GB1570929A - Azetidinones and process for their preparation - Google Patents

Description

(54) NOVEL AZETIDINONES AND PROCESS FOR THEIR PREPARATION (71) We, ELI LILLY AND COMPANY, a corporation of the State of Indiana, United States of America, having a principal place of business at 307 East McCarty Street, City of Indianapolis, State of Indiana, United States of America, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- This invention relates to novel compounds, which are useful as intermediates to antibacterially active compounds, and more particularly to compounds which can be classified as particularly substituted azetidin - 2 - ones and, for purposes herein, will be named as aerivatives of 1 - azetidine - acetic acid.

British Patent No. 1,315,995 discloses related compounds which are substituted azetidin - 2 - ones that are prepared from a substituted acetyl halide and a thioimidate derivative of an a-amino acid ester.

This invention provides compounds of the formula

wherein n is 0 or 1; Ra is C1-C4 alkyl; R1 is hydrogen or a carboxy protecting group; and R is (a) phthalimido: (b) an amido group of the formula

in which R2 is (1) hydrogen, C1-C3 alkyl, halomethyl, thienyl- 2 - methyl, 4 - protected amino - 4- protected carboxybutyl, benzyloxy, 4- nitrobenzyloxy, t butyloxy, 2,2,2 - trichloroethoxy, 4 methoxybenzyloxy; (2) a group of the formula R'--(O),,-CH, in which m is 0 or 1, and R' is phenyl or phenyl substituted with 1 or 2 halogens, protected hydroxy, nitro, cyano, tri fluoromethyl, C1-C4 alkyl, or C1-C2 alkoxy; (3) a group of the formula

in which R' is as defined above and W is protected hydroxy, protected carboxy, or protected amino; or (c) an imidazolidinyl group of the formula

in which R' is as defined above.

The compounds of the invention may all be derived from reaction of a penicillin sulfoxide with an ester of acrylic acid.

The invention further provides a process for preparing a compound of formula (I) in which n is 1, i.e. a compound of formula

which comprises contacting a penicillin -sulfoxide of the formula

with at least an equimolar amount of an acrylate ester of the formula

at a temperature of from 70"C. to 1 100C., wherein, in the above formulae, R, R, and Ra are as hereinbefore defined, and R1a is a carboxy protecting group, optionally followed by removal of the carboxy protecting group.

The compounds of formula I in which n is 1 may be named as derivatives of 2 sulfinyl - - isopropenyl - 4 - oxo - 3 - amido - (or imido)- I - azetidineacetic acids. Since these compounds contain an isopropenyl group and thus a double bond defined by a terminal methylene function, they will be referred to herein by the shorthand term "terminal double bond" compounds.

In the foregoing acrylate ester formula, formula III, Ra is C1-C4 alkyl, and, preferably, is methyl or ethyl. By "C1-C4 alkyl" is meant any of methyl, ethyl, n propyl, isopropyl, n - butyl isobutyl, tbutyl, and sec - butyl.

Typical of these acrylic acid esters are methyl acrylate, ethyl acrylate, n - propyl acrylate, isopropyl acrylate, n - butyl acrylate, isobutyl acrylate, t - butyl acrylate, and sec - butyl acrylate.

R, in the above formulae denotes hydrogen or a carboxylic acid protecting group, For purposes herein, this latter term can be considered equivalent to the terms "carboxy protecting group" and "protected carboxy". In the event that R, is a carboxylic acid protecting group, it is preferred that it be one which is removable by acid treatment or by hydrogenation.

Preferred such carboxylic acid protecting groups include, for example, C1-C3 alkyl, C4-C6 tert - alkyl, 2,2,2 - trichloroethyl, 2 - iodoethyl, benzyl, p - nitrobenzyl, succinimidomethyl, phthalimidomethyl, p methoxybenzyt, benzhydryl, C2Ce alkanoyloxymethyl, phenacyl, or phalophenacyl, in which halo denotes chloro, bromo, or iodo.

Specific illustrations of the preferred carboxylic acid protecting groups which are present in the compounds of formula I include, for example, methyl, t - butyl, t amyl, t - hexyl, 2,2,2 - trichloroethyl, 2 iodoethyl, benzyl, p - nitrobenzyl, succinimidomethyl, phthalimidomethyl, p methoxybenzyl, benzhydryl, acetoxymethyl, pivaloyloxymethyl, propionoxymethyl, phenacyl, p - chlorophenacyl, and p - bromophenacyl.

Highly preferred carboxylic acid protecting groups are t - butyl, benzyl, p nitrobenzyl, p - methoxybenzyl, benzhydryl, and 2,2,2 - trichloroethyl.

R represents the substituent which is present in the 3-position of the azetidinyl moiety of the compounds of formula I. R can be any of three possibilities or classes or possibilities. Of course, the structure of the R group in the compounds of formula I will depend upon the structure of the substituent R which appears in the 6-position of the penicillin sulfoxide starting material employed in the process of this invention and from which the compounds of formula I are prepared. First, R can be imido functions, specifically phthalimido.

Secondly, R can be amido function of the

Specific illustrations of the group R2 include, for example, hydrogen, methyl, ethyl, n - propyl, isopropyl, chloromethyl, bromomethyl, thienyl- 2 - methyl, 4 acetamido - 4 - p - nitrobenzyl oxycarbonylbutyl, benzyloxy, 4 nitrobenzyloxy, t - butyloxy, 2,2,2 - trichloroethoxy, and 4- methoxy benzyloxy.

Specific illustrations of the group R2 when it is R'O)rnCH2 and when m is 0 include, for example, benzyl, 3 - bromobenzyl, 2,5 dichlorobenzyl, 4 - chloroacetoxybenzyl, 2 nitrobenzyl, 3 - cyanobenzyl, 4 trifluoromethylbenzyl, 3 - methylbenzyl, 4 - n - butylbenzyl, 2 - methoxybenzyl, and 3 - ethoxybenzyl.

Specific illustrations of the group R2 when it is R'--(O),,-CH, and m is 1 include, for example, phenoxymethyl, 3 - iodophenoxymethyl, 4- fluorophenoxymethyl, 3 - benzyloxy- phenoxymethyl, 4 - benzhydryloxyphenoxymethyl, 3 - trityloxyphenoxymethyl, 4 - nitrobenzyloxyphenoxymethyl, 3 - nitrophenoxymethyl, 4- cyanophenoxymethyl, 2 - tri- fluorornethylphenoxymethyl, 3 - methylphenoxymethyl, 4 - n - propylphenoxy- methyl, 4 - n - butylphenoxymethyl, 3 methoxyphenoxymethyl, and 4- ethoxyphenoxymethyl.

Specific illustrations of the group R2 when it is

include, for example, a benzhydryloxybenzyl, a - (4 - methoxybenzyloxy)benzyl, a - (2,2,2 - trichloroethoxycarbonylamino)benzyl, a (benzyloxy)- 4- bromobenzyl, a - (benzhydryloxycarbonyl) - 3 chlorobenzyl, - (4 - nitrobenzyloxycarbonylamino)- 4- fluorobenzyl, a,4 - di(formyloxy)benzyl, a- (4 nitrobenzyloxycarbonyl) - 3 - chloroacetoxybenzyl, a - (4 - methoxybenzyloxycarbonylamino) - 4 - benzhydryloxybenzyl, a - benzyloxy - 3 - nitrobenzyl, a - (4 - nitrobenzyloxycarbonyl) - 2cyanobenzyl, a - (t - butoxycarbonylamino) - 4 - trifluoromethylbenzyl, - formyloxy - 4 methylbenzyl, - benzyloxycarbonyl - 3 n - butylbenzyl, a - (benzyl oxycarbonylamino) - 4 - methoxybenzyl, and a - formyloxy - 3 - ethoxybenzyl.

In those instances in which R is

it is preferred that R2 is benzyl or phenoxymethyl, thereby defining phenylacetamido or phenoxyacetamido, respectively.

In portions of the definition provided herein for the group R2, the terms "protected amino", "protected hydroxy", and "protected carboxy" are employed.

The term "protected amino", when employed herein, refers to an amino group substituted with one of the commonly employed amino blocking groups such as t butyloxycarbonyl (t - BOC), benzyloxycarbonyl, 4- methoxybenzyloxycarbonyl, 4- nitrobenzyloxycarbonyl, 2,2,2 - trichloroethoxycarbonyl, diphenylmethoxycarbonyl, isobutyloxycarbonyl.

cyclopentyloxycarbonyl, cyclohexyloxy carbon, chloroacetyl, dichloroacetyl, 2 - chloropropionyl,. 3 - phenylpropionyl, 4 - chlorobutyryl, benzyl, and trityl. Additional typical amino protecting groups are described by J. W.

Barton in Protective Groups in Organic Chemistry, J. F. W. McOmie, Ed., -Plenum Press, New York, N.Y., 1973, Chapter 2.

Any of these are recognized as useful within the meaning of the term "protected amino" employed herein.

The term "protected hydroxy" when employed herein, refers to the readily cleavable groups formed with a hydroxyl group such as formyloxy, chloroacetoxy, benzyloxy, benzhydryloxy, trityloxy, and 4 nitrobenzyloxy. Other hydroxy protecting groups, including those described by C. B.

Reese in Protective Groups in Organic Chemistry, supra, Chapter 3, are considered to be within the term "protected hydroxy" as used herein.

The term "protected carboxy", when employed herein, refers to a carboxy group which has been protected by one of the commonly used carboxylic acid protecting groups employed to block or protect the carboxylic acid functionality of a compound while a reaction or sequence of reactions involving other functional sites of the compound are carried out. Such protected carboxy groups are noted for their ease of cleavage to the corresponding carboxylic acid by hydrolytic or by hydrogenolytic methods. Any of those groups defined hereinabove for R1 are also included within the meaning of the term "protected carboxy". Examples of carboxylic acid protecting groups include methyl, t - butyl, benzyl, 4- methoxybenzyl, C2-C6 alkanoyloxymethyl, 2- iodoethyl, 4 nitrobenzyl, diphenylmethyl (benzhydryl), phenacyl, p - halophenacyl, 2,2,2 trichloroethyl, and succinimidomethyl. The nature of such ester forming groups is not critical; it is preferred, however, that the ester formed therewith be stable under the reaction conditions of the process of this invention. Other known carboxy protecting groups such as those described by E.

Haslam in Protective Groups in Organic Chemistry, supra, Chapter 5, are considered to be within the term "protected carboxy" as used herein.

Preferred groups within the term "protected carboxy" are tert- butyl, benzyl, p - methoxybenzyl, p - nitrobenzyl, benzhydryl, and 2,2,2 - trichloroethyl.

In the foregoing definitions, hydroxy, amino, and carboxy protecting groups, of course, are not exhaustively described. The purpose of these groups is to protect reactive functional groups during preparation of a desired product. They then are removed without disruption of the remainder of the molecule. Many such protecting groups are well known in the art, and their use is equally applicable in the process of this invention.

In addition, the group R of the compounds of formula I can be imidazolidinyl group of the formula

in which R' is phenyl or phenyl substituted with 1 or 2 halogens, protected hydroxy, nitro, cyano, trifluoromethyl, C1-C4 alkyl, or C1-C2 alkoxy.

R' in the above imidazolidinyl formula typically include, for example, phenyl, 3 bromophenyl, 2- chlorophenyl, 4fluorophenyl, 3 - iodophenyl, 3 - chloro 4 - fluorophenyl, 2 - chloro - 4 bromophenyl, 4 - formyloxyphenyl, 3formyloxyphenyl, 4- nitrophenyl, 2cyanophenyl, 3 - trifluoromethylphenyl, 4 methylphenyl, 3 - ethylphenyl, 4isopropylphenyl, 4 - t - butylphenyl, 3 methoxyphenyl, 2 - ethoxyphenyl, and 4 methoxyphenyl.

Compounds in which R is the aforedescribed imidazolidinyl group can be prepared in accordance with known techniques by reacting a penicillin compound in which R is

with acetone under moderately basic conditions to produce the corresponding compound in which R is a labile intermediate of the formula

This product then is converted to the stable N-nitroso derivative in which R is the aforedescribed imidazolidinyl group. The latter conversion is accomplished by treatment of the intermediate with sodium nitrite under acidic conditions and with cooling. The resulting penicillin product then is oxidized to its corresponding sulfoxide by routine methods, for example, by treatment with m- chloroperbenzoic acid.

The reaction between the penicillin sulfoxide and the C1-C4 alkyl ester or acrylic acid to prepare the external double bond compound of formula I preferably is carried out at an elevated temperature of from 70"C. to 1000C. The reaction may be accomplished employing molar equivalents of the penicillin sulfoxide and the acrylate ester. However, generally, a moderate excess, for example, about 10 percent on a molar basis, of the acrylate ester is employed when the reaction is carried out in the presence of an inert solvent. It is possible also to employ the acrylate ester itself as solvent. In such case, a large solvent excess of the acrylate ester is employed, and the penicillin sulfoxide reactant is added thereto. The resulting mixture then is heated to the temperature of reaction and maintained thereat for a time sufficient to accomplish production of the external double bond product.

As noted, an inert organic solvent can be employed in conjunction with the two reactants. Any solvent inert to the reactants and having a boiling point of sufficient elevation to permit the temperature of reaction to be obtained and maintained can be employed. Typical such solvents include, for example, ethers, such as tetrahydrofuran (THF), and dioxane; aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons, such as methylene bromide, chloroform, bromoform, dichloroethane, chlorobenzene, and dichlorobenzene; esters, such as ethyl acetate; and various other typical inert solvents.

The reaction mixture, whether in the presence of an inert solvent or not, is brought to the temperature of reaction and maintained thereat for a period sufficient to accomplish production of the external double bond compound of formula I.

Generally, this time of reaction will be from three hours to 48 hours.

Furthermore, in order to avoid undesirable side reactions, it is preferred that the reaction be carried out in the presence of an inert atmosphere, such as would be obtained by the continuous maintenance of the reaction system in a nitrogen environment.

Upon completion of the reaction, the product can be isolated by means of any of several generally recognized procedures.

Typically, the product will be isolated merely by evaporation of any excess acrylate ester as well as the solvent, if any of the latter is present. The resulting product residue can be further purified, if desired, by any of a number commonly used purification techniques, including column chromatography, gas chromatography, crystallization, and related methods.

The product of formula I wherein n is 1 is useful as an intermediate in the preparation of antibiotically active products. The intermediate can be cyclized to'produce the corresponding A3 - desacetoxycephalosporin ester. Ring closure of the external double bond compound to the cephalosporin ester is accomplished employing conditions such as those employed in the traditional penicillin sulfoxide ring expansion process. This process is taught in U.S. Patent No.

3,275,626. Ring closure to the A3 - desacetoxycephalosporin ester is effected by treating the external double bond compound of formula I under acidic conditions. Examples of suitable acids which can be employed to achieve ring closure to the A3 - desacetoxy-.

cephalosporin ester include sulfuric acid, phosphoric acid, and other mineral acids: sulfonic acids, such as p - toluenesulfonic acid, benzenesulfonic acid, and naphthalenesulfonic acid; Lewis acids, such as boron trifluoride, and aluminum chloride; acid anhydrides such as acetic anhydride, propionic anhydride, and benzoic anhydride.

The resulting A3 - desacetoxycephalosporin ester is converted to an antibiotically active cephalosporin compound by cleavage of the ester function in the 4-position to produce the corresponding A3 - desacetoxycephalosporin acid. This cleavage may be accomplished employing recognized techniques. Deesterification can be achieved, depending upon the nature of the protecting group, by any of several recognized procedures, including ( I ) treatment with an acid such as trifluoroacetic acid, formic acid, or hydrochloric acid; (2) treatment with zinc and an acid such as formic acid, acetic acid, or hydrochloric acid; or (3) hydrogenation in the presence of palladium, platinum, rhodium, or a compound thereof, in suspension, or on a carrier such as barium sulfate, carbon, or alumina. The literature well recognizes that the free acid cephalosporin which is obtained exhibits potent antibiotic activity.

The compounds of formula I wherein n=0 may be prepared by reduction of the sulfoxide moiety (n=l) to a sulfide. This can be accomplished by reacting the sulfoxide compound with at least one equivalent of phosphorous tribromide in an inert solvent.

The reaction generally is carried out at a temperature of from -20"C. to +30 C. for a period of from 5 minutes to 12 hours. The resulting product also a compound of formula I, is designated a 2- [(2substituted carboxyethyl)thiol - a - isopropenyl - 4 - oxo - 3 - imido - (or amido) - 1 - azetidineacetic acid ester. The thio compound can be converted to an antibiotically active compound by cleavage of the ester function of the azetidineacetic acid moiety. Cleavage can be carried out under conditions described hereinabove with respect to the A3 - desacetoxycephalosporin ester cleavage. Compounds of this class exhibit useful antimicrobial activity.

It will be recognized that the reaction sequences described hereinabove can be varied such that the ultimate products are derived through a different set of intermediates. Thus, the external double bond compound which results from the reaction of the penicillin sulfoxide with the acrylate ester can be cleaved to a compound in which R1 is hydrogen, also a compound of formula I. This cleavage may be accomplished in accordance with the methods described hereinabove. The resulting free acid external bond compound then can be converted by ring closure to the free acid A3 - desacetoxycephalosporin.

Examples of the compounds of formula I include the following: t - butyl 2 - [(2 - methoxycarbonyl)ethylsulfinyl] - a - isopropenyl - 4 - oxo - 3 phthalimido - I - azitidineacetate; benzyl 2- [(2 - methoxycarbonyl)ethylsulfinyl] - a - isopropenyl - 4 - oxo 3 - formamido - 1 - azetidineacetate; 2,2,2 - trichloroethyl 2 - [(2 - ethoxy- carbonyl)ethysulfinyl] - a - isopropenyl - 4 - oxo - 3 - acetamido - 1 - azetidineacetate; p - nitrobenzyl 2 - [(2 - ethoxycarbonyl)ethylsulfinyl] - a - isopropenyl - 4 - oxo - 3 - butyramido - 1 - azetidine- acetate; p - methoxybenzyl 2 - [(2 methoxy- carbonyl)ethylsulfinyl] - lr- isopropenyl- 4 - oxo - 3 - chloro-acetamido - 1 azetidineacetate; benzhydryl 2 - [(2 - ethoxycarbonyl) ethylsulfinyl] - a - isopropenyl - 4 - oxo - 3 (4' - chloroacetamido - 4' benzhydryloxycarbonylvaleramido) - 1 azetidineacetate; p- nitrobenzyl 2- [(2 - ethoxy carbonyl)ethylsulfinyl] - α - isopropenyl - 4- oxo - - 3 - (4' - nitrobenzyloxy carbamido) 1 - azetidineacetate; t - amyl 2 - [(2 - n - propoxycarbonyl) ethylsulfinyll - a - isopropenyl - 4 - oxo 3- benzyloxycarbamido - 1 - azetidineacetate; t - butyl 2 - [(2 - methoxycarbonyl)ethylsulfinyl] - a - isopropenyl - 4 - oxo 3 - t - butyloxycarbamido - 1 - azetidineacetate; 2 - iodoethyl 2 - [(2 - ethoxycarbonyl)ethylsulfinyl] - a - isopropenyl - 4 - oxo - 3 (2',2',2' - trichloroethoxycarbamido)- 1 - azetidineacetate; acetoxymethyl 2- [(2 - isopropoxycarbonyl)ethylsulfinyl] - a - isopropenyl - 4 - oxo - 3 -- (4' - methoxybenzyloxy carbamido) - 1 azetidineacetate; p - methoxybenzyl 2 - [(2 - ethoxycarbonyl)ethylsulfinyl] - a - isopropenyl4 - oxo - 3 - phenylacetamido - 1 azetidineacetate; 2,2,2 - trichloroethyl 2 - [2 - methoxycarbonyl)ethylsulfinyl] - a - isopropenyl - 4 - oxo - 3 - phenoxyacetamido - 1 - azetidineacetate; p - nitrobenzyl 2 - [(2 - ethoxycarbonyl)- ethylsulfinyl] - a - isopropenyl - 4 - oxo 3 - (2',5' - dichlorophenylacetamido) - 1 - azetidineacetate; benzyl 2- [(2 - methoxycarbonyl)ethysulfinyl] - cr - isopropenyl - 4 - oxo - 3 (3' - bromophenoxyacetamido) - 1 - azetidineacetate; t - butyl 2- [(2 - ethoxycarbonyl) ethylsulfinyli - a - isopropenyl - 4 - oxo 3 - (4' - chloroacetoxyphenylacetamido) 1 - azetidineacetate; t - hexyl 2 - [(2 - n - butoxycarbonyl)ethylsulfinyl] - ct - isopropenyl - 4 - oxo - 3 (3' - formyloxyphenoxyacetamido) - 1 - azetidineacetate; p - nitrobenzyl 2 - [(2 - ethoxycarbonyl)ethylsulfinyl] - a - isopropenyl - 4 - oxo 3 - (2' - nitrophenylacetamido) - 1 - azetidineacetate; p- methoxybenzyl 2 - [(2 - methoxy- carbonyl)ethylsulfinyl] - α - isopropenyl - 4- oxo - 3 - (4' - nitrophenoxy acetamido) - 1 - azetidineacetate; benzhydryl 2 - [(2 - ethoxycarbonyl ethylsulfinyl] - α - isopropenyl- 4oxo - 3 - (3' - cyanophenylacetamido) - I - azetidineacetate; p - bromophenyl 2 - [(2 - methoxycarbonyl)ethylsulfinyl] - α - isopropenyl - 4 - oxo - 3 - (2' - cyanophenoxy acetamido) - 1 - azetidineacetate; propionoxymethyl 2 - [(2 - t - butoxy- carbonyl)ethylsulfinyl] - α - isopropenyl4 - oxo - 3 - (4' - trifluoromethylphenylacetamido) - 1 - azetidineacetate; p - nitrobenzyl 2 - [(2 - ethoxycarbonyl)ethylsulfinyl] - α - isopropenyl - 4- oxo - 3 - (3' - trifluoromethylphenoxyacetamido) - 1 - azetidineacetate; t - butyl 2- [(2 - ethoxycarbonyl) ethylsuffinyfl - a - isopropenyl - 4 - oxo - 3 (2' - ethylphenylacetamido) - 1 - azetidine- acetate; acetoxymethyl 2 - [(2 - ethoxycarbonyl)ethylsulfinyl] - ez - isopropenyl - 4 - oxo 3 - (4' - isopropylphenoxyacetimido) - 1 azetidineacetate; t - butyl 2 - [(2 - methoxycarbonyl)ethylsulfinyl] - a - isopropenyl - 4 - oxo 3 - (3' - ethoxyphenylacetamido) - 1 - azetidineacetate; p- nitrobenzyl 2- (2 - methoxycarbonyl)ethylsulfinyl] - α - isopropenyl - 4 - oxo - 3 - (4' - methoxyphenoxy acetamido) - 1 - azetidineacetate; p - nitrobenzyl 2 - [(2 - sec - butoxy- carbonyl)ethylsulfinyl] - α - isopropenyl4- oxo - 3 - (a - formyloxyphenyl acetamido) - I - azetidineacetate; p - methoxybenzyl 2 - [(2 - methoxy- carbonyl)ethylsulfinyl] - α - isopropenyl - 4 - oxo - 3 - (a - benzhydryloxyphenyl acetamido) - 1 - azetidineacetate; benzhydryl 2 - [(2 - isobutoxycarbonyl)ethylsulfinyl] - cr - isopropenyl - 4 - oxo 3 - ( - benzhydryloxycarbonyl- phenylacetamido) - 1 - azetidineacetate; p - nitrobenzyl 2 - [(2 methoxycarbonyl)ethylsulfinyl] - aisopropenyl - 4 - oxo - 3 - (a - benzyloxycarbonylaminophenylacetamido) - 1 - azet- idineacetate; t- butyl 2- [(2 - ethoxycarbonyl)ethylsulfinyl] - a - isopropenyl - 4 - oxo 3(a - t - butyloxycarbonylaminophenylacetamido) - 1 - azetidineacetate; p - nitrobenzyl 2 - [(2 methoxycarbonyl)ethylsulfinyl] - aisopropenyl- 4- oxo - 3 - (2' thienylacetamido) - 1 - azetidineacetate; 2 - [(2 - methoxycarbonyl)ethylsulfinyl] - a isopropenyl - 4 - oxo - 3 phthalimido - 1 - azetidineacetic acid; 2 - [(2 - methoxycarbonyl)ethylsulfinyl] - a - isopropenyl - 4 - oxo 3 - formamidp - 1 - azetidineacetic acid; 2- [(2 - isopropoxycarbonyl)ethylsulfinyl] - a - isopropenyl - 4 - oxo - 3 acetamido - 1 - azetidineacetic acid 2- [(2 - n- butoxycarbonyl)ethyl- sulfinyl] - a - isopropenyl - 4 - oxo - 3 butyramido - 1 - azetidineactic acid; 2 - [(2 - methoxycarbonyl)ethylsulfinyl] - a - isopropenyl - 4 - oxo - 3 chloroacetamido - 1 - azetidineacetic acid; 2 - [(2 - n- propoxycarbonyl)ethylsulfinyl] - a - isopropenyl - 4 - oxo - 3 (4' - chloroacetamido -4' - benzhydryloxy carbonylvaleramido) - 1 - azetidineacetic acid; 2 - [(2 - ethoxycarbonyl)ethylsulfinyl] α - isopropenyl - 4 - oxo - 3 - (4' nitrobenzyloxycarbamido) - 1 - azetidineacetic acid; 2 - [(2 - isobutoxycarbonyl)ethylsulfinyl] - a - isopropenyl - 4 - oxo - 3 benzyloxycarbamido - 1 - azetidineacetate acid; 2- [(2 - sec - butoxycarbonyl)ethylsulfinyl] - a - isopropenyl - 4 - oxo - 3 t - butyloxycarbamido - 1 - azetidineactic acid; 2 - [(2 - ethoxycarbonyl)ethylsulfinyl] a - isopropenyl - 4 - oxo - 3 - (2',2',2' trichloroethoxycarbamia"o) - 1 - azetidineacetic acid; 2- [(2 - t - butoxycarbonyl)ethylsulfinyl] - a - isopropenyl - 4 - oxo - 3 (4' - methoxybenzyloxycarbamido)- 1 - azetidineacetic acid; 2- [(2 - isopropoxycarbonyl)ethylsulfinyl - a - isopropenyl - 4 - oxo - 3 phenylacetamido - 1 - azetidineacetic acid; 2- [(2 - methoxycarbonyl)ethylsulfinyl] - a - isopropenyl - 4 - oxo - 3 phenoxyacetamido - 1 - azetidineacetic acid; 2 - [(2 - ethoxycarbonyl)ethylsulfinyl] α - isopropenyl- 4 - oxo - 3 - (2',5' - dichlorophenylacetamido) - 1 azetidineacetic acid; 2 - [(2 - t - butoxycarbonyl)ethylsulfinyl] - α - isopropenyl - 4 - oxo - 3 - (3' bromophenoxyacetamido) - 1 - azetidineacetic acid; 2 - [(2 - ethoxycarbonyl)ethylsulfinyl] α - isopropenyl - 4 - oxo - 3 - (4' - chloroacetoxyphenylacetamido) - 1 - azetidineacetic acid; 2- [(2 - n - propoxyearbonyl)ethyl- su oxo - 3 - butyramido - 1 - azetidineacetate: p - methoxybenzyl 2 - [(2 - methoxy- carbonyl)ethylthio] - a - isopropenyl - 4 oxo - 3 - chloroacetamido - 1 - azetidineacetate; benzhydryl 2 - [(2 - t - butoxycarbonyl)ethylthio] - a - isopropenyl - 4 - oxo - 3 (4' - chloroacetamido -4' - benzhydryloxycarbonylvaleramido) - 1 - azetidineacetate; p- nitrobenzyl 2- [(2 - methoxycarbonyl)ethylthio] - a - isopropenyl - 4 - oxo - 3 - (4' - nitrobenzyloxycarbamido) 1 - azetidineacetate; t - amyl 2 - [(2 - ethoxycarbonyl)ethylthio]- α - isopropenyl- 4 - oxo - 3 - benzyloxycarbamido - I - azetidineacetate; i - butyl 2 - [(2 - n - propoxycarbonyl)ethylthio] - a - isopropenyl - 4 - oxo - 3 t - butyloxycarbamido - I - azetidineacetate; 2 - iodoethyl 2 - [(2 - ethoxycarbonyl)ethylthio] - a - isopropenyl - 4 - oxo - 3 (2',2',2' - trichloroethoxyvarbamido)- 1 - azetidineacetate; acetoxymethyl 2 - [(2 - t butoxycarbonyl)ethylthio] - α - isopropenyl - 4 - oxo - 3 - (4' - methoxybenzyloxycarbamido) - 1 - azetidineacetate; p - methoxybenzyl 2 - [(2 - n - butoxy carbonyl)ethylthio] - a - isopropenyl - 4 oxo - 3 - phenylacetamido - 1 - azetidineacetate; 2,2,2 - trichloroethyl 2- [(2 - n propoxycarbonyl) - ethylthio] - a isopropenyl - 4 - oxo - 3 phenoxyacetamido - 1 - azetidineacetate; p - nitrobenzyl 2 - [(2 - ethoxycarbonyl) ethylthio] - a - isopropenyl - 4 - oxo - 3 (2',5' - dichlorophenylacetamido) - 1 - azetidineacetate; benzyl 2- [(2 - methoxycarbonyl)ethylthio]- α - isopropenyl - 4 - oxo - 3 (3'- bromophenoxyacetamido)- 1 - azetidineacetate; t - butyl 2 - [(2 - ethoxycarbonyl)ethylthio] - a - isopropenyl - 4 - oxo - 3 (4' - chloroacetoxyphenylacetamido)- 1 - azetidineacetate; t - hexyl 2 - [(2 - sec - butoxycarbonyl)ethylthio) - cr - isopropenyl - 4 - oxo - 3 (3' - formyloxyphenoxyacetamido) - 1 - azetidineacetate; p- nitrobenzyl 2- [(2 - ethoxycarbonyl)ethylthio] - a - isopropenyl - 4 oxo - 3 - (2' - nitrophenylacetamido) - I - azetidineacetate; p - methoxybenzyl 2 - [(2 - methoxycarbonyl)ethylthio] - a - isopropenyl - 4 oxo - (4' - nitrophenoxyacetamido) - 1 azetidineacetate; benzhydryl 2 - [(2 - methoxycarbonyl)ethylthio] - a - isopropenyl - 4 - oxo - 3 (3' - cyanophenylacetamido) - 1 - azetidineacetate p- bromophenacyl 2 - [(2 - ethoxy carbonyl)ethylthio] - a - isopropenyl - 4 oxo - 3 - (2' - cyanophenoxyacetamido) 1 - azetidineacetate; propionoxymethyl 2 - [(2 - n - propoxy carbonyl)ethylthio] - a - isopropenyl - 4 oxo - 3 - (4' - trifluoro-methyl phenylacetamido) - 1 - azetidineacetate; p - nitrobenzyl 2- [(2 - ethoxy carbonyl)ethylthio] - a - isopropenyl - 4 oxo - 3 - (3' - trifluoromethyl phenoxyacetamido) - 1 - azetidineacetate; t - butyl 2- [(2 - ethoxycarbonyl) ethylthio] - cr - isopropenyl - 4 - oxo - 3 (2' - ethylphenylacetamido) - 1 - azet idineacetate; acetoxymethyl 2- [(2 - isopropoxy carbonyl)ethylthio] - a - isopropenyl - 4 oxo - 3 - (4' - isopropylphenoxy acetamido) - 1 - azetidineacetate; t - butyl 2 - [(2 - methoxycarbonyl) ethylthio] - α - isopropenyl - 4 - oxo - 3 (3' - ethoxyphenylacetamido) - I azetidineacetate; p- nitrobenzyl 2- [(2 - methoxy carbonyl)ethylthio] - a - isopropenyl - 4 oxo - 3 - (4' - methoxyphenoxy acetamido) - 1 - azetineacetate; p - nitrobenzyl 2 - [(2 - n - butoxy carbonyl)ethylthio] - a - isopropenyl - 4 oxo - 3(a - formyloxyphenylacetamido) - 1- azetindineacetate; p - methoxybenzyl 2 - [(2 - ethoxy carbonyl)ethylthio] - a - isopropenyl - 4 oxo - 3 - ( - benzhydryloxy phenylacetamido) - 1 - azetidineacetate; benzhydryl 2 - [(2 - isobutoxycarbonyl) ethylthio] - a - isopropenyl - 4 - oxo - 3 (a - benzhydryloxycarbonylphenylacet- - amido) - 1 - azetidineacetate; p- nitrobenzyl 2- [(2 - methoxy carbonyl)ethylthio] - a - isopropenyl - 4 oxo - 3 - (α - benzyloxycarbonyl aminophenylacetamido) - 1 - azetidine acetate; t - butyl - 2 - [(2 - ethoxy carbonyl)ethylthio] - a - isopropenyl - 4 oxo - 3 - (a - t - butyloxycarbonylamino phenylacetamido) - I - azetidineacetate; p - nitrobenzyl 2 [(2- ethoxycarbonyl) ethylthio] - a - isopropenyl - 4 - oxo - 3 (2' - thienylacetamido) - 1 - azetidine acetate; 2 - [(2 - methoxycarbonyl)ethylthio] a - isopropenyl - 4 - oxo - 3 phthalimido - 1 - azetidineacetic acid: 2 - [(2 - methoxycarbonyl)ethylthio] a- isopropenyl- 4 - oxo - 3 formamido - 1 - azetidineacetic acid; 2 - [(2 - ethoxycarbonyl)ethylthio] - a isopropenyl - 4 - oxo - 3 - acetamido - I - azetidineactive acid; 2 - [(2- - n - propoxycarbonyl)ethylthio] a - isopropenyl - 4 - oxo - 3 butyramido - 1 - azetidineacetic acid; 2 - [(2 - methoxycarbonyl)ethylthio] α - isopropenyl - 4 - oxo - 3 chloroacetamido - 1 - azetidineacetic acid; 2 - [(2 - isopropoxycarbonyl)ethylthio] a - isopropenyl - 4 - oxo - 3 - (4' - chloroacetamido - 4' - benzhydryloxycarbonylvaleramido) - 1 - azetidineacetic acid; 2 - [(2 - methoxycarbonyl)ethylthio] - a - isopropenyl - 4 - oxo - 3 - (4' nitrobenzyloxycarbamido) - 1 azetidineacetic acid; 2 - [(2 - t - butoxycarbonyl)ethylthio] - a - isopropenyl- 4 - oxo - 3 - benzyloxy- carbamido - 1 - azetidineacetic acid; 2 - [(2 - ethoxycarbonyl)ethylthio] - α - isopropenyl - 4 - oxo - 3 - t - butyloxy- carbamido - 1 - azetidineacetic acid; 2 - [(2 - ethoxycarbonyl)ethylthio] - a - isopropenyl- 4 - oxo - 3 - (2',2',2' - trichloroethoxycarbamido) - I azetidineacetic acid; 2 - [(2 - t - butoxycarbonyl)ethylthio] a - isopropenyl- 4 - oxo - 3 - (4' - methoxybenzyloxycarbamido) - 1 - azetidineacetic acid; 2 - [(2 - isobutoxycarbonyl)ethylthio] α - isopropenyl- 4- oxo - 3 phenylacetamido - I - azetidineacetic acid; 2 - [(2 - ethoxycarbonyl)ethylthio] - a isopropenyl- 4 - oxo - 3 - phenoxy- acetamido - I - azetidineacetic acid; 2 - [(2 - ethoxycarbonyl)ethylthio] - α - isopropenyl - 4 - oxo - 3 - (2',5' - dichloro phenylacetamido)- 1 - azetidineacetic acid; 2 - [(2 - isopropoxycarbonyl)ethylthio] a- isopropenyl- 4 - oxo - 3-- (3' - bromophenoxyacetamido) azetidineacetic acid 2 - [(2 - ethoxycarbonyl)ethylthio] - a - isopropenyl- 4- oxo - 3 - - (4' - chloroacetoxyphenylacetamido)- 1 azetidineacetic acid; 2 - [(2 - methoxycarbonyl)ethylthio] α - isopropenyl- 4 - oxo - 3 - (3' - formyloxyphenoxyacetamido) - I azetidineacetic acid 2 - [(2 - ethoxycarbonyl)ethylthio] - a - isopropenyl- 4- oxo - 3 - (2' nitrophenylacetamido) - 1 - azetidineactic acid; 2- [(2 - n- propoxycarbonyl)ethyl thiol - a - isopropenyl - 4 - oxo - 3 - (4' nitrophenoxyacetamido) - 1 - azetidine acetic acid; 2 - [(2 - methoxycarbonyl)ethylthio] - ,- isopropenyl- 4 - oxo - 3 - (3' cyanophenylacetamido - 1 - azetidine acetic acid; 2 - [(2 - ethoxycarbonyl)ethylthio] - α - isopropenyl - 4 - oxo - 3 - (2' cyanophenoxyacetamido) - I - azetidineacetic acid; 2 - [(2 - n - butoxycarbonyl)ethylthio] α - isopropenyl- 4 - oxo - 3 - (4' - trifluoromethylphenylacetamido) - I azetidineacetic acid; 2 - [(2 - ethoxycarbonyl)ethylthio] - α - isopropenyl - 4- oxo - 3 - (3' trifluoromethylphenoxyacetamido) - I azetidineacetic acid; 2 - [(2 - ethoxycarbonyl)ethylthio] - a! - isopropenyl - 4 - oxo - 3 - (2' ethylphenylacetamido) - 1 - azetidineacetic acid; 2 - [(2 - isopropoxycarbonyl)ethylthio] - isopropenyl - 4 - oxo - 3 - (4' isopropylphenoxyacetamido) - 1 - azetidineactic acid; 2 - [(2 - methoxycarbonyl)ethylthiol a - isopropenyl- 4 - oxo - 3 - (3' - ethoxyphenylacetamido) - 1 - azetidineacetic acid; 2- [(2 - methoxycarbonyl)ethylthio] α - isopropenyl- 4 - oxo - 3 - (4' - methoxyphenoxyacetamido) - 1 - azetidineacetic acid; 2 - [(2 - methoxycarbonyl)ethylthio] - a - isopropenyl- 4 - oxo - 3 - (α - formyloxyphenylacetamido] - I - azetidineacetic acid; 2 - [(2 - ethoxycarbonyl)ethylthio] - α - isopropenyl- 4- oxo - 3 - (α - benzhydryloxyphenylacetamido) - 1 - azet- idineacetic acid; 2 - [(2 - isobutoxycarbonyl)ethylthio] - a- isopropenyl- 4 - oxo - 3- (c- benzhydryloxycarbonylphenylacetamido) - 1 - azetidineacetic acid; 2- [(2 - methoxycarbonyl)ethylthio] α - isopropenyl- 4 - oxo - 3 - (α - benzyloxycarbonylaminophenylacetamido) I - azetidineacetic acid; 2 - [(2 - ethoxycarbonyl)ethylthio] - - isopropenyl- 4- oxo - 3 - (α - t - butyloxycarbonylaminophenylacetamido) 1 azetidineacetic acid; and 2 - [(2 - ethoxycarbonyl)ethylthio] - a - isopropenyl- 4 - oxo --3 - (2' - thienyl acetamido) - 1 - azetidineacetic acid.

The following examples are provided to illustrate the preparation and utility of the compounds of formula I. They are not intended to be limiting upon the broad scope of the invention.

Example 1 Preparation of 2 - [(2 - methoxycarbonyl) ethylsulfinyl] - a - isopropenyl - 4 oxo - 3 - phthalimido - I azetidineacetic acid, methyl ester.

To 100 ml. of methyl acrylate were added 5 g. of methyl 6- phthalimido - 2,2 dimethylpenam - 1 - oxo - 3 - carboxylate.

The solution was refluxed for 16 hours under a nitrogen atmosphere. The solvent then was removed in vacuo to leave a residual white foam. The foam was dissolved in methanol, the solution was cooled, and the resulting crystals were removed (250 mg.) by filtration.

The filtrate was concentrated in vacuo to give a white foam comprising the title compound.

nmr (CDCL3): 2.1 (3H, broad s), 2.8 (4H, m), 3.4 (3H, s), 3.5 (3H, s), 3.55 (3H, s), 3.6 (3H, s), 5.0--5.3 (3H, m), 5.4 (1H, d, J=4 cps), 5.75 (Ih, d, J=4 cps), 5.9 (1H, d, J=4 cps), and 7.9 Hz. (4H, broad m).

ir (Nujol): 1795, 1785, and 1735 cm~1.

Example 2 Preparation of 2 - [(2 - methoxycarbonyl) ethylsulfinyl]- - isopropenyl - 4- oxo - 3 - phthalidimo - 1 azetidineacetic acid, p - nitrobenzyl ester.

To 50 ml. of methyl acrylate were added 500 mg. of p - nitrobenzyl 6 - phthalimido 2,2 - dimethylpenam- 1 - oxo - 3carboxylate. The solution was refluxed for 18 hours under a nitrogen atmosphere.

Solvent then was removed in vacuo to leave a residual white foam. The mixture was crystallized from methanol to give 60 mg. of white crystals of starting material. The filtrate, upon evaporation of the methanol, gave the acrylate adduct product as a white foam.

nmr (CDCl3): 2.05 (3H, broad s), 2.83 (4H, broad s), 3.4 (3H, s), 3.65 (3H, s), 3.85 (3H, s), 5.-5.5 (6H, broad m), 5.8 (2d, 1H each, J=4 cps), 7.6 (2H, d), 7.8 (4H, s), and 8.2 Hz.

(2H, d). Example 3 Preparation of methyl 7 - phthalimido - 3 methyl - 3 - cephem -4 - carboxylate.

To a mixture of 10 ml. of N, N dimethylacetamide, 20 ml. of benzene, and 0.06 ml. of methanesulfonic acid - were added 650 mg. of 2- [(2- methoxycarbonyl)ethylsulfinyl] - a - isopropenyl 4 - oxo - 3 - phthalimido - 1 - azetidine- acetic acid, methyl ester. The resulting solution was refluxed for 1.5 hours on a steam bath, and the solvent then was removed in vacuo. The resulting residue was purified by preparative thin-layer chromatography using a 3:7 mixture of ethyl acetate and benzene as eluant. A fraction of 156 mg. was recovered and identified as the title compound by comparison with an authentic specimen thereof.

Example 4 Preparation of 2 - [(2 - methoxycarbonyl) ethylsulfinyl]- a - isopropenyl- 4 oxo - 3 - phenoxyacetamido - 1 - azetidineacetic acid, p- nitrobenzyl ester.

To 150 ml. of methyl acrylate were added 5 g. of p- nitrobenzyl 6 - phenoxyacetamido - 2,2 - dimethylpenam - 1 - oxo - 3- carboxylate. The resulting solution was refluxed for three days. The solvent then was removed in vacuo, and the resultant foam was dissolved in hot methanol. The methanol was cooled, and crystals of starting material (500 mg.) formed and were collected. An nmr spectrum of the filtrate indicated the presence of the title compound along with a small amount of starting material. An aliquot of the filtrate was purified by preparative thin-layer chromatography using a 3:7 mixture of ethyl acetate and benzene as eluant to obtain the title compound as a white foam.

nmr (CD3Cl): 2.0 (3H, s), 2.8 (4H, m), 3.75 (3H, s), 4.62 (2H, s), 5.2 (4H, m), 5.4 (2H, s), 5.82 (1H, q, J=4 cps and 10 cps), 7.07.6 (5H, m), 7.6 (2H, d, J=8 cps), and 8.3 Hz.

(2H, d, J=8 cps).

Example 5 Preparation of 2 - [(2 - ethoxycarbonyl) ethylsulfinyl] - a - isopropenyl - 4 oxo - 3 - phenoxyacetamido - 1 azetineacetic acid, p- nitrobenzyl ester.

To 50 ml. of ethyl acrylate were added 5 g. of p - nitrobenzyl 6 phenoxyacetamido - 2,2 - dimethylpenam - 1 - oxo - 3 - carboxylate. The mixture was refluxed for 24 hours. The solvent then was removed in vacuo. An nmr analysis of the residue indicated the presence of both starting material and the title compound. The residue was crystallized from methanol to recover 840 mg. of the starting material. The filtrate from the crystallization was chromatographed on silica gel using a 7:3 mixture of benzene and ethyl acetate as eluant to give 674 mg. of the title compound.

nmr (CD3CI): 1.18 (3H, t, J=8 cps), 2.0 (3H, s), 2.8 (4H, m), 4.1 (2H, q, J=8cps), 4.6 (2H, s) 5.05 (1H, s), 5.I (3H, broad s), 5.38 (2H, 2s), 6.2 (1H, q, J=4 cps and 11 cps), 6.8-7.5 (5H, m) 7.6 (2H, d, J=10 cps), and 8.23 Hz. (2H, d, J=10 cps).

Example 6 Preparation of 2 - [(2 - methoxycarbonyl) ethylthio] - cg - isopropenyl - 4 - oxo 3 - phthalimido - 1 - azetidineacetic acid, methyl ester.

The product from Example 1(500 mg.) was dissolved in a mixture of 50 ml. of carbon tetrachloride and 10 ml. of benzene, the latter containing 1 equivalent of phosphorus tribromide based upon 500 mg.

of the product from Example 1. The solution was refluxed for 1.5 hours and then washed with sodium bicarbonate solution and dried. The solvent then was removed in vacuo. The resulting residue was purified by preparative thin-layer chromatography on silica gel using a 3:7 mixture of ethyl acetate and benzene as eluant. The title compound (204 mg.) was obtained as a white foam.

nmr (CD3CI): 2.05 (3H, broad s), 2.7 (4H, m), 3.63 (3H, s), 3.9 (3H, s), 5.2 (3H, m), 5.75 (2H, s), and 7.8 Hz. (4H, s).

WHAT WE CLAIM IS: 1. A compound of the formula

wherein n is 0 or 1; Ra is C1-C4 alkyl; Rl is hydrogen or a carboxy protecting group; and R is (a) phthalimido (b) an amido group of the formula

in which R2 is (I) hydrogen, C1-C3 alkyl, halomethyl, thienyl- 2 - methyl, 4 - protected - amino - 4- protected carboxybutyl, benzyloxy, 4- nitrobenzyloxy, t butyloxy, 2,2,2 - trichloroethoxy, 4 methoxybenzyloxy; (2) a group of the formula R'--(O),,-CH, in which m is 0 or 1, and R' is phenyl or phenyl substituted with 1 or 2 halogens, protected hydroxy, nitro, cyano, trifluoromethyl, C1-C4 alkyl, or C1- C2 alkoxy; (3) a group of the formula

in which R' is as defined above and W is protected hydroxy, protected carboxy, or protected amino; or (c) an imidazolidinyl group of the formula

in which R' is as defined above.

2. A compound of claim 1, in which n is 1.

3. A compound of claim 1, in which n is0.

4. A compound of any one of claims I to 3 in which R, is a carboxy protecting group.

5. A compound of any of claims 1 to 4 in which Ra is methyl or ethyl.

6. A compound of any of claims 1 to 5, in which R is phenylacetamido or phenoxyacetamido.

7. A process for preparing a compound of claim 1 in which n is 1, which comprises contacting a penicillin sulfoxide of the formula

with at least an equimolar amount of an acrylate ester of the formula

in which Ra is C1-C4 alkyl at a temperature of from 70"C, to 1100 C., wherein the terms are defined in claim 1 and Ria is a carboxy protecting group, optionally followed by removal of the carboxy protecting group.

8. Process of claim 7 in which Ra is methyl or ethyl.

9. Process of claim 7 or 8, in which R is phenylacetamido or phenoxyacetamido.

10. Process of any one of claims 7 to 9 in which the reaction is carried out in the presence of an inert organic solvent.

11. Process for preparing a compound of formula (I) as defined in Claim I wherein n is 1, substantially as described in any one of Examples 1, 2, 4 and 5.

12. A compound of formula (I) as defined in Claim 1 wherein n is 1, whenever

**WARNING** end of DESC field may overlap start of CLMS **.

Claims (14)

**WARNING** start of CLMS field may overlap end of DESC **. and dried. The solvent then was removed in vacuo. The resulting residue was purified by preparative thin-layer chromatography on silica gel using a 3:7 mixture of ethyl acetate and benzene as eluant. The title compound (204 mg.) was obtained as a white foam. nmr (CD3CI): 2.05 (3H, broad s), 2.7 (4H, m), 3.63 (3H, s), 3.9 (3H, s), 5.2 (3H, m), 5.75 (2H, s), and 7.8 Hz. (4H, s). WHAT WE CLAIM IS:

1. A compound of the formula

wherein n is 0 or 1; Ra is C1-C4 alkyl; Rl is hydrogen or a carboxy protecting group; and R is (a) phthalimido (b) an amido group of the formula

in which R2 is (I) hydrogen, C1-C3 alkyl, halomethyl, thienyl- 2 - methyl, 4 - protected - amino - 4- protected carboxybutyl, benzyloxy, 4- nitrobenzyloxy, t butyloxy, 2,2,2 - trichloroethoxy, 4 methoxybenzyloxy; (2) a group of the formula R'--(O),,-CH, in which m is 0 or 1, and R' is phenyl or phenyl substituted with 1 or 2 halogens, protected hydroxy, nitro, cyano, trifluoromethyl, C1-C4 alkyl, or C1- C2 alkoxy; (3) a group of the formula

in which R' is as defined above and W is protected hydroxy, protected carboxy, or protected amino; or (c) an imidazolidinyl group of the formula

in which R' is as defined above.

2. A compound of claim 1, in which n is 1.

3. A compound of claim 1, in which n is0.

4. A compound of any one of claims I to 3 in which R, is a carboxy protecting group.

5. A compound of any of claims 1 to 4 in which Ra is methyl or ethyl.

6. A compound of any of claims 1 to 5, in which R is phenylacetamido or phenoxyacetamido.

7. A process for preparing a compound of claim 1 in which n is 1, which comprises contacting a penicillin sulfoxide of the formula

with at least an equimolar amount of an acrylate ester of the formula

in which Ra is C1-C4 alkyl at a temperature of from 70"C, to 1100 C., wherein the terms are defined in claim 1 and Ria is a carboxy protecting group, optionally followed by removal of the carboxy protecting group.

8. Process of claim 7 in which Ra is methyl or ethyl.

9. Process of claim 7 or 8, in which R is phenylacetamido or phenoxyacetamido.

10. Process of any one of claims 7 to 9 in which the reaction is carried out in the presence of an inert organic solvent.

11. Process for preparing a compound of formula (I) as defined in Claim I wherein n is 1, substantially as described in any one of Examples 1, 2, 4 and 5.

12. A compound of formula (I) as defined in Claim 1 wherein n is 1, whenever

prepared by a process according to any one of Claims 7 to 11.

13. A compound of formula (I) as defined in Claim 1 substantially as hereinbefore described.

14. A compound of formula (I) as defined in Claim 1 substantially as described in any one of Examples 1, 2, 4, 5 and 6.