CS216192B2 - Method of making the 2-+l 7-oxo-2,6diaza-4-oxa-bicyclo+l3,2 p hept-2-en-6-yl+p buten acids - Google Patents

Abstract

PURPOSE:To prepare the title cpds. easily, useful as intermediates for 1-oxadithia-3cephem-4-carboxylic acid having an optional substituent at the 3-methyl gp. as antibacterials, by halogenation or substituent interchange of the corresponding methyl cpds.

Description

The present invention relates to a process for the preparation of oxazolinoazetidinylpentenoic acid derivatives, in particular 2- [7-oxo-2,6-diaza-4-oxabicyclo [3.2.0] hept-2-en-6-yl) butenoic acids.

Oxazolinoazetidinylpentenoic acid derivatives of formulas II and IV '

(II)

R '' /

-Z-CH ₂ X (IV).

in which

R 'represents a hydrogen atom, an alkyl group, an aryloxyalkyl group, an aralkyl group or an aryl group,

Z 'represents the rest of the formula

CH 2 CH 3 —CH — C— or —C = C—

COB COB where

COB 'means a carboxyl group; or. protected carboxyl group,

Hal represents a halogen atom and

X 'represents a nucleophilic group, as described in our Czechoslovak patent specification 216,191, according to which these compounds are prepared from 2-subst. methyl 6α-amidopenamide derivatives by the action of heat and preferably a desulfurizing agent such as triphenylphosphine. However, the starting 6-epipenicillins containing a substituted methyl group on the penam nucleus are somewhat difficult to prepare, so. this procedure is not very suitable for practice. In order to solve this problem, the present inventors have sought more straightforward processes for the preparation of the above compounds by finding a new halogenation process and nucleophilic substitution, resulting in the formation of the desired compounds in a more expedient manner than allowed by the prior art. These efforts result in the procedures disclosed and protected in our related Czechoslovak patent specification 216,193 describing halogenation, and in this patent, which relates to the replacement of the below group Y by the action of a nucleophilic agent by another nucleophilic group within the meaning of the symbol X.

The differences between the earlier procedure and the procedure of the two related patents result from the following reaction schemes:

(Previous procedure)

(Procedures according to the aforementioned related patents)

RC

снссн _ъ сов

0 ^

NCHCCH3 Hal

COB © —НСНССН ^

CO0

The base can be used to induce the migration of the double bond at the (3) position and the nucleophilic group X may be replaced by another nucleophilic group X, by substitution or other reactions to give the desired compounds.

The produced compounds are used to prepare potent antibacterially active 1-dethia-1-oxacephalosporins as described below.

The compounds of formulas (II) and (IV ') can also be prepared by another synthetic method, for example by treating triphenylphosphine with 6-epipenicillin-1-oxides bearing a nucleophilic group on the methyl group attached to the 2-position of the penam core. However, the introduction of a suitable nucleophilic group on the methyl group at position 2 of the penam core is generally _; difficult, and our two related Czechoslovak patents disclose a preferred alternative process for preparing the subject compounds.

The present invention provides a process for the preparation of 2- (7-oxo-2,6-diaza-4-oxabicyclo [3], 2,0] hept-2-en-6-yl) butenoic acids of the general formula IV

R

in which

R represents a phenyl group optionally substituted by an alkyl or alkoxy group containing from 1 to 3 carbon atoms, a nitro group, a cyano group or a halogen atom, a phenylalkyl group having 1 to 3 carbon atoms in the alkyl moiety or a phenoxyalkyl group having 1 to 3 carbon atoms in the alkyl moiety;

Z represents a divalent radical of the formula

CH2CH3 —CH — C-- or - C = C-

II

COBCOB where

COB represents a carboxyl group or a carboxyl group protected in the form of an ester, for example the tert-butyl ester, the benzyl ester or the diphenylmethyl ester, and

X represents a halogen atom, a hydroxyl group, an alkanoyloxy group having 1 to 4 carbon atoms, optionally substituted with 1 to 3 halogen atoms, a nitrooxy group, a phenylthio group, a phenylsulfinyl group or a 1-alkyl-5-tetrazolylthio group having 1 to 3 carbon atoms; wherein the compound of formula III

in which

R and Z are as defined above and

Y represents a halogen atom or a nitro group, reacted with a nucleophilic agent replacing the residue Y by a residue X different from the residue Y.

The protected carboxyl group within the meaning of the COB moiety may generally be any protected group commonly used in β-lactam chemistry. Generally, the carboxyl group in the COB moiety is protected in the form of an ester, including an alkyl ester such as methyl, ethyl, tert-butyl or cyclopropyl ethyl ester, aralkyl ester such as benzyl ester, phenyl ester, diphenylmethyl ester or trityl ester, such as aryl ester, such as trimethylsilyl ester, ethoxydimethylsilyl or trimethylstannyl ester, or the like esters, amide (such as dilsopropylhydrazide), salt, anhydride or acid halide. The protecting moiety B may contain further substituents, in particular halogen atoms, hydroxyl groups, acyloxy groups, oxo groups, acylainino groups, nitro groups, alkyl groups, carboxyl groups, alkoxycarbonyl groups, cyano groups, carbamoyl groups, acyl groups and the aryl moiety also includes heteroaromatic moieties cyclic groups.

The protecting group is generally cleaved by a subsequent reaction and its structure can be varied widely without departing from the spirit and scope of the invention. However, in accordance with the invention, a preferred protected carboxyl group in the meaning of the COB moiety is a carboxy group protected in the form of an ester, for example the tert-butyl ester, the benzyl ester or the diphenylmethyl ester.

Generally, the nucleophilic group of X and Y may be any group introduced in place of the acetoxy group at the 3-position of the cephalosporins. Representative examples of such groups include halogen atoms (e.g., chlorine, bromine or iodine), hydroxyl, acyloxy (e.g., nitro, formyloxy, acetoxy, trifluoroacetoxy, p-4-cycloxypyridyl, n-haloacetoxy, alkyloxy, carbonyloxy, methoxy, ethoxy or tetrahydropyranyloxy), thiocarbamoylthio alkylthio, trylthio (for example, the corresponding heteroaromatic group including 1-alkyl- or 1-substituted-alkyl-5-tetrazolylthio, 1,3,4-thiadiazol-5-ylthio) -1,3,4-thiadiazol-5-ylthio, 1,2,3-trioazol-4-ylthio, 1-alkyl-5-hydroxy-6-oxo-1,6-dihydro-1,3,4-triazine -2-ylthio groups), alkylsulfin groups, arylsulfinyl groups or similar nucleophilic groups. However, in accordance with the invention, preferably Y and X have the meanings given above.

If the radicals R, COB, X and Y contain portions subject to undesired side reactions, such portions may be protected before the reaction itself and deprotected after the reaction. This case is also within the scope of the invention.

The reaction of the invention is carried out by contacting a compound of formula III with a nucleophilic agent in a solvent. Typical nucleophilic agents include free acids or acid salts selected from the group consisting of alkali metal salts (e.g., lithium, sodium, and potassium salts), heavy metal salts (e.g., silver, mercury, lead and copper salts), organic base salts (e.g. salts with triethylamine and 1,1,3,3-tetramethylguanidine), and quaternary ammonium salts (e.g. tetraethylammonium salts, zylammonium salts and methyltriphenylphosphonium salts) of carboxylic acids (e.g. formic acid, acetic acid, propionic acid, pivalic acid and benzoic acid) ), mercaptans (e.g., phenylmercaptan, 1-methyltetrazazole-5-mercaptan, 1-methylsubstituted-5-mercaptan, 2-mehilyl-1β-thiacΠazole-5-mercaptan, 1,3,4

-thiadiazole-S-1-t-capsule, 1-mp-2-thiazole-M216192

mercaptan and 1-methyl-4-hydroxy-5-oxo-1,6-dihydro-1,3,4-triazin-2-yl-mercaptan), sulfenic acids (e.g. phenylsulfenic acid), hydrogen halides and the like of acids.

The reaction described above is preferably carried out in an internal solvent. Representative examples of suitable solvents include hydrocarbons (e.g. pentane, hexane, cyclohexane and benzene), halogenated hydrocarbons (e.g. methylene chloride, ethylene chloride, chloroform, carbon tetrachloride and chlorobenzene), carbon disulphide, ethers (e.g. dirthyrether, 1,2-dimethoxyl ethane) , tetrahydrofuran and dioxane), esters (e.g. methyl acetate, ethyl acetate, isopropyl acetate and methyl benzoate), nitriles (e.g. acetonitrile and benzonitrile), amides (e.g. dimethylformamide, dimethylacetamide and hexamethylHosfortriamide), carboxylic acids (e.g. formic acid and acetic acid), bases (for example pyridine and quinoline), alcohols (for example methanol, ethanol and tert-butanol) and other inert solvents used in organic reactions as well as water, and mixtures of these solvents.

Of these solvents, polar solvents assisting ionic reactions, such as alcohols, amides, sulfoxides, ketones, nitriles, nitrated hydrocarbons, or various aqueous solvents are preferred.

The reaction may be carried out at a temperature of, for example, -30 ° C to 70 ° C (for the introduction of hydroxide ion) and is usually carried out at a temperature around room temperature. Under these conditions, the reaction time is from one hour (chlorine replacement with iodine) to 20 hours (chlorine replacement with a formyl group), and can be operated under an inert gas atmosphere and / or with stirring if necessary.

The reaction may be accelerated by the addition of crown ether (e.g., dibenzo-18-crown-6-ether or cyclohexyl-18-crown-6-ether) or another phase transfer catalyst (e.g. and onium bromide), or by increasing the anionic strength. In some cases, irradiation with light may also accelerate the reaction.

The products of formula (IV) can optionally be converted into compounds within or outside the scope of formula (IV) by various modification reactions. Such modification reactions include, for example, acid or base hydrolysis, oxidation with various oxidizing agents such as peroxides, reduction with reducing agents such as sodium borohydride or triphenylphosphine, heat, acid or base rearrangements, or the like.

For example

1. a product in which X is an alkanyloxy group can be converted by hydrolysis to a compound of formula IV in which X is a hydroxyl group;

2. the product in which X is a phenyl group may be treated with an oxidizing agent, such as a peracid, to form a compound of formula IV wherein X is a pheaylsulfinyl group, then rearranged with a base to form a compound of formula IV, in which X represents a γ-γ-n-oxy group which then hydrolyzes to give the corresponding compound having a hydroxyl group as X;

3. the product in which X is chlorine or bromine is reacted with sodium iodide to form a compound of formula II or IV in which X is iodine and then a heavy metal salt (e.g., silver nitrate, silver trillurethate, copper acetate) , lead acetate or copper nitrate), or an alkali metal perchlorate, to form a compound of formula IV wherein X is hydroxy or alkanyloxy. The acylates can then be hydrolyzed, for example by treatment with a base.

The products prepared by the above reactions can be isolated, for example, by concentration, extraction, washing or other conventional methods used to remove solvents, unreacted starting materials, by-products and other impurities, and then purified by reprecipitation, recrystallization, chromatography, adsorbent treatment or other conventional way.

Occasionally, double bond migration or isomerization may occur during the above-mentioned treatment. However, such cases are also within the scope of the invention.

The products produced by the process of the invention may be used as starting materials for the preparation of useful aatibacterially active 1-dethial-11-oxa-naphorosporins, for example by converting the residue X into a hydroxyl group or converting an exomethyleate into a vicialatio diol moiety. derhialllnxacelamderivatives, then introducing the double bond into the nucleus of these compounds and finally reconfiguring the amine function (7a) to give the desired 7 (381 ™ group) as described in the following reaction scheme:

Ph

Pb

N ^ o

X /) I

COB

0 '

Ph n

OsO4C * KCtO

* acid

'C HOH: ^KYS6JIN . I 5 ² '<....

—NCHCCH2X. OH bOB

SOCl _of v

C-X

I k cos

CH 3 OH

CCH}

PhCONH acid (X = H)

COB

COB

In this reaction scheme, X and COB are as defined above, Ph is phenyl and tBu is tert-butyl.

The invention is illustrated by the following non-limiting examples. . In all schemes and individual residue patterns, Ph is phenyl.

The nucleus structure, position numbering and nomenclature used for some compounds in the examples is based on the (1R, 5S) -7-oxo-4-oxa-2,6-diazabicyclo [3.2.0] hept-2-ene nucleus of the corresponding- formula

PhCCOH ^

Dt.BCCOl

2) C 6 H 3 O / CH 3 OH

IN

O

CW-H or X i

COB

Stereochemistry about carbon # 1 is identical to the stereochemistry of 6-epipenicillin at position 6, and stereochemistry about carbon # 5 is opposite to penicillins at position 5 and cephalosporins at position 6.

The stereochemistry around the α-carbon associated with the COB moiety is usually the same as that of penicillins, but the invention is not limited to this arrangement.

In the tables, the abbreviations and symbols have the following meanings:

Ac = acetyl

An = acetone

Ph == phenyl and q = aqueous —СвН4— = eenyeen

DMSO-dimethylaminobutyl KCl

DMF = М.Ы-ШтеШуИогтапМ

Et = ethyl

h == worthy (hours) i— = iso— min = minute (тЬпКу) pn = overnight refl. - reflux temperature tm ~ room temperature t— = teccUm!

Ts = p — CH3C6H4SO2—

Nucleophilic substitution

Example 11 - 1

The 2-oxazole mesazididinyl-3-sulfomethylbutenoates may be prepared from 2-oxazolinoazetidinyl-3-methylbenzenesate suitably substituted to the methyl group at the 3-position by reaction with a nucleophilic reagent under the reaction conditions outlined in Table 1 below.

The detailed embodiment illustrates the following procedure describing reaction # 53 in Table I:

V i

To a solution of 437 mg of diphenylmethyl- (2R) -2- (3-phenyl-7-oxo-4-oxa-2,6-diazabicyclo [3.2.0] hept-2-en-6-yl) -4- bromo-3-exomethylene butyrate in 10 ml of a 3: 1 mixture of acetone and methanol is added 250 mg of phenylmercaptan and 250 mg of sodium phenylmercaptide, stirred for 1 hour at room temperature and 1 hour at 35 ° C, then poured into water and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulphate and evaporated. The residue is chromatographed on a deactivated silica gel column. 10% water. Elution with mixtures of ethyl acetate and benzene (from 0: 1 to 1:10) gave 400 mg (yield 80%) of diphenylmethyl- (2R) -2- (3-phenyl-7-oxo-4-oxa-2,6-). diazabicyclo [3.2.0] hept-2-en-6-yl-3-phenylthiomethyl-3-butenoate.

CHCb

IC: ν 1787, 1755, 1636 cm -1.

max

COOCHPh-z

COOCHPh-

Table I (Part 1)

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CD CD

CM vM ttě

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R4 R1 1—1 I 1 1 R4 R4 ΓΙ R4 1 R1 1 R4 1 R4 1 r — 1 r ··! r-M pH 555 0 0 0 O O <5

Λ CM CM X · ω ( -R 1 α> д TJ * 0 1 ем Л си Д О | Л о < 1 ю Рч см Рч ем К ffi К о О ω OF 1 ( no

NazS2O3.5HžO (0.1)

C6H4NO2 — p - CHPh2 —Cl — I 0.49 An (10) Nal (0.41) tm 2.5 0.57

NazSíCk.5НгО (0.02)

o r4 number R ¹ R ² YX Ia solvent (ml) reagent temperature cais yield ______________________________________________________________ (g) __________________________ (g) СС (h) (g) (%) - C6H4CN — p - CHPh2 —Cl —I 0.50 An (6) Nal (0.5) tm 2 0.43 - —C6H4Cl — p —CHP12 - Cl —I 0.45 An (6) Nal (0.45) tm 2 0.45 - —Ph —CHPh2 - Cl - OH 0.20 DMSO (7) H2O (3) NaI (0.4) 45 16 0.07 39

I 18 8 8 8 N E 8

I ® 8. 1 1 1 1 1 Ί ¹ / —4 r-Γ CO

WHAT

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CM

CO bs in CM r-i

θ '

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X Ж Ж ООО

см л £ 3 J3 £ 3 £ а 3 я ем £ 3 ем £ 3 X Ой X Οι X X X CU X . X ж ж ж ж ж " ж ж WITH. Ж. / Ж о о о о о о о & ω ω

o o

см см см £ 3 £ 3 £ 3 см £ 3 см £ 5 XXX X X SIS Ж Ж UOU о ω

£ 3 £ 3 £ 3 £ 3 £ 3 £ 3 £ í £ Í £ 3 £! £} £ 3 £ 3 £ 3 £ 3 X X X X X X X X X X X XXX X X

СО bs 00 СП О гЧ г-г-4 гЧ СМ гЧ СМ СО

СМ СМ СМ СМ

О СО bs 00 см см см см

1П 00 o

со гЧ со number R ¹ R ² YX Ia solvent (ml) reagent mix time yield (g) (g) (° C) (4) (g) (θ / ο

СП U0 тН

rH U0 ш М <

ю

ЦО ш тН С? С \ Г r-Γ ГН

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ем • N ем см ем 4М см 33 см см ем см см ем ХЗ л ХЗ ХЗ хз | ХЗ XI X! ХЗ X ХЗ ХЗ AND а а а Он а О а Ой Oj а а а а а а CD Ж Ж Ж Ж Ж Ж Ж X X Ж Ж Ж Ж Ж Ж Ж о | CJ I CD | ω AND о AND ТГ CD I о | □ □ 1 1 no 1 CD 1 CD 1 ω 1 о I о | о I AND Q. а а 1 а 1 1 1 1 1 1 1 1 см 1 1 ХЗ ХЗ xs for CL4 (Ь X % ж О OF Г-М ч а ем а см, оо ХЗ ХЗ ХЗ ХЗ X ХЗ а см ж О of у Ж Ж ем. см • ΪΪ о о 1 1 а а а а а а ж о Ж ж ж СО CD % о о 1 1 1 1 1 1 сэ 1 о со и о ! 1 1

-СНгРЬ —CHPh2 —I —ONO2 0.22 п (2.2) AgNO1 (0.067) tm 1 0ДО9 —Ph —CHPh2 —Br —OCHO 0.053 CH2Cl2 (3) HCOOH (0.039) and 1.5 0.05 [( CH3) 2N] 2 CNH (0.115) м (о о <гэ

М * U0 со со со со

00ч 00 CD О гН СО СО СОМ * М *

No. R ¹ R ² YX Ia solvent (ml) reagent temperature time yield ___________________________________________________________________ (g) ______________ ___________________ (g) _____________- C) (h) (g) (Q / o —Ph —CHPh2 —I —OCOCFs 0.5 HCON (CH3) 2 AgOCOCF ₃ tm 1 0.45 92 (8) (0.21)> 2 —-Ph —CHPh2 — CI — SCeHs 2.03 An (12) PhSNa (0.8) 5 2/3 150 64

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Table I (Part

O O O < X X X t — 4 D O O O f ° 1 O O i o

O 1 O 1 O 1 at 1 ϊ Ϊ 43 Λ £ 1 43 43 43 Pu CM % Pj Du oq cu tu E E E E KS O O O O o o

43 43 43 43 43 43 (AT Cu here here CU here

r-Γ CO

CO 5K in. CO o

WHAT

PH '' fM

CHCCH3 SPh.

ČOOCHPh. _of (13)

PH

I- in ^HI- l_JpHCCH ₂ SPH

COOCHPbz (11)

CH10H ____>

Various modifications

Example III-1-chloroperbenzoic acid

Pii nA)

H \ nnchcch ₂ oh

COOCHP / 1 ₂

A solution of 220 mg of m-chloroperbenzoic acid in 7 ml of chloroform is added dropwise to a solution of 703 mg of compound (12) in 14 ml of chloroform, stirred for 10 minutes, then mixed with 700 mg of triphenylphosphine and 70 μΐ of methanol and temperature 75 ° C. After completion of the reaction, the reaction mixture was evaporated under reduced pressure and the residue was chromatographed on 30 g of deactivated 10% water. Elution with benzene containing 20-30% ethyl acetate and concentration of the eluate gave 401 mg (68 percent) of the title compound (14).

Example III - 2

Ph N? O t t

л \

CH ₂

II * l _of 0C0CF ₃

COOCHPbz

SiO *

СН ₂ С1 ₂ СН ₅ 0Н

H

L-NCHCCH ₂ OH

AND

C0QCHPh ₂

240 mg of diphenylmethyl- (2R) -2- (3-phenyl-7-oxo-4-oxadiazabicyclo [3.2.0] hept-2-en-6-yl) -3-trifluoro-acetyloxymethyl- 3-Butenoate in 10 ml of methanol / methylene chloride (4: 1) was added 4.8 g of silica gel containing 10% water, stirred for 30 minutes and then filtered. The filter cake formed by silica gel is washed several times with a mixture of methanol and methylene chloride, and the filtrate is combined with the washing liquids.

AND·

ČOOCHPhg.

and evaporated under reduced pressure. The oil-yellow residue is chromatographed on 12 g of silica gel. Elution with benzene / ethyl acetate (2: 1) afforded 106 mg (53% yield) of diphenylmethyl- (2R) -2- (3-phenyl-7-oxo-4-oxa-2,6-diazabicyclo [3.2.1] O] hept-2-en-6-yl) -3-hydroxymethyl-3-butenoate and 90 mg (35% recovery) of the starting material.

Example III - 3

— I — i №

L ^ nchcch ^ oh

C00CHPf2 _z

Diphenylmethyl - (2R) -2- (3-phenyl-7-oxo-4-oxa-2,6-diazabicyclo [3.2.0] hept-2-en-6-yl] -3-iodomethyl-3- butenoate is reacted with calcium carbonate and silver nitrate to form a diphenylmethyl- (2R) -2- (3-phenyl-7-oxo-4-oxa-2,6-diazabicyclo [3.2.0] hept-2) mixture -en-6-yl] -3-hydroxymethyl-3-butenoate and diphenylmethyl (2R) -2- (3-phenyl-7-oxo-4-oxa-2,6-diazabicyclo [3.2.0] Hept-2-en-6-yl] -3-nitro-oxymethyl-3-butenoate in a ratio of 1: 3. This mixture is dissolved in

4.5 ml of methylene chloride, 0.5 ml of acetic acid and then 300 mg of zinc are added dropwise to the solution, and the resulting mixture is stirred at 0 DEG C. for 15 minutes, diluted with methylene chloride, washed with water and evaporated. The residue is purified by thin layer chromatography to give 90 mg of diphenylmethyl- (2R) -2- (3-phenyl-7-oxo-4-oxa-2,6-diazabicyclo [3.2.0] hept-2-ene). 6-yl) -3-hydroxymethyl-3-butenoate.

The following is an example of the use of the compounds of the invention.

To a solution of 950 mg of crude diphenylmethyl- (2R) -2- (3-phenyl-7-oxo-4-oxa-2,6-diazabicyclo [3.2.0] hept-2-en-6-yl] - 3-hydroxymethyl-3-butenoate in 15 ml of methylene chloride is added at room temperature to 20 μΐ of boron trifluoride etherate, the mixture is stirred at the above temperature for 1.5 hours and then evaporated. 4: 1) 0.686 g (81% yield) of diphenylmethyl-7α-benzamido-3-exomethylene-1-oxa-1-dethiacepham-4α-carboxylate is obtained as a foam.

This material is isomerized with triethylamine to give diphenylmethyl-7α-benzoylamino-3-methyl-1-oxadethia-3-cephem-4-carboxylate.

The latter compound is treated with tert-butyl hypochlorite and lithium methoxide to give diphenylmethyl-7-i-benzoolamino-7α-methoxy-3-methyl-3-cephem-4-carboxylate.

Table 11 shows the physical constants of the compounds discussed in the specification and in the definition.

For NMR spectra, the abbreviations have the following meanings:

s - singlet d - doublet t = triplet q = quartet m = multiplet w = broad signal ω 'tti> Q

CO d4 f * o =

fO г N O (X ;O O OF O QllllllQ

Λ tú

Qi — 4

Zu 'o Q ω o ώ s z

Ю o X ω> ω

x cd e

О см <ф Гч 00 СО гЧ O σ> гЧ гЧ what what CM co r4 what т-Ч о со α 1П СО Г? cT Ю O cT co со τ — 1 ιη ο со -θ ' Гх ι-Ч СО гЧ R-4 co гЧ r θ 'τ — 1 2 1-4 Д i — 1 ч со ~ Гч ιη Гч Ю O гЧ WHAT Т 'Ч т-Ч 00 (X Гч т-Ч Гч r4 Гч »гЧ θ 'со 00 00 О) Гч СМ гЧ

со со со со 00 СО гЧ ш гЧ СО т-Ч со

гЧ Гч ιτγ Гч СО СО СО со гЧ со т-Ч оо гН

The product constants of the general formula

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it's you

гч oq co

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см см

to о

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WHAT O WHAT WHAT WHAT ”31 rH rH rH

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CD

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Claims (1)

A process for the preparation of 2- (7-oxo-2,6-diaza-4-oxabicyclo-3,2,0] hept-2-en-6-yl] butenoic acids of the general formula IV wherein: R is a phenyl group optionally substituted by an alkyl or alkoxy group containing from 1 to 3 carbon atoms, a nitro group, a cyano group or a halogen atom, a phenylalkyl group having 1 to 3 carbon atoms in the alkyl moiety or a phenoxyalkyl group having 1 to 3 carbon atoms in the alkyl moiety; Z represents a divalent radical of the formula CH2 СНз II I —CH — C— or —C = C— Where I am COB represents a carboxyl group or a carboxyl group protected in the form of an ester, for example the tert-butyl ester, the benzyl ester or the diphenylmethyl ester, and X represents a halogen atom, a hydroxyl group, an alkanoyloxy group having 1 to 4 carbon atoms, optionally substituted by 1 to 3 halogen atoms, a nitrooxy group, a phenylthio group, a phenylsulfinyl group or a 1-alkyl-5-tetrazolylthio group having 1 to 3 carbon atoms; by treating a compound of formula III (III) wherein: R and Z are as defined above and Y represents a halogen atom or a nitrooxy group, reacted with a nucleophilic agent replacing the residue Y by a residue X other than residue Y, in an inert solvent at a temperature of 10 to 70 ° C, optionally in the presence of a catalyst such as crown ether or phase transfer catalyst.