropyran-2'-yloxyalkoxy) -cyclopent-2-en-1-one-

ester

772

773

732

733 l \ -ß _r «T« 4-r », fey d ropy ran-2 ⁽ -y loxy thoxy-2- (6-carbo-ri-decyloxyhexyl) cyclopent-2-en-1-one

4-ß-Tetrahydropyran-2'-yloxypropoxy-2- (6-carbotetrahydropyran-2'-yloxyhexyl) cyclopent -2-en-l-on

409811/1203

Example 774

Preparation of 4- (4-hydroxybutoxy) -2- (6-carboxyhexyl) -cyclopent-2-en-1-one "" · *. *

A solution of 56 _f O g of crude 4-bromo-2- (6-carboxyhexyl) -cyclopent-2-en-l-one in 400 ml tetrahydrofuran and 133 ml of water at 3 ⁰ C is added under stirring with 44.1 g (0.226 Mol) silver fluorate added for 25 minutes. The mixture is stirred for 60 minutes at 0 to 5 C / diluted with water and ether and filtered. The aqueous portion of the filtrate is saturated with solid sodium chloride and extracted with further ether. The combined organic phases are washed successively with water and saturated sodium chloride solution, dried over magnesium sulfate and concentrated. Column chromatography of the residue gives the above compound as a mixture with 4-hydroxy-2- (6-carboxyhexyD-cyclopent-2-en-1-one, NMR (CDCl ₃ ) 3.60 (multitiplet, O-methylene hydrogen) and 4.60 f (multiplet, O-methine hydrogen).

Example 775

Preparation of 4- (4-tetrahydropyranylbotoxy) -2- (6-tetrahydropyranylcarboxymhexyl) yclopent-2-1-one

Following the procedure described in Example 651, the mixture of 4-hydroxy-2- (6-carboxyhexyl) cyclopent-2-en-ul-one is made and 4- (4-Hydroxybutoxy) -2- (6-carboxyhexyl-2-en-1-one (Example 774) from the compound mentioned in 4-Tetrahydropyranyloxy-2- (6-tetrahydropyranylecarboxyhexyl) -cyclopent-2-en-1-one with dihydropopyran and p-toluenesulfonic acid monohydrate converted into methylene chloride,

409811/1203

Example 776

Production of 2- (6, e-DicarbäthoxyheptyD ^ -cyclopentononmethoxim ^v «■ ·

The compound mentioned is made from sodium diethyl methyl malognate and 2- (5-methanesulfonyloxypentyl) -2-cyclopen- / tenon methoxime prepared according to the procedure described in Example 61.

Example 777

Preparation of 2- (6-carboxyheptyl) -2-cyclopentenone methoxime

By saponification of 2- (6,6-dicarbethoxyheptyl) -2-cyclopentenone methoxime (Example 776) with potassium hydroxide the procedure described in Example 20 is 2- {6,6-dicarboxyheptyl) -2-cyclopentenone methoxime whose decarboxylation following the procedure of Example 63 yields the above-identified compound.

Example 778

Preparation of 2- (6-carboxyheptyl) -2-cyclopentenone

The above-mentioned ketone is produced by methoxime cleavage from 2- (6 ~ carboxyheptyl) -2-cyclopentenone methoxime (Example 777) by the procedure of Example 22 obtained.

/ ♦ 0981 1/1203

? 3 3 7 B 8 1

example 779

Preparation of 2- (6-carbethoxyheptyl) -2-cyclopentenone

The esterification of the acid chloride derivative of 2- (6-carboxyheptyl) -2-cyclopentenone with ethanol following the procedure of Example 31 gives the abovementioned compound.

example 779_a

Production of 2- (6-carbethoxy-5-thiahexyl) -l-methoximino- -2-cyclopenten

A mixture of 1.465 g (0.0348 mole) sodium hydride ^; (57.2 percent in mineral oil) and 50 ml of dimethoxyethane are slowly mixed with 4.8 g (0.0347 mol) of ethyl 2-mercaptoacetate under nitrogen and with stirring. The reaction mixture is stirred for one hour at room temperature and then a solution of 7.8 g (0.0231 mol) of 2-Hp-toluenesulfonyloxybutyl-1-methoximino ^ -cyclopentene in 30 ml of dimethoxyethane is added dropwise, whereupon the mixture is stirred at room temperature for 18 hours . The solution is heated to reflux for one hour, cooled and poured into cold dilute hydrochloric acid and finally extracted with ether. The combined ether extracts are washed with brine, dried over magnesium sulfate and evaporated. 7.6 g of the compound mentioned are thus obtained as a yellow oil.

Λ 0981 T / 1203

Example 780

Preparation of 2- {6-carboxy-5-thiahexyl) -2-cyclopentenone

According to the procedure described in Example 22, 2- (6-carbethoxy-5-thiahexyl) -lmethoximino-2-cyclopentene is treated with acetone and 2N hydrochloric acid at reflux temperature, the compound mentioned turns yellow oil produced.

Example 781

Preparation of 2 ~ {6-carbethoxy-5-thiahexyl) ~ 2-cyclopentenone

Following the procedure described in Example 23, by treating 2- {6-carboxy-5-thiahexyl) -2-cyclopentenone with p-toluenesulfonic acid in ethanol the said Ester produced as a yellow oil.

Example 782

Preparation of tetrahydropyran-2-yl-9-oxo-llalpha-tetrahydropyranyloxo-20-triphenylmethoxy-8 -13-trans-prostanoate

In the procedure described in Example 781, 36.8 g (100 mmol) of 8-triphenylmethoxy-1-octyne are dissolved in 50 ml of benzene by treatment with 83.5 ml of 1.2 m diisobutyl aluminum hydride converted into an alanate reagent in hexane and 45 ml of 2.2m methyllithiura in ether. The reagent is stirred with 80 mmol of crude 2- (6-tetrahydropyranylcarboxyhexyl) -4-tetrahydropyranyloxycyclopent-2-en-1-one (Example 651) in 40 ml of ether at 5 to 10 ° for 10 minutes.

4098 11/1203

The mixture is stirred for one hour at ice temperature and 15 hours at ambient temperature, diluted with ether and poured into a mixture of ice and hydrochloric acid with stirring. The organic "phase is separated off, and the aqueous Phase is extracted with ether. The combined extracts are washed with cold η HCl, water and saturated sodium chloride solution washed, dried over magnesium sulfate and removed by evaporation under reduced pressure Solvents freed. The crude product of an oil is obtained; .ymax, 1730 (carbony groups), 1035 (tetrahydropyranyloxy groups), 975 (trans-vinyl group) and 705 cm (triphenylmethoxy group).

Example 783 -. ""

"Preparation of llalpha ^ O-dihydroxy-g-oxo-IS-trans-prosten acid

A 0.05 M solution of crude tetrahydropyran-2-yl-9-oxy-lltetrahydropyranyloxy-20-triphenylmethoxy-8-13-trans-prostenoate {Example 782) in glacial acetic acid / tetrahydrofuran / water (4: 2: 1) is 7 Hours at 45 °. warmed up. The solution is diluted with aqueous sodium chloride solution and extracted with ether. The extract is washed with water and concentrated using toluene to azeotropically remove aqueous acetic acid. The residue is purified by column chromatography on silica gel. An oil is obtained; Ϋ max, 1735 (ketone carbon group), 17Ϊ0 (acid carbon group) and 967 cm "(trans-vinyl group).

40981 1/1203

Example 784

Preparation of ethyl ^ O-triphenylmethoxy-iJ-oxo-IS, 19- dinor-8-13-trans-prostenoate. . j '

A solution of 16.35 g (48.0 mmol) of 1-triphenylmethoxy-5-hexyne (Example 92) in 24 ml benzene is added under stirring with 40 ml of 1.2 M in hexane are added Diisobutylaluminiuinhydrid _f · and the resulting solution is 2 Heated to 50 ° for hours. The solution is cooled, diluted with 35 ml of ether and treated at 3 to 10 ° with 27.5 ml of 1.6 M n-butyllithium in hexane. After 20 minutes at ambient temperature, the alanate solution is cooled to 0 and a solution of 9.53 g (40 mmol) of 2- (6-carbethoxyhexyl) cyclopent-2-en-1-one in 10 ml of ether is added. The reaction mixture is stirred for 18 hours at ambient temperature, diluted with ether and poured into a mixture of ice and 4N hydrochloric acid with stirring. The mixture is stirred for one hour at ambient temperature and the ether phase is separated off, washed successively with water and saturated sodium chloride solution and dried over magnesium sulfate. The residue obtained after evaporation of the solvent is purified by chromatography on silica gel and gives an oil; V max 1735 (carbony groups), 968 (trans-vinyl group) and 705 cm (triphenylmethoxy group).

Example 785

Preparation of ethyl 20-hydroxy-9-oxo-18,19-dinor-13-trans-prostenoate

A 0.05 m solution of ethyl 20-trlphenylmethoxy-9-oxo-18, lo-dinor-13-trans-prostenoate (Example 784 in Elsessig / -Tetrahydrofuran / Water (4: 2: 1) is 9 hours at 45 °

409811/1203

heated .Beifj obtained after evaporation of the solvent The residue is purified by chromatography on silica gel and gives an oil; max 3450 (hydroxyl group), 1735 (carbonyl groups) and 967 cm (trans-vinyl group).

Example 786

Preparation of 20-hydroxy-9-oxo-18,19-dinor-13-trans-prostate acid

A solution of 2.54 g (7.5 raMol) - ethyl-20-hydroxy-9 ~ oxo-18,19-dinor-13-trans-prostenoate (Example 785), 1.49 g (22.5 mmol) of 85 percent potassium hydroxide and 45 ml of water is left to stand for 20 hours at room temperature. After concentration, the solution is diluted with water, extracted with ether, acidified with 4N hydrochloric acid and extracted with ether. The extract finally obtained ; is successively with water and saturated sodium chloride solution washed, dried over magnesium sulfate and concentrated. An oil is obtained in this way; "\) max 1735 (ketone carbon! group), 1710 acid carbonyl group) and 967 cm (trans-vinyl group).

Example 787

Production of ethyl 16-triphenylmethoxy-9-oxo-8-13-trans-prostenoate

By treating the alanate solution by adding 24 ml (0.05 mol) of 2.1 M methyllithium in ether to a Solution of 18.4 g (0.05 mol) of 4-triphenylmethoxy-1-octyne in 25 ml of dry benzene treated with 34.6 g (0.05 mole of 1.45 M diisobutylaluminum hydride in benzene has been made, with 9.5 g (0.04 mol) 2- (6-Carbethoxyhexyl) cyclopent-2-en-l-one according to the procedure described in Example 784 with the exception the chromatography gives 27.65 g of an oily substance

Α0981Ί / 1 203

obtained; ^ max 5.78 (carboxyl groups), 10.25 (trans-vinyl group) and 14.20, u (triphenylmetoxy group).

Example 788

Manufacture of Ethy1-16-hydroxy-9-oxo-I3-trans-pfostenoate

A solution of 26.65 g
8-13-trans-prostenoate (Example 787) in glacial acetic acid / tetrahydrofuran / water (4: 2: 1) is heated to 45 ° C. for 3.5 hours. The one obtained after evaporation of the solvent

The residue is chromatographed on silica gel partially cleaned. Complete purification by partition chromatography produces an oil; / \ raax 2.88 (Hydroxyl group), 5.77 (carbonyl groups) and 10.25 (trans-Viny! Group).

_: Example 789
Preparation of 16-hydroxy-9-oxo-13-trans-prostenic acid

By treating 3.2 g of ethyl ie-hydroxy-g-oxo-IS-transprostenoate (Example 788) in 50 ml of methanol / water (1: 1) containing 1.37 g of potassium hydroxide, according to the example The procedure described in 786 forms 2.76 g of an oil; IR 5.80 (carbonyl groups and 10.25, u (trans-Viny! Group).

Examples 790-936

By conjugate addition of the alanates produced by the treatment of the triphenylmethoxy- (trityloxy) -l-alkyne (in the following Table given) with diisobutylaluminum halide, then with methyllithium have been obtained in the Cyclopentenones given in the table according to the procedure described in Example 782 and by subsequent de-O-tritylation the triphenylmethoxyprostenoate intermediates

409811/1203

using the procedure described in Example 763, the prostate acids also given in the table are obtained Lind -ester produced.

Those isolated and identified in the table as prostate acids Connections are made via the corresponding tetrahydropyran-2-yl esters and those compounds which have free hydroxyl groups in the llalpha position or as part of a llalpha- (omega-hydroxyalkoxy) group are carried over the corresponding tetrahydropyran-2-yl ethers are produced. The hydroxy function in the ß-side chain (the part of the molecule derived from the triphenylmethoxy-1-alkyne) aller The compounds given in the table are present from the outset in the molecule as the corresponding tetraphenylmethyl ethers before. During the treatment with acetic acid (de-O-tritylation stage) the triphenylmethyl ether "as well as the tetrahydropyran-2-yl ether and ester functions hydrolyzed, whereby the corresponding free hydroxy and carboxy groups of the compounds listed in the table develop.

/ »09811/1203

Table 31

example

790 791

792 793 79 ¹ »

795 796

797 798

used cyclopentene !!

2- (6-Csrbä1: hoxyhexy ι). cyclopenta- η-1 ~ οη

2- (6-carbo-n-butyloxy-

hexyl) cyclopent-2-ene

-1-on

2- (6-carboisopropoxy-

hexy1) cyclopent-2-ene

-1-on

2- (6 ~ carbomethoxyhexyl) cyclopent-2-en-l-one

2- (6-carbo-n-decyloxyheDlt ^ l

Tri tyloxy-1-alkyne used of example

113 96

98

105 102 106 109

obtained or obtained hydroxyprohenic acid or ester

Ethy I ~ 9 ~ oxo-16 ~ hydroxy ~ 20 ~ nor-13- trarie « -prostenoate

νprostenoate

Ä t hy 1-9-oxo -17-hyd roxy-19.2 O-d Ino r-13 - trans- -prostenoate

j £ ethyl ~ 9 -oxo -2 O-hyd roxyme thyl-13 - tear - -prostenoate

Butyl- ~ 9-oxo-16-hydroxy-19 -methyl-13- trans- -prostenoate

I sop ropy 1-9-oxo -17-hy d roxy-16-ä t hy 1 -13- ^ rans- -prostenoat '

Methy 1-9-0X0-20- (3-hydroxypropylJ-13-trans- ' -prostenoate *

, Pecyl ~ 9-oxo-16-hydroxy-13- tran3 -p, roetenoate

Tabel

31 (cont.)

799

Example used cyclopentenone

2- (3-Carbethoxypropyl) • cyclopent-2-en-1-one

2 ~ (7-carboethoxyoctyl) · cyclopent-2-en-1-one

2- (5,5-dimethyl ~ 6-carbo- Ethoxyhexyl) cyclopent-2 ~ l

800 801 O to 802 OO
. X X
"V. 803 fO O 804 805 806

2- (5-oxa-6-carbethoxy- · hexyl) cyclopent-2-en-1-one

2- (5-Carbethoxypentyl) -cyclopent-2 ~ en-l-one '

from example "· '593

2- (7-Carbethoxyheptyl) -cyclopent-2-en-1-one

used .. trityloxy-1-alkyne of example

103 93

101

93

108 93

593

obtained or obtained hydroxyprostenic acid or ester

Ethyl 5,6,7-trlnor-9-oxo-20 ~ {2-hydroxyethyl) -13- trans -prost enoate.

trans -prostenoat

Ethyl-7a, 7b-bishomo-9-oxo-19,20-dinor-16- -hydroxy-13-trans_prottenoate> ,

5,3-dimethyl ^ -oxo-ie-hydroxy-ethyl-SO 13 trans -prostenoat

Ethyl-3-oxa-9-oxo-16 ~ hydroxy-13-trans- ςρ

-prostenoate% r

Ethyl 3-oxa-9-oxo-19-hydroxy-20-nor-13- - trans -prostenoate

Ethyl 7-nor-9-oxo-16-hydroxy-13-tran £ - -prostenoate.

Xthyl-7-nor-9-oxo-16-methyl-17-hydroxy-18,19J20-trlnor-13- tran3 -pro3tenoate

S.'thyl-2-fluoro79-oxo-16-hydroxy-13-tran £ - -prostenoate * _u

-13- trans -prostenoate

Table 31 (cont.)

example

Cyclopentenone used

809 as for example 808 £ 10 of example 598 811

812

η Ii

598

2- (6-carb ethoxy octy I) -cyclopent-2-en-1-one

813 vfcn Ex. 779

781

815

H Il

816 "

817. "

818 "

781

781

679

680

Trityloxy-1-alkyne used of example

93 ^{; :} 107 113; ■ 93

93

113 '110.

93

93

obtained or obtained hydroxyprohenic acid or ester

Ethyl-7a ~ homo-9 ~ oxo-16-hydroxy-13- trana- -prostenoate -

Ethyl-2-phenyl-9-ox ~ o-16 "hydroxy-13- trans- -prostenoate *

-nor-13 trans -prostenoat>

Ethyl 2-ethyl-9 ~ oxo-20-hydroxy-13 -tran3 ~ -prostenoate,

& thyl-2-methyl-9-oxo-16-hydroxy-13 ~ tran £ - γ *

-prostenoat ■ '' 9

Ethyl - ^ - thia-g-oxo-ie-hydroxy-l ^ -trans - '-prostenoat

Ethy 1-3 -1hla-9-oxo-2O-hydroxy-13-tran £ - -prostenoate

Ethyl ^ -thla-g-oxo - ^ - hydroxy-ie-methyl- ^, 20 · -dlnor-13- trans -prostenoate

& thy 1-9-0x0-1104 thoxy-1S-hydroxy - ^ - trans - -prostenoate. ₍ .

Methy1-9-OXO-IIa-methoxy-16-hydroxyrl3 ~ tran3 - -prostenoate

Table 31 (cont.)

example

Cyclopentenone used

819 BC Example 680

820 «

821

822 "

823 "

824

825

826

827

828

681 682 686 688 690 692 69t 697 699

used trityloxy-1-alkyne from example

113

100

109

113

93

101,

106

105

obtained or obtained hydroxyprohenic acid or ester

Methyl-9-QXO-IIa-methoxy-20-hydroxy-13- trans -prostenoate

-17-hyd roxy-13-_trans-p rost enoa t

Ethyl ~ 9-oxo-lla-isopropoxy-5 "6.7" 19,20-pentanor-16-hydroxy-17 »-methyl-13 -trans prostenc" t

Ethyl-9-oxo-7a »7b-Mshomo-lla ~ isopropoxy-16 ~ -hydroxy-18,19, 20-trinor-13- trans -prostenoate

yygyy-hydroxy-18,19,20 ~ trinor-13-trans-prostenoate

"Athyl-3» ^ - -hydroxy-13-Jbrans_-prostenoate

£ ethyl-3-oxa-9-oxo-llct · &; thoxy-16-hydroxy-13- trans -prostenoate

Ethyl-2-fluoro-9 ~ oxo-lla-propoxy-19-hydroxy-20- -nor-13-trans-proatenoat »

yl-7-nor-9-oxo-lla -8ec ~ butoxy-16-hydroxy-19-methyl-13-trjBUT £ -prostenoate

^< ίithyl-7a-homo-9-oxo-llα-raetho> xy-.17-hydroxy-19.20- »di, nor-13-tran3-prostenoate

Table 31 (ports.)

example

830

831

835

836 "

837 ■

838

839

Cyclopentenone used

829 by Bei-sp ;. 700

701

702

O 832 η η 703 (O
approx
k 833 π η 7 ^ 8 χ
fo
O S3, η τ *.

734

735

736

737

738

used trityloxy-1-alki.n of example

^93: 93 93rd

93 113

99 102

110 96

101

obtained or obtained hydroxyprohenic acid or ester

ethyl-2-phenyl-9-oxo-lla-sithoxy-16-hydroxy- -2 0-methy 1- 13- * t rans- rust enoate.

Butyl-9-oxo-lla ~ me "thoxy-16-hydroxy-13- trans · » -prostenoate · ^rr "

Isopropyl ^ -oxo-lla-methoxy-ie-hydroxy-l ^ - -JiriköS -proet enoat. -

Decyl-9-oxo-lla-methoxy-16-hydroxy ~ 13 -tran3 -go -prostenoate ν,

9-Oxo-11α-methoxy-16-hydroxy-Ij5 - trans-ρ rust " acid '.' "

cn ι co

9-Oxo-lla-methoxy-20-hydroxy ~ 13-tLcan ^ -pro · - O stenr acid K

6 _> 7-Dinor-9-oxo-lla-methoxy-16-hydroxy-20- -ethyl-13- trans -prostenic acid I.

i 6, T-

-Mthoxy-20-hy'droxymethyl-

-13- trans -prost acid

7a, 7b-Bishomo-9-oxo-llα-methoxy-16-methJ5rl-17- -hydroxy-19,20-dlnor-13-trans-p rosten »säure1_Z

thyl-S-oxo-lla-methoxy-ie-hyd.rqxy-SO-aor- -13 - trans - ρ ros te η Jg '^ xieZ ^ S

-nor-13-trans-prostenric acid

Table 31 (cont.)

example

841

used cyclopentone

840 v. Ex. 739

740

842 " ■ 1 741 4 0 9 8 1 843 " π "742 844 " ti 743 ro
ο
**> 845 " H 744 846 « ti 745 847 " Il 746 848 " η 747 849 " Il 651

-trityloxy-1-alkyne used of example

obtained or obtained hydroxyprohenic acid or ester

93 103 104 106 107 93 93

113 94

93

^ -Oxa-g-oxo-lla-methoxy-lG-hydroxy-lJ-trans ^ - -p rost en acid-

2-Fluoro-9-oxo-11a-methoxy-20 >> (2-hydroxy, thyl) -13- trans -prostenic acid

7-Kor-9-oxo-lla-methoxy-2Q ~ (3 ~ hydroxypropyl) - t

-13- trans -prostenic acid 'u

7a-H omo-g-oxo-lla-methoxy-ie-hydroxy-lS-methyl- -lj-trans-prostenic acid ■■ '-

2-phenyl-9-oxo-llct-methoxy-16-ethyl-17-hydΓOxy- -19,20-dlnor-13- trans -prostenic acid

g-oxo-lla-ethoxy-ie-hydroxy-lj-trans- -prostenic acid - ^r

9 ~ Qxo ~ lla-propoxy ~ 16-hydroxy-13 " trans -prQ" standing acid · :. . ·,

9-oxo-lla-isopropoxy-20-hydroxy-13-transr

9-Oxo-lla-ri-butoxy-16-hydroxy-19,20-dinor-13-

- trans -prosten acid; ". · ■ -

_% 9 -Οχο-ΙΙα -hydroxy- 16-hydroxy ~ 13-trans-prostenic acid - '

example

Cyclopentenone used

850 v. Ex. 651 851

651

852 " η 651 O
(D
OO 853 " Il 651 —K
X 3 5I4 «ι Il 651 O 855 » Il 651 856 .. η 651 857 " η 651 858 » 'Il 651 859 " η 651

Table 31 (cont.)

Trityloxy-1-alkyn-n used of example

obtained or obtained hydroxyprohenic acid or ester

105

106

107 100 101 102

110

9-QXO-lla-hydyQxy-16-hydroxy ~ 20-nor - 13- trans - -p roste rv say.re. ~ j.

yyyy ^^ -dinor-l ^ - trans -prosten "acid _ '

g-Oxo-lla-hydroxy ^ lX
-trans-prosten acid

9-Oxo-lla-hydrqxyj ₁ 16 _r hydroxy-19-niethyl-15- - trans -ρrosten __ acid_ '

yy
-15 - trans -p ro st en __ acid

-lT- thyl-20-nor- , co -19.20-dinor-15-

9-Oxo-lla-hydroxy ~ 19-hydroxy-20-nor-13- trans- prostic acid

9-Oxo-lla-hydroxy-20-hydroxyinethyl-13-trans_- -prosten acid _

9TOxo-lla-hydroxy-20- (3-hydroxypropyl) -13- - trans -prosten acid T * "

9-0xo-lla-hydroxy> 16-methyl-17-: hydroxy-19.20 -dinor-l ^ -trans-prosten acid "·

Table 31 ( _For ts.)

example

Cyclopentenone used

860 v. Ex. 652

861 "" 653

π ι »

862 654

863 "" 654

864 "" 654

865 " ^M 655

866 "" 656

867 "" 656

868 - · "" 657

869 " ⁿ 658

used trityloxy-1-alki, n of example

obtained or obtained hydroxyprohenic acid or ester

99 113

93 113 102

93 113

93 108

9-0 xo-lla-hydroxy-6,7-dinor _j: 16-hydroxy-20- - ethyl-lj? - trans -p rost en '^ "1

9-oxo-lla-hydroxy-5 » ^6. * _ 7-trinor-20-hydroxy-13- - trans -prostenic acid

9-Qxo-lla-hydroxyy7jL _i J ^r b-bishonio-16-hydroxy-13- - trans -prost acid,.

9-oxo-lla-hydroxy-T'a.i ^ b-bishomo ^ O-hydroxy-lJ- ^

-t ran s -prosten jäure · , CjJ

9-oxo-lla-hydroxy-Ja-j, 7 ^b _i? JL ^s * ^loino ~ 20-hydroxymethyl-cn -1 ^ - trans- prosten · acid °°

ya-ethyl-jLe ^ hyd.roxy-18,19,20- -trinor-13- trans- proaten · säurjL '/> ·

9-Cκo-llαrhydroxy-3,5 ^ diInethyl- · 16-hydroxy-13 "f -trans -prosten acid _t

9 Q "co-lla trans -prosten

9-Qco-lla-hydroxy ~ 3-oxa-IS-hydroxy-13 -tran3 · »-prosten

9 .- 'Cxo-llα-hydroxy-2-fluoror ^ ~ 16 ^ methyl-17-hydroxy-18,19,20-trinor-13 -trans ~ prostQn's acid

Table 31 (cont.)

example

Cyciopentenone used

v.ex. 659 871

872

Il H

£ 873

S 875 "

876

877

878

879

■ ι η

η η

660

661

• 662

662

663

663

664

665

666

Trltyloxy-1 -alki'n used of example

93. 93 99 93

113 93

113 93

102

106

obtained or obtained hydroxyprohenic acid or ester

-prosten '"s'ä.urel." ._ ·

9-oxo-lla-hydroxy ~ 7 & -homo-16 ~ hydroxy-13- tran3 · - -prosten ^ ZT

9-Oxo-IIIa-hydroxy-2-phenyl-16 ~ hydroxy-20- ~ ethyl-13- trans ~ prosten'_ acid · _

9-Qxo ~ lla ~ hydroxy-2 ~ methyl - 16-hydroxy-13- - tra na-prosten "acid" · ■

9-0xo-llα-hydroxy-2-methyl-20-hydroxy-13- - trans -prosten "acid _._

Ethyl-g-oxo-lIa-hydroxy-lS-hydroxy - ^ - trane - "^

-prostenoati, ■ «

Kfchyl ~ 9-oxo-lla-hydroxy-20-hydroxy-13 - ^ ran £ - -prostenoate

Methyl-9-oxo ~ lla ~ hydroxy- »16-hydroxy-13- trana - -prostenoate

"thyl-9-oxo-lla-hydroxy-6,7-dinor-20-hydroxymethyl ~ 13 ~ trans -pro3tenoate · · '

' . * ·>'Thyl ~ 9-oxo-13ja-hydroxy-5,6 _J 7-trlnor-16-hydroxy-ig-methyl-l ^ trans prost'enoat

Tabel

31 (cont.)

example

Cyclopentenone used

880 B.C. Reispl. 667 881

882 "

887 "

888 "'

889

668

669

O 883 ti Il 670 CO OO - Λ
i. 884 11 η 671 N> 885 η π 672 O CO 886 673

674

675

675

used trityloxy-1-alkyne from example

obtained or obtained hydroxyprohenic acid or ester

101 107 105 102.

113

97 105

93 113

-hydroxy-20-nor-13- trans -prostenoate

. ^ ethyl-9-oxo-lla-hydroxy-2- ^ ethyl-16-hydroxy- ~ 17-ethyl-20-nor-13- trans -prostenoate

jethyl-9-oxo-IIIa-hydroxy-3,3-dimethyl-17- -hydroxy-19,20-dinor-13-Jbrans-prostenoate

rthyl-9 ~ oxo-lla-hydroxy-3-oxa ~ 20-hydroxy-

methyl-13- trans -prostenoate /

jίthyl-9-ΌXo-lla-hydroxy-2-fluoro -20-hydroxy- -l ^ - trans -prostenoate ^%

Ethyl-9-oxo-lla-hydroxy-7-noΓ-16-hydroxy-20- -methyl-15-Jbrans-prostenoate

Ethyl- ~ 9-oxo-lla-hydroxy-7a-homo-16-hydroxy- -17-methyl-19i20-dinor-13-trans_-prostenoate

Ethyl-9-oxo-lla-hyidroxy-2-phenyl-17-hydroxy- -19,2Q-dinor-13- trans -prostenpat ·,

-OXO-IIa -hydroxy-1ß-hydroxy-l ^ - trans «» -prostenoate _{1 (} · ·.

Buty 1-9 -oxo-11a -hy d roxy-2 O-hyd r oxy- XJ> -trans_- -prostenoat '. ·

CJ ' ¹ CO

Tabel

.21 (cont.)

example

used cyclopentene «!

890 B.C. 676 891 "

892 "

893

89 ¹ »

895

896 "

897

898

899 η

676

677

'677

'708

719

750

751

752

753

inserted

Trityloxy-1-alkyne from example "

93, 113 · ^;

93 113

93 113 102 106

93

obtained or obtained hydroxyprohenic acid or ester

Isopropyl-9-oxo-lla ~ hydroxy-16-hydroxy-13- - trans -prost enoate. ■

Isopropyl-9-oxo-lla-hyclroxy-20-hydroxy-13 ~ -trans-ρrostenoat

Decyl-9-oxo-lla-hydroxy-16-hydroxy-13-t £ ans_- -prostenoate. '

Decyl-9-
-prostenoate

Ethyl-9-oxo-lla- ^ b-butyloxy-16-hydroxy-13- ^ rans- ~ -prostenoate

Ethyl- 9-oxo-lla-(β-hydroxyethoxy) -16-hydroxy- -13- trans -prostenoate

Methyl 9-oxo-llct * - (β-hydroxyethoxy) -20-hydroxy- / -13- trans -prostenoate

Ethyl-9-oxo-lla- (- / - hydroxypropoxy) -6,7-dinoi- -2 0-hyd roxyraethyl-15-tjrans_-p ros t enoate

Ethyl-9-oxo-IIIa- (β-hydroxyethoxy) -5, 6,7-trinor -, - 16-hydroxy-19-methyl-13-trans_-prostenoate

9-oxo-lla- (ß-hydroxyethoxy) rl6-hydroxy-15- -trans-prostenoat /

Table 31 (cont.)

example

Cyclopentenone used

v.ex. 753 901
902

ο 903 "

η π

905

""

907

908

Κ η

"

753

753

753

753

751

755

757

757

756

Tri tyloxy-1-alkyne used, of example

113 100 101 102.1θ6 10 * 1 107 93 100

105

obtained or obtained hydroxyprohenic acid or ester

9-0 xo-ila- (ß-hydroxyethoxy) -20-hydroxy-13- - trans -prostenic acid

9-Oxo-IIIa- (β-hydroxygthoxy) -17-hydroxy-18,19,20-trlnor-13- trans -prosten IT acid

^ (ß-hydroxy äthj ^ y ^ J ^ hyd roxy-20- -nor-13- trana prosten ~ acid_ ^ J

9-Oxo-lla- (ß-hydroy ^; äthgx5) -20-hydroxymethyl- -13-trans ^ -prosten / säurje i '

- (ß-hydroxy ethoxy) -le- -methyl-13-trans-prostenic acid

9-nxo-lla- (ß-hydroxy-ethoxy) -β. 7-dlnor-20- -

- (5 ~ hydroxyp ropyl) -13 -t rans -prosten , acid ■ ^

9-Cxo-lla- (β-hydroxy ethoxy) -5,6,7,20-tetranor; - -18-hydroxy-17-ethyl-13- t rans -p rosten'gjjire.

9- Qjco-lla- (ß-hydroxy ethoxy) -Yes. Jb-bishomo-16- -hydroxy-13- trans -prosten ', __ ^u _ ·.

9-Oxo-LLA (ß-hydrox4 thoxy) -7a, _{7b.-bishomo: O:} 8r_ .. -'hydroxy-19,20-dinor-13 -trans -prosten säure_- ■

Ethyl-9-oxo-lla- (ß-hydroxyethoxy) -7a, 7b-bishorao-17-hydroxy-19,20-dinor-13- ^ ran £ -

-prostenoate

Table 31 (F _loc .)

example

911

η η

912 »

913 "

915

916

917

918

η π

Cyclopentenone used

910 v. Ex. 759

758 758 760 760 761 763

762

764

Trityloxy-1-alkyne used of example

obtained or obtained hydroxyprohenic acid or ester

95

93 113

93 105 101 110

93 93

χ thy 1-9-OXO-IIa- (■ / -hydroxypropoxy) -2-ethyl- -16-hydroxy-18,19,20-trinor-13-trans- -prostenoate

9t> xo-lla- (β-hydroxy ^ hoxy) -2 ~ ethyl-16-hydroxy- -13- trans -prosten "acid ~ T ~;

9-0 χο-ΙΙα- (β-hydroxygthoxy) ^ - ethyl-iO-hydroxy- -13- trans -prostenic acid j

9-Oxo-LLA (ß-hydroxyethoxy) -3,3-dimethyl-16-hydroxy-13 -trans -prostensaüre ™,

9-oxo-lla- (ß-hydroxyethoxy) -3,3-dimethyl-17 _j: -

-hydroxy-19,20-dinor-13- trans -prosten; acid. , **

Ethyl 9-oxo-LLA (ß-hydroxyethoxy) -3,3-dimethyl - ^ - hydroxy ^ O-nor-r ^ -trans -prostenoat

Ethyl 9-oxo-lla- (V-hydroxypropoxy) _T 3-oxa-16-

-methyl-lT-hydroxy-ig ^ O-dinor-l ^ -trans- -prostenoate

9-Oxo-lla- (ß-hydroxyathoxy) -3-oxa-16-hydroxy- -13- trans -prostenf acid__

9-0xo-lla- (ß-hydroxyethoxy) -2-fluoro -16-hydroxy- -13-trans-prosten acid 'y' · · #

Tabel

31 (cont.)

example

919 v. Ex.

920

Cyclopentenone used

921

η κ

927

928 "

764

765

ο 922 Il Il 766 IO OO
ι
λ 923 Il π 767 ro 924 η π 768 ο 925 π Il 769 926 Il Il 770

Il Il

770

771

used trityloxy-1-alkyne from example

113,

99.:

102 98

93 101

'93

93 '113 93

obtained or obtained hydroxyprohenic acid or ester

9-0χο-11α- (ß-hydroxyethoxy) -2-fluoro-20- -hydroxy-13- trans -prostent acid

9-OJco-lla- (ß-hydroxyethoxy) -2-fluoro-16 ~ __ -hydroxy-20-ethyl-13- trans -prosten säure_jL

Ethyl 9-oxo-llq- (ß-hydroxyethoxy) -2-fluoro- -2 Ö (2-hydroxy-thy 1) -13 -trans -prostenoat

- (ß-hydroxyethoxy) -77 nor »16-hydroxy- ^

9-Oxo-lla- (ß-hydroxyethoxy) -7p-horao-16-hydroxy- c · '-l ^ - trans -prostenggure co

9-0xo-lla- (ß-hydroxyethoxy) -2-phenyl-19n_ * "-

r-20- "~

Ethyl 9-oxo-lla- (ß-hydroxyethoxy) -2-phenyl-16- -hydroxy-13- trans -prostenoate

Butyl-9-οχο-ΙΙα- (ß-hydroxyethoxy) -16-hydroxy- -13- trans -prostenoate ^

Butyl-9-oxo-LLA (ß-hydroxygthoxy) -20-hydroxy- trans -13 -prostenoat '

Isopropyl-9-oxo-IIIa- (β-hydroxy-thoxy) -16-hydroxy -13-trans-prostenoate

Table 31 (cont.)

example

.used Cy ₁ C lopen tenon

771

930 Il Il 772 931 η Il
Il 772 4 0 9 8 1 1 932
933 Il
Η Il 773
773 / 12 0 93 * « Il 773 935 Il Il 775 936 Il 775

Trityloxy-1-alkyne used of example

obtained or obtained hydroxyprohenic acid or ester

113 93

113 93

113

110

93 113

Isopropyl 9-oxo-IIIa- (β-hydroxyethoxy) -20- -hydroxy-1 ^ - trans -prostenoate

Decyl 9-oxo-IIIa- (β-hydroxyethoxy) -16- -hydroxy-1 ^ -trang -prostenoate

Decyl 9-oxo-IIIa- (ß-hydroxyethoxy) -20-hydroxy- -13- trans -prostenoate

9- ^0l xo-lla- (ß-hydroxypropoxy) -16-hydroxy-13- - trans -prosten_ ^s. Acid_ '

9- ° txo-lla- (ß-hydroxypropoxy) -20-hydroxy-13- - trans -prostenic acid "" · "

9- ⁰ XO-IIa- (ß-hydroxypropoxy) -16- ethyl-17-

-hydroxy-19> 20-dinor-l · ^ - trans -prostenic acid

(jn oa

9 ~ ° XO-Ha - (^ - hydroxybutoxy) -16-hydroxy-13- - trans -prostenic acid

9- ^Q .xo-lIja- ( ² l-hydroxybutoxy) -20-hydroxy-13- tranG - -prostenic acid. "....

Examples 937-960

Saponification of the alkyl esters given in Table 32 according to the procedure described in Example 283 gives the Prosten acids according to the same table.

0 9 8 1 1/1203

example

937 938

939 940 941 942 94-3

945 946

947 948 949 950

951

23375 81 lie 32 9- ° ixo-20-hydroxy-13-trans-
prosten <acid - 220 - used alkyl
prostenoat of preserved
Example hydroxy-prostenic acid 9-o-xo-16-hydroxy-20-nor-13-
-trans-prosten ^ acid T a b e 790 go-xo-ie-hydroxy ^ O-methyl-
-13-trans-prosten _S änr <= ' 791 9-0 xo-17-hydroxy-19,20-dinor-
- ^ - trans-prostenjsänr * = »- \ 792 9-oxo-20-hydroxymethyl-13-
-trans-prosten · acid 'Z 793 9-oxo-20- (3-hydroxypropyl) -
-13-trans-prostenic acid '_j 794 5,6,7-trinor-9-oxo-20- (2-
-hydroxyethyl) -13-trans-pro-
stenic acid ~ * "* ~ 797 7a _> 7b-Eishomo-9-oxo-16-hydroxy-
-13-trans-prosten acid ■ 799 7B ^ b-BiShOmO-Q-OXO-Ig, 20- 800 801

802

803 804

805 8O6

807

7.7 99,

-dlnor-ie-hydroxy - ^ - trans - - rusting acid ^ '.

3,3-whore thyl-9-oxo-16-hydroxy- 1-20- 'thyl-13- trans -prosten; -J_

acid

3- Qca-groxo-ie-hydroxy-lJ- - trans -prosten _r acid

-13- trans -prost

7 gp ^

- trans -prostenic acid

7- Nor-9-oxo-16-raethyl-17- -hydroxy-iejig. ^ O-trinor - ^ - - trane -proste η acid

2-Eluoro-9-oxo-16-hydroxy-13- -trans-ρraetene acid

0 9 8 1 .1 / 1 2 0 3

808 2337581
- 221 - 7aΉ omo-9-oxo-l8-hydroxy-19 #
20-dinor-13-trans-prosten- ^r
Acid _ 809 Table 32 (cont.) 7a-H.omo-9-oxo-16-hydroxy-13-
-trans-prosten acid example 810 used alkyl
prostenoat of preserved
Example hydroxy-prostenic acid 2-p'henyl-9-oxo ~ 16-hydroxy-13-
-trans-pro8teno $? S "»! 5cfcä !: acid 952 811 2-phenyl-9-oxo-16-hydroxy-17-
- ethyl-2.0-nor-l3-trans-
-Protenic acid 953 "812 2-? Ethyl-9-oxo-20-hy_droxy-13-
-trmne-proitenqijnre - 95 ^ 813 2 4t ethyl-g-oxa-rie-hydroxy - ^ -
-trane-proeten _s CDCR <=> 955 81t 3 τ 1114-9-OXo-IS-HyUrOXy - ^ -
-trftni-proiten acid * - 956. 815 • 3-τ.hiÄ-9-oxo-20-hydroxy-13-
-1 ran β -ρ roe t en · acid " 957 816 3- ^T hia-g-oxo - ^ - hydroxy-ie-
-methyl-ig ^ O-dinor - ^ - trans- 958 95? . 960

409811/1203

Examples 961

Production of 16-hydroxy-9-oxo-prostanoic acid

A solution of 1.4 g (4.3 mmol) lo Prostenic acid (Example 789) in 45 ml of absolute ethanol is hydrogenated using 650 mg of 10% palladium on carbon. Filtration and then evaporation of the solvent gives 1.31 g of the above-mentioned compound as one oil; A max 5.78 (ketone carbonyl group) and 5.82, u (acid carbonyl group).

Examples 962-1060

By hydrogenation of the 13-prostate acids and esters listed in the table below according to that described in Example 961 Procedure, the prostanoic acids and esters also given in the table are produced.

409811/1203

ORIGINAL INSPECTED

- 223 table

13-prostatic acid used or

example -ester ve 962 803 963 8OiT 96H 805 965 806 966 * 807 967 809 968 810 .969 812 970 813 971- 790 972 791 973 792 974 793 975 ι
r 794 • *%
976 795 977 796 978 797 979 780

40981 obtained as prostanoic acid or esters

Ethyl-3-oxa-9-oxo-16-hydroxy- -prostanoate

£ ethyl-3-oxa-9-oxo-19-hydraxy- -20-nor-pjpos'tanoät '

Ethyl 7-nor-9-oxo-16-hydroxy -'-prostanoate

gthyl-7-nor-9- ° xo-16-methyl- -rf-hydroxy-iejO ^^ O -prostanoate

Ethyl 2-fluoro-9-oxo-16- hydroxy prostanoate

y9 -hydroxy-pyrostanoatt

Ethyl-2-phenyl-9-oxo-16-. -hydroxy prostanoate

Ethyl 2-ethyl-9-oxo-20- -hydroxy-prostanbat

Ethyl-2-methyl-9-oxo-16- -hydroxy prostanoate

Ethyl-9-oxo-20-hydroxy- -prostanoate.

iithyl-9-oxo-16-hydroxy-20- nor-prostanoate

* ~ 9 -oxo-16-hydroxy-20- -methyl prostanoate

lithyl-9-oxo-17-hydroxy-19.20 -dinor-13-prostanoate.

i> ethyl-9-oxo-20-hydroxymethyl -prostanoate

-methyl ^ prostanoate

Isopropyl-9-oxo-17-hydroxy-16 · -ethyl pröstanoate

Methyl 1-9-0x0-20- (3-hydroxypropyl) -prostanoate "·

Decyl 9-oxo-16-hydroxy-prostanoate

1/1203

37 &

Table

33 (cont.)

987

991

13-prostatic acid used or

example
980 -ester
781 981 782 982 783 983 . 784 984; 817 985 * 818 986 819

820

988 821 989 82-2 990 823

received as
Prostanoic acid or esters

Ethyl 5, e, 7-trinor-9-oxo- -Z 0- (2-hydroxyethyl) - -prostanoate

jsthyl 7a, 7b-bl8homo-9-oxo- -16-hydroxy-drostanoate *

S., thyl 7a, 7b-bishomo-9-oxo- - ^^ O-dinor.-ie-hydroxy- -prostanoate

Ethyl 3,3-dlmethyl-9-oxo-16- -hydroxy-20-ethyl-prostanoate

£ thyl 9-oxo-lla-ethoxy-ie- -hydroxy-proBtanoate '

992 - ■ 832 993 • 833 994 834 995 837 996 838 997 839 40981 1/1 5Π9

Methyl g-
-hydroxy prostanoate

Ethyl 9-oxo-7a, 7b-bishomo-lla- -lBopropoxy-ie-hydroxy-ie, 19 * 20-trinor-prostanoate

Ethyl 2-ethyl-9-oxo-lla- -butoxy-16-ethyl-17-hydroxy- -18,19,20-trinor-prostanoate

Ethyl 3,3-dimethyl-9-oxo-lla- methoxy-2 0-hydroxy-propo stanoate

Ethyl 3-oxa-9-oxo-lla-3thoxy- -16-hydroxy-prostanoa t

Ethyl 2-fluoro-9-oxo-lla-. · -Propoxy-ig
-prostanoate

Ethyl 7-nor-9-oxo-lla-sec- -butoxy-ie-hydroxy - ^ - methyl- -prostanoate

Decyl 9-oxo-lla-methoxy-16- -hydroxy prostanoate

9- ° xo-lla-methoxy-16-hydroxy- -prostanoic acid ''

9-oxo-lla-methoxy-20-hydroxy-prostane. " _Acid

7a, 7b-B ishomo-9-οχο-ΙΙα- -methoxy-16-raethyl-17-hydroxy- -19,20-dinor-prostanoic acid

2-ethyl-9-oxo-llα-methoxy-16- -hydroxy-20-nor-prostaric acid

3,3- ^D imethyl79-oxo-lla-methox. \ _I -lg-hydroxy ^ O-nor-prostan f

Debris

example
998

999

1000

1001

1002

1015

1016

.1λ * ^Λ ο "ϊ" 3 7 R R1

13-Pro- used received els stenic acid or prostanoic acid odsr ester -ester of example

840

841

842 _H.

. 843

844

1003 .845 1004 846 1005 847 1006 848 1007 849 1008 850 1009 852 1010 853 ion 855 1012 856 1013 " 857 1014 858

859

860 'Xa-9-oxo-lla-methoxy ~ 16-

2-fluorine-9-oxo-lla-methoxy- -2 0- (2-hydroxy-ethyl) -proatanic acid '~

7-tfPor-9-oxo ~ lla-methqxy-20-

- (3-hydroxypropyr) -prostan - _J acid

7a-i ^ .omo-9-oxo-llα-methoxy-16- -hydroxy-19-methyl-prostane> acid_

2-ί> henyl-9-oxo-lla-methoxy- -16-ethyl-17-hydroxy-19.20- -dinor-prostanoic acid.

9-0 xo-lla-ethoxy-16-hydroxy- -prostanoic acid "

9- ° xo-lla-propoxy-16-hydroxy-

9-0 xo-lia-isopropoxy-20-. -hycjroxy-prostarv Ä

9- £> xo-lla-n-butoxy-16-hydroxy-19 * 20-dinor-prostanoic acid

9-O xo-lla-hydroxy-16-hydroxy- -prostan3äμre

9- ^ xo-lla-hydroxy-16-hydroxy- -20-nor-prostan.acid_

9- Qco-lla-hydroxy-17-hydroxy- -19 , 20-dinor-prostane acid ^ "

g-Qjco-lla-hydroxy-ie-hydroxy- -19-methyl-prostanoic acid

9- ⁰ So-11a-hydroxy-l8-hydroxy-19,20-dinor-proBtan V

9- ⁰ Xo-11a-hydroxy-19-hydroxy -20-nor-prostanoic ~ _'l

9- ° xo-lla-hydroxy-20-hydroxymethyl-prostai> 5 acid _ '

9-0 xo-lla-hydroxy-20- (5-

-hydroxypropyl) -prostane -_

acid

9-Oxo-Ila-hydroxj "-16 -I"-hydroxy-19> 2 ^ - = ainor-prc- ~ stanoic acid

C ¹¹ O '"\' droxy-6 _f 7-DINOR -"^'ä -20- ^{thyl-prostane!} ~

BAD ÖRIGI

example
1017

1018

1026

1032

1033

13-prostate acid or ester used from Example 23315 * 4

obtained uls prostanoic acid or esters

862

863

1019 866 1020 . 867 1021 868 1022 "869 1023 ' 870 1024 871 • 1025 872

873

1027 875 1028 876 1029 '877 1030 ■ 883 1031

885

888

892

1035 893

40981 1/1203 9-Oxo-lla-hydroxy-7a, 7b- -bishomo-16-hydroxy-prostane_

acid_

9-oxo-lla-hydroxy-7a, 7b-

-bishomo-20-hydroxy-prostarv_- J

acid 9-oxo-lla-hydroxy-2 ,, J-dimethyl- -16-hydroxy-p ro stanic acid

9-Oxo-lla-hydrOxy-3, j5-dimethyl- -20-hydroxy-prostanoic acid "*

9-oxo-lla-hydroxy ~ j5-oxa-16- -hydroxy-prostanoic acid ~

9- ° xo-lla-hydroxy-2-fluoro ~ -lS-methyl-lT-hydroxy-lS, 19, 20-trinor-prostanoic acid "" "." * "

9- ^Q xo-lla-hydroxy-7-nor-16-hydroxy-prostane; acid ^

9-oxo-llo-hyd roxy-7 ^a -homo- -16-hydroxy-prostane "acid ~, - ·

9- Oxo-lla-hydroxy-2-phenyl- _ -le-hydroxy-SO-ethyl-prostane; -_

"acid 9-0) co-lla-hydroxy-2-methyl-16- -hy d roxy * -p ro s t a n

-hydroxy-prostanoic acid

Ethyl-9- ° xo-lla-hydroxy-16- -hydroxy prostanoate

^ ethyl-9-oxo-lla-hydroxy-20- -hydroxy prostanoate

Ethyl ^ -oxo-lla-hydroxy - ^ - oxa -20-hydroxymethyl prostanoate

-9-oxo-lla-hydroxy-7-nor -16-hydΓoxy-20-methyl- -prostanoate

Butyl — 9-0x0-1Ια-hydroxy-16- -hydroxy prostanoate

Decyl 9-oxo-lla-hydroxy-16-hydroxy-prostanoate

Decyl-9-oxo-lla-hydroxy-20 ~ -hydroxy-prostanoRt

Sthyl-9-oxo-llc ·· t-butoxy-16-hyd roxy-p rοs t an 5at

example -est 1036 895 1037 896 IO38 ν 899 1039 900 1040 '902 1041 904

1042

1043

1044

Ϊ045

1046

1047

1048

1049

1050

1051

1052

used 13-Pro received as

stenic acid or prostanoic acid odsr -3st: er

-ester of example

Ethyl-9-oxo-lla- (ß-hydroxythoxy) -16-hydroxy-prostanoate

Methyl-9-oxo-lla- (ß-hydroxyethoxy-20-hydroxy-prostanoate

907

908

909

911

912

913

914

917

918

919

922 9- (ß-hydroxy vrfchoxy) - -16-hy d r oxy -p ro stan acid- ■ --'- 7.

9-oxo-lia- (ß-hydroxy -20-hydrOxy-proBtan ^ aure_

9-Θ xo-lla- (ß-hydroxy M: hoxyJ-IO ^ -hydroxy-20-nor-prosten säjure

9-Qxo-lla- (ß-hydroxy ithoxy) - -prostan booze ~] _

9-oxo-lla- (ß-hydroxy thoxy) - -7a, 7b-b ishomo-16-hyd roxy- -prostanoic acid

9-Qxo-lla- (ß-hydroxyethoxy- -19,20-dinor-prostane acid "] ~ j

X.thyl 9-oxo-lla- (ß-hydroxyethoxy) -7a, 7b-b ± shomo-17- -hydroxy-l ^^ O-dinor-prostanoate

9-Oixo-lla-fß-hydroxyethoxy) - 2 thyl-lb-hdt ^

säür ¥

-2-ethyl-lb-hydroxy-prostan- ^ J

9-0 xo-lla- (ß-hydroxjä. Thoxy) - -2-ethyl-20-hydroxy-pro-εtane acid

9-0 xo-lla- (β-hydroxy ethoxy) - - 3 > 5 - d ime t hy 1 -16 -hyd r'oxy -prostane acid ^ _ "_ '

9-oxo-lla- (ß-hydroxjä thoxy) -

- ^, J-dimethyl- ^ - hydroxy-l ^^ O -dinor-prostanic acid.

9-oxo-lla- (ß-hydroxyä.thoxyl-3- -oxa-16-hyd roxy-ρ rο stanoic acid

9-oxo-lla- (ß-hydroxyethoxy) -2-

-fluor - * - 16-hydroxy-prostane'-

acid

9-oxo-lla- (ß-hydroxyethoxy) -2- -fluor ~ -20-hydroxy-prostane * -

SaUiC

9-oxo-lla- (ß-hydroxyethoxy) -7- -nor-16-hydroxy-20-raethyl- -prostan '! Tclc;., ^ * ■ · * -

BAD ORtQtNAU

Table 33 (cont.)

example
1053

13-prostate acid or esters used from Example

923 received as
Prostanoic acid or esters

1055

1056

930

931

1057 932 1058 933 1059 ■ 935 1060 936

9-Θ> xo ~ lla- (ß-hydroxyethoxy) -

-Ta-homo-lG-hydroxy-

-p r ο β t of acid ~

9-cxo-lla- (ß-hydroxyethoxy) - -2-phenyl-19-hydroxy-20-nor- -p rostan © aure [

Decyl 9-oxo-llct- (ß-hydroxy-

thoxy) -16-hydrpxy-
-prostanoate

Decyl 9-oxo-lla- (ß-hydroxy- ■

thoxy) -20-hydroxy-
-prostanoate

9-e xo-lla- (ß-hydroxypropoxy) -16-hydroxy-prostanoic acid ""

9- Qco-lla- (ß-hydroxypropoxy) -20-hydroxy-prostane acid * *

9 - ⁰ KO - 11α - ( K -hyd roxjrbut oxy) -16-hydroxy-prostan "acid

9-oxo-1Ια- (4-hydroxybutoxy) - -2 0-hyd roxy-p rostans acid. _w

40981 1/1203

Example 1061

Production of 9alpha, llalpha, 20-trihydroxy-13-transprostic acid

A solution of 459 mg (1.29 mmol) of llalpha, 20-dihydroxy-9-oxo-13-trans-prostenoic acid (Example 783) in 4.0 ml of tetrahydrofuran is mixed with 5.2 ml of a 0.65m solution of lithium perhydro- 9b-boraphenalyl hydride in tetrahydrofuran was added at -78 C under nitrogen. The solution is stirred for 45 minutes at -78 C and 15 minutes at ambient temperature, diluted with 10 ml of water and extracted with ether. The extract is back-extracted with 1/4 η sodium bicarbonate solution. The combined aqueous phases are acidified with 4N hydrochloric acid, saturated with sodium chloride and extracted with ether. The extract is washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated. The residue is purified by thin layer chromatography on silica gel. A colorless oil is obtained; sj max β 3310 (hydroxyl groups), 1705 (acid carbonyl group) and 970 cm '(trans-vinyl group).

Example 1062-1165

By reducing those listed in the table below 9-oxo derivatives with lithium perhydro-gβ-boraphenylalyl hydride following the procedure described in Example 1061, they are also listed in the table 9alpha-hydroxy derivatives generated.

/, 09811/1203

Table 3 4

example
1062 Beisj
790 1063 ■ ■ 79I 1064
IO65 ¹ . 792
* 793 1066 794 IO67 795 1068 796 1Q69. 798 1070- 800 1071 802 1072 803 1073 805 107 ^ 808 1Ό75 809 IO76 810 1077 812 1078 813

used 9-oxo derivative of

obtained 9-alpha-hydroxy derivative

Ethyl-9 <x, 2 0-d! Hydroxy-13- trans -prostenoate

-9di16-dihydroxy-20-nor -13 trans pros choose tenoat

-9a, 16-dihydroxy-20- -methyl-13-t_rans_-pros tenoat

9a, 17-dihydroxy-19,20- -dlnor-13- trans -prostenoate

Kthyl-9a-hydroxy-20-hydroxy-methyl-1 ^ - trans -prostenoate ^

Butyl-9a, 16-d! Hydroxy-19- -methyl-13- trans -pros tenoat '

Isopropyl 9a, 17-dihydroxy-16-ethyl-13- trans -prostenoate

.-9 <*> 16-dihydroxy-13- - trana -prostenoate

Ethyl-7a, 7b-bishomo-9a, 16- -d! Hydroxy-13- trans -prostenoate

;,] Ithyl 3,3-dimethyl-9a, 16-dihydroxy-20-ethyl-13- trans - -prostenoate

^Ä , thyl-3-oxa-9a, 16-d! Hydroxy- -13- trans -proste, noat -

^Ä thyl-7-nor-9, 16-dihydroxy -13- trans -prostenoat

Ä, ethyl-7a-homo-9 <2,18-dihydroxy- -19.20-dinor-13-t_ran_s- -prostenoate

9a, 16-dlhydroxy- -13- trans -prostenoate

'i ethyl 2-phenyl-9a, 16-dihydroxy-17-ethyl-20-nor-13- trans -prostenoate

Ethyl-2-methyl-9a, 16-dihydroxy-13- trans -prostenoatex

Ä: ethyl-3-thia-9a, 16-dihydroxy- -13-trans-prostenoate

A09811 / 1203

2337581 _Ta inserted
derivative of
example - 231 -
belle 34 (cont.) example 815 9-oxo-
received
9-alpha-hydroxy derivative 1079 817
S. 1080 818 1081 819 1082 '822 1083 823 1084 824 1085 826 1086 '827 1087 ■ · ■ · 828 1088 832. " 1089 833 1090 834 1091 836 1092 Ethyl 3-thia-9a, 20-dihydroxy-
-13-trans-proetfcnoat Ethyl lla-ethoxy-9a, X6-di-
hydroxy-13-trans-proßtenoate Methyl lla-methoxy-9a, 16-
-dihydroxy-13-trans-
-prostenoate Methyl lla-methoxy-9a, 20-di-
hydroxy-13-trane-proBtenoate flthyl 7a * 7b-bit homo-lla-ißo-
propoxy-9 <x, 16-dihydroxy-18,19,
20-trinor-13-trans-proßtenoate Ethyl 2-ethyl-lla-butoxy-16-
-ethyl-9a, 17-dihydroxy-18,19,
20-trinor-13-trans-prostenoate jithyl 3,3-dimethyl-IIIa-methoxy
-9a, 20-dihydroxy-13-trans-
-prostenoate K ^ thyl 2-fluoro-9-oxo-lla-pro-
poxy -9a, 19-dihydroxy-20-
-nor-13-trans-prostenoate Ethyl 7-nor-lla-sec-butoxy-9a,
le-dihydroxy - ^ - methyl-lJ-
-trans-prostenoat Ethyl 7a-homo-lla-methoxy-9a, -tranß-prostenoat Decyl lla-methoxy-9a, 16-di-
hydroxy-13-trans-prostenoate lla-methoxy-9a, 16-dihydjjpxy-
-13-trans-prostent acid * " lla-ethoxy-9a, 20-dihydroxy-
-13-trans-prosten.eti'nT · »? 5,6,7-trinor-9a-hydroxy-lla-
-ethoxy-2 O-hyd roxymethyl-13-
-t rans-p rust-acid '

1093

1094

837

838

7a, 7b- ishomo-lla-methoxy-16- -methyi-9a, 17-dihydroxy-19.20 -dinor-13-trans-prosten säü- \

2-ethyl-lla-methoxy-9a, 1 hydroxy-ao-npr- ^ - trans- -prostenic acid

Table 34 (cont.)

example
1095

1096
1097
1098

1106

1107
1108

1109

1110
1111

used 9-oxo derivative of Example

810

811

842

843

1099 .. 845 1100 846 HOl - 847 1102 848 1103 849 1104 850 1105 851

852

853 854

855

856 857, obtained 9-alpha-hydroxy derivative

3-oxa-lla-iiethoxy-9a, 16-dihydroxy-lj-trans-prosten acid "'' ~

2-fluoro-9a-hydroxy-Ua- -methoxy-20- (2-hyd roxyäthyl) - -13- trans -prostenic acid ^ _

7-N or-9a-hydroxy-lla-methoxy- -20- (3-hydroxypropyl) -13- - t rans -prost ere a ure

7a-il.omo-9-oxo-lla-methoxy-9a, 16-dihydro-y-19-methyl-15- - trans -prostenoic acid

Ha- & thoxy-9a, 16-dihydroxy- -13-tran s -prostenic acid.

Ha-4 * ropoxy-9a, 16-dihydroxy- -13- trans -prostenic acid ___

lla-r.sopropoxy-Oxz ^ O-dihydroxy -13-trans-prostic acid 1

lla-n-butoxy-9a, 16-dihydroxy -19,2Ό-dinor-13 trans - rust _-p: acid

9a, lla, 16-5! r ihydroxy - 1J> - 1 ran s -prosteric acid """~

9a, Ha, 16-trihydroxy-20 ^ normal -13- trans -prosten _s äure

9a, lla, 16-trihydroxy-17- -methyl-19,20-dinor-13-t_rans, - -prosten acid "

9a, Ha, i7 ^T rihydroxy-19,20- -dinor- 1J> - trans pros choose th acid

9α, 11α, 16- ^T-rihydroxy 197niethyl- -l3- t rans -ρ stainless acid _ ..

9α, 11α, 16-trihydroxy-17- - ethyl-20-nor-13- trans - -prostenic acid

9a, lla, l8-T.rihydroxy-19,20-_ -dinor-l ^ - trans -prosten ' * ~. acid

9a, Ha, 19- ^T .rihydroxy-20-nor- -13- trans -prostenic acid. "

9a, LLA ^D ihydroxy-20-hydroxy-methyl-13- trans -prosten ^acid

Tabel

3 4 (cont.)

example
1112

1113
1114

1115 "
1116

1117
1118

■

-

used 9-oxo derivative of Example obtained 9-alpha hydroiry derivative.

858 859 860 861. 862 863 865 866 867

1121 868 1122 869 1123 870 1124 871 1125 872 1126 873 1127 874

1128

875 9a, 11a-dihydroxy-20- (3-hydroxy-propyl) "13-trans-prostenic acid".

9a, lla, 17-Trih * ydroxy-16- -methyl-19,20-dinor-13-trans- -toast-

9a, lla, 16-trihydroxy-6,7- -dinor-20-ethyl-13-trans_-

-prosten ^ acid

9a, lla, 20-trihydroxy-5,6,7-_ -trinor-13- trans -prosten 'sa-

_re".,...

9α, 11α, 16-lrihydroxy-7a, Tb- .. -bi shorao-13- trans -pro st ens ä u-

re'',

9a, lla, 20-Trihydroxy-7a, Jb- -bi shomo-13 - trans -p rost en3äu - "_ re" ν

9a, 11,16-trihydroxy-2-ethyl- -18,19,20-trinor-13- trans - -prostenic acid

9a, lla, 16-trihydroxy-3, 3 ^ d ± - methyl-13- trans -prostenic acid ■

9α, 11α, 20-trihydroxy-3,3-dimethyl-13- trans -prostene -

acid "* 9α, 11α, 16-τ rihydroxy - ^ - oxa- -13 - 1 ran s -ρ ro st en .. ^s . ^ ^ur . ^ ~ ._

9α, 11α, 17-trihydroxy-2-fluoro- e-methyl-18,19,20-trinor- -13- trans -prostenic acid

9α, 11α, le-T-rihydroxy - ^ - nor - ^ - - trans -ρrostenic acid '"_

9α, 11α, le-trihydroxy- ^ a-homo- -13- trans -prostenic acid

9α, 11α, 16-Rrihydroxy-2-phenyl- -2Q-ethyl-13- trans -prosten- ^ acid

9α, 11α, 16-trihydroxy _T 2-methyl- -13-trans-prosten 'acid'

-13- tears -prosten acid "

Kthyl 9a, lla, 16-trihydroxy- - 13 .- ^ t. ..ran s -Ό ros tenoic acid

example
1129

1130
1131
II32
,

1134
1135
1136

1137

- ·

*
1140

1143

1144

1145

used derivative of example 876

888

892

• 894

• 895 896

. 899 900 901 902

903 904 907 911 912

⁹¹³ 2 3 3 7 D 3

received. ". te-nes

9-alpha-hydroxy derivative t , Dt, lla, 20-trihydroxy-13-trans-prostenoate

Butyl-9α, 11α, 16-trihydroxy- -13 - t_rans-ρ ro s t en oa t

Decyl 9a, 11a, 16-trihydroxy-13- trans -prostenoate

Decyl ~ 9a, lla, 20-trihydroxy- -13- trans -prostenoate

Sthyl-lla-jb-butoxy-9, 16- dihydroxy-13-tr ans - -prostensäure

Xthyl-lla- (ß-hydroxyathoxy) - -9a, 16-dihydroxy-13-tjrari £ - -prostenoate

Methyr-lla- (ß-hydroxyethoxy) - -9a, 20-dihydroxy-13-_traji £ - -prostenoate

9a, 16-dihydroxy-lla- (ß- -hyd roxye thoxy) -Σ} - trans - -prostenic acid

9a, 20-dihydroxy, - lla - (β-hydroxy-ethoxy) -13-trans-prosten-_ '"' 'acid

9α, 17 -dihydroxy- (ß-hydroxyethoxy) -18,19,2 0-1 rino γ-15- - trans -ρrostenic acid '

9α, 19-dihydroxy- (ß-hydroxy-? Ä t hoxy) -2 0-no r-13 - t_ranis_- ro s ten "sour

9α-hydroxy (β-hydroxyethoxy) - -2 0-hy d roxyme t hy 1-13 - t £ ans_- -prostenic acid "" "'

9a, 16-hydroxy- (β-hydroxy- .ethoxy) -19-methyl-13- trans -prostenic acid

9a, 16-dihydroxy- (ß-hydroxy-? Thoxy) -7a, 7b-bishomo-13- - trans -prostenic acid "

9a, 16-Dlhydroxy- lla- (β-hydroxy ethoxy) -2-ethyl-13-_tran £ - -prosten acid

ga ^ O-dihydroxy-lla-fß-hydroxy-ethoxy) -2-ethyl-13- trar.s - -prostenic acid

9a, 16-dihydroxy-ila- (β-hydroxy

Ä.thoxy) -3,3-dlmethyl-13- -trans-prostenic acid

example
11-6

used 9-oxo derivative of Example

1150

1151

1152

1153

-115 * 1

1155

917

918

922

923

.925

928

930

931

932

935

1156 993 4 0 9 811 1157 997 1158 1017 1159 1013 1160 1020 1161 1024 1162 1033

χ ο j / b 0 1

received

9-alDha-Hv (Tlrnxv (1privai-

9a, 16-dihydroxy-lla- (ß-hydroxyethoxy) -3-oxa-l ^ - trans - -prosten acid "*" ^J "

9a, 16-E> ihydroxy-lla- (ß-hydroxyethoxy) -2-fluoro-13- trans - -proBten acid "^"

9a, 16-dihydroxy-ila- (ß-hydroxyethoxy) -7-nor-2 0-methy.l-_13- ~ trans -p rost en acid.

9a, 16-hydroxy-lla- (ß-hydroxy n thoxy) - 7a -homo -1J> - trans- -ρ ro st en s aür ~ e '~ ~~~

Ethyl-9a, 16-dihydroxy-lla- (ß- -hydroxyethoxy) -2-phenyl-lj- - trans -pro sten acid ""

Isopropyl-9a> 16-dihydroxy-IIIa- (β-hydrpxy thoxy) -l ^ - trans - -prostenic acid "" T

Decyl-9a, 16-dihydroxy-IIIa- (β-hyd roxy gi thoxy) -1 ^ - trans - -prostenic acid

Decyl-9a, 20-dihydroxy-lla- (ß-hydroxyethoxy) -13 -trans - -prostenic acid

9a, 16-dihydroxy-lla- (ß-hydroxy propoxy) -l ^ - trans -p rosten · ¹ ""'"

saufe 9a, 16- dihydroxy-11a - (^ f -hydroxy butoxy) -13- trans -p rosten- ²

■ acid ₍ "*"

yes, 16-dihydroxy-lla-methoxy- -prostanoic acid.

9a, 19-dihydroxy-5,3-dimethyl-IIIa-methoxy-20-norprostanoate ⁴

9α, 11α, le-trihydroxy ^ a, 7b- -bishomo-prostane acid ~ d

9a, 11a-dihydroxy-20-hydroxymethyl-pros tan_acid ~~ "" ~ "

^^ yy ^ J methyl-prostane acid **

9α, 11α, 16-Trihydrpxy-7a-homo -prostanoic acid " J ~ _

Decyl ^ 9a, 11a, 16-trihydroxy - / - pj'jpjanoate

- 236 Tab le 34 (cont.)

example

used 9-oxo derivative of Example obtained 9-alpha-hydroxy derivative

1163 1164 1165

1038

1046

1232 9a, 16-nihydroxy-lla- (ß- -hydroxy thoxy) -prostanoic acid

yySähyllla - (ß-hyd roxye thoxy) -prostan-J

acid · ■>

9α, 20-dihydroxy-13-soak -ρrostensaufe ^ · '

/.09811/1203

Example 1166

Preparation of 9alpha / 9β, 11,20-trihydroxy-13-transprostic acid

An ice cold solution of 355 mg (1.00 ppm) llalpha, 20-dihydroxy-9-oxo-13-trans-prostenic acid (Example 783) in 50 ml of ethanol is stirred with 409 mg (10.8 mmol) Sodium borohydride was added in small portions over the course of one minute. The mixture is 5 minutes at 0 C and Stirred for 1.5 hours at ambient temperature. The main part of the ethanol is evaporated at room temperature, and the residue is treated with ether and then with dilute hydrochloric acid with cooling in an ice bath. the organic phase is separated off and washed with water and saturated sodium chloride solution. The solution is dried over magnesium sulfate and concentrated. The residue is purified by thin-layer chromatography on silica gel cleaned, and an oil is obtained; V max 3310

(Hydroxyl groups), 1705 (acid carbonyl group) and 970 cm (trans-vinyl group).

Examples 1167-1172

By treating the 9-oxo derivatives listed in the following table with sodium borohydride according to the example The procedure followed in 1160 produces the 9-hydroxy derivatives also given in the table. Each 'of these "derivatives is a mixture of 9alpha and 9ß-hydroxy compounds represent.

/.09811/1203

2 6 .5 /: ■ ö

Tab 1 le 3 5

used 9-oxo obtained

Example derivative of Example 9 alpha / ß-hydroxy denvate

1167 790 1168 • 814 1169 840 ι
1170 849 1171 863

1172

"99 ethyl 9cc / 9SS, 20-dihydroxy-13- trans -prostenoat *

9a / 9β, 16-dihydroxy-3-thIa-13- trans -prostenoate

3-oxa 9a / 9β, 16-dihydroxy-lla- -Aiethoxy-l ^ - trans -proBtan-: silure

9α / 9β, 11α, 16-τ rihydroxy-13- -trans -prostensäurg

9a / 9β, Ha, 20 ^ r rihydroxy-7a, 7b ■ -blshomo-13- trans -prosten- "_ acid

9a / 9β, 16-dihydroxy-IIIa- (β- -hydroxySthoxy) -1 ^ - trans - -prosteric acid

409811/1203

Example 1173

Preparation of 20-hydroxy-9-oxo-10,13-trans-prostadienoic acid

A solution of 355 mg (1.00 mmol) llalpha, 20-dihydroxy-9-oxo-13-trans-prostenic acid (Example 783) in 6.67 ml of 1.5 η hydrochloric acid and 13.3 ml of tetrahydrofuran is at Let stand room temperature for 70 hours. Saturated sodium chloride solution is added to the solution and extracted with ether. The extract is successively mixed with water and saturated sodium chloride solution washed and dried over magnesium sulfate. The crude product obtained after evaporation of the solvent is

purified by chromatography on silica gel. You get . «,. η MeOH

^υ 'Λ. max = 217 nyu (9500); Y "max = 1700 (acid

carbonyl group), 1690 (ketone carbonyl group), 1585 (conjugated olefin group) and 965 cm (trans-vinyl group).

£ 0981 1/1203

Examples 1174-1224

Acid treatment of the llalpha-hydroxy-9-oxo derivatives listed in Table 36 according to the procedure given in Example 1173 gives the / \ ^ derivatives according to the same table.

/ ♦ 09811/1203

1182

1183

1185
1186

- 241 Table 36

example 872 1174 873 1175 87 ^ 1176 875 1177 876 II78 877 1179 878 1180 879 1181

11alpha-hydroxy-9-oxo derivative used obtained from Example as 9-oxo-10-prostenic acid or ester

880 881 882

883 884

9-0) xo-2-phenyl-ie-hydroxy-20-

-äthyl-10.15-t_rans_-prostadieni ~ acid"

9-oxo-2-methyl-16-Jiydroxy-10,13- trans -prostadier? acid

9-O'Xo-2-raethyl-20-hydroxy-10> 13- trans -prostadienoäure "

jithyl - 9-oxo-16-hydroxy-10, Ij5- - trans -prostadienoate

Ethyl 9-oxo-20-hydroxy-10, Ij5- - trans -prostadienoate.

Methyl 9-oxo-ie-hydroxy-10, I3- - trans -prostadienoate

-9-oxo-6,7-dinor-20-hydroxymethyl-10,1 ^ - trans -prostadienoat '·

Ethyl-9-oxo-5,6,7-trinor-ie- hydroxy-19-methyl-10,1 ^ - trans - -prostadienoate

ithyl-9-oxo-Ta ₁ 7b-bishomo-19-hydroxy-20-nor-lO, 13- trans - -prostadienoat

Xthy1-9-0x0-2-ethyl-16-hydroxy-17-ethyl-20-nor-10, 1 ^ - trans -prostadienoate

~ 3,3-dimethyl-17- -prostadienoate

-oxo-3-oxa-20-hydroxy ~ luethyl-10, 1 ^ - trans -prostadienoate

Ethyl 9-oxo-2-fluoro -20-hydroxy--10,1 ^ -trans-prostadienoate

409811/1203

example
1187

1188

1189

11alpha-hydroxy-9-oxo derivative used of Example 2337S81

obtained as 9-oxo-IO-prostenic acid or esters

885

886

887

1190. * 12Ό1
* * 888 1191 1202 889 I. 1192 1203 890 -1193 1204 891 1194 1205 892 1195 893 • 1196 , 849 1197 - 850 1198 851 1199 852 1200 853 cn O
(N 854 "■ '" «.
OO 855 CD α 856 857 858

Ethyl 9-oxo-7-nor-16-hydroxy-20-methyl-10, 13- trans -prostadienoate

Ethyl 9-oxo-7a-homo-16-hydroxy- trans -prostadienoate

Ethyl-9-0x0-2-phenyl ^ 17-hydroxy- -19,20-dinor-10, 13- trans - -prostadienoate

Butyl 9-oxo-16-hydroxy-10,13- - trans -prostadienoate · ■

Butyl-9-oxo-20-hydroxy-10,13- - trans -prostadienoate

Isopropyl 9-oxo-IS-hydroxy-10,13- trans -proStadienoate

Isopropyl-g-oxo ^ O-hydroxy-lO, 13 -trans -prostadienoat

Decyl-g-oxo-ie-hydroxy-10, I3- - trans -prostadienoate

Decyl ~ 9-oxo-20-hydroxy-10, I3- - trans -prostadlenoate

9I) χο-16-hydroxy -10,13- trans - -prostadienäure

9-Oxo-16-hydroxy-20-nor-10,13- - trans - ρrostadi'en säü're ^

9-Oxo-16-hydroxy-17-Πlethyl-19, 20-dinor-10, 13- tra, ns -prostadien3 "acid" * """"""

9-O'XO-17-hydroxy-19,20-din_or-

9- ° xo-lö-hydroxy-ig-methyl-lO, 13-trans-T

9-0.xo-16-hydroxy-17-ethyl-20- -nor-10, ^ - trans -prostadlengäu- "'

.re.

9-Oxo-l8-hydroxy-19,20-dinor - ^ _ -10,13- t rans -prostadien "acid"

9-0 xo-19-hydroxy-2Q-nor-10,13- - trans -prostadien < ^acidic '"

9-oxo-20-hydroxymethyl-10,13- -t_rans_-prostadierif959i5öitJ * ä acid

9-0 xo-20- (5-hydroxypropyl) -10, -13-trans-prostadiene- " '

Tabel

36 (forte.)

11alpha-hydroxy-9-oxo derivative used Example by example

1206 ■ 859

1207 ^N 860 contained as 9-oxo-iO-prostenic acid or ester

1208 861 1209 862 1210 ' • 863 1211 865 - 1212 866 1213 867 1214
* · ■ 868 * ·
"1215 '869 1216 870 1217 871 1218 1007 1219. 1009 cn
O
Oi .1220 1012 ■ «- ¹ 1221 1015 OO σ 1222 1017 1223 1020 1224 1021

-20-dinor-10, 15- trans -prostadieric acid

9-OXO-6,7-dinor-16-hydroxy-20- -.ethyl- 10,15- trans -prostadien _r _

.acid. · J

9-oxo-5,6,7-trinor 20-hydroxy-trans _ -10.15 -prostadlensäure "^]"

9-oxo-7a, 7b-bishomo-16-hydroxy- -10,13- trans -prostadienaure "_

9-oxo-7a, 7b-bishomo-20-hydroxy- -10.15-trans-pro-dienoic acid ^

9-GXO-2-ethyl-16-hydroxy-lS, 19, 20-trinor-lO, l ^ - trans -prostadienic acid "^ J""J ^r ^

9-OXO-5,5-y

-10.15- trans -prostadienoic acid

9-OXO-5,5-dimethyl-20-hydroxy- -10,15- trans -pros.tadienoic acid ^ '

9-0 'XO-5-oxa-16-hydroxy-10.15- - trans -prostadien acid'

9-0? Co-2-fluoro '* - 16-methyl-17- -hydroxy-18,19,20-trinor_-10,15- - trans -prostadic acid

9-OXO-7-nor-16-hydroxy-10, 15- - trans -prostadien ^ aure _ "

9-OXO-7a-homo-16-hydroxy-10,15- - trans -prostadienoic acid ~

acid"

9- -10-prosten acid * * 1

g-axo - ^ - hydr
-prosten acid

g-Oxo - ^ - hydryylX ^ 20-dinor-lO-prosten acid ..'__ ..,.

9-oxo-16-hydroxy-7a, 7brbishomo- -10-prosten acid "* ~

9-Oxo-20-hydroxy-5 _J 5-dimethyl- -10-prosten _: 'acid ___

9-Oxo-16-hydroxy-5-oxa-10- -prostenic acid "

Example 1225 Preparation of ethyl 9-oxo-13-trans-prostenoate

A solution of 1.102 g of 1-octyne in 2 ml of benzene is treated with 11.5 ml of a 15% strength diisobutylaluminum hydride solution in toluene. The solution is then heated ^{at 50 ° C. for 2 hours.} The solution is cooled, the solvents are removed in vacuo and the resulting oil is treated with 5.45 ml of 5.1 above methyllithium in diethyl ether while cooling with ice. 1.830 g of 2- (6-carbethoxyhexyl) -2-cyclopentenone are added to the resulting solution and the solution is stirred at ambient temperature for 18 hours. The solution is poured onto ice and dilute hydrochloric acid and the mixture is extracted into diethyl ether. The organic phase is washed with dilute sodium bicarbonate, water and saturated brine, dried and evaporated. The residue

R is obtained by chromatography on Florisil and distillation

cleans to give 1.878 g of an oil, IR 1736 cm

mm Λ

(Ester and ketone carbonyl groups), 969 cm "(trans-vinyl group), NMR (CDCl ₃ ) S 5.14 to 5.87 (multiplet, 2H, vinyl protons, J trans = 15 Hz), mass spectrum, base peak at 350 m / rev .

Example 1226 Preparation of ethyl 20-chloro-9-oxo-13-trans-prostenoate

In the same manner as described in Example 1225, 2- (6-carbethoxyhexyl) -2-cyclopentenone is added to the reagent which is prepared from 8-chloro-i-octyne [WJGensler and GRThomas, J.Amer. Chem. Soc, 73, 4601 (1951)], diisobutyl aluminum hydride and methyl lithium. The crude product obtained by acid hydrolysis is purified by silica gel ^{chromatography to give an oil, IR 1740 cm "1} (ester and ketone carbonyl groups), 967 cm" ¹ (trans-vinyl group).

'·'. Π 9 B 11/1 2 D 3

2 3 3 7 h 8 Ί

Example 1227 Preparation of ethyl 20-iodo-9-oxo-13-trans-prostenoate

A stirred mixture of 30 g
prostenoate (Example 1226), 25 g of sodium iodide and 225 ml of acetone are refluxed for 12 hours. The reaction mixture is concentrated, diluted with water and extracted with ether. The extract is washed with saturated sodium chloride solution, dried and evaporated to give an oil.

Example 1228 Preparation of 9-0xo-13-trans-prostenoic acid

A mixture of 0.140 g of ethyl 9-oxo-13-trans-prostenoate (Example 1225) and 0.072 g of potassium hydroxide in 6 ml of 1: 1 aqueous methanol is stirred at room temperature for 17 hours. The resulting solution is acidified with hydrochloric acid and extracted with diethyl ether and the organic phase is washed with water and saturated saline, dried and the solvent is removed to obtain 0.128 g of an oil, IR 1739 cm "* ¹ (ketone carbonyl), 1706 cm ~ (Acid carbonyl), 969 cm (trans-vinyl group), NMR (CDCl ₅ ) 5.34 to 5.67 (multiplet, 2H, yinyl protons, J trans = 15 Hz), 10.47 (broad singlet, 1H, carboxyl proton, exchangeable), mass spectrum, base peak at 322 m / u.

Example 1229

Production of ethyl 9,9-ethylenedioxy-20-iodo-13-trans-prostenoate

A solution of 25.2 g of ethyl 20-iodo-9-oxo-13-trans-prostenoate (Example 1227), 5.6 ml of ethylene glycol and 110 mg of p-toluenesulfonic acid monohydrate in 170 ml of benzene is refluxed for 4 hours, the water being removed azeotropically. The solution is concentrated to a volume of 50 ml. Column chromatography

R.
graph of the solution on Florisil with benzene results in a liquid

/.09811/1203

233758Ί

speed, IR 1740 (ester carbonyl), 967 (trans-vinyl group) and 952 cm " ¹ (ethylene ketal).

Example 1230 , *, ''

Production of ethyl ^ O-benzoyloxy-g ^ -äthylendioxy - ^ - transprostenoat

A stirred mixture of 7.80 g (15 mmol) of ethyl 9,9-ethylenedioxy-20-iodo-13-trans-prostenoate (Example 1229), 8.65 g (60 mmol) of sodium benzoate and 100 ml of dry methylformamide is heated at 115 ° C for 2 hours. The mixture is cooled, diluted with water and extracted with ether. The extract is successively mixed with water, saturated sodium bicarbonate solution and saturated sodium chloride solution. The extract is dried over magnesium sulfate. After evaporation of the solvent, the crude product is obtained, which is purified by chromatography on silica gel, wherein one an oil is obtained, v'max 1745 (alkanoate ester group), 1730 (benzoate ester group), 967 (trans-vinyl group) and 948 cm (ethylenedioxy group).

Example 1231

Production of ethyl 20-benzyloxy-9-oxo-13-trans-prostenoate

A solution of 5.35 g (10.4 mmol) of ethyl 20-benzoyloxy-9,9-ethylenedioxy-13-trans-prostenoate (Example 1230), 99 mg (0.52 mmol) of p-toluenesulfonic acid monohydrate and 40 ml of acetone is kept at room temperature for 41 hours. The acetone is evaporated and the residue is dissolved in ether. the Solution is successively with sodium chloride solution, dilute sodium bicarbonate solution and saturated sodium chloride solution washed. The solution is dried over magnesium sulfate and concentrated to give an oil, \ 7 max 1740 (ketone and alkanoate ester groups), 1730 (benzoate ester group) and 967 cm (trans-vinyl group).

409811/1203

Example 1252

Preparation of 20-hydroxy-9-oxo-13-trans-prostenic acid

A solution of 4.75 g (10.1 mmol) of ethyl 20-benzoyloxy-9-oxo-13-trans-prostenoate (Example 1231), 3.31 g (50 mmol) 85 & Lgem Potassium hydroxide, 90 ml of methanol and 9 ml of water is at room temperature Stored for 24 hours. The solution is concentrated, diluted with water and extracted with ether. The extract will washed with saturated sodium chloride solution, dried over magnesium

sulfate dried and concentrated. Column chromatography of the crude product on silica gel gives an oil, \? Max 1735 (ketone carbonyl group), 1710 (acid carbonyl group) and 967 cm (trans-vinyl group).

Example 1253 -.

Production of g-Oxo-IS-hydroxy / ig-hydroxy - ^ - trans-prostenic acid

Inoculum production

A typical medium used to grow the inoculum is prepared according to the following formulation:

Sodium nitrate 3g

Dipotassium hydrogen phosphate 1 g

Magnesium sulfate heptahydrate 5 g potassium chloride - 5 g

Iron (II) sulfate heptahydrate 0.01 g

Sucrose '30 g

Water to 1000 ml

Remove the washed or chopped spores from an agar inclined plate from Lederle culture V89 (a strain of Diplodia malorum, contained by the Centraalbureau voor Schimmel cultures Baarn, The Netherlands) are used to inoculate a 250 ml flask containing 50 ml of the above medium. The flask is placed on a rotary shaker

A 09 81 1/1203

2 3 3 7 s 8 1

and shaken vigorously at 22 ^{° C. for 5 days.}

10 ml of the above inoculum from the first stage are poured into two further 250 ml flasks, each containing 50 ml of the medium filled using 5 ml per flask. The flasks are incubated for 72 hours under the same conditions as as described for the inoculum of the first stage.

100 ml of the second stage inoculum is used to inoculate a 4 liter glass fermentation device containing 2 liters of sterile medium. The fermentation device or the fermenter is ventilated with sterile air while cultivation is carried out ^{at 25 ° C. for 72 hours.} These 2 1 inoculum are used to make a 40 1 fermentation tank. the 20 1. contains liquid medium to inoculate.

fermentation

Fermentation medium is prepared using the same composition as specified for the inoculum medlura. The fermentation medium is ^{sterilized at 120 °} C. with steam at a pressure of 9.1 kg (20 pounds) for 45 to 60 minutes. The pH of the medium after sterilization is 6.6. 20 l of the sterile medium are inoculated with 2 l of the inoculum in a 40 l fermentation tank and the fermentation is carried out at 22 ^° C. using pig oil as a defoaming agent, if necessary. Aeration takes place in an amount of 1.0 1 sterile air / l mash / min. The mash is then stirred by air impellers moving at 400 rpm. Towards the end of the 42 hour fermentation time, a 5.15 g sample of CL82,680 is dissolved in 150 ml of acetone and added to the fermentation mixture. It is fermented for a further 5 hours and then the mash is processed or harvested.

/.09811/1203

insulation

20 1 fermentation mash (pH 7.5) are clarified by filtering through Hyflo, and the filtrate is three times with Extracted 1/5 of the volume of chloroform, the pH being adjusted to 2.8 beforehand with hydrochloric acid; the combined chloroform extracts are concentrated in vacuo, 4.85 g of residue is obtained which, after trituration with two 100 ml parts of cold hexane, 4.28 g of residue results.

This residue is further purified by adsorption chromatography on 100 g of Davison Grade No. 62 silica gel, as a slurry in Filled in chloroform, cleaned. The residue is dissolved in a small volume of chloroform and applied to the column and the column is gradient linearly between 1 liter each of chloroform and 10% ethanol-in-chloroform developed. Fractions of about 15 ml are each automatic collected. The progress of the development is followed by looking at the agent flowing out of the column Check 240 nm, and likewise by taking appropriate fractions examined by thin layer chromatography. Fractions 47 to 80, which contain the product according to the invention, are combined and concentrated in vacuo to a residue of 3.55 g.

This residue is further analyzed by partition chromatography

cleaned on 300 g Celite. The pillar is made, by adding 0.5 ml of the lower phase of the solvent system hexane-ethyl acetate-methanol-water (9: 3: 2: 1) with each

1 g Celite mixed. The residue from above is in 5 ml the lower phase dissolved and treated similarly and applied to the column, which is then eluted with this upper phase. Fractions of approximately 60 ml each are automatically collected. The progress of development is followed by the material flowing out of the column at 270 nm

A 0 9 8 ι W 1 2 0 3

examined and by also checking the appropriate fractions by thin layer chromatography. Fractions 16 to 36, containing the desired compound are combined and concentrated in vacuo to a residue (2.93 g). This is dissolved in some chloroform, onto 50 g of Davison Grade No. 62 silica gel, which is poured into chloroform as a slurry was given and then washed with chloroform. The column is eluted with 10% ethanol-in-chloroform, whereby after evaporation, 2.9 g of product are obtained which, according to NMR analysis, is a mixture of the 18-hydroxy and 19-hydroxy derivatives in a ratio of about 3: 1 to 1: 1.

Example 1234

Preparation of 9-0xo-18/19-oxo-13-trans-prostenic acid

A 1.5 g sample of the product from Example 1233 is dissolved in 20 ml of acetone and Jones reagent (6.68 g of CrO, in .5.75 ml of conc. E ^ SO. , diluted to 25 ml with water) is slowly stirred while stirring added until the color persists. The reaction mixture is stirred for an additional 15 minutes and then excess becomes Reagent destroyed by adding methanol. The mixture is diluted to approximately 200 ml, washed with water and washed with three 50 ml portions of chloroform. This will then dried with anhydrous sodium sulfate and evaporated to give 1.5 g of a pale yellow oil. This will dissolved in the same chloroform, on 30 g of Davison silica gel Grade No. 62 slurry filled in chloroform, poured, and after washing the column with chloroform this is eluted with 5% ethanol-in-chloroform, 1.46 g of the title ketones being obtained after evaporation.

Examples 1235 to 1257

Treatment of the 3-hydroxymethyl-1-alkynes listed in Table 37 below with triphenylmethyl bromide according to the The procedure described in Example 278 gives the 3-triphenylmethoxymethyl-1-alkynes, the are listed in the table

A0981 1/1203

Table 37

At starting 3-hydroxy-3-triphenylmethoxymethyl-i-alkyne play methyl-1-alkyne

1235 3-Hydroxymethyl-1-hexyne 3-triphenylmethoxymethyl-1-hexyne

1236 3-hydroxymethyl-1-heptyne 3-triphenylmethoxymethyl-i-

heptine

1237 3-hydroxymethyl-1-octyne 3-triphenylmethoxymethyl-i-octyne

+ A.Schaap, L. Brandsma and J.F.Arens, Rec.trav.chim. 86, 393 (1967)

Example 1238

Production of i-chloro-3-triphenylmethoxyhexane

A stirred solution of 27.3 g (0.20 mol) of i-chloro-3-hexanol, 77.6 g (0.24 mol) of triphenylmethyl bromide, 30.0 g (0.28 mol) of 2,6-lutidine and 200 ml of chlorobenzene is added for 1 hour 95 ° C heated. The cooled mixture is treated with water and the organic phase is successively with water and washed saturated sodium chloride solution. The solution is dried over magnesium sulfate and concentrated. Column chromatography the residue on Florisil gives the title compound as an oil, v> max 1600, 1030 and 705 cm (triphenylmethoxy group).

Example 1239

Preparation of 5-triphenylmethoxy-1-oc'tyne

A solution of 9.4 g (102 mmol) of lithium acetylide-ethylenediamine complex is added to a stirred solution of 32.2 g (85 mmol) of i-chloro-3-triphenylmethoxyhexane (Example 1238) in 25 ml of dimethyl sulfoxide (DMSO) 60 ml of DMSO for 10 minutes, the temperature being kept at 25 to 30 ^° C. After 3.5 hours the mixture is diluted with ether and treated successively with water and 4N hydrochloric acid while cooling in an ice bath. The phases are separated and the aqueous phase is extracted with ether-petroleum ether.

1 * 0 9 8 1 1/1203

The combined extracts are washed successively with water and saturated sodium chloride solution over magnesium sulfate dried and concentrated. The product is then purified by column chromatography of the residue on Florisil *.

Examples 1240-1265

The conjugate addition of the alanates obtained by treating triphenylmethoxy- (trityloxy) -1-alkynes (described in the following Table are listed) with diisobutylaluminum hydride and then with methyllithium, to those in the table listed cyclopentenones according to the method described in Example 782 with subsequent de-O-tritylation of the intermediates, namely the triphenylmethoxyprostenoate, following the procedure of Example 783 the prostate acids and esters listed in the table.

The compounds that are isolated and identified as prostate acids in the table are selected via the appropriate Tetrahydropyran-2-yl ester produced, and these compounds, which contain a free hydroxyl function in the 11 α-position or which are part of a 11 a - (^ - hydroxyalkoxy) part of the molecule are produced via the corresponding tetrahydropyran-2-yl ethers. The hydroxy function of the ß-side chain (the part of the molecule which is derived from the triphenylmethoxy-1-alkyne) of all compounds listed in the table are at the beginning in the molecule as the corresponding triphenylmethylether available. During treatment with acetic acid (the de-Q-tritylation step) the triphenylmethyl esters become like also the tetrahydropyran-2-yl ether and ester functions hydrolyzed, the corresponding free hydroxyl and carboxylic acid groups of the compounds listed in the table receives.

40981 1/1203

Table 38

Example starting cyclo-starting trityloxy game pentenone v.Beisp. 1-alkyne V. Example hydroxyprostenic acid or ester

1241
1242

S 1243
oo 1244

1245
1246
1247

1248
1249

2-lb-carbethoxyhexyl)
cyclopent-2-en-l-one

2- (8-carbethoxyoctyl) cyclopent-2-en-1-one >

2- (5 _} 5_D.inethyl-6-carbä thoxyhexy-dcyclopent-
-2-en-l-on

781

781

651
651

1235 1236

1237

1238 1238

1237 1237 1238

1235 1235 ethyl gy
- trans -prostenoate

Ethyl g-oxo - ^ - hydroxymethyl-gQ-nor-l ^ - trans - · -prostenoate. '|

Ethyl 9-0x0-15-hydroxymethyl-l ^ - trana - j -prostenoate,

Ethyl 9-oxo-17-hydroxy-13-transane-progtenoate

Ethyl 9-oxo-17-hyd roxy-7a, 7b-bi shorao-15-
trans -prostenoat

Ethyl 9-oxo-15-hydroxymethyl-3,3-dimethyl-
-13 trans -prostenoat ■ i

Ethyl 9-oxo-15-hydroxymethy1 - ^ - thia-13- trans -; -prostenoate

Ethyl 9.- ° ^xo ~ 17-hydroxy-3-thi "a-15-_tran_s-
-prostenoate »

9-Qxo-lla ', rr-dihydroxy-13- trans -prostenic acid

9-0xo-llα-hydroxy-15-hydroxymetKyl-19 _ί 20-
-dinor-l ^ -trans-p rost en - acid'-

Table 38 (continued)

< 1250 651 -1 ;
1236. j 9-oxo-llα-hydroxy-15-hydroxymethyl-20-nor-
-13-trans-prosten.acid 1251 651 1237 9-oxo-lla-hydroxy-15-hydroxymethyl-13-trans-
-rostenic acid 1252 655 1237 9-Oxo-llα-hydroxy-15-hydroxymethyl-2-ethyl-
-13-trans-pros acid 1253 656 1238 9-0xo-llα, 17-dihydroxy-3,3-dlmethyl-13-trans-
-prostenic acid CJ
id
OQ
-4 125 ¹ I. 657 1238 9-oxo-llα, 17-dlhyäroxy-3-oxa-13-trans-
- rusting acid -J 1255 657 1237 9-Oxo-llα-hydroxy-15-hydroxyπ ^ ethyl-3-oxa-13-
-trans-prosten acid σ 1256 658 1237 9-Oxo-lla-hydroxy-15-hydroxymethyl-2-fluoro -
-13-trans-prosten acid 1257 659 1236 9-oxo-lla-hydroxy-15-hydroxymethyl-7,20-dlnor-
-13-trans-pros th. Acid 1258 661 1237 9 - Oxo-lla-hydroxy-15-hydroxymet: hyl-2-phenyl-
- 13-trans-prostenic acid 1259
ι 662 1237
ι 9-Oxo-lla-hydroxy-15-hydroxymethy1-7a-homo-13-
-trans-prostenic acid .... ·. ' ^v

Table 38 (continued)

1260 7 ^ 8 1237 '. 9-Oxo-11a-methoxy-15-hydroxymethy1-13-träns- j
-rostenic acid 1261 748 1238 ^ Oxo-lla-methoxy-lf-hydroxy-rj-trans-
-prostenic acid 1262 753 1237 9-0xo-lla- (2-hydroxyethoxy) -15-hydroxymethyl-
-13-trans-pros acid P. 1263
CO 753 1238 9-oxo-lla- (2-hydroxyethoxy) -17-hydroxy-13-
-trans-prosten ^ acid

Examples 1264-1271

Saponification of the esters listed in Table 39 below according to the procedure of Example 786 gives the in prostate acids listed in the table.

Table 39

Example starting alkyl prostatic acid play prostenoate from

example 1264 '1240 1265 1241 1266 1242 1267 1243 1268 1244 1269- 1245

1270

1271

1246

1247

9-0xo-15-hydroxymethyl-19,20- -dinor-13- trans -prostenic acid:

9-OX0-I5-hydroxymethyl-20-nor- -1 ^ - trans -prostenic acid.

9- Oxo-15-hyd roxyme thy 1 -13-_t £ ans- -prostenic acid

9-0xo-17-hydroxy-13- trans - prostate acid

9-Oxo-17-hydroxy-7a, 7b-bishomo -13 -trans -prosten acid

9-oxo-15-hydroxymethyl-3,3- -dimethy1-13-trans-prosten acid

9-Oxo-15-hydroxymethyl-3-thia ■ -13- trans -prostenic acid

9-0 xo-17-hydroxy-3-thia-13-_trans-p rost en-acid

Examples 1272 to 1505

Hydrogenation of the prostate acids and esters listed in Table 40 below gives the prostate acids and esters, which are listed in the table.

'.0981 1/1203

ORIGINAL INSPECTED

2337 ^ 81

Table 40

example

Starting 13-prostanoic acid or ester ν. Example!

Prostanoic acid or esters

1272
1273

1275
1276

1277
1278

1279
1280.
1281

1282

1283
1284
1285
1286

1287

1288
1289

1240

1241

1242

1243

1244

1245

1246

1247

1248

1249

I25O 1251 I252 1253 I254

1255

I256 1257 Ethyl 9-oxo-15-hydroxymethyl-19,20-dlnor prostanoate

Ethyl 9-oxo-15-hydroxymethyl-20-nor-prostanoate

Ethyl 9-0x0-15-hydroxymethyl prostanoate

Ethyl 9-oxo-17-hydroxyprostanoate

Ethyl 9-oxo-17-hydroxymethyl-7a, 7b-bishomo-prostanoate

Ethyl 9-oxo-15-hydroxymethyl-3,3-dimethyl-prostanoate

Ethyl 9-oxor15-hydroxymethyl-3-thia-prostanoate <.

Ethyl 9-oxo-17-hydroxy-3-thiaprostanoate

9-oxo-lla, 17-dihydroxy-prostanoic acid

9-0xo-lla-hydroxy-15-hydroxy- x-.e.-t hy 1 -19, ^ 0 - d i.nor -pre ε tan ^ säur e

9-Oxo-IIα-hydroxy-15-hydroxymethyl-20-nor-prostanoic acid

9-Oxo-llo> hydroxy-15-hydroxymethyl prostanoic acid

9-Oxo-lla-hydroxy-15-hydroxymethyl-2-ethyl-prostanoic acid

9-Oxo-IIIa, 17-dihydroxy-3,3-dimethyl-prostanoic acid

9-Oxo-lla, ^ -dihydroxy ^ -oxaprostanoic acid

9-Qxo-lla-hydroxy-15-hydroxymethyl-3-oxa-prostanoic acid

9-Oxo-IIIa-hydroxy-15-hydroxymethyl ■ 2-fluoro-prostanoic acid

9-0 xo-lla-hydroxy-15-hydroxymethyl- 7, 20-dinor prostane acid 1/1203

/ LOD

J U

Table 40 (continued)

1290

1291

1292

1258

1259

1260

1293 1261 1294 ' 1262 1295 I263 1296 1264 1297 1265 1298 1266 1299 - 1267 1300 1268 I3OI 1269 1302 I270

1303

1271 ^ Oxo-lla-hydroxy-lS-hydroxynethyl-2-phenyl-prostane acid *

^ Oxo-lla-hydroxy - ^ - hydroxymethyl-7a-homo-prostanoic acid

! ^ - Oxo-lla-methoxy-lS-hydroxymethylprostarvic acid 1

S-Gxo-lla-methoxy-JT-hydroxyprostanoic acid

9-0χο-11α- (2-hydroxyethoxy) -15-hydroxymethyl-prostarv acid

9-oxo-lla- (2-hydroxyethoxy) 17-hydroxy-prostane acid. '

9-CKc-15-hydroxymethyl-19,20-dinor-prostane acid

9-'Gxo-15-hydroxymethyl-20-norp rostanic acid

9-oxo-15-hydroxymethyl prostanoic acid

9-0xo-17-hydroxy-prostanoic acid

9-0xo-17-hydroxy-7a, 7b-bishomoprostanoic acid

9-oxo-15-hydroxymethyl-3,5-dimethyl-prostane acid

9-Oχo-15-hydroxymethyl-3-thiaprostanoic acid

9-0xo-17-hydroxy - ^ - thia-prostanoic acid

Examples 1304-1356

Reduction of the 9-oxo derivatives listed in Table 41 below with lithium perhydro-9ß-boraphenalyl hydride according to the method described in Example 1061 gives the in the Table listed 9oc-hydroxy derivatives. '

09811/1203

BAD ORIQtNAL

ο ■ ' ■} υ ι

Table 41

at
game Starting 9-oxo-
derivative from example ga-Hyaroxyaerivai; 1304 "1240 ■ Ethyl Sa -hydroxy-15-hydroxy-
methyl-lS ^ O-dinor-lJ-trans-
-prostenoate 1305 1241 Ethyl Sa -hydroxy-15-hydroxy-
methyl-20-nor-13-trans-
-prostenoate 1306 1242 Ethyl 9 <* - hydroxy-15-hydroxy-
methyl-13-trans-prostenoate 1307 1243 Ethyl 9a, 17-dihydroxy-lJ-
-trans-prostenoat '13 08 1244 Ethyl 9a, 17-dihydroxy-7a, 7b-
-bishomo-lj-trans-prostenoat 1309 1245 Ethyl 9a-hydroxy-15-hydroxy-
methyl-5 »3-dimethyl-13-trans-
-prostenoate 1310 1246 Ethyl 9ct-hydroxy-15-hydroxy-
methy1-3-thia-IJ-trans-
-prostenoate- 1311 1247 Ethyl 9a, 17-dihydroxy-j5-thia-
-13-trans-prostenoate 1312 1248 9a, .lla, -17-trihydroxy-13-trans-
-prostenic acid 1313 1249 Sa, lla-dihydroxy-15-hydroxy-
methyl-19,20-dinor-13-trans-
-rostenic acid 1314 1250 9α, 11α-dihydroxy-15-hydroxy-
methy1-20-nor-13-trans-
-prosten acid 1315 1251 9a, lla-dihydroxy-15-hydroxy-
methyl-13-trans-prosten acid 1316 1252 9a, 1la-dihydroxy-15-hydroxy-
methyl-2-ethyl-l3-trans-
-prostenic acid 1317 1253 9a, 11a, 17-trihydroxy-3,3-di-
methyl-13-trans-prosten acid \ 1318 9a, lla, 17-trihydroxy-3-oxa-l3-
-trans-proGtehGäurc

/, 09811/1203

ό t OO 1

Table 41
1319

1320

1321

1322

. 1323

1325
1326

1327
.1328

1329

(Continuation) . 1255

I256

1257 1258

1259 1260 1261 1262

I263 1264

1265

1330 1266 1331 1267 I.
1332 1268 1333 1269

9α, Ila-Dlhydroxy-15-hydroxymethyl-5-oxa-I5- trans - -prostenic acid

9a, lla-Dlhydroxy-15-hydroxymethyl-2-fluoro-15- trans - '-prostenic acid

9a, lla-Dlhydroxy-15-hydroxy-

-prostenic acid

9a, lla-dihydroxy-15-hydroxymethyl-2-phenyl-13- trans -. -prostenic acid

9a, 1la-dihydroxy-15-hydroxyme t hy 1 -7a -homo -15- t £ ans_- -prostenic acid

9a-Hydroxy-lla-methoxy-15- -hydroxymethyl-1 ^ - trans - -prostenic acid

9a-Hydroxy-lla-methoxy-9ot, 17- -dlhydroxy- 1J> - trans -prostenic acid

9a-hydroxy-lla- (2-hydroxy-

ethoxy) -15-hydroxymethyl-15- - trans -prostenic acid

9a-Hydroxy-IIIa- (2-hydroxyethoxy) -17-hydroxy-15- trans - -prostenic acid

9a-hydroxy-15-hydroxymethyl -19.20-dinor-15-t_rans- -prosten acid

9a-hyd roxy-15-hyd roxymethy1- -20 - nor-15- ^ ran_s-prostenic acid

9a-Hydroxy-15-hydroxymethyl-15- - trans- prostatic acid

9α, 17-dihydroxy-15- trans - prostate acid

9a, 17-dihydroxy-7a, 7b-bishomo · -15- trans -prost acid

9a-hydroxy-15-hydroxymethyl- -5,5-dimethyl-15-trans- -prostenic acid

/, 09811/1203

Table 41 (continued) 1334 1270

1335

1336

133.7

1338

1339

1340

1341

1296

1297

"1298

1299

1300

1301

1280

1281

1343 1282 1344 1283 1345 1284 1346 1285 1347 1286 1348 1287 1349 1288

9a-Hydroxy-15-hydroxymethyl- -J), thla- 1J> - trans -prost acid

9ct-Hydroxy-15 -hyd roxyme thyl- -19.20-dinor-prostanoic acid.

9a-Hydroxy-15-hydroxyme thy I- -20-nor-prostane acid

9ct - Hydroxy-15 -hyd roxyme thy I -prostanoic acid

9a, 17-dihydroxy prostanoic acid

9a, lT- • prostanoic acid

9a -hydroxy-15 -hydroxymethy 1- -j5,2-dimethyl-prostanoic acid

9a, 11a, 17-trihydroxy prostanoic acid

9a, 11-dihydroxy-15-hydroxymethyl-19,20-dinor-prostane acid

9a, 11-dihydroxy-15-hydroxymethyl-20-nor-prostane acid

9a, 11-dihydroxy-15-hydroxymethyl prostane acid

9a, 11 -dihydroxy -15 -hyd roxymethyl-2-ethyl-prostanoic acid.

9a, 11a, 17-trihydroxy-3,3-dimethy1-prostanoic acid

9a, 11a, 17-trihydroxy-3-oxa- -prostanoic acid

9a, 11a-D! Hydroxy-15-hydroxyme thy 1-J-oxa-prostanoic acid e

9a, 1la-dihydroxy-15-hydroxymethyl-2-fluoro -prostanoic acid

9a, 11a -dihydroxy-15 -hydroxy methyl-7,20-dinor-prostanoic acid

/, 09811/1203

2 ό J / ^ ö

Table 41 (continued) 1351 ^% 1290

1352

1353

1355

1356

1291

1292

• 1293

1294

1295 9α, 11α-D! Hydroxy-15-hydroxymethyl-2-phenyl-ρrostanoic acid

9α, lla-dihydroxy-15-hydrpxymethyl-7a-homo-prostanoic acid

9a-Hydroxy-11a-methoxy-15-hydroxymethyl-prostanoic acid

9a-hydroxy-lla-methoxy-17- -hydroxy-prostanoic acid

9a, Ha- (2-hydroxy thoxy) -15- -hydroxymethyl-prostanoic acid

9a, Ha- (2-Kydroxy.thoxy) -17- -hydroxy-prostanoic acid

Examples 1357-1580

Acid treatment according to the procedure described in Example 1173 the 11a-

10 Hydroxy-9-oxoderivate gives the / \ -derivatives, which in the

Are listed in the table.

Table 42

Examples of starting Ucc-hydroxy-9-0xo-10 ^ prostanoic acids and esters play 9-oxo derivatives of
Example ■

9-0xo-17-hydroxy-10,13- trans prostadienoic acid

9-oxo-15-hydroxymethyl-19,20-dinor-10,13-trans-prostadlen acid

9-0xo-15-hydroxymethyl-20-nor-10, 13- trans -prostadienic acid

1358

12Ü9

1359 1250 1360 1251 1361 1252 1362 '. 1253

gOxolShydroxymethylO, 1J> - trans -prostadien. acid

9-0xo-15-hydroxymethyl-2-ethyl -10,13- trans -prostadic acid

9-0 xo-17-hydroxy-3> 3-dimethyl- -10,13-trans-prostadic acid

/ ♦ 09811/1203

233758Ί

Table 42 (continued) 1363 1251

136JJ 1255 1365 1256 1366 1257 1367 1258 1368 1259 1369 1280

1370

1281

1371 1282 1372 '1283 1373 • 1284 1374 1285 1375 "1286 1376 1287 1377 '. · 1288 1378 1289 1379 I29O 138O 1291

O'-Oxo-rr-hydroxy-J-oxa-10,13- - trans -prostadlenic acid

95yy

15-Jtrans_-p rost ad ienv acid -

9-0xo-15-hydroxymethyl-2-fluoro .. -10,13- trans -prostadlenic acid

9-0xo-15-hydroxymethyl-7,20-dinor "-10,13- trans -prostadienoic acid

^ OxolShyoyyp -10,13- trans -prostadien acid

9-oxo-15-hydroxymethyl-7a-homo- -10,13-t £ ans_-p ro stages acid

9-0 xo-17-hydroxy-10-prostenic acid

9-Qxo-15-hydroxyinethyl-19,20-dinor-prostenic acid

9-0 xo-IS-hydroxymethyl ^ O-norprostenic acid

9-Oxo-15-hydroxymethyl-prostenic acid

9-0xo-15-hydroxymethyl-2-ethylprostenic acid . . -

9-oxo-17-hydroxy-5,3-dimethylprostenic acid

9-oxo-17-hydroxy-5-oxa-prostenvic acid

9-0xo-15-hydroxymethyl-3-oxaprofileic acid

9-0xo-15-hydroxymethyl-2-fluoro ". prostenic acid

9-0xo-15-hydroxymethyl-7,20-dinor-pros ten acid

9-0xo-15-hydroxymethyl-2-phenylprostenic acid

9-Oxo-15-hydroxymethyl-7ft-hono ~ prosten acid

11/12

L ο ο ι -J υ ι - 264 -

Example 1381

Production of 8-chloro-i-octyne

The title compound is prepared according to the procedure of W.J. Gensler and G.R. Thomas, JACS 73, 4601 (1951).

Example 1382

Preparation of T.etrahydropyran-2-yl-iia-tetrahydropyranyloxy-9-oxo-8 ^ -13-trans-prostenoate

A solution of 7.16 g (65 mmol) of 1-octyne in 12 ml of benzene is treated with 52 ml of 1.2 M diisobutyl hydride in hexane and the solution is then heated at 50 ° C. for 2 hours. The solution is ^{cooled to 2 °} C. and treated with 28.5 ml of 2.1 M methyllithium in ether for 10 minutes. The resulting solution is stirred at ambient temperature for 20 minutes, cooled to 5 ⁰ C and treated with a solution of 20.1 g (50 mmol) of crude 4-tetrahydropyranyloxy-2- (6-tetrahydropyranyl-carboxyhexyl) -cyclopent-2-en-1 -on treated in 30 ml of ether for 10 minutes. The mixture is then stirred at room temperature for 20 hours, diluted to 450 ml with ether and poured into a stirred mixture of 400 g of ice and 90 ml of NH ^ Cl. The organic phase is separated off and the aqueous phase is extracted with further ether. The organic phase is extracted with more ether. The organic extract is washed successively with ice-cold j hydrochloric acid, water and saturated sodium chloride solution. The extract is dried over magnesium sulfate and concentrated under reduced pressure to give an oil, v? max 1735 (carbonyl groups), 1035 (tetrahydropyranyloxy groups) and 965 cm " ¹ (trans-vinyl group).

Examples 1385-1416

In the manner described in Example 1382, treatment of the 4-tetra-

/, 09811/1203

hydropyranyloxy-cyclopentenone-tetrahydropyran-Z'-yl ester with the alanate, which is produced from the listed 1-alkynes
was, by treatment with diisobutylaluminum hydride and subsequent treatment with methyllithium, those in the table
listed tetrahydropyran-2'-yl-11 oc-tetrahydropyran-2'-yloxy-9-oxo-8 ^ -13-trans-prostenoate.

/ »09811/1203

Example starting game Alkin

Table 43

Starting 4-oxy-cyclo-tetrahydropyran-2'-yl-11a-tetrahydropyran-2'-yl-oxypentenone ester of Example 9-oxo-13-trans-prostenoate

OO

1383 1-octyne 652 Tetrahydropyran-2'-yl-lla -tetrahydropyran-2 ¹ -
-yloxy-9-oxo-8 f-6,7-dinor-13-trans-prostenoate 1384 8-chlorine ~ 1-
octin: 652 _; : Tetrahydropyran-2 ¹ -yl-lla -tetrahydropyran-2'-
-yloxy-9-oxo-8 £ -20-chlori -S ^ -dinor - ^ - trans-
iprostenoatt. 1385 1-nonine 653 Tetrahydropyran-2'-yl ~ lla -tetrahydropyran-2'-
-yloxy-9-οχο-δ, ξ -5-, 6,7-trinor-20-methyl-13-
trans-prostenoate 1386 1-octyne 654 Tetrahydropyran-2 -yl-lla -tetrahydropyran-2'-
-yloxy-9-oxo-8 £ -7a, 7b-bishorao-13-trans-
-prostenoatv ' 1387 1-heptine 654 Tetrahydropyran-2'-yl-lla -tetrahydropyran-2'-
-yloxy-9-oxo-8 | -7a _J 7b-bishoπlo-20-nόr-13-trans-
-prostenoate ^x ; 1388 1-octyne 655. Tetrahydropyran-2'-yl-lla -tetrahydropyran-2 ¹ - j
-yloxy-9-οχο-δξ -2-ethyl-lj-trans-prostenoate; 1389 1-pentin 655 Tetrahydropyran-2'-yl-lla -tetrahydropyran-2'-
-yloxy-9-oxo-8 | -2-ethyl-18,19,20-trinor-13-
-trans-prostenoat>".: 1390 1-octyne 656 Tetrahydropyran-2'-yl-lla -tetrahydropyran-2'-
. -yloxy-9-oxo-8 % -J ^ -dimethyl-l ^ -trans-prostenoate 1391 cis-5-octen-
1-in Tetrahydropyran-2 ^l -yl-ll'ot -tetrahydropyran-2 · -
-yloxy-9 ~ oxo-8 ξ -J, 3 ~ dimethy1-IJ-trans, -17 ~ cis-
prostadienoat

Continuation of Table 43

1392 1-hexyne

656

1393 5-chloro-i-656 pentine

1394 1-octyne ₆₅₇ 1395 1-dodecyne

1396 1-0ctin 658 1397 1-0ctin 659

1398 8-chloro-1- 659 octyne

1399

1400 1-heptyne

Tetrahydropyrane'-yl-lla-tetrahydropyran-2 ¹ -; -yloxy-9-oxo-8 | - ^ jJdithlig ^ Odi '

-13- trans -prostenoate

Tetrahydropyran-2 "'- yl-lla-tetrahydropyran-2'- -yloxy-9-oxo-8 ξ - ^, J-dimethyl-lT-chlori -18.19» 20-trinor-13-t £ an £ - prostenoat

Tetrahydropyran-2 ¹ -yl-lla-tetrahydropyran-2 ¹ - -yloxy-9-oxo-8 £ -3-oxa-l ^ - trans prostenoate

Tetrahydropyran-2 ^T -yl-lla-tetrahydropyran-2'-

-yloxy-9-oxo-8f-3-oxa-20-butyl-13-t £ ans-

-prostenoate-.

Tetrahydropyran-2'-yl-lla-tetrahydropyran-2 ¹ - -yloxy-9-oxo-8 | -2-fluoro -ljS- trans -prostenoate "

Tetrahydropyran-2'-yl-lla-tetrahydropyran-2 - -yloxy-9-oxo-8 % -J-nor- 1J> - trans -prostenoate

Tetrahydropyran-2'-yl-lla-tetrahydropyran-2 ¹ - -yloxy-9-oxo-8 ξ-20-chloro -7-nor-13- trans -
-prostenoate ^:. .

Tetrahydropyran-2'-yl-lla-tetrahydropyran-2'-yloxy-9-oxo-8 g _i, ⁱ -7a HOMO-13 -trans -prostenoat-

Tetrahydropyran-2'-yl-lla-tetrahydropyran-2'- -yloxy-9 ~ oxo-8 ξ-7a-hono-20-nor-l3-trans-
-prostenoate

Table 43 (continued)

XtUX cis-5-octene
1-in 66C 1402 1-octyne 661 1403 8-chloro-1-
octine 661 O
(D
σ? 1404 1-heptine 651 1405 1-pentin 651 K)
ο 1406 1-decin 651 1407 8-chloro-1-
octine 651 1408 cis-5-octene
1-in 651 1409 5-chloro-1- 651

ρentin

Tetrahydropyran-2'-yl-lla-tetrahydropyran-2 · - -yloxy-9-oxo-8 | -7a-homo-I3 -trans , -17- cis - -prostadienoatv

Tetrahydropyran-2'-yl-lla-tetrahydropyran-2 ^f - -yloxy-9-oxo-8 £ -2-phenyl-13- trans -prostenoate

Tetrahydropyran-2'-yl-11a-tetrahydropyran-2'- -yloxy-9-oxo-8 f-20-chloro -2-phenyl-13- trans prostenoate · ·

Tetrahydropyran-2 ¹ -yl-lla-tetrahydropyran-2V -yloxy-9-oxo-8 {-2G -nor-13-trans -prostenoate

Tetrahydropyran-2'-yl-lla-tetrahydropyran-2 - -yloxy-9-oxo-8 % -18,19,20-trinor-13- trans - -prostenoate ^:

Tetrahydropyran-2'-yl-lla-tetrahydropyran-2'-yloxy-9-oxo-8f-20-ethyl-13- trans -prost enoate

T. tetrahydropyran-2'-yl-lla-tetrahydropyran-2'-yloxy-9-οχο-δ % -20-chloro'-13- trans -prostenoate

Tetrahydropyran-2'-yl-lla-tetrahydropyran-2 · - -yloxy-9-oxo-8 ^ -13 -trahs , 17-cis-prostadienoate

Tetrahydropyran-2 ¹ -yl-lla-tetrahydropyran-2'- -yloxy-9-oxo-8f-17-chloro -18, IS ^Λ ~ '"- trans -ρ rost enoate ·. · ■ ·

Table 43 (continued)

Q O ID a OO fNAL ^ JNSf IsJ m O 3

1410 1-0ctin

1411 5-methyl-1-

hexine

1412 4-methyl-1-

pentine

1413 5-methyl-1

hexine

1414 5-methyl-1-

hexine

1415 4-methyl-1- '

pentine

lilX6 1-Hep tin

062

651

654

662

Tetrahydropyran-2-yl ^{1-lla-tetrahydropyran-2 1} - yloxy-9-oxo-S β ■ -2-iuethyl-13-t £ £ in -prostenoat

Tetrahydropyran-2 ¹ -yl-lla-tetrahydropyran-2 ¹ -

-yloxy-9-oxo-8 ^ -17-methyl-19j20-dinor-13-_traris-

-prostenoat

Tetrahydropyran-2 ¹ -yl-lla-tetrahydropyran-2 ¹ -yloxy-9-oxo-8 ^ -16-methyl-18,19,20-trinor-13- ^; trans -prostenoat

Tetrahydropyran-2 '-yl-lla-tetrahydropyran-2' .- -yloxy-g-oxo-S ^ -J ^^ lT-trimethyl - ^^ O-dinor-lJ- - trans- prostenoate

Tetrahydropyran-2'-yl-lla-tetrahydropyran-2'-yloxy-9-oxo-8 | ^f -3-oxa-17-methyl-19,20-dinor- -13- trans -prostenoate

Tetrahydropyran-2 ¹ -yl-lla-tetrahydropyran-2 · - -yloxy-9-oxo-8 ξ -16-methyl-7a _J 7b-bishono-18j19, 20-trinor-13- trans -prostenoate

TetrahydropyraQ-2'-yl-lla-tetrahydropyran-2 ¹ - -yloxy-9-oxo-8t -2-r.ethyl-19-nor-15-tTans-
-prostenoate

2337531

Example 1417

Preparation of ethyl ha-tetrahydropyranyloxy-8 £ -9-0X0-13-trans-prostenoate

In the same manner as described in Example 1382
4-Tetrahydropyranyloxy-2- (6-carbethoxyhexyl) -cyclopent-2-en-1-one (Example 158) reacted with the alanate reagent, which is prepared from 1-octyne, diisobutylaluminum hydride and n-butyllithium. The crude product that you get after work-up
is purified by column chromatography on silica gel to give an oil, \ P max 1745 (ketone and ester carbonyl groups), 1035 (tetrahydropyranyloxy group), and
967 cm "(trans-vinyl group).

Examples 1418-1434

The alkyl-11cctetrahydropyran-2'-yloxy-9-oxo-8 "ζ -13-trans-prostenoate listed in the following Table 44 f are described in the same way as in Example 1382 from
the 4-tetrahydropyranyloxycyclopentenone esters used as starting material, which are listed in the table, and the alanates which are obtained from the listed 1-alkynes by treatment with diisobutylaluminum hydride and methyllithium
are produced.

409811/1203

Table 44

At- output-4-oxy- output game cyclopentenes-1-alkyne

ester ν example

laueiic -r-r

Alkyl 11α-tetrahydropyran-2'-yloxy-9-oxo-8 5-13-transprostenoate

1418 υϋ4 1-octyne 1419 6 * 3 cis-5-octene-1-in 1420 663 8-chloro-1-
octine 40981 1 / 1421
1422 667
668 1-heptine
5-methyl-1-
hexine 1203 1423
1424 I.
I.
t 669
669 1-0ctin
8-chloro-1-
dctin 1425 670 1-undecine ; 1426 '
i 671 1-pentin 1427 j 672 5-chloro-1-
pentine

Methyllla-tetrahydropyran-2 · -yloxy-9-oxo-8 % -13- - trans -prostenoate ■

Ethyl lla-tetrahydropyran-2'-yloxy-9-oxo-8 ξ-6,7- dinor-13- trans , 17- cis -prostadienoate

Ethyl lla-tetrahydropyran-2'-yloxy-9-oxo-8 ξ-20- -chlor -13-trans-prostenoate '

Ethyl Ίΐα-tetrahydropyran-2'-yloxy-9-oxo-8 ξ-7a, -7b-bishomo-20-nor-13-t £ ajTs-prostenoate

Ethyl lla-tetrahydropyran-2'-yloxy-9-oxo-8 % -2- -ethyl-iy-methyl-ig ^ Q-dinor-l ^ - trans -prostenoate

Ethyl lla-tetrahydropyran-2'-yloxy-9-oxo-8 % -Ί, ~?> - -dlmethyl-l ^ - trans -prostenoate

Ethyl lla-tetrahydropyran-2 '-yloxy-9-oxo-8 f - "! >> 3-dimethyl-20-chloro-13- trans -prostenoate

Ethyl lla-tetrahydropyran-2; -yloxy-9-oxo-8ξ-3- -oxa-20-propyl-13-t £ ans_-prostenoat "

Ethyl'lla-tet rahydropyran-2 '• -yloxy-9-pxp-8 | -2- -fluoro -18,19,20-trinor-13- ^ rans -prostehoate

Ethyl lla-tetrahydropyran-2'-yloxy-9-oxo-8 4-17 -chlor> -7,18,19,20-tetranor-13-trans_-prostenoate

Table 44 (continued)

1428

1 ^ 29 1 * 130 ο
to
co 1 * 31
1432 1203 1433

1434

673 4-methyl-1-
pentine 674 1-octyne 675 1-octyne 675 8-chloro-1-
octine 676 1-octyne 677 1-octyne 677 cis-5-octene
1-in

Ethyl-lla-tetrahydropyran-2'-yloxy-9-oxo-8 c-16- -methyl-7a-homo-18,19,20-trinor-13-tran_sprostenoate

Ethyl-lla-tetrahydropyran-2'-yloxy-9-oxo-8 | * -2- -phenyl-lj-trans-prostenoate

Butyl ~ lla-tetrahydropyran-2 -yloxy-9-oxo-8 £ -I5- -trans-prostenoate *

Butyl-lla-tetrahydropyran-2'-yloxy-9-oxo-8 ξ -20- -chloro-l ^ - trans -prostenoati

Isopropyl-lla-tetrahydropyran-2'-yloxy-9-oxo-8 ^ -l ^ -trans -proslenoat

Decyl-lla-tetrahydropyran-2 ¹ -yloxy-9-oxo-8 f-13- -trans-prostenoate

Decyl-lla-tetrahydrcpyran-2 -yloxy-9-oxo-8 f-13- -trans, 17-cis-prostadionoate

2337B81

Examples 1435 to 1459

In the same manner as described in Example 1382 gives
the treatment of the 4-alkoxycyclopentenone-tetrahydropyranyl ester listed in the following table 45, with the alanate, which is derived from the listed 1-alkyne, diisobutylaluminum hydride and methyllithium, the tetrahydropyran-2'-yl-11a listed in the following table alkoxy-9-oxo-8 S-13-trans-prostenoate.

409811 ./1203

At- output-4-output game alkoxycyclo- 1-alkyne pentenone v.Bsp.

Table 45
Tetrahydropyran-2 '-yl-11cc-alkoxy-9-oxo-8 £ -13-trans-prostenoate

CD
(O
OO

1435 1436 1437 1438 1439 1440 1441 1442 1443 1444

748 cis-5-octene-1-in

734 1-octyne

748 8-chloro-1-octyne

735 1-dodecine

748 1-heptyne 736 1-octyne

736 cis-5-octene-1-in

737 8-chloro-ioctyne

738 1-octyne

738 1-heptyne tetrahydropyran-2'-yl-lla-methoxy-9-οχο-δ K-IJ- - trans , 17- cis -prostadienoate ·

Tetrahydropyran-2 ¹ -yl-11α-ynethoxy-9-oxo-8 ξ -6,7- \ -dinor-ljS- trans -prostenoate. ■

Tetrahydropyran-2'-yl-lla-raethoxy-9-oxo-8 % -20- -chloro-13- trans -prostenoate /

Tetrahydropyran-2'-yl-lla-ethbxy-9-oxo-B ξ -5 ^ 6,7- -trinor-20-butyl-l ^ - trans -prostenoate

Tetrahydropyran-2 ^f -yl-lla-methoxy-9-oxo-8 % -20-nor-l ^ - trans -prostenoate

Tetrahydropyran-2'-yl-lla-methoxy-9-oxo-8 ξ-7a, 7b -bishomo-l ^ - trans -prostenoate

Tetrahydropyran-2'-yl-lla-methoxy-9-oxo-S ξ-7a, 7b -bishomo-l ^ - trans , 17- cis -prostadienoat ' ¹

Tetrahydropyran-2 ¹ -yl-lla-methoxy-9-oxo-8 ξ-2- -ethyl-20-chloro-l ^ -__tran £ -prostenoate

Tetrahydropyran-2 ^t -yl-lla-methoxy-9-oxo-8 ξ -3.5 "-dimethyl-'l ^ - trans -prostenoate,.

Tetrahydropyran-2'-yl-lla-methoxy-9-οχο-δ ξ -3, J- -dimethyl-20-nor-l ^ -trans-prostenoate

Table 45 (continued)

738 5-chloro-1 • pentyne

- 748 1-octyne

739 1-0ctin

739 1-pentin

1446 1447 1448

¹ SUN 1449 740 1-nonine ■ v. 1450 741 1-nonine IO
0 1451 742 1-octyne 1452
1453 742
743 8-chloro-i
octine
1-octyne 1454 744 . 1-octyne 1455 745 1-octyne

Tetrahydropyran-2 ¹ -yl-lla-methoxy-9-oxo-8 ξ -3 * 3-dimethyl-17-chloro-18,19,20-trinor-13-t_rans- -prostenoate

Tetrahydropyran-2'-yl-lla-methoxy-9-oxo-8ξ -13- - 1 rans -p ros tenoat

Tetrahydropyran-2 ¹ -yl-lla-methoxy-9-oxo-8 ξ -3-oxa- -13- trans -prostenoate

Tetrahydropyran-2'-yl-lla-methoxy-9-oxo-8 ξ -3-oxa- -18,19 j 20-trinor-13- trans -prostenoate.

Tetrahydropyran-2 ¹ -yl-lla-nethoxy-9-oxo-3 I-2-j, -fluor- -2 0-me thy ll ^ - trans -pros tenoat ν

Tetrahydropyran-2'-yl-lla-methoxy-9-οχο-δ | -20- -methyl-7-nor-13 ~ trans -ρrostenoate

Tetrahydropyran-2'-yl-lla-methoxy-9-oxo-8 | -7a- -homo-13- trans -prostenoate.

Tetrahydropyran-2 ¹ -yl-llα-methoxy-9-oxo-8 ξ-20- -chloro-7a-homo-13- trans -ρrostenoate

¹ Tetrahydropyran-2'-yl-lla-methoxy-9-oxo-S ξ-2- ": ί -phenyl-13- trans -prostenoate,:

¹ I ■. ·

Tetrahydropyran-2 '-yl-lla-ä-thoxy-g-oxo-a ξ -13-

- 1 rans -p rostenoat.

Tetrahydropyran-2'-yl-lla-propoxy-9-oxo-8 ξΐ3- -trans-orostenoat ■ -

Table 45 (continued)

to OO

IO O to

1-octyne tetrahydropyran-2'-yl-lla-isopropoxy-9-oxo-8.f -13-
- trans -prostenoate

1-octyne tetrahydropyran-2'-yl-lla-r; -butoxy-9-oxo-8C -13-
- trans -prosfrenoate:

cis-5-Oc- tetrahydropyran-2'-yl-lla-ethoxy-9-oxo-8 ζ -13- trans , ten-1- yn 17- ci s -p rostadlenoat- 'ι

^{li | 59} J ^^ 8-chloro- "tetrahydropyran-2'-yl-lla-ethoxy-9-oxo-8 ξ -20- | ■■

1, -octyne: -chloro -13- trans -prostenoate ■ I

NJ (Ti

Examples 1460-1482

The alkyl-11a-alkoxy-9-oxo-13-trans-prostenoates listed in the following table 46 are obtained by treating the listed alkyl-4-alkoxycyclopentenones in the table with the alanate, which is obtained from the listed alkynes, diisobutylaluminum hydride and methyllithium prepared by the procedure of Example 1382. The products thus obtained are dissolved in a large excess of 0.18 M potassium acetate in 99% methanol and the solution is kept at room temperature under nitrogen for 90 hours. The solution is concentrated at room temperature and the residue is partitioned between ether and water. The aqueous phase is adjusted to a pH of 4 by adding 4N hydrochloric acid and a 0.05M solution of the crude product in glacial acetic acid-tetrahydrofuran-water (4: 2: 1) is ^{heated to 45 °} C. for 3> 5 hours . The solution is diluted with water, extracted with ether. The extract is washed successively with water and saturated sodium chloride solution, dried over magnesium sulfate and concentrated. Column chromatography of the residue gives the title compounds.

/.09811/1203

At-output-4-output game alkoxycyclo-1-alkyne pentenon ester

Table 46
Alkyl-11cc-alkoxy-9-oxo-13-trans-prostenoate

1460 679 1-octyne Ethyl lla-ethoxy-9-oxo-13-trans-prostenoate 1461 680 1-nonine Methyl-llci-methoxy-9-oxo-20-methyl-13-trans-
-prostenoate 1462 680 5-chloro-1-
pentin ' Methyl-lld-methoxy-9-oxo-17-chloro -18,19,20-
-trinor-13-trans-prostenoate O
(O 1463 681 8-chlorine- j
1-octine j & thyl-lla-propoxy-9-oxo-20-chloro-6 _J 7, -dinor-lj-
-trans-prostenoat OO 1464 708 1-octyne Ethyl 11a-t-butoxy-9-oxo-13-trans-prostenoate. —Λ
KJ 1465
i 682 1-heptine Ethyl-llα-isopropoxy-9-oxo-5,6 _J 7,20-tetranor-13-
-trans-prostenoat O
u> 1466 686 1-octyne Ethyl-lla-isopropoxy-9-oxo-7a, 7b-bishomo-13-
-trans-prostenoat 1467
:
ι 686 cis-5-Oc-
ten-1-in Ethyl-lla-isopropoxy-9-oxo-7a., 7b-bishomo-13-1
-trans, 17-cij-prostadienoat! 1468 688 1-pentin Ethyl-lla-n_-butoxy-9-oxo-2-ethyl-18,19,20-trlnor-
-13-trans-prostenoat '■ ■ 1469 690 cis-5-Oc-
ten-1-in Ethyl-llα-methoxy-9-oxo-3,3-d! Methyl-13-trans,
^ -cis-Drostadienoat ' 1470
ι 690 1-nonine Ethyl-lla-methoxy-9-oxo-3,3,20-trimethyI-I3-
-trans-prostenoat

■■ _n ■

Table 46 (continued) 692 8-chlorine-

1-octyne

692 1-hexyne

1472

1 * 73 1474 O
IO
SO 1 ^ 75
1476 to
O 1 ^ 77
1478 1 ^ 79 1480 " 1481 1482

69h 1-octine

696 1-octyne

698 1-pentin

700 cis-5-octene-1-in

701 1-octyne

702 1-0ctin

703 1-octyne 703

Octene-1-in

703 5-methyl-1-hexyne

690 4-methyl-1-pentine- trans -prostenoate

Ethyl-
trans -prostenoat

- ^, 20-ainor-13-

Xthyl-lla-propoxy-9-oxo-2-fluoro, -13- trans - -prostenoate

Ethyl-11a-sec-but oxy-9-oxo-7-nor-lj5-tran £ - -prostenoa ^

-13- trans -prostenoate.

Ethyl-lla-ä; th'oxy-9-oxo-2-phenyl-13- trans , 17- cls - -prostadienoate

n-Butyl-lla-methoxy-9-oxo-13- trans- prostenoat Isopropyl-lla-methoxy-9-oxo-13- trans -prostenoat Decyl-lla-methoxy-9-oxo-13- ^ £ an_s_-prostenoat '

Decyl-lla-methoxy-g-oxo- ^ -trans , 17- cis -prostadlenoat ·,. '

Decyl-lla-methoxy-9-oxo-17 ¹ methyl-19,20-dinor-13-. - trans -prostenoate ·. , _

A: thyl-lla-methoxy-9-oxo-3, ^, i6-trimethyl-18,19> 20- -trlnor-13-trans-prostenoat '

Examples 1483-1515

The 11oc- (cc? -Tetra-
hydropyran-2 ^f -yloxy) -9-oxo-8 ξ -prostenic acid ester are made according to the method described in Example 1382
the listed 4 - (^ - tetrahydropyran-2'-yloxyalkoxy) -cyclopentenone esters and the alanate reagents prepared from the listed 1-alkynes, diisobutylaluminum hydride
and made methyllithium.

/, 09811/1203

At- output-4- (oJ- output game tetrahydropyran-1-alkyne

2'-yloxyalkoxy) -cyclopentenon- ester v.Bexample

Tabel

11a- (Co> -Tetrahydropyran-2 ¹ -yloxyalkoxy) -9-0X0-8 acid esters

1483 753 cis-5-Oc- Tetrahydropyran-2 '-yl llot- (ß-tetrahydropyran-2' -
-yloxyethoxy) -9-oxo-8 ξ-l> -trans, 17-cis-
-prostadienoat i 1484 753 8-chlorine-
1-octyne Tetrahydropyran-2. ¹ -yl lla- (ß-tetrahydropyran-2 '-
-yloxyethoxy) -9-oxo-8 ξ-20-chloro -rj-trans- ·
-prostenoate 1485 753 1-nonine Tetrahydropyran-2'-yl lla- (ß-tetrahydropyran-2 ^f -
-yloxyethoxy) -9-0x0-8 f ^ O-methyl-rj-trans-
-prostenoate 1486 753 1-heptine Tetrahydropyran-2'-yl lla- (ß-tetrahydropyran-2'-
-yloxyethoxy) -9-0x0-8 £ -20-nor-13-trans-
-prostenoate 1487 754 1-octyne Tetrahydropyran-2 ¹ -yl lla- (ß-tetrahydropyran-2'-
-yloxyethoxy) -9-0x0-8 ξ -S ^ -dinor-l ^ -trans-
-prostenoate 1488 755 Ί-Undecine Tetrahydropyran-2'-yl lld- (ß-tetrahydropyran-2 ¹ -
-yloxyethoxy) -9-0x0-8 ξ-5, 6,7-trinor-20-propyl-
-13-trans-prostenoate 14ö9 1-octyne Tetrahydropyran-2 '-yl Ha- (ß-tetrahydropyran-2' -
-yloxyethoxy) -9-0x0-8 ξ ^ a ^ b-bishomo-rj-trans-
-prostenoate

Table 47 (continued) 1490 758 1-Octyne

1491 1492

1493 1494 1495 1496 1497

7βΟ

1-octyne

7 ^β0 cis-5-

Octene-1-in

762 1-octyne

762 cis-5-octene-1-in

5-chloro-ipentin

764 5-methyl-1-hexyne

753 1-octyne tetrahydropyran-2'-yl lla- (ß-tetrahydropyran-2 '-yloxyethoxy) -9-0x0-8 ξ -2-ethyl-13- trans - -prostenoate

Tetrahydropyran-2'-yl lla- (ß-tetrahydropyran-2 '-yloxyethoxy) -9-0x0-8 ξ -j ^ -dimethyl ^ trans -prostenoate

Tetrahyd ropyran-2 ¹ -yl lla- (ß-tetrahydropyran-2'- -yloxyethoxy) -9-0x0-84 - ^ j ^ -dimethyl-l ^ - trans ^ 17- cis- prostadienoate

Tetrahydropyran-2'-yl Ila- (β-tetrahydropyran-2'-yloxyethoxy) -9-oxo-8f -3-oxa-13- trans - -prostenoate

Tetrahydropyran-2'-yl lla- (ß-tetrahydropyran-2'-fyloxyethoxy) -9-0x0-8 | -3-oxa-l ^ -trans , 17 -cis - -prostadienoate

Tetrahydropyran-2'-yl lla- (ß-tetrahydropyran-2 ·· -yloxyethoxy) -9-0x0-8! -J-oxa - ^ - chlorine. -18.19, 20-trlnor-l ^ -trans -prostenoat

Tetrahydropyran-2 ¹ -yl lla- (ß-tetrahydropyran-2 ^f -yloxyethoxy) -9-0x0-8 f -2-fluoro'-rf-methyl- ^, -20-dinor-13-trans_-prostenoate.

Tetrahydropyran-2 ¹ -yl ila- (ß-tetrahydropyran-2 '· -yloxyethoxy) -9-0x0-8? * · -1 ^ -trans-prostenoate

K) CO

to

Table 47 (Continuation) 1-octyne 1198 766 cis-5-Oc-
ten-1-in 1199 767 1-octyne 1500 768 1-dodecine, O 1501 749 i
I. co 5-chlorine- ^:
1-pentine co 1502 750 1-pentin ' O 1503 751 1-octyne ■ 759 4-methyl-:
1-pentine 1505 ^: 763 1-octyne 150.6 773 1-undecine 1507 752

Tetrahydropyran-2'-yl lla- (ß-tetrahydropyran-2 · - -yloxyethoxy) -9-oxo-8 ζ -7-nor-13-trans-prostenoate '

Tetrahydropyran-2'-yl JLIa- (ß-tetrahydropyran-2 ¹ -

i-8f -7a-l ■ - ·

-prostadienoat.

-yloxyätho.xy) -9-oxo-

-homo-15-trans, 17-cls-

Tetrahydropyran-2'-yl Hja- (ß-tetrahydropyran-2'- j -yloxyethoxy) -9-0x0-81-2-phenyl-IJ-j j

-prostenoate.

Ethyl IIIa- (ß-tetrahydropyran-2-yloxyethoxy) -9-oxo-; -8 \ -20-butyl-l3 trans -prostenoat · \

Methyl lla- (ß-tetrahydropyran-2-yloxyethoxy) -9oxor -8f -17-chloro -lSig ^ til t |

-prostenoate;

ethyl lla- (- / - tetrahydropyran-2 '-yloxypropoxy) S- oxo- -8 ^ -5.7, lOß 19,20 -pentanor-l3- trans- prostenoate \

Ethyl lla- (V-tetrahydropyran ^ ¹ -yloxypropoxy) -9-0x0- -8ξ ^ -. 'Thyl-l ^ -trahs -prostenoate>

Etiyrl lla- (y-tetrahydropyran-2 -yloxypropoxyi-9-'oxo- -85 O-oxa-lS-methyl-lSj.ig ^ O-trinor-lJ-trans- |

prostenoat '· · i

Tetrahydropyran-2 · -yl.lla- (ß-tetrahydropyran-2 · ^ -yloxypropoxy) -9-oxo-8f-13-tran £ -prostenate - ',

Ethyl IIIa- (β-tetrahydropyran-2'-yloxyabhoxy) -9-oxo -8Γ -5,6,7-trinor-20-propyl-13-trans-prostenoate:

Table 47 (continued)

1508 757 cis-5-Oc-
ten-1-in 1509 761 8-chloro-1-
octine 1510 765 1-nonine O
4O
OO 1511 769 1-pentin 1512 770 1-octyne χ
KJ
O 1513 771 1-octyne HM 772 1-octine. 1515 772 cis-5-Oc-
ten-1-in

Tetrahydropyran-2'-yl-lla- (ß-tetrahydropyran- _m \ -2'-yloxyethoxy) -9-oxo-8 ^ -Ta ^ Tb-bishomo-lJ-! - trana , 17 -c is -ρ ros tadlenoat

Ethyl-IIIa- (ß-tetrahydropyran-2'-yloxyethoxy) - 9-9-0X0-81 - ^, ^ - dimethyl-SO-chloro -13 -trans - -prostenoate

Ethyl-11α- · (β-tetrahydropyran-2 '-yloxyäthoxy) -9-oxo-81-2 -20-fluoro-l-methyl ^ - trans -prostenoat.

Ethyl-lla- (ß-tetrahydropyran-2'-yloxyethoxy) -9- -oxo-8 f-2-phenyl-18,19 _J 20-trinor-13- ^ ran £ - -prostenoate

Butyl-lla- (ß-tetrahydropyran-2 ^f -yloxyethoxy) -9- -oxo-8 ξ-l3- trans -prostenoate »

Isopropyl-IIIa- (β-tetrahydropyran-2'-yloxyethoxy) - -9-oxo-o f-1 ^ - trans -prostenoate

Decyl - lla- (ß-tetrahydropyran-2'-yloxyethoxy) -9- -oxo-8 ^ -l ^ - trans -prostenoate>

Decyl - lla- (ß-tetrahydropyran-2'-yloxyethoxy) -9- -oxo-8 £ -13- trans , 17- cls -prostadlenoate

3 3 7-81

Example 1516

Preparation of tetrahydropyran-2'-yl-11a- (4-tetrahydropyranyloxybutoxy) -9-0X0-8 Σ -13 "-trans-prostenoat

In the same way as described in Example 1382, the mixture of 4-tetrahydropyranyloxy-2- (6-tetrahydropyranylcarboxyhexyl) -cyclopenta-en-1-one and 4- (4-tetrahydropyranyloxybutoxy) -2- (6-tetrahydropyranylcarboxyhexyl) -cyclopent-2-en-1-one into a mixture of the title compound and tetrahydropyran-2 "-yl-i1a-tetrahydropyranyloxy-9-oxo-S ξ-13-transprostenoate transferred using the alanate reagent prepared from 1-octyne, diisobutylaluminum hydride and methyllithium is obtained.

Example 1517

Production of ethyl 11oc ~ acetoxy-9-oxo-13-trans-prostenoate

A solution of 4.97 g (45 mmol) of 1-octyne in 8 ml of benzene is treated with 37.5 ml of 1.2 M diisobutylaluminum hydride in hexane and the solution is then heated to 50 ° C. for 2 hours. The solution is cooled to 5 ° C. and diluted with 25 ml of ether. To the stirred solution is added 25 ml of 1.6 M n-butyllithium in hexane over 5 minutes and the resulting solution is then stirred at ambient temperature for 20 minutes. The solution of the Alanatreagens is cooled to 5 ⁰ C and treated with a solution of 8.90 g (30 mmol) of 4-acetoxy-2- (6-carbäthoxyhexyl) -cyclo ~ pent-2-en-1-one in 10 ml of ether treated for 10 minutes. The resulting solution is stirred at room temperature for 22.5 hours and diluted with ether. The solution is added to a stirred mixture of ice and hydrochloric acid over 5 minutes. The ether phase is washed with cold dilute hydrochloric acid and saturated sodium chloride solution, dried over magnesium sulfate and concentrated. A 0.05 M solution of the crude product in glacial acetic acid-tetrahydrofuran-water (4: 2: 1) is heated to 45 ° C. for 3.5 hours. The solution is diluted with water and extracted with ether.

/.09811/1203

The extract is successively mixed with water and saturated sodium chloride solution washed, dried over magnesium sulfate and concentrated.

Example 1518 Preparation of 11a-hydroxy-9-oxo-13-trans-prostenoic acid

A stirred solution of 23.9 g (50 mmol maximum content) crude tetrahydropyran-2-yl-11a-tetrahydropyranyloxy-9-oxo-13-trans'-prostenoate (Example 1382) in 1 l of glacial acetic acid-tetrahydrofuran-water (4: 2: 1) is stirred at 45 ° C for 3.5 hours. The cooled solution is treated with a solution that consists of 1 1 of water and 500 ml of saturated sodium chloride solution is prepared, and extracted with ether. The extract is made one at a time treated with water and saturated sodium chloride solution and dried over magnesium sulfate. That after vaporizing the crude product obtained from the solvent is purified by chromatography on silica gel to give an oil, v "max 1740 (ketone carbonyl group), 1710 (acidic carbonyl group) and 965 cm "(trans-vinyl group).

Example 1519

Preparation of 11a- (4-hydroxybutoxy) ~ 9-oxo-13-trans-prostenic acid

In the same way as described in Example 1518, the mixture of tetrahydropyran-2'-yl-11a-tetrahydropyranyloxy-9-OXO-8 % -13-trans-prostenoate and tetrahydropyran-2 '-yl-11 oc- (tetrahydropyranyloxybutoxy) -9-0X0-8 £ -13-trans-prostenoate (Example 1516) converted into a mixture of the title compound and 11oc-hydroxy-9-oxo-13-trans-prostenic acid by warming with glacial acetic acid-tetrahydrofuran-water. The products are separated and purified by column chromatography on silica gel. The title compound is obtained as an oil, ^? max 3420 (hydroxyl groups), 1740 (ketone carbonyl group), 1715

/. Q 9 8 1 1/1 2 Q 3

(acidic carbonyl group), 1102 (ether group) and 966 cm
(trans-vinyl group).

-1

Examples 1520-1598

In the same way as described in Example 1518, the various 11-oxy-9-oxo-13-trans-prostenoate esters listed in Table 48 below are hydrolyzed, with
the tetrahydropyranyl protective groups are split off and the 11-oxy-9-oxo-13-trans-prostenic acids listed in the table are obtained.

Examples output 9-Oxospiel prostenoat Bei game

Table 48
9-0x0-13-trans-prostenic acids

1520 1383 4Q9i lla-Hydroxy-g-oxo-e ^ -dinor-
-13-trans-prosten-acid 1521 1384 Ha-Hydroxy-9-ox6-20-chlorine -
-e ^ -dinor-rj-trans-prostencic acid 1522. '1385 lla-hydroxy-9-oxo-5, 6,7-trinor-
- ^ O-methyl-rj-trans-prostemic acid 1523 . 1386 lla-hydroxy-9-oxo-7a, 7b-bis-
homo-13-trans-prostenic acid 1524 1387 lla-hydroxy-9-oxo-7a, 7b-bis-
homo-20-nor-13-trans-prosten-
acid 1525 1388 lla-hydroxy-9-oxo-2-ethyl-13-
-trans-prostenic acid 1526 1389 Ha-hydroxy-9-oxo-2-ethyl-18,
^^ O-trinor-lJ-trans-prostenv-
acid 1527 1390 lla-Hydroxy-9-oxo-3,3-dimethyl »
-13-trans-prostenic acid 1528 1391 lla-hydroxy-9-oxo-3,3-dimethyl-
-13-trans, 17-cis-prostadia * -
acid 1529 1392 lla-hydroxy-9-oxo-3,3-dimethyl-
- ^, SO-dinor-lJ-trans-prosten-
ftrf203

_ TOO _

Table 48 (continued) 1530 1393

1531 1394 1532 1395 1533 1396 1534 1397 ι
1535 1398 1536 1399 1537 1400 1538 1401 1539 . 1402 1540 Ι4θ3 1541 Ι4θ4 1542 1405 1543 Ι4θ6 1544 1407 1545 1408 1546 1409

lla-Hydroxy-9-oxo-3,5-dimethyl- -17-chloro -18, l?, 20-trinor-13- - trans- prostatic acid

lla-Hvdroxv-q-oxo-3-oxa-13- trans - -prostenic acid

Ila-hydroxy-9-oxo-3-oxa-20-butyl-13- trans -prostenic acid

Ila-hydroxy-9-oxo-2-fluoro-13- trans -prostenic acid

Ila-hydroxy-9-oxo-7-nor-13- - trans -prostenic acid

lla-Hydroxy-9-oxo-20-chloro-7- -nor-13- trans -prostenic acid

lla-Hydroxy ^ -oxo-Ja-homo - ^ - -jbrans_-p r os t en «acid

-nor-13- trans -pro sten * acid

lla-Ijydroxy-9-oxo-7a-homo-13- - trans , 17- cis -prostadlen -

acid

lla-Hydroxy-9-oxo-2-phenyl-13- - trans -prostenic acid

lla-Hydroxy-9-oxo-20-chloro <-2- -phenyl-13-trans-prostenic acid

lla-Hydroxy-9-oxo-20-nor-13- -t_rans_-p rost en säure

lla-hydroxy-9-oxo-18,19,20- -trlnor-13-trans-pro st ent acid

lla-Hydroxy-9-oxo-20-Sthyl-lJ- - trans -prostenic acid

11α-Hydroxy-9-oxo-20-chloro-13- trans -prostenic acid

llq-Hydroxy-9-oxo-13-tr ans ^ 17- cis -prostadlen acid "~~

lla-Hydroxy-9-oxo-17-chloro-18,19,20-trlnor-13- trans - -proEtensäui'O

Λ Π 9 B1 1/12 0 3

2337B8 1

Table 48 (continued) 1547

1548

1550 1551 1552

1553

155 * 1

1412

1413

1414

1415

1435

1436

1555 ¹ 1437 1556 1438 1557 1439 1558 ₍ • 1440 1559 1441 1560 1442 1561 1443 156 2 1444

1563

1445 11a-Hydroxy-9-oxo-2-methyl- -13- trans -prostenic acid

lla-Hydroxy-Oy-oxo-lT-methyl- -19 _t 20-dlnor-13- trans -prosten

acid

yyg
-18,19,20-trinor-13- trans - -prostenic acid - ■

lla-Hydroxy-9-oxo-3,3,17-trimethyl-19f20-dinor-13- trans - -prostenic acid

lla-Hydroxy-9-oxo-J-oxa-17- -methyl-19,20-dlpor-l ^ - trans - -prostenic acid

llα-PIydroxy-9-oxo-16-methyl-7a, 7b-bißhomo-l8 ₄ 19,20-frinor-13- - tran s-prostengic acid

11a-methoxy-9-oxo-lj-jtrans_, 17- c is -prostenaure '.

lla-M.ethoxy-9-oxo-6,7-dinor- -13-trans-prostatic acid

lla-l-lethoxy-9-oxo-20-chloro-13- trans -prostenic acid

llα-Ä ■ thoxy-9-oxo-5J6 _ί 7-trlnor--20-butyl-13- trans -prostenic acid

lla-methoxy-9-oxo-20-nor-13- - trans -prostenic acid

11a-methoxy-9-oxo-7a, 7b-bishomo-13- trans -prpstenic acid

11a-methoxy-9-oxo-7a, 7b-bishomo-13-trans, 17- cls -prostadienoic acid

11a-methoxy-9-oxo-2-ethy1-20- -chlor -13- trans -prostemic acid

lla-methoxy-9-oxo-3i 3-dimethyl- -13- trans -prostenoic acid

IIIa-methoxy-9-oxo-3> 3-dimethyl-- 20-nor-13-trans -prostenic acid

lla-methoxy-9-oxo-3j3-diraethyl · -17-chloro -18,19,20-trinor- -13- trans -prostenic acid

4098 11/1203

ORtßfNAL INSPECTED

-j I ν, - Ö I

Table 48 (continued) 156k 1446

1565 1566

1567 156 8

¹ ^ 69 157 _Ο

1571

1447 1448

1449 1450

1572 1454 1573 1455 1574 1456 1575 . 1457 1576 1458 1577. "1459 1578 1483 1579 1484 1580 1485 1581 1486

l? q-Methoxy-9-oxo-'13- trans prostenic acid

11a-methoxy-9-0x0-3-oxa-15- - trans -prostenic acid

lla-methoxy-9-oxo-3-oxa-l8, 19, 20-trinor-13- trans -prosten--

acidic

lla-methoxy-9-oxo-2-fluoro -20- -methyl-13-trans-prostenic acid

-7-nor-13- trans -prostenic acid

lla-.Methoxy ^ -oxo ^ a-homo - ^ - - trans -prost enic acid

lla-methoxy-9-oxo-20-chloro-7a- -homo-13- trans -prostenic acid

lla-methoxy-g-oxo - ^ - phenyl- -13- trans -prostenic acid

Ila-ethoxy-9-oxo-13-t £ ans> -prostenic acid

1 la - prop oxy-9 - oxo -13 - tnms_- -prostenic acid. -

lla-isopropoxy-9-oxo-13-jtrans_- -prostenic acid. · ^J

lla-ri-butoxy-9-oxo-13-t £ ans_- -prostenic acid

lla-ethoxy-9-oxo-13-tran_s, 17- -cls -prostadlenic acid

llα-ethoxy-9-oxo-20-chlori -13- - trans -prostenic acid

lla- (ß-hydroxyethoxy) -9-0x0-13 * -trans, 17- cls -prostadlenic acid

lla- (ß-Hydroxyäfchoxy) -9-0x0-20- -chlor -13-t £ ans_-p rosten acid

lla- (ß-hydroxyethoxy) -9-0x0-20- -methy1-13- trans -pro st en acid

lla- (β-hydroxyethoxy) -9-0x0-20- -nor-13-trans-prostenic acid

U 0 9 8 1 1/12 0 3

ORlGfNAL INSPECTED

Table 48 (continued) 1582-1487

1583

1585
1586

1587
1588

1589

1590

1591

1488 1489 1490

1491 1492

1493 1494

1495 1496

1592 1498 1593 ' '1499 1594 1500 1595 1506 1596 1497

11α- ( β-Hydroxyethoxy) -9-oxo-6,7, -dinor-13-trans-prostenic acid

IIIa- (β-hydroxyethoxy) -9-0x0-5, 6,7-trlnor-20-propyl-13- trans - -prostenic acid

lla- (ß-hydroxyethoxy) -9-oxo- ^ a ^ b-bishomo-l ^ - trans -prosten-

acid

lla- (ß-hydroxyethoxy) -9-oxo-2-ethyl-lj-trans-prosten acid

lla- (ß-hydroxyethoxy) -9-0x0-5, 3-dimethyl-l ^ - trans -prostenic acid

lla- (β-hydroxyethoxy) -9-0x0-5, jS-dimethyl-rs- trans -iy- cis -prostadierßäure

lla- (ß-hydroxyethoxy) -9-0x0- -3-oxa-15- trans -prostenic acid

lla- (ß-hydroxyethoxy) -9-0x0-515 t 17- cls -

-prostatic acid

lla- (ß-hydroxyethoxy) -9-0x0- -5-oxa-lT-chlorine -18,19,20- -trlnor-15-trans-p.rostenic acid

lla- (ß-hydroxyethoxy) -9-0x0- -2-fluoro -lT-methyl-ig ^ O- -dinor-IJ-trans-prosten acid

LLA (ß-hydroxyethoxy) -7-nor--9-0x0- LJ5 -trans -prosten acid

lla- (β-hydroxyethoxy) -9-0x0- - 7a-homo -15 - t_rans_ ₇ i7. c3 ^ _p _{r 0}

■ stage acid

lla- (ß-hydroxyethoxy) -9-0x0- -2 -phenyl -lj-tranjä-p rost en. -

acid

lla- (β-hydroxypropoxy) -9-oxo- -15- trans -prostenic acid

lla- (ß-Hydroxyethoxy) -9-oxo-l> -trans-prosten acid

/, 0981 1/1203

Table 48 (continued)

1597-1508

1598 1416

lla- (ß-hydroxyethoxy) -9-oxo- -7a, 7b-bishomo-l3- trans , 17- ~ _c_is-prostadien acid '

lla-hydroxy-9-oxo-2-methyl-20- -nor-13-ixgllß-prosten acid

Example 1599

Manufacture of ethyl-Ha-hydroxy-g-oxo - ^ - trans-prostenoate

A solution of 4.51 g (10 mmol) of ethyl 11a-tetrahydropyranyloxy-9-oxo-8E-13-prostenoate (Example 1417) in 200 ml of glacial acetic acid-water-tetrahydrofuran (19: 11: 3) is added for 30 minutes heated to 45 ° C and held at this temperature for 60 minutes. The solution is cooled, diluted with water and extracted with ether. The extract is washed successively with water and saturated sodium chloride solution, dried over magnesium sulfate and concentrated. Column chromatography of the residue on acid-washed silica gel gives an oil, O max 3420 (hydroxyl group), 1745 (carbonyl groups) and 967 cm "(trans-vinyl group).

Examples I600 to 1616

In the same manner as described in Example 1599, the 11 oc-tetrahydropyranyloxy-alkyl esters of the following table are grounded 49 hydrolyzed to give the alkyl-11-oc-hydroxy-9-oxo-13-trans-prostenoate described in the table.

Table 49

Example starting Hct-Tetrahydro-alkyl-1 ioc-hydroxy-9-oxo-i 3-game pyran-2 ^f -yloxyderivate trans-prostenoate of example

1600 1418 Methyl llot-hydroxy-g-oxo-lj-
-trans-prostenoat 1601 14I ₉ Ethyl 11a-hydroxy-6,7-dinor-
-13-trans, 17-cis-prosta-
dienoat 1602 1420 Ethyl lla-hydroxy-20-chlorine -
-13-trans-prostenoate ·.

/ 4 0 9 8 1 1/12 0 3

2337böl

Table 49 (continued). “.

1603 ι ψ • 1421 Ethyl lla-hydroxy-7a, 7b-bis-
homo-2 O-nor-Γ5-tran s -pro
stenoate 1604 1422 1605 1423 Ethyl] Ια-hydroxy-2- ethyl-
-r / Vmethyl-ig ^ O-dlnor-lJ-
-trans-prostenoat Ι6θ6 1424 Ethyl lla-hydroxy-3,3-dimethyl
-lj-trans-prostenoate 1607 1425 Ethyl Ila-hydroxyr3,3-dimethyl
-20-chlorine -lj-trans-pro-
stenoate 1608 1426 Ethyl lla-hydroxy-3-oxa-20-
-propyl-13-trans-prostenoate ' 1609 1427 Ethyl lla-hydroxy-2-fluorine -
-18,19,20-trinor-lj5-trans-
-prostenoate Ethyl lla-hydroxy-17-chlorine -
7,18,19,20-tetranor-13-trans- 1610 1428 -prostenoate Ethyl lla-hydroxy-lß-methyl- 1611 1429 -trans-prostenoat 1612 1430 Ethyl llα-hydroxy-2-phenyl-13-
-trans-prostenoat 1613 1431 Butyl lla-hydroxy-13-trans-
-prostenoate 1614 1432 Butyl lla-hydroxy-20-chlorine -
-13-trans-prostenoate 1615 1433 Isopropyl Ila-hydroxy-lj5-
.-trans-prostenoat ■ 1434 ripnvl lla-hvdroxy-13-trans-
-prostenoate IuJlD Decyl lla-hydroxy-1? -trans, 17-cis-prostadienoate

U 0 9 8 1 1/1 2 Q 3

Examples 1617 to 1629

In the same manner as described in Example 1599, the various are listed in Table 50 below
Tetrahydropyranyloxyderivate hydrolyzed, giving the alkyl-11α- (tU-hydroxyalkoxy) -9-oxo-13-trans-prostenoate described in the table.

Table 50

At- starting tetrahydro-alkyl-11a- (cc> -hydroxyalkoxy) -9-

play pyran-2'-yl derivatives oxo-13-trans-prostenoate

of example

1617
1618

1619
1620
1621

1622
1623
1624 -

1625
1626

I50I 1502

1503 1504 1505 -

1507 1509 1510

1511 1512 Ethyl lla- (ß-hydroxyethoxy) - -9-oxo-20-butyl-13-trajTs- -prostenoate. · J

Methyl Ila- (ß-hydroxyethoxy) - -9-oxo-17-chloro -18,19,20- -trinor-13- trans -prostenpat

Ethyl LLA (v'-hydroxypropoxy) - -9-0x0-6, 7, 18,19,20-pentanor -l ^ - trans -prostenoat

Ethyl lla- (V-hydroxypropoxy) - -9-0x0-2-ethyl-13- _i trans _i - ". 'Prostenoate

Ethyl lla - (/ - hydroxypropoxy) - -g-oxo - ^ - oxa-lG-methyl-ie, I9, 2 0-trinor-1] 5-t_r * n8 -prostenoate

[Ethyl lla- (ß-hydroxyethoxy) -! -9-0x0-5,6,7-trinor-20-propyl- -13- tranB -prostenoate

Ethyl lla-ν0-hydroxyethoxy) - -9-0x0-3, J-dimethyl-20-chloro -13- trans -prostenoate.

Ethyl lla- (ß-hydroxyethoxy) - -9-oxo-2-fluoro -20-ITIe ^ yI-IJ- - trans -prostenoate

Ethyl lla- (ß-hydroxyethoxy) - -9-0x0-2-phenyl-18,19,20-trinor- -13- trans -prostenoate

Butyl lla- (ß-hydroxyethoxy) - -9-0x0-13- trans -prostenoate

/, 09811/1203

23

Table 50 (continued) 1627 1513

1628

1629

151 ¹ »

1515

[Isopropyl lla- (ß-hydroxyethoxy) -j -9-oxo-13-t £ ans-prostenoate

Decyl Ila- (J3-hydroxy ethoxy) -9- -oxo-13- trans -prostenoate

j decyl lla-fc-hydroxy ethoxy) -9-i -oxo-13- trans -17-CJLs-P rösta-, dienoate

Example 1650

Preparation of 9-oxo-10,13-trans-prostadienoic acid

A solution of 338 mg (T.00 mmol) of 11a-hydroxy-9-oxo-13-tr & nsprosteinäure (Example 1518) in 6.67 ml of 1.5N hydrochloric acid and 13.3 ml of tetrahydrofuran is stored at room temperature for 70 hours. The solution is treated with saturated sodium chloride solution and extracted with ether. The extract is washed successively with water and saturated sodium chloride solution and dried over magnesium sulfate. The crude product obtained after evaporation of the solvent is purified by chromatography on silica gel to give an oil, X ^ f? ^H 217 m / u (9500), v? max 1700 (acidic carbonyl group), 1690 (ketone carbonyl group), 1585

-1 (conjugated olefin group) and 965 cm ", (trans-vinyl group).

Examples 1631 to 1667

In the same manner as described in Example 1630, treatment of dilute hydrochloric acid gives the various Ha-hydroxy-13-trans-prostenoic acids listed in Table 51 or esters of the 9-oxo-10,13-trans-prostadienoic acids or esters listed in the table.

Table 51

At-output-11 a-Hydro xyspiel trans-prostenic acid

or -ester of example

9-0x0-10,13-trans-prostadic acid or ester

1631
1632

1520

1521

9-0x0-6,7-dinor-10,13-trans -prostadienäure · ·

-6,7-dinor- -lO-ljS- trans -proBtadlenic acid

/, 09811/1203

Table 51_ (continued) 1633. 1522

1634 ' 1523 1635 1524 1636 1525 1637
I. 1526 1638 1527 1639 "' 1528 I64o 1529 1641 1530 1642 1531 1643 1532 1644 1533 1645 1534 1646 1535 1647 1536 1648 ■ - 1537 1649 1538 1650 1539

9-0x0-5,6,7 ~ trinor-20-methyl- -10-13-trans-proetadiene acid

9- 0XO-7a, 7b-bishomo-10.13- -trans -prostadien acid

9-0xo-7a, 7b-birfhomo-2d-nor- -10,13-trans-pfostadlenv acid

9-0xo-2-ethyl-l0.13- trans -prostadienoic acid

9-0x0-2-ethyl-l8,19> 20 trinor 10.13 trans -prostadien acid

9-0x0-3,3-dimethyl-lO, 13- trans -prostadien acid.

9-Oxo-3,3-dimethyl-10,13- - trans , 17-cls-prostatrienic acid

9-oxo-3,3-dimethyl-19,20- -dinor-10,13- trans -prostadien, -

acid

9-0xo-3,3-dimethyl-17-chloro-18,19,20-trlnor-10,13- trans prostadienic acid

9-0xo-3-oxa-10,13- trans -, prostadienv acid. E

9-0xo-3-oxa-20-butyl-10,13- - trans -prostadien. acid

9-Oxo-2-fluoro · -10,13- trans - -prostadienic acid

9-0xo-7-nor-10,13- trans - -prostadien acid

9-Qxo-20-chloro-7-nor-10, l3- - trans- prostadlenic acid _Λ

9- 0xo-7a-homo-10.13 -trans - -pros tad ien-acid

9-0xo-7a-homo-20-nor-10,13- - trans -prostadienoic acid

9-0xo-7a-homo-10,13- trans , 17 -cis -prostatrienoic acid

9-0xo-2-phenyl-l0,13-trans- -pro3tadicn. '.;. ^: iuro

• ^ 09811/1203

continuation Table 51 1651 15 ^ 0 1652 • 1541 1653 1542 1654 ' *
1543 1655 1544 1656
ι 15- ¹ IS 1657 1546 165-8 1546 1659 " 1547

1660
1661
1662
1663

1664

1565
1666

1667

1548

1549 1550

1551

1599 1602 9-0xo-20-chloro-2-phenyl-10, 13- trans -ρrostadlenic acid

9-0xo-20-nor-10.13- trans prostadic acid

9-OX0-18,19,20-trinor-10, 13- - trans -prostadlenic acid

9 - Oxo-2 0-ethy 1 * 10,! J - t £ ans_- -prostadienic acid

9-0xo-20-chloro -10,13- trans - -prostadienoic acid

9-Oxo-10, 13- trans , 17- cis - -prostatrienoic acid

9-0xo-17-chloro-18,19,20- -trinor-10,13- trans -prostadienoic acid

9-Oχο-2-methyl-10, 13- trans - -prostadienoic acid

9-0x0-17 -πι

-10,13- trans -prostadien.acid

9-0xo-16-methyl-18,19,20-trinor-10,13- trans -prostadienoic acid

9-0xo-3,3,17-trimethyl-19,20-dinor-10,13- trans -prostadienoic acid

9-0xo-3-oxa-17-methyl-19,20- dinor-10,13- trans -prostadienic acid

9-0xo-16-methyl-7a> 7b-bishomo • -18,19,20-trinor-10,13- trans -ρrostadienoic acid

Ethyl 9-oxo-10, 13- trans - -prostadienoate

Ethyl 9-oxo-20-chloro -10,13- -trans-prostadienoate

1616 butyl 9-oxo-lO.13-t £ ans- -prostadienoät

Decyl 9-oxo-10,13-trans, 17- -cls-prostatrienoa ^

/, 09811/1203 BAD ORiQINAU ¹

■ - 298 -

Example 1668 Preparation of 9a, 11a-dihydroxy-13-trans-prostenoic acid

5.2 ml of a 0.65 M solution are added to a stirred solution of 437 mg (1.29 mmol) of Ί1α-hydroxy-9-OXO-13-trans-prostenic acid (Example 1518) in 4.0 ml of tetrahydrofuran Lithiumperhydro-9b-boraphenalyl hydride in tetrahydrofuran at -78 ⁰ C under nitrogen. The solution is stirred at -78 ⁰ C for 45 minutes and at room temperature for 15 minutes. The solution is diluted with 10 ml of water and mixed with. Ether extracted. The extract is back-extracted with ^ -sodium bicarbonate solution. The combined aqueous phases are acidified with 4N hydrochloric acid, saturated with sodium chloride and extracted with ether. The extract is washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated. The residue is purified by thin-layer chromatography on silica gel, giving a colorless oil, V * max 3310 (hydroxyl groups), 1705 (acidic carbonyl group)

mm "1

and 970 cm "(trans-vinyl group).

Examples 1669 to 1696

The ketone reduction of the 9-oxo derivatives in the following Table 52 listed with lithium perhydro-9b-boraphenalyl hydride following the procedure described in Example 1668 gives the 9a-hydroxy derivatives listed in the table.

Table 52

at
game Starting 9-oxo-
derivative from example 11 ct-oxy-9a-hydroxy-13-trans-
prostenic acid or esters 1669 1519
I. 1670 1523 1671 1528. 11α- (4-hydroxybutoxy) - ^ - hy
droxy-Ij5-tän s-ρ rost en-acid lla-, 9a_Dihydroxy-7a, 7b-bis-
homo-lj-trans -prost en-acid lla-, 9a_dihydroxy-3,5-dimethyl-
-13-trans, 17-cis-prostadiene-
acid

409811/1203

Table 52 (continued)

1672 1531 1673 15Ί1 1674 1544 1675 15 * J5 1676 1553 1677 "1564 1678 1559 1679 1572 1680 1576, 1681 1575 1682 1596 1683 1578,

1684

1685

1686
1687
1688
1689

1588 1579

1595 1599 1612 1615 11α-, Sta-DihydroxyO-oxa-lJ- - trans -protenoic acid

LLA, 9a-iy-hydroxy-20-nor-l, 5 ^"4 -trans -prostemsäure

Ila-, 9a-dihydroxy-20-chloro-13- trans -pros tervic acid

11α-9α- DLhydroxy-13- trans , 17- -c ± s_-prostadic acid

lla-M2thoxy-9a-hydroxy-13- - trans , 17-cls-prostadlenic acid

ygy
trans -prosten · acid

lla- M ^ thoxy-ga-hydroxy-Ta, 7b- -b i s homo -15- ^ rans -17- £ is_-p rostadienic acid

lla- & hoxy-9a-hydroxy-13- trans -prostenic acid "-

lla - ethoxy-9a-hyd roxy-13-17- cls -prostadlenic acid

lla-eutoxy-9a-hydroxy-13-trans -p rost en acid

lla- (ß-hydroxyethoxy) -9a-hydroxy-13- trans -prostenic acid

lla- (β-hydroxyethoxy) -9a-hydroxy-13-_trans_, 17- cls prostadienoic acid

lla- (ß-hydroxyethoxy) -9a-hydroxy-3-oxa-lj? - trans -prosten '

• ^J acid

lla- (ß-hydroxyethoxy) -9a-hydroxy-20-chloro -l ^ - trans -prostenic acid

lla- (ß-hydroxypropoxy) -9a-hydroxy-l ^ - trans -prostenic acid

Ethyl 11α, 9α-dihydroxy-13- trans -prostenoate

Butyl
trans -prostenbftt ■

Decyl 1la, 9a-dihydroxy -trans-ρrostenoat

/. 0 9 8 1 1/1 2 Q 3

BAD ORIGINAI.

- JCO -

Table 52 (continued) 1690 1616

1691

I692

1629

1618

1693 1460 1694 1-461 1695 ■ 1480 1696 1469

Decyl 11a, ^ -dihydroxy- Ij5- - trans3 j 17- cls -prostadlenoate.

Decyl llcc- (β-hydroxyethoxy) - -9a-hydroxy-l ^ - trans , 17 -cis - -prostadienoate

Methyl lla- (ß-hydroxy ethoxy) * -9a-hydroxy-17-chloro-18,19 * 20- -trinor-l ^ - trans -prostenoate

Ethyl l-lla-thoxy-9a-hydroxy-l> - trans -prostenoate "

Methyl lla-methoxy ~ 9a-hydroxy-20-methyl-13- trans -prostenoate

Decyl lla-methoxy-9a-hydroxy- -13- trans , 17- cis -prostadienoate

Ethyl lla-methoxy-9cx-hydroxy- -?, 3-dimethyl-13- trans , 17-cis- -prostadienoate

Example 1697

Production of ethyl-11a-acetoxy-9oc ,! pros tenoat

J-hydroxy-8 5-13-trans-

409 mg (10.8 mmol) are added to a stirred, ice-cold solution of 409 mg (1.00 mmol) of ethyl Ha-acetoxy-g-oxo-e S-13-trans-prostenoate (Example 1517) in 50 ml of ethanol ) Sodium borohydride for 60 seconds. The mixture is ^{stirred at 0} ° C. for 5 minutes and at ambient temperature for 80 minutes. The solution is concentrated to a volume of 15 ml, diluted with water, acidified with 4N hydrochloric acid with cooling and then extracted with ether. The extract is washed successively with water and saturated sodium chloride solution, dried over magnesium sulfate and concentrated to give an oil, \? max 3460 (hydroxy group), 1740 (carbonyl group), 1240 (acetoxy group) and 967 cm " ¹ (trans-vinyl group).

U 0 9 8 1 ι / 12 0

BAD OBlGfNAL

Examples 1698 to 1705

The ketone reduction of those listed in Table 53 below 9-oxo derivatives with sodium borohydride according to the procedure from example 1697 results in the mixture of »9 <* / 9ß-hydroxy derivatives, which are listed in the table.

At- starting-11oc-oxy game 9-oxo-derivatives v example

Table 53

11a-oxy-9a, 9β-hydroxy-13-transprostic acid or esters

1698 1699 1700 1701 1702 1703 170 * 1705

1525 1538 1558 1580 161 * Ethyl IIIa-isopropoxy ~ 9a, 9β- -hydroxy-Ij5-1 rans. , 17- cls- pro ·? stadlenoat _. _,

Ethyl llcc-ethoxy-9a, 9ß-hydroxy-3-oxa-20-chloro-13 » trans · ■ prostenoate ·

11a. üydroxy-9ct> 9ß-hydroxy- -7a _i 7b-blshomo-20-nor-15-t_rans_- -prostenäure

11a-hydroxy-9a, 9ß-hyclroxy-2 · -.

-prosten acid

Ha-Hydroxy-9a, 9ß-hyciy -homo-lJ-trariSj, X7-cis-prostadien ^ aure

, 9β-hydroxy-2Ö-

etenic acid

11a- {B -hydroxyäsho
-h; / ■; -. '. roxy -20-methy I.
-prostenic acid

9 *

I sop ropy 1 lla-hydroxy- ^, 9ßhyd roxy-Ij5-trans-prosten acid

/, 09811/1203

Example 1706

Production of ethyl 11a-acetoxy-9a, 9ß-hydroxy-8 % -13-trartsprostenoate

409 mg (10, 8 mmol) sodium borohydride for 60 seconds. The mixture is ^{stirred at 0} ° C. for 5 minutes and at ambient temperature for 80 minutes. The solution is concentrated to a volume of 15 ml, diluted with water, acidified with 4N hydrochloric acid with cooling, and extracted with ether. The extract is washed successively with water and saturated sodium chloride solution, dried over magnesium sulfate and concentrated to give an oil, -J max 3460 (hydroxyl group), 1740 (carbonyl groups), 1240 (acetoxy group) and 967 cm "" ( trans-Vinyigruppi).

Example 1707 Prepared paste from 9oc * 9ß-dihydroxy-8 % -13-trans-prostenic acid

A solution of 196 mg (C, 477 mmol) of ethyl-11a-acetoxy-9a, 9öhydroxy-3 jj-i ^ -trans-prc-stenoate (Example 17Od), 158 mg (2,3r ailiol) 65% xgem Kalirmhyäroxycl, 4.0 ml of methanol and 0.4 ml of water are kept at room temperature for 3 hours. The Ieis ·; mg is diluted with water, extracted cult ether, acidified with 4N CnlorvasserEr ^ fi acid and saturated with sodium chloride. The acid released is extracted with ether. The extract is washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated. The residue is purified by thin layer chromatography to give an oil \? max 3340 (hydroxyl groups), 1710 (acidic carbonyl group) and 967 cm ~ (trans-vinyl group).

Example 1708

Preparation of 2a- (6-carbethoxyhexyl) -3ß-methyl-4a-tetrahydropyranyloxy-cyclopentan-1-one

4 0 3 8 1 1/12 0 3

6.7 ml of 2.1 M methyllithium (0.01915 mol) in ether are added under nitrogen to a suspension of 1.90 g (0.01 mol) of copper iodide in 5 ml of diethyl ether, the temperature being kept at -5 to - Holds 10 ° C. To the resulting solution is added 1.69 g (5 mmol) of 2- (6-Carbäthoxyhexyl) -4-tetrahydropyranyloxy-cyclopent-2-en-1-one and the mixture is stirred for 1 hour at -10 ^0C. The mixture is hydrolyzed with saturated ammonium chloride solution and the organic phase is separated, washed with water and saturated brine, dried (MgSO ^) and evaporated to give 1.46 g (72%) of the title compound as a yellow oil.

Example 1709

Production of 2a- (6-carbethoxyhexyl) -3ß-methyl-4oc-hydroxycyclopentan-1-one

A mixture of 1.46 g (4.15 mmol) of 2oc- (6-carbethoxyhexyl) -3β-methyl-4oc-tetrahydropyranyloxy-cyclopentane-1 -on (Example 1708) in 85 ml of a mixture of acetic acid, tetrahydrofuran and water (19:13:11) is taken at 45 ° C for 1 hour Stir heated. The solution is cooled ^ M in 150 ml of water poured and extracted with diethyl ether. The extr cJ - 3 .- / earth washed with water, saturated brine, dried (MgSO.) and evaporated. The crude product obtained is through Purified chromatography on silica gel, using 300 mg (46? $, Based on unrecovered starting material) of a pale yellow oil, IR 1740 cm (ester and Ketone carbonyl) and 3500 cnT (hydroxyl).

Example 1710

Production of 2a- (6-carboxyhexyl) -3ö-methy! -4a-hydroxycyclopentan-1-one

Treatment of 4- (tetrahydropyran-2'-yloxy) -2- (6-carbotetrahydropyran-2 ' -yloxyhexyl) -eye "'. opent = -2-en-1» on with Li uii

/, 0981 1/1203

methylcuprate according to the procedure of Example 1708 gives the 2 "$ - (6-carbotetrahydropyran-2 ^f -yloxyhexyl) -3ß-methyl-4a-tetrahydropyran-2'-yloxycyclopentan-1-one, which in the acid hydrolysis according to the procedure of Example '1709 gives the title compound.

Example 1711

Preparation of 2- (6,6-dicarbethoxyheptyl) -2-cyclopentenone ~ methoxime

The title compound is made from sodium diethyl methylmalonate and 2- (5-methanesulfonyloxypentyl) -2-cyclopentenone methoxime (Example 60) prepared according to the procedure described in Example 61.

Example 1712 Preparation of 2- (6-carboxyheptyl) -2-cyclopentehone

Saponification of 2- (6,6-dicarbethoxyheptyl) -2-cyclopentenone methoxime (Example 1711) with potassium hydroxide according to the procedure of Example 20 gives 2- (6,6-dicarbethoxyheptyl) -2-cyclopentenone methoxime, its decarboxylation in the manner described in Example 63 gives the title compound.

Example 1715 Preparation of 2- (6-carboxyheptyl) -2-cyclopentenone

The cleavage of the methoxime group in the 2- (6-carboxyheptyl) -2-cyclopentenone methoxime (Example 1712) on the Yfeise described in Example 22 gives the title ketone.

Example 1714 Preparation of 2- (6-carbethoxyheptyl) -2-cyclopentenone esterification with ethanol of the acid chloride, which is different from

. '. 0 9 8 1 1/1 2 0 3

2- (6-Cart> oxyheptyl) -2-cyclopentenone derives on the same Manner as described in Example 31 gives the title compound.

Example 1715 . . _rf

Preparation of 2a- (6-carboxyhexyl) -3ß-methyl-1cc, 4a-dihydroxycyclopentane

Treatment of 2a- (6-carboxyhexyl) -3ß-methyl-4a-hydroxycyclopentan-1-one (Example 1710) with lithium perhydro-9b-boraphenalyl hydride following the procedure of Example 1668 gives the title compound.

Example 1716

Preparation of 2oc- (6-carboxyhexyl) -3ß-methyl-cyclopent-4-en-1-one

Treatment of 2a- (6-carboxyhexyl) -3ß-methyl-4oc-hydroxycyclopentan-1-one with hydrochloric acid to that in Example 163O manner described gives the title compound.

The products according to the invention can be in the form of various pharmaceutical forms are used, such as injectables, tablets, capsules, pills, etc., for the immediate or delayed release by mixing them with suitable carriers. They can be in the form of unit doses for a single therapeutic dose or in the form of small units for multiple doses or in larger units for Division into individual doses are available. In addition to the therapeutic compound, of course, excipients can be used or diluents, binders, fillers and other therapeutically inert ingredients necessary for the Formulation of the desired pharmaceutical preparations are necessary.

/.09811/1203

Example 1717

Manufacture of capsule formulations

Ingredients mg / capsule

9-Oxo-i 1 ocylö-dihydroxy-S-cis - ^ -
trans-prostadic acid 5

Strength 80

Magnesium stearate 5

The active ingredient, starch and magnesium stearate are mixed well together. The mixture is used to fill hard shell capsules of suitable size, using a fill weight of 90 mg / capsule.

Example 1718

Manufacture of tablet formulations Ingredients mg / tablet

9-Oxo-i1a, i6-dihydroxy-5-cis-13-trans-prostadic acid 2

Lactose 200

Corn starch (for the mixture) 50

Corn starch (for paste formation) 50

Magnesium stearate. 6th

The active ingredient, lactose and corn starch (for the mixture) are mixed together. The corn starch (for paste formation) is mixed in water in an amount of 10 g corn starch / 80 ml water and heated with stirring to form a paste. This paste is then used to granulate the mixed powders. The wet granules are passed through a no. 8 screen and dried at 49 ⁰ C (120 ° F). The dry granules are then passed through a No. 16 sieve. The mixture is lubricated with magnesium stearate and compressed into tablets on a suitable tabletting machine. Each tablet contains 2 mg of an active ingredient.

Λ09811 / 1203

5 mg 40 ml 150 mg 90 mg 10 mg 10 mg 50 mg 100 ml

Example 1719

Manufacture of syrup formulations for oral administration

Component , quantity

9-0x0-11 α, 16-dihydroxy-5-cis-13-transprostadienoic acid

Sorbitol solution (70% N.F.) Sodium benzoate sucaryl

Saccharin red dye (F.D. & C.Nr.2) Cherry flavor

distilled water . on

The sorbitol solution is added to 40 ml of distilled water and the active ingredients are suspended therein. That Sucaryl, the saccharin, the sodium benzoate, the flavor * and the color are added and in the above Solution solved. The volume is adjusted to 100 ml with distilled water.

Other ingredients can be those listed in the formulation above substitute. For example, you can use as a suspension agent such as bentonite magma, tragacanth, carboxymethyl cellulose or Use methyl cellulose. Phosphates, citrates or tartrates can be added as a buffer. As preservatives one can use parabens, sorbic acid and the like, and one can also instead of the specified flavors and colors use other such substances.

Example 1720

Manufacture of capsule formulations Ingredient mg / capsule

9-0x0-11a, 1S-dihydroxy-S-cis-IJ-trans-

prostadic acid 0.5

Strength 80

Magnesium stearate 5

/, 09811/1203

The active ingredient, starch and magnesium stearate are mixed well together. The mixture is used to fill hard shell capsules of suitable size with a fill weight of 86 mg / capsule.

Example 1721

Manufacture of tablet formulations Ingredient mg / tablet

9-0x0-11a, 16-dihydroxy-5-cis-13-trans-

prostadic acid 0.25

Lactose 200

Corn starch (for the mixture) 50

Corn starch (for paste formation) "50

Magnesium stearate 6

The active ingredient, lactose and corn starch (for the mixture) are mixed together. The corn starch (for paste formation) is mixed in water in an amount of 10 g corn starch / 80 ml water and heated with stirring to produce a paste. The paste is then used to granulate the mixed powders. The solid granules are passed through a Nr- 8 screen and dried at 49 ° C (120 ⁰ F). The dry granules are passed through a No. 16 sieve. The mixture is then lubricated with magnesium stearate and processed into tablets in a suitable tableting machine. Each tablet contains 2 mg of active ingredient.

', ü 9 8 I' / 12 0 3

Claims (2)

Patent claims: 1. Process for the preparation of diastereomers, enantiomers, Racemates and racemic mixtures of prostaglandin compounds of the formulas I. Il 'ΙΓ " 2-CR, ^v -τ. ^ - ο and h'x R ^R i \ " ζ ² v / orin R ₁ denotes hydrogen, hydroxy, lower alkoxy, tetrahydropyranyloxy, lower alkanoyloxy, ca -hydroxy-substituted- lower alkoxy or cj -tetrahydropyranyloxy-substituted-lower alkoxy, R _{2 is} a part of the molecule of the formulas CH ₀ P CH ₀ P I ² . I ² -CH = CH-CH-R ', -CH ₂ -CH ₂ -CH-R'-, -CH-CH-CH ₂ -R "Or means in which P is a hydroxy or triphenylniethoxy group, R ^! a straight-chain alkyl group with 2 to 10 carbon atoms or a straight-chain alkyl group with 2 to 6 carbon atoms, which is a branched alkyl group with 1 to 3 carbon atoms 40981 1/1203 Substance atoms, contains, and R "denotes a straight alkyl group with 2 to 10 carbon atoms and substituted by a hydroxy or triphenylnethoxy group or a straight alkyl group with 2 to 6 carbon atoms, around the
contains a branched alkyl group with 1 to 3 carbon atoms and which is substituted with a hydroxy or triphenylmethoxy group, means, R ^ is hydroxy, an alkoxy group with 1 to 12 carbon atoms or tetrahydropyranyloxy,
Y is a divalent group of the formulas Ο 'HO, .H · H .0H means and- Z is a second group of formulas _n OCH ₂ -, - (CH ₂ ) _n -CH- '- (CH ₂ ) _n -O-CH ₂ - Or. - (CH ₂ > _n -S-CK ₂ - means where η is an integer from 3 to 8 inclusive means, R, an alkyl group of up to 3 carbon atoms means and R, - denotes an alkyl group with up to 3 carbon atoms, a fluorine atom or a phenyl group,
and where the molecular part · of the formula Λ 0 9 8 1 1/1203 r- _ .. ^ _L ,.-..., ₃₃₇₅₈₁ a c a divalent group of the formula I! / ^c - KC ₁₀ K-C XX can mean when R_ is a hydroxyl or an alkoxy group with 1 to 12 carbon atoms means of the formulas Ia 0 0 Il H [1 H and I j H H ** VT X wherein R> 1 denotes hydrogen, lower-alkyl, lower-alkanoyl, CO hydroxy-lower-alkyl, 6t> -tetrahydropyranyloxy-lower-alkyl, or tetrahydropyranyl, R ₂ (a) a straight chain alkyl group having 2 to 10 carbon atoms, (b) a straight chain alkyl group having 2 to 6 carbon atoms and a branched alkyl group having /, 0981 1/1203 1 to 3 carbon atoms, (c) a straight-chain alkylniethyl group with 3 to 7 carbon atoms and (d) one straight chain Haloger.alkylgruppe denotes 3 to 7 carbon atoms, R ^ hydrogen, an alkyl group of 1 to 12 carbon atoms and tetrahydropyranyl means, Y is a divalent group S HO, HH _x ,, 0H Ä 'κ \ ^odei "/ ^c ' ^ means and Z - a divalent group like - (CH ₉ ) - ·, - (CH) -C-CH ₂ - - (CHp) _n -CH-, and means ^ et, v, ^r orin m an integer from 3 up to and including 9, η is an integer from 3 to 6 inclusive, R is a lower alkyl group with up to 3 carbon atoms and R _{r is} a lower alkyl group with up to 3 carbon atoms, fluorine or phenyl mean, and where the part of the molecule Il R ₁ O "I ¹ K 0981 1/1203 BAD ORIGINAL the divalent group Il H-C . Il H-C- may be, wherein R _{3 is} a hydrogen atom or an alkyl group, of the formulas Ib, Il ZC-OR ₃ and 0 · _γ ZCOR ₃ ^X cC / Λ .MR v / orin R ₁ denotes hydrogen, lower alkyl, lower alkanoyl, CO hydroxy lower alkyl, e ^ ~ tetrahydropyranyl ~ lower alkyl or tetrahydropyranyl, R ₂ (a) a straight chain alkyl group with 2 to 10 carbon atoms, (b) a straight chain alkyl group with 2 to 6 carbon atoms and a branched alkyl group with 1 to 3 carbon atoms, (c) a straight chain alkenyl group with 3 to 7 carbon atoms and (d) a straight chain3 Cc? -Haloalkyl group with 3 to 7 carbon atoms, an alkyl group with 1 to 12 carbon atoms or tetrahydropyranyl, 4 09811/1203 BAD ORIGINAL Y is a divalent group of the formulas ° ^H0 V ' ^H H OH UV / η / \ / \ or s means and Z is a divalent group of the formulas " ^(CH 2 ^} m-. ( ₂ ) _n C ^R R denotes where m is an integer from 3 to 9, including 9ι η an integer from 3 to 6 inclusive, R »a lower alkyl group with up to 3 carbon atoms and Rfeine lower alkyl group with up to 3 carbon atoms, fluorine or phenyl,
and where the part of the molecule ^c \ RO 'j ^:
H the divalent group 409811/1203 Il : Η3Ε «ΞίΟ | -ΠΊ H-C Ii HC- can mean when R _{3 means} hydrogen or an alkyl groupj or öer Formulas Ic, R _x r CH CH- (CH ₂ J _n -CR ₃ and 0
11 * .. I c. • (CHa) _n -CR ₃ R.
L. I ι S ^2Xv CH ^ ^ i ^ "CH« CH-R
trans H H \
CH = CH-R ₂ trans before η is an integer from 1 to 5 inclusive, R "is hydrogen and lower-alkyl groups with up to 3 carbon atoms, R ^ V. 'hydrogen, hydroxy, tetrahydropyranyloxy and are tri- (lower-alkyl) -silyloxy, 40981 1/1203 ORIGINAL BATHROOM * an I molecule part of the formulas and -CH-R '- 2 Vrorin P denotes a hydroxy or triphenylmethoxy group, R ¹ denotes a straight-chain alkyl or alkenyl group with 3 to 10 carbon atoms or a straight-chain alkyl or alkenyl group with 3 to 7 carbon atoms and with one or two branched alkyl groups with 1 to 3 carbon atoms and R "is a straight-chain alkyl or alkenyl group with 3 to 10 carbon atoms, optionally substituted with a hydroxy or triphenylmethoxy group, or a straight-chain alkyl or alkenyl group with 3 to 7 carbon atoms and with one or two branched alkyl groups with 1 to 3 carbon atoms and optionally substituted with a hydroxy or triphenylmethoxy group and a straight-chain co -haloalkyl group with 2 to 7 carbon atoms, R, hydroxy, alkoxy with 1 to 12 carbon atoms, Means tetrahydropyranyloxy and lower trialkylsilyloxy, Y is a two-part group of the formulas 0 un u " ^u \, ' ^H and H _v Λ / \ X means, and vrobei the molecular part of the formula 40981 1/1203 BAD OfliafNAL - 317 -, τ- 337 5 81 a divalent group of the formula (B) can be, with the proviso that if (A) is not (3), at least one of the radicals R ₁ and R _{2 is} an oxygen function contains, characterized in that one a) a corresponding ω-hydroxy-substituted 1-alkyne with Triphenylmethyl chloride or bromide converts and so to a compound of the formula H-C = C-R ,. wherein R, is a part of the molecule of the formulas CH-OC (C ^ H _1. ) _ Or -CH-R '"-CH-R ¹ means in which R ^{1 is} a straight-chain alkyl group with 2 to 10 carbon atoms or a straight-chain alkyl group with 2 to 6 carbon atoms and with a branched alkyl group with 1 to 3 carbon atoms and R ¹ "is a straight-chain alkyl group with 2 to 10 carbon atoms and substituted with one Triphenylmethoxy group or a straight-chain alkyl group with 2 to 6 carbon atoms and with a branched alkyl group with 1 to 3 carbon atoms and substituted with a triphenylmethoxy group, arrives, 40981 1/1203 T NACHe ^ ₁ -JQHrJ 337 581 and then either b) the compounds obtained according to process step a) with disiamylborane produced from diborane and 2-methyl-2-butene and then with anhydrous trimethylamine oxide reacted, the resulting reaction mixture with aqueous sodium hydroxide: and then a tetrahydrofuran solution treated with excess iodine, and treated the iodine compounds thus obtained with alkyllithium, thereby making compounds of the formula ' ^R 6 W "H wherein R- is a part of the molecule of the formula -0-C (C, HJ- or -CH ₀ -R ₀ Z bbJ Zo -CR ¹ denotes where R ¹ denotes a straight-chain alkyl or alkenyl group with 3 to 10 carbon atoms, or a straight-chain alkyl or alkenyl group with 3 to 7 carbon atoms and with a branched alkyl group with up to 3 carbon atoms, R_ denotes a straight-chain Alkyl or alkenyl group with 3 to 10 carbon atoms and substituted with a triphenylmethoxy group or a straight chain alkyl or alkenyl group with a or two branched alkyl groups having 1 to 3 carbon atoms and substituted with a triphenylmethoxy group means, and W is iodine or a lithium atom, 409811/1203 and their optical isomers, enantiomers, diastereomers, Receives racemates and racemic mixtures, c) those compounds obtained after process step b) in which W is lithium, with a compound of Formula _ R- -Al 'ί * 7 where R_ denotes a straight-chain lower alkyl group, which do not necessarily have to be the same in each case, and so to compounds of the formula X trans / 6 C «c ' R, R ₇ -L where R has the above meaning and Rg the meaning given under process stage a) possesses, and their optical isomers, enantiomers, diastereomers, racemates and racemic mixtures, arrives, or 409811/1203 ~ ³² ° " d) the compounds obtained in process step a) with compounds of the formula R-C-CH-A1-H , 2 R-C-H R where R is lower alkyl, and so on Compounds of the formula "\ Trans η \: - ~ I / ^{C C} \ RC-CH -Al HI 2 IH CH ₂ . R-C-H, wherein R has the above meaning and R _{6 has} the meaning given in process step a), and its optical isomers, enantiomers, diastereomers, racemates and racemic mixtures, and e) the compounds obtained in process step d) with a lithium compound of the formula R ° - Li in which R ° stands for lower alkyl, and thus to compounds of the formula 409811/1203 - R ° ^X H CH ₂
RCR where R ° has the above meaning, R is the meaning given for process stage d) owns and R, which has the meaning given in process stage a), arrives, v / o up man
either f) an epoxy ketone of the formula -'-- CH " ^cis = o H' H - (CH ₀ ) -C- I. η in which R ^{1 is} alkyl having 1 to 3 carbon atoms, treated with a mild base, the compounds of the formula thus obtained HO ' ^ -CH H' C = C R ¹ CH 40981 1/1203 or the formula
0 Γ R ¹ 0 I i! CH - (CH ₂ ) _n ~ C-OH on their hydroxyl and / or carboxy groups by alkoxy rait 1 to 12 carbon atoms, tetrahydropyranyloxy or lower alkylsiIyloxy groups blocked and so on Compounds of the formula P. ¹ , c «c ^ P. ¹ 0 I yy CH- (CIt) _n -CE wherein R ^{1 is} an alkyl group having 1 to 3 carbon atoms, R ₁ denotes hydrogen, hydroxy, tetrahydropyranyloxy and tri-lower-alkylsilyloxy groups, R hydroxy, alkoxy with 1 to 12 carbon atoms, Is tetrahydropyranyloxy or lower trialkylsilyloxy groups and η is an integer from 1 to 5 inclusive, and their optical isomers, diastereomers, enantiomers, Racemates and racemic mixtures arrives, 409 811/1203 \ NACHGEREIQHTJ g) compounds of the formula or the formula wherein R »hydroxy / tetrahydropyraryloxy or an alkoxy group with 1 to 12 carbon atoms and V is a divalent group of the formulas ^R 3 ^ 4 1. or - (CH ₀ ) -O-CH - means where η is an integer from 3 up to and including 6, R- a lower alkyl group with up to 3 carbon atoms and Usually a lower alkyl group with up to 3 Mean carbon atoms, fluorine or phenyl and in stands for an integer from 3 to 9, halogenated in position 4, converts the halogen-substituted compounds obtained into hydroxy-substituted compounds and in position 4 optionally a lower alkoxy , (jJ -hydroxynoweralkoxy-, lower alkanoyloxy-, 409811/120 3 Tetrahydropyranyloxy or tetrahydropyranyloxy lower alkoxy group introduces, whereby one compounds of the formula v / orin R _{1 is} halogen, hydroxy, lower-alkoxy, ^ -hydroxy-lower-alkoxy, lower-alkanoyloxy, tetrahydropyranyloxy or <o -tetrahydropyranyloxy-lower-alkoxy, R- hydroxy, tetrahydropyranyloxy or an alkoxy group rait means 1 to 12 carbon atoms and V is a divalent group of the formulas f3 «4 - fr ^ H \ - Γ " ¹ - Γ * υ - (f ^ XZ \ —ptl-. ζ η j 2. Δ η ^R 3 or - (CH-) -O-CH-- Z Ti Z means where η is an integer from 3 to 6 inclusive R_ is a lower alkyl group with up to 3 carbon atoms and R is a lower alkyl group with up to carbon atoms, fluorine or phenyl, or Compounds of the formula : - ^ * "" - (CH-) -CR., 2 ΤΛ 0 9 8 11/12 where m is an integer from 3 up to and including 9, R is hydroxy, tetrahydropyranyloxy or an alkoxy group with 1 to 12 carbon atoms and R lower-alkyl, i ^ -hydroxy-lower-alkyl, u.) -Tetrahydropyranyloxy-lower-alkyl or tetrahydropyranyl mean, receives,
what to h) for the preparation of compounds of the formula I mentioned at the outset, a compound of the formula. ... II Y / orin R ¹ ^ is hydrogen, lower-alkoxy, tetrahydropyranyloxy, nledrig-alkanoyloxy or tü-tetrahydropyranyloxy-lower alkoxy and R ¹ ^ is tetr-ihydropyranyloxy or an alkoxy group with up to 12 carbon atoms,
with a lithium alanate of the formula _L ß R-Xl-R ^N H. ...in /.09811/1203 ο ο Ο 7 C Q 1 ^{10 J} ' ^oö ' - 326 - implements what R denotes an alkyl group having 1 to 7 carbon atoms, the groups R not necessarily being the same must be, and in what Rg a part of the molecule of the formulas CH ₀ OC (C ^ H-). I - and .. -CH-R « means in which R ^{f has} the meaning given above and R " ^{1 is} a straight-chain alkyl group having 2 to 10 carbon atoms and substituted with a triphenylmethoxy group
or a straight-chain alkyl group with 2 to 6 carbon atoms and with a branched alkyl group with 1 to 3 carbon atoms and substituted with a triphenylmethoxy group,
being a compound of the formula .- .. IV receives what R ¹ ^, R '; z, Rg and Z have the definitions given above, 40981 and then the protecting groups of the ether and ester groups splits off with weak acids, whereby nan a compound the formula receives what 2 and Rr have the definitions given above. R "^ has the meaning given above for FL · with with the exception that it is not tetrahydropyranyloxy or co-tetrahydropyranyloxy-low-alkoxy means, and R ", which has the meaning given above for R-, with except that it does not mean tetrahydropyranyloxy, and optionally hydrogenating the, A ₁ ¹ ^ double bond, a compound of the formula . ..vi receives, v / orin R "^, R", and Z have the definitions given above and R ¹ P is a part of the molecule of the formula CH ₂ OH -CH ₂ -CK ₂ -CH-R ' and -CH ₂ -CH ₂ -CH ₂ -R "" 409811/1203 BATH ORIGINAL means, v.Orin R ^{1 has} the meaning given above and R "» is a straight-chain alkyl group with 2 to 10 carbon atoms and substituted with a hydroxyl group a straight-chain alkyl group with 2 to 6 carbon atoms and with a branched alkyl group with 1 to 3 carbon atoms and substituted with denotes a hydroxy group, and if necessary the compound of the formula V or formula VI is treated with dilute mineral acid, a compound of the formula C. ο η R " I.
I. I! 3 I.
J «. ζ-σ > ... VII receives what Z and R " _{7 have} the meanings given above R "p is a part of the molecule of the formulas CH OH CH OH 2 ι -CH = CH-CH-R ', -CH = CH-CH -R "", -CH-CH-CH-R ^{1 2} 2 2 >: -CH-CH -CH -R '' · ' means in which R ¹ and R ^{MIJ have} the meanings given above ^ and if desired, the compound is treated with a hydride reducing agent and the product is obtained from the reaction mixture 098 1 1/1 20 3 i) zui "Production of compounds of the aforementioned Formula Ia a compound of the formula R'iO v / o r in R '. has the definition given above for R ^, with the exception that hydrogen or a cc2-hydroxy-lower alkyl group are not included, and R ¹ has the meaning given above for R ₇ , with the exception that hydrogen is not included therein, with a lithium alanate reagent of the formula ... III implements what Rp has the definition given above and R ^{1 is} an alkyl group having 1 to 8 carbon atoms, which do not necessarily have to be the same, means being a compound of the formula ... IV H ^N R A 0 9 8 1 f / 1 2 0 3 receives what Z, R'- |, Rp and R ¹ ^ have the definitions given above, and one concludes the ether and ester functions with weaker ones Hydrolyzed acid, whereby a compound of the formula o ■ o ■ · Ii Π ¹¹ ZCOR " obtained, wherein Z and R _{2 have} the definitions given above and R ",, and R" ^ hydrogen or an alkyl group with Mean 1 to 12 carbon atoms, and all of the compounds of the formula IV are desired treated dilute mineral acid, whereby a compound of the formula 0 ° "Z-C-OR" .. .VI receives what R ₂ , Z and R "have the definitions given above, and, if desired, a compound of the formula V with treated with a hydride reducing agent and the product gains from it, 409811/1203 "^{> (} submitted) k) for the preparation of compounds of the formula Ic mentioned at the outset, a compound of the formula R 0 _TT eis I - Κ • " ^il . C« C <~ - (CH) - (CH ₅ ) ^ - C-R ' » K H ^{d n 3} _R i> ·. _ t v / orln R and η have the definitions given above and R ^1,. Y / hydrogen, tetrahydropyranylGxy or tri- (lower-alkyl) -siloxy and R 'alkoxy of 1 to 12 carbon atoms, tetrahydropyranyloxy or mean a low-trialkylsiloxy group, with a lithium alanate of the formula . © H. trans J * '2 C «C ι <- implements what R ¹ P has the meaning given above for Rp, with the exception that it does not comprise a hydroxy-substituted group, and Rc- denotes an alkyl group with 1 to 8 carbon atoms,
or with a lithium alanate of the formula Cf) ^ ^ LiV R ..- A1-R ,. H 5 ι 5 ^R 5 '.09811 / 1203 2337b81 . 332 - ¹ V ACHGE REIOHT j implements what R ¹ and Rj- have the meanings given above and not all values for R ^ necessarily have to be the same and where one is a compound of the formula £ is / (CH) - (CH ₂ J _n -CR;.,. V CK = CH If H trans ^R a receives what R, Ri ₁ , R « ₂ and own, and then the ether and ester protection groups with splitting off its weaker acid, a compound of the formula R ¹ τ · the definitions given above els (CH) - (CH ₂ ) -CR ⁿ ... VI receives, vrarin R has the definition given above, R "^ hydrogen and hydroxyl groups, R" p those given for R ^ Definition, with the exception that a triphenylmethoxy-substituted group is not included and R "^ is hydroxy and alkoxy with 1 to 12 carbon atoms, and, if desired, the compound of formula V or VI treated with dilute mineral acid, resulting in a compound of the formula 40981 1/1203 R. ice (CH) - (CF ^) _n -CR »3 CH-CIK 'η ... VII is obtained in which R, R "- and R" _{v have} the "definitions given above", and if necessary the Ca.rbons _; acid of the formulas VI or VII esterified, the corresponding alkyl esters being obtained, and if necessary the compound of the formula VI is treated with a hydride reducing agent and the products are obtained therefrom. 40981 1/1203 , Attachment to input voir, j NACHQERh; -. htJ 11/26/1973 Patent claims 2. Process for the preparation of diastereomers, Enantiomers, racemates and racematic mixtures of the following general formulas · Ir ' - Z-G-R. -csy "- π R, j denotes hydrogen, hydroxy, lower-alkoxy, tetrahydropyranyloxy, lower-alkanoyloxy, Cc / -hydroxy-substituted-lower- alkoxy or cj> -tetrahydropyranyloxy-substituted-lower-alkoxy, R _{2 is} a part of the molecule of the formulas CH ₂ P ^ H ₂ P -CH'CH-CH-R ', -CH ₂ -CH ₂ -CH-R'- -CH-CH-CH ₂ -R "or denotes where P is a hydroxy or triphenylmethoxy group, R ^{1 is} a straight-chain alkyl group with 2 to 10 carbon atoms or a straight-chain alkyl group with 2 to 6 carbon atoms which contains a branched alkyl group with 1 to 3 carbon atoms, and R "denotes a straight-chain alkyl group with 2 to 10 carbon atoms and substituted with a hydroxyl or triphenylmethoxy group or a straight-chain alkyl group with 2 to 6 carbon atoms, unid which contains a branched alkyl group with 1 to 3 carbon atoms and which is substituted with a hydroxyl or triphenylmethoxy group, Λ 09811/1203 f K-AOf- - 335 - R, hydroxy, an alkoxy group with 1 to 12 carbon atoms or tetrahydropyranyloxy, Y is a divalent group of the form in O-HO H · B, .OH means and. Z is a divalent group of the formulas R ₁ , · ■ R _c I · ^; 'I ⁵ J _n -, - (CH ₂ ) _n -6-CH ₂ -, - (CHg) _n -CH- '- (CH ₂ ) _n -O-CH ₂ - or, - - (CH ₂ ) _n -S-CH ₂ - means where η is an integer from 3 to 8 inclusive means, R ^ is an alkyl group with up to z, u 3 carbon atoms means and R ^ is an alkyl group with up to 3 carbon atoms, denotes a fluorine atom or a phenyl group, and wherein the molecular part · of the formula a divalent group of the formula HC ₁₀ .8th H-Cn 098 1 1/1203 "can mean when IU is a hydroxyl or an · alkoxy group with 1 to 12 carbon atoms means, characterized in that a compound the formula S ■ - - '-1 ... II I.
ZC-R'a R ¹ ;, hydrogen, lower-alkoxy, tetrahydropyranyloxy, lower-alkanoyloxy or cü-tetrahydropyranyloxy-lower alkoxy and R ¹ denotes tetrahydropyranyloxy or an alkoxy group having 1 to 12 carbon atoms,
with a lithium alanate of the formula Li <±> R-A1-R ^ H. ... Ill implements what R denotes an alkyl group having 1 to 7 carbon atoms, the groups R not necessarily being the same must be, and in what Rt- part of the molecule of the formulas -CH-R- ■■■ ™ ^d means in which R ^{1 has} the meaning given above and / 409811/1203 "-" 7337 5 8 1 R " ¹ denotes a straight-chain alkyl group with 2 Ms 10 'carbon atoms and substituted with a triphenylmethoxy group or a straight-chain alkyl group with 2 to 6 carbon atoms and with a branched alkyl group with 1 to 3 carbon atoms and substituted with a triphenylmethoxy group,
being a compound of the formula receives what , R ¹ - and Z the definitions given above own, and then the protecting groups of the ether and ester groups split off with weak acids, a compound of the formula receives what Z and Rg have the definitions given above, R "^ has the meaning given above for R ^, with except that it is not tetrahydropyranyloxy or co-tetrahydropyranyloxy-lower alkoxy b. means, and R ", which has the meaning given above for R, with except that it does not mean tetrahydropyranyloxy, 0 9 8 1 1/1203 233758Ί and optionally hydrogenating the ^ double bond, wherein one compound of the formula Il , Z-C-R " R ... VI receives what R ".j, R" -r and Z have the definitions given above and a part of the molecule of the formula CH ₂ OH -CH ₂ -CH ₂ -CH-R ¹ and -CH ₂ -CH ₂ -CH ₂ -R "» means in which R ^{1 has} the meaning given above and R "" is a straight-chain alkyl group with 2 to 10 carbon atoms and substituted with a Kydroxygruppe ^ ine straight-chain alkyl group with 2 to 6 carbon atoms and with a branched alkyl group with 1 to j5 carbon atoms and substituted with one Hydroxy group, and if desired, the compound of the formula V or formula VI is treated with dilute mineral acid, a compound of the formula ^ T ^ * W 4 0, Z-C-R " ^ R "a receives what Z and R "have the meanings given above and R " _{2 is} a part of the molecule of the formulas 409811/1203 CH OH ι * · · · ι ² -CH = CH-CH-R ¹ , -CH = CH-CH ^ -R "' ¹ / -CH-CH-CH-R ¹ ■> y -CH -CH -CH -R"''. 2 2 2 means in which R ¹ and R ^{1111 have} the meanings given above, and, if desired, the compound is treated with a hydride reducing agent and the product is recovered from the reaction mixture. 3. Process for the preparation of diastereorneres, Enantiomers and racemates and racemic mixtures of the following general formula and p. Il ..Z-C-O-R R ^ hydrogen, lower-alkyl, lower-alkanoyl, CJ hydroxy-lower-alkyl, c *> - tetrahydropyranyloxy-lower-alkyl, or tetrahydropyranyl means R _{2 is} (a) a straight chain alkyl group having 2 to 10 carbon atoms, (b) a straight chain alkyl group having 2 to 6 carbon atoms and a branched alkyl group having 1 to 3 carbon atoms, (c) a straight chain alkenylinethyl group having 3 to 7 carbon atoms, and (d ) is a straight-chain haloalkyl group with 3 to 7 carbon atoms, R, hydrogen, an alkyl group having 1 to 12 carbon atoms and means tetrahydropyranyl, 40981 1/1203 Y is a divalent group 2 ^HO v, » Λ 'A ^or means and Z -a twofold group like T * -CCH _{2 2} ) _n .C- ^R H I ⁵
- (CH ₂ ) _n -CH-, and - (CH ₂ ) _n -0-CH ₂ - means where m is an integer from 3 to 9 inclusive, _f η an integer from 3 to 6 inclusive, R, a lower-alkyl group with up to 3 carbon atoms and R ₁ - a lower-alkyl group with up to 3 carbon atoms, fluorine or Mean phenyl, and where the part of the molecule the divalent group .... H 0
Il .1 Hv
H'' 0
Il R ₁ O '" • Hi- 40981 1/1203 may be where R ^ is a hydrogen atom or an alkyl group means, characterized in that a compound of the formula R ^f x0 ... II R ¹ . has the definition given above for R ^, with the exception that hydrogen or a CtJ-hydroxy-lower alkyl group are not included, and R ¹ V has the meaning given above for R ^, with the exception that hydrogen is not included therein, with a lithium alanate reagent of the formula H trans : r C = C R ¹ -Al. R ¹ ... III ■ R ¹ implements what R _{2 has} the definition given above and R ^{1 is} an alkyl group having 1 to 8 carbon atoms, which do not necessarily have to be the same, means being a compound of the formula Il Il .ZCOR ¹ ... IV R'O ^H X- 4098 1 * 1/1203 'QHGEiOHT receives what Z, R ^1. , Rp and R '^ have the definitions given above, and the ether and ester functions are then hydrolyzed with a weak acid, a compound of the formula 'I ^ Z-C-O-R " Η ' obtained, wherein Z and Rp have the definitions given above and R ".. and R ¹ U are hydrogen or an alkyl group with 1 to 12 carbon atoms, and if desired, the compounds of the formula IV with treated dilute mineral acid, whereby a compound of the formula , Z-C-OR " .. .VI receives what Rp, Z and R ", have the definitions given above, and if desired, a compound of the formula V is treated with a hydride reducing agent and the product wins from it. 409811/1203 ^4. Process for the preparation of diastereomers, enantiomers, racemates and racemic mixtures of the following general formula Il 0 ^z - ^c - ° «s" ü "" and R ₁ O IY I H H H " MR in which. R ^ means hydrogen, lower-alkyl, lower-alkanoyl, OJ - hydroxy-lower-alkyl, ct ^ -Tetrahydropyranyl-lower-alkyl or tetrahydropyranyl, R ₂ (a) a straight chain alkyl group having 2 to 10 carbon atoms, (b) a straight chain alkyl group having 2 to 6 carbon atoms and a branched alkyl group having 1 to 3 carbon atoms, (c) a straight chain alkenyl group having 3 to 7 carbon atoms and (d) denotes a straight-chain CO -haloalkyl group with 3 to 7 carbon atoms, an alkyl group with 1 to 12 carbon atoms or tetrahydropyranyl , Y is a divalent group of the formulas 0
ti
Λ » and X " or Formulas means Z one bivalent Group of 409811/1203 NACHGERBCl · ^X 4 -CCH ₂ ) _n -C-CH ₂ - Bj ₁ ISPS 81 R ₁ or * denotes where m is an integer from 3 to 9, including 9, η is an integer from 3 to 6 inclusive, R »a lower alkyl group with up to 3 carbon atoms and R, -a lower alkyl group with up to 3 carbon atoms, fluorine or Mean phenyl,
and where the part of the molecule If the divalent group (I. H-C I! H-C- can mean, if R means hydrogen or an alkyl group » ⁵ · Process for the preparation of enantiomers, diastereomers, racemates and racemic mixtures of the following general formulas /.0981 1/1203 _345 _ CH-R ₀
trans ² • and R 0 cis "CH- (CHa) _n -CR ₃ ' trans η is an integer from 1 to 5 inclusive, R is hydrogen and lower alkyl groups with Ms too 3 carbon atoms, R ₁ denotes hydrogen, hydroxy, tetrahydropyranyloxy and tri- (lower-alkyl) -silyloxy, R _{2 is} a part of the molecule of the formulas I ² ■. -cn, -CH-R ¹ · - means where P is a hydroxy or T-riph R ^{1 is} a straight-chain alkyl or alkonyi group with 3 to 10 carbon atoms or a straight-chain alkyl or alkenyl group with 3 to 7 carbon atoms and with one or two branched alkyl groups with 1 to 3 carbon atoms and R "is a straight-chain alkyl or alkenyl group with 3 to 10 carbon atoms, optionally substituted by a hydroxy or triphenylmethoxy group _r or · a straight-chain alkyl or alkenyl group with 3 to 7 carbon atoms 40981 1/1203 'fvSACHC: IRE! OHT atoms and with one or two branched alkyl groups with 1 to 3 carbon atoms and optionally substituted with a hydroxy or triphenylmethoxy group and a straight-chain CO 2 haloalkyl group with 2 to 7 carbon atoms, R-z hydroxy, alkoxy with 1 to 12 carbon atoms, Means tetrahydropyranyloxy and lower trialkylsilyloxy, Y is a divalent group of the formulas S ^H0 \, '«and H means, and where is the molecular part of the formula ff a sweiwertigo group of the formula can be, with the proviso that if (A) is not (B), at least one of the radicals R ₁ and Rp contains an oxygen function, characterized in that a compound of the formula 409811/1203 "7581 ⁰ DD PJ. * »· * R. I. Il ... JLJL ² .C * Cς - (CH) - (CH ^) _n -C-R '. H ^ ^ H 2η. R and η have the definitions given above and R ¹ .. hydrogen, tetrahydropyranyloxy or tri- (lower-alkyl) -siloxy and RU alkoxy with 1 to 12 carbon atoms, tetrahydropyranyloxy or mean a lower trialkylsiloxy group, with a lithium alanate of the formula
_. © H ^ trans s 2 CH. 3 nij ... 111 CH_ implements what R ¹ 2 has the meaning given above for R ^, with the exception that it does not include a hydroxy-substituted group, and R ^ denotes an alkyl group with 1 to 8 carbon atoms,
or with a lithium alanate of the formula t —Δ 1 _R H »* β IV I ⁵ R, - /.09811/1203 (JVAC-. _. ^, H EIGHT [ implements what R 'and R ₁ - have the meanings given above and not all values for R, - necessarily have to be the same and where one is a compound of the formula ! R. ' b I Il • ^ CH. .eis (CH) - (CH ₂ J _n -CR; ... V Γ l "^ CH = CH ^ receives what R, R ' _1f R' ₂ and -R ' _{3 have} the definitions given above, and then the ether and ester protective groups are split off with a weak acid, a compound of the formula Ro SiS ^ CH) - (CH) -C ... VI H " K ^: receives what R has the definition given above, R "^ hydrogen and hydroxyl groups, R" _{2 has} the definition given for R ₂ , with the exception that a triphenylraethoxy-substituted group is not included and R "denotes hydroxyl and alkoxy with 1 to 12 carbon atoms, and if necessary Treated the compound of the formula V or VI with dilute mineral acid, whereby a compound of the formula 4 0 9 8 1 1/12 0 3 R O ice (CH) - (CHa) -C- CH-CH ^ ... VII is obtained, in which R, R "p and R ¹ U have the definitions given above, and, if desired, the carboxylic acid of the formulas VI or VII is esterified to give the corresponding alkyl esters are, and if desired, the compound of the formula VI treated with a hydride reducing agent and recovering the products therefrom. 6. All diastereomers, enantiomers, racemates and racemic mixtures of the following general formula 0 \ 0 "ZCR ₃ . , ZCR ₃ and Ri R ₂ - wherein R. Hydroxy, lower alkoxy, tetrahydro pyrany]? ^x ^ ilow-alkanoyloxy, a. '> -Hydroxy- · subst , "ntearig-alkoxy or OP ~ means tetrahydropyranyloxy-substituted-lower alkoxy, Rp a part of the molecule of the formulas CH ₂ P CH ₂ P -CH-CH-CH-R ', -CH ₂ -CH -CH-R ¹ - or -CH-CH-CH _n -R " - ■ -OH -CH -CU -R" ■ '.0981 1/1203 j r'-ACi-iCiiifSK -350 - means where P means a hydroxy or triphenylmethoxy group, R ^{1 means} a straight-chain alkyl group with 2 to 10 carbon atoms or a straight-chain alkyl group with 2 to 6 carbon atoms and with a branched alkyl group with 1 to 3 carbon atoms and R "means a straight-chain alkyl group with 2 to 10 carbon atoms and substituted with a hydroxy or triphenylmethoxy group or a straight-chain alkyl group with 2 to 6 carbon atoms and with a branched alkyl group with 1 to 3 carbon atoms and substituted with a hydroxy or triphenylmethoxy group, R ^ is a hydroxyl, an alkoxy group with 1 to 12 carbon atoms or is tetrahydropyranyloxy, Υ is a divalent group of the formulas HO or 0H means and Z is a divalent group of the formulas -CCH ₂ ) _n -C-CH ₂ - I * , -iCH ₂ ) _n -CH- _or denotes v / orin η an integer of 3 Ms including 8, R. denotes an alkyl group with up to 3 carbon atoms and Rj- denotes an alkyl group with up to 3 carbon atoms, a fluorine atom or a phenyl group,
and. where is the molecular part of the formula /, 09811/1203 "~ / j j / 581 c IXO a divalent group of the formula It H-C XX can be when R ^ hydroxy or an alkoxy group with 1 to Means 12 carbon atoms. 7. Compound of Formula ο ο , ZCR ₃ wherein Ro a part of the molecule of the formulas CH ₂ P CH ₂ P -CH-CH-CH-R ', -CH ₂ -CH ₂ -CH-Rt- -CH-CH-CH ₂ -R " ^U * lt. -CH ₂ -CH ₂ -CH ₂ -R", V / orin P denotes a hydroxy or triphanylmethoxy group, R ¹ denotes a straight-chain alkyl group with 2 to 10 carbon atoms or a straight-chain alkyl group with 2 to 6 carbon atoms and a branched alkyl group ml \, 1 to 3 carbon atoms and R ^{: |} a straight chain alkyl /, 098 1-1 / 1203 group rait 2 to 10 carbon atoms and substituted with a hydroxy or triphenylmethoxy group or a straight-chain alkyl group with 2 to 6 carbon atoms and with a branched alkyl group having 1 to 3 carbon atoms and substituted with a hydroxy or triphenylmethoxy group means, R is a hydroxy group, an alkoxy group with 1 to Represents 12 carbon atoms or a tetrahydropyranyloxy group and Z is a divalent group of the formulas | 4 | 5 V - (CH ₂ ) _n -C-CH ₂ - _or ~ (CH ₂ ) _n -S-CH ₂ _ means where η is an integer from 3 to 8 inclusive, R ^ is an alkyl group with up to 3 carbon atoms and R ^ is one Denote an alkyl group with up to 3 carbon atoms, a fluorine atom or a phenyl group, and the pharmaceutically acceptable cationic salts thereof when R- is hydroxy. 8. Compound of Formula HCCR ₆
wherein Rg a part of the molecule of the formulas CH ₂ -OC (C ₆ H ₅ ) _{3 or} , -CH ₂ -R ¹ "-CH-R · ... means in which R ^{1 is} a straight-chain alkyl group having 2 to 10 carbon atoms or a straight-chain alkyl group having /, 09811/1203 _ 353 _ 2 to 6 carbon atoms and having a branched alkyl group having 1 to 3 carbon atoms and R "'is a straight-chain alkyl group with 2 to 10 carbon atoms and substituted with a triphenylmethoxy group or a straight-chain alkyl » group having 2 to 6 carbon atoms and a branched alkyl group having 1 to 3 carbon atoms and substituted mean with a tiphenylmethoxy group. 9. Compound of Formula R-C-CH-Al I ² IR CH ₂ . R-C-H wherein R is a lower alkyl group and Rg is a part of the molecule of the formulas Ic ο 5 3
-CH-R · ... ^Or '"-CH ₂ -R" means where R ^{1 is} a straight chain alkyl group having 2 to 10 carbon atoms or a straight chain alkyl group having 2 to 6 carbon atoms and a branched alkyl group having 1 to 3 carbon atoms and R "'is a straight chain alkyl group having 2 to 10 carbon atoms and substituted with a triphenylmethoxy group or a straight-chain alkyl group having 2 to 6 carbon atoms and having a branched alkyl group having 1 to 3 carbon atoms and substituted with a triphenylmethoxy group. Λ09811 / 1203 Compound of formula R.
RC- ( trans / - R ° ^X CH ₂
RCR R is a lower alkyl group and R ° is a lower alkyl group and R, - part of the molecule of the formulas CH ₂ -OC (C ₆ H ₅ K -CH-R ' or -CH ₂ -R "' R ¹ denotes a straight-chain alkyl group with 2 to 10 carbon atoms or a straight-chain alkyl group with 2 to 6 carbon atoms and with a branched alkyl group with 1 to 3 carbon atoms and R "'a straight-chain alkyl group with 2 to 10 carbon atoms and substituted with a triphenylmethoxy group or a straight-chain alkyl group with 2 to 6 carbon atoms and with a branched alkyl group with 1 to 3 carbon atoms and substituted with a triphenylmethoxy group. Compound of formula /.09811/1203 wherein R _{2 is} a straight-chain alkyl group with 2 Ms 10 carbon atoms, a straight-chain alkyl group with 2 to 6 carbon atoms and with a branched alkyl group with 1 to 3 carbon atoms, a straight-chain alkenylmethyl group with 3 to 7 carbon atoms or a straight-chain C ^ -haloalkyl group with 3 to 7 Carbon atoms means R ^ represents a hydrogen atom or an alkyl group 1 to 12 carbon atoms and Z is a divalent group of the formulas - {CH _{2) m} -, - - (CH _{2) n} -C-CH ₂ g) _n -CII- or ... - (CH ₂ ) _n -O-CH ₂ - mean, where m is an integer from 3 to 9 inclusive, η is an integer from 3 to 6 inclusive, R ^ a low one Alkyl group with up to 3 carbon atoms and Rf- a lower one Alkyl group with up to 3 carbon atoms, fluorine or phenyl mean, and the pharmaceutically acceptable kaionic salts thereof, when R 1 is hydrogen. 12. Compounds of the formula R ₁ 'VCR ₂ wherein R _{1 is} halogen, hydroxy, lower-alkoxy, cj-hydroxy-lower alkoxy, lower-alkanoyloxy, tetrahydropyranyloxy or /, 09811/1203 ■ ι ι ι ι ,, ι, ι! UP-tetrahydropyranyloxy-lower-alkoxy means, Rp hydroxy, tetrahydropyranyloxy or an alkoxy group having 1 to 12 carbon atoms and V is a divalent group of the formulas ? 3 '^<R iJ ·, ' - (CH ₀ ) -C-CH ₀ , - (CH ₀ ) -CH- ..R ₃ or - (CH ₂ J _n -O-CH ₂ - means where η is an integer from 3 to 6 inclusive, R ^, a lower alkyl group of up to 3 carbon atoms and R ^ is a lower alkyl group with up to 3 carbon atoms, Mean fluorine or phenyl. 13. Compounds of the formula 0 ' II '(CH ₂ J -C-Ei m is an integer from 3 to 9 inclusive, I hydroxy, tetrahydropyranyloxy or an alkoxy group having 1 to 12 carbon atoms and R ₅ is lower alkyl, & low-alkyl, CO -tetrahydropyranyloxy-lower alkyl or tetrahydropyranyl mean. 14. All diastereomers, enantiomers, racemates and racemic mixtures of the following general formulas R 0 I! CH ^ 09811/1203 I NACHQEREjQHtJ and .9 ■ ο. , CH ₂ SlS. CH- (CH ₂ ) - CR _{3 k} .trans
«Ι. ^ CH = CH-R ₂ ■ . jr wherein η 'denotes an integer from 1 to 5 inclusive, R is hydrogen and lower-alkyl groups with up to 3 carbon atoms means R ^ hydrogen, hydroxy, tetrahydropyranyloxy and Means tri- (lower-alkyl) -silyloxy groups, Ro a part of the molecule of the formulas CH _p P I.
-CH-R ^f and means where P is a hydroxy or triphenylmethoxy group, R ^{1 is} a straight-chain alkyl or alkenyl group with 3 to 10 carbon atoms or a straight-chain alkyl or alkenyl group with 3 to 7 carbon atoms and one or two branched alkyl groups with 1 to 3 carbon atoms and R "a straight-chain alkyl or alkexiyl group with 3 to 10 carbon atoms, optionally substituted with a hydroxy or triphenylmethoxy group, or a straight-chain alkyl group or alkenyl group with 3 to 7 carbon atoms and with one or two branched alkyl groups with 1 to 3 carbon atoms and optionally substituted with one Hydroxy or triphenylmethoxy group and a straight-chain CO haloalkyl group with 2 to 7 carbon atoms mean, R-z hydroxy, alkoxy with 1 to 12 carbon atoms, Tetrahydropyranyloxy and trialkylsilyloxy lower groups means, 4 09811/1203 Y is a divalent group of the formulas 0 HO, H H. ΛΗ means, and where the molecular part of the formula Il Bi a divalent group of the formula Il H π at least one of the radicals R ^ or R2 is an oxygen function can be, with the proviso that if (A) does not mean (B) ", at least includes. 15. Linking the formulas O R CH - CH ' CH »CH-R ₂ trans 4Q981 1/1203 j NACKaEREJO HTJ R Ό ,CM. £ * £ CH- (CH ₂ ) Jc- ^ CHCH "" ^ CH = CH-R ₂ trans lind the enantiomers, diastereomers, racemates and racemic Mixtures thereof wherein η is an integer from 1 to 5 inclusive, R hydrogen or an alkyl group with up to 3 carbon atoms, Rp a part of the molecule of the formulas CH ₂ P I or -CH -R "-CH-R ^{1 2} where P is hydroxy or triphenylmethoxy, R ^{1 is} a straight-chain alkyl or alkenyl group with 3 to 10 carbon atoms or a straight-chain alkyl or alkenyl group with 3 to 7 carbon atoms and one or two branched alkyl groups with 1 to 3 carbon atoms and R "is a straight-chain co-haloalkyl group with 2 to 7 carbon atoms, a straight-chain alkyl or alkenyl group with 3 to 10 carbon atoms and optionally substituted with a hydroxy or triphenylmethoxy group or a straight-chain alkyl or alkenyl group with 3 to 7 carbon atoms and with one or zv / ei branched Denote alkyl groups with 1 to 3 carbon atoms and optionally substituted with a hydroxyl or triphenylmethoxy group, R., hydroxy, an alkoxy group with 1 to 12 carbon atoms, Is tetrahydropyranyloxy or tri- (lower-alkyl) -silyloxy, and the pharmacologically acceptable cationic salts thereof when R- is hydroxy. ^ 0981 1/1203 16. Compound of Formula H\ / C - Ct VT ^ H and the optical isomers, enantiomers * !, diastereomers, racemates and racemic mixtures, in which R _{c is} a 1-molecule part of the formula CH ₂ -OC
CR ¹ or -CH ₂ -R ₈ means where R ^{1 is} a straight-chain alkyl or alkenyl group with 3 to 10 carbon atoms, or a straight-chain alkyl or alkenyl group with 3 to 7 carbon atoms and a branched alkyl group with 1 to 3 carbon atoms, R _{Q is} a straight-chain alkyl or alkenyl group with 3 to 10 carbon atoms and substituted with a triphenylmethoxy group or a straight-chain alkyl or alkenyl group with one or two branched alkyl groups with 1 to 3 carbon atoms and substituted with a triphenylmethoxy group, and ¥ means iodine or a lithium atom. Compound of formula 0 9 8 1 1/1203 and the optical isomers, enantiomers, diastereoisomers, Racemates and racemic mixtures thereof, wherein Ri- is a part of the molecule of the formula CH ₂ -OC (C ₆ H ,.) I. and .. -CH ₀ -R ₀ CH-R ', 2 8 denotes where R 'is a ·;: straight-chain alkyl or alkenyl group with 3 to 10 carbon atoms or a straight-chain alkyl or alkenyl group with 3 to 7 carbon atoms and with a branched alkyl group with 1 to 3 carbon atoms, R _Q a straight-chain alkyl or And Ry means a straight-chain lower alkyl group, which need not necessarily be the same for the respective use. 18. Compound of Formula R ¹ 0. eis / CH- (CHa) _n -CR ₃ / ^CC \, H
ι ι R ₁ and the optical isomers, diastereomers, enantiomers, Racemates and racemic mixtures thereof, wherein R ^{1 is} an alkyl group with 1 to 3 carbon atoms, R _{1 is} hydrogen, hydroxy, tetrahydropyranyloxy and tri-lower alkylsilyloxy groups, 409811/1203 passed [ R-, hydroxy, alkoxy with 1 to 12 carbon atoms, Tetrahydropyranyloxy or lower trialkylsilyloxy groups means and η ejLne means an integer from 1 to 5 inclusive, 40981 1/1203 COPY