IE42190B1

IE42190B1 - Method of preparation of 3-methylenecephams

Info

Publication number: IE42190B1
Application number: IE2596/75A
Authority: IE
Original assignee: Lilly Co Eli
Priority date: 1974-12-24
Filing date: 1975-11-28
Publication date: 1980-06-18
Also published as: HU175226B; HU177431B; FR2300080B1; PL113883B1; FR2333804B1; GB1536288A; RO68478A; SE7514550L; ES457884A1; NL182880B; CS191291B2; DK157137B; CA1056372A; GR59922B; YU206481A; AT341672B; SE444810B; AU8708475A; BG31072A4; DD130933A5

Abstract

3-Methylenecepham 1-sulphoxides of the formula in which the substituents are defined in Claim 1 are prepared. These compounds are prepared by bringing about ring closure in a corresponding sulphinylazetidinone of the formula in which X is chlorine or bromine, an alcohol or thioalcohol residue, an ester or a thioester residue, or an amino radical. If X is chlorine or bromine, the compound II is reacted with a Friedel-Crafts catalyst of the Lewis acid type, with a Friedel-Crafts catalyst of the Bronsted protonic acid type or with a metathetical cation former in a dry inert organic solvent, or is dissolved in an organic Bronsted acid. If X in compounds II is an alcohol, thioalcohol, ester or thioester residue or an amino radical, reaction is carried out with a Friedel-Crafts catalyst of the Bronsted protonic acid type in a dry inert organic solvent, or the compound is dissolved in an organic Bronsted acid. The resulting compounds can be used for the preparation of cephem antibiotics.

Description

TATENT APPLICATION BY (71) 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 STPEET, CITY OF INDIANAPOLIS, STATE OF INDIANA, UNITED STATES OF AMERICA. prtet I2ip The present invention provides a novel process for preparing 3-methylenecepham sulfoxides by the intramolecular cyclization of penicillin sulfoxide-derived azetidinonesulfinyl chlorides and related, sulfinic acid derivatives by reaction with Friedel-Craft catalysts or metathetic cationforming agents. The 3-methylenecepham compounds are useful intermediates in the preparation of cephem antibiotics.

A process for preparing penicillin sulfoxide-derived azetidinone-sulfinyl halides is described and claimed in Patent Specification No. tf,2,l · Penicillins and more recently cephalosporins have been recognized for their high degree of antibacterial activity and have been used extensively for the treatment of infectious diseases in man. There has been a considerable research effort directed toward the chemical modification of these compounds in search of yet more active beta-lactam antibiotics. More emphasis has been placed specifically on the variation of the Cg-acylamino substituent on the penicillin compounds and both the C^-acylamino substituent and the C^substituent on the cephem compounds.

Recently R. R. Chauvette and P.A. Pennington reported the use of 3-methylenecephams both in the preparation of 7-amino-dosacetoxycephalosporanic acid and biologically active derivatives thereof ^Journal of Organic Chemistry, ^8, 2994 (1973)J, and in the preparation of novel 3-methoxyand 3-halo cephems ^Journal of the America! Chemical Society, 96, 4986 (l974)j. In each case the 3-methylenecepham intermediates were prepared from cephalosporanic acids by first treating the cephalosporanic acids with selected sulfur nucleophiles such as thiourea, thiobenzoic acid, potassium ethyl xanthate or sodium thiosulfate and then reducing the respective product Cj-(substituted)thiomethyl cephem derivatives with either Raney nickel in aqueous ethanol or zinc in 42180 formic acid-dimethylformamide. The demonstrated versatility of the 3-methylenecephams as intermediates for novel cephem antibiotics has prompted a search for alternative procedures for preparing such compounds from readily available, econom5 ical starting materials.

The present invention provides a novel process for preparing 3-methylenecepham sulfoxides by the intramolecular cyclization of penicillin sulfoxide derived azetidinone- 2-sulfinyl chlorides and sulfinic acid, sulfinate ester, thiosulfinate ester, sulfinamide, and sulfinimide derivatives thereof with Friedel-Crafts catalysts or metathetic cation forming agents. Some of the azetidinone sulfinic acid derivative starting materials are themselves novel.

The present invention provides a process for preparing 3-methylenecepham sulfoxides of the formula X'x Ahs COOR' which comprises reacting a compound of the formula Ri II SX Xa IX COOR 2o with a Lewis acid type Friedel-Crafts catalyst, a Bronsted proton acid type Friedel-Crafts catalyst or a metathetic -3. # 42190 cation-forming agent in a dry inert organic solvent; or dissolving such compound in an organic Bronsted acid; wherein in the above formulae R is a carboxylic acid protecting group; R' is R or hydrogen; Rj- is (1) an imido group of the formula II II wherein R2 is C2-C4 alkenylene, C2~C4 alkylene, 1,2phenylene or 1,2-cyclohexenylene; or (2) an amido group of the formula II RaCNHwherein R3 is (a) hydrogen, alkyl, halomethyl,cyanomethyl or 3- (2-chlorophenyl)-5-methylisoxazol-4-yl; (b) benzyloxy, 4-nitrobenzyloxy, 2,2,2trichloroethoxy, tert-butoxy, or 4methoxybenzyloxy; (®) the group R wherein R is 1,4-cyclohexadienyl, phenyl or phenyl substituted with 1 or 2 substituents, independently 2q selected from halo, protected hydroxy, nitro, cyaho, trifluoromethyl, C^-C^ alkyl, and C^-C4 alkoxy; (d) a substituted, alxyl group of the formula R - (0) -CH-m 2 -443190 wherein R is as defined above, and m is 0 or 1; (e) a substituted alkyl group of the formula R' CH— I W wherein R''' is R as defined above and W is protected hydroxy, or protected amino; (3) an imido group of the formula II R '0 Z A“ R-(0) CHG m e|( wherein R and m are as defined hereinabove and R21 is C|-C3 alkyl, Cj-Cg haloalkyl, C1-C3 alkoxy or 2,2,2-trichloroethoxyj or (4) an imidazolidinyl group of the formula II wherein· R is as defined above and Y is acetyl or nitroso; and X is (1) chloro or bromo; (2) a group of the formula -QR^ wherein R4 is hydrogen, Cj-C.^ alkyl, aryl(C^-c3 alkyl) or C^-Cg haloalkyl; -543ΐθ° (3) a group of the formula -SR^ wherein Rg is C^-Cg alkyl, aryl or aryl(C1-Cg alkyl); or ZR. (4) a group of the formula -N. 13 R wherein (a) Rg is hydrogen and Rg is hydrogen, R as defined hereinabove, or a group of the formula -NHRg wherein Rg is aminocarbonyl, C^-Cg alkylaminocarbonyl, C^-Cg alkoxycarbonyl, C^-Cg alkylcarbonyl or tosyl; or wherein (b) Rg is -COORg or -CORg and Rg is -NHCOOR. or -NHCOR. wherein R„ is C,-C, 9 9 1 6 alkyl, or phenyl; or wherein (c) Rg, R? and the nitrogen atom to which they are bonded taken together form an imido group of the formula II II wherein Rg is as defined hereinabove: and when R. is -COOR. or -COR. and R. is 6 9 9 7 -NHCOORg or -NHCORg, Rg is additionally a heteroarylmethyl group of the formula R'^'CHg- wherein 43' ' ' ' is 2-thienyl, 3thienyl, 2-furyl, 3-furyl, 2-thiazolyl or -isoxazolyl; -642190 with the limitations that when X is bromo, R^ is only an imido group of the formula II II when a metathetic cation-forming agent or a Lewis acid is 5 employed, X is only chloro or bromo; and when R is an acid labile carboxylic acid protecting group, the product is a 3-methylenecepham-4-carboxylic acid sulfoxide.

The pounds of the present invention is also directed to cornformula R Π » /-’γ'co II COOR and X are as defined hereinabove with the wherein R, R exception that X is other than chloro, bromo, or a group of the formula -Νξ e wherein Rg is -COORg or -CORg and R? ^7 is -NHCOORg or -NHCORg.

In the foregoing definition of the process of the present invention the term C^-C^ alkyl refers to methyl, ethyl, n-propyl, or isopropyl. The term alkyl includes methyl, ethyl, propyl, isopropyl, cyclohexyl, secbutyl, heptyl, octyl, isooctyl, decyl, or menthyl. C^-Cg Haloalkyl represents groups such as chloromethyl, bromoethyl, iodoethyl, 2-chloropropyl, 2-chlorocyclohexyl, or 2-chlorobutyl. The term aryl(C^-C3alkyl) includes benzyl, -74 2 J. 9 Ο 2- phenylethyl, 2-phenyl propyl, 4-chlorobenzyl, naphthylmethyl, or 3-(2-nitrophenyl) propyl. Exemplary of the term ti II C1-C3 alkoxycarbonyl are methoxycarbonyl, ethoxycarbonyl, and isopropoxycarbonyl. Exemplary of halomethyl groups are chloromethyl, bromomethyl or iodomethyl. Imido groups represented when R3 is C3-C4 alkenylene are maleimido, 3- ethylmaleimido, or 3,4-dimethylmaleimido. Imido groups represented when R is 1,2-cyclohexenylene or 1,2-phenylene are 3,4,5,6-tetrahydrophthalimido or phthalimido respec10 tively.

When in the above definition R represents a substituted phenyl group, R can be a mono or disubstituted halophenyl group such as 4-chlorophenyl, 2,6-dichlorophenyl, 2,5-dichlorophenyl, 3,4-dichlorophenyl, 3-chlorophenyl, 315 bromophenyl, 4-bromophenyl, 3,4-dibromophenyl, 3-chloro-4fluorophenyl, or 2-fluorophenyl; a protected hydroxyphenyl group such as 4-benzyloxyphenyl, 3-benzylOxyphenyl, 4-tertbutoxyphenyl , 4-tetrahydropyranyloxyphenyl, 4-(4-nitrobenzyloxy)phenyl, 2-phenacyloxyphenyl, 4-benzhydryloxyphenyl, or 4-trityloxyphenyl; a nitrophenyl group such as 3-nitrophenyl or 4-nitrophenyl; a cyanophenyl group, for example, 4- cyanophenyl; a mono or dialkyl substituted phenyl group such as 4-methylphenyl, 2,4-dimethylphenyl, 2-ethylphenyl, 4-isopropylphenyl, 4-ethylphenyl, or 3-n-propylphenyl; or a mono- or dialkoxyphenyl group, for example, 2,6-dimethoxyphenyl, 4-methoxyphenyl, 3-ethoxyphenyl, 4-isopropoxyphenyl, 4-tert-butoxyphenyl, or 3-ethoxy-4-methoxyphenyl. Also, R represents disubstituted phenyl groups wherein the substituents can be different for example, 3-methyl-430 methoxyphenyl, 3-chloro-4-benzyloxyphenyl, 2-methoxy-4-842190 bromophenyl, 4-ethyl-2-methoxyphenyl, 3-chloro-4-nitrophenyl or 2-methyl-4-chlorophenyl, The term protected amino as employed in the above definition has reference to an amino group substituted with one of the commonly employed amino blocking groups such as the tert-butoxycarbonyl group (t-BOC); the benzyloxycarbonyl group, the 4~methoxybenzyloxycarbonyl group, the 4-nitrobenzyloxycarbonyl group, the 2,2,2-trichloroethoxycarbonyl group, or the l-carbomethoxy-2-propenyl group ]q formed with methyl acetoacetate. Like amino protecting groups such as those 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 also are recognized as suitable.

The term protected hydroxy has reference to the readily cleavable groups formed with an hydroxyl group such as the formyloxy group, the chloroacetoxy group, the benzyloxy group, the benzhydryloxy group, the trityloxy group, the 4-nitrobenzyloxy group, the trimethylsilyloxy group, the phenacyloxy group, the tert-butoxy group, the methoxymethoxy group, or the tetrahydropyranyloxy group. Other hydroxy protecting groups, including those described by C. B, Reese in Protective Groups in Organic chemistry, supra, Chapter 3 also are considered as within the term protected hydroxy as used herein.

The term carboxylic acid protecting group has reference to the commonly used carboxylic acid protecting groups employed to block or protect the carboxylic acid functionality while reactions involving other functional _9_ 42ΐθθ sites of the compound are carried out. Such carboxy protecting groups are noted for their ease of cleavage by hydrolytic or by hydrogenolytic methods to the corresponding carboxylic acid. Examples of carboxylic acid ester pro5 tecting groups include methyl, tert-butyl, benzyl, 4methoxybenzyl, C2~Cg alkanoyloxymethyl, 2-iodoethyl, 4nitrobenzyl, diphenylmethyl (benzhydryl), phenacyl, 4halophenacyl, 1,1- and 3,3-ditnethylallyl, 2,2,2-trichloroethyl, tri(Cj-C^ alkyl)silyl, or succinimidomethyl. Other known carboxy protecting groups such as those described by E. Haslam in Protective Groups in Organic Chemistry, supra. Chapter 5, also are recognized as suitable. The nature of such ester forming groups is not critical.

When the azetidinone sulfinic acid derivative j5 starting material for the process of this invention is protected with an acid labile carboxy protecting group such as 4-methoxybenzy1, benzhydryl, tert-butyl or triiC^C^alkyl)silyl the product of the cyclization of the present invention is a 3-exomethylenecepham sulfoxide acid. Like20 wise, if the starting materials have Similar acid labile hydroxy or amino protecting groups, such groups will usually be removed under the acidic conditions of the present cyclization process. The removal of certain acid labile protecting groups under the reaction conditions of the present process is not a critical feature of the present invention. The protecting groups on the azetidinone starting materials for the process of this invention are present because of the necessity of protecting their precursor penicillin sulfoxides during the preparation of the intermediate azetidinone sulfinyl halides. Thus, the -1043190 primary purpose of the protecting groups is to protect the reactive functional groups during the preparation of the starting materials. The nature of the protecting group is not critical to the present process. No significant reduction in yield of exomethylenecepham sulfoxide is noted when acid labile protecting groups are employed. Xn such case, the only difference is that the products are typically cepham acids instead of cepham esters. Since subsequent conversions are usually contemplated for the exomethyl 10 enecepham sulfoxide products of the present invention, it is preferred that the reactive functional groups on these products remain protected during the cyclization process of this invention. Non-acid labile protecting groups are therefore preferred. The preferred carboxylic acid ester protecting groups are methyl, 2-iodoethyl, 4-nitrobenzyl, 4-halophenacyl and 2,2,2-trichloroethyl.

In the foregoing definitions, hydroxy, amino, and carboxy protecting groups are not exhaustively defined. The function of such groups is to protect the reactive func20 tional groups during the preparation of the starting materials and then be removed at some later point in time without disrupting the remainder of the molecule. Many such protective groups are well known in the art and the use of other groups equally applicable to the process and compounds of the present invention is recognized as suitable. Thus, there is no novelty or inventiveness asserted with regard to the protecting groups alluded to in this specification. tl Representative of the acylamino group, R^CNH-, as defined hereinabove are formamido, acetamido, propion-11amido, butyramido,chioroacetamido or bromoacetamido.

Illustrative of the particular acylamino group, O RCNH-, are benzamido, 2,6-dimethoxybenzamido, 4-chlorobenzamido, 4-methylbenzamido, 3,4-dichlorobenzamido, 4cyanobenzamido, 3-bromobenzamido, or 3-nitrobenzamido.

Exemplary of the acylamino group R^CNII, when R3 is a group of the formula R(OJ^CI^- and m is 0, are cyclohexa-l,4-dienylapetamido, phenylacetamido, 4-chlorophenylacetamido, 3-methoxyphenylacetamido, 3-cyanophenylacetamido, 3- methylphenylacetamido, 4-bromophenylacetamido, 4-ethoxyphenylacetamido, 4-nitrophenylacetamido, or 3,4-dimethoxyphenylacetamido; and when m is 1, representative acylamino groups are phenoxyacetamido, 4-cyanophenoxyacetamido, 4- chlorophenoxyacetamido, 3,4-dichlorophenoxyacetamido, 2- chlorophenoxyacetamido, 4-methoxyphenoxyacetamido, 2ethoxyphenoxyacetamido, 3,4-dimethylphenoxyacetamido, 4isopropylphenoxyacetamido, 3-cyanophenoxyacetamido, or . 3- nitrophenoxyacetamido.

Illustrative of the acylamino groups when R3 is a substituted arylalkyl group of the formula R'''-CH- and I w when W is protected hydroxy are 2-formyloxy-2-phenylacetamido, 2-benzyloxy-2-(4-methoxyphenyl)acetamido, 2-(4nitrobenzyloxy)-2-(3-chlorophenyl)acetamido, 2-chloroacetoxy-2-(4-methoxyphenyl)acetamido, 2-benzyloxy-2-phenylacetamido, 2-trimethylsilyloxy-2-(4-chlorophenyl)acetamido, or 2-benzhydryloxy-2-phenylacetamido. Representative of such groups when W is protected amino are 2-(4-nitrobenzyl-1242190 oxycarbonylamino)-2-phenylacetamido, 2-(2,2,2-trichloroethoxycarbonylamino)-2-phenylacetamido, 2-chloroacetamido2-(1,4-cyclohexadien-l-yl)acetamido, 2-(4-methoxybenzyloxycarbonylamino)-2-(4-methoxyphenyl)acetamido, 2-benzhydryl5 oxycarbonylamino-2-phenylacetamido, or 2-(1-carbomethoxy2-propenyl) amino-2-phenylacetamido.

Representative of R^ wherein Rg is an imido group of the formula II R 'C Λ R -(0) CH C m S|| jQ are N-acetyl-N-phenylacetylamino, N-trichloroethoxycarbonyl-N-phenoxyacetylamino, N-propoxycarbonyl-N-(4-ehlorophenoxy)acetylamino, or N-(2-bromoacetyl)-N-phenoxyacetylamino.

II Exemplary of the acylamino group RgCNH- when Rg is a heteroarylmethyl group of the formula R-CH2- are 2thienylacetamido, 3-thienylacetamido, 2-furylacetamido or a 2-thiazolylacetamido group of the formula s -1343ΐ3θ Representative of R^ when R^ is an imidazolidinyl group of the formula ll CH are the 2,2-dimethyl-3-nitroso-5-oxo-4-phenyl-l-imidazolidinyl group, the 2,2-dimethyl-3-nitroso-5-oxo-4-(4-benzyloxyphetiyl)-1-imidazolidinyl group or the 2,2-dimethyl-3acetyl-5-oxo-4-(1,4-cyclohexadien-l-yl)-1-imidazolidinyl group .

In general, the process of this invention is 10 directed to the cyclization of penicillin sulfoxide derived azetidinone sulfinic acid derivatives by the Friedel-Crafts catalyst induced intramolecular reaction of the sulfinyl and olefinic functionalities on the azetidinone ring. This internal alkylsulfination reaction can be regarded as an J 5 analog of a Friedel-Crafts acylation reaction, in which a II sulfinyl group {—S—) is substituted for a carbonyl group -1442190 ο Η (—C—), and the product is a sulfoxide instead of a ketone.

The literature contains at least three reports of FriedelCrafts type sulfinylation reactions. Specifically, the intermolecular arenesulfinylation of aromatics giving diaryl sulfoxides has been described [C. Courtot and J. Frenkiel, C. R. Acad, Sci., 199, 557 (1934); George A. Olah and Jun Nishimura, J. Org. Chem., 39, 1203 (1973); and Irwin B. Douglass and Basil Said Farah, J. Org, Chem., 23, 805 (1958)]. In an analogous reaction alkyl or arylsulfenyl chlorides react with aromatic hydrocarbons in the presence of aluminium chloride catalyst to give thioethers with good yields [H. Britzinger and M. Langheck, Ber., 86, 557 (1953)]. The reaction of alkyl or arylsulfonic acid chlorides with aromatics to provide sulfones has been more extensively investigated. See e.g., George A. Olah, Friedel-Crafts Chemistry, John Wiley and Sons, Inc., New York, N.Y., 1973, pp. 122-123, 146, 507. There have been no previous reports of intramolecular alkylsulfinylation of the sort described hereinbelow. The intramolecular cyclization of carboxylic acids and derivatives thereof with Friedel-Crafts catalysts to prepare cyclic ketones is, however, well documented in the chemical literature. See William S. Johnson in Organic Reactions, Roger Adams et al., Eds., John Wiley and Sons, Inc., New York, N.Y., 1944, Chapter 4, pp. 130-177 and Friedel-Crafts Chemistry, supra. It has been found in this invention that conventional Friedel-Crafts acylation procedures, including reaction conditions, solvents, and catalytic reagents are successfully applied generally to the intramolecular cyclization of the azetidinone sulfinyl chlorides and derivatives thereof -1542190 The azetidinone sulfinyl chloride starting materials for the process of the present invention are derived from the corresponding known penicillin sulfoxide esters by reacting such esters at elevated temperatures with a reagent serving as a source of positive halogen, preferably an N-haloimide such as N-chlorosuccinimide (NCS). The conversion of 6-imido penicillin sulfoxide esters to the corresponding azetidinone sulfinyl chlorides with sulfuryl chloride has been described in the literature [S. Kukolja and S. R.

Lammert, Angew. Chem., 12, 67-68 (1973)], Generally the sulfinyl chloride starting materials for the process of this invention are prepared by reacting a penicillin sulfoxide ester with about 1.1 equivalents of N-chlorosuccinimide in a dry inert organic solvent, preferably 1,1,2-trichloroethane or toluene at a temperature of about 70° to 120°C., the preferred temperature being dependent primarily on the nature of the Cg-substituent. The conversion of Cg-imido penicillin sulfoxides is usually accomplished at 70-100°C., while slightly higher temperatures (100-120°C.) are pre20 ferred for the sulfinyl chloride preparation from Cgacylamino penicillin sulfoxides. The reaction is usually complete in 45-90 minutes at the preferred reaction temperature. The penicillin sulfoxide ester precursors to the sulfinyl chlorides are either known or readily available compounds, many of which have been used in the preparation of cephem compounds. They are prepared from known 7-acylamino and 7-imido penicillin acids by (1) esterification and (2) subsequent oxidation, usually with meta-chloroperbenzoic acid or sodium periodate. -164219 Exemplary of the preparation of the azetidinone sulfinyl chloride starting materials of the present invention is the following brief description of the preparation of 4'-nitrobenzyl 3-methyl-2-(2-chlorosulfinyl-4-oxo5 3-acetamido-l-azetidinyl)-3-butenoate: A solution of 5 mmoles of 4'-nitrobenzyl 6-acetamidopenicillanate 1-oxide in 200 ml. of toluene is heated to reflux and dried azeotropically by allowing approximately 20 ml. of toluene to be distilled from the mixture. After cooling the mixture briefly, 5.5 mmoles of N-chlorosuccinimide is added. The mixture is refluxed for 90 minutes after which time the solution is cooled to room temperature and filtered. Evaporation in vacuo of the filtrate provides 41-nitrobenzyl 3-methyl-2-(2-chlorosulfinyl-4-oxo-3-acetamido-l-azetidinyl)15 3-butenoate as a froth. The azetidinone sulfinyl chlorides thus obtained can be employed in the cyclization process of this invention directly without purification. Indeed, it is often the case that the Friedel-Crafts catalyst reagent is added directly to the final reaction mixture of the preparation of the azetidinone sulfinyl chloride.

In a reaction analogous to the reaction of penicillin sulfoxide esters with NCS to provide azetidinone sulfinyl chlorides, penicillin sulfoxide esters having an imido group at C-6 can be reacted with N-bromosuccinimide (NBS) to provide the corresponding azetidinone sulfinyl bromides. The reaction conditions for this conversion are identical to those employed in the aforedescribed sulfinyl -174 219 0 chloride preparation using NCS. The aforedescribed azetidinone sulfinyl chlorides and the corresponding sulfinyl bromides exhibit similar chemical reactivity in regard to the cyclizing agents described in detail hereinbelow.

The azetidinone sulfinic acids of the formula II wherein R and R^ are as defined hereinabove, are generally prepared from the corresponding sulfinyl chlorides by slurrying an ethyl acetate solution of the sulfinyl chloride jo with an aqueous sodium bicarbonate solution at room temperature for about one hour. The aqueous layer containing the sulfinic acid salt is separated, washed with ethyl acetate, layered with another portion of ethyl acetate and then acidified. The organic layer is separated, washed with brine, dried over anhydrous sodium sulfate, and then evaporated in vacuo to dryness. The sulfinic acids thereby isolated are generally obtained as colorless amorphous solids.

Representative of the sulfinic acids of this in20 vention are the following: 4'-nitrobenzyl 3-methy1-2-(2-sulfino-4-oxo-3phenylacetamido-l-azetidinyl)-3-butenoate, 2',2',2'-trichloroethyl 3-methy1-2-(2-sulfino-4oxo-3-acetamido-l-a2etidinyl)-3-butenoate, -1842180 2'-iodoethyl 3-methy1-2-(2-sulfino-4-oxo-3chloroacetamido-1-azetidinyl)-3-butenoate, 4'-methoxybenzyl 3-methyl-2-(2-sulfino-4-oxo3-phthalimido-1-azetidinyl)-3-butenoate, tert-butyl 3-methyl-2-[2-sulfino-4-oxo-3-(2bromoacetamido)-1-azetidinyl]-3-butenoate, benzhydryl 3-methy1-2-[2-sulfino-4-oxo-3-(4chlorophenoxyacetamido)-1-azetidinyl]-3-butenoate, 4'-nitrobenzyl 3-methy1-2-[2-sulfino-4-oxo-3(4-nitrobenzyloxycarbonylamino)-1-azetidinyl]-3-butenoate, 2',2',21-trichloroethyl 3-methy1-2-[2-sulfino-4oxo-3-(2,2-dimethyl-3-nitroso-5-oxo-4-phenyl-l-imidazolidinyl)-1-azetidinyl]-3-butenoate, 2*-iodoethyl 3-methy1-2-[2-sulfino-4-oxo-3-acetamido-l-azetidinyl]-3-butenoate, and 4l-nitrobenzyl 3-methy1-2- [2-sulfino-4-oxo-3(4-chlorobenzamido)-1-azetidinyl]-3-butenoate.

It is recognized that other derivatives of the azetidinone sulfinyl chlorides, including sulfinate esters, thiosulfinate esters, and euifinamide and sulfinimide derivatives thereof, can be prepared from the sulfinic acids and from their precursor sulfinyl chlorides. Such derivatives can be prepared by well-known conventional procedures employed in the preparation of carboxylic acid derivatives e.g. esters, thioesters, amides and imides, from carboxylic acids and carboxylic acid chlorides. Some azetidinone sulfinamide derivatives have been prepared directly from penicillin sulfoxides [S. Terao, T. Matsuo, S. Tsushima, N.

Matsumoto, T. Miyawaki, and M. Miyamoto, J. Chem. Soc (C), 1304 (1972)]. It is further recognized that such derivatives can be cyclized to 3-methylenecepham sulfoxide compounds by the procedures and conditions set forth hereinbelow.

Azetidinone sulfinic acid esters (sulfinates) of the formula II ,SOR Ioor wherein R and R^ are as defined hereinabove and is C^-C^o alkyl, aryl(C1-C3alkyl) or C^-Cg haloalkyl are prepared from the aforedescribed penicillin sulfoxide derived azetidinone sulfinyl chlorides by reacting the sulfinyl chloride with the corresponding C^-C^q alkanol, aryl(C^-C3 alkanol) or C.-C, haloalkanol, respectively. Typically the sulfinic -L o acid esters are prepared by adding the desired alcohol directly to the reaction mixture in which the azetidinone sulfinyl chloride has been generated from a penicillin sulfoxide. The product sulfinic acid ester is then isolated using standard isolation techniques including evaporation, crystallization and chromatography.

Exemplary of alcohols which can be employed in the preparation of the sulfinic acid esters of this invention are methanol, ethanol, isopropanol, cyclohexanol, 4-chlorocyclohexanol, sec-butanol, n-heptanol, menthol, benzyl alcohol, 2-phenylethanol, 3-phenylpropanol, 2-chlorobenzyl alcohol, 4-methoxybenzyl alcohol, 2-(4-nitrophenyl) ethanol, -2042190 2-chloroethanol, 2-bromoethanol, 3-bromocyclohexanol, 4chlorobutanol, or 3-chloropropanol.

Representative of the azetidinone sulfinic acid esters are 41-nitrobenzyl 3-methyl-2-(2-isobutoxysulfinyl4-oxo-3-acetamido-l-azetidinyl)-3-butenoate, benzhydryl 3-methyl-2-[2-(2-chloropropoxysulfinyl)4-oxo-3-phenoxyacetamido-1-azetidinyl]-3-butenoate, 2',2',2'-trichloroethyl 3-methyl-2-[2-(2-bromoethoxysulfinyl)-4-oxo-3-(2-formyloxy-2-phenylacetamido)-1azetidinyl]-3-butenoate, 2'-iodoethyl 3-methyl-2-[2-(4-bromobenzyloxysulfinyl)-4-oxo-3-phthalimido-l-azetidinyl]-3-butenoate, tert-butyl 3-methyl-2-(2-methoxysulfinyl-4-oxo3-benzyloxycarbonylamino-l-azetidinyl)-3-butenoate, 4'-chlorophenacyl 3-methyl-2-[2-(2-phenylisopropoxysulfinyl)-4-oxo-3-(2-chlorobenzamido)-1-azetidinyl]-3butenoate, 41-methoxybenzyl 3-methyl-2-[2-cyclohexyloxysulfinyl-4-oxo-3-(2,2-dimethyl-3-nitroso-5-oxo-4-phenyl1-imidazolidinyl)-l-azetidinyl]-3-butenoate, and methyl 3-methyl-2-[2-(3-phenylpropoxysulfinyl)4-ΟΧΟ-3-(4-chlorophenoxyacetamido)-1-azetidinyl]-3-butenoate.

Azetidinone thiosulfinate esters of the formula II R Lor -2143190 wherein R and R^ are as defined hereinabove and R^ is C^-Cg alkyl, aryl, or aryl(C^-C3 alkyl) are prepared from the aforedescribed azetidinone sulfinyl chlorides by their reaction with the corresponding C^-Cg alkylthiol, arylthiol or aryl(C^-C3 alkyl)thiol respectively. The thiosulfinate esters are prepared and isolated using standard experimental techniques. Their preparation is directly analogous to the preparation of carboxylic acid thioesters from carboxylic acid chlorides.

Representative of thiols or mercaptans which can be employed in the preparation of the azetidinone thiosulfinate esters are methanethiol, ethanethiol, 2-propanethiol, 2-methyl-2-propanethiol, hexanethiol, 2-pentanethiol, 1-butanethiol, thiophenol, 4-chlorothiophenol, 2-phenylethanethiol, and benzyl mercaptan.

Representative of the azetidinone thiosulfinate esters of this invention are 41-nitrobenzyl 3-methy1-2-(2-methylthiosulfinyl 4-oxo-3-formamido-l-azetidinyl)-3-butenoate, 2'-iodoethyl 3-methy1-2-[2-(2-methyl-l-propanethiosulfinyl)-4-oxo-3-(4-methoxybenzyloxycarbonylamino)-1azetidiny1J -3-butenoate, 2',2',2'-trichloroethyl 3-methyl-2-[2-(1-hexanethiosulfinyl)-4-oxo-3-(4-trifluoromethylbenzamido)-1azetidinyl]-3-butenoate, benzhydryl 3-methy1-2-[2-benzylthiosulfiny1-4oxo-3-(4-methylphenoxyacetamido)-1-azetidinyl]-3-butenoate, and -224219ο tert-butyl 3-methy1-2-[2-phenylthiosulfinyl-4oxo-3-(4-nitrobenzyloxycarbonylamino)-1-azetidinyl]-3butenoate.

The sulfinamide and sulfinimide derivatives of the 5 penicillin sulfoxide derived azetidinone sulfinyl chlorides are represented by the formula wherein R and R^ are as defined hereinabove and wherein (a) Rg is hydrogen and R? is hydrogen, R as defined hereto inabove, or a group of the formula -NHRg wherein Rg is aminocarbonyl, Cg-Cg alkylaminocarbonyl, Cg-Cg alkoxycarbonyl, Cj-Cg alkylcarbonyl or tosyl; or wherein (b) Rg and R? and the nitrogen atom to which they are bonded taken together form an imido group of the formula wherein Rg is as defined hereinabove.

Generally the azetidinone sulfinamides and sulfinimides are prepared from the corresponding sulfinyl chlorides in the same manner carboxamides and carboximides 2o are prepared from carboxylic acid chlorides; that is, by reacting the acid chloride with from about 1 to about 2 equivalents of an appropriate amine base. Typically this -2343190 reaction, like the aforedescribed preparation of sulfinic acid esters and thiosulfinic esters, is carried out in an inert organic solvent such as benzene, toluene, methylene chloride, chloroform, or ethyl acetate. The following table illus5 trates the particular bases employed to prepare individual sulfinamides and sulfinimides: Lor Amine base -SNH2 -SNHR O 0 -SNHNHCNH2 0 0 -SNHNHCNH(Cg-Cg)alkyl 0 0 -SNHNHCO(Cg-Cgalkyl) O 0 -SNHNHC(Cg-Cgalkyl) 0 0 .-. ’’ / \ nh4ci -SNHNHS+ .•-CH R-NHg 0 H2NNHCNH2 HgNNHCNH(Cg-Cgalkyl) 0 HgNNHCO(Cg-C3alkyl) HgNNHC(Cg-Cgalkvl) H.NNHS-.f >-CH 2 I Sm/ 0 o K-<>a Succinimidosulfinyl azetidinones can also be prepared in accordance with the following reaction sequence. -2442190 The penicillin sulfoxide ester is heated in diroethylformamide at about 105°C. with an excess of N-trimethylsilylsuccinimide in the presence of acetic acid. The azetidinone sulfenimide thereby derived i,s then oxidized with m-chloroperbenzoic aoid to provide the corresponding sulfinimide derivative.

Representative of the azetidinone sulfinamides and sulfinimides are: 4'-nitrobenzyl 3-methyl-2-(2-phthalimidosulfihyl4-oxo-3-phenylacetamido-l-azetidinyl)-3-butenoate, 2'-iodoethyl 3-methy1-2-[2-(4-chloroanilinosulfinyl)-4-oxo-3-phenoxyacetamido-l-azetidinyl]-3-butenoate, benzhydryl 3-methy 1-2- [2-carbamoylhydrazosulfinyl4-oxo-3-(4-nitrobenzyloxycarbonylamino)-1-azetidinyl)-3butenoate, 4'-chlorophenacyl 3-methy1-2-(2-ethylearbairoylhydrazosulfinyl-4-oxo-3-formamido-l-azetidinyl)-3-butenoate, -2542190 tert-butyl 3-methyl-2- /2-carbethoxyhydrazosul” 1 4 finyl-4-oxo-3-(2-formyloxy-2-phenylacetamido)-1-azetidinyl]3- butenoate, 2^2^21 -trichloroethyl 3-methyl-2- (2-propionylhydrazosulfinyl-4-oxo-3-phthalimido-1-azetidinyl)-3-butenoate, methyl 3-methyl-2-[2-(4-tolylsulfonylhydrazosulfinyl)-4-oxo-3-(2-chlorobenzamido)-1-azetidinyl]-3butenoate, 4‘-methoxybenzyl 3-methy1-2-(2-succinimidosulfinyl4- oxo-3-propionamido-1-azetidinyl)-3-butenoate, 4'-nitrobenzyl 3-methyl-2-[2-(4-methoxyanilinOsulf inyl)-4-oxo-3-phehoXyacetamido-l-azetidinyl]-3-butenoate, 21-iodoethyl 3-methyl-2-(2-carbomethoxyhydrazosulfinyl-4-oxo-3-chloroacetamido-l-azetidinyl)-3-butenoate, and 2’,2’,21-trichloroethyl 3-methyl-2-[2-acetylhydrazosulfinyl-4-oxo-3-(2-tert-butoxycarbonylamino-2-phenylacetamido)-1-azetidinyl]-3-butenoate.

In addition to the aforedescribed sulfinamides, other sulfinamides can be employed as starting materials in the cyclization process of this invention. In particular, azetidinone sulfinamides of the formula NHCOOR 111 /S-N-C00Ra η a :·-Μ.

NHCOR„ ll I l-NCOR i\ Π 1 . u γ COOR COOR wherein R and R^ are as defined hereinabove, and Rg is C^-Cg alkyl or phenyl, can by cyclized under the acidic -2643190 conditions of the present process to provide the corresponding 3-methylenecepham sulfoxides. Such azetidinone sulfinamides are known compounds. [S. Terao et al., supra].

They are prepared directly from penicillin sulfoxides by their reaction with azodicarboxylates or diacyldiimides.

With the somewhat milder reaction conditions (compared with those reaction conditions for sulfinyl halide preparation) for the preparation of these azetidinone sulfinamides, a wider range of penicillin sulfoxide starting materials may be employed.

Thus R-j in the sulfinamide formula immediately hereinabove can represent, in addition to those groups described hereinO before, an amide group of the formula R''''CH2CNH- wherein R11'' is 2-thienyl} 3-thienyl, 2-furyl3 3-furyl, 2-thiazolyl, or -isoxazoIyl.

Exemplary of the sulfinamide starting materials derived directly from penicillin sulfoxides and azodicarboxylates or diacyldiimides, for the process of this invention are 4'-nitrobenzyl 3-methyl-2-[2-(N,N'-dicarbotertbutoxyhydrazosulfinyl)-4-oxo-3-(2-thienylacetamido)-1azetidinyl]-3-butenoate, 2'-iodoethyl 3-methyl-2-[2-(Ν,Ν'-dibenzoylhydrazosulfinyl)-4-oxo-3-phenoxyacetamido-l-azetidinyl]-3-butenoate, 2' , 2' ,2'-trichloroethyl 3-methyl-2- [2- (N,N'dicarboethoxyhydrazosulfinyl)-4-oxo-3-phenylacetamido-lazetidiny1]-3-butenoate, -2742190 benzhydryl 3-methyl-2-[2-(N,N'-dicarbomethoxyhydrazosulfinyl)-4-oxo-3-(2-formyloxy-2-phenylacetamido)-1azetidinyl]-3-butenoate, and ' -chlo-rophenacyl 3-tnethyl-2- [2- (N,N'-dicarbo5 propoxyhydrazosulfinylj-4-oxo-3-acetamido-l-azetidinyl]-3butenoate.

The scope of reagents suitable for effecting the intramolecular sulfinylation of the process of this invention is essentially coextensive with that of those reagents which have been recognized as capable of effecting acylation reactions of the Friedel-Crafts type. An extensive survey of Friedel-Crafts acylations, related reactions, and catalysts therefor is presented by George A.

Olah in Friedel-Crafts Chemistry, John Wiley and Sons, New York, N.Y., 1973.

Suitable reagents which can be employed in the process of this invention to effect intramolecular cyclization of the aforedescribed azetidinone sulfinyl chlorides and sulfinyl bromides are the conventional Friedel-Crafts catalyst reagents, including Lewis acid type catalysts, Bronsted proton acid type catalysts, and metathetic cationforming agents. Preferred of the Lewis acid type FriedelCrafts catalysts are the metal halide Lewis acid type catalysts. The Bronsted proton acid type catalysts include acidic chalcides (particularly acidic oxides), conjugate Friedel-Crafts catalysts of the formula HMA^ or HMAg, where M is B, Al or As and A is F, Cl or Br, and both the organic and the inorganic Bronsted proton acids themselves.

Cyclization of the aforedescribed azetidinone sulfinic acids, esters, thioesters, amides, and imides -284819ο is accomplished, with Bronsted proton acid type catalysts.

The Lewis acid type catalysts are characterized by the presence of a vacant orbital which can accept an available electron pair, either unshared, e.g. on an oxygen, sulfur, or halide atom, or in a π orbital, of a Lewis base type compound to form a covalent bond. Exemplary of suitable Lewis acid type metal halide catalysts are aluminium chloride, stannic chloride, stannic bromide, zinc chloride, zinc bromide, antimony pentachloride, titanium tetrachloride, ferric chloride, gallium trichloride, zirconium tetrachloride, mercuric chloride, chromium trichloride and like metal halide agents exhibiting Friedel-Crafts type catalytic activity. Preferred of such catalysts are stannic chloride, zinc chloride, zinc bromide, zirconium tetrachloride and titanium tetrachloride. Stannic chloride is most preferred.

The Bronsted proton acid type catalysts differ from the acidic halide Lewis acid type Friedel-Crafts catalysts in that, in the proton acid case, the electron acceptor quality is due to a positively charged entity, a proton. Exemplary of suitable organic Bronsted proton acid catalysts are methanesulfonic acid, ethanesulfonic acid, trifluoroacetic acid, trichloroacetic acid and dichloroacetic acid. Suitable inorganic Bronsted proton acid catalysts for the process of this invention include sulfuric acid, phosphoric acid, polyphosphoric acid, perchloric acid, chlorosulfonic acid and fluorosulfonic acid. Preferred of the Bronsted proton acid catalysts are methanesulfonic acid, trifluoroacetic acid, phosphoric acid, sulfuric acid, and polyphosphoric acid. - 29 42190 The chalcide catalysts include a wide variety of solid oxides and sulfides. Olah, in Friedel-Crafts Chemistry supra, reported that as far as Friedel-Crafts acylations are concerned, acidic solid chalcide catalysts seem to be the most attractive catalysts of the future. Of the acidic chalcides, acidic oxides or mixed acidic oxides are preferred for the process of this invention. Representative of such acidic oxides are alumina, silica, C^O^, P2Og, T3_O2' AljO^’CoO and A^O^’MnO. Phosphorous pentoxide is most preferred. Generally for Friedel-Crafts acylations dehydrated chalcides are inactive as catalysts; the addition of small amounts (about 1-5ΐ by weight) of water, however, activates the catalytic activity of these catalysts.

Absorbed protons seem to be essential to the catalytic activity of acid chalcide catalysts. The effect of water suggests that Bronsted acidity is responsible for the catalyst activity of the acid chalcides [F. E. Condon in t Catalysts, Vol. VI, ed. Ρ. H. Emmet, Reinhold Publ. Corp., New York, N.Y. (1953), p 43]. Thus for the purpose of this invention acid chalcides are classified as Bronsted proton type catalysts.

It should also be noted that, as is sometimes the case in Friedel-Crafts type acylations, a metal halide Lewis acid catalyst can be used in conjunction with a Bronsted proton acid catalyst, the effective catalyst agent being a conjugate Friedel-Crafts acid catalyst of the type HMA^ or HMAg, where M is B, Al or As and A is F, Cl or Br.

Bronsted acid type activity is presumed to be responsible for the effectiveness of this type of catalyst reagent.

Thus, for the purpose of this invention it is intended that -304219ο such conjugate catalysts be classified as Bronsted type catalysts. Exemplary of such conjugate acid catalysts are HBF4, HA1C14, HAsFg, and HAlBr4· Although their activity in the real sense is not catalytic (because they are generally consumed in the cationforming reaction), metathetic cation-forming agents, particularly anhydrous silver salts, such as silver £-toluenesulfonate, silver perchlorate, silver phosphate, silver tetrafluoroborate and silver trifluoroacetate are effective ’’catalysts in the Friedel-Crafts type cyclization of azetidinone sulfinyl halides in the process of this invention. These silver salts act as metathetic cation-forming substances when reacted with halide reagents and not as acids. Thus the proposed intermediate sulfinium type cation is generated from the sulfinyl chloride by chloride abstraction with the silver cation and not by an acid-base type reaction as is the case with the aforedescribed acid catalyst reagents. The insoluble byproduct silver chloride precipitates. Silver p-toluenesulfonate is a preferred metathetic cation-forming agent for the process of this invention.

The metathetic cation-forming agents are effective only with azetidinone sulfinyl halide starting materials; such reagents are not suitable for the cyclization of any of the other corresponding sulfinic acid derivatives. Such other sulfihic acid derivatives are cyclized using a Bronsted proton acid type catalyst.

The azetidinone sulfinyl halide starting materials for the process of the present invention can thus be cyclized -3142190 by their reaction with a Lewis acid type metal halide catalyst, a Bronsted proton acid type catalyst, or a metathetic cation-forming agent. The best yields of 3-methylenecepham sulfoxides from azetidinone sulfinyl chlorides, preferred starting materials for the process of this invention, are achieved when Lewis acid type metal halide catalysts are employed. However, good yields of the product sulfoxides from sulfinyl halide starting materials have been achieved with Bronsted proton acid type catalysts and metathetic cation-forming agents. Lewis acid type metal halide catalysts are preferred in the process of the present invention when azetidinone sulfinyl chlorides and sulfinyl bromides are employed as starting materials. Bronsted proton acid type catalysts are preferred in the process of this invention when the azetidinone sulfinic acids, and the corresponding sulfinate esters, thiosulfinate esters, sulfinamides and sulfinimides are employed as starting materials.

Any of a wide variety of dry inert organic solvents may be employed as the medium for the cyclization process of this invention. By inert organic solvent is meant an organic solvent which, under the conditions of the process, does not enter into any appreciable reaction with either the reactants or the products. Since the sulfinyl chloride starting materials, like other acid halide type reagents, are susceptible to hydrolysis and to attack by other protic compounds, e.g. alcohols and amines, moisture and other such protic compounds in the reaction medium should be rigorously excluded. A dry aprotic organic -3242190 solvent is thus preferred. Trace amounts of water such as that found in commercially dried solvents can be tolerated; however, it is generally preferred that the process of this invention be carried out under anhydrous conditions. Suitable solvents include, for example, aromatic hydrocarbons, such as benzene, toluene, xylene, chlorobenzene, nitrobenzene, or nitromesitylene; halogenated aliphatic hydrocarbons, such as chloroform, methylene chloride, carbon tetrachloride, 1,2-dichloroethane (ethylene chloride), 1,1,2-trichloroethane, l,l-dibromo-2-chloroethane; and other solvents recognized by those skilled in the art as suitable for Friedel-Crafts type reactions, including carbon disulfide and nitromethane. The preferred solvents are aromatic hydrocarbons and halogenated aliphatic hydrocarbons. Most preferred aromatic hydrocarbon solvents are benzene and toluene. Most preferred of the halogenated aliphatic hydrocarbons are methylene chloride, ethylene chloride, and 1,1,2-trichloroethane.

The temperature at which the process of the present invention is carried out is dependent on the particular catalyst or agent employed; the temperature must be sufficient to effect the cyclization of the starting material. It is well known by those skilled in the art that different Friedel-Crafts reagents are effective at different temperatures in accomplishing, for example, a given acylation. Moreover, such is known to be true even within a particular class of Friedel-Crafts reagents. The process of the present invention can be carried out generally at a temperature ranging from 5° to 150°C. -3342190 The cyclization of both the azetidinone sulfinic acid derivatives and the sulfinyl halides can be carried out .. with Bronsted proton acid type catalysts in an inert organic soLvent at a temperature of 70° to 115°C., typically the reflux temperature of the medium in which the cyclization is ; being carried out.

Alternatively, any one of the aforedescribed azetidinone sulfinyl derivatives can be cyclized to the corresponding exomethylenecepham sulfoxide by its dissolution in a neat organic Bronsted proton acid such as methanesulfonic acid, trlfluoromethanesulionic acid, trifluoroacetic acid, trichloracetic acid or dichloroacetic acid.

The time required for cyclization under such conditions is dependent upon the nature of the sulfinyl derivative, the particular acid employed and the temperature of the reaction. Typically azetidinone sulfinamide and sulfinimide derivatives arc cyclized within 5 to 10 minutes at room temperature in methanesulfonic acid while cyclization of the sulfonic acids and esters and thioesters thereof is complete after 30 minutes at room temperature.

Advantageously the compound of formula IX is dissolved in methanesulfonic acid, ethanesulfonic acid, trifluoroacetic acid, trichloroacetic acid or dichloroacetic acid at ambient temperature and maintained in solution for 10 to 30 minutes.

The cyclization of the aforedescribed azetidinone sulfinyl halides is preferably carried out at a temperature ranging from 10° to 115°C. More preferably the reaction is accomplished at a temperature between 20° and S5°C., advantageously between 20°C and 80°C, the most preferred temperature being dependent primarily upon the solubility and the catalytic activity of the particular cyclizing agent employed. When a Bronsted proton acid type catalyst (including acid chalcide catalysts and conjugate Friedel-Crafts acid catalysts) is - 34 43190 employed as the catalyst reagent to cyclize a sulfinyl halide derivative in an inert organic solvent, preferably an aromatic hydrocarbon solvent or a haiogenated aliphatic hydrocarbon solvent the preferred reaction temperature ranges from 70° to 115°, typically the reflux temperature of the medium in which the cyclization is being carried out.

However, cyclization of methyl, ,1-inetliy 1-2-(2-chlorosulfinyl4-oxo-3-phfchalimido~l-azetidinyl)-3-butenoate is effected in neat polyphosphoric acid at room temperature. The intra10 molecular suifinylation, when effected by a metathetic cation forming agent, is preferably carried out at a temperature between 20° and 80°; most preferred is room temperature.

When a metal halide Lewis acid type catalyst, preferred for tiie cyclization of the sulfinyl halides, is employed, the J 5 preferred temperature at which the process can be carried out is particularly dependent on the individual metal halide catalyst reagent. Thus, when stannic chloride, stannic bromide or antimony pentachloride, which reagents are usually soluble in the solvents for the process, are employed, the cyclization is carried out preferably at a temperature from ° to 40°C.; the most preferred temperature when such reagents are used is room temperature. However, when titanium tetrachloride, a liquid which is also soluble in * most of the reaction solvents, is employed, an elevated temperature of 40°C to 100°C. is preferred for the conversion When metal haiide Lewis acid type catalysts, other than those few specifically referred to immediately hereinabove, are employed in the process of this invention, an e.levated temperature of 40°C to 115°C is generally preferred; a .!» temperature of about 4»°C to about 8 5°C is most preferred.

When stannic chloride i:: employed ns the cyclizing agent in the process of the present invention in a toluene medium, an intermediate stannic chloride-sulfinyl halide complex can be isolated simply by filtering the reaction mixture. The complex can be dried and stored or it can be dissolved in ethyl acetate and washed successively with hydrochloric acid, water, and brine to provide the corresponding exomethylenecepham sulfoxide.

In order to ensure completion of the cyclization reaction of a sulfinyl halide, at least a stoichiometric (mole per mole) amount of a Lewis acid type Friedel-Crafts catalyst or of a metathetic cation-forming agent is employed. Using less than one molar equivalent of such reagents results in lower yields of the product 3-methylenecepham sulfoxide and leaves a portion of the sulfinyl chloride unreacted. Typically the amount of catalyst reagent employed will range from slightly over one equivalent to about two equivalents per mole of sulfinyl chloride. Preferably about 1.1 equivalents of metal halide Lewis acid or of metathetic cation-forming agent are employed for each mole of azetidihone sulfinyl halide starting material. Although less than a stoichiometric amount of a Bronsted proton acid type Friedel-Crafts catalyst can be employed to effect complete’cyclization of either a sulfinyl chloride or an other sulfinic acid derivative, approximately an equivalent amount or more of such an acid catalyst is typically employed. As stated hereinabove, the cyclization can also be effected in a neat protic acid; such is a preferred method.

The time of the reaction under the aforedescribed conditions will range generally from 5 minutes to about 2 -364 219 hours with the reaction time being dependent to some extent upon the particular reactants, the solvents employed and the temperature at which the reaction is carried out. Usually, the reaction will be completed after the reactants have been maintained in contact at the preferred temperatures for about 45 to 90 minutes; however, as indicated hereinabove, shorter reaction times are appropriate under certain conditions. The reaction mixture can easily be monitored for example, by comparative thin-layer chromatography, to determine when the cyclization reaction has reached completion The mechanism by way of which the process of the present invention accomplishes the desired results has not been established with certainty, but the intermediacy of a sulfinium ion Lor Ri. h I CHv COOR or a complex thereof, wherein the C-2 substituent on the azetidinone ring is / l .. or X:M I 9=0 (M = H+ or metal halide Lewis 20 Cyclization of the deuterated from methyl 6-phthalimidoacid) is highly probable, sulfinyl chloride prepared -3742190 ·. ο II ‘SC! II I. Λ-Ζ< ': M a oz \/ \ COOCHa Snt:i4 II 3B-methyl-3a-trideuteriomethylpenam-3-carboxylate la-oxide [R.D.G. Cooper, Journal of the American Chemical Society, 92, 5010 (1970)], with stannic chloride provides methyl 75 phthalimido-2,2-dideUterio-3-methylenecepham-4-carboxylate 1-oxide.

The following are representative of the conversions which can be accomplished by the process of the present inventiqh: tert-Butyl 3-methyl-2-(2-chlorosulfinyl-4-oxo-3phthalimido-1-azetidinyl)-3-butenoate, derived from tertbutyl 6-phthalimidopenicillanate sulfoxide, is cyclized to 7-phthalimido-3-methylenecepham-4-carboxylic acid sulfoxide; Benzyl 3-methyl-2-(2-chlorosulfinyl-4-oxo-315 benzyloxycarbonylamino-l-azetidinyl)-3-butenoate, derived from benzyl 6-benzyloxycarbonylaminopenicillanate sulfoxide, is cyclized to benzyl 7-benzyloxycarbonylamino-3methylenecepham-4-carboxylate sulfoxide; 4'-Methoxybenzyl-3-methyl-2-(2-sulfino-4-oxo-32() phenoxyacetamido-1-azetidinyl)-3-butenoate, derived from 4'-methoxybenzyl 6-phenoxyacetamidopenicillanate sulfoxide, is cyclized to 7-phenoxyacetamido-3-methylenecepham-4-carboxylic acid sulfoxide; -3842190 Μ 2',2',21-Trichloroethyl 3-methyl-2-(2-chlorosulf inyl)-4-oxo-3-phenylacetamido-1-azetidinyl)-3-butenoate, derived from 2',2',2'-trichloroethyl 6-phenylacetamidopenicillanate sulfoxide, is cyclized to 2',2',2'-trichloroethyl 7-phenylacetamido-3-methylenecepham-4-carboxylate sulfoxide; 4'-Nitrobenzyl 3-methy1-2-[2-(N,N*-di(carbomethoxy)hydrazosulfinyl)-4-oxo-3-(2-thienylacetamido)-1-azetidinylJ 3-butenoate, derived from 41-nitrobenzyl 6-(2-thienylacetamido) penicillanate sulfoxide, is cyclized to 4'-nitrobenzy1 7-(2-thienylacetamido)-3-methylenecepham-4-carboxylate sulfoxide; Benzhydryl 3-methy 1.-2- [2-chlorosulf inyl-4-oxo3-(2,2-dimethyl-3-nitroso-5-oxo-4-phenyl~l-imidazolidinyl)l-azetidinylJ-3-butenoate, derived from benzhydryl 6-(2,215 dirnethyl-3-nitroso-5-oxo-4-phenyl-l-imidazolidinyl)penicillanate sulfoxide [hetacillin benzhydryl ester], is cyclized to 7-(2,2-dimethyl-3-nitroso-5-oxo-4-phenyl-l-irnidazolidinyl)3- methylenecepham-4-carboxylic acid sulfoxide; 2'-Iodoethyl 3-methyl-2-(2-sulfino-4-oxo-3-chloro20 acetamido-l-azetidinyl)-3-butenoate, derived from 2'-iodoethyl 6-chloroacetamidopenicillanate sulfoxide, is cyclized to 2'-iodoethyl 7-chloroacetamido-3-methylenecepham-4carboxylate sulfoxide; Dimethylallyl 3-methyl-2-(2-chlorosulfinyl-425 oxo-3-maleimido-l-azetidinyl)-3-butenoate, derived from dimethylallyl 6-maleimidopenicillanate sulfoxide, is cyclized to dimethylallyl 7-maleimido-3-methylenecepham4- carboxylate sulfoxide; Succinimidomethyl 3-methyl-2-(2-chlorosulfinyl30 4-oxo-3-cyanoacetamido-l-azetidinyl)-3-butenoate, derived -3942190 from succinimidomethyl 6-cyanoacetamidopenicillanate sulfoxide, is cyclized to succinimidomethyl 7-cyanoacetainido3- methylenecepliam-4-carboxylate sulfoxide; 4'-Nitrobenzyl 3-methy1-2-[2-sulfino-4-oxo-35 (4-nitrobenzyloxycarbonylamino)-1-azetidinyl]-3-butenoate, derived from 4'-nitrobenzyl 6-(4-nitrobenzyloxycarbonylamino) penicillanate sulfoxide, is cyclized to 4'-nitrobenzyl 7-(4-nitrobenzyloxycarbonylamino)-3-methylenecepham-4carboxylate sulfoxide; 41-Nitrobenzyl 3-methy1-2-[2-chlorosulfiny14- ΟΧΟ-3-(4-chlorobenzamido)-1-azetidinyl]-3-butenoate, derived from 4'-nitrobenzyl 7-(4-chlorobenzamido)penicillanate sulfoxide, is cyclized to 4'-nitrobenzyl 7-(4-chlorobenzamido) -3-methylenecepham-4-carboxylate sulfoxide; Benzhydryl 3-methy1-2-[2-chlorosulfinyl-4-oxo3-(2-tert-butoxycarbonylamino-2-phenylacetamido)-1-azetidinyl]-3-butenoate, derived from benzhydryl 6-(2-tertbutoxycarbonylamino-2-phenylacetamido)penicillanate sulfoxide, is cyclized to 7-(2-amino-2-phenylacetamido)-ΒΙΟ methylenecepham-4-carboxylic acid sulfoxide; 4'-Methoxybenzyl 3-methyl-2-[2-chlorosulfiny1-4oxo-3-(2-benzyloxy-2-phenylacetamido)-1-azetidinyl]-3butenoate, derived from 4'-methoxybenzyl 6-(2-benzyloxy-2phenylacetamido)penicillanate sulfoxide, is cyclized to 7-(2-benzyloxy-2-phenylacetamido)-3-methylenecepham-4-carboxylic acid sulfoxide; 2',2',2'-Trichloroethyl 3-methyl-2-[2-chlorosuif inyl—4—oxo—3—(2-benzy loxy-2-phenyl.acetamido)-l-aze tidinyl]-3-butenoate, derived from 2',2',2'-trichloroethyl -4042180 6-(2-benzyloxy~2-phenylacetamido)penicillanate sulfoxide, is cyclized to 2',2',2'-trichloroethyl 7-(2-benzyloxy-2phenylacetamido)-3-methylenecepham-4-carboxylate sulfoxide; 4'-Nitrobenzyl 3-methyl-2-(2-isoproxysulfinyl4-oxo-3-benzamido-l-azetidinyl)-3-butenoate, derived from 4'-nitrobenzyl 6-benzamidopenicillanate sulfoxide, is Cyclized to 4'-nitrobenzyl 7-benzamido-3-methylenecepham4-carboxylate sulfoxide; 2'-Iodoethyl 3-methyl-2-(2-cyclohexyloxysulfinyl4-oxo-3-chloroacetamido-1-azetidinyl)-3-butenoate, derived from 2'-iodoethyl 6-chloroacetamidopenicillanate sulfoxide, is cyclized to 2'-iodoethyl 7-chloroacetamido-3-methylehecepham-4-carboxylate sulfoxide; 2',2',2'-Trichloroethyl 3-methyl-2-[2-N,N'-di(carbethoxy)hydrazasulfinyl-4-oxo-3-(2-thienylacetamido)-1azetidinyl]-3-butenoate, derived from 2',2',2'-trichloroethyl 6-(2-thienylacetamido)penicillanate sulfoxide, is cyclized to 2',2',2'-trichloroethyl 7-(2-thienylacetamido)3-methylenecepham-4-carboxylate sulfoxide; Methyl 3-methyl-2-[2-carbamylhydrazosulfinyl-4oxo-3-(3-nitrophenoxyacetamido)-1-azetidinyl]-3-butenoate, derived from methyl 6-(3-nitrophenoxyacetamido)penicillanate sulfoxide, is cyclized to methyl 7-(3-nitrophenoxyacetamido)3- methylenecepham-4-carboxylate sulfoxide; Benzhydryl 3-methyl-2-[2-(4-chloroanilinosulfinyl)4- OXO-3-(4-nitrobenzyloxycarbonylamino)-1-azetidinyl]-3butenoate, derived from benzhydryl 6-(4-nitrobenzyloxycarbonylamino) penicillanate sulfoxide is cyclized to 7-(4-nitrobenzyloxycarbonylamino)-3-methylenecepham-4-carboxylic acid sulfoxide; -4143190 4·-Nitrobenzyl 3-methyl-2-(2-phthalimidosulfiny14-oxo-3-phenylacetamido-1-azetidinyl)-3-butenoate derived from 41-nitrobenzyl 6-phenylacetamidopenicillanate sulfoxide, is cyclized to 4'-nitrobenzyi 7-phenylacetamido-3-methylene5 cepham-4-carboxyJ.ate sulfoxide; 2'-Iodoethyl 3-methyl-2-(2-bromosulfinyl-4-oxo3- phthalimido-l-azetidinyl)-3-butenoate, derived from 2'iodoethyl 6-phthalimidopenicillanate sulfoxide, is cyclized to 2'-iodoethyl 7-phthalimido-3-methylenecepham-4-carboxylate sulfoxide; 4'-Nitrobenzyi 3-methy1-2-(2-phenylthiosulfinyl4- oxo-3-phenoxyacetamido-l-azetidinyl)-3-butenoate, derived from 4'-nitrobenzyi 6-phenoxyacetamidopenicillanate sulfoxide, is cyclized to 4'-nitrobenzyi 7-phenoxyacetamido-3-methylene15 cepham-4-carboxylate sulfoxide; i’henacyl 3-methyl-2-[2-(2-phenylethylthiosulfinyl)4-oxo-3-(2-benzyloxy-2-phenylacetamido)-1-azetidinyl)-3butenoate derived from phenacyl 6-(2-benzyloxy-2-phenylacetamido)penicillanate sulfoxide, is cyclized to phenacyl 7-(2-benzyloxy-2-phenylacetamido)-3-methylenecepham-4-carboxylate sulfoxide; tert-Butyl 3-methy1-2-[2-methylcarbamylhydrazosulfinyl-4-oxo-3-(4-methoxyphenylacetamido)-1-azetidinyl]-3butenoate, derived from tert-butyl 6-(4-methoxyphenylacet25 amido)penlcillanate sulfoxide, is cyclized to 7-(4-methoxyphenylacetamido) -3-methylenecepham-4-carboxylic acid sulfoxi do; Trimethylsilyl 3-methyl-2-(2-carbomethoxyhydrazosulfiny1-4-oxo-3-phenylacetamido-l-azetidinyl)-3-butenoate, derived from trimethylsilyl 6-phenylacetamidopenicillanate -4243190 sulfoxide, is cyclized to 7-phenylacetamido-3-methylenecepham4-carboxylic acid sulfoxide; and 41-chlorophenacyl 3-methyl-2-[2-(2-chloroethoxysulfinyl)-4-oxo-3-formamido-l-azetidinyl]-3-butenoate, derived from 4'-chlorophenacyl 6-formamidopenicillanate sulfoxide, is cyclized to 41-chlorophenacyl 7-formamido-3methylenecepham-4-carboxylate sulfoxide.

The yield of the products will vary depending upon the particular reactants which are employed, the relative quantities of reagents and the other aforementioned conditions of reaction.

The products produced in accordance with the process of this invention can be isolated and purified byemploying conventional experimental techniques. These include chromatographic separation, filtration, crystallization, or recrystallization.

The most preferred side chains, R^ in the above formulae, for the process of the present invention are those side chains found on penicillins produced directly by fermentation, primarily the phenylacetamido and phenoxyacetamido side chains. Such penicillins can be esterified and oxidized (not necessarily in that order) to the respective penicillin sulfoxide esters from which the sulfinyl chloride intermediates, and other starting materials for the process of the present invention, are derived. It should be noted that the aforementioned preferred side chains are so preferred primarily for economic reasons. Penicillin precursors having such side chains are readily available and relatively inexpensive; the advantage of performing the process of this invention with the aforedescribed sulfinyl intermediates derived therefrom is readily discernible. Of course, penicillin sulfoxides bearing other known side chains may easily be prepared (by acylation of 6-APA or 6-APA esters and subsequent oxidation) and employed in the process of the present invention.

The product 3-methylenecepham sulfoxides of the process of this invention are useful as intermediates in the preparation of antibiotic compounds. The sulfoxides can be reduced by known procedures, typically with phosphorus trichloride or phosphorous tribromide in dimethylformamide, to provide the corresponding 3-methylenecephams which are predictably converted in high yield to desacetoxycephalosporins of the formula Ri I—I J-CHs !o COOR upon treatment with triethylamine in dimethylacetamide. [Robert R. Chauvette and Pamela A. Pennington, J. Org.

Chem., 38, 2994 (1973).]. The desacetoxycephalosporin esters are converted to active antibiotics by cleavage of the ester function. Deesterification can be achieved, depending on the nature of the protecting group, by any one of several recognized procedures, including (1) 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, -4442190 rhodium or a compound thereof, in suspension, or on a carrier such as barium sulfate, carbon, or alumina.

Alternatively the exomethylenecephams can be employed in the preparation of novel cephem antibiotics of the formula wherein Y is, for example, chloro, bromo or methoxy. Such chemical conversions of 3-exomethylenecepham compounds have been disclosed in the chemical literature [Robert R. Chauvette and Pamela A. Pennington, Journal of the American Chemical Society, 96, 4986 (1974)].

In general, the exomethylenecepham compounds are converted by low temperature ozonolysis to 3-hydroxycephems which are in turn treated with diazomethane in methylene chloride/ether at room temperature to afford the 3-methoxycephem derivatives. The 3-halocephems are derived from the 3-hydroxycephem esters by treatment with a halogenating reagent such ae thionyl chloride or phosphorous tribromide in dimethylformamide. The corresponding cephem acids exhibit potent antibacterial activity.

The following examples are provided to further illustrate the present invention. It is not intended that this invention be limited in scope by reason of any of these examples. In the following examples and preparations nuclear magnetic resonance spectra are abbreviated nmr. The nuclear magnetic resonance spectra were obtained on a Varian Associates -4543190 T-60 Spectrometer (Vartan11 is a registered Trade Mark) using tetramethyl.sil ane as the reference standard. The chemical shifts are expressed in δ values in parts per million (ppm), coupling constants (J) are expressed as Hz in cycles per second and temperatures are in degrees Centigrade. . „ Example 1 Methyl^JT^Phthalimido^^jnethyl^iecegham^A^carboxylate^l^. oxide.

A. Stannic Chloride A mixture of 18.8 g. (50 mmol.) of methyl 6phthalimidopenicillanate sulfoxide and 6.7 g. (50 mmol.) of N-chlorosuccinimide in 1 1. of dry carbon tetrachloride was refluxed for 70 min. The crude product was cooled to room temperature, filtered, washed with water (1 X 500 ml.), and dried (MgSO^). The solvent was then evaporated in vacuo to dryness. The nmr spectrum indicated a complete conversion to the sulfinyl chloride; nmr (CDCl^) δΐ.97 (broad s, 3), 3.86 (s, 3), 5.05 (br. s, 2), 5.2 (d, 1, J-2 Hz), 5.77 (d, 1, J=4 Hz), 5.9 (d, 1, J=4 Hz), and 7.83 (m, 4). The product sulfinyl chloride was then dissolved in 1 1. of dry CH2C12 and 6 ml. (50 mmol.) of anhydrous stannic chloride was added. The resulting solution was stirred for 45 min., washed with IN, hydrochloric acid (2 x 200 ml.), and dried (MgSO4). Evaporation in vacuo gave 18.4 g. (98.4%) of a mixture of R- and S-sulfoxides (ca. 3:2 by nmr) as a light yellow foam. A portion of this mixture (1.26 g.) was separated by chromatography over silica gel using chloroform/ethyl acetate as a solvent. Fractions 6-10 contained pure R-sulfoxide (340 mg.) which was recrystallized from methylene chloride/cyclohexane (m.p. 201-202°); nmr (CDC13) δ3.62 and 4.12 (ABq, 2, J=14 Hz), 3.85 (s, 3), -4642180 4.88 (d, 1, J=4.5 Hz), 5.25 (br. s, 1), 5.58 (m, 2), 5.97 (d, 1, J=4.5 Hz), and 7.84 (m, 4); mass spectrum m/e 374, 358, 346, 298, 287, 239, 220; ir (KBr): 1780, 1745, and 1390 cm-1.

Anal. Calcd. for CggH-^NgOgS (374.37): C, 54.54; H, 3.77; N, 7.48; 0, 25.64; S, 8.56.

Found: C, 54.41; H, 4,06; N, 7.26; 0, 25.59; and S, 8.41.

Fractions 11-18 contained a mixture of the R- and S-sulfoxides and fractions 19-35 gave 210 mg. of the Ssulfoxide, which was recrystallized from methylene chloride/ cyclohexane; nmr (CDClg) 63.63 (s, 2), 3.82 (s, 3), 4.90 (d, 1, J=4.5 Hz), 5.32 (s, 1), 5.46 (br. S, 1), 5.64 (d, 1, J= 4.5 Hz), 5.77 (s, 1), and 7.84 (m, 4); mass spectrum m/e 374, 358, 346, 298, 287, 239, 200; ir (KBr) 1775, 1745, 1725, 1390, 1205, 1111, 1051, 730, and 715 cm Anal. Calcd. for cx7Hq4N2O6S: C, 54,54; H, 3.77; N, 7.48.

Found: C, 54.33; H, 3.76; N, 7.36.

B. Titanium tetrachloride A solution of 0.41 g. of methyl 3-methyl-2-(2chlorosulfinyl-4-oxo-3-phthalimido-1-azetidinyl)-3-butehoate and 0.12 ml. of titanium tetrachloride in 30 ml, of dry 1,2-dichloroethane was refluxed for 30 minutes. The mixture was then cooled to room temperature, washed with 1N.HC1 and brine and dried (MgSO^). Evaporation in vacuo to dryness provided 0.34 g. of methyl 7-phthalimido-3-methylenecepham4-carboxylate 1-oxide. -4742190 C. Aluminum Chloride.

A mixture of 0.41 g. of methyl 3-methyl-2-(2chlorosulfinyl-4-oxo-3-phthalimido-l-azetidinyl)-3-butenoate and 0.13 g. of aluminum chloride was refluxed in 30 ml. of dry 1,2-dichloroethane. The mixture was then cooled to room temperature, washed with 1N.HC1 and brine and dried (MgSO^). Evaporation in vacuo to dryness provided 0.35 g. of the 3methylene cepham sulfoxide as a yellow foam.

D. Zinc bromide.

A mixture of 0.41 g. of methyl 3-methyl-2-(2chlorosulfinyl-4-oxo-3-phthalimido-l-azetidinyl)-3-butenoate and 0.27 g. of zinc bromide in 30 ml. of dry methylene chloride was refluxed for 1 hour. The mixture was cooled to room temperature, washed with 1N.HC1 and dried (MgSO^).

Evaporation in vacuo to dryness provided a mixture of the R- and S-3-methylenecepham sulfoxide as a yellow foam.

E. Antimony pentachloride.

A solution of 0.41 g. of methyl 3-methy1-2-(2chlorosulfinyl-4-oxo-3-phthalimido-l-azetidinyl)-3-butenoate and 0.12 ml. of antimony pentachloride was stirred at room temperature for 60 minutes. The reaction mixture was washed with 1N.HC1 and brine, dried (MgSO^) and evaporated in vacuo to dryness to provide the desired 3-methylenecepham sulfoxide as a yellow foam. The nmr spectrum of the product sulfoxide mixture was poor. To confirm the presence of the cepham sulfoxide, the reaction product was dissolved in 3 ml. of dimethylformamide and reacted with 0.09 ml. of phosphorous trichloride. After the mixture was stirred at 0° for 30 minutes, it was poured over cracked ice/water. -4842190 The yellow precipitate which then formed was collected by filtration and dried under vacuum. An nmr spectrum of the product (0.15 g.) showed it to be methyl 7-phthalimido3-methylenecepham-4-carboxylate: (CDClg) S3.47, 3.96 (ABq, 2, J=17 Hz, Cg-H), 3.87 (s, 3, C4-H) , 5.20 (d, 1, J=4.5 Hz), .80 (d, 1, J=4.5 Hz), and 7.83 (m, 4).

F. Mercuric chloride.

A mixture of 0.20 g. of methyl 3-methyl-2-(2chlorosulfinyl-4-oxo-3-phthalimido-1-azetidinyl)-3-butenoate and 0.14 g. of mercuric chloride in 10 ml. of dry 1,2dichloroethane was refluxed for 1 hour. The mixture was cooled to room temperature, washed with 1N.HC1, dried (MgSO4) and evaporated in vacuo to dryness to provide 0.14 g. of the 3-methylenecepham sulfoxide as a mixture of Rand S-sulfoxide isomers.

G. Ferric chloride.

The same procedure was followed as in (F) above with the exception that 0,08 g. of ferric chloride was employed as the catalyst instead of mercuric chloride. Comparative thin-layer chromatography confirmed the sulfinyl chloride to 3-methylenecepham sulfoxide conversion.

H. Zirconium tetrachloride.

The same procedure was followed as in (F) above with the exception that 0.12 g. of zirconium tetrachloride was employed as the catalyst instead of mercuric chloride. Comparative thin-layer chromatography confirmed a clean conversion of the sulfinyl chloride to the 3-methylenecepham sulfoxide. The nmr spectrum of the product was identical to that of the product in (A) above. -494 219 0 I. Polyphosphoric acid.

Methyl 3-methy1-2-(2-chlorosulfinyl-4-oxo-3phthalimido-l-azetidinyl)-3-butenoate (0.20 g.) was stirred I in about 27 g. of polyphosphoric acid for 20 minutes. Ice water and ethyl acetate (25 ml.) was added to the reaction mixture. The organic layer was separated and washed successively with water, aqueous sodium bicarbonate, and brine, dried (MgSO^), and evaporated in vacuo to dryness to give methyl 7-phthalimido-3-methylenecepham-4-carboxylate 1oxide (0.05 g.) as a white foam.

J. Sulfuric acid.

A solution of 0.20 g. of methyl 3-methyl-2-(2chlorosulfinyl-4-oxo-3-phthalimido-1-azetidinyl)-3-butenoate and 2 drops of concentrated sulfuric acid in 10 ml. of dry 1,2-dichloroethane was refluxed for 1 hour. The reaction mixture was cooled, washed with brine, dried (MgSO^) and evaporated in vacuo to dryness to provide 0.09 g. of a colorless foam, the nmr spectrum of which shows it to be primarily the desired 3-methylenecepham sulfoxide.

K. Methanesulfonic acid.

The same procedure was followed as in (J) above with the exception that 0.03 ml. of methanesulfonic acid was employed as the catalyst instead of sulfuric acid. The product, as identified by nmr' spectroscopy, was the desired 3-methylenecepham sulfoxide.

L. Trifluoroacetic acid.

A solution of 0.29 g. of methyl 3-methy1-2-(2chlorosulfinyl-4-oxo-3-phthalimido-l-azetidinyl)-3-butenoate in 10 ml. of trifluoroacetic acid was refluxed for 30 min-5043190 utes and then was evaporated in vacuo to dryness. The product was dissolved in 20 ml. of ethyl acetate. The resulting solution was washed successively with aqueous sodium bicarbonate (3X) , water, and brine, dried (MgSO4), and evaporated in vacuo to dryness to provide methyl 7phthalimido-3-methylenecepham-4-carboxylate 1-oxide.

M. Silver p-toluenesulfonate.

Silver g-toluenesulfonate (0.80 g.) was added to a solution of 1.0 g. of methyl 3-methy1-2-(2-chlorosulfinyl10 4-oxo-3-phthalimido-1-azetidinyl)-3-butenoate in 75 ml. of dry toluene. The reaction mixture was stirred at room temperature for 2.5 hours and then filtered. The filtrate was evaporated in vacuo to dryness, and the residue thereby obtained was dissolved in 50 ml. ethyl acetate. The solution was washed with brine, dried (MgS04)and evaporated in vacuo to dryness, The product was identified by nmr spectroscopy as methyl 7-phthalimido-3-methylenecepham —4-carboxylate 1-oxide.

Example 2 Methyl 7-phthalimido-2,2-dideuterio-3-methylenecepham-4carboxylate.

A mixture of 3.76 g. (10 mmol) of methyl 613phthalimidopenicillanate sulfoxide, 5 ml. deuterium oxide, and 500 ml. dry carbon tetrachloride was refluxed for 3 hr.

The layers were then separated and the organic layer dried (MgSO4). Evaporation in vacuo gave 3.59 g. of a whits 2 amorphous foam. The nmr spectrum showed deuterium (H ) incorporation into the 2a-methyl group only and the residual hydrogen (H1) in that group of less than 29% (by integration).

Mass spectral analysis gave the following deuterium distribution in the 2a-methyl group: dQ, 5.8%; d3, 20.5%; d2, -5142190 41.3%; d^, 32.4% + 2%. Recrystallization from acetone/diethyl ether gave colorless prisms, mp 148-151°; mass spectrum, m/e 379, 378, 377, 376, 361, 360, 359, 358, 302,/301, 300, 299; ir (KBr) 1800, 1775, and 1725 cm-1; nmr (CDC13) 61.83 (s, 3); 3.85 (s, 3); 4.62 (s, 1); 4.85 (d, 1, J=4.5 Hz), 5.86 (d, 1, J=4.5 Hz); 7.83 (m, 4).

Anal. Calcd. for C^H^OgS (376.387): C, 54.25; H, 4.28; N, 7.44; 0, 25.50; S, 8.52.

Found: C, 54.05; H, 4.28; N, 7.26; O, 25.61; S, 8.53.

A solution of 0.57 g. (1.5 mmol.) of the methyl -methyl-2a-trideuteriomethyl-6β-phthalimidopenicillanate1-oxide and 0.20 g. (1.5 mmol) N-chlorosucCinimide was refluxed for 30 min. in 25 ml. of dry 1,1,2-trichloroethane, cooled, washed with water (1 x 50 ml) and brine (1 x 50 ml), and dried (MgSO4). The solvent was then evaporated in vacuo to provide 0.69 g. of a mixture of R- and S-sulfinyl chlorides as a light yellow amorphous foam. This mixture was then dissolved in 25 ml. of dry methylene chloride and 0.20g(1.7 mmol) of anhydrous stannic chloride was added. The re20 suiting mixture was stirred for 50 min., washed with IN. hydrochloric acid, dried (MgSO4), and evaporated in vacuo yielding 0.57 g. of a mixture of R- and S^sulfoxides as a yellow foam. The material so obtained was dissolved in 4 ml. of dry Ν,Ν-dimethylformamide, cooled in an ice bath and 0.14 ml. (1.6 mmol) of phosphorus trichloride was then added. After 35 min. the crude mixture was poured onto water-cracked ice and stirred. The resulting precipitate was collected by filtration and dried under vacuum. Yield was 0.38 g. The nmr spectrum exhibited only a very small -5242190 signal for the C2 position (<10% of theory by nmr integration) while the signal for the exomethylene C'3 position was normal indicating selective incorporation of the deuterium into the C2 position. Mass spectral analysis gave 2 the following deuterium (H ) distribution in the C2 position: άθ, 2.2%; d^ 25.5%; d2, 72.3% + 2%. Recrystallization from methylene chloride/cyclohexane gave colorless crystals, mp 198-201° (dec); mass spectrum m/e 360, 273, 174; ir (KBr) 1770, 1740, and 1710 cm-1; nmr (CDC13) 53.80 (s, 3), 5.32 (m, 3), 5.46 (d, 1, J=4.5 Hz), 5.67 (d, 1, J=4.5 Hz), 7.83 (m, 4).

Anal. Calcd. for C17H14N20gS (358.372): C, 56.98; H, 3.94; N, 7.82; 0, 22.32; S, 8.95.

Found: C, 56.96; H, 3.85; N, 7.94.

Example 3 4'-Nitrobenzyl 7-phenoxyacetamido-3-methylenecepham-4carboxylate-1-oxide.

A. Stannic chloride.

A mixture of 6.0 g. (12 mmol) of 4'-nitrobenzyl6-phenoxyacetamidopenicillanate 1-oxide and 500 ml. of dry toluene was refluxed for 10 minutes by using a Dean-Stark trap to remove a trace amount of water. Then 1.8 g. of N-chlorosuccinimide was added and the mixture was refluxed for 90 minutes and cooled to ca. 50°. To the resulting solution of sulfinyl chloride 1.8 ml. of anhydrous stannic chloride was added. The mixture was stirred at room temperature for 90 minutes. Then 100 ml. of water and 100 ml. of ethyl acetate was added. The organic layer was separated and washed (1N.HC1, aqueous NaHCO3, brine), and dried (MgSO4). Evaporation in vacuo to dryness provided a product -5342190 which crystallized from ethyl acetate to give 2.16 g. (36%) of the title product. A sample was recrystallized from ethyl acetate/acetone to give large prisms (m.p. 200-201°): nmr (CDClg) ·\3.5 and 3.75 (ABq, 2, J=14 Hz), 4.55 (s, 2), 4.83 (d, 1, J=4.5 Hz), 5.3 (s, 2), 5.33 (s, 1), 5.5 (s, 1) , .78 (s, 1), 5.94 and 6.1 (q, 1, J=4.5 Hz and 8.0 Hz), 6.9-8.3 (m, 9).

Anal. Calcd. for CggH^NgOgS (499.5) : C, 55.31; H, 4.24; N, 8.41; 0, 25.62; s, 6.42. 10 Found: C, 55.06; H, 4.14; N, 8.30; 0, 25.62; s, 6.26.

B. Zinc chloride. 4'-Nitrobenzyl 3-methyl-2-(2-chlorosulfinyl-4oxo-3-phenoxyacetamido-l-azetidinyl)-3-butenoate was prepared by refluxing a solution of 1 g. of 4'-nitrobenzyl 6.J5 phenoxyacetamidopenicillanate sulfoxide and 0.27 g. of N-chlorosuccinimide in 40 ml. of 1,1,2-trichloroethane for 30 minutes. Then 0.27 g. of zinc chloride was added to the reaction mixture. The mixture was then refluxed for an additional 45 minutes. After cooling the mixture to room temperature, it was washed with 1N.HC1 (2X), dried (MgSO^), and evaporated jn vacuo to dryness. An nmr spectrum of the product showed it to be the desired 4'-nitrobenzyl 7-phenoxy acetamido-3-methylenecepham-4-carboxylate 1-oxide.

C. Silver g-toluenesulfonate.

A solution of 1 g. of 4'-nitrobenzyl 6-phenoxyacetamidopenicillinate 1-oxide and 0.27 g. of N-chlorosuccinimide in 10 ml. of dry toluene was refluxed for 1 hour. Silver g-toluenesulfonate (0.61 g.) was added to the hot solution. The mixture was stirred for 45 minutes (while 30 cooling to room temperature). The reaction mixture was -5442190 filtered, washed with water (2X) and brine, dried (MgSO^), and evaporated in vacuo to dryness to provide 0.43 g. 4'-nitrobenzyl 7-phenoxyacetamido-3-methylenecepham-4carboxylate 1-oxide (with some impurities) as a yellow foam.

Example 4 41-Nitrobenzyl 7-phthalimido-3-methylenecepham-4-carboxylate 1-oxide^ To a solution of 23.1 g. of 4'-nitrobenzyl 3methyl-2-(2-chlorosulfinyl-4-oxo-3-phthalimido-1-azetidinyl)3-butenoate in 400 ml. of dichloromethane at room temperature was added 6.1 ml. of anhydrous stannic chloride. An increasing amount of precipitate was noted as the reaction progressed. After 45 minutes the reaction mixture was washed with IN. sulfuric acid, water, sodium bicarbonate solution, and brine. The organic layer was dried and evaporated in vacuo to dryness to provide 16.72 g. (78%) of the title product. The R- and S-sulfoxide isomers were separated by fractional recrystallization from acetone and dichloromethane.

The R-sulfoxide is obtained as colorless prisms which softened at 155°C and melted completely at 213°C: ir (CHClg) 1790, 1780, 1738 and 1723 011-½ mass spectrum m/e 495, 479, 367, 343; nmr (CDClg) 63.58 and 4.10 (ABq, 2, J=13 Hz), 4.87 (d, 1, J=4.5 Hz), 5.33 (s), 5.57 (m, 2), 5.95 (d, 1, 0=4.5 Hz), 7.4-8.4 (m, 8, ArH).

Anal. Calcd. for C23H17N3°8S (495 .5) : C, 55.76; H, 3.46; N, 8.48; 0, 25.83; S, 6.47. Found: C, 55.50; H, 3.45; N, 8.65; 0, 25.17; S, 6,32. The S-sulfoxide was isolated as colorless prisms (mp 190-192°): ir (mull) 1780, 1775, : 1741 and 1728 αηΆ nmr (CDClg) 63 .5 and 3.7 (ABq, 2, 0=15 HZ) , 4.9 (d, 1, -5542190 ίο J=4.5 Hz), 5.34 (s, 2), 5.46 (m, 2), 5.6 (d, 1, J=4.5 Hz), .8 (s, 1), 7.4-8.4 (m, 8).

Anal. Calcd. for C23^i7N3°8S C, 55.76; H, 3.46; N, 8.48; 0, 25.83; S, 6.47.

Found: C, 55.58; H, 3.62; N, 8.25; 0, 25.19; S, 6.18.

Example 5 21,21,2'-Trichloroethyl 7-phenylacetamido-3-methylenecepham4-carboxylate 1-oxide.

A mixture of 1.0 g. of 2',2',2'-trichloroethyl 7-phenylacetamidopenicillanate 1-oxide, 0.5 g. of Nchlorosuccinimide and 80 ml. of dry toluene was refluxed for 90 minutes,'then cooled, and washed (water and brine). To the resulting solution of sulfinyl chloride was added 0.28 ml. of anhydrous stannic chloride. The resulting mixture was stirred for 90 minutes. After washing (water and brine) the solvent was evaporated in vacuo to dryness. The product was recrystallized from ethyl acetate-ether to provide the title product as colorless prisms: m.p. 187-189 °C; nmr (Ct>Cl3) 63.5 and 3.81 (ABq, 2, J=14 Hz); 3.63 (s, 2), 4.8 (m, 2), 4.9 (d, 1, J=4.5 Hz), 5.37 (s, 1), 5.5 (s, 1), 5.82 (s, 1), 5.9 and 6.07 (q, 1, J=4,5 Hz and 10.0 Hz), 7.0 (d, NH, J=10 Hz), 7.33 (s, 5).

Example 6 Methyl 7-(2,2-dimethyl-3-nitroso-5-oxo-4-phenylimidazolidin1-yl)-3-methylenecepham-4-carboxylate 1-oxide.

A mixture of 0.896 g. of N-nitrosohetacillin sulfoxide methyl ester and 0.536 g. of N-chlorosuccinimide in 55 ml. of dry benzene was refluxed under nitrogen for about 1 hour. The reaction mixture was cooled and a 5 ml. aliquot of the mixture was evaporated in vacuo to dryness. The nmr spectrum of the residue thereby obtained was consistent wilh -5642190 the structure of the desired intermediate sulfinyl chloride.

The remainder of the reaction mixture was cooled under nitrogen in an ice bath, and 0.33 ml. of stannic chloride was added. A light orange precipitate formed immediately.

After stirring the mixture for 2 hours and 15 minutes at room temperature, 5.5 ml. of dimethylacetamide and 55 ml. of ethyl acetate was added. The resulting solution was washed with water and brine, dried over CaSO^, and evaporated in vacuo to dryness to provide 1.3 g. of a yellow oil. The product was dissolved in methylene chloride and applied to 4 preparative thin-layer chromatography plates. The plates were developed with a 1:1 mixture of benzene and ethyl acetate. Two primary bands were noted, the one having the lower rf value representing the title compound. The 315 methylenecepham sulfoxide (a mixture of R- and S-sulfoxides) was isolated by extracting the identified band with acetonitriles nmr (CDClg) 62.07 (s, 6, gem-dimethyl), 3.73 {s, 3, COOCHp, 4.7-5.6 (m), and 7.3 (s, ArH).

Example 7 4'-Nitrobenzyl 3-methy1-2-(2-sulfino-4-oxo-3-phthalimido-1azetidiny1) -3-butenoate.

A solution of 49.7 g. {0.1 mol) 4'-nitrobenzyl 6phthalimidopenicillanate 1-oxide and 13.4 g. of (0.1 mol) of N-chlorosuccinimide in 1.5 1. of 1,2-dichloroethane was refluxed for 70 minutes. After cooling the reaction mixture was washed with water and brine and dried (MgSO^). The solvent was evaporated in vacuo to dryness to provide 52.0 g. of the azetidinone sulfinyl chloride product: nmr (CDClg) 61.97 (s, 3), 5.05 (s, 1), 5.4 (s, 2), 5.76 (d, 1, J=5 Hz), 5.91 (d, 1, J=5 Hz), 7.83 (m, 8, ArH). -5742190 The sulfinyl chloride was converted to the sulfinic acid by slurrying an ethyl acetate solution thereof wiih a 5% solution of sodium bicarbonate at room temperature £01 2 hours. Acidification of the aqueous layer with hydrochloric acid in the presence of ethyl acetate provided, after separation, drying (MgSO^), and evaporation in vacuo of the organic layer, the desired sulfinic acid as a colorless foam: nmr (CDCl^) 61.92 (s, 3), 4.88 (s, 1, J=4.5 Hz), 5.00 (s, 2), 5.18 (broad s, 1), 5.38 (s, 2), 5.67 (d, 1, J=4.5 Hz), and 7.5-8.3 (m, 9, ArH).

Example 8 2^2^21 -Trichloroethyl 7-phenoxyacetamido-3-methylenecepham4-carboxylate-l-oxlde.

A mixture of 4.82 g. (10 mmol) of 2',2',2'-trichloroethyl 6-phenoxyacetamidopenicillanate 1-oxide, 150 ml. of dry toluene, and 2.0 (11 mmol) of N-chlorophthalimide . was refluxed for 60 minutes using a Dean-Stark adapter. A 5 ml. aliquot of the mixture was evaporated; the nmr spectrum thereof showed a complete conversion to the expected sulfinyl chloride.

The solution of the sulfinyl chloride in toluene was cooled to ca. 40°C, and 1.4 ml. of stannic chloride was added. The mixture was stirred for 60 minutes and then was washed successively with IN.HCl, aqueous NaHCO^, and brine and dried (MgSO^). After evaporation of the solvent, 30 ml. of chloroform was added to the residue, and the insoluble phthalimide was filtered. The filtrate was evaporated to dryness and the yellow amorphous product was dried in vacuo. Yield: 3.4 g. (70 percent) of the title compound; nmr (CDC13) 3.56 and 3.80 (ABq, 2, J=14 Hz), 4.48 (s, 2), 4.75 (m, 2, CH2CC13), 4.89 (d, 1, J=4.5 Hz), 5.33 (s, 1), 5.48 -5842190 (s, 1), 5.78 (s, 1), 5.9 and 6.07 (q, 1, J=4.5 Hz), 6.8-7.4 (m, 5, ArH), and 8.1 (d, NH, J=10 Hz).

Example 9 Methyl 3-methyl-2-(2-sulfino-4-oxo-3-phthalimido-1-azetidinyl)3-butenoate.

A mixture of 3.76 g. of methyl 6-phthalimidopenicillinate sulfoxide and 1.4 g. of N-chlorosuccinimide in 250 ml. of dry (CaClj) carbon tetrachloride was refluxed for 70 minutes. The mixture was cooled to room temperature, filtered, washed with water and brine and dried (MgSO^). Evaporation in vacuo to dryness provided methyl 3-methyl2-(2-chlorosulfinyl-4-oxo-3-phthalimido-l-azetidinyl)-3butenoate as a white foam (See Example 1A).

To a solution of 0.20 g. of the sulfinyl chloride in 25 ml. of chloroform was added 2 drops of water. The mixture was refluxed for 30 minutes, cooled, dried (MgSo^) and evaporated in vacuo to dryness to provide the title product as a colorless foam; nmr (CDClg) 61.93 (s, 3, -CHj), 3.80 (s, 3, -COOCH3), 4.88-5.15 (m, 4, Cj-H, =CH2, β-lactam H), 5.70 (d, 1, J=5.0 Hz, β-lactam H), 7.80 (m, 4, ArH).

The sulfinyl chloride is also converted to the title sulfinic acid upon standing at room temperature open to the air for 2 days.

Example 10 Methyl 7-phthalimido-3-methylenecaphaiii-4-carboxylate-1 -oxidi« TTrpm aaetUHnone sulfinic acid). ' .....

A. Phosphorus Hentoxlde.

A solution of 0.10 g. of methyl 3-methyl-2-(2sulfino-4-oxo-3-phthalimido-l-azetidinyl)-3-butenoate and 0.04 g. of phosphorus pentoxide in 20 ml. of 1,2-dichloroethane was stirred at room temperature for 1 hour. A tic of -5942190 the reaction mixture indicated only trace amounts of the methylenecepham sulfoxide. The mixture was then refluxed for 30 minutes, cooled to room temperature, and combined with 25 ml. of ethyl acetate and 50 ml. of brine. The organic layer was separated, washed with aqueous sodium I bicarbonate and brine and dried (MgSO^). Evaporation in vacuo to dryness provided 0.04 g. of the title product as a white froth. , B. Sulfuric acid.

The same procedure was followed as that described in Example 1 (J) above except 0.20 g. of methyl 3-methy12-(2-sulfino-4-oxo-3-phthalimido-l-azetidinyl)-3-butenoate was employed as the starting material instead of the sulfinyl chloride. The procedure provided 0.03 g. of the title compound.

C. Polyphosphoric acid.

The same procedure was followed as in Example 1 (I) above except 0.20 g. of methyl 3-methy1-2-(2-sulfino4-oxo-3-phthalimido-l-azetidinyl)-3-butenoate was employed as the starting material instead of the sulfinyl chloride.

The reaction provided 0.10 g. of the title compound.

D. Trifluoroacetic acid.

The same procedure was followed as described in Example 1 (L) above except 0.20 g. of methyl 3-methyl-2-(225 sulfino-4-oxo-3-phthalimido-l-azetidinyl)-3-butenoate was employed as the starting material instead of the Corresponding sulfinyl chloride. An nmr spectrum of the product showed the title compound to be the major constituent. -6042190 Fxamp.lt» 11 4'-Nitrobenzyl 3-methy1-2-(2-chlorbsull'inyl-4-oxo-3-(Nphenoxyacetyl-N-(2,2,2-tnchloroethoxycarbonyl)amino)-1a2etidmyl] -3-butenoate.

A. A mixture of 4.855 g. (10 mmol) of 4'-nitrobenzyl 6-phenoxyacetamido-2,2-dimethylpenam-3-carboxylate, 16.94 g. (80 mmol) of 2,2,2-trichloroethyl chloroformate, 18 ml. of N,0-(bis-trimethylsilyl)trifluoromethylacetamide, and 20 ml. of methylene chloride was prepared. The mixture was permitted to stand at room temperature overnight. The mixture then was heated at reflux for 7 hours,after which it was again permitted to stand at room temperature overnight.

Heating then was continued for an additional 6 hours. The mixture then was evaporated to a residue; the residue was dissolved in benzene, and the resulting solution then was added to a large excess of heptane. The resulting insoluble material was filtered off, dissolved in benzene, and chromatographed over silica gel using a benzene-ethyl acetate elution gradient. 4'-Nitrobenzyl 6-[N-phenoxyacetyl-N(2,2,2-trichloroethoxycarbonyl)amino]-2,2-dimethylpenam-3carboxylate (4.76 g.; 72 percent) was obtained as product: nmr (CDC13) 61.41 (s, 3), 1.62 (s, 3), 4.61 (s, 1), 4.84 (d, 1, J=12 Hz), 4.99 (d, 1, J=12 Hz), 5.20 (s, 2), 5.30 (s, 2), 5.56 (s, 2), 6.8-7.4 (m, 5), 7.53 (d, 2, J=9 Hz), and 8.22 (d, 2, J=9 Hz).

B. Sulfoxide preparation.

To about 75 ml. of acetone were added 2.54 g. (3.84 mmol) of the above product. The mixture was cooled to -70°C., and an excess of ozone was admitted to the reaction mixture at approximately 1.17 mmol per minute for nine minutes, during which time the reaction mixture turned blue. 6142190 The mixture was maintained at -70°C. for about 35 minutes, after which it was warmed to room temperature. The solvent was removed in vacuo to obtain 2.76 g. of 4'-nitrobenzyl 6-[N-phenoxyacetyl-N-(2,2,2-trichloroethoxycarbonyl)amino)5 2,2-dimethylpenam-3-carboxylate-1-oxide. nmr (CDClg) 61.22 (s, 3), 162 (s, 3), 4.60 (s, 1), 4.78 (d, 1, J=5 Hz), 4.93 (s, 2), 5.26 (s, 2), 5.30 (s, 2), 5.93 (d, 1, J=5Hz), 6.8-7.4 (m, 5), 7.51 (d, 2, J=9 Hz) and 8.20 (d, 2, J=9 Hz).

C. Sulfinyl chloride preparation.

To 40 ml. of dry benzene were added 792 mg. (about one mmol) of the above product and 155 mg. (about 1.2 mmol) of N-chlorosuccinimide. The resulting mixture was heated at reflux for one hour. An nmr of the reaction mixture indicated the presence of the title compound: nmr (CDClg) 61.92 (s, 3), 4.89 (s, 1), 4.96 (s, 2), 5.05 (s, 2), 5.23 (s, 2), .26 (s, 1), 5.34 (s, 2), 5.64 (d, 1, J=5 Hz), 5.95 (d, 1, J=5 Hz), 6.10 (d, 1, J=5 Hz), 6.8-7.5 (m, 5), 7.56 (d, 2, J=9 Hz), and 8.23 (d, 2, J=9 Hz).

D. Conversion to 4'-Nitrobenzyl· 7-[N-phenoxyacetyl-N(2,2,2-trichloroethoxycarbonyl)amino]-3-methylenecepham4-carboxylate-1-oxide.

To the reaction mixture from (C) above, cooled to room temperature, were added 390 mg. (1.5 mmol) of stannic chloride. The mixture was maintained at room temperature for 75 minutes, and 5 ml. of methanol then were added. Additional benzene was added, and the resulting mixture was 2£ washed three times with a mixture of HC1 and aqueous sodium chloride. The benzene layer was separated, dried over sodium sulfate, and evaporated in vacuo to dryness. The residue was chromatographed over silica gel (15% water) with a benzene-ethyl acetate gradient to obtain 246 mg. of the -62exomethylenecepham sulfoxide: nmr (CDCl^) 53.42 (d, 1, J=13 Hz), 3.98 (d, 1, J=13 Hz), 4.64 (d, 1, J=5 Hz), 4.94 (s, 2), 5.25 (s, 2), 5.30 (s, 2), 5.34 (s, 1), 5.47 (s, 1), 6.04 (d, 1, J=5 Hz), 6.8-7.4 (m, 5), 7.55 (d, 2, J=9 Hz), and 8.23 (d, 2, J=9 Hz), Example 12 41-Bromophenacyl 7-phenoxyacetamido-3-methylenecepham-4carboxylate-1-oxide.

To 200 ml. of dried toluene were added 5.6 g. (10 mmol) of 4'-bromophenacyl 6-phenoxyacetamido-2,2dimethylpenam-3-carboxylate-l-oxide and 5.2 g. (50 mmol) of sodium bisulfite. The mixture was heated at reflux, and 1.5 g. (11 mmol) of N-chlorosuccinimide were added. The resulting mixture was stirred and refluxed for one hour, cooled in an ice bath, and 1.3 g. (11 mmol) of stannic chloride then were added. The resulting mixture was stirred at room temperature for about two hours and then was poured into a mixture of ethyl acetate and water. The organic layer was separated and washed successively with 5 percent hydrochloric acid, 5 percent sodium bicarbonate solution, and brine. The mixture then was dried over magnesium sulfate. Upon evaporation to near dryness in vacuo, 1.75 g. (31 percent) of the title compound crystallized and was collected. An nmr analysis of the product was consistent with the structure of the title compound.

Anal. Calcd. for C24H21N2°7SBr: C, 51,35; H, 3.77; N, 4.99; Br, 14.23.

Found: C, 51.03; H, 3.91; N, 5.10; Br, 14.46. -6342190 Example 13 7-Phenoxyacetainido-3-methylenecepham-4-carboxylic acid1-oxide.

To 200 ml. of dried toluene were added 4.95 g. (10 mmol) of 4'-methoxybenzyl 6-phenoxyacetamido-2,2-dimethyl5 penam-3-carboxylate-l-oxide and 5.2 g. (50 mmol) of sodium bisulfite. The mixture was heated at reflux, and 1.5 g, (11 mmol) of N-chlorosuccinimide were added. The mixture then was stirred and refluxed for one hour, after which it was cooled in an ice bath, and 1.3 gms. (11 mmol) of stannic JO chloride were added. The mixture then was stirred at room temperature for about 2 hours,after which it was poured into a mixture of ethyl acetate and water. The organic layer was separated and washed successively with 5 percent hydrochloric acid and brine. The organic layer then was ex1 $ tracted with 5 percent sodium bicarbonate solution. The extract was slurried with ethyl acetate, and acidified to pH 2.5. The ethyl acetate layer was separated, washed with water, dried over magnesium sulfate, and concentrated in vacuo to a small volume,from which 1.3 gms. (35 percent) of 2o the title compound were obtained as crystals. Analysis of the product by nmr was consistent with the structure of the title compound.

Anal. Calcd. for C.-H.^N-O.S: - 16 16 2 6 C, 52.74; H, 4.43; N, 7.69.

Found: C, 52.99; H, 4.64; N, 7.51.

Example 14 Benzhydryl 3-methy1-2-(2-chlorosulfinyl-4-oxo-3-phenoxyacetamido-1-azetidinyl)-3-butenoate.

A. To 800 ml. of dried toluene were added 20 g. of benzhydryl 6-phenoxyacetamido-2,2-dimethylpenam-3-carboxyl-6442180 ate-l-oxide. The mixture was refluxed in a system having a Dean-Stark water trap to azeotropicalIv remove any moisture. To the mixture then were added 12.2 g. of N-chlorosuccinimide. Refluxing was continued for 1.5 hours. The product was analyzed by nmr analysis which was consistent with the structure of the title compounds nmr (CDC13) 61.88 (s, 3), 4.53 (s, 2), 4.90 (s, 1), 5.14 (s, 2), 5.54 (d, 1, J=4 Hz), 6.24 (g, 1, J=4 Hz and 8 Hz), 6.95 (s, 1), 7.15-7.4 (m, 15), and 8.0 (d, 1, J=8 Hz).

B. Conversion to exomethylene sulfoxide.

In accordance with the procedure described in Example 13 hereinabove, the azetidinone sulfinyl chloride from (A) was cyclized with stannic chloride to 7-phenoxy~ acetamido-3-methylenecepham-4-carboxylic acid-1-oxide.

Example 15 2',2',2'-Trichloroethyl 3-methy1-2-[2-chlorosulfinyl-4-oxo3-(4-nitrobenzyloxycarbonylamino)-l-azetidinyij-3-butenoate.

A_._ A mixture of 300 ml. of 1,1,2-trichloroethane and 10.26 g. of 2',2',2'-trichloroethyl 6-(4-nitrobenzyloxycarbonylamino )-2, 2-dimethylpenam- 3-carboxylate- 1-oxide was prepared. The mixture was refluxed with removal of about 75 ml. of the solvent to promote drying of the reaction medium. The mixture then was cooled, and propylene oxide was added,followed by 4 g. of N-chlorosuccinimide. The temperature of the mixture was raised to 102°C., and the mixture was refluxed for 2.5 hours. A sample of the read ion mixture was removed; the solvent was evaporated. An nmr analysis of the residue was consistent with the structure of the title compound: nmr (CDC13) 61.94 (bs, 3), 4.83 (s, 2), 5.25 (s, 2), 5.0-5.4 (m, 3), 6.2 (d, 1, J=4 Hz), 7.55 (d, 2, J=8 Hz), and 8.24 (d, 2, J=8 Hz). -65Β. Conversion to 2',2',2'-trichloroethyl 7-(4-nitrobenzyloxy carbonyl-amino )-3-niethylcncccpham-4-cai'boxylatc-l-oxido..

A portion representing about one-third of the reaction mixture from (A) above was* evaporated, and the residue was dissolved in 100 ml. of dried methylene chloride.

To the resulting mixture were added 5 ml. of stannic chloride. The mixture was treated in accordance with the method of Example 12 to obtain 700 mg. of the 3-methylenecepham sulfoxide: nmr (CDCl^) 53.60, 3.88 (ABq, 2, J=15 Hz), 4.82 (s, 2), 4.94 (d, 1, J=4.5 Hz), 5.23 (s, 2), 5.40 (s, 1), 5.56 (s, 1), 5.83 (s, 1), 6.37 (d, 1, J=10 Hz), 7.46 (d, 2, J=9 Hz), and 8.20 (d, 2, J=9 Hz).

Example 16 41-Nitrobenzyi 3-methyl-2-(2-chlorosulfinyl-4-oxo-3-acetamido1-azetidinyl)-3-butenoate.

A. Toluene (500 ml.) was heated in equipment having j5 a Dean-Stark water trap to azeotropically remove any moisture.

To the resulting dried toluene was added 1.0 g. ¢2.4 mmol) of 4'-nitrobenzyi 6-acetamido-2,2-dimethylpenam-3-carboxylate1-oxide. The resulting mixture was refluxed again using a Dean-Stark water trap to remove any additional amounts of water. The mixture then was cooled, and 400 mg. (2.9 mmol) of N-chlorosuccinimide were added. The mixture then was refluxed for 1 hour. A sample of the reaction mixture was withdrawn, and the solvent was removed. The product which was obtained was consistent by nmr analysis with the structure of the title compound: nmr (CDCl^) 51.86 (bs, 3), 2.04, 2.09 (2s, 3), 4.80 (m, 1), 5.2 (m, 2), 5.28 (s, 2), 5.63 (m, 1), 6.05 (d, 1, J=4 Hz), and 7.4-8.4 (q, 4, ArH). -6642190 B. Conversion to 4'-Nitrobenzyl 7-acetamido-3-methylenecepham- ί - carboxy I ate-1-oxide.

The reaction mixture from (A) above was cooled in an ice bath, and 1 ml. of stannic chloride was added. The mixture was maintained for two hours at room temperature after which it was evaporated in vacuo to dryness. The resulting residue was dissolved in ethyl acetate, and the ethyl acetate mixture was washed once with a mixture of NCI and aqueous sodium chloride and twice with aqueous sodium chloride, dried over magnesium sulfate, and evaporated in 10 vacuo to dryness. The residue was dissolved in a minimum of ethyl acetate, and, after standing overnight, crystals of the 3-methylenecepham sulfoxide formed and were collected: nmr (CDC13) 51.92 (s, 3), 3.80 (bs, 2), 5.00 (d, 1, J=4 Hz), 5.32 (s, 2), 5.45-5.80 (m, 5), 7.60 (d, 2, J=8 Hz), 1S 7.86 (d, 1, J=9 Hz), and 8.20 (d, 2, J=8 Hz).

Example 17 41-Nitrobenzyl 7-phenoxyacetamido-3-methylenecepham-4carboxylate-1-oxide. (Complex isolation) Toluene (750 ml.) was refluxed for 15 minutes using a Dean-Stark trap. To the dried toluene were added 35 ml. of propylene oxide, 25 g. of 4'-nitrobenzyl 6-phenoxyacetamidopenicillanate-1-oxide and 7.37 g. of N-chlorosuccinimide. The reaction mixture was refluxed at 100eC. for 2 hours, after which time 120 ml. of toluene was distilled from the mixture. After cooling, 7.3 ml. of stannic chloride was added. Filtration of the reaction mixture provided 17.1 g. of an orange complex which was dissolved in ethyl acetate and washed with aqueous HC1 and brine. The ethyl acetate solution was dried and evaporated in vacuo to dryness to provide 6.9 g. of the title product. -6743190 Example 18 Methyl 3-methyl-2-(2-bromosulfinyl-4-oxo-3-phthalimido-lazetidinyl)-3-butenoate.

A. A mixture of 1.88 g. of methyl 6-phthalimidopenicillanate- 1-oxide and 890 mg. of N-bromosuccinimide in 150 ml. of carbon tetrachloride was refluxed for 80 minutes.

The reaction mixture was cooled, washed with water and brine, dried over anhydrous MgSO^, and evaporated in vacuo to dryness to provide 1.82 g. of the title product: nmr (CDC1,) 01.98 (bs, 3), 3.82 (s, 3, COOCH,), 5.0-5.35 (m, 3), .8-6.2 (m, 2, (3-lactam H), and 7.80 (bs, 4, ArH).

B. Conversion to exomethylenecepham sulfoxide.

The azetidinone sulfinyl bromide from above was dissolved in 20 ml. of methylene chloride; 0.6 ml. of jj stannic chloride was added to the solution. After 45 minutes at room temperature the reaction mixture was washed with water and brine, dried over anhydrous MgSO^, and evaporated in vacuo to dryness to provide 1.15 g. of methyl 7-phthalimido-3-methylenecepham-4-carboxylate-l-oxide (a 20 mixture of R- and S-sulfoxide isomers). For the predominant isomer: nmr (CDC13) 63.64, 4.20 (ABq, 2, J=13.0 Hz, C2~H), 3.84 (s, 3, COOCH3), 4.90 (d, 1, J=4.0 Hz, β-lactam H), .3-5.7 (m, 3), 5.97 (d, 1, J=4.0 Hz, β-lactam H), and 7.84 (bs, 4, ArH).

„ Example 19 4'-Nitrobenzyl 3-methy1-2-(2-isopropylthiosulfinyl-4-oxo3-phenoxyacetamido-1-azetidinyl)-3-butenoate.

A. To a solution of 10 g. of 4'-nitrobenzyl 3methyl-2-(2-chlorosulfinyl-4-oxo-3-phenoxyacetamido-lazetidinyl)-3-butenoate in 450 ml. of toluene was added 1.9 ml. of isopropyl mercaptan and 3.5 ml. of propylene oxide. -6842190 The mixture was allowed to stand for several days at room temperature and then was evaporated in vacuo to dryness to provide an oil which was chromatographed on a silica gel column using a toluene-ethyl acetate gradient. A total of 6.62 g. of the title product was isolated: nmr (CDCl^) 61.40 (d, 6, J-6.0 Hz, SCH(CH.3)2), 2.01 (s, 3), 3.55 (m, 1, SCII(CH3)2), 4.60 (s, 2, side chain CH2), 5.1-5.4 (m, 3), .33 (s, 2, ester CH2) , 6.20 (dd, 1, ,7=4.5 and 10.0 Hz, Rlactam H), 6.9-8.3 (m, 9, ArH) and 8.6 (d, 2, 7=10.0 Hz, NH) .

B. Conversion to exomethylenecepham sulfoxide.

The title product (682 mg.) was dissolved in 3.4 ml. of methanesull'onic acid. After 30 minutes the solution was poured into a separatory funnel containing ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic layer was separated, washed successively with aqueous sodium bicarbonate, water and brine (2X), and dried over anhydrous Mgso^. The product crystallized from ethyl acetate upon standing overnight. A total of 60 mg. of 4'-nitrobenzyl 7-phenoxyacetamido-3-methylenecepham-4carboxylate-1-oxide was isolated.

Example 20 4'-Nitrobenzyl 3-methyl-2-(2-tert-butylthiosulfinyl-4-oxo3-phenoxyacetamido-1-azetidinyl)-3-butenoate.

A. The same procedure was followed as described in Example 19 except 2.4 ml. of tert-butyl mercaptan was used in place of isopropyl mercaptan. 4.69 g. of the title product was isolated after chromatography: nmr (CDC13) 61.43 (s, 9, tert-butyl), 2.01 (s, 3), 4,57 (s, 2, side chain -CH2), 5.0-5.4 (m, 5), 6.20 (dd, 1, 7=4.0 and 11.0 Hz, -6942190 β-Lactam H), 6.8-8.2 (m, 9, ArH) and 8.64 (d, 1, J=11.0 Hz, NH) .

B. Conversion to exomethylenecepham sulfoxide.

The title product (700 mg.) was dissolved in 3.5 ml. of methanesulfonic acid. Following the same procedures as described in the second paragraph of Example 19, 190 mg. of 4'-nitrobenzyl 7-phenoxyacetamido-3-methylenecepham-4carboxylate-l-oxide was isolated.

Example 21 4'-Nitrobenzyl 3-methy1-2-(2-methoxysulfinyl-4-oxo-3phenoxyacetamido-1-azetidinyl)-3-butenoate.

A. To a solution of 41-nitrobenzyl 3-methyl-2-(2chlorosulfinyl-4-oxo-3-phenoxyacetamido-l-azetidibyl)-3butenoate, derived from 10 g. of 4'-nitrobenzyl 6-phenoxyacetamidopenicillanate-l-oxide and 2.68 g. of N-chloro15 succinimide, in 400 ml. of toluene was added 25 ml. of dry methanol. The reaction mixture was stirred at room temperature overnight, and then was washed successively with aqueous sodium bicarbonate (2X), water, and brine (2X). Evaporation in vacuo to dryness yielded 10 g. of the impure 2o title product which was purified by chromatography over acid-washed silica gel using a toluene-ethyl acetate gradient. The product was isolated as a mixture of isomers (R- and S- sulfinates). For the predominant isomer: nmr (CDC13) 61.90 (s, 3), 3.74 (s, 3, -0CH3), 4.52 (s, 2, side chain CH2), 4.8-5.3 (m, 5), 5.32 (s, 2, ester CH2), 5.76 (dd, 1, J=5.0 and 9.0 Hz, β-lactam H), and 6.8-8.2 (m, 9, ArH) . -704 319 0 B. Conversion to exomethylenecepham sulfoxide.

The title product (590 mg.) was dissolved in 2.0 ml. of methanesulfonic acid. After 30 minutes at room temperature, the mixture was worked-up in accordance with the procedures described in the second paragraph of Example 19 hereinabove to provide 0.13 g. (40%) of 4'-nitrobenzyl 7-phenoxyacetamido-3-methylenecepham-4-carboxylate-l-oxide.

Example 22 4'-Nitrobenzyl 3-methyl-2-(2-menthyloxysulfinyl-4-oxo-3phenoxyacetamido-1-azetidinyl)-3-butenoate.

A. The same procedure was followed as described in Example 21 except 3.12 g. (20 mmol) of menthol was employed instead of methanol. The product sulfinate ester was isolated by chromatography on an acid-washed silica gel column using a toluene-ethyl acetate gradient. The product was isolated as a mixture of isomers (R- and S- sulfinates). For the predominant isomer: nmr (CDClg) 60.6-2.4 (m, 18, menthyl H), 1.86 (s, 3), 3.98 (bs, 1), 4.52 (s, 2, side chain CHg), 4.72 (d, 1, J=5.0 Hz, β-lactam H), 4.8-5.2 (m, 3), 5.36 (s, 2, ester CH2> , 5.72 (dd, 1, J=5.0 and 9.0 Hz, β-lactam H), 6.8-8.2 (m, 9, ArH), and 7.85 (d, 1, J=9.0 Hz, -NH). §_·. Conversion to exomethylenecepham sulfoxide.

The title product (906 mg.) was dissolved in 4.6 ml. of methanesulfonic acid. After 30 minutes at room temperature, the reaction mixture was worked-up in accordance with the procedure described in the second paragraph of Example 19 hereinabove. Conversion to 4'-nitrobenzyl 7phenoxyacetamido-3-methylenecepham-4-carboxylate-1-oxide was confirmed by comparative thin-layer chromatography and nmr spectroscopy. -7142190 Example 23 4'-Nitrobenzyi 3-methyl-2-(2-anilinosulfinyl-4-oxo-3phenoxyacetamido-1-azetidinyl)-3-butenoate.

A. To a solution of 4'-nitrobenzyi 3-methyl-2-(2chlorosulfinyl-4-oxo-3-phenoxyacetamido-l-azetidinyl)-35 butenoate, derived from 10 g. of 41-nitrobenzyi 6-phenoxyacetamidopenicillanate-l-oxide and 2.68 g. of N-chlorosuccinimide, in 400 ml. of toluene were added 3.6 ml. of aniline. After 5 minutes at room temperature the reaction mixture was washed with water (2X) and brine, dried over anhydrous MgSO^, and evaporated in vacuo to dryness to provide the title product: nmr (CDCl^) 61.96 (s, 3), 4.5 (s, 2, side chain CH2), 5.34 (s, 2, ester CHj), 5.0-5.3 (m, 3), 5.77 (dd, 1, J=4.5 and 10.0 Hz, H-lactam H), and 6.8-8.4 (m, 14, ArH). j5 B. Conversion to exomethylenecepham sulfoxide.

The title product (2.07 g.) was dissolved in 10 ml. of methanesulfonic acid. After 30 minutes, the solution was poured slowly into a cold mixture of saturated aqueous sodium bicarbonate and ethyl acetate. The ethyl acetate 2o layer was separated, washed successively with aqueous sodium bicarbonate (2X), water (2X), and brine (2X), dried over anhydrous MgSO^ and evaporated in vacuo to dryness. 41Nitrobenzyi 7-phenoxyacetamido-3-methylenecepham-4-car~ boxylate-1-oxide (373 mg., 21%) crystallized from an ethyl acetate solution of the impure product.

Example 24 Methyl 3-methy 1-2-(2-succinimidosul£inyl-4-oxo-3-phenylacetamido-1-azetidinyl)-3-butenoate.

A. A solution of 2.55 g. (7 mmol) of 4'-nitrobenzyi 6-phenylacetamidopenicillanate-1-oxide, 5.6 ml. (34 mmol) of -724219 , N-trimethylsilylsuccinimide and 0.18 ml. of acetic acid in 41 ml. of dimethylacetamide was stirred for 3.5 hours at 105oC. After cooling, the reaction mixture was poured into a cold mixture of 50 ml. of ethyl acetate and 150 ml. of water. The water layer was extracted twice with ethyl acetate. The ethyl acetate extracts were combined, washed with water, dried over anhydrous MgSO^, and evaporated in vacuo to dryness to provide 3.3 g. of methyl 3-methy1-2(2-succinimidothio-4-oxO“3-phenylacetamido-l-azetidinyl)10 3-butenoate: nmr (CDC13) 51.84 (s, 3), 2.78 is, 4, succinimide), 3.65 (s, 2, side chain CR^), 3.74 (s, 3, COOCH^), 4.66 (s, 1), 5.0-5.5 (m, 4, ,β-lactam H + olefinic Cf^) , 7.26 (s, 5, ArH), and 7.58 (d, 1, J=8.0 Hz, -NH) .

The sulfenimide from above was dissolved in 50 ml. of methylene chloride at 0°C. and oxidized with 1.48 g. of m-chloroperbenzoic acid. After 1 hour at 0°C. the reaction mixture was washed successively with saturated aqueous sodium bicarbonate, water, and brine, dried over anhydrous MgSO^ and evaporated in vacuo to dryness to provide the title product: nmr (CDC13) 51.86 (s, 3), 2.60 (s, 4, succinimido H), 3.54 (s, 2, side chain CH2), 3.78 (s, 3, COOCH3), 4.8-5.2 (m, 3), 5.6-5.9 (m, 1, (3-lactam H) , 6.04 (d, 1, J=5.0 Hz, 3-lactam H), and 7.3 (s, 5, ArH).

B. Conversion to exomethylenecepham sulfoxide.

The title product (469 mg., 1 mmol) was dissolved in 2.3 ml. of methanesulfonic acid. After 30 minutes at room temperature the solution was poured slowly into a mixture of saturated aqueous sodium bicarbonate and ethyl acetate. The ethyl acetate layer was separated, washed successively with aqueous sodium bicarbonate, water and -7342190 brine, dried over anhydrous MgSO^, and evaporated in vacuo to dryness. Conversion to methyl 7-phenylacetamido-3methylenecepham-4-carboxylate-1-oxide was confirmed by comparative thin-layer chromatography and nmr spectroscopy.

Example 25 4'-Nitrobenzy! 3-methy1-2-[2-(N,N1-dicarboethoxyhydrazosulfinyl)-4-oxo-3-phenoxyacetamido-l-azetidinyl]-3-butenoate.

A. A solution of 10 g. of 4’-nitrobenzyl 6-phenoxyacetamidoperticillanate-l-oxide in 300 ml. of dry 1,1,2-trichloroethane was refluxed and dried using a Dean-Stark trap. After about 50 ml. of the solvent was distilled, the mixture was cooled and 6 ml. of diethyl azodicarboxylate was added. The reaction mixture was refluxed for 45 minutes and thereafter was evaporated in vacuo to dryness. The residue was triturated with hexane to remove excess diethyl azodicarboxylate. Further drying provided the title product as an impure yellow gum which was not further purified before conversion to the exomethylenecepham sulfoxide: nmr (CDCip 61.40 (t, 3, J=7 Hz, CH2CH3), 1.95 (bs, 3), 3.8-4.7 (m, 6), 5.0-5.6 (m, 5) and 6.7-8.4 (m, 9, ArH).

B. Conversion to exomethylene sulfoxide.

One gram of the product from (A) above was dissolved in 20 ml. of methanesulfonic acid. The mixture was stirred at room temperature for 20 minutes and then poured into aqueous sodium chloride solution. The aqueous solution was then extracted with 200 ml, of ethyl acetate.

The ethyl acetate extract was washed with aqueous sodium bicarbonate, dried (MgSO^) and evaporated in vacuo to dryness. The residue was purified by preparative thin layer chromatography using silica gel plates developed with 90% -7443190 ethyl acetate-benzene. A total of 160 mg. of 4'-nitrobenzyl 7-phenoxyacetamido-3-methylenecepham-4-carboxylate-l-oxide was isolated.

Example 26 4'-Nitrobenzyl 3-methyl-2-[2-(N ,N1-dicarbo-tert-butoxyhydrazosuif inyl) ^-oxo^-acetamido-l-azetidinyl] -3-butenoate.

A. In accordance with the procedures described in Example 25 820 mg. of 4'-nitrobenzyl 6-acetamidopenicillanate- 1-oxide was reacted with 465 mg. of di-tert-butyl azodicarboxylate to provide the title product: nmr (CDClj) 61.50 (s, 18, tert-butyl) 1.90 (bs, 3), 2.00 (s, 3, CHjCNH-) , .40 (s, 2, ester CHj), 5,0-6.0 (m, 5) and 7.6-8.4 (m, 4, Aril) .

B. Conversion to exomethylene sulfoxide.

The title product from (A) was dissolved in 15 ml, of methanesulfonic acid and after 10 minutes at room temperature was poured into saturated aqueous sodium chloride solution. The aqueous solution was extracted with ethyl acetate. The organic extract was washed with aqueous sodium bicarbonate, dried (MgSO^), and evaporated in vacuo to dryness, chromatographic purification of the residue provided 90 mg. (12%) of 4'-nitrobenzyl 7-acetamido-3methylenecepham-4-carboxylate-l-oxide: nmr (CDClj) 62.04 (s, 3, CH3CNH-), 3.66 (bs, 2, C2~H), 4.90 (d, 1, J=4.0 Hz, Cg-H), 5.26 (s, 3, C4-H + ester CH2), 5.45, 5.74 (2s, 2,=CH2), 5.92 (dd, 1, J=4.0 and 8.0 Hz, C?-H), 6.97 (d, 1, 7=8.0 Hz, -NH), and 7.4-8.4 (m, 4, ArH). -7542190 Example 27 21,2',2'-Trichloroethyl 7-(2-thienyiacetamido)-3-methylenecepham-4-carboxylate sulfoxide. Λ solution of 1 g. of 2',2',2'-trichloroethyl 6-(2-thienylacetamido)penicillanate-l-oxide and 525 mg. of di-tert-butyl azodicarboxylate in 50 ml. of 1,1,2-trichloroethane was refluxed for 45 minutes. The reaction mixture was then cooled and evaporated in vacuo to dryness. The residue thereby obtained was dissolved in methanesulfonic acid and after 15 minutes at room temperature the acid solution was poured into saturated aqueous sodium chloride. The aqueous solution was extracted with ethyl acetate. The organic extract was washed with sodium bicarbonate solution, dried (MgSO^) and evaporated in vacuo to dryness to provide 72 mg. (7%) of the title product: nmr (CDCl^) 52.87 (bs, 2, C2-H) , 3.75 (s, 2, side chain CH2) , 4.80 (s, 2, ester CH.,) , 5.28 (d, 1, J=4.0 Hz, Cg-H), 5.46, 5.77 (2s, 2,=CH2), 5.90 (dd, 1, J=4.0 and 8.0 Hz, C^-H) and 6.8-7.3 (m, 3, ArH).

Example 28 4'-Nitrobenzyl 3-methy1-2-[2-(N ,N1-dibenzoylhydrazosulfinyl)-4-oxo-3-phenoXyacetamido-l-azetidinyl]-3-butenoate.

A. In accordance with the procedures described in Example 25 10 g. of 41-nitrobenzyl 6-phenoxyacetamidopenicillanate-l-oxide was reacted with 7.8 g. of dibenzoyldiimide in dry 1,1,2-trichloroethane.

B. Conversion to exomethylene sulfoxide.

One gram of the unpurified product from (A) above was dissolved in 20 ml. of methanesulfonic acid. After 20 minutes the mixture was poured into 300 ml. of saturated aqueous sodium chloride. The aqueous solution was extracted with 200 ml. of ethyl acetate, and the organic extract was -7643190 washed with sodium bicarbonate solution, dried (MgSO^), and evaporated in vacuo to dryness. 4'-Nitrobenzyl 7-phenoxyacetamido-3-methylenecepham-4-carboxylate-1-oxide (90 mg., 407,) was isolated by preparative thin-layer chromatography.

Example 29 4' -Nitrobenzyl 3-πΐΘί1^1-2-Ε2~(2-3θ(;Ογ1ΙιγάΓαζθ5α1£ίηγΐ)-4·-οχο3-phenoxyacetainido-i-azetidinyl3-j-butenoate.

A. To a solution of 4'-nitrobenzyl 3-methyl-2-(2chlorosulfinyl-4-oxo-3-phenoxyacetamido-1-azetidinyl)-3butenoate (derived from 50 g. of 4'-nitrobenzyl 6-phenoxyacetamidopenicillanate-1-oxide and 15 g. N-chlorosuccinimide in 1000 ml. of 1,1,2-trichloroethane) at room temperature was added 14.8 g. of acetyl-hydrazide. After stirring for about 30 minutes at room temperature the reaction mixture was washed 3 times with 500 ml. portions of saturated sodium chloride solution, dried (MgSO^) and evaporated in vacuo to dryness. The residue was dissolved in ethyl acetate. Upon standing in the refrigerator 29.7 g. (52%) of the title product crystallized: nmr (CDClg) 61.94 (s, 6, CHgC- + allylic CHg), 4.65 (s, 2, side chain CH^), 4.9-5.4 (m, 5), 5.55 (s, 2, ester CHg) and 6.8-8.4 (m, 9, ArH).

B. Conversion to exomethylene sulfoxide.

Two grams of the title product were dissolved in ml. of methanesulfonic acid. After 15 minutes at room temperature the acid solution was poured into a separatory funnel containing 200 ml. of ethyl acetate, 250 ml. saturated sodium chloride and 250 ml, of saturated sodium bicarbonate solution. The organic layer was separated, washed with sodium bicarbonate solution, dried (MgSO4), and -7742190 evaporated in vacuo to dryness. The residue was dissolved in a minimum amount of ethyl acetate, and upon standing 879 mg. (51%) of 41-nitrobenzyl 7-phenoxyacetamido-3-methylenecepham-4-carboxylate-l-oxide crystallized.

Example 30 ' -Nitrobenzyl 3-methy 1-2- L2-(2-carbomethoxyhydrazosulfitiyl)-4oxo-l-phenoxyacetamido-l-azetidiny12-3-butenoate.

A. In accordance with the procedures described in Example 29 carbomethoxyhydrazide (4.5 g.) was reacted with the sulfinyl chloride derived from 15 g. of 4'-nitrobenzyl 6-phenoxyacetamidopenicillanate-l-oxide to provide the title product as a yellow gum: nmr (CDCl^) 61.92 (bs, 3), 3.66 (s, 3, COOCHg), 4.56 (s, 2, side chain CH2), 4.8-5.6 (m, 7, ester CH2, β-lactam H, olefinic H) and 6.7-8.4 (m, 9, ArH), B. Conversion to exomethylene sulfoxide.

In accordance with the procedure described in the second paragraph of Example 29, the title product (640 mg.) was cyclized in methanesulfonic acid (10 ml.) to provide 240 mg. (45%) of 41-nitrobenzyl-7-phenoxyacetamido-3-methylenecepham-4-carboxylate-1-oxide. 2 Example 31 4'-Nitrobenzyl 3-methyl-2-C2-(2-toly 1 sulfonylhydrazosulfinyl)-4oxo-3-phenoxyacetamido-l-azetidinyT]-3-butenoate.

A. In accordance with the general procedure described in Example 29, tosyl hydrazide (18 g.) was reacted with the sulfinyl chloride derived from 30 g. of 4'-nitrobenzyl 625 phenoxyacetamidopenicillanate-l-oxide to provide the title product as a yellow gum which did not crystallize.

B, In accordance with the procedure described in the second paragraph of Example 29, the title product was cyclized in methanesulfonic acid (150 ml.) to provide 7.0 g. -7843190 (230) of 4'-nitrobenzyl 7-phenoxyacetamido-3-methylenecepham-4-carboxylate-l-oxide.

Example 32 4'-Nitrobenzy! 3-methy 1.-2-(2-aminosuli'inyl-4-oxo-3-pbenoxyacetamido-1-azetidinyl)-3-butenoate, A. To a solution of 5 g. of 4'-nitrobenzyl 3-methyl2- (2-chlorosulfinyl-4-oxo-3-phenoxyacetamido-l-azetidinyl)3- butenoate in toluene was added a solution of 5 g. of sodium cyanate in 100 ml. of water. After 1 hour at room temperature, the organic phase was separated, dried (MgSO^) and evaporated in vacuo to dryness to provide a mixture of the title product and 4'-nitrobenzyl 6-phenoxyacetamidopenicillanate sulfoxide. For the title product: nmr 0 (CDClg) 61.96 (s, 3), 4.55 fs, 4, side chain CH2 + -SNH2), 4.88 (d, 1, J=4.5 Hz, β-lactam H), 5.0-5.5 (m, 5), 5-72 (dd, 1, J=4«5 and 9.0 Hz, β-lactam H), 7.74 (d, 1, J=9.0 Hz, -NH) and 6.9-8.4 (m, 9, ArH).

Anal. Calcd. for C23H24N4°8S: c, 53.48; H, 4.68; N, 10.85; 0, 24.7«; S, 6.21.

Found: C, 53-69; H, 4.77; N, 10.62; S, 5.90.

B. Conversion to the exomethylene sulfoxide.

In accordance with the procedure described in the second paragraph of Example 29, the title product was cyclized in methanesulfonic acid to provide 4'-nitrobenzyl 7-phenoxyacetamido-3-methylenecepham-4-carboxylate-loxide.

Claims

Cl.A IMS: 1. Λ process for preparing 3-mel.bylenecepham sulfoxides of the formula f) II r, A Ri. / \ ioOR'

1. « I 12. The process of any of claims 1 or 6 to 9 wherein the reaction is effected with aluminum chloride, zinc chloride, zinc bromide, ferric chloride, gallium trichloride, zirconium tetrachloride, mercuric chloride or 2. -iodoethyl, 4-nitrobenzyl, diphenylmethyl (benzhydryl), phenacyl, 4-halophenacyl, 1,1- or 3,3-dimethylailyl,2,2,2-trichloroethyl., tri (C^-C^alkyl) si lyl or succini.midomethyl. 30. The compound of claim 28 or 29 wherein X is a group of the formula -OR^. -8942130 31. The compound of claim 30 wherein is hydrogen. 32. The compound of c la inf 28 or 2!) wherein X is a group of the formula -SR r . R, / 6 33. The compound of claim 28 or 29 wherein X is j a group of the formula -N 34. The compound of claim 33 wherein Rg is hydrogen and Ry is hydrogen, R, or a group of the formula -NfIRg. *·θ 35. The compound of claim. 33 wherein R, , R_, and the nitrogen atom to which they are bonded taken together form an imido group of the formula II -n; > \ z II 36. The compound of any of claims 28 to 35 wherein 15 Rj is an imido group of the formula II Z C rti. .11— 37. The compound of claim 36 wherein R^ is phthalimido. -9042190 38. The compound of any of claims 28 to 35 wherein is an imido group of the formula II R.' -C. h— / R-(0) CH C: m 2|| 39. The compound of any of claims 28 to 35 wherein (2) a group of the formula -SR,, wherein Rg is C^-Cg alkyl, aryl or aryl (C-j-C^alkyl),- or (3) a group of the formula -N wherein r? (a) Rg is hydrogen and R 7 is hydrogen, R as defined hereinabove, or a group of the formula -NHRg wherein Rg is aminocarbonyl, C^-Cg alkylaminocarbonyl, C^-Cg alkylcarbonyl, C^-Cg alkoxycarbonyl or tosyl; or (b) Rg, R 7 and the nitrogen atom to which they are bonded taken together form an imido group of the formula ο II —h ;r< V 2 II wherein R 2 is as defined hereinabove. 29. The compound of claim 28 wherein R is methyl, tert-butyl, benzyl, 4-methoxybenzyl, C 2 ~C 4 alkanoyloxymethyl,

2. The process of claim 1 wherein a metathetic cation-forming agent is employed. -834219° (2) a group of the formula -OR^ wherein R^ is hydrogen, alkyl, arylCC^-C.^ alkyl) or Cj--Cg haloalkyl; 3. (3) an imido group of the formula II R '0. ;n— R'-(0) CH f/ m « |( wherein R and m are as defined hereinabove and R 2 1 is Cg-C, alkyl, Cg-Cg haloalkyl, Cg-Cg alkoxy, or 2,2,2-trichloroethoxy; or (4) an imidazolidinyl group of the formula ο II Y til, -881 i

3. The process of claim 1 or 2 wherein the metathetic cation-forming agent is an anhydrous silver salt. (3) a group of the formula -SR,, wherein Rg is C^-Cg alkyl, aryl or aryl(C^-Cj alkyl); or ,R (4) a group of the formula -N^ ” wherein R f (a) Rg is hydrogen and R ? is hydrogen, R as defined hereinabove, or a group of the formula -NiIR_ wherein R_ is aminoΟ O carbonyl, C^-C^ alkylaminocarbonyl, C^-C-j alkylcarbonyl, C^-C-j alkoxycarbonyl or tosyl; -824219( (b) Rg is -COORg or -COR g and R ? is -NHCOORf, or -NHCOR- wherein R Q is C. -Cy 9 9 16 alkyl or phenyl? or wherein (c) Rg, Ry and the nitrogen atom to which $ they are bonded taken together form an imido group of the formula II Λ, \ / • II wherein R 2 is as defined hereinabove? and when R, is -COOR- or -COR- and R-, is 6 9 9 7 1() -NHCOORg or -NHCORg, R^ is additionally a heteroarylmethyl group of the formula R ,,,, CH 2 - wherein R'''' is 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-thiazolyl or 5-isoxazolyl; 15 with the limitations that when X is bromo, R^ is only an imido group of the formula o II '· II Ci when a metathetic cation-forming agent or a Lewis acid is employed, X is only chloro or bromo; and when R is an acid labile carboxylic acid protecting group, the product is a 3-methylenecepham-4-carboxylic acid sulfoxide. 4. -mcthoxybenzyloxy. -9142190 w,. 45. The· compound of claim 40 wherein R n is the group -R, wherein R is 1,4—cyclohexadienyl, phenyl or phenyl, substituted ?. with 1 or 2 substituents independently selected from halo, protected hydroxy, nitro, cyano, trifluoromethyl, C^-C^ alkyl, and Cj-C^ alkoxy. 46. The compound of claim 40 wherein R^ is a substituted alkyl group of the formula R’ ’ »CII. I W 47· 4’-Nitrobenzyl 3-methyl-2-(2-sulfino-4-oxo-3phtbalimido-1-azetidinyl)-3-butenoate. 48. Methyl 3-methyl-2-(2-sulfino-4-oxo-3-phthaLiinido-1azetidinyl)-3-butenoatc. * 49. 4 *-Nitrobenzyl 3-methyl-2-(2-isopropylthiosulfinyl-4oxo-3-phonoxyacetamido-l-azetidinyl)-3-butenoate. 50. 4’-Nitrobenzyl 3-mettiyl-2-(2-tert-butylthiosulfInyl4-0 xo-3-phenoxyacetamido-1-azetidinyl)-3-butenoate. 51. 4’-Nitrobenzyl 3-methyl-2-(2-methoxysulfinyl-4-oxo3-phenoxyacetamido-l-azetidinyl)-3-butenoate. 52. 4’-Nitrobenzyl 3-methyl-2-(2-anilinosulfinyl.-4-oxo3- phenoxyacetamido-l-azetidinyl)-3-butenoate. 53· Methyl 3-methyl-2-(2-succinimidosulfinyl~4-oxo-3phenylacetamido-1-azetidinyl)-3-butenoate. 54. 4 ’-Nitrobenzyl 3-methyl-2-(2-mentuyloxysulfinyl)-4oxo-3-phcnoxyacetamido-l-azetidinyl)-3-butenoate. 55. 4’-Nitrobenzyl 3-methyl-2-£2-(2-acetylhydrazosulflnyl)4- oxo-3-phenoxyacetamido-l-azetidinylj-3-butenoate. 56. 4’-Nitrobenzyl 3-methyl-2-/ 2-(2-carbomethoxyhydrazosul L'inyl)-4-oxo-3-phenoxyacetamido-l-azetidinyl} -3-butenoate. 92 4 2190 57. 4’-Nitrobenzyi 3-methyl-2-f2-(2-tolylsulfonyihydrazosulfiny.l.)-4-oxo-3-phenoxyacetamido- 1-azetidinyl] -3butenoate. 58. 4’-Nitrobenzyi 3-methyl-2-(2-aminosulfinyl-4-oxo5 3-phenoxyacetamido-l-azetidinyl)-3-butenoate. 59. Sulfinyl-azetidinone compounds of formula II wherein R, Rj and X are as defined in claim 28, substantially as hereinbefore described with reference to any one of Examples 7, 9) 19 to 24, 27 and 29 to 32. 4 219 0 wherein R is as defined above and Y is acetyl or nitroso; and X is (1) a group of the formula -OR^ wherein R^ is hydrogen, C l _C 10 aryl (Cj-Cjalkyl) or C^-Cg haloalkyl;

4. The process of any of claims 1 to 3 wherein the metathetic cation-forming aqent is silver p-toluene5 sulfonate. 5. R| is an imidazolidinyl group of the formula II CH 40. The compound of any of claims 28 to 35 wherein It R^ is an amido group of the formula R^CNH-. 41. The compound of claim 40 wherein Rj is a substituted 10 alkyl group of the formula R-(0) m -CH2-. 42. The compound of claim 40 or 41 wherein R^ is benzyl or phenoxymethyl. 43. The compound of claim 40 wherein is hydrogen or C^-Cj alkyl, halomethyl, or 3-(2-chlorophenyl)-ΞΙ 5 methylisoxazol-4-yl. 44. The compound of claim 40 wherein R^ is benzyloxy, 4-nitrobenzyloxy, 2,2,2-trichloroethoxy, tert-butoxy or 5 chromium trichloride at a temperature of 40° to 115°C. 13. The process of any of claims 1 or 6 to 9 wherein titanium tetrachloride is employed at a temperature of 70° to 100°C. 14. The process of claim 1 wherein a Bronsted 10 proton acid type catalyst is employed. 15. The process of claim 1 or 14 wherein the reaction is effected in an aromatic hydrocarbon solvent or a haiogenated aliphatic hydrocarbon solvent at a temperature of 70° to 115°C. i5 16. The process of any of claims 1, 14 or 15 wherein the Bronsted proton acid catalyst is methanesulfonic acid, ethanesulfonic acid, trifluoroacetic acid, trichloroacetic acid, dichloroacetic acid, sulfuric acid, phosphoric acid, polyphosphoric acid, perchloric acid, 20 chlorosulfonic acid, or fluorosulfonic acid. 17. The process of any of claims 1, 14 or 15 wherein a conjugate Friedel-Crafts acid catalyst of the type HMA. or 4 HMA.^ is employed, wherein M is B, Al or As and A is F, Cl or Br. 18. The process of claim 17 wherein the Friedel25 crafts catalyst is HBF^, HA1C1 4 , HAsF or HAlBr 4 . 19. The process of any of claims 1, 14 or 15 wherein an acidic chalcide is employed. 20. The process of claim 19 wherein the acidic chalcide is phosphorus pentoxide. -85i 21. The process of claim 1 or 14 wherein the compound of formula II is dissolved in methanesulfonic acid, ethanesulfonic acid, trifluoroacetic acid, trichloroacetic acid or dichloroacetic acid at ambient temperature and main5 tained in solution for 10 to 30 minutes. 22. The process of any of claims 1 or 14 to 21 wherein X is a group of the formula -OR^, a group of the Z R, formula -SR_ or a group of the formula -N R ? 23. The process of any of claims 1 to 21 wherein X is chloro. 24. The process of any of claims 1 to 21 wherein X is bromo. 25. The process of any of claims 1 to 23 wherein Rg is an amido group of the formula RgCNH- and Rg is a substituted 15 alkyl group of the formula R*’-(0) -CH„-. irt & 26. The process of any of claims 1 to 25 wherein R is methyl, tert-butyl, benzyl, 4-methoxybenzyl, C^-C^ alkanoyloxymethyl, 2-iodoethyl, 4-nitrobenzyl, diphenylmethyl (benzhydryl), phenacyl, 4-halophenacyl, 1,1- or 3,3-dimethyl20 allyl, 2,2,2-trichloroethyl, tri(Cg-Cgalkyl)silyl or succinimidomethyl. 27. The process of any of claims 1 to 26 wherein R is benzhydryl, 4-methoxybenzyl, tert-butyl, or tri(Cg-Cgalkyl) silyl and R' is hydrogen. -8642190 28. Sulfinyl azetidinone compounds of the formula II Ri, ,SX / wherein R is a carboxylic acid protecting group; R^ is (1) an imido group of the formula II Λ / \ Rn /1— V II wherein R^ is Cg-C^ alkenylene, alkylene, 1,2-phenylene or 1,2-cyclohexenylene; or (2) an amido group of the formula R CNHwherein R^ is (a) hydrogen, C^-c' 3 alkyl, halomethyl, cyanomethyl or 3-(2-chlorophenyl)-5-methylisoxazol-4-yl; (b) benzyloxy, 4-nitrobenzyloxy, 2,2,2trichloroethoxy, tert-butoxy, or 4methoxybenzyloxy; (c) the group R wherein R is 1,4-cyclohexadienyl, phenyl or phenyl sub-874219^ ίο stituted with 1 or 2 substituents independently selected from halo, protected hydroxy, nitro, cyano, trifluoromethyl, Cj-Cg alkyl, and Cg-C^ alkoxy; (d) a substituted alkyl group of the formula R ” - <°>m- C11 2wherein R is as defined above, and m is 0 or 1; (e) a substituted alkyl group of the formula R' '’ CHW wherein R''' is R' 1 as defined above and W is protected hydroxy or protected amino;

5. The process of any of claims 1 to 4 wherein the reaction temperature is 20 to SO°C. 5 (b) benzyloxy, 4-nitrobenzyloxy, 2,2,2trichloroethoxy, tert-butoxy, or 4methoxybenzyloxy; (c) the group R wherein R is 1,4-cyclohexadienyl, phenyl or phenyl substituted j 0 with 1 or 2 substituent;; independently selected from halo, protected hydroxy, nitro, cyano, trifluoromethyl, C 1 ~C 3 alkyl, and Cj-C^ alkoxy: j5 (d) substituted alkyl group o£ the formula R (0) m- CH 2wherein R is as defined above, and m is 0 or 1; (e) a substituted alkyl group of the formula R' '' CHI W wherein R' 11 is R as defined above and W is protected hydroxy or protected amino; -8142190 (3) an imido group of the formula a II R *c i: N~ R -((>) CII C wherein R” and m are as defined hereinabove and R 2 ' is alkyl, C^-Cg haloalkyl, C^-C^ alkoxy or 2,2,2-trichloroethoxy; or (4) an imidazolidinyl group of the formula II R <* K x z . wherein R is as defined above and Y is acetyl or nitroso; and X is (1) chloro or bromo; 5 which comprises reacting a compound of the formula (J II Lor with a Lewis acid type Friedel-Crafts catalyst, a Bronsted proton acid type Friedel-Crafts catalyst or a metathetic cation-forming agent in a dry inert organic solvent; or 10 dissolving such compound in an organic Bronsted acid; wherein in the above formulae R is a carboxylic acid protecting group; R' is R or hydrogen; Rj is (1) an imido group of the formula II ,c II wherein R 2 is C 2 -C 4 alkenylene, C 2 -C 4 alkylene, 1,2phenylene or 1,2-cyclohexenylenc; or -8042190 (2) an amido group of the formula o II IteCNIIwherein is (a) hydrogen, C^-C^ alkyl, halomethyl, cyanomethyl or 3-(2-chlorophenyl)-5-methylisoxazol-4-yl;

6. The process of claim 1 wherein a.metal halide Lewis acid type catalyst is employed. 10

7. The process of claim 1 or 6 wherein the catalyst is aluminum chLoride, stannic chloride, stannic bromide, zinc chloride, zinc bromide, antimony pentachloride, titanium tetrachloride, ferric chloride, gallium trichloride, zirconium tetrachloride, mercuric chloride or 15 chromium trichloride.

8. The process of any of claims I, 6 or 7 wherein the solvent medium is an aromatic hydrocarbon solvent or a halogenated aliphatic hydrocarbon solvent.

9. The process of any of claims 1 or 6 to 8 wherein X is 20 chloro or bromo, and about 1.1 equivalents of the metal halide Lewis acid type catalyst is employed, in an aromatic hydrocarbon solvent or a halogenated aliphatic hydrocarbon solvent at a temperature of 10° C to 115°C. 10. The process of any of claims 1 or 6 to 9 25 wherein stannic bromide, stannic chloride or antimony pentachloride is employed at a temperature of 10° to 40°C. 11. The process of any of claims 1 or 6 to 10 wherein the reaction is effected at room temperature with J 30 stannic chloride. ; -84'1

10. 60. A process for preparing 3-methylenecepham sulfoxides of formula I wherein and R* are as defined in claim 1, substantially as hereinbefore described with reference to any one of Examples 1,3 to 6,8, and 10 to 32.