DE2401763A1 - OPTICALLY ACTIVE HYDROXYENONE - Google Patents

Description

The invention relates to chemical intermediates and, more particularly, to optically active chemical intermediates, which are used for the production of optically active prostaglandins and prostaglandin-like compounds that have the same configuration on the C-15 like the naturally occurring prostaglandins.

According to the invention, therefore, there are optically active hydroxyenones of the formula and absolute stereochemistry

409829/1089

suggested, where R stands for the following:

A branched or unbranched alkyl or alkenyl radical having 4 to 10 carbon atoms;

12 1

a radical of the formula -A .0R, where A is an alkylenra-

p is dical with 1 to 9 carbon atoms and R is an alkyl radical with 1 to 9 carbon atoms or a cycloalkyl radical with 5 to 7 carbon atoms, with the restriction that A and R together contain no more than 10 carbon atoms;

2-5 2

a radical of the formula -A R, where A is a direct bond or an alkylene radical having 1 to 3 carbon atoms stands, and R ^ stands for an aryl radical which is unsubstituted or that can be substituted by .calogen atoms, nitro- radical, alkyl, halogenoalkyl or alkoxy radicals each with 1 to 3 carbon atoms or dialkylamino radicals, wherein each alkyl has 1 to 3 carbon atoms;

a radical of the formula -A .A .R, in which kr stands for an alkylene radical with 1 to 3 carbon atoms which has 0, 1 or 2 alkyl radicals with 1 to 3 carbon atoms as substituents

H.

carries material atoms, A for an oxygen or sulfur atom, a sulfinyl radical or an alkylimino radical with up to 4 carbon atoms and R stands for an aryl, Benzyl or furfury! Radical, which optionally is substituted by hydroxy, nitro or phenyl radicals, Ealogen atoms, alkyl, alkenyl, halogenoalkyl, alkoxy, alkenyloxy or acylamino radicals with 1 to 4 · Carbon atoms or dialkylamino radicals wherein each alkyl has 1 to 3 carbon atoms; or a radical of the formula -A .A .R, where A ^ the above Has meaning, A .for an oxygen or sulfur atom, a sulfinyl, sulfonyl, imino or alkylimino radical with up to 4 carbon atoms or a direct one

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Bond or A ^ and A each represent a direct bond stand and R ^ for an aromatic heterocyclic radical with one or two 5- or 6-membered rings that are in only one ring have 1 or 2 non-adjacent nitrogen heteroatoms and optionally 1 to 3 alkyl radicals or carry halogen atoms as substituents.

A suitable value for R when it is an alkyl or alkenyl radical having from 4 to 10 carbon atoms is for example an n-pentyl, n-heptyl, 1,1-dimethylpentyl, 1,1-dimethylheptyl or cis-pent-2-enyl radical.

A suitable value for A when it is for an alkylene radical with 1 to 9 carbon atoms is, for example, a methylene, ethylene, isopropylidene, 1,1-dimethylethylene, Trimethylene, tetramethylene or pentamethylene radical,

2
and a suitable value for R is, for example, a methyl, ethyl, n-propyl, isopropyl, η-butyl, isobutyl, n-pentyl or n-hexyl radical.

12 12

Suitable values for the group -A -OR, in which A and R together do not contain more than 10 carbon atoms, are therefore, for example, n-propoxymethyl-, n-butoxy-.methyl-, isobutoxymethyl-, n-pentyloxymethyl-, n-hexyloxymethyl-, 2-n-butoxyethyl, 3-n-propoxypropyl, 4-ethoxybutyl and 5-methoxypentyl radicals. -

2
A suitable value for A is a methylene, ethylene, trimethylene, 1-methylethylene [-CH (CH ₃ ) .CH ₂ -], 1-ethylethylene - [- CH (C ₂ H ₅ ) .CH ₂ - ^], 2-methylethylene- [-CH ₂ -CH (CH. Or 1,1-dimethylethylene- [^ (CH ^ .CH ^ radical, and a suitable value for R ^ when it is an aryl radical _x that is optionally substituted, is for example

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wise a phenyl or naphthyl radical, which is optionally substituted. Suitable halogen substituents in Ir are, for example, chlorine, bromine or fluorine atoms. Suitable
Alkyl or alkoxy substituents with 1 to 3 carbon atoms in Ή? are, for example, methyl, ethyl, methoxy or ethoxy radicals, and suitable halogenoalkyl substituents with 1 to 3 carbon atoms in R 1 are, for example, chloroalkyl or fluoroalkyl radicals, such as, for example, trifluoromethyl radicals. Suitable dialkylamino substituents in R ^
are for example dialkylamino radicals in which the two alkyl radicals are the same, such as a dimethylamino radical. Suitable substituted aryl radicals are therefore, for example, chlorophenyl, bromophenyl, IPluorojhenyl, chloronaphthyl, tolyl, trifluoromethylphenyl, ethoxyphenyl,
Nitrophenyl, dimethylaminophenyl and tetrahydronaphthyl radicals. Preferred aryl radicals contain no more than 2 substituents as defined above. Particular examples of Ir are therefore the phenyl, 2-naphthyl, 3- and
^ ■ -Chlorophenyl, 2- and 4-fluorophenyl, 3,4-dichlorophenyl and 3-trifluoromethylphenyl radicals.

A suitable value for A when it is an alkylene radical with 1 to 3 carbon atoms which has 0, 1 or 2 alkyl radicals each with 1 to 3 carbon atoms as substituents is, for example, a methylene, ethylene or trimethylene radical with 0, 1 or 2 methyl substituents such as the methylene, ethylidene, isopropylidene
and trimethylene radicals.

A suitable value for A if it is an alkyleneimino radical with up to 4 carbon atoms is, for example, the methylimino radical.

A suitable value for R when it is for an aryl radical
stands, which is optionally substituted, is for example

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wise a phenyl or naphthyl radical, which is optionally

is substituted »Suitable halogen atom substituents in R are, for example, chlorine, bromine or fluorine atoms. Suitable Alkyl, alkoxy, alkenyl or alkenyloxy substituents with 1 to 4 carbon atoms in R are, for example, methyl, t-butyl, allyl, methoxy or allyloxy radicals. Suitable halogenoalkyl substituents with 1 to 4 carbon atoms in R are, for example, chloroalkyl or Pluoro alkyl radicals, such as trifluoromethyl radicals. Suitable Dialkylamino radicals in which each alkyl has 1 to 3 carbon atoms and the substituents in R are, for example, dialkylamino radicals in which the two alkyl radicals are the same, such as a Dimethylamino radical. Suitable substituted aryl radicals are, for example, chlorophenyl, chloronaphthyl, bromophenyl, Fluorophenyl, tolyl, xylyl, methylnaphthyl, t-butylphenyl-, methylchlorophenyl-, trifluoromethylphenyl-, Hydroxyphenyl, methoxyphenyl, methoxynaphthyl, biphenylyl, Dimethylaminophenyl and tetrahydronaphthyl radicals.

Preferred aryl radicals contain no more than 2 substituents as defined above. Special values for R are therefore the phenyl, benzyl, furfuryl, I-haphthyl, 2-naphthyl, 2-, 3- and 4-chlorophenyl-, 4-bromophenyl-, 2-, 3- and 4-fluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, .3,4- and 3,5-dichlorophenyl-, 2-, 3- and 4-tolyl-, 2,3-, 3,4- and 3,5-xylyl-, 4-t-butylphenyl-, 3-allylphenyl-, 3-trifluoromethylphe.nyl-, 4-hydroxyphenyl-, 2-, 3-r and 4-methoxyphenyl-, 4-biphenylyl-, 3-dimethylaminophenyl-, 2-chloro-4-methylphenyl-, i-chloro-2-naphthyl, 4-chloro-2-naphthyl, 6-methyl-2-naphthyl, 6-methoxy-2-naphthyl and 5,6,7,8-tetrahydro-2-naphthyl radicals.

A0982S / 1089

A suitable fourth for A if it is an alkyleneimino radical with up to 4 carbon atoms is, for example, a methylimino radical.

Suitable values for R are, for example, pyridyl, pyrimidinyl, quinolyl, indolyl, indolinyl, benzimidazolyl, thiazolyl, benzothiazolyl, benzofuranyl or benzothienyl radicals, in particular the 2-, 3- and 4-pyridyl and 5-Ittd.olyl radicals. Suitable halogen substituents in R are, for example, chlorine, bromine and iodine atoms, and suitable alkyl or alkoxy substituents in Ή? are, for example, methyl or methoxy radicals. Thus, special substituted heterocyclic radicals are, for example, 6-methyl-2-pyridyl-, ^, e-dimethyl ^ -pyridyl-, 5-chloro-3-pyridyl-, 2,5-dichloro-3-pyridyl- and 5-indolyl- radical.

A preferred group of hydroxyenones of the invention are those compounds in which R is an alkyl radical with 4 to 9 carbon atoms, especially one

3 1L 4.

n-heptyl radical or a radical of the formula -A, A .R is,

Z IL.

v / orinA stands for a methylene radical, A for an acid substance atom and R stands for a phenyl radical that is substituted by a halogen atom, e.g. a chlorine or bromine atom, or a trifluoromethyl radical, in particular, a 3-chlorophenyl or 3-trifluoromethylphenyl radical *

Specific hydroxyenones of the invention are (3aR, 4R, 5R, 6aS) -2,3,3a, 6a-tetrahydro-5-hydroxy-2-oxo-4- (3-oxodec-i-transenyl) cyclopentene jb] furan, (3aR, 4R, 5R, 6aS) -4 — Qf - (3-chloro- · phenoxy) -3-oxobut-1-trans-enyl] -2,3,3a, 6a-tetrahydro-5- hydroxy ^ -oxocyclopenteno JV] furan and (3aR, 4R, 5R, 6aS) -2,3,3.a, 6a-Tetrahydro-5-hydroxy-2-oxo-4 ~ f ~ 3-oxo-4 ~ (3-trifluoromethylphenoxy) but-1-trans-enylj cyclopentene [bj furan.

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According to the invention there is also a method for the production proposed the optically active hydroxyenones of the invention, which is carried out by having an optically active hydroxyenol of the formula

II

CH (OH) R ¹

oxidized.

The oxidation can, for example, using manganese dioxide or using a 1,4-benzoquinone oxidizing agent, such as 2,3-dichloro-5,6-dicyano ~ 1,4-benzoquinone, executed v / earth.

The hydroxyenol of formula II used as the starting material in the above processes can be prepared by the following Reaction sequence can be obtained:

7-syn-Dimethoxymethylbicyclo [] 2,2, iJhept-2-en-5-one (III) sua corresponding alcohol IV is reduced, which is esterified with phthalic acid, whereby the hemiphthalate V is formed. The reaction of the hemiphthalate V with (-) - amphetamine results in the crystallization of the optically active (-) - Amphetamine salt, which leads to the optically active hemiphthalate VI is hydrolyzed. (All subsequent intermediates

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in this row are of course optically active). The hemiphthalate VI is hydrolyzed to alcohol VII, which is oxidized to ketone VIII with Jones reagent. Eaeyer-Villiger oxidation results in lactone IX, which is rearranged to iodohydrin X with potassium triiodide. The iodohydrin X is protected as the 4-phenylbenzoate ester XI (R = 4-phenylbenzoyl), and the iodine is removed with tributyltin hydride to give the deiodinated lactone XII, which is hydrolyzed to the aldehyde XIII. The aldehyde XIII is reacted with a phosphonate reagent of the formula (CIi ₇ O ^ PO. CB ^ COR in the presence of a strong base to give the protected enone XIV, which is then reduced to the protected enol XV Phenylbenzoyl group is removed by hydrolysis to give the desired hydroxyenol starting material II.

The hydroxyenone according to the invention can be converted into a prostaglandin or a prostaglandin-like compound can be converted, by reduction, preferably stereo-selective Reduction (where, for example, a microbiological reduction is carried out with the organism Trechispora brinkmannii available from the Commonwealth Mycological Institute, Kew, Surrey, England under reference number 804-39 is), whereby a single epimeric hydroxyenol is obtained, protection of the two hydroxyl groups, reduction of lactone with diisobutyl aluminum hydride, reaction with (4 ~ carboxybutyl) triphenylphosphonium bromide and removal of the hydroxyl skin groups.

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(CH-O) ₅ CK

(CH ₃ O) ₂ CH

IV

(cn, O) ₀ C ₄ H η

VI

COOH

VII

(CH-O) ₂ CH ---- H

(CH ₃ O) ₂ CH

VIII

IX

829/1089

2A01763

CH (OCH,)

3'2

HO

TT

CH (OCH ₃ ;

ι /

CH (0CH.) ₂

R ⁶ O

XII

CHO

R ⁶ O. . XIII

or

CH (OH) R-

XIV XV

II

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

Example 1

5G (3aR, 4R, 5R, 6aS) -2,3,3a, 6a-tetrahydro-5-hydroxy-4 - (3-hydroxydec-1-trans-enyl) -2-orcocyclopenteno [b J furan dissolved in 90 nl of dry methylene dichloride, before the solution was then added to a suspension of 4-3 g of manganese dioxide in 100 ml of dry methylene dichloride. The mixture was stirred rapidly at room temperature for 4- 1/2 C hours. The mixture was then filtered through Celite (trademark) and the filter cake was washed five times with 50 ml of acetone. The filtrate and washings were combined, the solvents were evaporated and the residue was chromatographed on 200 g of Florisil (trade mark). Elution with 20 #, Äthylacet.at in ether gave (3aR, 4-R, 5R, 6aS) -2,3,3a, 6a-tetrahydro-5-hydroxy-2-OXO-A - (3-oxodec-1 - trans-enyl) -cyclopenteno J bj furan as a white crystalline solid with a mp of 4-7.5 "to 4-9 ⁰ C., [PQ ^ ⁵ = -3 ° (c = 0.66 in chloroform)..

The (3aR, 4-R, 5Rj6aS) -2.3, 3a, 6a-Tetrahydro-5-hydroxy-4- (3-hydroxydec-1-trans-enyl) - 2-oxocyclopenteno [VJfuran was obtained as follows:

316 g of (+) - 7-Dimetho> ^ Taethylbicyclo [2,2ji] hept-5-en-2-one (III) were dissolved in 2 liters of absolute ethanol, and the solution was at ⁰ ° C. in an ice / salt -Bath stirred. Then 18 g of sodium borohydride was added to this solution at such a rate that the temperature of the solution did not exceed 5 ° C. After the addition had ended, the solution was ^{stirred for one hour at 0} ° C., after which 500 g of crushed ice and 1 liter of saturated sodium hydrogen tartrate solution were added. The genic was then 1 1

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Methylene dichloride and then extracted four times with 300 ml of methylene dichloride. The extracts were combined and dried, and the solvent was evaporated under reduced pressure, leaving (+) - 7-dimethoxymethylbicyclo- [2,2,1] hept-5-en-2-endo-ol (IV) as a colorless liquid, R = 0.5 (silica gel, ethyl acetate) obtained which was contaminated with approximately 5 % of the isomeric exo-alcohol. The KMR spectrum in deuteriochloroform showed the following characteristic signals (6 values):

0.79, 111, double doublet (J = 3 and 13 Hz), C-3 endo proton 1.4, 1H, broad, hydroxy

1.91, 1H, doublet (J = 10 Hz), C-7 proton 2.17, 111, multiplet, C-3 exo proton 2.76, 1H, broad)

2.98, IH, broad) G-Λ-ηηά «protons

3.23j 6H, singlet, methoxy
4.20, 1H, doublet (J = 10 Hz), -CH (OCI! ^ 4 _Λ 4, 1H, multiplet, C-2 proton
5.93, 1H, multiplet)
.6,31, 1H, multiplet) C-5 and C-6 protons

This product was used in the next step without further purification.

313 s (+) - 7-dirnethoxymethylbicyclo [2,2, i] hept-5-en-2-endool and 257 g of phthalic anhydride in 1 liter of anhydrous Pyridine dissolved, and the solution was 18 hours at seam temperature ditched. Most of the pyridine was evaporated under reduced pressure and the residue evaporated Made alkaline with saturated sodium bicarbonate solution. The alkaline solution was four times with 250 ml of methylene chloride extracted and the extracts discarded. The basic solution was then adjusted to pH 1 with 2N hydrochloric acid

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2401783

acidified, and 'the acidic solution was extracted four times with 250 ml of methylene dichloride. These extracts of the acidic solution were combined and dried, and the solvent was evaporated under reduced pressure. The remaining solid was crystallized from isopropanol, whereby (+) - 7-dimethoxymethylbicyclo ^^ jijhept ^ -en ^ -endo-yl-hydrogen phthalate (V) with a melting point of 128 to 130 ^° C. was obtained.

383 g of the (+) - hydrogen phthalate ester were dissolved in 3.83 liters of ether and 250 ml of isopropanol dissolved by refluxing. Then 156 g of (-) - amphetamine was added and dissolved, and the solution was left to stand at room temperature for 2 days. The solid that crystallized out was filtered off, washed twice with 500 ml of ether, dried and on isopropanol crystallized, whereby the levorotatory amphetamine

121

-73.5 ° (c = 1.2 in chloroform). The NMR spectrum in Deuterio- chloroform showed the following characteristic peaks. -Values):

1,1, 4H, doublet, CH ₃ -CH (NH *) - and C-3 endo proton

1.85, 1H, doublet (J «= 8Hz), C-7 proton 2.06, 1H, multiplet, C-3 exo proton

3.10, 3H, singlet)

3.18, 3H, singlet) ^nethox ?

4.16, IH, doublet (J = 8 Hz), -CH (OCHj) ₂

5.32, 1H, multiplet, C-2 proton

5.88, 1H, Kultiplet)

6.15, 1H, multiplet) C-5 and C-6 protons 6.9-7.8, 9H, multiplet, aromatic
8.4, 3H, broad, ammonium

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177 S of this salt were dissolved in 1.76 l of ethylene dichloride, and the solution was shaken with 500 μl of saturated oxalic acid solution and 500 ml of v / water. The mixture was filtered, the organic layer in the filtrate was separated and the aqueous layer was extracted with two times 500 ml of methylene dichloride. The extracts combined with the organic layer were washed with a 1: 1 mixture of saturated saline and water and dried, and the solvent was evaporated under reduced pressure, whereby (-) - 7 ~ dimethoxymethylbicyclo [2,2, i] hept- 5-en-2-endo-yl-hydrogen phthalate (JFI) was obtained, mp. 144 to 14-5 ⁰ C, [d] p ¹ '= -87 ° (c = 1.07 in chloroform). The KKR spectrum was identical to that of the racemic hydrogen phthalate ester described above.

1.29 g of this (-) - IThydrogen phthalate ester was dissolved in 4-, 6 μl 10% aqueous potassium hydroxide solution under an argon atmosphere, and the mixture was refluxed for one hour. The mixture was cooled and extracted four times with 5 ml of methylene dichloride each time, and the combined extracts were washed with 5 ml of sodium chloride solution and dried. The solvent was evaporated under reduced pressure to give (-) - 7-dimethoxymethylbicyclo [2,2, i [] hept-5-en-2-endo-ol (VII), [öc] | ⁴ = -92 ° (c = 0.93 in chloroform). The IiHR spectrum was identical to that of the corresponding racemic alcohol described above.

662 mg (-) - 7-Dimethoxymethylbicyclo [2,2, i [] hept-5-en-2-endo-ol were dissolved in 6.6 ml acetone and the solution was stirred and ^{cooled to 0} ° C., whereupon then 1.8 ml of Jones reagent was added. After half an hour, 1 ml of isopropanol was added, whereupon the mixture was mixed with 10 ml of water

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24Ü1763

was diluted and extracted with four times 5 nil methylene dichloride. The extracts were combined, washed with 2 ml of saturated sodium bicarbonate solution and dried, and the solvent was then evaporated under reduced pressure. The remaining oil was distilled, whereby the ketone, (-.) - 7_Di _m ethoxyinethylbicyclo [2 , 2, iJhept-5-en-2-one (VIII) was obtained, bp 95 ° C / 0.1 mm, Mjf "=" 5 ^ 5 ° (c = 0.16 in chloroform).

111 g of the ketone (VIII) were dissolved in 550 ml of ether were then 39.7 ml of a 10? Oicen aqueous sodium hydroxide solution was added, and finally the mixture was stirred and cooled to ⁰ ° C. Then 186 ml of a 27 #igen (w / v) solution of V / asserstoffperoxid were added dropwise to the stirred mixture while the temperature was kept below 10 ⁰ C. After the addition had ended, the mixture was stirred for three hours, whereupon the ether layer was separated off and the aqueous layer was extracted twice with 100 ml of ether each time. The aqueous layer was adjusted to pH 7.4 with glacial acetic acid and ^{cooled to 0} ° C., whereupon a solution of 887 g of potassium iodide and 451 g of iodine in 1758 ml of water was added. The mixture was ^{stirred at 0} ° C. for 20 hours, and then the excess iodine was decomposed by adding solid sodium sulfate. The aqueous suspension was extracted four times with 500 ml of methylene dichloride each time, and the combined organic extracts were dried. The solvent was evaporated under reduced pressure to give the (-) - iodohydrin (X) as an oil, R-, = 0.3 (5 % ethyl acetate in methylene dichloride). The NKR spectrum in deuteriochloroform showed the following features (6 values): ■

3j 39, .. 6H, singlet, methoxy

4.0, 2H, multiplet, C-5 and C-6 protons

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4-, 40, 1H ₁ doublet, ₅₂
4.96, 111, multiplet, C-6a proton

3 S (39 mmol) of the iodohydrin (X) were dissolved in 60 ml of pyridine which had been dried over potassium hydroxide pellets, followed by the addition of 9.7 g (44 mmol) of 4-phenylbenzoyl chloride. The solution was then heated to 50 ° C. under argon for 27 hours. The solution was cooled to room temperature, 0.2 ml of water was added, and the mixture was stirred at room temperature for 50 minutes. The pyridine was evaporated under reduced pressure and the residue was dissolved in 500 ml of methylene chloride. This solution was washed successively with three times 100 ml of 2N hydrochloric acid, three times with 1C0 ml of saturated sodium bicarbonate solution and 100 ml of v / water. The organic layer was dried and the solvent evaporated to give a white solid which was crystallized from a mixture of methylene chloride and ether to give the (-) - 4-phenylbenzoate ester (XI) as a white solid, R ^. = 0.2 by thin layer chromatography on Merck silica gel plates using methylene chloride as the eluent.

The ITMR spectrum of the 4-phenylbenzoate ester in deuteriochloroform showed. the following characteristics (£ values):

2,4-2, 1H, cultiplet, C-3a proton

2.72, 2H, singlet + doublet, C-3 protons 3.25, 1E, multiplet, C-4 proton

4-, 4-1, 1H, double doublet, (J = 3 and 5 Hz), C-6 proton 4j7-4, 9, 4-E, Kultiplet, -CH ₂ -O-.
5.1, 2H, multiplet, C-6a proton

5.73, 1H, triplet, (J "= 5 Hz), C-5 proton

7.0 - ^ 8.1, I3H, Kultiplet, aromatic protons

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A mixture of 14.0 g (24 mmol) of the 4-phenylbenzoate ester (XI) and 500 ml of benzene which had been dried over 4A molecular sieves was heated to reflux until dissolution was complete. The refluxed solution was purged with argon for 30 minutes and then a solution of 8.6 g (29 mmol) of iri-n-butyl tin hydride in 10 ml of benzene was added. The reaction mixture was refluxed for 20 hours and allowed to cool to room temperature, after which the benzene was evaporated under reduced pressure. The solid obtained was triturated with three times 50 ml of n-pentane and crystallized from a mixture of methylene chloride and ether, the decoded (-) - lactone (XlI) being obtained as a white crystalline substance, melting point = 188 to 189 ° C, R. ^ ₁ = 0.3 for thin layer chromatography on Merck silica gel plates using a 1: 1 mixture of ethyl acetate -

did and pentane as the eluent.

The NMR spectrum of the decoded lactone (XII) in Deuterio- Chloroform showed the following characteristics (£ values):

2,3-3,2, 6H, complex, C-3i 3a-, 4- and 6-protons 4.86, 4H, multiplet —CH ₂ .0-.

-0

5.05, 2H, multiplet, 0-6a and -O-CH- protons 5.50, 1H, multiplet, C-5 proton
7.1 - 8.1, 1311, multiplet, aromatic protons. '

39.5 S <3- decoded ^it lactone (XII) were dissolved in 1980 ml of chloroform containing 2 vol .- # isopropanol. Then 495 ml of concentrated hydrochloric acid were added and the resulting two-phase system was stirred for 11/2 hours at room temperature. The chloroform layer was then separated and the aqueous layer was extracted with two 50 ml portions of chloroform. The combined extracts

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were washed with 200 ml of saturated sodium bicarbonate solution, and the organic solvent was evaporated under reduced pressure in the presence of 50 ml of sodium bicarbonate solution. The resulting suspension was then extracted three times with 50 ml of ethyl acetate, the combined extracts were dried and the solvent was evaporated under reduced pressure, until crystallization began. The solution was allowed to stand, ice crystallization was finished, and the product -.rarde then filtered off and dried to give (3a R, 4-R, 5 ", 6 £) -2,3,3a, ^8a-r. L ^! Etra] x7drc- 2-oxo-5- (4 - phenylbenzoyloxy) cyclopentene jb ^ furan - ^ - cartaldehyde (XIII).

A solution of 1.125 g of 2-Oxonor.ylphosphonsäure-ai ^ fch.ylester in 11 al of dry 1,2-dimethoxyethane was at -78 C with 2.8 ml of a 1.4 M solution of n-eutyl-lithium in Treated hexane and the mixture was stirred for 15 minutes. A solution of 1.05 g of (3aR, 4-R, 5R, 6aS) -2., 3 »3a, 6a-tetrahydro-2-oxo-5- (4-phenylbenzoyloxy) cyclopenteno (bjfuran-4 carbaldehyde in 6 ml of 1,2-dimethoxyethane was added, and after 1 hour the reaction mixture was neutralized with glacial acetic acid, whereupon all solvents were removed by evaporation under reduced pressure below 35 G. The residue was chromatographed on Florisil, with solutions of ethyl acetate in toluene as eluent. 2Js, the protected (-) - enone (XIV) (R ¹ = n-heptyl) was obtained as a clear oil, IU = 0.6 (50 % ethyl acetate in toluene) .. The HMR- Spectrum

in deuteriochloroform showed the following characteristic features (6 values):

0.73, 3Ξ, broad triplet, methyl

- 1.5, 1OH, multiplet, -CHp.CEp-GHp-

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24017S3

1.92-2.52, 8H, Multiplet, C-3, C-Ja *, G-4, and C-6 protons

and -CH ₂ -GO-

4.16-4.53, 2H, Kultiplet, C-5 and G-6a protons 5.17, HI, doublet (J = 16 Hs), -CK: CK.CO-5.56, 1H, double Doublet (J = 16?: S, J = 7 Hz), -CH ₂ -CH: CH. CG-5.95 - 6.75, 9II »Kultiplet, aromatic protons.

A solution of 4.9 ml of a 0.323 reading of diisobornyloxyaluminum isopropoxide was added to a solution of 500 mg of the protected (-) - Snons in 5 rl of dry toluene under an argon atmosphere at hem temperature. The mixture was stirred for 3 1/2 hours at room temperature, shaken with 2 ml of a 1: 1 mixture of saturated sodium hydrogen tartrate solution and sodium chloride solution and extracted three times with 3 ml of ethyl acetate each time. The organic extracts were combined, dried over sodium sulphate and eir.gedair.pft to dryness, the crude piced (-) - Snol (XV) (R = n-heptyl) being obtained, R ₁₃ , = 0.4- (1 : 1 ethyl acetate / toluene). The crude enol (XV) (R = n-heptyl) was vigorously stirred for two hours with 97 mg of finely powdered anhydrous potassium carbonate in a mixture of 3 ml of methanol and 0.1 ιαΧ kethylene dichloride. 1.2 ml of 1N hydrochloric acid were then added, followed by the addition of 20 ml of ethyl acetate. The organic layer was then separated, washed successively with saturated sodium bicarbonate solution and saturated saline solution and dried, after which the solvents were evaporated. The residue was chromatographed on 15 g of uPlorisil. Elution with ether removed the by-products. Subsequent elution with ethyl acetate. gave (3aR, 4R, 5R, 6aS) -2,3,3a, 6a-tetrahydro-5-hydroxy-4 ~ (3-hydroxydec-1-trans-enyl) -2-oxocyclopenteno Qf] furan (II, R ¹ = n-heptyl) as a clear OI ₁ R ₅₁ = 0.1 (50 % ethyl acetate in toluene). The M-IR spectrum in deuteriochloroform showed the following characteristic features (S values):

40982 97 1089

0.75, 3H, broad triplet, methyl 0.95-1.4-5, 1OH, multiplet, -CH ₂ -GH ₂ 1.4-5-2.9, 8H, multiplet, C-3-, C -3a-; 0-Ή C-6-and

2-hydroxyl protons

3.32, 2H, multiplet, C-5 ~ and side chains]> CH (OH) protons 4.06, 1H, multiplet, C-6a proton
4,6, 2H, multiplet, olefinic protons.

Example 2

The procedure described in Example 1 was repeated using (3aE, 4E, 5E, 6aS) -4- [ft ~ (3-chlorophenoxy) -3-hydroxybut-1-trans-enylj -2,3, 3a, 6a-tetrahydro -5-hydroxy-2-oxocyclopentenojb] furan instead of (3aB, 4-B, 5E, 6aS) -2,3,3a, 6a-tetrahydro-5-hydroxy-4 ~ (3-hydroxydec-1-trans- enyl) -2-oxocyclopenteno [b] furan was used. (3aE, ^/ iE, 5E, 6aS) -4- [4- (3-chlorophenoxy) -3-oxobut-1-trans-enyl] -2,3, 3a, 6a-tetrahydro-5-hydroxy-2 —Oxocyclopenteno [Vj furan as a white crystalline solid with an ip. obtained from 127 to 128.5 ⁰ C, E _F "0.2 (50% Ithylacetat in toluene), H ψ = + 0.7 ° (c = 1.3 in chloroform).

The (3aE, 4-E, 5S, 6aS) -4- Ql- (3-chlorophenoxy) -3-hydroxybut-1 trans-enyl] -2,3,3a, öa-tetrahydro ^ - used as the starting material in the above process hydroxy ^ -oxocyclopenteno {V} furan can be obtained by repeating the last part of Example Λ , but instead of 2-oxonopnyl-phosphonic acid dimethyl ester 3- (3-chlorophenoxy) -2-oxopropyl-phosphonic acid dimethyl ester used. The following intermediate products are obtained:

Enone (XIV, E = 3-chlorophenoxy-ethyl), white crystalline solid with a melting point of 171 to 173 ° C, Ep = ·. 0.6 (50 # ethyl acetate in toluene), [oCJ ψ = -135 °, (c = 1.07 in chloroform);

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protected enol (XV, R = 3-chlorophenox-methyl), R ^ = 0.4 (50 # ethyl acetate in toluene);

Hydroxyenol (II, R. «" 3-chlorophenoxymethyl), a clear oil, R _p = 0.1 (50 % ethyl acetate in toluene).

Example 3

The procedure described in Example 1 was repeated using (3aR, 4R, 5R, 6aS) -2,3,3a, 6a-tetrahydro-5-hydroxy-4- [3-hydroxy-4- (3-trifluoromethylphenoxy) but- 1 —trans — enyl] —2— oxocyclopentenojVjfuran instead of (3aR, 4R, 5R, 6aS) -2,3, 3a, 6a-tetrahydro-5-hydroxy-4- (3-hydroxydec-1-trans-enyl ) -2-oxocyclopentenojib] furan was used. (3aR, 4-R, 5R, 6aS) -2,3, 3a, 6a-Te.trahydro-5-hydroxy-2-oxo-4 ~ [3-0x0-4- (3-trifluoromethylphenoxy) but- 1-trans-enyl] cyclopenteno QTJ furan was obtained as a white crystalline solid with a melting point of 100 to 102.degree. R _p = 0.25 (50 % ethyl acetate in toluene), [pc] ^ = + 0.5 ° (c = 3.01 x in chloroform). The MR spectrum in deuteriochloroform showed the following characteristic features' (ο "values):

4.15, 1H, multiplet, -CH (OH) -

4.7, 2H, singlet, - -CO.CH ₂ .0-

4.95, 1H, multiplet, ^ CH.O.CO, -

6.5, 1H, doublet (J = 16 Hz), -CH: CH.CO-6.9, 1H, double doublet (J = 16 Hz, -J = 8 Hz), -CH: CH.CO-7.0 - 7.5, 4H, multiplet, aromatic protons.

The starting material used in the above procedure can be prepared by the procedure described in the last part of Example 1 be obtained if you replace the 2-oxononylphosphonic acid dimethyl ester 2-Oxoro-3- (3-trifluoromethylphenoxy) propylphosphonic acid dimethyl ester used. - The following intermediate products are obtained:

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Enone (XIV, R = 3-trifluoromethylphenoxymethyl), white crystalline solid, R ^ ₁ = 0.5 (50 % ethyl acetate in toluene). The HMR spectrum in deuteriochloroform showed the following characteristic features (ο values):

4.7, 211, singlet, -CO.CH ₂ .0-

5.0-5.5, 2E, multiplet, C-5β and C-6ass protons 6.55, 1H ₁ doublet (J = 16 Hz), -CH: CH.CO-6.8-8.2 , 14-H, Hultiplet, -CH: CH.CO- and aromatic protons,

Protected enol (XV, R = 3-trifluoromethylphenoxymethyl), Rg, = 0.3 (50 ¹ P ethyl acetate in toluene).

Hydroxyenol (II, R = 3-trifluoroniethylphenoxymethyl), a clear oil, R _p = 0.1 (50 μl of ethyl acetate in toluene) '. The UhIR spectrum in deuteriochloroform showed the following characteristic features (6 values):

3. »3-4.1, 5H, multiplet, 2-hydroxy-; -CH (OH) .CH ₂ -O- 'and

C-5β protons

4.5, 1H, multiplet, -CH (OH) -4.9, 1H, multiplet, C-6ass proton
5.7, 2H, multiplet, olefinic protons 7.0 - 7.5i 4H, multiplet, aromatic protons.

409829/1089

Claims (1)

P a te n claims 1. Optically active hydroxyenones of formula and absolute stereochemistry .1 where R stands for the following: a branched or unbranched alkyl or alkenyl radical having 4 to 10 carbon atoms; 12 1 is a radical of the formula -A .0R, where A is an alkylenra- p is radical with 1 to 9 carbon atoms and R is an alkyl radical with 1 to 9 carbon atoms or a cycloalkyl radical with 5 to 7 carbon atoms, with the restriction, that A and R together do not have more than 10 carbon atoms contain; p 7 ρ a radical of the formula -A R, where A is a direct bond or an alkylene radical having 1 to 3 carbon atoms stands, and R stands for an aryl radical which is unsubstituted or which can be substituted by halogen atoms, nitro radicals, Alkyl, haloalkyl or alkoxy radicals each having 1 to 3 carbon atoms or Dxalkylamino radicals, A09829 / 1089 wherein each A, alkyl has 1 to 3 carbon atoms; 7. Il Il X a radical of the formula -A .A .R, where A is an alkylene radical with 1 to 3 carbon atoms, the substituent O, 1 or 2 alkyl radicals with 1 to 3 carbon atoms carries, A for an oxygen or sulfur atom, a sulfinyl radical or an alkylimino radical up to 4 carbon atoms and R stands for an aryl, benzyl or furfuryl radical, which optionally is substituted by hydroxy, nitro or phenyl radicals, halogen atoms, alkyl, alkenyl, halogenoalkyl, Alkoxy, alkenyloxy or acylanino radicals having 1 to 4 carbon atoms or dialkylamino radicals wherein each alkyl has 1 to 3 carbon atoms; or -5 5 5 7> a radical of. Formula -A “A .R, where A has the meaning given above, Ar stands for an oxygen or sulfur atom, a sulfinyl, sulfonyl, imino or alkylimino radical with up to 4 carbon atoms or a direct bond, or A and kr each stand for a direct bond and Ή? represents an aromatic heterocyclic radical with one or two 5- or 6-membered rings which. in only one ring have Ί or 2 non-adjacent nitrogen heteroatoms and optionally carry 1 to 3 alkyl radicals or halogen atoms as substituents. 2. Hydroxyenones according to claim 1, characterized in that Ί Ί that in R A for a methylene, isopropylidene, ethylene, 1,1-dimethylethylene, trimethylene, tetramethylene or ρ
Pentamethylene radical and R represents a methyl, ethyl, n-propyl, isopropyl, η-butyl, isobutyl, n-pentyl or p
n-Hexyl radical, A stands for a direct bond or a methylene, ethylene, trimethylene, 1-methylethylene, 1-ethylethylene, 2-methylethylene or 1,1-dimethylethylene 409829/1089 stands radical and Έ? represents a phenyl or naphthyl radical which is optionally substituted by chlorine, bromine or fluorine atoms, methyl, ethyl, methoxy, itoxy or dimethylamino radicals or a chloroalkyl or fluoroalky radical with 1 to 3 carbon atoms, A ^ for a methylene, itylidene, isopropylidene, ethylene or trimethylene radical, A stands for an oxygen or sulfur atom or a sulfinyl or methylimino radical and R stands for a'Phenyl- or naphthyl radical, which optionally is substituted by chlorine, bromine or iodine atoms, methyl, t-butyl, allyl, methoxy, allyloxy or dimethylamino radicals or chloroalkyl or fluoroalkyl radicals with 1 to 3 carbon atoms, or A for an oxygen or sulfur atom or a sulfinyl , Imino or methylimino radical and R ^ is a pyridyl, pyrimidinyl, quinolyl, indolyl, indolinyl, benzimidazolyl, thiazolyl, benzothiazolyl, benzofuranyl or benzothienyl · radical, which is optionally subst is ituted by chlorine, bromine or iodine atoms or methyl or methoxy radicals. 3. Hydroxyenones according to claim 1 or 2, characterized in that indicates that R stands for an n-pentyl, n-heptyl, 1,1-dimethylpentyl, 1,1-dimethylheptyl or cis-pent-2-enyl radical stands. 4. Hydroxyenones according to claim 1 or 2, characterized Ί Λ 2 indicates that in R the radical -A .OR .for an n-propoxymethyl-, n-butoxymethyl-, isobutoxymethyl-, n-pentyloxymethyl-, n-hexyloxymethyl-, 2-n-butoxyethyl-, 3-n-propoxypropyl- , 4-ethoxybutyl or 5-methoxypentyl radical, R ^ for a chlorophenyl, bromophenyl, fluorophenyl, chloronaphthyl, tolyl, trifluoromethylphenyl, ethoxy 409829/1089 phenyl, nitrophenyl, dimethylaminophenyl or tetra-ZI hyäronaphthylradikal, R stands for a chlorophenyl, Chloronaphthyl, bromophenyl, fluorophenyl, tolyl, Xylyl, methylnaphthyl, t-butylphenyl, methylchlorophenyl, Trifluoromethylphenyl, hydroxyphenyl, methoxyphenyl, Methoxynaphthyl, biphenylyl, dimethylaninophenyl or tetrahydronaphthyl radical or R ^ is a 2-, 3- or 4-pyridyl-, 5-indolyl-, 6-methyl-2-pyridyl-, 4,6-Dimethyl-2-pyridyl, 5-chloro-3-pyridyl or 2,5-dichloro-3-pyridyl radical stands. 5. Hydroxyenonenach claim 4-, characterized in that in R ¹ R ^ is a phenyl, 2-naphthyl, 3- or 4-chlorophenyl, 2- or 4-fluorophenyl, 3, ^ - dichlorophenyl or 3 -Trifluoromethylphenylradikal, R stands for a phenyl, benzyl, furfuryl, 1-naphthyl-, 2-naphthyl-, 2-, 3- or 4-chlorophenyl-, Λ-bromophenyl-, 2-, 3- or 4- ]? luoroph.enyl-, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dichlorophenyl-, 2-, 3- or 4-tolyl-, 2,3-, 3,4- or 3,5-xylyl-, 4-t-butylphenyl-, 3-allylphenyl-, 3- ^ rifluoromethylphenyl-, 4-hydroxyphenyl-, 2-, 3- or 4-methoxyphenyl- , 4-biphenylyl-, 3-diraethylaninophenyl-, 2-chloro-4-methylphenyl-, chloro-1-naphthyl-, 4-chloro-1-naphthyl-, 6-methyl-2-naphthyl-, 6-methoxy-2- naphthyl or 5,6,7,8-tetrahydro-2-naphthyl radical. 6. Hydroxyenones according to claim 1, characterized in that that R is an n-heptyl radical or a radical of the formula 3 4- 4- 3 -A-A -R is where A is a methylene radical, H ' Il A stands for an oxygen atom and R for a 3-chlorophenyl- or 3-Ti * ifluoromethylphenylradikal. 7. (3aR, 4-R, 5R, 6aS) -2,3,3a, 6a-0? Etrahydro-5-hydroxy-2-oxo-4- (3-pxodec-1-trans-enyl) cyclopenteno [bjfuran, (3aR, 4-R, 5S, 6aS) -4— [4— (3-chlorophenoxy) -3-OXObUt-I -trans-enyl] -2.3 »3a, 6a- 409829/1089 2A01763 tetrahydro - ^ - hydroxy-S-oxocyclopentenoJjDj furan and · (3aR, 4-R, 5R, 6aS) -2,3,3a, 6a-Tetrahydro-5 ~ hydroxy - 2-oxo-4 ~ [j> -oxo-4 ~ - (3 ~ trifluoroniethylphenoxy) but ~ 1 -trans-enyl] cyclopenteno QdJfuran. 8. Process for the preparation of a hydroxyenone according to Claim 1, characterized in that an optically active hydroxyenol of the formula "CH (OH) R oxidized. 9. Process according to claim 8, characterized in that the oxidation is carried out by manganese dioxide or by a Λ , 4-benzoquinone oxidizing agent « • W-ΗΜβ. I ITABUt atm 409829/1089