KR790000944B1 - Process for preparing sulfinyl chlorides - Google Patents

Abstract

2-chlorosulfinyl azetidine-4-ones [ I, R1 = car-boxylic acid-protecting group: R = imido (1: R2 = C2-4 alkenylene, 1, 2-phenylene, R3-CO-NH-(R3 = H, C1-3 alkyl, halomethyl, benzyloxy, 4-nitrobenzyloxy, ph, protected hydroxyl), imidazolydinyl (2: u = ni-troso, acetyl), or R4-CO-N-CO-CH2-(O)m-R1 (R4 = C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, 2, 2, 2-trichloroethoxy) were prepd. by reacting the penicillin sulfoxide (II) with N-chlorohalogenating agent at 75≰-135≰C in anhydrous inert solvent.

Description

Process for preparing sulfinyl chloride

The present invention relates to a novel process for preparing 2-chloro sulfinyl azetidine-4-silver compounds by treating penicillin sulfoxide esters with an N-chloro halogenating agent at a temperature of about 75-135 ° C.

Sulfinyl chloride may be treated with ditin tin chloride to prepare 3-exomethylene cepam sulfoxide, which is an intermediate in the preparation of cephalonporin antibiotics.

Recent US Pat. No. 3,843,682 discloses 3-methyl-2- (2-chloro sulfinyl-4-oxo-3-imido-1-azetidyl) -3-butenoate ester ie usually 2-chloro sulfinyl A method for preparing a substance called 3-imido-azetidin-4-one is described. These compounds are prepared by reacting the corresponding penicillin sulfoxide esters with sulfinyl chloride at a temperature of about 75-120 ° C. Compounds prepared by this known method are limited to 3-imido substituted 2-chloro sulfinyl azetidine-4- because this reaction is limited to using 6-imido penicillin sulfoxide ester as starting material. . It is not described which one is more desirable or easier to use. That is, no mention is made of penicillin sulfoxide esters which are readily available from natural penicillin G and / or penicillin V. When attempting to carry out the reaction described in US Pat. No. 3,843,682 using 6-amino penicillin sulfoxide ester as starting material, the product obtained is either 2-chloro sulfinyl azetidine-4-silver free or at most. This material is obtained as a complex mixture containing traces that are undetectable by conventional analytical techniques. Therefore, this prior art requires the absence of amide hydrogen at the 6-position of the starting material penicillin sulfoxide and then first replaces the original 6-substituents of penicillin with an already substituted substituent and then cleaves the substituent already. Recyclization introduces a substituent of the intended final antibiotic product.

We have now found that sulfinyl chloride intermediates can be prepared from 6-amido penicillin sulfoxide esters by changing the reaction conditions and changing the halogenating agents available. This method eliminates the need to block amide hydrogens by converting it into an imido derivative at the 6-position of the penicillin sulfoxide starting material.

2-Chloro sulfinyl azetidin-4-one prepared by the method of the present invention can be ring closed to prepare 3-exo methylene cefesulfoxide ester. Illustrating the 2-chloro sulfinyl azetidin-4-one with the corresponding 3-exo methylene sefam sulfoxide involves the preparation of a Friedel Craft catalytic molecule comprising an olefin moiety of sulfinyl chloride and the starting material azetidine-4-silver. Can be achieved by reaction.

It is therefore an object of the present invention to provide a novel reaction for preparing sulfinyl chloride of formula (I).

The compound is prepared by reacting the penicillin sulfoxide of the following formula (II) with an N-chloro halogenating agent in an inert solvent in an inert solvent at a temperature range of about 75-135 ° C.

Wherein R ₁ is a carboxylic acid protecting group,

R is

(1) Imager of the following structure

R ₂ is a C ₂ -C ₄ alkenyl group or 1,2-phenylene group.

(2) Amido groups of the following structure

Where R ₃ is

a. Hydrogen, C ₁ -C ₃ alkyl, halomethyl, benzyloxy, 4-nitro benzyloxy, t-butyloxy, 2,2,2-trichloro ethoxy, 4-ethoxy benzyloxy, 3- (2-chloro Phenyl) -5-methyl isoxazol-4-yl:

b. R 'group wherein R' is 1,4-cyclo hexadienyl, phenyl, or phenyl substituted with 1-2 halogen, protected hydroxy, nitro, cyano, tripulomethyl, C ₁ -C ₄ alkyl, or C ₁ -C ₄ alkoxy group):

c. Structural formula R '-(O) _m -CH _2- , wherein R' is as described above and m is 0 or 1:

,여기에서 R'는 상술한 바와같고, W는 보호된 하이드록시 또는 보호된 아미노기이다 :d. Next structural formula

Where R 'is as described above and W is a protected hydroxy or protected amino group:

(3) is an imidazolidinyl group of the following structure, or

Wherein R 'is as described above and U is a nitrozo or acetyl group.

(4) The imager is of the following structure.

Wherein R 'and m are as described above and R ₄ is C ₁ -C ₃ alkyl, C ₁ -C ₃ haloalkyl, C ₁ -C ₃ alkoxy or 2,2,2-trichloro ethoxy.

The reaction of the present invention prepares new sulfinyl chloride having the following structure (III).

Wherein R ₁ is a carboxylic acid protecting group and R ₃ is as described above.

In the above structural formula, R ₁ means a carboxylic acid protecting group, which can be removed by acid treatment or hydrogenation. Selectable carboxylic acid protecting groups are for example C ₁ -C ₄ alkyl, 2,2,2-trihaloethyl, 2-iodoethyl, benzyl, P-nitrobenzyl, succinimidomethyl, ptylamidomethyl, P-meth Oxybenzyl, benzhydryl, C ₂ -C ₆ alkanoyloxymethyl, dimethylalkyl, phenacyl, or P-halofenacyl, where halogen represents chlorine, cancel or iodine.

Examples of optional carboxylic acid protecting groups of the sulfinylchloride of formula (I) are as follows.

Methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, + -butyl, 2,2,2-trichloroethyl 2,2,2-tribromomethyl, 2-iodoethyl , Benzyl, P-nitrobenzyl, succinimidomethyl, phthalimidomethyl, P-methoxybenzyl, benzhydryl, acetoxymethyl, pivaloyloxymethyl, propion oxymethyl, phenacyl, P-chlorophenacyl, P -Bromophenacyl.

를 가지며, 이 아마이드 관능기의 선택할만한 것으로 R₃가 다음의 기인 것들이다.The most selectable carboxylic acid protecting groups are methyl, benzyl, P-nitrobenzyl, P-methoxybenzyl, benzhydryl, and 2,2,2-trichloroethyl. Amide functional groups of the novel sulfinyl chloride of formula (III)

Of these amide functional groups, R ₃ is the following.

a. Hydrogen, C ₁ -C ₄ alkyl, halomethyl, benzyloxy, 4-nitrobenzyloxy, t-butyloxy, 2,2,2-trichloroethoxy, 4-methoxybenzyloxy, 3- (2-chloro Phenyl) -5-methylisocarzol-4-yl:

b. R 'group wherein R' is 1,4-cyclohexadiyl, phenyl, or phenyl substituted with 1 or halogen thereof, protected hydroxy, nitro, cyano, trifluoromethyl, C ₁ -C ₄ alkyl , Or C ₁ -C ₄ alkoxy or

c. Structural formula R '-(O) _m- CH ₂ -group, wherein R' is as described above and m is 0 or 1.

Examples as the R ³ group are as follows;

Hydrogen, methyl, ethyl, n-propyl, isopropyl, chloromethyl, bromomethyl, benzyloxy, 4-nitrobenzyloxy, t-butyloxy, 2,2,2-trichloroethoxy, 4-methoxybenzyl Oxy, 1,4-cyclohexadienyl, phenyl, 2-chlorophenyl, 3,4-dichlorophenyl, 3-chloro-4-fluorophenyl, 3-formyloxyphenyl, 4-nitrophenyl, 2-cyano Phenyl, 4-trifluoromethylphenyl, 3-methylphenyl, 2-ethylphenyl, 4-n-propylphenyl, 4-t-butylphenyl, 2-methoxyphenyl, 4-ethoxyphenyl, 3-isopropyloxyphenyl , 4-isobutyloxyphenyl, 1,4-cychlorohexadienylmethyl, benzyl, 3-bromobenzyl, 2,5-dichlorobenzyl, 4-chloroacetoxybenzyl, 2-nitrobenzyl, 3-cyano Benzyl, 4-trifluoromethylbenzyl, 3-methylbenzyl, 4-n-butylbenzyl, 2-methoxybenzyl, 3-isopropoxybenzyl, 1,4-cyclohexadienyl oxymethyl, phenolmethyl, 3 -Dodophenoxymethyl, 4-fluorophenoxymethyl, 3-benzyloxyphenoxymethyl, 4-benz Hydryloxyphenoxymethyl, 3-trityloxyphenoxymethyl, 4-nitrobenzyloxyphenoxymethyl, 4-trimethylsilyloxyphenoxymethyl, 3-nitrophenoxymethyl, 4-cyanophenoxymethyl, 2 -Trifluoromethylphenoxymethyl, 3-methylphenoxymethyl, 4-n-propylphenoxymethyl, 4-nbutylphenoxymethyl, 3-methoxyphenoxymethyl, 4-ethoxyphenoxymethyl, α -(Chloroacetoxy) -1,4-cyclohexadienylmethyl, α- (4-nitrobenzyloxycarbonylamino) -1,4-cyclohexadienylmethyl, α-trityloxybenzyl, α- ( 4-methoxybenzyloxy) benzyl, α- (2,2,2-trichloroethoxycarbonylaminobenzyl, α- (trimethylsilyloxy) -4-bromobenzyl, α- (trimethylsilylamino) -4 -Fluorobenzyl, α, 4-di (formyloxy) benzyl, α- (4-methoxybenzyloxycarbonylamino) -4-benzhydryloxybenzyl, α-benzyloxy-3-nitrobenzyl, α- (t-butoxycarbonylamino) -4-triflomethylbenzyl, α-formyloxy-4-methylbenzyl, α- ( Quality butyloxycarbonylamino) -4-methoxy-benzyl, α- formyl-3- isopropoxy-benzyl, or 3 - (2-chlorophenyl) oxazol-5-thiazolyl methylisobutyl.

In the text, the terms "protected amino" and "protected hydroxy" are used in the R ₃ group.

The term "protected amino" as used herein refers to t-butyloxycarbonyl, benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 2,2,2-trichloroethoxy It refers to an amino group substituted with a conventional amino blocking group such as 1-carbomethoxy-2-propenyl or trimethylsilyl forming carbonyl, methyl acetoacetate.

More examples of these amino protecting groups are described in J.W. Protective Groups in Organic Chemistry by Barton J.F.W. McOmie, Ed., Plenum press, New York, N.Y. 1973. Chapter 2). These are useful within the meaning of "protected amino" as used in the text.

The term "protected hydroxy" refers to groups formed with hydroxyl groups such as formyloxy, chloroacetoxy, benzyloxy, benzhydryloxy, trityloxy groups, 4-nitrobenzyloxy groups, or trimethylsilyloxy groups that are easily removed. It means you can. Other hydroxy protecting groups, including these groups, are C.B. Reese described in Chapter 3 of "Protecting Groups in Organic Chemistry."

In the above definition, of course, not all hydroxy, amino and carbosi decoders are described. The function of these groups is to protect the reactive functional groups during the product manufacturing process described above. They are then removed without inhibiting other functions in the molecule. Many such protecting groups are well known in the literature and they are applicable to the present invention as well.

The R group in the compound of formula (I) may be a cyclic imide group of the following structure.

This cyclic imide group consists of R ₂ and the nitrogen-carbonyl bond to which it is bonded, and reacts the ester of 6-aminophenicsilane (6-APA) or 6-APA with dicarboxylic acid or its anhydride or other reactive compounds. The resulting material is prepared by reacting a C ₁ -C ₄ alkyl haloformate, for example ethylchloroformate in the presence of an organic base. R ₂ is C ₂ -C ₄ alkenylene or 1,2-phenylene and is considered a residue of the dicarboxylic acid. Cycloimides can thus be prepared from these dicarboxylic acids, their anhydrides or suitable derivatives thereof.

Cycloimides can be prepared, for example, from maleic, methyl maleic or phthalic acid or their respective anhydrides and related compounds and compounds with similar reactivity. Examples of such cyclic anhydrides in organic solvents are given in Organic Chemistry Vol. 26, pages 3,365-3,367 (September 1961) and the like. 6-phthalimidophenicylanic acid can be prepared from the method of Y.G.ferons from 6-APA and N-carboethoxyphthalimide (Medicinal Chemistry Vol. 5, (1962) 1,016 p.).

R group may also be an imidazolidinyl group of the following structure.

Wherein U is nitrozo or acetyl and R 'is 1,4-cyclohexadienyl, phenyl substituted by phenyl or halogen 1,2, protected hydroxy, nitro, cyano, tripulomethyl, C _1- C ₄ alkyl or C ₁ -C ₄ alkoxy group.

These groups include 2,2-dimethyl-3-nitrozo-5-oxo-4- (substituted) -imidazolidin-1-yl group or 2,2-dimethyl-3-acetyl-5-oxo-4- ( Substituted) -imidazolidin-1-yl group. The 4-substituent (R ') in the imidazolidinyl group is particularly the following 1,4-cyclohexadienyl, phenyl, 3-bromophenyl, 2-chlorophenyl 4- pullophenyl, 3-iodophenyl, 3- Chloro-4- pullophenyl, 2-chloro-4-bromophenyl, 4-formyl-oxyphenyl, 3-formyloxyphenyl, 4-nitrophenyl, 2-cyanophenyl, 3-tripulomethylphenyl, 4-methylphenyl, 3-ethyphenyl, 4-isopropylphenyl, 4-t-butylphenyl, 3-methoxyphenyl, 2-ethoxyphenyl, 4-n-propoxyphenyl, 3-isopropoxyphenyl, or 4-isobutoxyphenyl etc. are mentioned.

Moreover, the R group may be an imager of the following structure.

Wherein R 'is 1,4-cyclohexadienyl, or phenyl substituted by halogen 1-2, protected hydroxy, nitro, cyano, trilomethyl, C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy group, m is 0 or 1; R ₄ is C ₁ -C ₃ alkyl, C ₁ -C ₃ haloalkyl, C ₃ -C ₁ alkoxy, or 2,2,2-trichloroethoxy group.

The imido group defined in this way represents a diacylamino group, wherein one of the acylamino residues includes a R- (O) _m -CH ₂ -group, as described above.

Other acylamino residues include R ₄ and R ₄ is methyl, ethyl, n-propyl, isopropyl, chloromethyl, isopropyl, chloromethyl, bromomethyl, 2-chloroethyl, 2-doethylethyl, 3-chloro Propyl, 1-chloropropyl, 2-chloropropyl, 2-bromoethyl, floromethyl, 2-fluoroethyl, methoxy, ethoxy n-propoxy, isopropoxy or 2,2,2-trichloro It includes an ethoxy group.

Penicillin sulfoxide, the starting material of the process of the present invention wherein R is the above-mentioned imidazolidinyl group, is a known method by reacting penicillin of formula (IV) or its corresponding free acid with acetone under appropriate basic conditions. The intermediate of the following structural formula (V) is generated.

The product is then cooled under acidic conditions and treated with sodium nitrite or acetic anhydride to convert to stable N-nitrozo or N-acetyl derivatives. The resulting product is then oxidized by known methods to the corresponding sulfoxide. This process is described in detail in Gottstein's organic chemistry magazines 37, (1972) 2765 and in Hossler's Helvetica Chimica Acta 55, (1972) 388.

As will be apparent to those skilled in the art of penicillin and cephalosporin, penicillin sulfoxide, the starting material used in the process of the present invention, can be readily prepared from penicillin sources such as natural penicillin G and / or penicillin V. .

6-Aminophenicylic acid (6-APA) can be prepared by separating the 6-acyl function from the aforementioned natural penicillin by a known method.

Starting materials of the process of the invention can be prepared in 6-APA by known techniques. For example, 6-APA can be converted to the desired ester by esterifying the 3-carbonyl function using an esterification technique.

Moreover, the amino group of 6-APA can be acylated and it can be set as the compound which has group defined by R in this text. This is obtained by reacting 6-APA with the active form of the acid of the acyl group to be acylated. Such activated forms include the corresponding acid halides, anhydrides or activated esters (eg pentachloro phenylesters).

Likewise, penicillin can be oxidized under various known conditions to produce sulfoxides. In this way penicillin is oxidized to m-chloroperbenzoic acid or sodium periodate.

This conversion, degradation to 6-APA, esterification, acylation and oxidation can be done with the desired structural transformation. In any case, all such conversions are readily applicable or can be accomplished using techniques, conditions and reagents known to those of ordinary skill in the art.

Selectable penicillin sulfoxide esters used in the reaction of the present invention have the following structural formula (VI).

Wherein m is 0 or 1 and R ₁ is a carboxylic acid protecting group.

Thus, the selectable sulfinylchloride of formula (I) is a compound of formula (VII)

Wherein m is 0 or 1 and R ₁ is a carboxylic acid protecting group.

In the process of the present invention sulfinylchloride is prepared by reacting penicillin sulfoxide ester with an N-chloro halogenating agent at elevated temperature.

"N-chlorohalogenating agent" means a nitrogen-containing compound having at least one chlorine directly bonded to a nitrogen atom, and the remaining portion of the structure of the reagent having sufficient constituent properties as a by-product from the sulfinylchloride preparation with the following properties: It means a reagent to be. The nitrogen-containing compound thus prepared firstly corresponds to the N-chloro halogenating agent, but contains a chlorine atom substituted with a hydrogen atom. Secondly, nitrogenous compounds are primarily inert to sulfinylchloroide products due to the nature of the sovereign portion.

The N-chlorohalogenating agent used in the reaction of the present invention is preferably a compound having the following structure.

또는-SO₂-기이며, 또는 R₇과 R₅가 이들이 결합된 질소와 함께 다음 구조의 복소환 구조를 형성하거나,Wherein R ₇ is hydrogen, chloro, C ₁ -C ₃ alkyl, cyclohexyl, phenyl or a phenyl group substituted with chlorine, bromine, methyl or nitro group, R ₅ is R ₆ -X-, where R ₆ is C ₁ -C ₃ alkyl, cyclohexyl, phenyl or phenyl substituted with chlorine, cancel, methyl or nitro group and X is

Or —SO ₂ — or R ₇ and R ₅ together with the nitrogen to which they are attached form a heterocyclic structure of the following structure,

Where Y is 0-phenylene or-(CH ₂ ) _n-

n is 2 or 3.

To form a heterocycle of the following structure:

이며, 여기에서 A는 수소 또는 메틸기이다.Where Z is the aforementioned Y or structure

Wherein A is hydrogen or a methyl group.

Among the N-chloro compounds that can be used to prepare sulfinyl chlorides, it is reasonable to select from the above-mentioned definitions: (a) urea, (b) amide, (c) urethane, (d) sulfonamide, (e) sulfi Mead, (f) imide (g) hydantoin, and (h) isocyanuric acid.

Selectable-chloroureas usable in the present invention have the following structure.

Wherein R ₇ is hydrogen, chlorine, C ₁ -C ₃ alkyl, cyclohexyl, phenyl, or a phenyl group substituted with chlorine, bromine, methyl or nitro group, and R ₆ is C ₁ -C ₃ alkyl, cyclohexyl, phenyl Or a phenyl group substituted with a chlorine, bromine, methyl or nitro group.

Examples of these ureas are as follows.

N, N'-dichloro-N-methylurea;

N, N'-dichloro-N-ethyl-N'-cyclohexylurea;

N, N'-dichloro-N-phenylurea;

N, N'-dichloro-N, N'-diphenylurea;

N, N'-dichloro-N- ( P -tolyl) urea;

N, N'-dichloro-N- ( m -chlorophenyl) -N'-methylurea;

N, N'-dichloro-N, N'-dicyclohexylurea;

N, N'-dichloro-N-diisopropyl-N '-( P -tolyl) urea;

N, N'-dichloro-N-phenyl-N'-propylurea;

N, N'-dichloro-N-cyclohexyl-N '-( P -nitrophenyl) urea;

N, N, N'-trichloro-N-methylurea; or

N, N, N'-trichloro-N-phenylurea

Selectable N-chloroamides that can be used in the present invention have the following general formula.

Wherein R ₇ and R ₆ are as described above.

Examples of these amides include N-chloroacetamide,

N-chloropropionamide,

N-chloro-N-methylacetamide,

N, N-dichloroacetamide,

N-chloro-N-cyclohexylacetamide,

N-chloro-N-ethylbenzamide,

N-chloro- P -ethylbenzamide,

N-chloro- P -toluamide,

N-chloro-N-phenylpropionamide,

N-chloroP- (m-bromophenyl) butylamide,

N-chlorohexahydrobenzamide or

N2,4-trichloroacetanilide and the like.

의 것이 일반적으로 좋다. 여기서 R₇,R₆은 전술한 바와같다.-Chloro urethane that can be used in the preparation of sulfinylchlorides according to the present invention is represented by the formula R ₆ -O

Is generally good. Where R ₇ and R ₆ are as described above.

Illustrative of such urethanes are methyl N, N-dichlorocarbamate, ethyl N, N-dichlorocarbamate, phenyl N, N-dichlorocarbamate, cyclohexyl N, N-dichloromethylcarbamate, methyl N-chlorocarba Mate, ethyl N-chlorocarbamate, ethyl N-cyclohexyl-N-chlorocarbamate, phenyl N-chlorocarbamate, phenyl Nphenyl-N-chlorocarbamate, P -tolyl N-chlorocarbamate, m -chloro Phenyl-N-methyl-N-chlorocarbamate, cyclohexyl N-cyclohexyl-N-chlorocarbamate, isopropyl N- P -tolyl-chlorocarbamate, phenyl N-propyl-N-chlorocarbamate or cyclohexyl N- P -nitrophenyl-N-chlorocarbamate and the like.

의 것이 일반적으로 좋다. 여기서 R₇,R₆는 전술한 바와같다.N-chlorosulfonamides that can be used in the preparation of sulfinyl chlorides according to the present invention include

Is generally good. Where R ₇ and R ₆ are as described above.

Examples of such sulfonamides include N, N-dichlorobenzenesulfonamide, N, N-dichloromethanesulfonamide, N, N-dichloro-cyclohexanesulfonamide, N, N-dichloro- P -toluenesulfonamide, N- Chloromethanesulfonamide, N-cyclohexyl-N-chlorobenzenesulfonamide, N-cyclohexyl-N-chloroethanesulfonamide, N-chlorobenzenesulfonamide, N-phenyl-N-chlorobenzenesulfonamide N-chloro- P -toluenesulfonamide, N-ethyl-N-chloro- m -nitrobenzenesulfonamide, N-methyl-N-chloro- m -chloro-benzenesulfonate amide, N-methyl-N-chloro- P -toluenesulfone Amide, N-cyclohexyl-N-chlorocyclohexylsulfonamide, N- P- N tolyl-N-chloroisopropenesulfonamide, N-propyl-N-chlorobenzenesulfonamide, or N- P -nitrophenyl -N-chlorocyclohexenesulfonamide and the like.

Further preferred as the N-chlorohalogenating agent which can be used in the preparation of sulfinyl chlorides according to the present invention is sulfimide of the following structural formula.

Where Y is O-phenyl lean or -CH ₂ -CH ₂ - is, -CH ₂ -CH ₂ -CH _2. Among these compounds include 0-sulfobenzoic N-chloroimide, P-sulfopropionic N-chloroimide, γ-sulfobutyric N-chloroimide, and the like.

의 N-클로로이미드류가 있다. 여기서 Z는 O-페닐렌이나 -CH₂-CH₂-, -CH₂-CH₂-CH₂이다.Also good N-chlorohalogenating agents used in the preparation of sulfinyl chlorides according to the present invention

N-chloroimides are mentioned. Where Z is O-phenylene or -CH ₂ -CH _2- , -CH ₂ -CH ₂ -CH ₂ .

Among these compounds are N-chlorophthalimide, N-chlorosuccinimide, N-chloroglutarimid, and the like.

이고 여기서 A는 수소나 메틸이다.N, N-dichlorohydantoin can also be used as a halogenating agent. Structural formula

Where A is hydrogen or methyl.

Among these, 1,3-dichlorohydantoin,

1,3-dichloro-5-methylhydantoin,

1,3-dichloro-5,

5-dimethyl hydantomin and the like.

의 N,N',N"-트리클로로 이소시아누리산과 같은 이소시아누린산류 계열의 것이 있다.Another type of halogenating agent is a structural formula

Isocyanuric acid series such as N, N ', N "-trichloro isocyanuric acid.

Many N-chlorohalogenating agents used in the present invention are commercially available and either can be prepared by chemical techniques. For further literature on the preparation of N-chlorohalogenating agents, see Bachand et al., J. Org. Chem. 39, (1974) pp. 3,136 3,138 Theilacker et al. Liebigs Ann. Chem. 703 (1967) pp. 34 36 Houben-Wegl, Methodender Organischen Chemie Vol. V / 3, pp. 796-810, and the like.

Extremely good N-chlorohalogenating agents in the present invention are N-chloroimides, particularly N-chlorosuccinimide and N-chlorophnimide.

The reaction of penicillin sulfoxides with N-chlorohalogenating agents generally employs at least one to 1.5 water halogenating agents for one penicillin sulfoxide. More excess halogenating agent can be used. But there is no advantage to doing so. Therefore preferably halogenating agent 1.0-1.1 water is used for penicillin sulfoxide 1 water. The mixture of two reaction solutions is heated to 75-135 ° C. in a suitable solvent. Preferably it is 100-120 degreeC, and most preferably about 110 degreeC.

"Inert organic solvent means that it does not react with any of the reactants and products as an organic solvent under sulfinyl chloride production conditions. A suitable inert organic solvent is a boiling point at least higher than the reaction temperature, for example, benzene, toluene, ethylbenzene. Or aromatic hydrocarbons such as cumene: hydrogen tetrachloride, benzene chloride, bromoform, benzene bromide, halogenated hydrocarbons such as ethylene dichloride, 1,1,2-trichloroethane, ethylene bromide: such as acetonitrile or propionitrile Aliphatic nitrile: There are many other suitable inert solvents, preferably those in which the boiling point of the solvent can reflux the reaction mixture, especially when used in toluene or 1,1,2-trichloroethanol solvents under reflux conditions. This goes well.

The reaction of the present invention should be carried out under anhydrous conditions. “Anhydrous condition” means not to be completely excluded from water, but to avoid a significant amount of water. Since the halogenating agent reacts with water, it is not considered as a water source in the reaction mixture. The excess moisture present in the solvent is usually troublesome. Therefore, it is better to pretreat the solvent to release moisture. Moisture in the solvent can be removed using a drying agent such as a water binder. Typical desiccants include anhydrous sodium sulfate, magnesium sulfate, sodium carbonate, potassium carbonate, calcium hydride, potassium sulfate, calcium oxide, molecular sieves and the like.

The azeotrope of the solvent with water can be azeotropically separated using a Dean-Stark trap or a Bart-type device to separate the water.

The starting material penicillin sulfoxide ester itself also contains water. This is removed by drying in a vacuum drying oven at low temperature to 50 ° C. Penicillin sulfoxide esters may also be added to the solvent to effect azeotropic treatment.

The mixture of penicillin sulfoxide ester and N-chloro halogenating agent is generally heated to room temperature for 0.5-4 hours, preferably 1-2 hours, to separate the sulfinyl chloride from the reaction mixture by vacuum evaporation. Although sulfinyl chlorides can be separated from the reaction mixture, they do not have to be separated before for the next reaction. (Only as described below)

It was found that it is preferable to contain a non-basic acid treatment agent in the reaction mixture. For some reason it is not clear that a small amount of hydrogen chloride can be released to the reactor. The nonbasic acid treatment agent is completely inert in the reaction medium in which normal hydrogen chloride is not present, but is activated enough to react with the released hydrogen chloride gas to remove it from the reaction medium.

Typical nonbasic acid treatment agents include epoxide compounds such as ethylene oxide, propylene oxide, epichlorohydrin, or 1,2-epoxy-3-phenoxypropane. These materials exhibit non-basic properties, but react with and remove acidic substances from the reaction system. The study of these reagents is described in Hunsberger and Tien Chem. In d88 (1959) Buddrus Argew. Chem. Internat, Edit, Vol. II (1972), pp. Well done at 1,041-1,050.

The amount of nonbasic acid treatment agent used is not constant. However, the amount corresponding to the hydrogen chloride produced should be. Although the use of an excess of non-basic acid treating agent has little adverse effect on the preparation of sulfinyl chloride, the presence of an excess of non-basic acid treating agent has a significant effect on the conversion of sulfinyl chloride to the 3-hexmethylene cefe sulfoxide described below. Inflicted. Therefore, it is advisable to separate the sulfinyl chloride from the excess non-basic acid treatment agent and other products produced by the reaction with hydrogen chloride before the ring-closure reaction using ditin tin chloride.

Typical sulfinyl chloride preparations according to the present invention are prepared by mixing an equivalent amount of penicillin sulfoxide and an N-chlorohalogenating agent in a suitable dehydrating solvent to produce 6-amino penicillin sulfoxide starting material for the 6-amino penicillin sulfoxide starting material. Heat it to a suitable temperature at a slightly higher temperature than that for the case. The reaction mixture is heated for the desired time. Preferably, the solvent used can achieve a reaction and reflux the reaction mixture. After completion of the reaction, the reaction mixture is cooled to room temperature, washed with water and dehydrated with a suitable organic desiccant. The solvent is evaporated to give the sulfinyl chloride product as an amorphous solid.

Alternatively, the penicillin sulfoxide ester is dissolved in the selected solvent and heated to room temperature, and the N-chlorohalogenating agent alone or the solution is added dropwise to the heating mixture. After completion of the dropwise addition, the reaction is performed under the defined conditions and the same or similar operation as described above is performed. Examples of sulfinyl chlorides of formula (I) include the followings.

Methyl 3-methyl-2- (2-chlorosulfinyl-4-oxo-3-maleimido-1-azetidinyl) -3-butenoate: tert-butyl 3-methyl-2- (2-chloro Sulfinyl-4-oxo-3-phthalimido-1-azetidinyl) -3-butenoate: benzyl 3-methyl-2-) 2-chlorosulfinyl-4-oxo-3-formamido- 1-azetidyl) 2,2,2-trichloroethyl 3-methyl-2- (2-chlorosulfinyl-4-oxo-3-acetamido-1-azetidinyl) -3-butenoate :

P-nitrobenzyl 3-methyl-2- (2-chlorosulfinyl-4-oxo-butylamido-1-azetidinyl) -3-butenoate:

P-methoxybenzyl 3-methyl-2- (2-chlorosulfinyl-4-oxo-3-chloroacetamido-1-azetidinyl) -3-butenoate:

P-nitrobenzyl 3-methyl-2- [2-chlorosulfinyl-4-oxo-3- (4-nitrobenzyloxycarbamido) -1-azetidinyl] -3-butenoate:

Isobutyl 3-methyl-2- (2-chlorosulfinyl-4-oxo-3-benzyloxycarbamido-1-azetidinyl) -3-butenoate:

Ethyl 3-methyl-2- [2-chlorosulfinyl-4-oxo-3-butyloxycarbamido) -1-azetidinyl] -3-butenoate:

2-iodoethyl 3-methyl-2- [2-chlorosulfinyl-4-oxo-3- (2 ', 2', 2'-trichloroethoxycarbamido) -1-azetidinyl] -3 Butenoate:

Acetoxymethyl 3-methyl-2- [2-chlorosulfinyl-4-oxo-3- (4'-methoxybenzyloxycarbamido) -1-azetidinyl] -3-butenoate:

Benzyl 3-methyl-2- [2-chlorosulfinyl-4-oxo-3- (1 ', 4'-cyclohexadienylcarbamido) -1-azetidinyl] -3-butenoate:

Ethyl 3-methyl-2- (2-chlorosulfinyl-4-oxo-3-benzamido-1-azetidinyl) -3-butenoate: phenacyl 3-methyl-2- [2-chlorosulpy Nyl-4-oxo-3- (4'chlorobenzamido) -1-azetidinyl] -3-butenoate:

P-chlorophenacyl 3-methyl-2- [2-chlorosulfinyl-4-oxo-3- (3'-formyloxybenzamido) -1-azetidinyl] -3-butenoate:

Fibaroyloxymethyl 3-methyl-2- [2-chlorosulfinyl-4-oxo-3- (4'-nitrobenz amido) -1-azetidinyl] -3-butenoate:

Isopropyl 3-methyl-2- [2-chlorosulfinyl-4-oxo-3- (2'-cyanobenzamido) -1-azetidinyl] -3-butenoate:

Succinimidomethyl 3-methyl-2- [2-chlorosulfinyl-4-oxo-3- (4'-trifluoromethylbenzamido) -1-azetidinyl] -3-butenoate:

Phthalimidomethyl 3-methyl-2- [2-chlorosulfinyl-4-oxo-3- (3'-methylbenzamido) -1-azetidinyl] -3-butenoate:

Secondary-Butyl 3-methyl-2- [2-chlorosulfinyl-4-oxo-3- (2'methoxybenzamido) -1-azetidinyl] -3-butenoate:

n-butyl 3-methyl-2- [2-chlorosulfinyl-4-oxo-3- (1 ', 4'-cyclohexadienylacetamido) -1-azetidinyl] -3-butenoate :

P-nitrobenzyl 3-methyl-2- [2-chlorosulfinyl-4-oxo-3- (1 ', 4'-cyclohexadienyloxyacetamido) -1-azetidinyl] -3-part Tenoate:

P-methoxybenzyl 3-methyl-2- (2-chlorosulfinyl-4-oxo-3-phenylacetamido) -1-azetidinyl) -3-butenoate:

2,2,2-trichloroethyl 3-methyl-2- (2-chlorosulfinyl-4-oxo-3-phenoxyacetamido) -1-azetidinyl) -3-butenoate:

P-nitrobenzyl 3-methyl-2- [2-chlorosulfinyl-4-oxo-3- (2 ', 5'-dichlorophenylacetamido) -1-azetidinyl-3-butenoate:

Benzyl 3-methyl-2- [2-chlorosulfinyl-4-oxo-3- (2'-bromophenoxyacetamido) -1-azetidinyl] -3-butenoate:

Tert-butyl 3-methyl-2- [2-chlorosulfinyl-4-oxo-3- (4'-chloroacetoxyphenylacetamido) -1-azetidinyl] -3-butenoate:

Isobutyl 3-methyl-2- [2-chlorosulfinyl-4-oxo-3- (3'formyloxyphenoxyacetamido) -1-azetidinyl] -3-butenoate:

P-nitrobenzyl 3-methyl-2- [2-chlorosulfinyl-4-oxo-3- (2'-nitrophenylacetamido) -1-azetidinyl] -3-butenoate:

P-methoxybenzyl 3-methyl-2- [2-chlorosulfinyl-4-oxo-3- (4'-nitrophenoxyacetamido) -1-azetidinyl] -3-butenoate:

Benzhydryl 3-methyl-2- [2-chlorosulfinyl-4-oxo-3- (3'-cyinophenylacet amido) -1-azetidinyl] -3-butenoate:

P-bromophenacyl 3-methyl-2- [2-chlorosulfinyl-4-oxo0-3- (2'-cyanophenoxyacetamido) -1-azetidinyl] -3-butenoate :

Propynoxymethyl 3-methyl-2- [2-chlorosulfinyl-4-oxo-3- (4'-trifluoromethylphenylacytamido) -1-azetidinyl] -3-butenoate:

2,2,2-tribromoethyl 3-methyl-2- [2-chlorosulfinyl-4-oxo-3- (3'-trifluoromethylphenoxyacetamido) -1-azetidinyl] -3-butenoate:

2-iodoethyl 3-methyl-2- [2-chlorosulfinyl-4-oxo-3- (2'-ethyphenylacetamido) -1-azetidinyl-3-butenoate:

Acetoxymethyl 3-methyl-2- [2-chlorosulfinyl-4-oxo-3- (4'-isopropylphenoxyacetamido) -1-azetidinyl] -3-butenoate:

n-butyl 3-methyl-2- [2-chlorosulfinyl-4-oxo-3- (3'-ethoxyphenylacetamido) -1-azetidinyl] -3-butenoate:

P-nitrobenzyl 3-methyl-2- [2-chlorosulfinyl-4-oxo-3- (4'-isopropoxyphenoxyacetamido) -1-azetidinyl] -3-butenoate:

P-nitrobenzyl 3-methyl-2- [2-chlorosulfinyl-4-oxo-3- (α-formyloxyphenylacetamido) -1-azetidinyl] -3-butenoate:

P-methoxybenzyl 3-methyl-2- [2-chlorosulfinyl-4-oxo-3- (α-benzhydroxyphenylacetamido) -1-azetidinyl] -3-butenoate:

P-nitrobenzyl 3-methyl-2- [2-chlorosulfinyl-4-oxo-3- (α-benzyloxycarbonylamidophenylacetamido) -1-azetidinyl] -3-butenoate :

Tert-butyl 3-methyl-2- [2-chlorosulfinyl-4-oxo-3- (α-tert-butyloxycarbonylaminophenylacetamido) -1-azetidinyl] -3-part Tenoate:

Benzyl 3-methyl-2-[[3-chlorosulfinyl-4-oxo-3-3 '-(2 "-chlorophenyl) -5'-methylisoxazole-4'-ylcaramido-1-ase Tidinyl]]-butenoate:

P-nitrobenzyl 3-methyl-2- [2-chlorosulfinyl-4-oxo-3- (2 ', 2'-dimethyl-3'-acetyl-5'-oxo-4'-phenylimidazolidine -1'-yl) -1-azetidinyl] -3-butenoate

Benzyl 3-methyl-2- [2-chlorosulfinyl-4-oxo-3-((2 ', 2'-dimethyl-3'-nitrozo-5'-oxo-4'-(4 "-formyloxy Phenyl) -imidazolidin-1'-yl))-1-azetidinyl] -3-butenoate:

As described above, sulfinyl chlorides prepared according to the present invention can be ring-closed with their corresponding 3-exomethylene sefam sulfoxides with Friedel Kraft catalysts such as stannous chloride as useful intermediates.

The closed ring reaction product, 3-exo methylenecepam sulfoxides, is a useful intermediate for the preparation of antibiotics. The sulfoxides can be converted to the corresponding 3-exomethylene sepam by reduction by a known method such as treatment with phosphorus tribromide or phosphorus trichloride in dimethylformamide.

Exomemethylene sepam may be used to prepare novel cefem antibiotics, such as

Where B is for example chlorine, bromine or methoxy. Chemical conversion of such 3-exomethylenecepam compounds is described in the literature. Robert R. Chauvette and Pamela A. Pennington. J. Am. Che. Soc. 96, 4,986 (1974)

The invention can also be illustrated by the following examples.

The following examples are illustrative only and not limitative of the invention.

Example 1

Preparation of Methyl 3-methyl-2- (2-chlorosulfinyl-4-oxo-3-phthalimido-1-azetidinyl) -3-butenoate

A solution of 18.8 g (50 mmol) methyl 6β-phthalimido-2,2-dimethylphenam-3-carboxylate-1-oxide in 1,000 ml of anhydrous carbon tetrachloride is refluxed for 70 minutes, cooled, and washed with water and brine. . After drying over MgSO ₄ the solvent is evaporated to give 19.5 g (95%) of the title compound as a colorless solid. The nmr spectrum (CDCl ₃ ) confirms that it is sulfinylchloride.

Example 2

Preparation of P-nitrobenzyl 3-methyl-2- (2-chlorosulfinyl) -4-oxo-3-phthalimido-1-azetidinyl) -3-butenoate

49.7 g (0.1 water) of P-nitrobenzyl 6β-phthalimido-2,2-dimethylphenam-3-carboxylate-1-oxide in 1.5 l of 1,2-dichloroethane and 13.4 g of N-chlorosuccinimide ( 0.1 mole) of the solution is refluxed for 70 minutes. The mixture is cooled, washed with water and brine and dried over MgSO ₄ . The solvent is evaporated and the residue is dried in vacuo for 3 hours to give 52.0 g of the title compound.

Example 3

Preparation of P-nitrobenzyl 3-methyl-2- (2-chlorosulfinyl-4-oxo-3-phenoxyacetamido-1-azetidinyl) -3-butenoate

Well dehydrated 1,500 mg (1 mmol) of P-nitrobenzyl 6β-phenoxyacetamido-2,2-dimethylphenam-3-carboxylate-1-oxide and 134 mg (1 mmol) N-chlorosuccinimide 40 ml of 1,2-trichloroethane solution was refluxed for 90 minutes, cooled, washed with water and brine, dried and the solvent was evaporated in vacuo. According to the nmr spectrum, the compound of the title is obtained almost quantitatively.

Example 4

Preparation of P-nitrobenzyl 3-methyl-2- (2-chlorosulfinyl-4-oxo-3-phenoxyacetamido-1-azetidinyl) -3-butenoate

6.0 g (12 mmol) of P-nitrobenzyl 6-phenoxy acetamido-2,2-dimethylphenam-3-carboxylate-1-oxide in 500 ml of anhydrous toluene was used to remove traces of water using a Dean-Stark trap. Reflux for 10 minutes. After removal of water, 1.8 g of N-chlorosuccinimide was added and refluxed for 90 minutes, then cooled to about 50 ° C. and evaporated to obtain a sulfinyl chloride product.

Example 5

Preparation of P-nitrobenzyl 3-methyl-2- (2-chlorosulfinyl-4-oxo-3-formamido-1-azetidinyl) -3-butenoate

A solution of 1.43 g of P-nitrobenzyl 6β-formamido-2,2-dimethylphenam-3-carboxylate-1-oxide and 500 g of N-chlorosuccinimide in 40 ml of anhydrous 1,1,2-trichloroethane was prepared. Reflux for 90 minutes. The mixture is cooled, washed with water and brine, dried over MgSO ₄ and the solvent is evaporated. The nmr spectrum confirms that the compound is the title.

Example 6

2,2,2-trichloroethyl 3-methyl-2- (2-chlorosulfinyl-4-oxo-3-phenylacetamido-1-azetidinyl) -3-butenoate

A solution of 500 mg of 2,2,2-trichloroethyl 6β-phenylacetamido-2,2-dimethylphenam-3-carboxylate-1-oxide and 134 mg of N-chlorosuccinimide in 40 ml of anhydrous toluene for 90 minutes It is refluxed, cooled and washed with water and brine, dried over MgSO ₄ and the solvent is evaporated on rotavapor. The title compound is obtained as a colorless foam.

Example 7

Methyl 3-methyl-2- [2-chlorosulfinyl-4-oxo-3- (2 ', 2'-dimethyl-3'-nitrozo-5'-oxo-4'-phenylimidazolidine-1 Preparation of '-yl) -1-azetidinyl] -3-butenoate

In 55 ml of azeotropically dehydrated anhydrous benzene, methyl 6- (2,2-dimethyl-3-nitrozo-5-oxo-4-phenylimidazolidin-1-yl) -2,2-dimethylphenam-3- 0.896 g (2 mmol) of carboxylate-1-oxide and 0.536 g (4 mmol) of N-chlorosuccinimide are added. The mixture is passed through nitrogen gas and refluxed for about 1 hour, after which the pale yellow mixture is cooled and a portion of the mixture is evaporated to yield the product. nmr analysis shows the presence of sulfinylchloride.

Example 8

Preparation of Methyl 3-methyl-2- (2-chlorosulfinyl-4-oxo-3-phthalimido-1-azetidinyl) -3-butenoate

In 300 ml of carbon tetrachloride, 3.7 g (10 mmol) of methyl 6-phthalimido-2,2-dimethylphenam-3-carboxylate-1-oxide and 2.2 g (10 mmol) of N-chloro-N-methyl-P-toluenesulfonamide ) Heated to reflux for 90 minutes, cooled to room temperature, washed with water and brine, dried over MgSO ₄ , and divided into 2 portions.

The first minute is evaporated to dryness in vacuo to afford the title compound. (confirmed by nmr analysis)

Example 9

Preparation of nitrobenzyl 3-methyl-2- (2-chlorosulfinyl-4-oxo-3-phenoxyacetamido-1-azetidinyl) -3-butenoate

3.0 g (6 mmol) of N-chloro-N- and P-nitrobenzyl 6-phenoxyacetamido-2,2-dimethylphenam-3-carboxylate-1-oxide in 150 ml of toluene distilled and dried with molecular sieve. 1.3 g (6 mmol) of methyl-P-toluenesulfonamide are added and the mixture is refluxed for 60 minutes and then cooled to room temperature. 15 ml is separated, washed with water and brine, dried over MgSO ₄ and dried in vacuo. The nmr spectrum confirms that N-methyl-P-toluenesulfonamide is a slightly contaminated compound of the title.

Example 10

Preparation of P-nitrobenzyl 3-methyl-2- (2-chlorosulfinyl-4-oxo-3-phenoxyacetamido-1-azetidinyl) -3-butenoate

425 ml of toluene is heated azeotropically to dehydrate in a Dean-Stark trap, where 25 ml of toluene is decanted. 10.0 g (20 mmol) of P-nitrobenzyl 6-phenoxyacetamido-2,2-dimethylphenam-3-carboxylate-1-oxide is added to the remaining toluene and kept at a temperature slightly below the reflux temperature. 200 ml of toluene is distilled separately and 4.0 g (22 mmol) of N-chlorophthalimide are added. This warm solution is added dropwise to the penicillin sulfoxide ester solution over 30 minutes. It stays pale yellow during the dropping. Then, refluxing for 55 minutes, taking a sample, and performing an nmr analysis showed that the penicillin sulfoxide ester was completely converted to the title compound.

Example 11

Preparation of benzhydryl 3-methyl-2- (2-chlorosulfinyl-4-oxo-3-phenoxyacetamido-1-azetidinyl) -3-butenoate

To 800 ml of anhydrous toluene was added 20 g of benzhydryl 6-phenoxyacetamido-2,2-dimethylphenam-3-carboxylate-1-oxide and refluxed to remove water in a Dean-Stark trap apparatus, where 100 ml of toluene was added. Follow. Then, 13.2 g of N-chlorosuccinimide was added to the mixture, and the mixture was further refluxed for 1.5 hours. nmr analysis shows that the compound is the title.

Example 12

Preparation of P-nitrobenzyl 3-methyl-2- (2-chlorosulfinyl-4-oxo-3-acetamido-1-azetidinyl) -3-butenoate

500 ml of toluene was heated azeotropically in a Dean-Stark trap to dehydrate water, and to this dehydrated toluene P-nitrobenzyl 6-acetamido-2,2-dimethylphenam-3-carboxylate-1-oxide 1.0 g (2.4 mmol) is added. The mixture is refluxed in a Dean-Stark trap to remove any water that may be present again. After cooling, 400 g (2.9 mmol) of P-chlorosuccinimide was added and refluxed for 1 hour. A sample is taken to remove solvent and nmr analysis confirms that this is a compound of the title.

Example 13

2,2,2-trichloroethyl 3-methyl-2- [2-chlorosulfinyl-4-oxo-3- (4'-nitrobenzyloxy-carbamido) -1-azetidinyl) -3-part Preparation of Tennoate

300 ml of 1,1,2-trichloroethane and 10,26 g of 2,2,2-trichloroethyl 6- (4'-nitrobenzyloxycarbamido) -2,2-dimethylphenam-3-carboxylate-1-oxide The mixture was refluxed while removing 75 ml of solvent to promote dehydration of the reaction medium. After cooling, propylene oxide is added and 4 g of N-chloro succinimide is added. The temperature of the reaction mixture is raised to 102 ° C. and refluxed for 2.5 hours. A sample is taken to evaporate the solvent and subjected to nmr analysis to confirm that it is a compound of the title.

Example 14

P-nitrobenzyl 3-methyl-2- (2-chlorosulfinyl-4-oxo-3- (N-phenoxyacetyl) -N- (2 ', 2', 2'-trichloroethoxycarbonyl) Preparation of Amino) -1-acetidinyl] -3-butenoate

4.855 g (10 mmol) of P-nitrobenzyl 6-phenoxyacetamido-2,2-dimethylphenam-3-carbosylate and 16.94 g (80 mmol) of 2,2,2-trichloroethyl chloroformate, A mixture of 18 ml of N, O- (bis-trimethylsilyl) trifluoromethylacetamide and 20 ml of methylene chloride was prepared and reacted overnight at room temperature. It was then refluxed for 7 hours, and then left to stand at room temperature overnight, and heating was continued for another 6 hours. The residue obtained by evaporating the reaction mixture is then dissolved in benzene and excess heptane is added. The insoluble material was filtered and dissolved in benzene and chromatographed on silica gel with benzene-ethyl acetate to give P-nitrobenzyl 6- [N- (phenoxyacetyl) -N- (2,2,2-trichloroethoxycarbonyl 4.76 g (72%) of amino] -2,2-dimethylphenam-3-carboxylate are obtained as a product.

2.54 g of the product was added to about 75 ml of acetone, and after cooling to −70 ° C., an excess of ozone was passed for 1 minute at a rate of 1.17 mmol for 1 minute to turn blue. After maintaining at -70 DEG C for 35 minutes, warming to room temperature, the solvent was evaporated in vacuo to P-nitrobenzyl 6- [N- (phenoxyacetyl) -N- (2,2,2-trichloroethoxycarbonyl) 2.76 g of amino] -2,2-dimethylphenam-3-carboxylate-1-oxide are obtained.

792 g (about 1 mmol) of the product and 155 mg (about 1.2 mmol) of N-chlorosuccinimide were added to 40 ml of anhydrous benzene, followed by reflux for 1 hour to confirm that the title compound was obtained by nmr analysis.

Claims (1)

A process for preparing sulfinyl chloride of formula (I) by reacting penicillin sulfoxide of formula (II) with an N-chloro halogenating agent in an inert solvent at 75-135 ° C. in anhydrous conditions.

Wherein R ₁ is a carboxylic acid protecting group, R is (1) Imager of the following structure

R ₂ here is a C ₂ -C ₄ alkenylene or 1,2-phenylene group. (2) Amido groups of the following structure

Where R ₃ is a. Hydrogen, C ₁ -C ₃ alkyl, halomethyl, benzyloxy, 4-nitrobenzyloxy, t-butyloxy, 2,2,2-trichloroethoxy, 4-methoxybenzyloxy, 3- (2-chloro Phenyl) -5-methylisoxazol-4-yl b. R 'group where R' is 1,4-cyclohexadienyl, phenyl, or phenyl substituted with 1-2 halogen, protected hydroxy, nitro, cyano, tripulomethyl, C ₁ -C ₄ alkyl, or C ₁ -C ₄ alkoxy group) c. Structural formula R '-(O) _m -CH _2- , wherein R' is as described above and m is 0 or 1. d. Next structural formula

Wherein R 'is as described above and R' is a protected hydroxy or protected amino group. (3) is an imidazolidinyl group of the following structure, or

Wherein R ¹ is as described above and U is a nitrozo or acetyl group. (4) The imager is of the following structure.

Wherein R ¹ and m are as described above, and R ₄ is C ₁ -C ₃ alkyl, C ₁ -C ₃ haloalkyl, C ₁ -C ₃ alkoxy or 2,2,2-trichloroethoxy group.