DE2811514A1 - ESTER OF 7-OXO-1-AZABICYCLO SQUARE CLAMP ON 3.2.0 SQUARE CLAMP FOR HEPT-2-EN-2-CARBONIC ACID AND ITS DERIVATIVES, METHOD FOR PRODUCING THESE COMPOUNDS AND PHARMACEUTICAL PREPARATIONS CONTAINING THESE COMPOUNDS - Google Patents

Description

Esters of 7-0xo-1-azabicyclo / 3 ".2. £ 7h ^e Pt-2-en-2-carboxylic acid and derivatives thereof, process for the preparation of these compounds and pharmaceutical preparations containing these compounds

claimed ig. March 1977 - United Kingdom - No. II747 / 77 priorities. ^ ^ _{March 77} _ _GrO ß _Britain - No. 11749/77.

The invention relates to antibacterial compounds having a β-lactam ring, processes for their preparation and these compounds containing pharmaceutical preparations. Another object of the present invention are compounds that are valuable as transition products in the processes mentioned

In GB-PS 1 4β7 4Γ5, that of DE-OS 25 1? 855 corresponds, it is disclosed that the compound of formula I

809838/0942

HO ₃ SO

28115H

. Ak.

S-C = C-NH-CO-CH

(D

and their salts by fermentation of strains of Streptomyces olivaceus can be obtained. It has now been found that a certain class can have an antibacterial effect of synthetic compounds.

The present invention accordingly relates to esters of 7-0xo-1-azabicyclo _i /3^2.07hept-2-en-2-carboxylic acid and their derivatives of the general formula II substituted in the J> - and / or 6-position

(II)

2 ^R 1

in which the group -COpR is an esterified carboxyl group, A- is a hydrogen atom or the methyl group and Ap is a hydrogen atom or the radical -CRpIUR ^, where Rp is a hydrogen atom or the hydroxyl group, R ^. represents a hydrogen atom or an alkyl radical with 1 to 8 carbon atoms and R ₁ , a hydrogen atom, the benzyl or phenyl group or an alkyl radical with 1 to 8 carbon atoms or together with R-, a carbocyclic ring with 5 to 7 carbon atoms or for one Remainder of the general formulas -CH (OH) R, - or -CHX,

809838/0942

-, χ-. ^ 28115U

in which Rc- is a hydrogen atom or an alkyl radical having 1 to 8 carbon atoms and X is an oxygen atom or the radical = CRgiU, where Rg is a hydrogen atom, the nitrile or phenyl group, an alkyl radical having 1 to 8 carbon atoms or one of the radicals -COpRo or -CO.Rg, in which Rg stands for the benzyl or phenyl group or for an alkyl radical with 1 to 8 carbon atoms, and R "stands for a hydrogen atom or an alkyl radical with 1 to 8 carbon atoms or together with Rg a carbocyclic radical with Forms 5 to 7 carbon atoms.

The alkyl radicals expediently contain 1 to 6 carbon atoms and they are preferably straight-chain alkyl radicals having 1 to 4 carbon atoms.

A suitable subgroup of the esters of the general formula II are esters of the general formula III

^CO 2 ^R 1

in the R, and A. those indicated in the general formula II Have meanings. Appropriately, A, but the methyl group is preferably a hydrogen atom,

Another suitable subgroup of esters of the general formula II are esters of the general formula IV

809838/09 ^ 2

28115U

(IV)

in which R ₁ , Rp, R ^ and R ^ have the meanings given for general formula II.

Appropriately, Rp is a hydrogen atom. For other suitable compounds, Rp is the hydroxyl group. Appropriately, Rh is a hydrogen atom, the methyl, ethyl, n-propyl, phenyl or formyl group or one of the radicals -CH = CHCO ₂ R ₀ , -CH = CHCOR ₉ and -CH = CHR ₁₀ , in which R _g is the methyl, ethyl or benzyl group and R _{10 is} a hydrogen atom or the methyl, ethyl or benzyl group.

Appropriately, R ^, a hydrogen atom or the methyl, Ethyl or n-propyl group.

Both for R and for R ^ is in each case the hydrogen atom or the methyl group is preferred.

Another suitable subgroup of esters of the general formula IV are esters of the general formula V

X = CH-CH ₂

(V)

809838/0942

-g- "28115U

in which R and X have the meanings given for general formula II.

Conveniently, X is an oxygen atom. In other suitable compounds, X is the radical = CRgR- _ri where Rg and R _{7 have} the meanings given for general formula II.

The radical ²¹ CRgR ₇ is advantageously one of the radicals ^ or -CHCOpRgj, in which R _{Q has} the meanings given for the general formula IV. In other suitable compounds, the radical -CRgR ₇ is advantageously the group = CHCN.

Another suitable subgroup of esters of the general formula IV are esters of the general formula VI

OH

(VI)

CO ₂ R ₁

in which R, which has the meanings given for general formula IV, R ,, is a hydrogen atom or an alkyl radical having 1 to 8 carbon atoms and R _{12 is} a hydrogen atom or an alkyl radical having 1 to 8 carbon atoms.

Appropriately, both the radical R ₁₁ and the radical R _{12 represent} a hydrogen atom or the methyl group.

Finally, a suitable subgroup of esters of the general formula III represents esters of the general formula VII

9838 / 09A2

(VII)

in which R has the meanings given in general formula II and R, _{7 is} a hydrogen atom or the methyl, ethyl or hydroxymethyl group.

The esters of the general formulas IV to VII can be used in terms of the ß-lactam ring both in the cis and in the trans configuration. Optionally, these esters can also be present as mixtures of the cis and trans compounds, although this case is usually not preferred.

The esters of the general formulas II to VII are usually formed as mixtures of the 5R and SS forms, but are according to the invention also includes the respective separate forms.

The radical R 1 is expediently the general one in the case of the esters Formulas II to VII an alkyl radical having 1 to 12 carbon atoms, an alkenyl radical having 1 to 8 carbon atoms Alkynyl radical with 1 to 8 carbon atoms or the phenyl or benzyl group, the above-mentioned radicals also by halogen atoms, nitro groups and / or alkoxy and / or acyloxy radicals may be substituted with 1 to 8 carbon atoms each.

Appropriately, R-, an alkyl radical with 1 to 8 carbon atoms, that by alkoxy radicals with 1 to 8 carbon atoms

809838/0942

PL is suitably the benzyl group ₃ which can be substituted by a chlorine atom, a nitro group or an alkoxy radical with 1 to 8 carbon atoms «

Advantageously, R _{1 is} a residue of sub-formulas (a) or

-CHA ₃ -O-CO-A ₄

where A ^, a hydrogen atom or the methyl group, A ^, the phenyl, phenoxy, benzyl or benzyloxy group or an alkyl or alkoxy group with 1 to 8 carbon atoms each, A ₁ - a hydrogen atom or the methyl or represents methoxy group and Ag represents a hydrogen atom or the methyl or methoxy group.

In a certain way preferred radicals R are the methyl, methoxymethyl, Benzyl, p-methoxybenzyl, acetoxymethyl, trimethylacetoxymethyl 1-, oi-thoxycarbonyloxyethyl, phthalidyl, Phenacyl and the phthalimidomethyl group.

Preferably R _{1 is} the phthalidyl group. Another preferred group is the benzyl group for the radical R ₁ - Another preferred group is the p-nitrobenzyl group for the radical R ₁ .

809838/09 * 2-

■ ^ß - ■ So-

The present invention also relates to pharmaceuticals Preparations which contain an ester of the general formula II. Appropriately, the Agents in single dosage forms and contain 25 to 1000 mg, expediently 50 to 500 mg, of an ester of general formula II.

The ester of the general formula II is preferably in such pharmaceutical preparations as a form hydrolyzable to the parent acid or its salt in vivo.

The pharmaceutical preparations according to the present invention can furthermore carrier materials, diluents, Contain excipients and / or additives. The pharmaceutical preparations advantageously have additives as additives Penicillins or cephalosporins. Certain particularly expedient penicillins for use in the pharmaceutical preparations are amoxycillin trihydrate or the sodium salt of amoxycillin.

The pharmaceutical preparations according to the invention can be used for the treatment of bacterial infections due to sensitive Bacteria such as Gram-positive bacteria such as Staphylococcus aureus can be used.

The pharmaceutical preparations according to the invention can be used in a customary manner, for example parenterally or also during treatment for mastitis in cattle in the udder.

809838/0942

, 28115Η

Another object of the present invention is a process for the preparation of the esters of the general formula II, which is characterized in that one connection of the general formula VIII

Ö (VIII)

CO ₂ R ₁

in which R ,, A, and Ap have the meanings given for general formula II and A ₁₇ , Ag and Aq are phenyl or methoxyphenyl groups or lower alkyl radicals, with cleavage of a compound of the general formula O = PA ₇ AgAg carries out a ring closure reaction.

The radicals A ₇ , Ag and A "are expediently all phenyl groups. They can also all represent p-methoxyphenyl groups.

Appropriately, Ap is a hydrogen atom or the remainder -CRpR ^ Rh, as indicated in the general formula IV · .is.

The cleavage can take place spontaneously at relatively low temperatures, for example -20 to ⁰ ° C. if A ^ is a hydrogen atom, or about 100 ^° C. if A is the methyl group.

A solvent used to speed up the process is an inert organic solvent such as ethyl acetate, Benzene or toluene.

809838/0942

28115U

. aa.

The esters of the general formula VIII, in which A. is a hydrogen atom can be prepared according to the following reaction scheme will:

CH

/ V

-NH

-N _n -OH

R ₃ - ^ C

N ^ PA ₇ A ₈ A ₉ CO ₂ R ₁

y ^ /

-> (VIII)

The invention also comprises a process for the preparation of an ester of the general formula VIII, which is characterized is that a compound of the general formula IX

_Ν γ ^ΡΑ 7 ^Α 8 ^Α 9

(ix)

CO ₂ R ₁

809838/0942

28115U

in the R., A ,, Ap, A ", Ao and A" those in the general formula VIII have given meanings, subjected to ozonolysis in the presence of an excess of trifluoroacetic acid and then neutralized the trifluoroacetic acid.

This ozonolysis is usually carried out in an inert solvent, such as ethyl acetate or methylene chloride carried out.

The process is normally at a low temperature, for example ⁰ to -20 C, conveniently at about -70 to -50 ⁰ C, -80 performed. In general, ozone is bubbled through the solution until it turns light blue. At this point, excess ozone can be removed by passing an inert gas through the solution. The ozonide formed as an intermediate product can then be reduced by adding a customary reducing agent such as triphenylphosphine. The trifluoroacetic acid must now be neutralized, for example by adding a base, such as a sodium bicarbonate solution, at about O C.

When neutralization has occurred, the temperature of the reaction mixture is usually allowed to rise. Under these conditions the ester cyclizes spontaneously.

The invention also includes a method of production of an ester of the general formula IX in which Ap the Remainder -CRpR- ^ Rh, with the characteristic that one an ester of the general formula X

809838/0942

. 3 (4th

(χ)

t ~ ^l

CO ₂ R ₁

in which A ₇ , Ag, A _Q and R _{1 have} the meanings given for the general formula VIII, are reacted with a base in order to form an anion of the general formula XI

(XI)

in the A ₇ , Ag, Aq and

those in the general formula VIII

have given meanings, and then this ion with a Compound of the general formulas XII, XIII or XIV implemented

C = O

CH-y

(XIII)

(XIV)

_{in which R 1} , R ^ and R 1 - have the meanings given for general formula II and Y denotes a radical which can be easily replaced by a nucleophilic radical.

809838/0942

Suitable radicals for Y are the chlorine, bromine or iodine atom or the groups -OSOpCH, -O.SOg.CgH ^ CH ·, or the like. The chlorine, bromine or iodine atom are particularly useful for the radical Y-.

The preparation and implementation of the anion of the general formula XI are carried out under aprotic conditions in an inert organic medium. Suitable solvents for this reaction are hydrocarbons, such as hexane, tetrahydrofuran., Dimethoxyethane, dimethylformamide, hexamethylphosphoric triamide or their mixtures.

Since the anion is highly reactive, its generation and conversion is usually carried out at low temperatures, for example at or below!
-80 to -60 ⁰ C carried out.

doors, for example at or below O ⁰ C, but expediently at

The one used to prepare the anion of general formula XI Base is a strong base of low nucleophilicity. Suitable bases are lithium alkyls, such as lithium butyl, also lithium amides, such as lithium diisopropylamine, or else Lithium hexamethyldisilylamide or the like.

When the anion has formed, it is by adding an anhydrous compound of the general formulas XII, XIII or XIV implemented. The compounds of the general formulas XII, XIII or XIV can be used undiluted or dissolved in an anhydrous inert solvents are added.

80 9838/0942

It is most expedient to carry out the reaction under an inert atmosphere, e.g. under anhydrous nitrogen or anhydrous Argon.

In the aforementioned reactions, a mixture of the cis and trans compounds of the general formulas XV and XVI

(XV)

A ₇ A ₈ A ₉

H H

(XVI)

generated in a mixture with their C ^ enantiomers.

These cis and trans isomers can be used in the usual V / eise means Chromatography, for example on silica gel, are separated from one another, using solvent mixtures as eluents, such as ethyl acetate and hexane, used with gradually increasing content of one ingredient.

The esters of the general formula X can by reacting an ester of the general formula XVII

Cl

(XVII)

CO ₂ R ₁

809838/0942

in which R-, which has the meanings given in the general formula II, are _{prepared with a phosphine of the general formula PA 7} AgAq, where A ₇ , Ag and A _{q have} the meanings given in the general formula X.

This reaction is usually carried out in an inert solvent such as dioxane, tetrahydrofuran or the like in the presence at least one equivalent of a base such as 2,6-lutidiri or a similar base with relatively low nucleophilicity. In general, the implementation takes place at not extreme temperatures, such as about 5 to 35 C, instead.

The esters of the general formula XVII can by the action of thionyl chloride on a corresponding ester of the general Formula XVIII

(XVIII)

CO ₂ R ₁

in which R has the meanings given for general formula II owns, are produced.

This reaction takes place under similar conditions as the preparation of the esters of the general formula X, but with the measure that a low temperature, for example -30 to -10 ⁰ C, is used.

809838/0942

The esters of the general formula XVIII can also be prepared by reacting a compound of the general formula XIX

.NH

(XIX)

with a compound of the general formula XX

CHO

^CO 2 ^R 1

in which R ^ the meanings given for the general formula II owns, are produced.

This reaction is conveniently carried out by reacting the compounds are carried out with one another in boiling benzene in such a way that the water formed is continuously removed will.

The esters of the general formula II in which the radical is the radical -CH ₂ -CH = X, where X has the meanings given for the general formula II, can also be prepared according to the following reaction scheme:

809838 / 09A2

-NH

(XXI)

Q (XXIV)

28115U

Ö9-

(XXII)

CO-R _n

(XXIII)

CO ₂ R ₁

(XXV)

CO ₂ R ₁

(XXVII)

The compounds of formula XXI can be prepared by the method of Paquett and coworkers in ¹¹ J. Amer. Chem. Soc. "90: 2897 (1968).

809838/0942

28115H

The compounds of the formula XXI prepared in this way have the cis configuration at the ring linkage, and this configuration is general for the connections Retain formulas XXII to XXVII.

The esters of the general formula XXII can be prepared by reacting the compound of the formula XXI with one previously described Compound of the general formula XX can be prepared under conditions similar to those used for the reaction of the compound of the formula XIX has been described with a compound of the general formula XX.

.The implementation of a compound of the general formula XXII with Thionyl chloride under conditions similar to those used for the reaction of thionyl chloride with an ester of the general Formula XVIII have been described can be used to prepare the esters of the general formula XXIII.

The esters of the general formula XXIII can be converted into the esters of the general formula XXIV by reacting with a phosphine general formula PA „AgAq converted under similar conditions as they have been described for the preparation of an ester of the general formula X.

The present invention also includes a method of manufacture of esters of the general formula XXV

OHC

CHO

CO,

809838/0942

CO ₂ R ₁

28115K

in which A ₇ ,, Ag, A _Q and R, have the meanings given for the general formula X, with the characteristic feature that an ester of the general formula XXIV

(XXIV)

in which R- ,, A ₇ , Ao and A _{Q have} the meanings given for the general formula IX, is subjected to ozonolysis.

The ozonolysis is carried out under conditions similar to those described for the ozonolysis of the esters of the general formula IX. When the esters of the general formula XXV have formed, they undergo spontaneous cyclization with elimination of a compound of the general formula 0-PA ₇ AnAg, an ester of the general formula XXVI being formed. This cyclization also forms part of the present invention.

The esters of the general formula XXVI can have a certain instability have, so that it is often more convenient to treat them in situ with a substance such as a compound of the general Formula XXVIII

^R 7

C = PPh,

. ³ (XXVIII)

or a chemically equivalent compound in which Rg and FU has the meanings given in general formula II

809838/0 94 2

. 28115U

implements. > o «i *

This reaction of the esters of the general formulas XXVI and XXVIII takes place under the usual reaction conditions for the Reaction of an aldehyde with a phosphorane takes place and gives olefins of the general formula XXVII.

The esters of the general formulas XVIII and XXII can also by reacting the compounds of the formulas XIX or XXI with Glyoxalic acid and subsequent esterification of the compounds of the formulas XXIXa and XXIXb obtained

(XXIVa) (XXIVb)

be prepared in the usual way. The condensation is carried out under conditions similar to those for the Reaction of a compound of the formula XIX with a compound of the general formula XX have been described.

Certain trans compounds can be made according to the following reaction scheme be prepared, wherein an allyl halide, such as allyl bromide, with an anion of the general formula XI in analog Way is implemented for the alkylation described above. Ozonolysis of the compound obtained can be in the form be carried out as has been described for the ozonolysis of a compound of the general formula XXIV, and the Ring closure of a compound of the general formula XXXI can

809838/0942

28115U "^ - .33.

be carried out in the same manner as has been described for a compound of the general formula XXV.

OHC.

CO ₂ R ₁

H H

f ~

CO ₂ R ₁

Ή0

H H

CO ₂ R ₁

(XI)

(XXX)

(XXXI)

(XXXII)

809838 / 09A2

The esters of the general formula VIII, in which A _{1 is} the methyl group, can be prepared according to the following reaction scheme:

CH,

• NH

CH,

Cl

CO ₂ R ₁

NH

I /

CH,

CH,

(VIII; A ₁ = CH ₃ )

The 4- (propan-2-one) -azetidin-2-one can be prepared as in Example 22 will. The reaction of this compound with a glyoxalic acid ester to give a compound of the general formula XXXIII can be carried out under conditions similar to those for the analogous reaction of the corresponding vinyl compound have been described. Optionally, 4- (propan-2-one) -azetidin-2-one reacted with glyoxalic acid and then esterified the compound obtained. Implementation of the obtained hydroxyl compound with thionyl chloride and the implementation

809838/0942

tion of the chlorine compound obtained with a phosphene is carried out in a manner analogous to that described above for the preparation a compound of the general formula X has been described.

The examples illustrate the invention.

example 1

6- (2-0xoethyl) -7-oxo-1-azabicyclo / 5 ° 2.Q7hept-2-en-2-carboxylic acid benzyl ester

(i) 7- (1-Hydroxy-1-benzyloxycarbony! methyl) -8 ~ oxo-7-a2abicyolo / ¥ 2.Q7oct-3- en

3.4-

.0H

(1 )

Benzene 2.73 g of benzyl glyoxalate are heated in 25 ml / under reflux in order to remove water. After ^; 1.23 S 8-0xo-7-azabicyclo / T.2.07oct-3-en (1) is given for 15 minutes (cf. IA Paquette and T. Kakihana, "J. Amer. Chem. Soc." 90 (1968 ), 2897) and the reaction mixture is allowed to reflux for a further 3 hours. After evaporation of the solvent under reduced

809838/09 4 2

Pressure and subsequent chromatography are obtained in
90 percent yield separated the two isomers of alcohol (2).

Isomer I: mp 92-93 ° C

IR spectrum in chloroform: VL, __ = 3450, 1750 (wide) cm " ¹ .

Nuclear Magnetic Resonance Spectrum in CDCl ₅ : S = 1.76-2.73 (4Hi m, 2-CH ₂ ); 3.12-3.33 (IH, m, β-lactam proton); 3.76-3.93 (IH, m, β-lactam proton); 4.40 (IH, d, J = 6 Hz, exchanged for D ₂ O); 5.16 (2H, s, CH _2); 5.47 (IH, d, J = 6 Hz, after DpO exchange to a singlet
coincident, CH-OH); 5.67-5.83 (2H, m, CH = CH); 7.34 (5H, Ar).

Mass spectrum M '* at m / e: 287

analysis for ^C l6 ^H 17 ^N0 4 ^: 66 C. (*) H (#) N ( ber .: 66 , 9 6, 0 4, 9 found: , 2 5, 9 4, 9

Isomer II: m.p. 100-10l ° C.

IR spectrum in CHCl 2: * J " _av = 3450, 1750 (broad) cm" ¹ .

j nidx

NMR spectrum in CDCl3,: £ = 1.80-2.63 (4h, m, 2-CH ₂ ); 3.13-3.36 (IH, m, β-lactam proton); 3.93-4.13 (IH, m, β-lactam proton); 4.20 (IH, broad singlet, exchangeable for D ₂ O);
5.16 (2H, s, CHo); 5.50 (IH, wide, in exchange for
D ₂ O tapering to a singlet); 5.50-6.00 (2H, m, CH = CH); 7.34 (5H, Ar).

M ⁺ at m / e: 287.

809838/0942

28115U

Analysis for

NOj ₊ : calc .: found:

C (J

66.9
67.2

6.0 6.0

4.8

(ii) T-Cl-Benzyloxyoarbonyl-1-triphenylphosphoranylidenemethyl) -8-oxo-7-azabicyclo / ^:! l.2.o7oct-3-en

OH

(3)

CO ₂ CH ₂ PIi

2.2 g of the alcohol (2) (as an isomer mixture) in 50 ml of tetrahydrofuran is cooled to -2O ⁰ C. 1.5 g of lutidine and 1.0 ml of thionyl chloride are then added in succession. After stirring for 20 minutes at -20 ⁰ C, the solution is filtered and evaporated to dryness, the Piltrat. Excess thionyl chloride is completely removed by taking up the residue twice in toluene and evaporating again. The residue is dissolved in 20 ml of dioxane and treated with 4.02 g of triphenylphosphine and 1.64 g of lutidine by stirring the reaction mixture overnight at room temperature. The precipitated lutidine hydrochloride is then filtered off, the filtrate is evaporated to dryness and chromatographed the residue. 1.5 g of compound (j5) are obtained as an amorphous solid.

IR spectrum in CHCU: >> _v = 1730, 1620 cm " ¹ .

809838/0942

(iii) 6- (2-Oxoethyl) -7-QXO-1-azabicyolo / 3.2.07hept-2-en-2-carboxylic acid benzyl ester

(4)

0.2 g of phosphorane 0) in 10 ml of ethyl acetate are treated with 0.25 ml of trifluoroacetic acid. The solution is cooled to -65 ° C. and then treated with ozone until the reaction solution shows a pale blue color. Argon is then blown through the solution to remove excess ozone, and 0.1 g of triphenylphosphine is then added. After 5 minutes, the reaction mixture is placed in an ice bath and stirred vigorously for 45 minutes with 10 ml of 5 ppm aqueous sodium bicarbonate solution. The organic layer is separated, dried, evaporated and chromatographed. 42 mg of compound (4) are obtained as a rubbery substance.

IR spectrum in

= I780, 1725, I610 cm

NMR spectrum in CDCl3,: S = 2.50-3.00 (4h, m, 2 χ CH ₂ ); 5.87-4.11 (IH, m, C6-H); 4.46 (IH, dt, J = 6 Hz, 9 Hz, C5-H .; coinciding to a doublet, J = 6 Hz when irradiated at <£ = 2.60) j 5.21 (2H, s, benzyl- CH ₂₎ j 6.45 (IH, t, J = 2 Hz, C35-H); 7.30 (5H, s, Ar); 9.70 (IPI, s, CHO).

M ⁺ at m / e: 285.

809838/0942

The ß-lactamase inhibition, i.e. the Ι, -Q value in jag / ml for the Connection (4) is as follows:

Enierobacter P99 Pseudomonas aeruginosa A Proteus mirabilis C889 Klebsiella aerogenes E70 Escherichia cöli JT4 Pseudomonas dalgleish Staphylococcus aureus

Russell

1.6

2.1

1.0

example

6- (3-Methox ycarbonyl-2-propen-1-yl) ~ 7-oxo-1-azabicyclo / 3.2.q7-hept-2-en-2-carboxylic acid benzyl ester

MeO ₂ C

COgCH ₂ Ph

O ₂ CH ₂ Ph

MeO ₂ I.

CO ₂ CH ₂ Ph

0.2 g of phosphorane (5) is treated in 10 ml of ethyl acetate with 0.25 ml of trifluoroacetic acid. subjects the reaction mixture the ozonolysis and works it up as in Example 1 (iii). The crude product obtained with the compound (4) is dissolved in 5 ml of ChIo-

0983 8/09

-28- ^ ₀ 281151A

roform and dissolved with 0.124 g of methoxycarbonylmethylene triphenylphosphorane Treated for 1 hour at room temperature. Then the solution is evaporated to dryness and chromatographed. Man receives 45 mg of compound (5) with a melting point of 81 ° -82 ° C. after recrystallization from ether.

IR spectrum in CHCl _x : \> ^ = I78O, 1720, 1650, 1610 cm " ¹ .

J) HIaA

NMR spectrum in CDCl,: S = 2.68 (2H, dd, J = 9 Hz, 3 Hz, C4-CH ₂ ; coinciding to a doublet with J = 3 Hz on irradiation at 6 = 4.3) j 2 , 40-2.90 (2H, m, C6, side chain CHg); 3.67 (3H, s, OMe); 3.67-3.74 (IH, m, .C6-H); 4.35 (IH, dt, J = 6 Hz, - 9 Hz, C5-H, coinciding to a doublet with J = 6 Hz on irradiation at £ = 2.6) j 5.20 (2H, s, benzyl- CH ₂ ); 5.80 (IH, d, J = 15 Hz, trans -MeO ₂ CCH = CH-); 6.45 (IH, t, J = 3 Hz, C3-H, coincident to the singlet on irradiation at 8 = 2.6); 6.84 (IH, dt, J = 15 Hz, 6 Hz, trans-CH = CH-CH _2); 7.32 (5H, s, Ar).

M ⁺ for C ₁₉ H ₁₉ NO ₅ :

calc .: 341.1263
Found: 341.1270

The concentrations of this compound required to inhibit the growth of the following bacteria will be listed below:

Minimum inhibitory organism concentrations (µg / ml) agar

Bacillus subtilis A 20

Citrobacter freundii E8 20

Klebsieila aerogenic A 20

Shigella sonnei MB II967 20

Staph. aureus Russell 2

Staph. aureus I517 2

809838 / 09Ä2

It becomes a small amount (6 mg) of the cis isomer of the compound (5) (double bond on the C6 side chain).

B e i s ρ ie I 3

6- (3-methoxycarbonyl-2-propen-l> yl) _-7-oxo-l-il a2abicyclo /J.2.q7-hept-2-en-2-carbonsäure-2 , 2.2- trichloroethyl ester

MeO ₂ I.

O ₂ CH ₂ CCl ₃

(i) 7- / T-Hydroxy-1- (2 _J 2 _J 2-trichloro-ethoxycarbonyl) -methyl7-8-oxo-7-azabicyclo /? '. 2.o7oct -3-en

_v

HH

(1 )

(6)

. CO ₂ CH ₂ CCl ₃

0> 78 g of glyoxylic acid-2 _{J i} 2 2-trichlorathylester 30 minutes in 15 ml of benzene under reflux boiling allowed to entfernen.Dann water is added 0.287 g of the azetidinone (1) is added and refluxing continued βθ minutes . After removing the solvent and after chromatography, the alcohol (6) is obtained in a yield of 80 %. I isomer: mp 85-88 ^0C.

IR spectrum in CHCU: \> _v = 3500, 1770 (ester), I75O (ß-lactam)

j max

cm

-1

809838/0962

NMR spectrum in CDCl ₃ : S = 2.00-2.80 (4H, m, 2 χ CH ₃ ); 5.30-3.4-0 (IH, m, β-lactam proton); about 3.70 (IH, broad singlet, exchangeable for D ₂ O, OH); 4.10-4.2S (IH, ra, β-lactam proton); 4.80 (2H, s, CH ₂₎ J 5.50 (IH, s, CH); 5.72-5.91 (211, m, CH = CH);

Analysis for C ₁₁ H ₁

C. (*) H 7th N Ö f) ber .: 40, 2 3, 7th 4, 3 found: 40, 3 3, 4th 2

The isomer II of mp. 119-121 ⁰ C has the same spectroscopic properties.

(ii) 7- (1-Trichlorethoxycarbonyl-1-triphenylphosphoranylidenemethyl) -8-oxo-7-azabicyclo / T.2.07oc t-3-6n

OH /

( I.

λιλ ^ TI ρΛΠ / * Λ

6.0 g of the alcohol (6) as a mixture of the isomers in 75 riI of tetrahydrofuran are converted into the chloride as in Example 1 (ii) using 2.61 ml of thionyl chloride and 4-.25 ml of lutidine. The crude chloride is then reacted in 75 ml of dioxane with 9.6 g of triphenylphosphine and 4.25 ml of lutidine, as has been described for the benzyl ester, and 6.0 g of phosphorane (7) is obtained as a foam-like compound.

IR spectrum in CHCl 2: v> _v = 1740, 160 cm " ¹ .

j max

809833/0942

(iii) 6- (3-Methoxycarbonyl-2-propen-l-yl) ^ - oxo-l-aza bicyclo- / 3\2 .(^hept-2-en~2-carbonsäure-2,2,2- trichloroeth ylester

PPh ₃

(7-) C0 ₂ «

0.2 g of phosphorane (7) are dissolved in 10 ml of ethyl acetate and 1 ml
Trifluoroacetic acid dissolved. The solution is subjected to ozonolysis and then worked up as for the benzyl ester according to Example 1 (iii). The crude reaction product in 3 ml of chloroform is
treated with 117 mg of carbomethoxymethylene triphenyl phosphorane for 30 minutes at room temperature. After evaporation and chromatography to obtain 40 mg of the substance (8), mp. 101-102 ⁰ C.

IR spectrum in CHCl ^: ¹ P = 1785, 1735, 1720, 1660, 1615 cm " ¹ .

NMR spectrum in CDCl _5: ^ = 2.74 (2H, dd, J = IO Hz, 3 Hz, C4-CH _2); 2.30 to 2.90 (2H, m, CH _2); 3.65 (3H, s, OMe); 3.60-3.90 (IH, m,
C6 ~ H); 3.38 (IH, dt, J = 6 Hz, 10 Hz, C5-H); 4.70 and 4.86
(2H, ABq, J = 12 Hz, CH ₂ CCl ₃ ); 5.80 (IH, d, J = 15 Hz plus further
slightly coupling trans-MeO ₂ C-CH = CH-CH ₂ ); 6.60 (IH, t, J = 3 Hz,
C3-H); 6.84 (IH, dt, J = 15 Hz, 6 Hz, trans-CH = CH-CH ₂ ).

UV spectrum in ethanol: λ _fflax = 209 nm (£ = 12100),

273 nm (£ = 3110).

The concentrations of this compound used to inhibit the
Growth of the following bacteria are required,
are listed below:

809838/09 42

28115H

Organisms

B. subtilis A Citrobacter feundii e8 Klebsiella aerogenes A Shigella sonnei MB 11967 Staph. aureus Oxford Staph. aureus Russell Staph. aureus I517 Strep, faecalis I Strep, pneumoniae Strep, pyogenes CN10

(pg / tnl (agar)

20 20 20 20

20 20 20

A small amount (6 mg) of the cis isomer (on the C6 double bond) of m.p. 70-72 ° C is also obtained.

example

6- (2-Hydroxy-2-propyl) -7-oxo-1-azabicyclo / J. 2.Q7hept-2-en-2-carboxylic acid benzyl ester

Me OH

(i) 4-Allyl-1- (1-benzyloxycarbonyl-1-triphenylphosphoranylidenemethyl) -3- (2-hydroxy-2-propyl) -azetidin -2-one

Me

OH H

(9)

PHi,

CO ₂ Bz

Me OH

Me

PPh,

PPh ₇

(ΙΟ)

dl)

809838/0942

A solution of 0.60 g of N-isopropyl-cyclohexylamine in 10 ml of anhydrous tetrahydrofuran is stirred under argon and the solution is cooled to -78 ° C. It is then treated with a 2.5 molar solution of n-butyllithium in 1, 70 ml η-hexane. After 10 minutes, a solution of 1.00 g of 4-allyl-1- (1- benzyloxycarbonyl-1-triphenylphosphoranylidene-methyl) -azetidin-2-one in 10 ml of anhydrous tetrahydrofuran is added. After 5 minutes the carbanion forms on the CJ atom, which is then cooled by adding 0.71 tnl anhydrous acetone. After removing the cooling bath, the mixture is stirred for a further 10 minutes before being neutralized with 0.56 g of acetic acid. After evaporation of the solvent under reduced pressure and after chromatography of the residue on silica gel 60 with a particle size of less than 0.06 mm, elution is carried out with mixtures of ethyl acetate and petroleum ether boiling from 60 to 80 ° C with increasing ratios from 1: 1 to 7 " 3 · A mixture of the cis and trans isomers of ^ -allyl-1-il-benzyloxycarbonyl-1-triphenylphosphoranylidene-methyl) -3- (2-hydroxy-2-propyl) -azetidin-2-one is obtained in one Yield of 0.76 g (= 71 % of theory), corresponding to compounds (10) and (11).

IR spectrum in CHCl 3: V>"= 300, 1735 and 1620 cm" ¹ .

2 nicLX

It is possible to achieve a practically complete separation of the cis from the trans isomer by repeated chromatography on silica gel 60 with a particle size of less than 0.06 mm, if you gradually use mixtures of ethyl acetate and petroleum ether with a boiling point of 60 to 80 ° C increasing ratios from 1: 1 to ¹ J: 3 eluted.

809838/09 ^ 2

28115U

(ii) 6- (2-Hydroxy-2-propyl) -7-oxo-l-azabicycloZ3 * .2.07hept-2-

en-2-carboxylic acid benzyl ester
OH

CHO N PPh,

CO ₂ Bz

CO ₂ Bz

Cl3)

0.188 g of the cis isomer of 4-allyl-l- (l-benzyloxycarbonyl-l-triphenylphosphoranylidene-methyl) -3- (2-hydroxy-2-propyl) -azetidin-2-one (10) are dissolved in 14 ml of ethyl acetate. Is then added an excess of trifluoroacetic acid (0.37 g) was added and the mixture is cooled to -78 C. ^P ozone is then passed through the reaction mixture until a pale blue color appears. Argon is then bubbled through the solution until the excess ozone has been removed. A solution of 0.085 g of triphenylphosphine in ethyl acetate is then added and argon is bubbled through the mixture for a further 10 minutes. The reaction vessel is then placed in an ice bath and 20 ml of a saturated aqueous sodium bicarbonate solution are added to the reaction mixture, and the mixture is stirred vigorously under argon for a further 30 minutes. The ethyl acetate layer is separated off, washed with sodium chloride solution and dried.

809838/0942

-zT- ^ 28115H

The solution containing the compound (12) is allowed to stand at room temperature for 36 hours. During this time, the cyclization is followed by thin layer chromatography and it is found that a slow moving spot gradually decreases in intensity while a faster moving spot increases in intensity corresponding to the desired cis compound. The ethyl acetate is then evaporated off under reduced pressure and the residue is purified by chromatography on silica gel 60 with a particle size of less than 0.06 mm and eluted with a mixture of ethyl acetate and petroleum ether boiling from 60 to 80 ° C. in a ratio of 1: 1. 0.048 g of a crystalline compound is obtained, which is obtained from a mixture of. Ethyl acetate and petroleum ether boiling from 60 to 80 ° C could be recrystallized. Mp 122-124 ° C. (yield corresponding to 49 % of theory).

IR spectrum in CHCU: v> = 2950, 1770 and 1720 cm " ¹ .

UV spectrum in ethanol: λ _mQV = 273 nm (£ = 48θθ).

NMR spectrum in CDCl3,: S = 7.36 (5H, broad s, phenyl); 6.59 (IH, t, J = 2.5 Hz, C3-H); 5.28 and 5.30 (2H, signals of an AB quartet inside, -CHg-Ph); 4.35 (IH, dt, J = 6.5 Hz and 9 Hz, C5-H); 3.83 (IH, ddd, J = 18, 9 and 2.5 Hz, C4-H); 3.59 (IH, d, 3 = 6.5 Hz, C6-H); 2.68 (IH, ddd, J = 18, 9 and 2.5 Hz, C4-H); 1.74 (IH, broad s, -OH); 1.30 and 1.54 (6H, 2 singlets, C-CH ₅ (2nd χ)). ·

M ⁺ at m / e for C ₁₇ H ₁₉ NO ^:

ber .: 301.1314 'found: 301.1315

809838/0942

Analysis for

ber .:
found:

C (J 67.8 67.7

part

6.4 6.5

28115U

4.7

4.5

The concentrations of this compound required to inhibit the growth of the following bacteria will be listed below:

Organisms jjg / ml (agar) Enterobacter cloacae Nl 20th Klebsieila aerogenes A <2 Serratia marcescens US20 20th Shigella sonnei MB 11967 «2 Staph. aureus oxford «2 Staph. 'Aureus Russell <2

(I)) OH

Me

OH
/

Me

H H

(14)

OH Me I H H

TO

COgBz

(I ₅ )

809838 / 09ί2

g of the trans isomer of 4-allyl-l- (l-benzyloxycarbonyl-l-triphenylphosphoranylidene-methyl) -3- (2-hydroxy-2-propyl) -azetidin-2-one (11) are described as under (a) above treated. In this case, however, the formation of the bicyclic system is completed after stirring the basic reaction mixture from ozonolysis for 30 minutes. After chromatography, Ο, θ48 g (= 25 % of theory) of the desired compound are obtained.

IR spectrum in CHCl ₃ : V> _max = 2950, Γ780 and I720 cm " ¹ »

Nuclear Magnetic Resonance Spectrum in CDCl3,: <£ = 7.28 (5H, broad, phenyl)] 6.36 (IH, t, J = 2 Hz, C>H); 5.20 (2H, s, -CHgPh) J 4.20 (IH, dt, J = 3 and 8.Hz, ■ C5-H); 3.16 (IH, d, J = 3 Hz, C6-trans-H) j 2.95 and 2.65 (2H ₅ two ddd, J = 18, 8 and 2 Hz, C4-H's); 1.78 (IH, broad s, -OH); 1.30 and 1.37 (6h, two singlets, C-CH ^ (2 x)).

M ⁺ at m / e for C ₁₇ H ₁ QNO _2,:

ber .:
found: 301.1303

(c) The process described in section (ii) (a) is carried out on a mixture of the cis and trans isomers of 0.76 g of 4-allyl-1- (l-benzyloxycarbonyl-l-triphenylphosphoranylidene-methyl) - ^ - (2-hydroxy-2-propyl) -azetidin-2-one, which is obtained according to Example (a), carried out. After working up and after chromatographic separation, 0.045 g (= 11 % of theory) is obtained

pure
des / cis isomers and 0.100 g (= 25 % of the theory) of the pure tans isomer of 6- (2-hydroxy-2-propyl) -7-oxo-1-azabicyclo _i /3h2.o7-hept -2-en-2-carboxylic acid benzyl ester.,

809838/0942

" .50-

(lii) Preparation of 4-allyl-azetidin-2-one

28115U

O = C = N-SO ₀ Cl

(16)

HH

30 g of 1,4-pentadiene (16) and 35.4 ml of chlorosulfonyl isocyanate (17) are mixed with one another and left to stand for 3 days at room temperature in a pressure bottle. The thick dark colored syrup obtained is diluted with 500 ml of methylene chloride and added dropwise to a stirred solution of 66 g of sodium sulfate in 240 ml of water. The pH value is maintained between 6.5 and 7.5 by adding a 10 percent aqueous potassium hydroxide solution (a total of 600 ml). The lower organic phase is separated off and the aqueous phase is extracted twice with ethyl acetate. The combined organic extracts are dried over anhydrous magnesium sulfate, filtered and evaporated. 16.05 g of the crude azetidinone (18) are obtained as a red oil. Be further purified for the subsequent reactions as described in Example 4 (iv) said compound is present in sufficient purity, but they can be obtained by distillation at bp. 76-80 ⁰ C below 26.6644 Pa (0.2 mm Hg).

IR spectrum in CHCl,: V> = 3490, I770 (strong), I65O (weak)

Jj mäX

cm ~.

Nuclear Magnetic Resonance Spectrum in CDCl ₃ : & = 2.39 (2H, t, J = 6 Hz, CH ₂ ); 2.61 (IH, ddd, J = 14, 2, 1.5 Hz, coinciding with DpO to dd, J = 14, 2 Hz, C3-H); 3.10 (IH, ddd, J = 14, 5.5 Hz, coinciding with DgO to dd, J = 14.5 Hz, C3-H); 3.55-3.91 (IH, m, C4-H);

809838/0942

28115H

4.98 - 6.21 (3H, complex BUd, CH = CH ₂ ); 6.67 (IH, broad singlet, exchangeable for DpO) ..

M ⁺ for C ₆ H ₉ NO:

calc .: 111.0684
found: 111.0683

(iv) Preparation of 4-allyl-1- (1-hydroxy-1-benzyloxycarbonyltethyl) azetidin-2-one

-N OH

JiE

(Β) (L9)

6 g glyoxalic acid benzyl ester hydrate in 120 ml benzene Refluxed for 30 minutes in a Dean-Stark apparatus to remove water. Then add 2.13 g of azetidinone (18) and the reaction mixture is allowed to reflux for 4 hours. The solution is then cooled, evaporated and chromatographed the residue of silica gel. After eluting with mixtures of ethyl acetate and petroleum ether, 5.6 g of one are obtained colorless oil, which consists mainly of the isomer (19) and is sufficiently pure for further reactions. Chromatograph a small portion of this oil again, after eluting with chloroform, yields the compound (19) as oil.

IR spectrum in CHCl,: ^ _max = 3 ^ 20, 1750 (strong), 164O (weak)

cm

809838/0942

■ _ «f- .sä. 28115H

NMR spectrum in CDCIy S = 1.90-3.05 / ~ "4H, m, including 5 = 2.55 (IH, dd, J = 15.2 Hz, C3-H); 2.92 (IH, dd, J = 15, 5 Hz, C5-H), concealing 2H, CH ₂ _7; 4.52 (IH, broad singlet, interchangeable with DPO, -OH); 4.85 to 5.90 / "6H, m , included <£ = 5.4θ (IH, broad, _{coinciding with D 0} O to singlet, HC-OfI) + complex picture for Cg ₂ Ph and CH = CH ₂ _7; 7.29 (5H, s).

(v) Preparation of 4-allyl-l- (l-benzyloxycarbonyl-l-triphenylphosphoranylidene-methyl) -azetidin -2-one

(9)

A stirred solution of 6.6 g of the alcohol (19) in 200 ml of anhydrous tetrahydrofuran is cooled under argon to -20 ⁰ C and treated with 5 * 13 g lutidine in 10 ml of tetrahydrofuran. 5/70 g of thionyl chloride in 20 ml of tetrahydrofuran are then added dropwise. After the temperature has reached 0 ° C. in the course of 20 minutes, the precipitated solid is filtered off and washed with anhydrous toluene.

Filtrate and wash water are combined and evaporated to dryness. The residue is taken up in anhydrous toluene and the solution is filtered and evaporated. The received The gummy substance is taken up in 200 ml of dioxane and treated with 12.6 g of triphenylphosphine and 53 ml of lutidine. To Stirring for every hour under argon at room temperature and leaving to stand The precipitated solid is filtered off overnight. That

809838/0942

Piltrat is evaporated to dryness. After chromatography on silica gel and after eluting with mixtures of ethyl acetate and petroleum ether one receives 5 * 70 g of the desired phosphorane as foam that is recrystallized from Kther. Of the The melting point of the phosphorane is at

IR spectrum in CHCl 3: 9 = 1730, 1638, 16IO cm " ¹ .

Example 5 '

6- (l-hydroxyethyl) -7-oxo-l-azabicyclo _>! ^ 5.2.07hept-2-en-2-carboxylic acid benzyl ester

(i) ¹ I-AlIyI-1- (1-benzyloxy carbonyl-1-triphenylphosphoranylidenemethyl) -3- (1-hydroxyethyl) azetidin -2-one

The mixture is stirred a solution of 0.60 g of N-isopropyl-cyclohexylamine in i0 ml of anhydrous tetrahydrofuran under argon and then cooled to -78 ⁰ C. This solution is then 1.70 ml of a 2.5 m l ° ^a ^ ^e treated solution of n-butyllithium in n-hexane η. After 10 minutes a solution of 1.00 g of 4-AlIyI-

809838/0942

28115U

Add l- (l-benzyloxycarbonyl-l-triphenylphosphoranylidene-methyl) -azetidin-2-one (9) in 10 ml of anhydrous tetrahydrofuran. 5 minutes are sufficient for the formation of the C ^ -carbanion, which is quenched by adding 0.5 ^ · ml of acetaldehyde. The mixture is then stirred for a further 10 minutes under argon before it is neutralized with 0.56 g of acetic acid. After evaporation of the solvent under reduced pressure and after chromatographing the residue on silica gel 60 with a particle size of less than 0.06 mm and eluting with mixtures of ethyl acetate and cyclohexane in increasing ratios of 1: 1 up to pure ethyl acetate, 0.71 g ( = 65 % of theory) of a mixture of the cis and trans isomers of 4-allyl-l- (l-benzyloxycarbonyl-1-triphenylphosphoranylidene-methyl) - ^ - (1-hydroxyethyl) -azetidin-2-one (20) and (21).

IR spectrum in CHCl,: v> _β = 3000, 1735 and 1620 cm " ¹ .

_p max

809833/0942

28115H

(ii) 6- (1-Hydroxyethyl) -7-oxo-1-azabicyclo _i /3.2.o7hept-2-en-2-carboxylic acid ben2yl ester

EO

Me

• κι

Cad)

¹ Ph,

CO ₂ Bz

H H

(aa)

CHO

0.79 g of a mixture of the cis and trans isomers of 4-allyl-1- (1-benzyloxycarbonyl-1-triphenylphosphoranylidene-methyl) -3- (l-hydroxyethyl) -azetidin-2-one, as described in section (i) are dissolved in 70 ml of redistilled ethyl acetate. Is then added an excess of trifluoroacetic acid (1.60 g) was added and the mixture is cooled to -78 ⁰ C. Then it passes into the reaction mixture an ozone until a pale blue color

809838 / 09Ä2

μ 2β115 U

.56-

has formed. Argon is then bubbled through the solution until the excess ozone has been removed. Then you put one Add a solution of 0.37 g of triphenylphosphine in ethyl acetate and passes argon through the reaction mixture for a further 10 minutes. The reaction vessel is then placed in an ice bath, and that Reaction geraisch is with 104 ml of a saturated aqueous Sodium bicarbonate solution is added to produce the phosphoranes (22) and (23). The mixture becomes brisk for 30 minutes Argon stirred. Then the ethyl acetate layer is separated, washed with sodium chloride solution and over anhydrous sodium sulfate dried.

The solution is left at room temperature for 3 days to achieve complete cyclization. Then the mixture is evaporated the ethyl acetate under reduced pressure and the residue chromatographed on 8o g silica gel 60 with a particle size below Ο, Οβ mm and eluted with mixtures of ethyl acetate and petroleum ether of boiling range 60 to 8o ° C with increasing ratios of 3 '7 to 7 : 3 · Only two of the four possible diastereoisomers of 6- (l-hydroxyethyl) -7-oxo-lazabicyclo ₍ /3.2.o7hept-2-en-2-carboxylic acid benzyl ester could be isolated from the reaction mixture one cis and one trans isomer with respect to the β-lactam ring, giving 0.030 g (= 7, b% of theory) of pure crystalline cis isomer (25), which is obtained from a mixture of ethyl acetate and petroleum ether in the boiling range It could be recrystallized at 60 to 80 ° C. P.p. 94-99 ° C.

809838/0942

28115H

IR spectrum in CHCl,.: -O = 3000, 1775, 1725 and 1615 cm.

j max

NMR spectrum in (CD ^) ₂ COtC? = 7.22-7.40 (5H, m, phenyl); 6.46 (IH, t, J = 2.5 Hz, C3-H); 5.17 (2H, s, -CH ₂ -Ph); 4.25 (IH, ddd, J = IO, 8 and 6 Hz, -C5-H) overlapping with 3.94-4.23 (IH, m, side chain -CH); 3.51 (IH, dd, J = 6 and 6 Hz, C6-H); 3.25 (IH, ddd, J = 18, 8 and 2.5 Hz, C4-H); 2.63 (IH, ddd, J = 18, 10 and 2.5 Hz, C4-H); 1.25 (3H, d, J = 6 Hz., -CH,).

M ⁺ at m / e for C ₁₆ H ₁₇ NO ₄ :

ber .: 287.1157 found: 287.1150

0.07 g (= 17.4 % of theory) of the pure trans isomer (24) are also obtained.

IR spectrum in CHCl ^,: ^ " _o = 30000, 1780, 1725 and 1610 cm" ¹ .

2 max

Nuclear Magnetic Resonance Spectrum in (CD ^) ₂ CO: S = 7.2-7.5 (5H, m, phenyl); 6.3β (IH, t, J = 2.5 Hz, C3-H); 5.17 (2H, s, -CH ₃ -Ph); 4.20 (IH, td, J = 9 and 3 Hz, C5-H) overlapping with 3.94-4.23 (IH, m, side chain -CH); 3.31 (IH, dd, J = 3.5 and 3 Hz, C6-H); 2.96 (IH, s, -OH); 2.77 (2H, dd, J = 9 and 2.5 Hz, C4-H's); 1.25 (3H, d, J = 6 Hz, -CH ₃ ).

M ⁺ at m / e for C ₁₆ H ₁₇ NO ₄ :

calc .: 287.1157 Found: 287.1156

809838/0962

28115U

Example 6

6- (1-Hydroxy-1-phenylmethyl) -7-oxo-1-a-zabicyclo / 3.2.o7hept-2-en-2-carboxylic acid benzyl ester

! 00CE ₂ Ph

(i) 4-Allyl-1- (1-benzyloxycarbonyl-1-triphenylphosphoranylidenemethyl) -3- (1-hydroxy-1-phenylmethyl) -azetidin-2-one

E E

COOCH ₂ Ph

COOCH ₂ Ph

(26)

A solution of 1.20 g of N-isopropyl-eyclohexylamin in 20 ml of anhydrous tetrahydrofuran is stirred under argon and cooled to -78 ⁰ C. Then treating the solution with 5j50 ^m l of a 1.6 molar solution of n-butyllithium in η-hexane. After 10 minutes, a solution of 2.00 g of 4-allyl-1- (l-benzyloxycarbonyl-1-triphenylphosphoranylidene-methyl) -azetidin-2-one (9) in 4θ ml of anhydrous tetrahydrofuran is added. 5 minutes are sufficient for the formation of the C3 carbanion, which is then quenched by adding 1.0 ml of benzaldehyde. The temperature of the solution is kept at −78 ^° C. for a further 10 minutes and then allowed to rise to room temperature before the solution is neutralized with acetic acid. After the solvent has been evaporated off under reduced pressure, the residue is chromatographed on SiIi-

809838/0942

28115H 9

kagel 60 with a grain size below Ο, Οβ mm and after eluting with mixtures of ethyl acetate and petroleum ether boiling from 60 to 80 ⁰ C with increasing ratios from 1: 1 to 3: 1, 1.52 g (= 63 %) of a mixture of cis and trans isomers of ^ -allyl-1-il-benzyloxycarbonyl-1-triphenylphosphoranylidene-methyl) ~ 3- (1-hydroxy-1-phenylmethyl) -azetidin-2-one (26) and (27).

IR spectrum in CHCU: v>

uldx

, 3000, I725 and I6I5 cm

(ii) 6- (l-Hydroxy-l -phenylmethyl) -7-oxo-l -azabicyclo / 3 '»2.o7-

Hi

hept-2-en-2-carboxylic acid benzyl ester HO

00CH ₂ Ph

COOCH ₂ Ph

HO

AS

COOCH ₂ Ph

(27)
HO

Aj

(29)

! HO

OOCH Ph

(30) '

OOCHgPh

(3D

00CH ₂ Ph

809838/0942

. Go-

0.80 g of a mixture of the cis and trans isomers of 4-allyll- (l-benzyloxycarbonyl-l-triphenylphosphoranylidene-methyl) -3- (uaydroxy-l-phenylmethyl) -azetidin-2-one _J as described in section (i) are dissolved in 40 ml of ethyl acetate. Is then added an excess of trifluoroacetic acid (1.50 g) was added and the mixture is cooled to -78 ⁰ C. is then introduced into the ozone Heaktionsgemisch until forming a pale blue color. Argon is then bubbled through the solution until all of the excess ozone has been removed. A solution of 0.3 g triphenylphosphine in ethyl acetate is then added and argon is allowed to bubble through the reaction mixture for a further 10 minutes. The temperature of the reaction mixture is then allowed to rise to room temperature and 20 ml of a saturated sodium bicarbonate solution are added to the reaction mixture in order to produce the phosphoranes (28) and (29). Argon is bubbled through the reaction mixture for a further 50 minutes. Then the ethyl acetate layer is separated, washed with sodium chloride solution and dried over anhydrous sodium sulfate.

The solution is left to stand at room temperature for 3 days to allow the cyclization to proceed to completion. The ethyl acetate layer is then evaporated under reduced pressure and chromatographed the residue on silica gel 60 with a grain size below 0.06 mm and eluted with a mixture of ethyl acetate and Cyclohexane in a ratio of 1: 1. From the reaction mixture could only two of the four possible diastereoisomers of 6- (1-hydroxyl-phenylmethyl) -7-oxo-1-azabicyclo ^ / 3.2.07hept-2-en-2-carboxylic acid benzyl ester isolated v / earth. It is a cis and a trans isomer with regard to the ß-lactam ring. Man

809838/0942

receives 0.12 g (= 27 % of theory) of pure crystalline cis isomer (30), which could be installed from a mixture of ethyl acetate and petroleum ether with a boiling range from βθ to 80 ° C. Pp. 124 ⁰ C.

IR spectrum in CHCl,: * v> _v = 3550, 3010, 1775λ, 1725 and

1610 cm " ¹ .

NMR spectrum in C ^ D ^: £ = 1.5-1.9 (1H, m, C4-H); 2.2-2.7 (2H, m, C4-H and OH); 3.2-3.7 (2H, m, C5-H and C6-H); 4.43 (IH, dd, J = 7 and 3 Hz, CH-O); 5.09 and 5.11 (2H, center lines of an AB-quartet, benzyl-CH ₂ ); 6.12 (IH, t, J = 3 Hz, CJ-H) and 7.0-7.4 (1OH, m, phenyl protons);

UV spectrum in ethanol rλ = 277 nm (6th = 4830).

Ill el ^ s.

Of the other, 0.12 g (= 27 %) of the pure trans isomer (31) is obtained

IR spectrum in CHCl,: i> _v = 36ΟΟ to 3 ^ 00, 3020, 1775,

1715 and 1610 cm " ¹ .

Nuclear Magnetic Resonance Spectrum in CgDg: S = 1.89 (2H, dd, J = 9 and 3 Hz, C4-H ₂ ) j 2.70 (IH, broad, OH) j 3.15 (IH, dd, J = 5 and 3 Hz, C6-H); 3.69 (IH, td, J = 9 and 3 Hz, C5-H) ; 4.67 (IH, d, J = 5 Hz, CH-O); 5.01 and 5.03 (2H, center lines of an ABq, benzyl-CHg); 5.90 (IH, t, J = 3Hz, C3-H); and 6,9-7, ^ (1OH, m, phenyl protons).

The ß-lactamase inhibition, i.e. the I (- ₀ value in ^ ig / ml for the compound (30), is as follows:

803838/0942

28115U

Proteus mirabilis C889
Staph. aureus russell

0.27 0.052

Example ¹ J

6 - (! - Hydroxycyclohex-1-yl) -7-oxo-l-azabicyclo / 3.2.07hept-2-en-2-carboxylic acid benzyl ester

(i) 4-Allyl-1- (1-benzyloxycarbonyl-1-triphenylphosphoranyl-den-methyl) -3- (1-hydroxycyclohex-1-yl) -azetidln -2-one

OH

9 h

CO ₂ CH ₂ Ph

CO

(9)

(32)

(33)

CO ₂ CH ₂ Ph

It is cooled, a solution of Ο, βΟ g of N-isopropyl-cyclohexylamine in 5 ml anhydrous tetrahydrofuran at -78 ⁰ C and stirred under argon. The solution is treated with 2.7 ml of a 1.6 molar solution of n-butyllithium in hexane and after 10 minutes with a solution of 1.00 g of 4-allyl-l- (l-benzyloxycarbonyl-l-triphenylphosphoranylidene-methyl) - azetidin-2-one (9) in 15 ml of anhydrous tetrahydrofuran were added. The resulting red-brown solution is stirred for a further 10 minutes and then treated with 0.40 ml of cyclohexanone. Then leave the temperature of the realo

809838/0942

_ ~ 28115U

tlonsgeraisches rise to about 0 C and the implementation run completely. The solution turns pale yellow. It is then neutralized with 0.56 g of acetic acid and the solvent is evaporated off under reduced pressure. The residue is partitioned between ethyl acetate and sodium chloride solution. The ethyl acetate solution is separated off, dried over anhydrous sodium sulfate and then evaporated. The residue is then chromatographed on silica gel 60 with a particle size of less than 0.06 mm and eluted with mixtures of ethyl acetate and petroleum ether boiling from 60 to 80 ° C. with gradually increasing ratios from 1: 1 to 7: 3. 0.76 is obtained g (= 6k fo the theory) of a mixture of the cis and trans isomers of ^ -allyl-l- (1-benzyloxycarbonyl-l-triphenylphosphoranylidene-methyl) -3- (l-hydroxycyclohex-l ~ yl) -azetidine- 2-ons (32) and (33).

IR spectrum in CHCl,: \> _v = 3 ^ 00, 298Ο, 2920, 2850, 1735

p max

and I615 cm

809838/0942

28115H

(ii) 6- (l-Hydroxycyclohex-ly ^^ - oxo-l-azabicyclo / J »2.Oy] IePt-2-en-2-carboxylic acid benzyl ester

CO CH Hi (33) ^{2 2}

A solution of 0.75 g of the isomer mixture of 4-allyl-l- (1-benzyloxycarbonyl-1-triphenylphosphoranylidene-methyl) -3- (l-hydroxycyclohex-l-yl) -azetidin-2-one. (32) and (33) in 50 ml of ethyl acetate is treated with 2.0 ml of trifluoroacetic acid. Then the solution is cooled to -78 ⁰ C and passes through ozone until the solution turns blue precisely. Excess ozone is then blown out of the reaction mixture by means of a stream of argon and a solution of 0.32 g of triphenylphosphine in 5 ml of ethyl acetate is added. The solution is continued to bubble with argon for 30 minutes and then the reaction vessel is placed in an ice bath. 60 ml of a saturated aqueous sodium bicarbonate solution are then added all at once with vigorous stirring in order to neutralize the reaction mixture. After a further 30 minutes, the ethyl acetate solution is separated off and washed

09838/0942

with sodium chloride solution and dry it over anhydrous sodium sulfate. To. Standing overnight, the solution is evaporated and the residue is chromatographed on silica gel 60 with a particle size of less than 0.06 mm. It is eluted with mixtures of ethyl acetate and petroleum ether boiling from 60 to 80 ° C. with gradually increasing ratios from 3: 7 to 1: 1. The first substance to be isolated with a ß-lactam ring is the cis-isomer of 6- (l-hydroxycyclohex-l-yl) -7-oxo-l-azabicyclo- / 3 • 2.0 / ^r hept-2-en-2- carboxylic acid-benzyl-ester (34) in a yield of 0.04 g (= 10% of theory) and after recrystallization from a mixture of ethyl acetate and petroleum ether of boiling range 60 to 8o ° C, a melting point of 125 to 126 ⁰ C.

IR spectrum in CHCl,: v> ^ = 3600, 30000, 2920, 2850, 1770,

_) max

1720 and 1615 cm ". UV spectrum in ethanol: ^ _max = 275 nm (6 = 424θ).

Nuclear Magnetic Resonance Spectrum in CDCl ₃ : T = 2.6-2.8 (5H, m, phenyl) j 5.50 (IH, t, J = 3 Hz, C>H); 4.73 and 4.89 (2H, ABq, J = 12 Hz, benzyl-CH ₂ ) j 5.76 (IH, td, J = 9 and 5.5 Hz, C5-H); 6.24 (IH , ddd, J = 18, 9 and 3 Hz, C4-H); 6.39 (IH, d, J = 5.5 Hz, C6-H) j 7.42 (IH, ddd, J = 18, 9 and 3 Hz, C4-H) j 8.36 (IH, s, OH) and 8.1-8.8 (1OH, m, cyclohexyl).

Analysis for C ₂₀ H ₂₃ NO ^: C (%) H ($) N {%)

calc .: 70.4 6.8 4.1 found: 70.4 6.8 4.1

809838/0942

• (oQ> ·

According to a further eluting the column 0.18 g (= 43% of theory) of the corresponding trans-isomer which after recrystallization from a mixture of ethyl acetate and petroleum ether of boiling range 60 to 80 ° C at 102-104 ⁰ C melts.

IR spectrum in CHCl,: 0 = 3550, 30000, 2920, 2850, 1775,

_p max

1725 and 1615 cm " ^1. UV spectrum in ethanol: \ _max = 279 nm (£ = 4530).

NMR spectrum in CDCl ₃ : r = 2.6-2.8 (5H, m, phenyl); 3.61 (IH, t, J = 2.5 Hz, C3-H); 4.71 and 4.87 (2H, ABq, J = 12 Hz, benzyl-CH _2); 5.76 (IH, td, J = 8 and 3 Hz, C5-H); 6.78 (IH, d, J = 3Hz, C6-H); 7 ^ 09 (IH, ddd, J = 18, 8 and 2.5 Hz, C4-H); 7 ^ 3 ^ (IH, ddd, J = 18, 8 and 2.5 Hz, C4-H); 8.25 (IH, s, OH); and 8.1-8.8 (1OH, m, cyclohexyl).

Analysis for C ₂₀ H ₂₃ NO ^: C (#) H {%) N {%)

calc .: 70.4 6.8 4.1

found i 70.4 6.7 4.0

The ß-lactamase inhibition, ie the If- ₀ value in pg / ml for the

Connection (3 ^) » is as follows:

Enterobacter P99 5

Pseudomonas aeruginosa A 1.4

Escherichia coli JT 4 16 Staph. aureus Russell 4.6

809839/0962

(oil-

55 -

28115U

Example 8

o-Benzyl - ^ - oxo-l-azabicyclo ^^. o / hept - ^ - en - ^ - carboxylic acid benzyl ester

(i) 4-Allyl-3-benzyl-1- (1-ben2yloxycarbonyl-1-triphenylphosphoranylidene-methyl) -azetidin- 2-one

"7

CO ₂ CH ₂ Ph

(9)

A solution of 0.60 g of N-isopropyl-cyclohexylamine in 5 ml anhydrous tetrahydrofuran is stirred under argon and then cooled to -7-8 ° C. The solution is then treated with 3 * 0 ml of a 1.6 molar solution of n-butyllithium in hexane and after 10 minutes a solution of 1.00 g of 4-allyl-l- (l-benzyloxycarbonyl-l-triphenylphosphoranylidene-methyl) -azetidin-2-one is added to the reaction mixture (9) in 12 ml of anhydrous tetrahydro-

added
• furan / A red solution is obtained. After a further 10 minutes, the reaction mixture is treated with 0.36 g of benzyl bromide and, 5 minutes later, the reaction vessel is removed from the cooling bath in order to allow the reaction to proceed to completion. The reaction mixture is then neutralized with about 0.5 g of acetic acid and then evaporated. After chromatography on silica gel 60 with a particle size below 0.06 mm and eluting with

809838 / 09A2

& 28115H

Mixtures of ethyl acetate and petroleum ether boiling from 60 ° to 80 ° C. with gradually increasing ratios from 1: 1 to 7: 3 give 0.38 g (= 32 % of theory) of 4-allyl-3-benzyl-l - ^ - benzyloxycarbonyl -l-triphenylphosphoranylidenemethyl) -azetidin-2-one (36).

IR spectrum in CHCl,: v? _v = 2980, I73O and I6IO cm " ¹ .

j) max

On further elution, 0.42 g (= 42 % of theory) of the starting phosphorane (9) is recovered.

(ii) 6-Benzyl-7-oxo-1-azabicyclo / 3 ~ -2.07hept-2-en-2-carboxylic acid benzyl ester

CO ₂ CH ₂ Ph

A solution of 0.38 g of 4-allyl-3-benzyl-l- (l-benzyloxycarbonyl-triphenylphosphoranylidene-methyl) -azetidin-2-one (36) in 20 ml of ethyl acetate is treated with 1.0 ml of trifluoroacetic acid. Then the solution is cooled to -78 C and ozone is passed through until the solution just has a blue color. Excess ozone is blown out of the solution by means of a stream of argon and then mixed with a solution of 0.16 g of triphenylphosphine in 2 ml of ethyl acetate. Over the next 30 minutes, the reaction mixture is flushed with argon and then the reaction vessel is placed in an ice bath. While stirring vigorously, add 30 ml of a saturated aqueous sodium "

809838/0942

bicarbonate solution is added, and after a further 30 minutes, the ethyl acetate solution is separated off, washed with sodium chloride solution and dried over anhydrous sodium sulfate. After dsm chromatography on silica gel 60 with a particle size of less than 0.06 mm and eluting with mixtures of ethyl acetate and petroleum ether boiling from 60 to 80 ° C. in a ratio of 3: 0.09 g (= h2% of theory) 6-benzyl is obtained -7-oxo-l-azabicyclo ^ / 3.2 .o7hept-2-en-2-carboxylic acid benzyl ester in the form of the trans isomer. (37) The compound is a colorless, rubbery substance.

IR spectrum in CHCl ^: \> _a = 3020, 2960, 1785, 1725 and 1610 cm " ¹

j? Max

NMR spectrum in CDCl ₃ : T = 2.6-3.0 (1OH, m, phenyl-H); 3.66 (IH, t, J = 3Hz, C3-H); 4.80 (2H, s, benzyl-CHg-O); 6.02 (IH, td, J = 8.5 and 3 Hz, C5-H); 6.60 (IH, ddd, J = 9, 6 and 3 Hz, c6-H); 6.88 (IH, d, J = 6 Hz, inside signal from ABX for PhCHg-CO); 6.97 (IH, d, J = 9 Hz, inside signal from ABX for PhCH ₂ -C6) j 7.29 and 7.32 (2H, each a dd, J = 8.5 and 3 Hz, inside Signals of an AB for C4-H ₂ ).

Example 9

benzyl ester

(i) 4-Allyl-3-methyl-1- (1-benzyloxycarbonyl-1-triphenylphosphoranylidene-methyl) -azetidin-2-one

809838/0942

(9) ^W (38)

A solution of 0.30 g of N-isopropyl-cyclohexylarnin in 5 ml of anhydrous tetrahydrofuran is stirred under argon and then cooled to -78 ⁰ C. The solution is then treated with 0.85 ml of a 2.5 molar solution of n-butyllithium in hexane and stirred for a further 10 minutes. A solution of 0.50 £ 4-allyl-1-Cl-benzyloxycarbonyl-1-triphenylphosphoranylidenemethyl) azetidin-2-one (9) in 5 ml of tetrahydrofuran is then added and the mixture is quenched after 5 minutes by adding 0.12 ml Methyl iodide removes the anion. After a further 10 minutes, the reaction vessel is placed in an ice bath, and after a further 10 minutes the reaction mixture is neutralized by adding 0.16 ml of acetic acid. After the solvent has evaporated, the residue is partitioned between ethyl acetate and sodium chloride solution. The ethyl acetate solution is separated off, washed with sodium chloride solution and dried over anhydrous sodium sulfate. The compound obtained is carefully chromatographed on silica gel 60, with one for eluting mixtures of cyclohexane and fithylacetat with gradually increasing ratios of 1: 1 'to 3 - used. 7 0.10 g (= 19 % of theory) of 4-allyl-3-methyl-1- (1-benzyloxycarbonyl-1-triphenylphosphoranylidene-methyl) -azetidin-2-one (38) are obtained.

IR spectrum in CHCU: 0 = 3000, 1735 and 1610 cm " ¹ .

_p max

809838/0942

Immediately after this connection, on elution, Oj 17 S (= 33 % ^de * "theory) of the starting phosphorane (9) is recovered.

(ii) 6-Methyl-7-oxo-1-azabicyclo / 5 «2.Q7h ^e Pt-2-- ^e n-2-carboxylic acid benzyl ester

Me

(38)

CO ₂ CH ₂ Ph

A solution of 0.29 g of 4-allyl-3-diethyl-l- (l-benzyloxycarbonyl-triphenylphosphoranylidene-methyl) -azetidin-2-one (38) in 25 ml of ethyl acetate is treated with 0.4 ml of trifluoroacetic acid and then cooled to -78 C. Ozone is then bubbled through the solution until a pale blue color begins to develop. Excess ozone is blown out of the solution by means of a stream of argon, which is then washed with an ethyl acetate solution with a content of 0.14 g triphenylphosphine is added. After a further 10 minutes, the reaction vessel is in a Put an ice bath, and the reaction mixture with 45 ml of a saturated aqueous sodium bicarbonate solution is added with vigorous stirring. Stirring is continued for 30 minutes and then separated the ethyl acetate solution was washed with sodium chloride solution and dried over anhydrous sodium sulfate. The solution is evaporated and chromatographed on silica gel 60 with a particle size below 0.0β mm. Mixtures are used for elution from ethyl acetate and petroleum ether with a boiling range of 60 to 80 ° C gradually increasing ratios from 3: 7 to 6: 4. Man receives 0.08 g (= 55 $ of theory) of the trans isomer of

809838/0942

^ 28115U

6-methyl-7-oxo-l- ^a zabicyclo _/ /3^.2.o7hept-2-en-2-carboxylic acid benzyl ester (39)

IR spectrum in CHCIy ^ _max = 3000, 1780, 1725 and 1615 cm " ¹ .

Nuclear Magnetic Resonance Spectrum in (CJX) ₂ CO: S = 1.34 (3H, d, J = 7 Hz, CH ₃ ); 2.85 (2H, dd, J = 9 and 2 Hz, C4-H ₂ ) j 3.24 (IH, dq, J = 3 and 7 Hz, C6-H); 3.91 (IH, dt, J = 3 and 9 Hz, C5-H); 5.20 (2H, s, benzyl CH _2); 6.45 (IH, t, J = 2 Hz, C3-H), · and 7.2-7.5 (5H, m, phenyl).

M ⁺ at m / e for C ₁₅ H ₁₅ NO ₃ :

calc .: 257.1051
Found: 257.1052

Example 10

6- (3-methoxycarbonyl-2-propen-1-yl) -7-oxo-1-azabicyclo / 3 * -2 .0 / ~ hept-2-en-2-carboxylic acid phthalidyl ester

H H

(i) Preparation of 7- (1-phthalidyloxycarbonyl-1-triphenyl phosphoranylidene-methyl) -8-oxo-7-azabicyclo /? '. 2.07oct-3-en

809638/09 ^ 2

28115U

—HH

O)

0.6 g azetidinone (1), 0.46 g glyoxalic acid monohydrate, 3 ml anhydrous dimethylformamide and 4 3.175 mm pellets of molecular sieves with a pore diameter of 0.4 are stirred together for 5 hours at room temperature. The mixture is then cooled to 0 ^° C. and 0.3 ^ 5 g of potassium carbonate are added. The temperature of the mixture is then allowed to rise to room temperature and stirred for 5 minutes. Then 1.07 g of bromophthalide are added and the mixture is stirred for a further 16 hours. The solution obtained is poured into 25 ml of 0.1N hydrochloric acid and 25 ml of ethyl acetate. The organic layer is washed again with 25 ml of 0.1N hydrochloric acid, then with 25 ml of saturated aqueous sodium bicarbonate solution and finally with 25 ml of sodium chloride solution. Each aqueous wash water is extracted again with 25 ml of ethyl acetate. The combined organic extracts are dried with anhydrous sodium sulfate, the solvent is evaporated off under reduced pressure and 0.73 g of a white solid is obtained. A stirred solution of this Peststoffes in 30 ml of anhydrous tetrahydrofuran is cooled to -20. ⁰ C under argon, then subsequently treated with 0.52 ml of 2,6-lutidine and 0.33 ml of thionyl chloride in 2 ml of tetrahydrofuran. After stirring for 20 minutes at -20 ⁰ C the temperature of the mixture to room temperature is allowed to rise and filtered

809838/0942

. "Hf.

the mixture. The precipitated solid is washed with toluene. The combined filtrates and washing water are evaporated to dryness under reduced pressure. The residue will dissolved in toluene and evaporated again to remove excess thionyl chloride.

The oil obtained is dissolved in 25 ml of anhydrous tetrahydrofuran and mixed with 0.52 ml of 2,6-lutidine and 1.2 g of triphenylphosphine treated. After stirring for 16 hours, the mixture is filtered and the filtrate is washed with 25 ml of ethyl acetate. Then united the filtrate and wash water and the solvent is evaporated off under reduced pressure. The residue is dissolved in 50 ml of ethyl acetate and dissolved 25 ml of 0.5N hydrochloric acid. The organic layer is separated and the aqueous layer is made up again with 25 ml Washed ethyl acetate. The combined organic extracts are dried over anhydrous sodium sulfate and evaporated Solvent off.

After chromatography on silica gel and eluting with mixtures of petroleum ether and ethyl acetate, this is obtained Phosphorane (40), which crystallizes after the addition of ether. Obtained after recrystallizing from ethyl acetate and petroleum ether 0.9 g of the compound of melting point 14.5-145 C.

IR spectrum in CHCl,: 0 _av = 1780, 17 * 0, I67O (shoulder) and

^ P Hld> Ä

I64o cm " ¹ .

- Analysis for C ₃₅ H ₂₈ NPO ₅ : C (#) H {%) N

calc .: 75.3 4.9 2.4 found: 73.4 5.0 2.3

809838/0942

(ii) Preparation of the 6 ~ O-methoxycarbonyl-2-propen-1-yl) -7-

phthalidyl ester

0.345 g of the phosphorane ( ¹ IO) are dissolved in 15 ml of a mixture of 5 parts of ethyl acetate and 1 part of trifluoroacetic acid. Then the solution is left stand at room temperature for 10 minutes, cooling them to -7O ⁰ C. then passes to ozone through the solution until it turns pale blue. Argon is then bubbled through the solution to remove excess ozone. The solution is then mixed with 0.2 g of triphenylphosphine in 2 ml of ethyl acetate. The temperature of the mixture is allowed to rise to OC by means of an ice bath and 50 ml of a saturated sodium bicarbonate solution are carefully added to the mixture with vigorous stirring. The mixture is then allowed to separate into layers and the aqueous layer is extracted again with 25 ml of ethyl acetate. The combined organic phases are dried over anhydrous sodium sulfate, filtered and left to stand for 3 hours at room temperature. 0.21 g of methoxycarbonylmethylene-triphenyl-phosphorane dissolved in ethyl acetate is added to the solution and it is left to stand for 1 hour. The solution is then evaporated to dryness. After rapid chromatography on silicon dioxide / "Hyflo" (filter aid)

809838/0942

and eluting with a mixture of 1 part ethyl acetate and

1 part of petroleum ether is followed by a slower chromatography on silica gel and eluted with a mixture of 1 part Ethyl acetate and 1 part petroleum ether. 0.084 g of the phthalide ester (4l) are obtained as a white solid with a melting point of 140-145 ° C after recrystallization from a mixture of ethyl acetate and petroleum ether.

IR spectrum in CHCU: J _mav = 1795, 1745, 1725, 1665, 1615 and

_P IHdX

980 'cm " ¹ .

NMR spectrum in CDCU: S = 2.4-2.9 (4H, m, methylene protons); 3.70 (3H, s, CH4); 3.6-3.9 (IH, m, C4-H); 4.4 (IH, m, C5-H); 5.8 (IH, broad d, J = 16 Hz, MeO ₂ C-CH =); 6.50 and 6.62 (IH,

2 χ t, J = 3 Hz, C3-H for both isomers); 6.85 (IH, dt, J = 6,

16 Hz, MeO ₂ CCH = CH-); 7.41 and 7.47 (IH, 2 χ s, phthalid-methine-H); and 7.55-7.95 (4h, m, aromatic).

UV spectrum in ethanol: λ- _Q = 208, 274 (6 = 69ΟΟ) and 28o nm

Analysis for

(£ = 67ΟΟ) H (Ji) N (*) 5H ₂ O : C (Ji) 4, 5 3, 6th ber. : 62.0 4, 4th 6th found : 62.0

The concentrations of this compound required to inhibit the growth of the following bacteria will be listed below:

809838/0942

- 03 - 28115U µg / ml (agar) Organisms' 25th B. subtilis A 50 E. coil. Olli 50 Klebsiella aerogenes A 100 Proteus mirabilis C977 50 Salmonella typhimurium CT 10 50 Shigella spnnei MB 11967 ^ 0.8 Staph. aureus oxford ^ 0.8 Staph. aureus russell Staph. aureus 1517 <o, 8 Strep, pyogenes CN 10

Example 11 6- (3-Methoxycarbonyl-2-propen-1-yl) -7-oxo-1-azabiGyclo / 3.2.0 / - h.ept-2-en-2-carboxylic acid phthalimide omethyl ester

H H

(i) Preparation of 7- (1-Hydroxy -! - phthalimidomethoxycarbonylmethyl) -8-oxo-7-azabicyclo / ¥ .2.07oGt-3-Gn

bra

(D

00CH ₂ N

02)

809838 / 09A2

0.6 g azetidinone (1), 0.48 g glyoxalic acid monohydrate, 3 ml Anhydrous dimethylformamide and 6 3 * 175 mm pellets of a molecular sieve with 0.4 nm pore diameter are 5 hours stirred together at room temperature. 0.365 g of potassium carbonate and then 1.25 g of phthalimidomethyl bromide are then added and stir the mixture for 16 hours. The solution obtained is poured into 25 ml of ethyl acetate and 25 ml of 0.1 N hydrochloric acid. The organic layer is washed with 25 ml of saturated sodium bicarbonate solution and with sodium chloride solution and extracted each wash water again with 25 ml of ethyl acetate each time. After drying over anhydrous magnesium sulfate and evaporation the solvent from the combined extracts and after chromatography .tography on silica gel, followed by elution with mixtures of ethyl acetate and petroleum ether, 0.91% of the alcohol is obtained (42) as a white solid. The alcohols can be separated by an even more careful chromatography.

Isomer I:. Pp 132-134 ⁰ C after recrystallization from a mixture of ethyl acetate and petroleum ether.

IR spectrum in CHCl,: i? _v = 1790, 1735 * I670 and I390 cm " ¹ .

_p max

NMR spectrum in CDCl ₃ : 5 = 1.85-2.75 (4H, m, allylic, CH ₂ ); 3.27 (IH, m, β-lactam-H); 4.05 (IH, m, β-lactam-H); 4.37 (IH, d, J = 7 Hz, OH); 5 * 38 (IH, d, J = 7 Hz, CHOH); 5 * 77 (4h, m, olefinic and -CHg-N); and 7.76 (4H, m, aromatic).

Analysis for C ₁₈ H ₁₆ NgOg: C (#)

calc .: 60.7 found: 60.5

H W) N W. 4, 5 7 * 85 4, 75 7 * 75

809838/0942

2811 51A

Isomer II: melting point 145 ° C. after recrystallization from a mixture of ethyl acetate and petroleum ether.

NMR spectrum in CDCl ₃ : S = 1.85-2.6 (4h, m, allylic, CH ₂ ); 3.29 (IH, m, β-lactam-H); 4.14 (IH, m, β-lactam-H); 4.71 (IH, broad, OH); 5.36 (IH, broad, CH-OH); 5.67 (2H, m, olefinic); 5.73 (2H, s, -CHp-N); and 7.77 (4h, m, aromatic).

analysis for ^C 18 ^H 16 ^N 2 ° 6 ^: C. {%) H (*) N (fo ber .: 60, 7th , 5 1, 85 found: 60, 8th , 20 1, 75

(ii) Preparation of 7- (1-phthalimidomethoxycarbonyl-1- triphenylphosphoranylidene-methyl) -8-oxo-7-azabicycloZ ¥ .2.07- oct-3-en

"7

A stirred solution of 0.91 g of the alcohol (42) in 20 ml Viasserfreiem tetrahydrofuran under an argon atmosphere is cooled to -20 ⁰ C, then 0.59 ml of 2,6-lutidine and then treated with 0.366 ml of thionyl chloride in 3 ml of tetrahydrofuran . After stirring for 20 minutes at -20 ° C., the temperature of the mixture is allowed to rise to room temperature and the reaction mixture is filtered. The precipitated solid is washed with toluene. The combined filtrates and wash water are evaporated to dryness. The residue is dissolved in toluene and

809838/0942

. Sb-

- 68 evaporated again to remove thionyl chloride.

The oil obtained is dissolved in 20 ml of anhydrous tetrahydrofuran and treated with 0.59 ml of 2,6-lutidine and with 1.33 g of triphenylphosphine. After stirring for 1 hour, the mixture is filtered and the solvent is removed from the filtrate. After chromatography on silica gel by eluting with a mixture of petroleum ether and Ä'thylacetat obtained the phosphorane (JV5) _s which crystallizes upon addition of ether. Yield: 1.23 g.

IR spectrum in CHCl-: ■? "= 1790, 1735 and 1625 cm" ¹ .

(iii) Preparation of 6- (3-methoxyoarbonyl-2-propen-1-yl) -7-oxo-1-azabicyclO / ^^. oThept ^ -en ^ -carboxylic acid phthalimidomethyl ester

I = PPh COOCH _{2 II}

(U3)

(IA)

0.24 g of the phosphorane (43) are dissolved in 10 ml of ethyl acetate and treated with 0.32 ml of trifluoroacetic acid. Cool the reaction mixture to -70 ⁰ C and leaves ozone bubbled through until the solution turned pale blue. Argon is then passed through the solution in order to remove excess ozone, and finally 0.16 g of triphenylphosphine in 2 ml of ethyl acetate is added. The temperature of the mixture is left in an ice bath

809838/0942

- 69 - 281 151 A

O ⁰ C rise and then add 10 ml of a saturated sodium bicarbonate solution with vigorous stirring. After 1 hour at room temperature, the layers are separated and 0.14 g of methoxycarbonylmethylene-triphenyl-phosphorane is added to the ethyl acetate layer. After 1 hour, the solvent is removed and the oil obtained is first purified by chromatography on silica and eluted with mixtures of petroleum ether and ethyl acetate white solid of Pp. 132-137 ⁰ C.

IR spectrum in CHCl,: v> _v = 1790, 1740, ΙββΟ and 1620 cm " ¹ .

_p max

.NMR spectrum in CDCIy S = 2.4-2.8 (4H, m, methylene-H) j 3.5-3.85 (IH, m, C6-H); 3.7 (3H, s, CH _5); 4.35 (IH, dt, J = 6 Hz, 9 Hz, C5-H) j 5.65-5.95 (3H, m, MeO ₂ CCH = and OCH ₂ N); 6.46 (IH, t, J = 3 Hz, C3-H) j 6.83 (IH, dt, J = 7 Hz, 16 Hz, MeO ₂ CCH = CH-) j and 7.6-7.95 (4H ₉ m, aromatic).

Analysis for Cg ^ gNgO ^.

ber .: found .:

. C. {%) H (*) N (^ 6ο A. 4, 55 β, 70 6ο ,1 4, 5 6, 65

09838/09 ^

- $ 2-
-'zo - 28115U

Example 12

6- (2-Oxoethyl) -7-oxo-1-azabioyclo ^ 5.2.o7hept-2-en-2-carboxylic acid phthalidyl ester

H H

(i) Production of 7- (3-phthalide.>'loxycarbonyl-l-tris- (p-methoxyphenyl) -phosphoranylidene-methyl) -8-oxo-7-azabiGyclo-

-NH

(D

V- /

The phosphorane (45) is prepared as in Example 10 (i), but with the proviso that 1.2 g of tris (p-methoxyphenyl) phosphine are used instead of triphenylphosphine. After chromatography to obtain 0.71 g of the phosphorane (45) from the Pp. 194-196 ⁰ C after recrystallization from a mixture of ethyl acetate and petroleum ether.

809838/09 ^ 2

IR spectrum in CHCl3: O = I78O, 17 ^ 5, I650, I6OO, I265

and III5 cm " {%) H (*) N (*) Analysis for C ₅₈ H ₅ ^ PNO ₈ -H ₂ O: C. , 95 5, 3 2, O ber .: 66 _: , 35 5, 0 1, 8th found: 67,

(ii) Preparation of the 6- (2-0xoethyl) -7-oxo-1-azabicyclo / 3.2,, 07-hept-2-en-2-carboxylic acid phthalidyl ester

0.133 g of the phosphorane (^ 5) are dissolved in 6 ml of a Geraisches of 5 parts of ethyl acetate and 1 part of trifluoroacetic acid. The solution is left for 10 minutes at room temperature and then cool it to -70 ^0C then allowed by the solution of ozone pearls, until they become pale blue and entSrnt finally schüssiges ozone with argon. Then 0.07 g of tris (p-methoxyphenyl) phosphine in 1 ml of ethyl acetate is added and the temperature of the solution is allowed to rise to ^{0 ° C. on an ice bath.} 5 ml of saturated aqueous potassium bicarbonate solution are then carefully added with vigorous stirring and the solution is allowed to separate into layers. The aqueous layer is washed twice with 5 ml of ethyl acetate each time. The combined organic layers are dried over anhydrous magnesium sulfate.

809838/0942

■ 9k-

-τ * - 28115H

warms this solution to 45 ° C for 45 minutes and then removes it the solvent under reduced pressure. After rapid chromatography on silica and eluting with a mixture of 1 part petroleum ether and 1 part ethyl acetate 0.02 g of the aldehyde (46) is obtained as a white solid after trituration with ether.

IR spectrum in CHCl ^: v? = 2950, 1795, 1740, 1610 and

980 cm " ¹ .

NMR Spectrum: S = 9.17 (s, aldehyde-CH).

Example I3

6- (4-0xo-2-penten-1-yl) -7-oxo-1-azabicyclo / J.2.'07hept-2-en-2-carboxylic acid phthalidyl ester

(i) Preparation of acetonyl tris (p-methoxyphenyl) phosphonium chloride

+ CICBLCOCH,

A solution of 2.66 g of tris (p-methoxyphenyl) phosphine and 0.65 g of chloroacetone in 6 ml of chloroform is taken for 45 minutes Allowed to reflux. The solution is then poured into 60 ml of ether and the solid is filtered off. The chloride (47) is obtained.

809838 / ÖS42

2811 51 A

IR spectrum on KBr: _v = 2800, 1710, 1595 and I270 cm " ¹ .

UV spectrum in ethanol: A _max = 212 (& = 57100) and 247 nm

(£ = 458OO).

Nuclear Magnetic Resonance Spectrum in CDCl ₃ : £ = 2.48 (3H, d, J = 2 Hz, COCH ₃ ); 5.88 (9H, s, OCH ₃ ); 5.77 (2H, d, J = II Hz, CH ₂ ); and 6.95-8.0 (12H, m, aromatic).

(ii) Preparation of acetylmethylene-tris- (p-methoxyphenyl) -phosphorane

(U8)

0.055 S sodium carbonate in 5 ml of water is added to a suspension of 0.445 g of the chloride (47) in 5 ml of benzene. After 5 minutes The organic layer is separated and dried with stirring over anhydrous magnesium sulfate and the benzene evaporated. reduced pressure. The oil obtained crystallizes from a Mixture of ether and cyclohexane and melts after recrystallization from a mixture of ethyl acetate and petroleum ether 148.5-149 ° C.

NMR spectrum on CDCl ₃ : <£ = 2.07 DH, d, J = 2 Hz, COCH ₃ ); 3.83 (10H, s, obscured broad singlet, = CH and OCH ₃ ) and

₃ )

6.85-7.75 (12H, m, aromatic H).

Analysis for C ₂₄ H ₂₅ PO ₄ : C {%) H

calc .: 70.59 6.15 found: 70.44 6.25

809838/0942

(ii) Preparation of the 6- (4-0xo-2-penten-1-yl) -7-oxo-1-azabi cyclo / 5 »2.07hept-2-en-2-carboxylic acid phthalidyl ester

0.4 g of the phosphorane (45) prepared according to Example 12 (i) are dissolved in 18 ml of a mixture of 5 parts of stylacetate and 1 part of trifluoroacetic acid. The solution is left 10 minutes at room temperature and then cools to -70 ⁰ C. Then it passes through the solution Oaon until it turns pale blue. Argon is then passed through the solution to remove excess ozone and 0.2 g of tris (p-methoxyphenyl) phosphine in 2 ml of styl acetate is added. Allowing the temperature of the mixture on an ice bath to 0 ⁰ C to rise and then carefully added with vigorous stirring to the reaction mixture 15 ml of saturated Kalxumbicarbonatlosung added. The mixture is then allowed to separate into layers and the aqueous layer is extracted twice with 25 ml of stylacetate each time. The combined organic layers are dried over anhydrous magnesium sulfate, filtered and heated I5 minutes at 50 ⁰ C. Are then added 0.2 g Aeetylmethylen-tris- (p-methoxyphenyl) phosphorane added and the solution was heated 90 minutes 5O ⁰ C and allowed to finally at room temperature overnight. After chromatography on silica and after eluting with mixtures from

809838/0942

28115U

Ethyl acetate and petroleum ether give 0.015 g of the ketone (49) as an oil.

IR spectrum in CHCl ₅ : v> _max = 1795, 1750, 1680, 1635, 1615

and 985 cm ".

NMR spectrum in CDCl ₃ : S = 1.8-3.0 (4H, m, methylene-H); 2.23 (3H, s, CH _3); 3.75 (IH, m, C6-H); 4.41 (IH, m, C5-H); 6.02 (IH, broad d, J = 16 Hz, CH ₃ COCH =); 6.4-6.9 (2H, m, C3-H and -CH = CH-COCH ₃ ); 7.40 and 7.46 (IH, 2 χ s, phthalidyl-methine-H); and 7.5-7.95 (4h, m, aromatic).

Example 14

6- (3-methoxycarbonyl-2-propen-1-yl) -7-oxo-1-azabicyclo / 3.2 .0 / - hept-2-en-2-carboxylic acid trimethylacetoxymethyl ester

MeO ₂ C

(i) 7- (1-Trimethylacetoxymethyloxycarbonyl-1-triphenylphosphoranylidene-methyl) -8-oxo-7-azabicyclo ₁ /? i ^: .2.o7o-ct -3-en

, 0H

(50)

₂ CH ₂ OCO C (CH ₃ ).

809838/09

0.4 g of azefcidin-2-one (1) in 2 ml of dimethylformamide are mixed with 0.32 g of glyoxalic acid monohydrate and 4 pellets of a molecular sieve with a pore size of 0.4 nm together for 5 hours stirred. First 0.248 g of potassium carbonate and then 1.2 g of trimethylacetoxymethyl bromide are then added. To Stirring overnight, the solution is diluted with ethyl acetate, washed with water and dried over anhydrous magnesium sulfate and steam them down. 0.8 g of oil on silica gel is obtained 60 is chromatographed with a grain size below 0.06 mm. After eluting with mixtures of ethyl acetate and petroleum ether boiling from 60 to 80 ° C, the alcohol (50) is obtained as Mixture of isomers.

IR spectrum of CHCl _x : 0 _v = 3460, 3300, 1755 (broad) cm " ¹ .

_p max

0.26 g of this mixture in 3 ml of tetrahydrofuran is cooled to -20 ⁰ C and then with agitation treated with 0.21 ml of 2,6-lutidine and then with 0.14 ml of thionyl chloride. After 30 minutes the reaction mixture is filtered and the filtrate is evaporated to dryness after adding toluene. The residue is dissolved in 2 ml of dioxane and then 0.45 g of triphenylphosphine and 0.21 ml of 2,6-lutidine are added. The mixture is then stirred at room temperature overnight and then filtered. The filtrate is evaporated and chromatographed on silica gel 60 with a particle size of less than 0.06 mm. 0.291 g of the phosphorane (51) is obtained as a foam.

IR spectrum in CHCl _x : ^ = ΐγ4θ and I630 cm " ¹ .

2 max

809838/0942

. 2.07hept-2-en-2-carboxylic acid-trim thy lace t oxy me thy! Ester

CO ₂ CH ₂ OCOC (CH ₃ )

0.1 g of the phosphorane (5I) is dissolved in 5 ml of ethyl acetate and 1 ml of trifluoroacetic acid at room temperature. After cooling to -7O ⁰ C, the solution is treated with ozone until it shows a pale blue color. Argon is then bubbled through the solution to remove excess ozone. 0.075 g of triphenylphosphine dissolved in ethyl acetate is then added. After 5 minutes, the reaction vessel is placed in an ice bath and the reaction mixture is treated with JO ml of saturated sodium bicarbonate solution while stirring vigorously. The ethyl acetate layer is then separated off, dried over anhydrous magnesium sulfate and warmed to room temperature for 45 minutes. Then add 0.075 g of methoxycarbonylmethylene triphenyl phosphorane in the smallest possible volume of methylene chloride to the ethyl acetate solution. After 60 minutes, the solvent is evaporated and the residue is chromatographed on silica gel 60 with a particle size of less than 0.06 mm and eluted with a mixture of ethyl acetate and petroleum ether with a boiling point of 60 to 80.degree. This gives? 5 mg of the compound (52) from the Pp. 110-112 ⁰ C after recrystallization from ether.

809838/0942

9ο

UV spectrum in ethanol: k _mav = 210 and 275 nm (£ = 4θ6θ).

IR spectrum in CHCl ^: 3 _v = 1785, 1750, 1725, 1660, 1610 cm " ¹ .

2 u 'cAJC

NMR spectrum in CDCl3,: S = 1.22 (9H, s, tert-Bu); 2.75 (2H, dd, J = 9 and 3 Hz, C4-H ₂₎ j 2.40-2.90 (2H, m, CHg); 3.70 (3H, s, OMe); 3 * 65-3.90 (IH, m, C6-H); 4.4θ (IH, dt, J = 6 and 9 Hz, C5-H); 5.81 (IH, dd, «£ = 15 and 1 Hz, MeO ₂ C-CH = CHCH ₂ ) J 5.81 and 5.84 (2H, signals from ABq, COgCHgO inside); 6.54 (IH, t, J = 3Hz, C3-H); 6.86 (IH, dt, J = 6 and 15 Hz, MeO ₂ C-CH = CHCH ₂ ).

M ⁺ for ( α8 ^Η 23 ^Ν0 7 : 365. : 1475 H {%) H (*) ber. •
• 365. •
• 1498 6, 3 3, 8th found •
* •
• C (%) 6, 4th 3, 8th analysis for C ₁₈ H ₂₃ N0 ₇ 59.2 ber. 59.2 found

The concentrations of this "compound used to inhibit the Growth of the following bacteria are required are listed below:

Organisms Aig / ml (agar) B. subtilis A 20th E. coli Olli 20th Klebsiella aerogenes A 20th Salmonella typhimurium CT 10 20th Shigella sonnei MB II967 20th Staph. aureus oxford 2 Staph. aureus russell 2 Staph. aureus 1517 2

809838/0942

28115U

Example 15

6- (3-methoxycarbonyl-2-propen-1-yl) ^ - oxo-1-azabicyclo / f. 2 .0 / ~ hept-2-en-2-carboxylic acid p-nitrobenzyl ester

MeO ₂ C- -

/ V-H

(i) 7- (1-Hydroxy-1-p-nitrobenzyloxycarbonyl-methyI) -8-0x0-7-

OH

(D

(5U)

9> 08 g of p-nitrobenzyl glyoxalate hydrate are allowed to boil in 150 ml of benzene under reflux in order to remove water. After 60 minutes, 2.46 g of S-Oxo ^ -azabicyclo / i ^ .0 / ⁷ OCtj5-en (1) are added and refluxing is continued for 210 minutes. After cooling, the solution is washed twice with water and then with sodium chloride solution. After back-extracting the first aqueous extract with ethyl acetate, the
organic solutions dried over anhydrous magnesium sulfate, filtered together and evaporated. After chromatographing on silica and eluting with mixtures off
Ethyl acetate and petroleum ether are obtained separately in a percentage yield of the two isomers of alcohol (54).

809838/0942

The less polar isomer I is after recrystallization from a mixture of ethyl acetate and ether as crystalline Platelets of pp. 153-155 ° C before.

IR spectrum in CHCl ₃ : O _majL = 5400. (Broad), 1760, 1745, 1520,

1350 cm " ¹ .

NMR spectrum in CDCl ₃ : S = 1.90-2.8 ;? (4H, m, 2-CH _2); 3.23-3.55 (IH, m, β-lactam proton); 4.00-4.20 (IH, m, β-lactam proton); 4.27 (IH, d, J = 8 Hz, exchangeable with D ₃ O, OH); 5.33 (2H, s, CH ₂ Ar, obscured IH, CHOH); 5.67-5.88 (2H, m, CH = CH); 7.55 (2H, d, J = 8.5 Hz, Ar); -8.23 (2H, d, J = 8.5 Hz, Ar).

analysis for ^C 16 ^H 16 ^N 2 ° 6 ^: C. {%) H (*) N 06) ber .: 57 , 83 4, 85 8th, 43 found: 58 , 07 5, 15th 8th, 51

The more polar isomer II is after recrystallization from a mixture of ethyl acetate and ether in fine crystalline needles, mp. 118-120 ⁰ C before.

IR spectrum in CHCl ₃ : v> _max = 3400 (broad), I76O-I745, I520

and I350 cm.

Nuclear Magnetic Resonance Spectrum in CDCl ₃ : S = 1.83-2.77 (4H, m, 2-CH ₂ ); 3.25-3.55 (1H, m, β-lactam proton); 4.02-4.37 (2H, m, β-lactam proton and CHOH, -OH interchangeable with DgO); 5.31-5.98 / pH, 5.35 (2H, s, CH ₂ Ar), obscuring IH, tapering to s, at <? = 5.4θ on D ₂ O exchange, CHOH, and 2H, m, CE = CE /; 7.56 (2H, d, J = 8 Hz, Ar); 8.23 (2H, d, J = 8 Hz, Ar).

Analysis for

N ₂ O ₆ : 9 8th C. {% \ ) U 2 H 06 ) N 06) ber .: 57, 83 4, 85 8th, 43 found: 57, 95 4, 95 8th, 50 80 38 / 0 9

- ■ si- 28115H

(ii) 7- (1-p-Nitrobenzyloxycarbonyl-1-triphenylphosphoranylidene methyl) -8-oxo-7-azabieyclo / ¥ .2.07oe t-j5-en

IH

(55)

1.86 g of alcohol (5 ^) as a mixture of isomers in 60 ml of anhydrous Tetrahydrofuran is mixed with 1.37 ml of lutidine under argon treated. To this solution, which has been cooled to -20 C, a solution of 0.87 ml of thionyl chloride in 20 ml of tetrahydrofuran were added dropwise. A white solid separates out of the solution. The temperature of the mixture being stirred the mixture is allowed to rise to room temperature in the course of 20 minutes, filtered and evaporated to dryness. The residue is taken up in 60 ml of anhydrous dioxane and treated with 3.12 g of triphenylphosphine and 1.37 ml of lutidine. Man leave the mixture to stand overnight at room temperature with stirring. Then separated lutidine hydrochloride is filtered and the filtrate evaporates. The residue is taken up in ethyl acetate, "with water / water, then with water / water, which little drips Contains hydrochloric acid, then washed again with water and then with sodium chloride solution over anhydrous magnesium sulfate dried and finally filtered and evaporated. After chromatography on silica and after elution with mixtures of ethyl acetate and petroleum ether, 2.68 g of phosphorane (55) are obtained as an amorphous solid.

809838/0942

• 91. ·

- 82 -

IR spectrum in CHCU: * £>

2 * '

= 1738, 1620 (shoulder), I605, 1520 and I35O cm

(iii) 6- (3-Methoxycarbonyl - ^ - propen-1-yl) -7-oxo-1-azabicyclo- / 3 ~ '2.07hept-2-en-2-carboxylic acid p-nitrobenz yl ester

(SS)

(53a)

= z / 2

0.4 g of phosphorane (55) in 30 ml of ethyl acetate are treated with 1.61 ml of trifluoroacetic acid. After cooling to -7O ⁰ C, the solution is treated with ozone until it is pale blue in color. Argon is bubbled through the solution to remove excess ozone, and 0.272 mg triphenylphosphine in 5 ml ethyl acetate is added to the solution. After 5 minutes, the reaction vessel is placed in an ice bath and the reaction mixture is vigorously stirred with 30 ml of saturated aqueous sodium bicarbonate solution for 10 minutes. After the organic phase has been separated off, it is dried over anhydrous magnesium sulfate and filtered. The pale colored solution is left to stand for 75 minutes at room temperature, then concentrated to 15 ml and treated with 0.26 g of carbomethoxymethylene triphenyl phosphorane. After 30 minutes the solution is evaporated. After a

809838/0942

281 1 51 A

rapid chromatography of the residue on 4 g of silicon dioxide and after eluting with mixtures of ethyl acetate and petroleum ether, 132 mg of the trans isomer (53a) are obtained (at the C6 double bond) of melting point 156-159 ° C after recrystallization from ethyl acetate and petroleum ether.

UV spectrum in ethanol: A _{> viQv} = 269 nm (£ = 14300).

invited. X

IR spectrum in CHCl,: ^ _mnv = I782, 1722, 1655 (weak), I605

(weak), 1525 and 1350 cm ".

Nuclear Magnetic Resonance Spectrum in CDCl ₃ : <5 = 2.73 (2H, dd, J = 9.5 Hz, 3 Hz, C4-H); -partly obscuring 2.25-2.90 (2H, m, side chain CHg); 3.69 (3H, s, CH _3); - partially obscuring 3.74 (IH, td, J = 9.5 and 6 Hz, C5-H); 4.39 (IH, td, J = 9.5 and 6 Hz, c6-H); 5.20 and 5.42 (2H, ABq, J = H Hz, CHgAr); 5.80 (IH, d, J = 16 Hz, trans-CH = CHCH ₂ ); 6.53 (IH, t, J = 3 Hz, C> H) J 6.85 (IH, td, J = 6 and 16 Hz, trans -CH = CHCH ₂ ); 7.52 (2H, d, J = 8 Hz, Ar); 8.14 (2H, d, J = 8 Hz, Ar).

Analysis for C ₁₉ FI ₁ QN ₂ O ₇ : C {%) H {%) N (fa)

calc .: 59.06 4.70 7.25 found: 58.90 4.70 7.08

The concentrations of this compound required to inhibit the growth of the following bacteria will be given below:

Organisms ug / ml (agar)

Staph. aureus Russell - 2.46 Strep, pneumoniae 7.4

Strep, pyogenes 0.8

809838/0942

It is the cis-isomer (53 ^'D) mg a small amount in a yield of 4 and having a melting point of 109-111 ° C after recrystallization from ether.

UV spectrum in ethanol: A ^ _ax = 269 nm (6 = 13950).

IR spectrum in CHCl ₃ : 0 _max = 1778, 1720, I650 (weak),

I520 and 1350 cm " ¹ .

NMR spectrum in CDCIyS = 2.40-3.50 (4h, m, 2-CH ₂ ); 3.66 (3H, s, CK ₅ ); partially occluding 3.73 (IH, td, J = 8 and 6 Hz, C6-H); 4.35 (IH / td, J = 9.5 and 6 Hz, C5-H) j 5.19 and 5.40 (2H, ABq, J = 14 Hz, CH ₂ Ar); 5.84 (IH, d, J = II Hz, cis-CH = CHCH ₂ ); 6.22 (IH, ddd, J = II, 8 and 6 Hz, cis -CH = CHCH ₂ ); 6.55 (IH, t, J = 3Hz, C3-H); 7.52 (2H, d, J = 8 Hz, Ar); 8.14 (2H, d, J = 8 Hz, Ar).

Example 16

6- (3-Cyano-2-propen-1-yl) -7-oxo -! - azabicyclo / ^. 2.07hept-2-en-2-carboxylic acid benzyl ester

O CH Ph 2 2

1 g of the phosphorane (3) is dissolved in 50 ml of ethyl acetate and treated with 1.25 ml of trifluoroacetic acid. After 5 minutes at room temperature, the reaction mixture is cooled to -7O ⁰ C. Then ozone is blown into the solution until it is pale blue. Excess ozone is removed using an argon stream. Then 0.5 g of triphenylphosphine in ethyl acetate is added. After 5 minutes, the reaction mixture is placed in an ice bath and

809838/0942

- JB5 - '28115U

40 ml of a saturated sodium bicarbonate solution are added with vigorous stirring. The organic phase is separated off, dried over anhydrous magnesium sulfate and treated with 0.55 g of cyanomethylene triphenyl phosphorane while stirring. After 50 minutes at room temperature, the solution is evaporated to dryness. The residue is chromatographed on silica gel 60 with a particle size of less than 0.06 mm. After eluting with a mixture of 3 parts of ethyl acetate and 7 parts of petroleum ether boiling from 60 to 80 ° C., 0.05 g of the pure compound (56) and then 0.183 g of the compound contaminated with a little triphenylphosphine oxide are obtained.

IR spectrum in CHCl ^: J _v = 2250 (CN), 1785, 1730, 16 ^ 0

and I620 cm.

Nuclear Magnetic Resonance Spectrum in CDCl ₃ : & = 2.45-2.90 (2H, m, CR ₂ ); 2.73 (2H, dd, J = 9 and 3 Hz, C 1-4 H ₂ ); 3.60-3.90 (IH, m, C6-H); 4.40 (IH, dt, J = 9 and 6 Hz, -C5-H); 5.25 (2H, s, CH _2); 5 ^ 0 (IH, dd, J = 16 and 1 Hz); 6.53 (IH, t, J = 3 Hz); 6.60 (IH, dt, J = 16 and 7 Hz); 7.30 (5H, s, Ar).

M ⁺ for C ₁₈ H ₁₆ N ₂ O ₃ :

ber .: .308,1161
found .:. 308.1120

The concentrations of this compound required to inhibit the growth of the following bacteria will be given below:

809838/0942

- 86 -

Organisms
B. subtilis A
Citrobacter freundii E8 Enterobacter cloacae Nl E. coli Olli
Klebsiella aerogenes A Proteus mirabilis C977 Proteus morganii I 580 Proteus rettgeri WMI6 Salmonella typhimurium CTlO Serratia marcescens US20 Shigella sonnei MB 11967 Staph. aureus Oxford Staph. aureus Russell Staph. aureus 1517

28115H

jug / ml (agar) 20 20 20 20 20 20 20 20 20 20 20

'C 2

Example I7

6- (4-0xo-2-penten-l-yl) -7-oxo-l-azabicyclo / J.2.07hept-2-en-2- · benzyl carboxylate

H H

1 g of the phosphorane (3) is dissolved in 50 tnl ethyl acetate and 1.25 ml trifluoroacetic acid. After cooling the solution to -70 ⁰ C ozone is passed into the solution until it is colored pale blue.

"Ozone

excess is then removed with a stream of argon. then 0.5 g of triphenylphosphine in 10 ml of ethyl acetate is added. After 5 minutes, the solution is placed in an ice bath and, with vigorous stirring, with 40 ml of saturated sodium bicarbonate solution neutralized. The organic phase is separated, over what-

809838/0942

serfreiera magnesium sulfate, dried, filtered and washed with ethyl acetate aif 100 ml filled up. 50 ml of this solution containing the aldehyde (4) contains 0.295 g of acetylmethylene triphenyl phosphorane with stirring treated. The reaction mixture is then left to stand at room temperature overnight (18 hours). then The ethyl acetate is evaporated off under reduced pressure and the residue is rapidly chromatographed on 15 g of silica gel 60 with a grain size below 0.06 mm and eluted with a mixture of 3 parts of ethyl acetate and 7 parts of petroleum ether from the boiling range 60 to 80 ° C and then with a mixture of 1 part ethyl acetate and 1 part petroleum ether. The compound (57) is with triphenylphosphine oxide contaminated, and therefore it is chromatographed again. 0.05 S of the pure compound (57) is obtained as a gummy substance.

IR spectrum in CHCl 2: ¹ O ^ = 1785, 1730, 1680, 1630 and 1620 cm " ¹

_P IQdX

NMR spectrum in CDCl ₅ : S = 2.25 (3H, s, COCH ₃ ); 2.50-3.00 (4H, m, 2.x CH ₂ ); 3.55-3.95 (IH, m, 'C6-H); 4.40 (IH, dt, J = 9 and 6 Hz, C5-H); 5.25 (2H, s,); 6.15 (IH, d, J = 16 Hz); 6.50 (IH, t, J = 3 Hz, C3-H); 6.75 (IH, dt, J = 16 and 7 Hz); 7.30 (5H, s, Ar).

M ⁺ for C ₁₉ H ₁₉ NO ₄ :

ber .: 325.1376
found: 325.1345

809838/0942

28115H

Example l8

6- (3-methoxycarbonyl-2-propen-1-yl) -7-oxo-1-azabicyclo / 5 »2.o7 hept-2-en-2-carboxylic acid p-bronphenacy! ester

MeO ₂ C

0 CH C
2 2

■ Br

(i) 7 - (^ - Hydroxy-lp-bromophenacyloxycarbonyl-methyl) -8-0x0-7-azabicyclo / ¥ .2.07oct -3-en

O)

0H

(58)

0.4 g of azetidinone (1) in 2 ml of anhydrous dimethylformamide with 0.2 g of glyoxalic acid hydrate in the presence of 0.1 ml of hexamethylphosphoric acid triamide and 4 pieces of a molecular sieve with a pore size of 0.3 nm were stirred together for 5 hours. 0.226 g of potassium carbonate is then added and the solution is stirred for about 5 minutes until the foaming has stopped. then 1.00 g (1.05 equivalents) of p-bromo-phenacyl bromide are added in 1.0 ml of dimethylformamide and -0.25 ml of hexamethylphosphoric acid triamide and stir the solution overnight. The solution is then diluted with ethyl acetate and washed three times with saturated solution aqueous sodium chloride solution, dry it over anhydrous sodium sulfate and evaporate it. 1.9 g of one are obtained rubber-like substance that is chromatographed on silica gel /

809838/0342

281 Ί 51

After eluting with a mixture of ITeil ethyl acetate and 1 part of petroleum ether gives the glyoxalic acid ester (58).

The isomers I is present as foam at the ithylacetat in the presence of "and crystallized slowly petroleum ether. (Theory = 4-7 fo) to give 0.60 g of needles by Pp. I35- ⁰

IR spectrum in CHCl ^: -O ^ = 3250 (broad), I76O (shoulder),

1750, I7IO, 1590 and 970 cm " ¹ .

NMR spectrum in completely deuterated dimethyl sulfoxide: <£ = 1.9-2.8 (4h, m); 3.35 (IH, m); 4.17 (IH, m); 5.51 (IH, d, J = 6.5 Hz; tapering to a singlet on DpO exchange); 5.55 (2H, s, phenacyl-CH _2); Broad 5.72 (2H, s) j 6.81 (IH, d, J = 6.5 Hz, interchangeable with D ₃ O) J 7.75 (2H, d, J = 9 Hz); and 7.90 (2H, d, J = 9 Hz).

Analysis for C ₁₇ H ₁₆ BrNO ₅ : C (fo) H (fo) N (fo) Br {%)

calc .: 51.8 4.1 3.6 20.3 found: 51.9 '4.2 3.6 20.00 ^

After further elution, the more polar isomer II is obtained, which crystallizes from a mixture of ethyl acetate and petroleum ether in the form of platelets. Yield: 0.55 g (= 43 % of theory) with a melting point of 144-146 ° C.

IR spectrum in CHCl: v> _v = 3200 (broad), 1760 (shoulder),

I75O, 1710, 1590 and 965 cm " ¹ .

NMR spectrum in completely deuterated dimethyl sulfoxide: £ = 1.9-2.8 (4h, m) j 3.33 (IH, m) j 4.15 (IH, m); 5, ^ 7 (IH, d, tapering to a singlet on DpO exchange); 5.51 (2H, s, phenacyl CH ₂₎ j 5.71 broad (2H, s); 6.90 (IH, d, J = 7 Hz, ex-

809838/0942

28115H

exchangeable rait D ₃ O); 7.73 (2H, d, J = 9 Hz); and 7.91 (2H, d, J = 9 Hz).

Analysis for C ₁₇ H ₁₆ BrNO ₅ : C (Ji), H {%) N {%) Br {%)

calc .: 51.8 4.1 3.6 20.3

found: 51.7 4.3 3.3 20.6

(ii) 7- (lp-bromophenacyloxycarbonyl-1-triphenylphosphoranylidene-methyl) -8-oxo-7-azabicyclo / ¥ .2.07oc t-3-en

(58)

CO CH C 2 2

0.383 S of the glyoxylic acid-p-bromphenacylesters (58) having an isomer ratio of 1: 1 in 8 ml of tetrahydrofuran with 230 uLiter lutidine and then treated with thionyl chloride 139 uLiter 210 minutes at -20 ⁰ C. The reaction mixture is quickly filtered through diatomaceous earth and washed with ethyl acetate. The filtrate and wash water are evaporated under reduced pressure. The residue in 4 ml of anhydrous dioxane is treated with 0.51 g of triphenylphosphine and 2 ^ 0 μl of lutidine overnight at room temperature. After chromatography on silica gel and after eluting with a mixture of ethyl acetate and petroleum ether in a ratio of 7: 3, 0.536 g of phosphorane (59) is obtained as a gummy substance, which after recrystallization from a mixture of ethyl acetate, ether and petroleum ether as narrow rods crystallized. Yield: 0.499 g (= 80% of theory) of Pp 200-202 ⁰ C..

809838/0942

IR spectrum in CHCl,:

UlciX

28115H

= 174θ (strong), I7IO, 1620, 1590 and 1480 cm

" ¹

Analysis for C ₃₅ H ₂₉ BrNO ^ P: C {$) H {%) N (Jg)

calc .: 65.8 4.6 2.2

found: 65.7 4.7 2.0

Br

12.5 12.1

(iii) 6- (3-methoxycarbonyl-2-propen-l-yl) -7-oxo-l-azabicyclo-

(59)

(60)

0.104 g of the phosphorane (59) are converted into the .bicyclic ester according to the procedure described for the benzyl ester in Example 2 (60) transferred and isolated. 35 mg of the compound are obtained (60), which melts at 134-136 ° C after recrystallization from a mixture of ethyl acetate and petroleum ether.

IR spectrum: ^ _mQv = 1785, 1725 (shoulder), 1715, 1700, I66O, max

Max

" ¹

1610 and 1590 cm " ¹ .

UV spectrum in ethanol: λ _a = 275 (bend), 258 (£ - = 219ΟΟ),

210 nm (€ = 26ΟΟΟ).

Nuclear Magnetic Resonance Spectrum in CDCl ₅ : S = 2.45-2.9 (2H, m, C6 side chains-CH ₂ ); 2.74 (2H, dd, J = 9 and 3 Hz, C4-H ₂ T; 3.68 (3H, s): 3.6-3.9 (IH, m, C6-H); 4.40 (IH ₃ dt, J = 9 and 6 Hz, C5-H); 5.36 (2H, s); 5.8O (IH, dt, J = 15 and 1 Hz); 6.60 (IH, t, J = 3 Hz, C3-H);

809838 / 09A2

28115U

6.86 (IH, dt, J = 15 and 6 Hz); 7.55 (2H, d, J = 9 Hz) and 7.74 (2H, d, J = 9 Hz).

Analysis for C ₂₀ H ₁ QBrNOg: C {%) H ($) N {%) Br {%)

calc .: 53.6 4.0 3.1 17.8

found: 53.4 4.1 3.2 17.9

Example 19

2-carboxylic acid phthalidyl ester

E E

0.3 ^ 5 g of the phosphorane (4o) are in 15 ml of a mixture dissolved from 5 parts of ethyl acetate and 1 part of trifluoroacetic acid. The solution is left to stand for 15 minutes at room temperature, then cooled then bring it to -70 C and pass ozone through it until the solution turns light blue. Argon is then passed through the solution to remove excess ozone, and 0.2 g is added to the solution Triphenylphosphine in 10 ml of ethyl acetate. The reaction mixture is then placed in an ice bath and diluted with 50 ml of ethyl acetate and then 75 ml of saturated sodium bicarbonate solution are added with vigorous stirring. The organic phase is separated off and the aqueous phase is extracted again with 30 ml of ethyl acetate. The combined organic layers are dried over anhydrous sodium sulfate and filtered

809838/0942

- 28115U

and 270 minutes over molecular sieves with a pore size of Left 0.4 nm at room temperature.

0.18 g of cyanomethylene triphenyl phosphorane are dissolved in 50 ml of ethyl acetate. The reaction mixture is filtered to remove the molecular sieve and then treated with the solution of the phosphorane. The reaction mixture is then concentrated to about 50 ml under reduced pressure and left to stand at room temperature for 60 minutes. Then the solution is evaporated to dryness and quickly through a column of 5 g of silica gel with a particle size less than 0.06 of a mixture of 1 part ethyl acetate and 1 part petroleum ether mm using a boiling range of 60 to 80 ⁰ C chromatographed. This gives 62 mg of the compound containing a small amount of triphenylphosphine oxide, which is triturated with a mixture of 1 part ethyl acetate and 1 part of petroleum ether of boiling range 60 to 80 ⁰ C. 12 mg of the ester (61) are obtained as a white solid.

IR spectrum in CHCl,: V> ". = 2225 (C = N), 1790 (ß-lactam and Laq-

jr max

ton), 1745 (ester), 1640 (side chain double bond) and I615 (ring double bond) cm ~.

The "concentrations" of this compound required to inhibit the growth of the following bacteria become given below:

809838/0942

• / (06 · Organisms 28115U Citrobaoter freundii e8 Mg / ml (agar) Enterobacter cloacae Nl 1.3 E. coli Olli 22nd Klebsieila aerogenes 1.3 Proteus mirabilis C977 . 1.3 Proteus morganii I 58O 66.6 Proteus rettgeri WM 16 22nd Proteus vulgaris WO 9I 22nd Salmonella typhimurium 66.6 Serratia marcescens US 20 7th Shigella sonnei MB II967 22nd Staph. aureus oxford 22nd Staph. aureus russell 2Λ

Example 20
7-0xo-la-zabicyclo ^ 3'.2.07hept-2 ~ en-2-carboxylic acid benzyl ester

CO ₂ CH ₂ Ph

(i) Preparation of the 7-0xo-l-azabicyclo / 3.2.07hept-2-en-2-carboxylic acid benzyl ester

CO ₂ CH ₂ Ph

CO ₂ CH ₂ Ph

(62)

(63)

500 mg of the phosphorane (62) in 60 ml of ethyl acetate are treated with 0.7 ml of trifluoroacetic acid. After cooling to -70 ⁰ C ozone is bubbled into the solution until it turns pale blue. Argon is then passed through the solution to remove excess ozone

809838/0942

28115U

to remove, and mixed them with 250 mg triphenylphosphine in 5 μl of ethyl acetate. After stirring for 5 minutes, place the reaction vessel in an ice bath and the reaction mixture is treated with 50 ml of saturated aqueous sodium bicarbonate solution. After 40 minutes vigorous stirring, the mixture is diluted with more ethyl acetate, the organic phase is washed with sodium chloride solution, dry it over anhydrous magnesium sulfate and evaporate it to a gummy substance that is chromatographed on silica gel will. After eluting with mixtures of stylacetate and petroleum ether, 110 mg of the bicyclic compound are obtained (63) as oil.

IR spectrum in CHCl-,: v> _v = 1782 and 1725 cm " ¹ .

_? ΓΠα, Χ

Nuclear Magnetic Resonance Spectrum in CDCl ₅ : S = 2.68 (1H, ddd, J = Io, 9 and 3 Hz, C ¹ IH); 2.90 (IH, ddd, J = 16, 9 and 3 Hz, C4-H); / 2.92 (IH, dd, J = 16 Hz, 3.5 Hz) and 3.45 (IH, dd, J = 16 Hz and 5.5 Hz), coinciding with the AB quartet with J = 16 Hz Irradiation at <? = 4.23, Co-C 4.24 (IH, m, coinciding with d with J = 5 * 5 Hz for irradiation at S = 2.80, C5-H); 5 ^ 20 (2H ₅ s, CH ₂ Ph); 6.44 (IH, t, J = 3 Hz, coinciding with s on irradiation at «f = 2.8θ (C3-H); 7.30 (5H, s, Ph).

M ⁺ for

calc .: 243.0895
Found: 243.0883

809838/0942

Example 21

7-0xo-l-azabicyclo _i / 5'2 .o / hept ^ -en ^ -carboxylic acid tert-butyl ester

(i) Preparation of 4-allyl-l- (l-hydroxy-l-tert-butyloxycarbonyl-methyl) -azetidin -2-one

ΓΗ

Α ν

C64)

6.22 g of glyoxalic acid tert-butyl ester hydrate in 120 ml of benzene are refluxed for 60 minutes in a Dean-Stark apparatus to remove the water. Then 2.31 g of azetidinone (18) are added and the reaction mixture is refluxed for 4 hours. Chromatography of the crude product as indicated in Example 4 (iv) gives 4.48 g of the alcohol (64) as a pale yellow oil.
IR spectrum in CHCl ,: v> ^ = 3490, 1755, 1735 and 1640 (weak)

cm

NMR spectrum in CDCl ₃ : S = 1.50 (9H, s, tert-Bu); 2.20-3.25

; 2.66 (IH, dd, J = 3 and 14 Hz, C>H); and 3.09 (IH, dd, J = 14 and 5 Hz, C3-H) masking 2H, CH ₂ J ⁷ ; 3.68-4.10 (IH, m, C4-H); 4.47 (IH, broad s, interchangeable rait D ₂ O, OH); 4.98-5.37 (3H, m, tapering with D ₃ O); 5.52 to 6.23 (IH, m, CH = CH _2).

M ⁺ at m / e: 241 and (m / e +1).

809838/0942

ί |. 281 Ί

(ii) Preparation of 4-allyl-1- (1-tert-butyloxycarbonyl-1-triphenylphosphoranylidene-methyl) -azetidin-2-one

64)

> H

(65)

A stirred solution of 4.2 g of alcohol (64) in 120 ml of anhydrous tetrahydrofuran is cooled to -20 ° C. under argon and treated with 4.03 ml of lutidine in 15 ml of tetrahydrofuran. 2.54 ml of thionyl chloride in 15 ml of tetrahydrofuran are then added dropwise. In the course of 30 minutes, the temperature is allowed to rise to .0 ⁰ C, the solution is filtered and the filtered lutidine hydrochloride is washed with toluene. ^:

The combined filtrates and wash water are evaporated to dryness. The residue is taken up in 100 ml of anhydrous dioxane and treated with 4.03 ml of lutidine and 9 * 1 g of triphenylphosphine. After stirring overnight at room temperature, the phosphorane (63) is such as 4 (v) isolated in Example indicated and there is obtained 4.62 g of white crystals after recrystallisation from ether, mp. 188-189 ⁰ C.

IR spectrum in CHCl.,: V> _v = 1730, 1638 and 1610 cm " ¹ .

_p max

Analysis for

NO ₅ P: C. {%) H i / o) N (fo) P. (JB) ber .: 74 , 2 6, 6th 2.9 6, 4th found: 74 ,1 6, 8th 3.0 6, 2

809838/0942

. MO- ¹ ^ B-28115H

(iii) Preparation of the 7-oxo-1-azabicycl0 / 3.2.C / 7hept-2-en-2-carboxylic acid tert-butyl ester

LU

(f CO ₂ Bu- (65). (66)

242 mg of the phosphorane (65) in 15 ml of ethyl acetate are treated with 0.38 ml of trifluoroacetic acid. After cooling to -7O ⁰ C, ozone is passed into the solution until it becomes pale blue. Argon is then passed through the solution in order to remove excess ozone, and 13I mg of triphenylphosphine in 1 ml of ethyl acetate are added. After stirring for 5 minutes, the reaction vessel is placed in an ice bath and 20 ml of saturated aqueous sodium bicarbonate solution are added to the reaction mixture. The mixture is then stirred vigorously for 30 minutes and then the organic phase is separated off and washed with water. The aqueous phase is re-extracted with ethyl acetate. The combined organic extracts are dried over anhydrous magnesium sulfate and evaporated. The residue is chroma tographiert on silica gel. After eluting with mixtures of ethyl acetate and petroleum ether, 50 mg of the bicyclic compound (66) are obtained as an oil.

IR spectrum in CHCl,.: V> = 1780, 1710 and 1610 cm " ¹ .

NMR spectrum in CDCl ₅ : S = 1.49 (9H, s, tert-Bu); 2.70 (IH, ddd, J = 19 Hz, 10 Hz, 2 Hz, C4-H) j 2.87 (IH, ddd, J = 19 Hz, 9 Hz, 2 Hz, C4-H); 2.86 (IH, dd, J = 14 and 2.5 Hz, C6-H) j 3.40 (IH, dd, J = 14 Hz, 5 Hz, C6-H); 3.99-4.33 (IH, m, C5-H); 4.26 (IH, t, J = 2 Hz, C3-H).

809838/0942

28ΊΊ5Η

W for

•AT THE

calc .: 209.1052
found: 209.1050

Example 22

^ -Methyl-T-oxo-l-azabicyclo ^. 2.Q7hept-2-en-2-carboxylic acid tert-butyl ester

CO ₂ Bu ¹

(i) Preparation of 4- (propan-2-one) -azetidin-2-one

(18)

(67)

0.22 g (2 mmol) 4-allyl-azetidin-2-one (18) and 0.64 g (2 mmol) Mercury (II) acetate is stirred in 6 ml of methanol at room temperature for 2 hours. That solution then becomes a solution of 1.0 ^ g (6 mmol) of copper (II) chloride dihydrate and 0.0 ^ 4 g (0.2 mmol) of palladium (II) chloride in 6 ml of methanol. To The reaction mixture is cooled after heating to 60 ° C. for 1 hour and mixed with a saturated aqueous sodium bicarbonate solution, until the solution has a pH of 9. The reaction mixture is then filtered and the methanol is reduced under reduced pressure Pressure evaporated. After extracting the aqueous three times Phase with 25 ml of ethyl acetate each, subsequent drying of the Extracts over anhydrous magnesium sulfate and evaporation of the solvent gives a green colored oil. After chromatography on silicon dioxide and after eluting with mixtures of petroleum ether, ethyl acetate and ethanol, 0.17 g is obtained

(= 70 % of theory) of the ketone (67) as an oil. IR spectrum in CHC] U: \> _Qv = 3420, 3000, 1760 and 1720 cm " ¹ .

NMR spectrum in CDCl ₃ : S = 2.14 (3H, s, CH ₃ ); 2.4-3.4 (4h, m, methylene-H); 3.86 (IH, m, C4-H); and 6.75 (IH, broad, NH).

M ⁺ for C ₆ H _Q N0 ₂ :

ber .: 127.0634 Found: 127.0628

(ii) Preparation of l- (l-hydroxy-l-tert-butoxycarbonylmethyl) -4- (propan-2-one) -azetidi n-2-one

< ⁶⁷ > C68)

0.3 g (2.33 mmol) of glyoxalic acid tert-butyl ester hydrate are refluxed for 60 minutes in an apparatus for separating out water in 1.0 ml of benzene. 0.14 g (1.1 mmol) of the ketone (67) in 3 ml of anhydrous benzene is then added and the mixture is refluxed for a further 4 hours. After evaporation of the solvent under reduced pressure and after chromatography on silicon dioxide and sluicing with a mixture of petroleum ether and ethyl acetate, 0.196 g (= 82 <fo of theory) of the keto alcohol (68) and 0.022 g of unchanged ketone are obtained.

NMR spectrum in CDCIy £ = 1.55 (9H, s, tert-Bu); 2.23 (3H, s, CH _3); 2.5-3.5 (4H, m, methylene-H); 4.20 (IH, m, C4-H); and 4.6-5.5 (2H, m, CHOH).

809838/0942

-> βι - 28115H

(iii) Preparation of l- (l-tert-butoxycarbonyl-l-triphenylphosphoranylidene-methy 1) ^-1 J- (propan-2-one) -azetidin-2-one

(68) ^ά (69)

To a stirred solution of 0.196 g (0.763 rrJVIol) of the keto alcohol (68) in 5 ml of anhydrous tetrahydrofuran is added at -20 ⁰ C successively 0.163 g (0.177 ml; 1.52 ramol) of 2,6-lutidine and 0.181 g (0 , 11 ml; 1.52 tnmol) thionyl chloride in 1 ml tetrahydrofuran was added. Stirring is continued for 20 minutes at -20 ⁰ C. The solution is then filtered, the solvent is evaporated off under reduced pressure and the residue is dried by azeotropic distillation twice with 10 ml of toluene each time. The resulting slurry is dissolved in 7 ml of dioxane, and 0.163 g (0.177 ml; 1.52 mmol) of 2,6-lutidine and 0.4 g (1.52 mmol) of triphenylphosphine are added successively. After stirring for several hours, the solution is filtered and the solvent is evaporated off under reduced pressure. After chromatography on silica and eluting with a mixture of petroleum ether and ethyl acetate, a semicrystalline oil is obtained which can be crystallized by adding ether. You get

0.255 g (= 70 % of theory) of the phosphorane (69) as white needles of mp.

IR spectrum in CHCl,: V * ^ = 2990, 1740, 1720 and 1640 cm " ¹ .

_p max

NMR spectrum in CDCl ₃ : 5 = 0.9 (9H, s, tert-Bu); 1.4 (3H ₅ s, CH ₃ ); 2.18 (4h, m, methylene-H); 3.14 (IH, m, C4-H); and 7.1-7.9 (15H, m, Ph).

809838/0942

- 1P2 -

28115H

analysis for C- C. (*) H 4th F. ( 71 ,8th 6, 4th 2, 8th 71 ,8th 6, 2, 7th 50 ^H 32 ^N0 4 ^P: ber .: found:

(iv) making the ^ -

2-en-2-carboxylic acid tert-butyl ester

(το)

0.062 g (0.124 mmol) of the phosphorane (69) are heated for 90 minutes under argon at 100 ^D C in 5 ml of anhydrous toluene. The toluene is then evaporated off under reduced pressure and the residue is chromatographed on silicon dioxide and eluted with a mixture of petroleum ether and ethyl acetate. 0.023 g (= 83 % of theory) of the bicyclic compound (70) is obtained as an oil.

IR spectrum in CHCIy ^ _max = 2970, 1775, 1700 and 1635 cm " ^1. UV spectrum in ethanol: ^ _max = 272 nm (C = 4000).

NMR spectrum in CDCl3,: S = 1.51 (9H, s, tert-Bu); 2.04 (3H, t, J = 1.5 Hz, CH ^); 2.73 (2H, broad d, J = 9 Hz, C4-H); 2.77 (IH, dd, J = 3 and 16 Hz, c6-H); 3.35 (IH, dd, J = 6 and 16 Hz, C6-H) j and 4.05 (IH, m, C5-H).

M ⁺ for

ber .: 223.1208 found: 223.1212

809838/0942

• AAS

28115H

Example 23

3-Methyl-7-oxo-1-azabicyclo / 3 \ 2.07hept-2-en-2-carboxylic acid ep-nitrobenzyl ester

(i) Preparation of 1- (1-hydroxy-lp-nitrobenzyloxycarbonylmethyl) - ^j l - (propane-2-one) -azetidin-2-one

jra

(67)

(71) COOCHg!

2.64 g (11.6 mmol) of glyoxalic acid p-nitrobenzyl ester hydrate are refluxed in 50 ml of benzene for 60 minutes in a water separation apparatus / in order to separate off water. Then 0.8 g ("5 * 5 mmol) of the ketone (67) in 10 ml of anhydrous benzene is added and the mixture is heated under reflux for 7 hours. After the solvent has been distilled off under reduced pressure and after the residue has been chromatographed on silica and Eluting with a mixture of petroleum ether and ethyl acetate gives 1.39 S (= 75 % of theory) of the keto alcohol (71) as a colorless oil.

IR spectrum in CHCl ₇ : \> ^ = 3 ^ 50, ΐγβΟ, 1715, Ι6θ5, 1520

" ¹

and

809838 / 09A2

NMR spectrum in CDCl ₃ : £ = 2.17 (3H, d, CH ₃ ); 2.46-3 * 54 (4h, m, β-lactam-H and cd-ketomethylene-H); 4.20 (IH, m, C4-H); 4.50-5.8 (2H, m, CHOH); 5.40 (2H, d, benzylraethylene-H), · and 7.50-8.40 (4h, m, aromatic).

(ii) Preparation of! - (lp-Nitrobenzyloxycarbonyl-1-triphenylphosphoranylidene-methyl) -4- (propan-2-one) -azetidi n-2-one

COOCHg (71)

To a stirred solution of 0.611 g (1.84 mmol) of the keto alcohol (71) in 13 ml of anhydrous tetrahydrofuran is added at -20 ⁰ C successively 0.39 g (0.424 ml; 3.68 mmol) of 2,6-lutidine and Add 0.433 g (0.264 ml; 3.68 mmol) of thionyl chloride in 2 ml of tetrahydrofuran. The stirring at -20 ⁰ C for 20 minutes continuously. Then-the solution is filtered, the solvent is evaporated under reduced pressure and the residue is dried-by twice azeotroping with 20 mL of toluene. The resulting slurry is dissolved in 15 ml of dioxane and 0.39 g (0.424 ml; 3.68 mmol) of 2,6-lutidine and 0.59 g (3.68 mmol) of triphenylphosphine are added successively. After stirring for 2 hours, the solution is filtered and the solvent is evaporated off under reduced pressure. After chromatography on silicon dioxide and eluting with a mixture of petroleum ether, ethyl acetate and dioxane, 0.73 g (= 70 % of theory) of phosphorane (72) are obtained as yellow crystals with a melting point of 185-187 ° C.

809838/0942

.Aft-

" ^{1 <P5} " 28115U

IR spectrum in CHCl: V ^ _x = 2990, 1740, 1715, 1630, 1610,

1520 and I350 cm " ¹ .

(iii) Preparation of the 3-methyl-7-oxo-1-azabicyclo / 3.2.o7hept-2-en-2-carboxylic acid p-nitrobenzyl ester

.PPh

(72) (73)

COOCH ^ ^

0.2 g (0.345 mmol) of the phosphorane (72) are heated for 10 hours under argon at 100 ⁰ C in 10ml of anhydrous toluene. After the toluene has been evaporated off under reduced pressure, the residue is chromatographed on silicon dioxide and eluted with a mixture of petroleum ether and ethyl acetate. 0 is obtained in addition to 05 g * unchanged phosphorane 0.05 g (= 64% of theory) of the bicyclic compound (73) as colorless needles from Pp. 116 ⁰ C after recrystallization from a mixture of Ä'thylacetat and petroleum ether.

IR spectrum in CHCl: v> _v = 3000, 1785, 1725, 1635, 1610,

1415 and I35I cm " ¹ .

NMR spectrum in CDCl ₃ : ί = 2.12 (3H, s, CH ₃ ); 2.7-3.0 (3H, m, C4-H and C-6H); 3.4 (IH, dd, J = 6 and 16 Hz, C6-H); -4.12 (IH, m, C5-H); 5.3 (2H, ABq, J = 14 · Hz, benzylic); and 7.45-8.25 (4h, m, aromatic).

809838/0942

Example 24
7-0xo-1-azabicyclo / 3 ^ 2.07hept-2-en-2-carboxylic acid methyl ester

(i) Preparation of 4-allyl-l- (l · -hydroxy-l-methoxycarbonylmethyl) -azetidin -2-one

(18)

(74)

CO ₂ CH ₃

9j75 g of methyl glyoxalate hydrate in 500 ml of benzene refluxed in a Dean-Stark apparatus for 60 minutes to remove the water. Then add 2.68 g of azetidinone (18) and the reaction mixture is heated under reflux for 2 hours » Then a further portion of 1.3 g of the azetidinone is added (18) and continue refluxing for 3 hours. After chromatography of the crude product as-χη example 4 (iv), 5.33 g of the alcohol (74) are obtained as a pale yellow oil.

IR spectrum in CHCIy v> _max = 35ΟΟ, 3350 (broad), Ι7βθ -Vjko

(strong), 1640 (weak) cm ".

NMR spectrum in CDCIy S = 2.24-2.90 (3H, m, including / TH, dd, J = 3 Hz, 14.5 Hz at <£ = 2.68-7; 3.11 (IH, dd, J = 4.5 Hz, and 14.5 Hz); 3.72-4.42 (5H, including / JE, s, at S = 3, IH, interchangeable with D ₂ Oj 5.00-6.29 ( 4h, m, including

809838/0942

- 28Ί 1514

/ ~ 1Η, ε, at S = 5 ^ 8 J). '* ^'

(ii). Production of ^ -allyl-l-fl-methoxycarbonyl-l-triphenylphosphoranylidene-methyl) -azetidi n-2-one

.0H

(74) (75)

A stirred solution of 5> 23 g of the alcohol mixture is cooled (7 ^) in 150 ml of anhydrous tetrahydrofuran under argon to -20 ⁰ C and treated with β, Οβ ml lutidine in 20 ml of tetrahydrofuran. 3.83 ml of thionyl chloride in 20 ml of tetrahydrofuran are then added dropwise. After temperature rise of over 20 minutes at 0 ⁰ C the solution is filtered and washed the abfiitrJerte lutidine hydrochloride with toluene.

The filtrate is combined with the wash water and evaporated to dryness. The residue is then taken up in 150 ml of anhydrous dioxane and treated with 6.06 ml of lutidine and 13.7 g of triphenylphosphine. After stirring overnight at room temperature, the phosphorane (75) is isolated as in Example 4 (v) and 7.3 g of white crystals have a melting point of 208-212 ° C. after recrystallization from ether.

IR spectrum in CHCl3: V> _v = 1738, 1640 and 1620 cm " ¹ .

j max

Max

Analysis for C ₂₇ H ₂₆ NO ₃ P: C (Ji) H (fo) N (fo)

calc .: 73.1 5.9 3.2

found: 72.6 5.9 3.0

809838/0942

- AZO

.. 28115U

(iii) Preparation of the 7-0xo-l-azabicyclo / 3.2.Q_7hept-2-en-2-carboxylic acid methyl ester

CO ₂ CH ₃

(75)

(76)

0.886 g of phosphorane (75) in 60 ml of ethyl acetate are treated with 1.52 ml of trifluoroacetic acid. After cooling to -70 ⁰ C ozone is passed into the solution until it turns pale blue. Argon is then passed through the solution in order to remove excess ozone and then 5 mg triphenylphosphine in 5 ml ethyl acetate is added. After stirring for 10 minutes, the reaction vessel is placed in an ice bath and 50 ml of saturated aqueous sodium bicarbonate solution are added to the reaction mixture. The mixture is stirred vigorously for 1 hour, then extracted and chromatographed as in Example 21 (iii). 150 mg of the bicyclic compound (76) are obtained. After recrystallization from a mixture of ethyl acetate and petroleum ether of boiling range 60 to 8o ° C to produce compound (76) as pale yellow needles of Pp. 72 to 72.5 ⁰ C

IR spectrum in CHCl,: V = 1785 and 1738 cm " ^1. UV spectrum in ethanol: A _fflax = 272 nm (€ = 4500).

NMR spectrum in CDCIy S = 2.66 (IH, ddd, J = 3 Hz, 8.5 Hz and 19 Hz); 3.04 (IH, ddd, J = 3 Hz, 11.5 Hz and 19 Hz); 2.90 (IH, dd, J = 3 Hz and 16.5 Hz); 3.45 (IH, dd, J = 5.5 and 16.5 Hz); 3.79 (3H, s); 4.23 (IH, m); 6.43 (IH, t, J = 3 Hz).

809838/0942

for Cg H ₉ NO ₃ : - 109- - 0582 H , 39 N (*) analysis ber .: C ($) 0589 5 , 63 8th, 38 found: 57Λ9 5 8th, 24 ber. : 167, 57.47 M ⁺ for C
■ I found : I67,

28115H

Example 25

7-Oxo-l-azabicyclo _l /32.o7hept.p-nitrobenzylester

(i) Preparation of ^ -Allyl-l-Cl-hydroxy-lp-nitrobenzyloxycarbonyl-methyl) -azetidin-2-one

(18)

< ⁷⁷ >

6..8 g of p-nitrobenzyl glyoxalate hydrate are heated in 120 ml of benzene for 60 minutes under reflux in a Dean-Stark apparatus in order to remove the water. 3 S acetivlinone (18) is then added and the reaction mixture is refluxed for 2 hours. The solution is cooled, the solvent is evaporated and the residue is chromatographed. After eluting with a mixture of 80 fo A'thylacetat and 20% petroleum ether from

B0S8 38 /

Compound (77), which is chromatographed again for complete purification, is obtained at a boiling point of βΟ to 80 ° C. Finally, 3 * 2 g (= 37% of theory) of the compound are obtained as an oil.

IR spectrum in CHCl,: v> _ = 3500 (OH), 1755 (broad), 1530

and 1355 cm "·

NMR spectrum in CDCl3,: £ = 2.39 (2H, m, CH ₂ CH = CH ₂ ); 2.61 (IH, dd, J = 16 and 4 Hz, C3-H); 3.05 (IH, dd, J = 16 and 6 Hz, C3-H); 3.92 (IH, tn, C4-H); 4.63 (IH, m, coinciding with the singlet on DgO exchange, CH-OH); 4,8θ-5,8θ (6H, complex picture, including CH ₂ Ph-P-NO ₂ at 5.35, OH / "exchangeable / and CH = CH ₂ ); 7.56 and 8.23 (4h, ABq , J = 8 Hz, aromatic H).

(ii) Preparation of 4-allyl-l- (l -p-nitrobenzyloxycarbonyl-l-triphenylphosphoranylidene-methyl) -azetidin-2-one

<^ s

(78)

A stirred solution of 1.6 g of the alcohol is treated (77) in 100 ml of anhydrous tetrahydrofuran with 1.07 S 2,6-lutidine and 1.19 g of thionyl chloride in 20 ml of tetrahydrofuran at -20 ⁰ C and stirred for a further 20 Minutes. The mixture is then filtered, the solvent is evaporated off and the residue is dried by azeotropic distillation twice with toluene. The residue is then dissolved in 100 ml of dioxane, and 1.01 g of 2,6-lutidine and 2.62 g of triphenylphosphine are added. The reaction mixture

809838/0942

.423-

is stirred overnight at room temperature and then filtered. After evaporation of the solvent and chromatography of the residue, after decolorization with activated charcoal in a solution of ethanol and ethyl acetate, the compound (78) is obtained, which is triturated with ether after evaporation. 1 * 5 S (= 53 % of theory) of a pale yellow solid with a melting point of 182-183 ° C. is obtained.

" ¹

IR spectrum in CHCl,: i? „= VJhQ, 1620, 1525 and 1355 cm

Analysis for C ₅₅ H ₂₉ N ₂ O ₅ P:

ber .: found .:

(iii) Preparation of the 7-0xo-1-azabicyclo / 3.2.07hept-2-en-2- carboxylic acid p-nitrobenzyl ester

C. (*) H (*) N (%) 70 , 21 5, 14th 4, 96 70 , 26 "5, 33 4, 80

(78)

1.0 g of the phosphorane (78) in 50 ml of ethyl acetate is treated at room temperature with 1.5 ml of trifluoroacetic acid and then cools the ReaktionsgemJsjh to -7O ⁰ C. Then it passes ozone through the solution until it becomes slightly blue. Argon is then passed through the solution in order to remove excess ozone, and 0.51 S triphenylphosphine in 10 ml of ethyl acetate is then added. The reaction vessel is placed in an ice bath and the reaction mixture is stirred vigorously, and aqueous sodium bicarbonate solution is then added until the solution is weakly basic

809838/0942

■ Alk

■ ^ ² - 28115U

(pH 8). The organic phase is separated off, dried over anhydrous magnesium sulfate, filtered and left to stand for 150 minutes at room temperature. After evaporation of the solution, the gummy substance obtained is chromatographed on silica gel (Merck 60) with a particle size of less than 0.06 mm and eluted with a mixture of 1 part of ethyl acetate and 1 part of petroleum ether with a boiling point of 60 to 80 ° C. 0.21 g (= 41 % of theory) of the compound (79) is obtained as yellow crystals with a melting point of 144-147 ° C.

UV spectrum in ethanol: X. _mQV = 270 nm (£ = 13550). IR spectrum in CHCU: v> = I78O, 1720, 1610, I525 and

_p max

I35O cm ".

NMR spectrum in CDCl ₅ : δ = 2.55-3.15 (2H, m, C4-H ₂ ); 2.95 (IH, dd, J = 16 and 3 Hz, C6-H); 3.50 (IH, dd, J = 16 and 6 Hz, C6-H); 4.10-4.40 (IH, m, C5-H); 5.21 and 5.41 (2H, ABq, J = 12 Hz, CH ₂ PhPNO ₂ ); 6.53 (IH, t, J = 2.5 Hz); 7.55 (2H, d, J = 8 Hz); 8.15 (2H, d, J = 8 Hz).

Analysis for Ci ^ H · ,, •
• < C (Ji) H (#) N (*) •
• 58.3 4, 2 9, 7th ₂ N ₂ 0 ₅ : 58.2 4, 2 9, VJl M ⁺ calculated for C ber .: found: 288.0746 288.0773 2 ^N 2 ° 5 ber. found '14 ¹¹ I.

809838/0942

Example 26

(i) Preparation of 4-allyl-l- (l-phthalidyloxycarbonyl-l tris- (p-methoxyphenyl) -phosphoranylidene-methyl) -azetidin- 2-one

ra

\ / (80)

(18)

6.3 g of allyl azetidinone (18), 5.52 g of glyoxalic acid monohydrate, * 30 ml of anhydrous dimethylformamide and 30 3 * 175 mm pellets of a molecular sieve with 0.4 nm pore size are stirred together for 6 hours at room temperature. The mixture is then cooled to 0 ^° C. and 4.14 g of powdered potassium carbonate are added. The temperature of the reaction mixture is then allowed to rise to room temperature and it is stirred for a further 5 minutes. Then 12.8 g of bromophthalide are added and the mixture is stirred for 16 hours. The solution obtained is poured into 250 ml of 0.1 N hydrochloric acid and 250 ml of ethyl acetate. The organic layer is again with 250 ml of 0.1 N hydrochloric acid, then with 250 ml of saturated aqueous sodium bicarbonate solution and 250 ml of sodium

809838/0942

■ Α% ·

Washed chloride solution. Each wash water is extracted again with 250 ml of ethyl acetate. The united organic Extracts are dried over anhydrous sodium sulfate and evaporated under reduced pressure. 10 g of one are obtained Oil.

A stirred solution of this oil in 25Ο ml of anhydrous tetrahydrofuran is cooled under argon to -20 ⁰ C and then with J, 6 ml of 2,6-lutidine and then treated with 4.8 ml thionyl chloride in 30 ml of tetrahydrofuran. After stirring for 20 minutes at -20 ⁰ C, the temperature of the reaction mixture to room temperature is allowed to rise. The reaction mixture is then filtered and the deposited solid is washed with toluene. The filtrate and washing water are combined and evaporated to dryness under reduced pressure. The residue is dissolved in toluene and again evaporated to dryness in order to remove excess thionyl chloride.

The oil obtained is dissolved in 250 ml of anhydrous tetrahydrofuran and treated with 7.6 ml of 2,6-lutidine and 15 g of tris (p-methoxyphenyl) phosphine. After stirring for 16 hours, the mixture is filtered and the solvent is evaporated from the filtrate under reduced pressure. The filtered off is dissolved in 25Ο ml of ethyl acetate and 250 ml of 0.1 N hydrochloric acid and added to the evaporated filtrate. The organic layer is separated and washed with 250 ml of 0.1N hydrochloric acid and with sodium chloride solution. Each wash water is extracted with 250 ml of ethyl acetate. The combined organic extracts are dried over anhydrous sodium sulfate and concentrated under reduced pressure.

809838/0942

steams. Obtained after chromatography on silica gel and after eluting with mixtures of petroleum ether, ethyl acetate and dioxane one first 10 g of the desired phosphorane (8θ), which upon addition crystallized by ether. After recrystallization from a mixture of ethyl acetate and petroleum ether, 6.25 g of the is obtained Connection from pp. 136-139 °°.

IR spectrum in CHCl,: v> _β = 3000, 1780, 1745, 1β50, 16Ο5,

j max

Analysis for C ₅₇ H _521- PNOg:

calc .: 64.68

found: 64.98

1260 and 1115 cm C (%) N {%)

" ¹

5.58 5.24

2.04

2.13

(ii) Preparation of the 7-0xo-l-azabicyclo / 5.2.07hept-2-en-2-carboxylic acid phthalidyl ester

S ~ Lp- ^ λ.

(80). ~

0> 325 g of the phosphorane (80) are dissolved in 12 ml of a mixture of 5 parts of ethyl acetate and 1 part of trifluoroesslgic acid. The solution is allowed to stand 10 minutes at room temperature and then cools it at -7O ⁰ C. Then it passes ozone through the solution until it turns pale blue. Argon is then passed through the solution to remove excess ozone, and 0.17 g of tris (p-methoxyphenyl) phosphine in 2 ml of ethyl

809838 / 09A2

acetate. The temperature is then allowed to rise to ⁰ ° C. in an ice bath and the reaction mixture is carefully mixed with 10 ml of saturated potassium bicarbonate solution while stirring vigorously. The layers are separated and the aqueous layer is extracted twice with 10 ml of stylacetate each time. The combined organic extracts are predried over anhydrous sodium sulfate and then left to stand for 16 hours over a molecular sieve with a pore size of 0.4 nm and in the presence of 0.4 g of diisopropylaminomethyl polystyrene. The solution is then filtered and the solvent is evaporated off under reduced pressure. A yellow oil is obtained which is rapidly chromatographed on highly selective and extremely white, powdery magnesium silicate. After eluting with a mixture of 1 part of petroleum ether and 1 part of ethyl acetate, 17 mg of the phthalidyl ester (81) are obtained as a white solid.

IR spectrum in CHCl,: '\> _v = 1800, 1755, 1615 and 985 cm " ¹ .

_p uld.X

NMR spectrum in CDCl ₃ : ^ = 2.7-3.2 (3H, m, C4-H ₂ and C6-H _A ); 3.50 (IH, 2 χ dd, J = 6 and 17 Hz., C6-H _ß ); 4.23 (IH, m, C5-H); 6.49 and 6.62 (IH, 2 χ t, J = 3 Hz, C3-H); 7, ^ 5 and 7.51 (IH, 2 χ s, phthalidylmethine-H); and 7.55-7.95 (te, m, aromatic).

The concentrations of this compound required to inhibit the growth of the following bacteria will be listed below:

Organisms / ig / ml (agar) B. subtilis A 20th Citrobacter freundii E8 20th Enterobacter cloacae Nl 20th E. coli Olli 20th Klebsieila aerogenes A 20th 809838/0942

- Vf-

Port setting

Proteus mirabilis C977 Pseudomonas aeruginosa A Salmonella typhimurium CTlO Serratia marcescens US20 Staph. aureus oxford Staph. aureus russell

439.

28115H

20th

160 20 20 20 20

Example 27

7-0xo-1-azabicyclo / 5'2.Q7hept-2-en-2-carboxylic acid trimethylacetoxymethyl ester

CO ₂ CH ₂ OCOBu ¹

(i) 4-Allyl-1- (1-trimethylacetoxymethoxycarbonyl-1-triphenylphosphoranylidene-methyl) -azetidin-2-one

(18)

IH

CO ₂ H

JO ₂ CH ₂ OCOBu

(82)

CO ₂ CH ₂ OCOBu '

(83)

809838/0942

- / 130-

2.0 g of 4-allyl-azetidin-2-one (18) and 1.75 g of glyoxalic acid monohydrate are together with 10 ml of anhydrous dimethylformamide in the presence of a molecular sieve with a pore size of 0.4 nm stirred together for 6 hours. The mixture is then cooled in an ice bath and 1.31 g of powdered material are added Potassium carbonate. Then the temperature of the reaction mixture is allowed to rise to room temperature and it is stirred for 5 minutes, before adding 5 * 3 g of trimethylacetoxymethyl bromide. Man stir the reaction mixture overnight and then pour it into a mixture of 80 ml of 0.1N hydrochloric acid and 80 ml of ethyl acetate. the The organic phase is separated off and the aqueous solution is washed again with 5 ml of ethyl acetate. Ethyl acetate solutions are combined, washed with saturated aqueous sodium bicarbonate solution and then with sodium chloride solution and finally dried over anhydrous sodium sulfate. After evaporation under reduced pressure, 4.7 g of des are obtained crude ester (82) as a yellow oil.

4 ", 7 g of the crude ester (82) are dissolved in 80 ml of anhydrous tetrahydrofuran and stirred under argon at -20 ⁰ C. Then the solution was treated with 3> 7 ml of 2,6-lutidine and then in the course of 5 Minutes with a solution of 2.3 ml of thionyl chloride in 20 ml of tetrahydrofuran, then the temperature of the reaction mixture is allowed to rise to room temperature over 30 minutes and the reaction mixture is filtered, the separated pesticide is washed with anhydrous toluene and the combined filtrates are incorporated Traces of thionyl chloride are removed by taking up the residue in toluene and evaporating and repeating this operation, and the chloride (83) is obtained as

809838 / 09A2

brown oil.

281-5 A3A-

The chloride (8j5) is dissolved in 80 ml of anhydrous dioxane and treated with 8.2 g of triphenylphosphine and 3.7 ml of 2,6-lutidine. The reaction mixture is stirred overnight and then filtered. The piltrate is concentrated and redissolved in 100 ml of ethyl acetate. The solution is washed free of base with about 100 ml of 0.1N hydrochloric acid, then washed with sodium chloride solution and finally dried over anhydrous sodium sulfate. The solution is then evaporated and chromatographed on silica gel 60 with a particle size of less than 0.06 mm. After eluting with a mixture of ethyl acetate and petroleum ether of boiling range to 8O ⁰ C in a ratio of 7: 3 to obtain a foam which is dissolved in 20 ml Diäthylather. White crystals quickly separate out. After recrystallization from a mixture of ethyl acetate and petroleum ether with a boiling point of 60 to 80 ° C, ~ 5, Οβ g of 4-allyl-l- (l-trimethylacetoxymethoxycarbonyl-l-triphenylphosphoranylidene-methyl) -azetidin-2-one are obtained (84) from pp. l40-142 ⁰ C.

IR spectrum in CHCU: 0 = 2980, 1740 and 16 ^ 5 cm " ¹ .

J UlaX

(ii) 7-0xo-1-azabicyclo / 5.2.Q7hept-2-en-2'-carboxylic acid trimethylacetoxymethyl ester

C0 ₂ CH ₂ 0C0Bu ^above
(84) (85)

80 9 838/0 9 A2

28H514

A solution of 0.50 g of 4-allyl-l- (l-trimethylacetoxymethoxycarbonyl-l-triphenylphosphoranylidenemethyl) -azetidin-2-one (84) in 15 ml of ethyl acetate is ^{stirred in a bath at +10 0} C and then with 5 ml of trifluoroacetic acid treated. After I5 minutes the solution is cooled to -78 ⁰ C and passes through ozone ^ until the reaction is completed. Excess ozone is expelled with a stream of argon and an ethyl acetate solution of 0.24 g of triphenylphosphine is then added. After 50 minutes, the reaction vessel is placed in an ice bath and 40 ml of ethyl acetate are added to the reaction mixture, followed by 90 ml of saturated aqueous sodium bicarbonate solution with vigorous stirring. The ethyl acetate phase is separated off immediately, washed with sodium chloride solution and dried with calcium chloride by stirring for 15 minutes. The solution is then filtered and a molecular sieve with a pore size of 0.4 nm is added. The supernatant solution is concentrated 3 hours later and rapidly chromatographed on a small column of silica gel 60 with a particle size below Ο, Οβ mm. It is eluted with a mixture of 1 part of ethyl acetate and 1 part of petroleum ether with a boiling point of 60 to 80.degree. A further cleaning is carried out on a small column with magnesium silicate with a grain size of 0.05 to 0.075. mm. It is then eluted with a mixture of 35 parts of ethyl acetate and 7 parts of petroleum ether with a boiling point of 60 to 80.degree. 0.022 g of 7-oxo-1-azabicyclo ^ are obtained. 2.O / liept ^ -en ^ -carboxylic acid trimethylacetoxymethyl ester (85) as a colorless rubber-like substance.

IR spectrum in CHCl,: -0 _v = 2970, 1790, 1750 and 160 cm " ¹ .

2 max

809838/0942

NMR spectrum In CDCl ,; T = 3.51 (IH, t, J = 3 Hz, C3-H) j 4.15 and 4.24 (2H, ABq, J = 5.5 Hz, OCH ₂ O); 5.78 (IH, tdd, J = 9, 5.5 and 3-Hz, C5-H) i 6, ^ 4 (IH, dd, J = 17 and 5.5 Hz, C6-H); 7.03 (IH, ddd, J = 19, 9 and 3 Hz ^ C4-H); 7.10 (IH, dd., J = 17 and 3 Hz, C6-H); 7.31 (IH, ddd, J = I ^, 9 and 3 Hzj C4-H); and 8.80 (9H, s, t-butyl).

M ⁺ at m / e for C ₁₅ H ₁₇ NO ₅ :

ber .: 267.1107 found: 267.1118

809838/0942

Claims (2)

-1. Esters of 7-0xo-l-azabicyclo / 3 ^ 2.07hept-2-en-2-cartonic acid and their derivatives substituted in the 3- and / or 6-position of the general formula II (II) CO ₂ R ₁ in which the group -CO ₂ R _{1 is} an esterified carboxyl group, A _{1 is} a hydrogen atom or the methyl group and .A _{2 is} a hydrogen atom or the radical -CR ₂ R ^ Ri, where R _{2 is} a hydrogen atom or the hydroxyl group is, R ^ is a hydrogen atom or an alkyl radical having 1 to 8 carbon atoms and Rh represents a hydrogen atom, the benzyl or phenyl group or an alkyl radical with 1 to 8 carbon atoms or, together with R ^, forms a carbocyclic ring with 5 to 7 carbon atoms or for a radical of the general formula -CH (OH) R ₁ - or - CHX. in which R ^ is a hydrogen atom or an alkyl radical with 1 to 8 carbon atoms and X is an oxygen atom or the radical ^ CRgR ₇ , where Rg is a hydrogen atom, the nitrile or phenyl group, an alkyl radical with 1 to 8 carbon atoms or one of the Radicals -CO ₂ Rn or -CO.Ro, in which Rg stands for the benzyl or phenyl group or for an alkyl radical with 1 to 8 carbon atoms, and R "denotes a hydrogen atom or an alkyl radical with 1 to 8 carbon atoms or together with Rg a carbocyclic one 809838/09 ^ 2 Λ- Forms a residue with 5 to 7 carbon atoms. λ ο ι ι γ ι / Zo I I ο I 4 2. Esters according to claim 1 with the general formula III in which R and A _{1 have} the meanings given in claim 1. J. Ester according to Claim 2, characterized in that the radical A ₁ in the general formula III is a hydrogen atom. 4. Esters according to claim 1 with the general formula IV R -> -? C * _ _. (IV) in which R ₁ , R ₂ J R- * and R ₁ have the meanings given in claim 1. 5 · Esters according to claim 4, characterized in that in the general formula IV the radical R ₂ ^ is a hydrogen atom, the methyl, ethyl, n-propyl, phenyl or formyl group or one of the radicals -CH = CHCO ₂ RqJ -CH = CHCORq or -CH = CHR ₁₀ , where R _{9 is} the methyl, ethyl or benzyl group and R _{10 is} a hydrogen atom or the methyl, ethyl or benzyl group 809838/0942 6. Esters according to claims 4 or 5> characterized in that in the general formula IV the radical Rj is a hydrogen atom or the methyl, ethyl or benzyl group. 7 · Esters according to at least one of claims 4 to 6, characterized characterized in that in the general formula IV the radical R ^ is a hydrogen atom or the methyl group. 8. Esters according to at least one of claims 4 to 7 * thereby characterized in that in the general formula IV the radical Rh is a hydrogen atom or the methyl group. 9. Esters according to claim 4 with the general formula V. X = CH-CH ₀ ² V ^ \ (V) in which R and X have the meanings given in claim 4 own. 10. Ester according to claim 9? characterized in that in of the general formula V the radical X is an oxygen atom. 11. Ester according to claim 9, characterized in that in the general formula V, the radical X is the radical -CK ^ Kj , where R / - and K _{7 have} the meanings given in claim 1. 809838/09 ^ 2 12. Ester according to claim 11, characterized in that in the general formula V the radical -CR ^ ilj is one of the radicals = CHCOR _q or = CHCOpRq, where R _{Q has} the meanings given in claim 5. 13. Ester according to claim 11, characterized in that in the general formula V the radical = CR ^ Rj is the group = CHCN. 14. Esters according to claim 4 with the general formula VI OH (VI) in which R, which has the meanings given in claim 4, R _{11 is} a hydrogen atom or an alkyl radical having 1 to 8 carbon atoms and R-, ρ is a hydrogen atom or an alkyl radical having 1 to 8 carbon atoms. 15. Ester according to claim 14, characterized in that in the general formula YI the radical R _{11 is} a V / water atom or the methyl group. 16. Ester according to claims 14 or 15, characterized in that in the general formula VI the radical R _{12 is} a hydrogen atom or the methyl group. 17 · Esters according to claim 4 with the general formula VII 809838/0942 ^R 13 " ^CH 2 _r _ 28115U • 5- (VII) in 'the R, has the meanings given in claim 4 and R, -, a hydrogen atom or the methyl, ethyl or Is hydroxymethyl group. 18. Ester according to at least one of claims 4 to IJ, characterized in that the ß-lactam ring has the cis configuration. 19 esters according to at least one of claims 4 to 17, characterized in that the ß-lactam ring has the trans configuration having. 20. Esters according to at least one of claims 1 to 19 *, characterized in that in the general formulas II to VII the radical R _{1 is} an alkyl radical having 1 to 12 carbon atoms, an alkenyl radical having 1 to 8 carbon atoms, an alkynyl radical having 1 to 8 carbon atoms or the phenyl or benzyl group, it being possible for the aforementioned radicals to be substituted by halogen atoms, nitro groups and / or alkoxy or acyloxy radicals, each having 1 to carbon atoms. 21. Esters according to at least one of claims 1 to 19 * characterized in that in the general formulas II to VII 80S838 / 09Ä2 • feder radical R _{1 is} an alkyl radical with 1 to 8 carbon atoms, which is substituted by an alkoxy radical having 1 to 8 carbon atoms can be. 22. Ester according to at least one of claims 1 to 19, characterized in that in the general formulas II to VII the radical R _{1 is} the benzyl group which can be substituted by a chlorine atom, the nitro group or an alkoxy radical having 1 to 8 carbon atoms. 23. Esters according to at least one of claims 1 to 19 * thereby characterized in that in the general formulas II to VII the radical R- is a radical of the sub-formulas (a) or (b) (away) in which k is a hydrogen atom or the methyl group, Au denotes the phenyl, phenoxy, benzyl or benzyloxy group or an alkyl or alkoxy radical each having 1 to 8 carbon atoms, A ₁ - a hydrogen atom or the methyl or methoxy group represents and Ag represents a hydrogen atom, the methyl or methoxy group. 24. Esters according to at least one of claims 1 to I9, characterized in that in the general formulas II to VII the radical R _{1 is} the benzyl group. 809839/0942 -iss- 281T5U 25. Esters according to at least one of claims 1 to 19 »characterized in that in the general formulas II to
VII the radical R ₁ is the p-nitrobenzyl group. 26. Esters according to at least one of claims lq to 19, characterized in that in the general formulas II to
VII the radical R _{1 is} the phthalidyl group. 27. 6- (2-0xoethyl) -7-oxo-l-azabicyclo ^ .2.07hept-2-en-2- benzyl carboxylate. 28. 6- (3-Methoxycarbonyl-2-propen-1-yl) -7-oxo-1-azabicyclo-.2.0_7hept-2-en-2-carboxylic acid benzyl ester. 29 6- (3-methoxycarbonyl-2-propen-l-yl) -7-oxo-1-azabicyclo- 30. 6- (2-Hydroxy-2-propyl) -7-oxo-1-azabicyclo / ^. 2.07hept-2-en-2-carboxylic acid benzyl ester. 31. 6- (1-Hydroxyethyl) -7-oxo-1-azabicyclo ^ 5.2.O / hept-2-en-2-carboxylic acid benzyl ester. 32. 6- (1-Hydroxy-1-phenylmethyl) -7-oxo-1-azabicyclo ^ ,, 2.o7-hept-2-en-2-carboxylic acid benzyl ester o 33 6- (l-Hydroxycyclohex-l-yl) -7-oxo-l-azabicyclo ^ 3.2.07hept-2-en-2-carboxylic acid benzyl ester " 809838/0942 28115U 34. 6-Benzyl-7-oxo-1-azate) icyclo _i /^ '2.o7hept-2-en-2-carboxylic acid benzyl ester. 35 o
acid benzyl ester. 3β. 6 - (^ - methoxycarbonyl-2-propen-l-yl) -7-oxo-l-azabicyclo- ^ .2.07hept-2-en-2-carboxylic acid phthalidyl ester. 37. 6 - (^ - Methoxycarbonyl - ^ - propen-1-yl) -7-oxo-l-azabicyclo- ^ .2.07hept-2-en-2-carboxylic acid phthalimidomethyl ester. 38. 6- (2-Oxoethyl) -7-oxo-1-azabicyclo / ^ ". 2.07hept-2-en-2-carboxylic acid phthalidyl ester. 39. 6- (4-0xo-2-pehten-1-yl) -7-oxo-1-azabicyclo / J.2. ^ 7hept-2-en-2-carboxylic acid phthalidyl ester. 40. 6- (3-Methoxycarbonyl-2-propen-1-yl) -7-oxo-1-azabicyclo- - 2.07hept-2-en-2-carboxylic acid trxmethylacetoxymethyl ester. 41. 6- (3-Methoxycarbonyl-2-propen-1-yl) -7-oxo-1-azabicyclo- / 3.2.07-hept-2-en-2-carboxylic acid p-nitrot> enzyl ester. 42. 6- (3-Cyano-2-propen-1-yl) -7-oxo-1-azabicyclo / ^ ". 2. £ 7hept-2-en-2-carboxylic acid-benzyl sulfcer. 43. 6- (4-Oxo-2-penten-1-yl) -7-oxo-1-azabicyclo / 3.2.o7hept-2-2-carboxylic acid benzyl ester. 809838 / 09Ä2 44. 6- (3-methoxycarbonyl-2-propen-l-yl) -7-oxo-l-azabicyclo- 2.07hept-2-en-2-carboxylic acid p-bromophenacyl ester. 45. 6- (5-Cyano-2-propen-1-yl) -7-oxo-1-azabicyclo / 5.2. 2-en-2-carboxylic acid phthalidyl ester. 46th T
benzyl ester. 47. 7-0xo-1-azabicyclo / J.2.07hept-2-en-2-carboxylic acid tert-butyl ester. 48. 3-Methyl-7-oxo-1-azabicyclo / J.2.07 ^r tert-butyl hept-2-en-2-carboxylate. 49. 3-Methyl-7-oxo-1-azabicyclo / 3.2.07hept-2-en-2-carboxylic acid p-nitrobenzyl ester. 50. 7-0xo-l-azabicyclo / 5.2.07hept-2-en-2-carboxylic acid methyl ester. 51.7-0xo-l-azabicyclo / 5 · 2.07hept-2-en-2-carboxylic acid ep-nitrobenzyl ester. 52. 7-0xo-1-azabicyclo ^ '. 2.07hept-2-en-2-carboxylic acid phthalidyl ester. 53 · 7-0xo-l-azabicyclo _ί / 3 · 2o07hept-2-en-2-carboxylic acid trimethylacetoxymethyl ester. 809838/09 ^ 2 54. Process for the preparation of the esters according to claim 1, characterized in that a compound of the general Formula VIII U ^ yea ά a ^ VIlX; CO ₂ R ₁ in which R ,, A, and Ap have the meanings given in claim 1 and A ₇ , Ag and Aq are phenyl or methoxyphenyl groups or lower alkyl radicals, with cleavage of a compound O = PA ₇ AgAq carries out a ring closure reaction. 55 · Process according to claim 54, characterized in that a compound of the general formula VIII is used in which A ₇ , Ag and A _{Q are} all phenyl groups. 56. The method according to claim 54, characterized in that a compound of the general formula VIII is used in which A ₇ , Ag and A "are all p-methoxyphenyl groups. 57. The method according to any one of claims 54 to 56, characterized characterized in that a compound of the general formula VIII is used in which Ap is a hydrogen atom. 58. The method according to any one of claims 54 to 57, characterized characterized in that a compound of the general formula VIII is used in which A, is a hydrogen atom. 809 838/0942 59 · Process according to one of claims 5 ^ to 58 1, characterized in that a compound of the general formula VIII is used in which A _{2 is} the radical -CRgR ^ R ^, where R ₂ , R, and R ₁ , which are in Claim 1 have given meanings. 60. A method for producing an ester according to claim 4, characterized in that a compound of the general formula XI is used in the form of its ion (XI) CO ₂ R ₁ in which A " _s Ao, A" and R, which have the meanings given in claims 5 ^ to 56, with a compound of the general formulas XII, XIII or XIV (XII) CH-Y (XIII) (XIV) converts, in which R- ,, Rh and Rf- those specified in claim 1 Have meanings and Y denotes a radical which can be easily replaced by a nucleophilic radical. 809838 / 09A2 28115U 61. The method according to claim 60, characterized in that that a compound of the general formula XIII is used in which Y is a chlorine, bromine or iodine atom. 62. Pharmaceutical preparations, characterized by a Content of at least one ester according to claims 1 to 55 63. Pharmaceutical preparations according to claim 62, characterized by a content of 50 to 500 mg of at least one ester of claims 1 to 55 64. Pharmaceutical preparations according to claims 62 or 63, characterized by an additional content of pharmacologically acceptable carrier materials, diluents, excipients and / or additives. 65. Pharmaceutical preparations according to claims 62 to 64, characterized by a content of at least one Penicillin and / or cephalosporin as an additive. 809838/0942