GB2152497A

GB2152497A - Process for the preparation of azetidinone derivatives

Info

Publication number: GB2152497A
Application number: GB08429528A
Authority: GB
Inventors: Sigeru Torii; Hideo Tanaka; Michio Sasaoka; Shigemitsu Nagao; Seiryu Uto; Syozo Hayase; Takashi Shiroi
Original assignee: Otsuka Chemical Co Ltd
Current assignee: Otsuka Chemical Co Ltd
Priority date: 1983-11-28
Filing date: 1984-11-22
Publication date: 1985-08-07
Also published as: CH661503A5; FR2555578A1; DE3443225C2; FR2555578B1; DE3443225A1; GB2152497B; GB8429528D0

Abstract

A process for preparing an azetidinone derivative represented by the formula <IMAGE> wherein R<1> is hydrogen, halogen or lower alkoxy, R<2> is hydrogen, halogen, lower alkoxy, amino or a group <IMAGE> (in which R<5> is substituted or unsubstituted phenyl, substituted or unsubstituted phenylmethyl, substituted or unsubstituted phenoxymethyl, or substituted or unsubstituted benzoyl), or R<1> and R<2>, when taken together, are carbonyl, R<3> is substituted or unsubstituted phenyl, and R<4> is hydrogen, optionally substituted hydrocarbon residue or acyl, silyl, sulfonyl or phosphonyl derived from inorganic acid or organic acid, the process comprising reacting a dithioazetidinone derivative represented by the formula <IMAGE> wherein R<1>, R<2> and R<4> are as defined above and R<9> is substituted or unsubstituted, nitrogen-containing aromatic heterocyclic residue with a compound represented by the formula R<3>SO2R<10> (VII> wherein R<3> is as defined above and R<10> is hydrogen, a group -CN or a group -SR<9> (in which R<9> is as defined above).

Description

SPECIFICATION Process for preparation of azetidinone derivatives This invention relates to a process for preparing azetidinone derivatives.

The azetidinone derivatives prepared by the process of the present invention are represented by the formula

wherein R' is hydrogen, halogen or lower alkoxy, R2 is hydrogen, halogen, lower alkoxy, amino or a group

(in which R5 is substituted or unsubstituted phenyl, substituted or unsubstituted phenylmethyl, substituted or unsubstituted phenoxymethyl, or substituted or unsubstituted benzoyl), or R' and-R2, when taken together, are carbonyl, R3 is substituted or unsubstituted phenyl, and R4 is hydrogen, optionally substituted hydrocarbon residue or acyl, silyl, sulfonyl or phosphonyl derived from inorganic acid or organic acid.

The azetidinone derivatives of the formula (I) are useful as the intermediates for synthesizing p-lactam antibiotics and can be made into a variety of p-lactam antibiotics depending on the selection of substituents.

For example, an azetidinone derivative of the formula (I) wherein R4 is a group

(in which R6 is hydrogen or carboxy protecting group) can be converted into a cephalosporin compound of the formula (III) by the process disclosed in Tetrahedron Letters, 23, 2187 (1982) which is shown in the following reaction scheme.

An azetidinone derivative of the formula (I) wherein R4 is hydrogen, silyl, sulfonyl or phosphonyl can be made into various monocyclic ss-lactam antibiotics.

Conventional processes for preparing azetidinone derivatives of the formula (I) are described, for example, in Japanese Unexamined Patent Publication (Kokai) No. 129,590/1975. This process comprises, as indicated below by a reaction equation, reacting an azetidinone derivative of the formula (IV) with a heavy metal salt of sulfinic acid of the formula (V) to obtain an azetidinone derivative of the formula (lb).

In the foregoing reaction equation, R3 and R6 are as defined above, R1, is hydrogen, R2 is amino or a group - NHR8 (wherein R6 is acyl), R7 is an aromatic hetrocyclic group, aliphatic thioacyl group, aromatic thioacyl group, aromatic aliphatic thioacyl group or alicyclicthioacyl group, M is heavy metal such as copper, silver, mercury, tin or the like and n is the valence of heavy metal. However, the above process, when commercially carried out, involves the disadvantage of using a heavy metal salt of sulfinic acid of the formula (V) which is harmful or expensive.

It is an object of the present invention to provide a commercially advantageous process for preparing the azetidinone derivatives of the formula (I).

It is another object of the invention to provide a process for preparing the azetidinone derivative of the formula (I) without use of a heavy metal salt of sulfinic acid which is harmful or expensive.

It is a further object of the invention to provide a process for preparing the azetidinone derivative of the formula (I) with a high purity and in a high yield by carrying out a simple procedure.

These objects and other features of the present invention will become more apparent from the following description.

According to the present invention, the azetidinone derivative of the formula (I) can be prepared by reacting a dithioazetidinone derivative represented by the formula

wherein R7, R2 and R4 are as defined above and R9 is substituted or unsubstituted, nitro-containing aromatic heterocyclic residue with a compound represented by the formula R3S02R10 (ill) wherein R3 is as defined above, R10 is hydrogen, a group -CN or a group -SR9 (in which R9 is as defined above).

Examples of the halogen atoms represented by R1 in the formulae (I) and (VI) are F, Cl, Br, I and the like.

Exemplary of the lower alkoxy groups represented byR1 are those having 1 to 4 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, butoxy,fert-butoxy, etc.

Examples of the halogen atoms represented by R2 in the formulae (I) and (VI) are F, Cl, Br, I and the like.

Illustrative of the lower alkoxy groups represented by R2 are those having 1 to 4 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, butoxy and tert-butoxy, etc. Examples of the substituted phenyl groups represented by R5 are phenyl substituted with 1 to 3 C1-C4 alkyl groups such as tolyl; phenyl substituted with 1 to 3 halogen atoms such as 4-chlorophenyl, 2,4-dichlorophenyl, 2,4,6-trichlorophenyl, 4-bromophenyl and 2,4-dibromophenyl; phenyl substituted with 1 to 3 C1-C4 alkoxy groups such as 4-methoxyphenyl, 2,4-dimethoxyphenyl and 3,4,5-trimethoxyphenyl; phenyl substituted with 1 to 3 nitro groups such as 4-nitrophenyl and 2,4-dinitrophenyl; etc.Examples of the substituted phenylmethyl groups represented by R5 are phenylmethyl substituted with 1 to 3 C1-C4 alkyl groups on the phenyl ring such as tolylmethyl; phenylmethyl substituted with 1 to 3 halogen atoms on the phenyl ring such as 4chlorophenylmethyl, 2,4-dichlorophenylmethyl, 2,4,6-trichlorophenylmethyl, 4-bromophenylmethyl and 2,4-dibromophenylmethyl; phenylmethyl substituted with 1 to 3 C1-C4 alkoxy groups on the phenyl ring such as 4-methoxyphenyl methyl, 2,4-dimethoxyphenylmethyl and 3,4,5-trimethoxyphenyl methyl; phenyl methyl substituted with 1 to 3 nitro groups on the phenyl ring such as 4-nitrophenylmethyl and 2,4 dinitrophenylmethyl; phenylmethyl having methylene substituted with halogen, hydroxy, hydroxyimino, C1-C4 alkoxyimino, amino or the like such as phenyldichloromethyl, phenylhydroxymethyl, phenylhydroxyiminomethyl, phenylmethoxyiminomethyl, phenylaminomethyl and phenylacetoxymethyl; etc.Examples of the substituted phenoxymethyl groups represented by R5 are phenoxymethyl substituted with 1 to 3 C1-C4 alkyl groups on the phenyl ring such as tolyloxymethyl; phenoxymethyl substituted with 1 to 3 halogen atoms on the phenyl ring such as 4-chlorophenoxymethyl, 2,4-dichlorophenoxymethyl, 2,4,6trichlorophenoxymethyl, 4- bromophenoxymethyl and 2,4-dibromophenoxymethyl; phenoxymethyl substi tuted with 1 to 3 C1 -C4 alkoxy groups on the phenyl ring such as 4-methoxyphenoxymethyl, 2,4dimethoxyphenoxymethyl and 3,4,5-trimethoxyphenoxymethyl; phenoxymethyl substituted with 1 to 3 nitro groups on the phenyl ring such as 4-nitrophenoxymethyl and 2,4-dinitrophenoxymethyl; etc.Examples of the substituted benzoyl groups represented by R5 are benzoyl substituted with 1 to 3 C1-C4 alkyl groups on the phenyl ring such as toluoyl; benzoyl substituted with 1 to 3 halogen atoms on the phenyl ring such as 4-chlorobenzoyl, 2,4-dichlorobenzoyl, 2,4,6-trichlorobenzoyl, 4-bromobenzoyl and 2,4-dibromobenzoyl; benzoyl substituted with 1 to 3 C1-C4 alkoxy groups on the phenyl ring such as 4-methoxybenzoyl, 2,4-dimethoxybenzoyl and 3,4,5-trimethoxybenzoyl; benzoyl substituted with 1 to 3 nitro groups on the phenyl ring such as 4-nitrobenzoyl and 2,4-dinitrobenzoyl; etc.

Examples of the substituted phenyl represented by R3 in the formulae (I) and (VII) are phenyl substituted with 1 to 3 C1-C4 alkyl groups such as tolyl and xylyl; phenyl substituted with 1 to 3 halogen atoms such as 4-chlorophenyl, 2,4-dichlorophenyl, 2,4,6-trichlorophenyl, 4-bromophenyl and 2,4-dibromophenyl; phenyl substituted with 1 to 3 C1-C4 alkoxy groups such as 4-methoxyphenyl, 2,4-dimethoxyphenyl and 3,4,5-trimethoxyphenyl; phenyl substituted with 1 to 3 nitro groups such as 4-nitrophenyl and 2,4dinitrophenyl; etc.

The groups represented by R4 in the formulae (I) and (VI) are hydrogen, acyl, silyl, sulfonyl and phosphonyl derived from inorganic or organic acid, and optionally substituted hydrocarbon residue. Of these groups, the optionally substituted hydrocarbon residue is preferred. Exemplary of the substituted hydrocarbon residue are groups

wherein R6 is hydrogen or carboxy protecting group. The wide range of carboxy protecting groups as disclosed in Theodora W. Greene: "Protective Groups in Organic Synthesis," Chapter 5 are usable in the present invention.Typical examples of the groups are phenyl C1 -C4 alkyl optionally having 1 to 3 substituents, e.g., C1-C4 akoxy, halogen, methylenedioxy, C1-C4 alkyl or nitro on the phenyl ring such as benzyl, p-methoxybenzyl, trimethoxybenzyl, trimethoxydichlorobenzyl, piperonyl, diphenylmethyl, bis(pmethoxyphenyl)methyl, ditolylmethyl, phenyl-p-methoxyphenylmethyl, e-p-methoxyphenylmethyl, trityl, ci-diphenylethyl, p-nitrobenzyl, o-nitrobenzyl and o,p-dinitrobenzyl;; C1-C4 alkyl which may have at least one substituent selected from halogen, phenyl substituted with 1 to 3 C-C4 alkoxy groups, benzoyl, benzoyl substituted with 1 to 3 halogen atoms on the phenyl ring, C1-C4 alkoxy, C1-C4 alkoxy substituted with 1 to 3 Cs-C4 alkoxy groups, benzyloxy, C1 -C4 alkanoyl and C1 -C4 alkoxycarbonyl, such as tert-butyl, trichloroethyl, x-p-methoxyphenyl-ss-trichloroethyl, phenacyl, p-bromophenacyl, methoxymethyl, isopropoxymethyl, methoxyethoxymethyl, benzyloxymethyl and 1-methoxycarbonyl-2-oxopropyl; cumyl; fluorenyl; etc.Z' and Z2 are the same or different and are each hydrogen, halogen, sulfur-containing group, oxygen-containing group, nitrogen-containing group or the like. Examples ofthe substituents represented by Z1 and Z2 are halogen such as bromine, chlorine and fluorine; sulfur-containing groups, e.g., C1-C4 alkylthio such as methylthio and ethylthio, phenylthio, optionally substituted with 1 to 5 nitro groups or halogen atoms on the phenyl ring such as phenylthio, p-nitrophenylthio and pentachlorophenylthio, 2-pyridylthio, 2 benzothiadiazolylthio, 1 ,3,4-thiadiazol-5-ylthio, 2-substituted-l ,2,4-thiadiazol-5-ylthio, 1,2,3,4-tetrazol-5- ylthio, 1-substituted-i ,2,3,4-tetrazo I-5-ylth io, 0-ethyldithiocarbonate, N, N-diethyldithiocarbamate, pheny- Isulfonyl and p-methylphenylsulfonyl; oxygen-containing groups, e.g., hydroxy, Cr-C4 alkoxy such as methoxy and ethoxy, C1-C4 acyloxy such as acetoxy, benzoyloxy, nitrosoxy, nitriloxy, diphenylphosphonyloxy, methanesulfonate, N-morphonyl and diphenylmethoxy; nitrogen-containing groups, e.g., di(C1-C4 alkyl)amino such as dimethylamino, and piperidin-1-yl; etc.

Examples of the substituted or unsubstituted nitrogen-containing aromatic heterocyclic residue represented by R9 in the formula (VI) are those optionally having 1 to 3 substituents, e.g., with C1-C4 alkyl, phenyl, C1-C4 alkoxy, nitro or halogen, such as thiazol-2-yl, 4-methylthiazol-2-yl, 5-methylthiazol-2-yl, 4- phenylthiazol-2-yl, 5-methylth iazol-2-yl, 4-phenylthiazol-2-yl, 5-phenylthiazol-2-yI, thiadiazol-2-yl, 5methylthiadiazol-2-yI, 5-phenylthiadiazol-2-yl, 5-methoxycarbonylthiadiazol-2-yl, benzothiazol-2-yl, 4methyl benzothiazol-2-yl, 6-methylbenzothiazol-2-yl, 5-methoxybenzothiazol-2-yl, 6-nitrobenzothiazol-2-yl, 5-chlorobenzothiazol-2-yl, benzoxazol-2-yl, 4-methylbenzoxazol-2-yl, 6-phenyl benzoxazol-2-yI, 5methoxybenzoxazol-2-yl, 5-chlorobenzoxazol-2-yl, benzimidazol-2-yl, 5-methylbenzimidazol-2-yl, 6chlorobenzoimidazol-2-yl, pyrimidin-2-yl, 5-methylpyrimidin-2-yl and 2-pyridyl, etc.

The dithioazetidinone derivatives of the formula (VI) used as one of the starting materials in the present invention are known and can be synthesized by various processes. The synthesizing processes using penicillin are disclosed, for example, in Tetrahedron Letters, 3001(1973), J. Amer. Chem. Soc., 86, 5307 (1964): Japanese Examined Patent Publication (Kokoku) No. 14665/1981; Japanese Unexamined Patent Publications (Kokai) Nos. 29587/1982,59896/1982, 183793/1982 and 183794/1982; and The Collection of Drafted Research ReportsforThe9th International Convention on Heterocycle, page 300 (1983). The derivatives of the formula (VI) can be produced also by a combination of processes described in these publications. These known processes are shown, for example, in the following reaction scheme.

In the above reaction scheme, Ra, R2, R4, R5, R6 and R9 are as defined above.

However, the dithioazetidinone derivatives of the formula (VI) as used in the present invention are not limited to those producible by these processes. An extensive range of dithioazetidinone derivatives of the formula (VI) produced by various processes including those other than the foregoing processes can be used as the starting material in the present invention.

The compounds of the formula (ill), namely the other starting material used in the present invention, are also known. More specifically the compounds of the formula (VII) can be classified into the compounds of the formulae (Vlla), (Vllb) and (Vllc) as given below.

R3So2H (Vlla) R3So2CN (Vlib) R3So2SR9 (Vllc) wherein R3 and R9 are as defined above.

The compounds of the formula (Vllb) can be synthesized, for example, by the process as setforth in Tetrahedron Letter, (1969) or can be produced in the reaction system of the present invention using the corresponding sulfonyl halide and alkali metal cyanide.

The compound of the formula (Vllc) can be synthesized, for example, by the process disclosed in U.S.

Patent No. 3786063 which can be indicated in the following reaction equation.

In the foregoing reaction equation, R3 and R9 are as defined above.

According to the present invention, the dithioazetidinone derivative of the formula (VI) is reacted with the compound of the formula (VII) usually in a suitable solvent. Examples of the solvent which can be used in the present invention is not particularly limited as far as the solvent is capable of dissolving the compound of the formula (VI) and the compound of the formula (VII). Since these compounds need not be completely dissolved in the present invention, even solvents capable of partially dissolving them are usable. Useful solvents include organic solvents used singly or in conjunction with water.Examples of suitable organic solvents are ketones such as acetone, methyl ethyl ketone, diethyl ketone and methyl isobutyl ketone; esters such as methyl formate, ethyl formate, propyl formate, methyl acetate, ethyl acetate, propyl acetate, methyl propionate and ethyl propionate; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as dichloromethane, dibromomethane, chloroform, bromoform, carbon tetrachloride, dichloroethane, dibromoethane and trichloroethane; ethers such as diethyl ether, dipropyl ether, dibutyl ether, tetrahydrofuran and dioxane; nitroalkanes such as nitromethane, nitroethane and nitropropane; nitriles such as acetonitrile, propionitrile, butyronitrile and valeronitrile; alcohols such as methanol, methanol, propanol, isopropanol and butanol; etc.These organic solvents can be used singly or at least two of them are usable in admixture. The amount of the solvent is usually about 1 to about 400 times, preferably about 1 to about 100 times, more preferably about 1 to about 50 times, the weight of the compound of the formula (Vl).

The proportions of the compounds of the formula (VI) and (VII) used in the present invention are not particularly limited and can be suitably determined over a wide range. Usually about 1 to about 5 moles of the compound of the formula (VII) is used per mole of the compound of the formula (VI). It is adequate to use, as the compound (VII), about 1 to about 2 moles, preferably of about 1 to about 1.5 moles, of the compound of the formula (Vlla), about 1 to about 2 moles of the compound of the formula (Vllb), or about 1 to about 1.2 moles of the compound of the formula (Vllc), all per mole of the compound of the formula (VI).

The reaction of the present invention can be usually carried out at a temperature ranging from about -200C to the temperature at which the solvent used is refluxed. Preferred reaction temperature is in the range of 0 to about 50 C in use of the compound (Vlla), about 20"C to the solvent-refluxing temperature in use of the compound (Vllb) and 0 to about 80"C, preferably about 10 to about 40"C, in use of the compounds (Vllc) as the compound (VII). The reaction time in the present invention varies depending on the reaction temperature, kinds of the compounds (VI) and (VII) and the other conditions, but usually ranges from about 0.1 to about 15 hours.

When the compound of the formula (Vlla) is used as the compound of the formula (VII), the reaction system need not contain a catalyst. When the compound (Vllb) or (Vllc) is used as the compound (VII) in the present invention, it is preferred to incorporate into the reaction system at least one kind of catalyst selected from a sulfonicacid of the formula R3SO2H (Vlla) wherein R3 is as defined above or a salt thereof, a thiol of the formula R9SH (veil) wherein R9 is as defined above or a salt thereof, and a nucleophilic compound capable of producing R3SO20 when reacted with the compound (Vllb) or (Vllc). The presence of the foregoing catalyst in the reaction system results in the production of the desired compound (I) of higher purity in higher yields.

Examples of the substituted or unsubstituted phenyl represented by R3 in the sulfinic acid (Vlla) are the same as those exemplified above. Examples of the sulfinic acid (Vlla) as used above are benzenesulfinic acid, tolylsulfinic acid, xylylsulfinic acid, 4-chlorophenylsulfinic acid, 2,4-dichlorophenylsulfinic acid, 2,4,6- trichlorophenylsulfinic acid, 4-bromophenylsulfinic acid, 2,4-dibromophenylsulfinic acid, 4methoxyphenylsulfinic acid, 2,4-dimethoxyphenylsulfinic acid, 3,4,5-trimethoxyphenylsulfinic acid, 4nitrophenylsulfinic acid, 2,4-dinitrophenylsulfinic acid, etc.Examples of the salt of the sulfinic acid (Vlla) as used above are salts of alkali metals such as lithium, sodium, potassium and rubidium, salts of alkaline earth metals such as magnesium, calcium, strontium and barium, ammonium salts such as ammonium, tetra (C-C4 alkyl)ammonium, e.g., tetramethylammonium, tetraethylammonium and trimethyl ethyl ammonium, pyridium salt, etc. Of these salts, an alkali metal salt is preferably used.Preferred examples of the alkali metal salts are sodium benzenesulfinate, potassium benzenesulfinate, lithium benzenesulfinate, rubidium benzenesulfinate, sodium tolysulfinate, potassium tolylsulfinate, sodium xylylsulfinate, sodium 4 chlorophenylsulfinate, potassium 4-chlorophenylsulfinate, sodium 2,4-dichlorophenylsulfinate, sodium 2,4,6-trichlorophenylsulfinate, sodium 4-bromophenylsulfinate, sodium 2,4-dibromophenylsulfinate, sodium 4-metoxyphenylsulfinate, potassium 4-methoxyphenylsulfinate, sodium 2,4dimethoxyphenylsulfinate, sodium 3,4,5-trimethoxyphenylsulfinate, sodium 4-nitrophenylsulfinate, potassium 4-nitrophenylsulfinate, sodium 2,4-dinitrophenylsulfinate, potassium 2,4-dinitrophenylsulfinate, etc.

Examples of the substituted or unsubstituted, nitro-containing aromatic heterocyclic residue represented by R9 in the thiol (VIII) are the same as those exemplified above. Examples of the thiol (VIII) as used above are 2-thiazole thiol, 2-(4-methyl)thiazole thiol, 2-(5-methyl)thiazole thiol, 2-(4;;phenyl)thiazole thiol, 2-(5phenyl)thiazole thiol, 2-thiadiazole thiol, 2-(5-methyl)thiadiazole thiol, 2-(5-phenyl)thiadiazole thiol, 2thiadiazole thiol, 2-(5-methyl)thiadiazole thiol, 2-(5-phenyl)thiadiazole thiol, 2-(5methoxycarbonyl)thiadiazole thiol, 2-benzothiazole thiol, 2-(4-methyl)benzothiazole thiol, 2-(6 methyl)benzothiazole thiol, 2-(5-methoxy)benzothiazole thiol, 2-(4-nitro)benzothiazole thiol, 2-(6nitro)benzothiazole thiol, 2-(5-chloro)benzothiazole thiol, 2-benzoxazole thiol, 2-(4-methyl)benzoxazole thiol, 2-(6-phenyl)benzoxazole thiol, 2-(5-methoxy)benzoxazole thiol, 2-(5-chloro)benzoxazole thiol, 2benzimidazole thiol, 2-(6-methyl)benzimidazole thiol, 2-(6-chloro)benzimidazole thiol, 2-pyrimidine thiol, 2-(5-methyl)pyrimidine thiol, 2-pyridyl thiol, etc. Examples of the salt of the thiol (VIII) as used above are salts of alkali metals such as lithium, sodium, potassium and rubidium, salts of alkaline earth metals such as magnesium, calcium, strontium and barium, ammonium salts such as ammonium, tetra(C1-C4 alkyl) ammonium, e.g., tetramethylammonium, tetraethylammonium and trimethyl ethyl ammonium, pyridium salt, etc. Of these salts, an alkali metal salt is preferably used. Preferred examples of the alkali metal salts are sodium 2-thiazole thiolate, sodium 2-(4-methyl)thiazole thiolate, sodium 2-(5-methyl)thiazole thiolate, sodium 2-(4-phenyl)thiazole thiolate, sodium 2-(5-phenyl)thiazole thiolate, sodium 2-thiadiazole thiolate, sodium 2-(5-methyl)thiadiazole thiolate, sodium 2-(5-phenyl) thiadiazole thiolate, sodium 2-(5methoxycarbonyl) thiadiazole thiolate, sodium 2-benzothiazole thiolate, sodium 2-(6-methyl)benzothiazole thiolate, sodium 2-(5-methoxy)benzothiazole thiolate, sodium 2-(4-nitro) benzothiazole thiolate, sodium 2-(6-nitro)benzothiazole thiolate, sodium 2-(5-chloro)benzothiazole thiolate, sodium 2-benzoxazole thiolate, sodium 2-(4-methyl)benzoxazole thiolate, sodium 2-(6-phenyl)benzoxazole thiolate, sodium 2-(5methoxy)benzoxazole thiolate, sodium 2-(5-chloro)benzoxazole thiolate, sodium 2-benzimidazole thiolate, sodium 2-(6-methyl)benzimidazole thiolate, sodium 2-(6-chloro)benzimidazole thiolate, sodium 2-pyrimidine thiolate, sodium 2-(5-methyl)pyrimidine thiolate, sodium 2-pyridyl thiolate, potassium 2-benzothiazole thiolate, potassium 2-(4-methyl)benzothiazole thiolate, potassium 2-(6-methyl)benzothiazole thiolate, potassium 2-(6-nitro)benzothiazole thiolate, potassium 2-(5-methoxy)benzothiazole thiolate, potassium 2-(5methyl)thiadiazole thiolate, lithium 2-benzothiazole thiolate, rubidium 2-benzothiazole thiolate, etc.

Examples of useful nucleophilic compounds are water; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; alcohols having 1 to 4 carbon atoms such as methanol, ethanol, propanol, isopropanol, butanol and inorganic or organic salts thereof; phenols such as phenol, cresol, p-methoxyphenol, p-nitrophenol and inorganic or organic salts thereof; thiols other than the compounds (VIII) such as methanethiol, ethanethiol, propanethiol, thiophenol, thiocresol, p-nitrothiophenol and inorganic or organic salts thereof; sulfinic acids other than the compounds (Vlla) such as methanesulfinic acid, ethanesulfinic acid, propanesulfinic acid and inorganic or organic salts thereof; carboxylic acids such as acetic acid, propionic acid and inorganic or organic salts thereof; etc.When an alcohol having 1 to 4 carbon atoms is used as a solvent, no catalyst is required because the alcohol acts as a nucieophilic compound.

The reaction of the present invention with the reaction system containing the aforesaid catalyst is shown in the following reaction equation.

In the foregoing reaction equation, R1, R2, R3, R4 and R9 are as defined above.

When at least one molecule of R3SO2 or R9Ss is present in the reaction system, the catalytic reaction as illustrated above can proceed between the compound (VI) and the compound (Vllb) or (Vllc), thereby giving a compound (I).

More specifically, when a sulfinic acid (Vlla) or a salt thereof is used as a catalyst, the sulfinic acid (Vlla) or the salt thereof is reacted with a compound (VI) to form a compound (I) and a thiol (VIII) or a salt thereof. The thiol (VIII) or the salt thereof thus obtained is reacted with a compound (Vllb) or (Vllc), producing a compound (IX) or (X), respectively and regenerating a sulfinic acid (Vlla) or a salt thereof. The compound (IX) or (X) is precipitated as crystals due to its low solubility. The regenerated sulfinic acid (Vlla) or the salt thereof is reacted with a compound (VI).

When a thiol (Vlil) or a salt thereof is used as a catalyst, the thiol (VIII) or the salt thereof is reacted with a compound (Vlib) or (Vllc), affording a sulfinic acid (Vlla) or a salt thereof and a compound (IX) and (X). The compound (IX) or (X), which has a low solubility, is deposited as crystals. The sulfinic acid (Vlla) or the salt thereof is reacted with a compound (VI), producing a compound (I) and regenerating a thiol (VIII) or a salt thereof.

When a sulfinic acid (Vlla) or a salt thereof is used in conjunction with a thiol (VIII) or a salt thereof, the foregoing reactions simultaneously proceed.

When the above-mentioned nucleophilic compound is used as a catalyst, the reaction proceeds in the same manner as in use of the sulfinic acid (Vlla) or the salt thereof as a catalyst.

While reaction can proceed with a system containing one molecule of the catalyst, usually about 0.001 to about 0.1 mole, preferably about 0.001 to about 0.05 mole, of the catalyst is used per mole of the compound (VI).

Afterthe completion of the reaction, the azetidinone derivative (I) of the present invention can be separated from the reaction mixture by conventional methods such as filtration, centrifugation, distillation, extraction, etc. The azetidinone derivative (I) thus obtained is substantially pure, but can be easily purified by recrystallization, column chromatography or like means if further purification is needed.

According to the present invention, a desired compound (I) of high purity can be prepared in high yields without use of expensive or harmful heavy metal salt of sulfinic acid by carrying out a simple procedure. The process of the present invention has the following additional advantage. When a compound (Vllc) is used as the compound (VII), a compound (X) is formed as a by-product. But the compound (X) of high purity can be recovered in high yields by a simple filtration and the recovered compound (X) is available as the starting material for synthesizing a compound (Vllc) which is used as the starting material in the present invention.

The present invention will be described below in more detail with reference to the following Examples to which, however, the present invention is limited in no way and in which the code Ph refers to phenyl.

Example 1

Dissolved in 10 ml of acetone was 1.0 g of p-methoxybenzyl 2-[3-phenylacetamido-4-(2benzothiazolyldithio)-2-azetidinon-1-yll-3-methyl-3-butenoate. To the solution was added 0.28 g of benzenesulfinic acid and the mixture was reacted with stirring at room temperature for 4 hours. The acetone was distilled off under reduced pressure and the resulting residue was purified by silica gel column chromatography, giving p-methoxybenzyl 2-(3-phenylacetamido-4-benzensulfonylthio-2-azetidinon-1 -yl)-3methyl-3-butenoate in a yield of 97%. The NMR spectrum data of the compound thus obtained were identical with those of the desired compound. Table 5 shows the NMR spectrum data of the compound.

Example 2 p-Methoxybenzyl 2-[3-phenylacetamido-4-(2-benzothiazolyldithio)-2-azetidinon-1 -yIj-3-methyl-3- butenoate was reacted in the same manner as in Example 1 by using the solvents as shown below in Table 1, producing p-methoxybenzyl 2-(3-phenylacetamido-4-benzenesulfonylthio-2-azetidinon-1 -yl)-3-methyl-3- butenoate in the yields listed below in Table 1. The NMR spectrum data of the compounds thus obtained were identical with those of the compound produced in Example 1.

TABLE 1 Solvent Yield 1%1 Acetone-water (20: 1) 95 Acetonitrile 93 Tetrahydrofuran 98 Dioxane 90 Example 3

A 10 g quantity of p-methoxybenzyl 2-[3-phenylacetamido-4-(2-benzothiazolyidithio)-2-azetidinon-1 -yl]-3- methyl-3-butenoate was dissolved in 100 ml of acetone. To the solution was added 2.8 g of benzenesulfinic acid, and the mixture was reacted with stirring at room temperature for 4 hours. The reaction mixture was mixed with 0.91 g of a 30% aqueous solution of hydrogen peroxide and the resulting mixture was reacted with stirring at room temperature for 1 hour. The precipitated 2-benzothiazolyl disulfide was filtered and the acetone was removed from the filtrate under reduced pressure by distiliation.The residue was dissolved in benzene and the solution was washed sequentially with an aqueous Na2S203 solution and with water and dried over anhydrous sodium sulfate. The benzene was distilled off under reduced pressure to give p-methoxybenzyl 2-(3-phenylacetamido-4-benzenesulfonylthio-2-azetidinon-1-yl)-2-methyl-3-butenoate.

The compound thus obtained was purified by recrystallization from benzene (yield 92%). The NMR spectrum data of the compound were identical with those of the compound produced in Example 1.

Example 4

The compounds shown below in Table 2 were produced by following the general procedure of Example 1.

The NMR spectrum data of these compounds were identical with those of the compounds as contemplated.

Table 5 below lists the spectral data thereof.

TABLE 2

R7 R2 R9 R4 RS Yield (O/o) CH2 O tN0cOCI13 + CI13 Ph 90 PhOCH2CNH COOCH2Ph " D w 5CH3 ,, " 92 N-N cfl N 2 ii I XCiI CI13 9 8 PhCH2CNH- S 3 POOCH3 TABLE 2 (continued)

R1 R2 R9 R4 RS Yield O n CJJ2 to II COOL PhOCH2CNH- 0 ,~gOCI13 COOC}l < or113 H I CH2 Ph 94 PhOCH2CNH X CH3 COOCI12eoci3 CH2 " Ngg 90 ::II,PII CII 2 CH3 NJ%CII3 C 0 0 CH2)4\oCH3 c e OCH3 CH2 " ~Ngs t wJCHC2H3 " 91 COOCflCOBr CH2 3 < CI13 Ph 90 PhOCH2CNH- S Coo I) 0 ii'I ,, " 92 PhCH2CNH- CH2 WyCH3 98 C00CH2t3N02 CII yYCH3 90 CooCH2 NO2 TABLE 2 (continued)

R1 R2 R9 R4 R3 Yield (%) Cir2 0 N - CH3 H PhOCH2CNH - COOCH-COCH3 Ph 95 CO2CI13 CII2 O 7 CI13 cs-- 90 COOCH C 90 PhCH2CNH - 3 3 ws n 1l Cy2 CII, NO, COOCH2Ph O CIT2 H II CV çf[C2fl3 CH 0 91 PhCH2CNH- S COOCHaP A CUIT2 CH30- " D ftCH3 Ph 94 cOOcii2t*No 2 ', ,, 94 CII 2 H " U KyCH3 92 COOC,-(OCH, ~ CH3 .CII, CHI--T- 93 COOCH2CC3 CII3off/\ 96 Example5

A 560 mg quantity of p-methoxybenzyl 2-[3-phenylacetamido-4-(2-benzothiazolyldithio)-2-azetidinon-1 -yl]- 3-methyl-3-butenoate and 302 mg of benzenesulfonyl cyanide were dissolved in 5 ml of acetone.To the solution was added 0.5 ml of water and the mixture was reacted with heating for 1.5 hours while refluxing the acetone. The acetone was distilled off under reduced pressure and the residue was dissolved in 10 ml of benzene. The benzene solution was washed with water, dried over Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography, giving p-methoxybenzyl 2-(3-phenylacetamido-4-benzenesulfonylthio-2-azetidinon-1-yl)-3-methyl-3-butenoate in a yield of 95%. The NMR spectrum data of the compound thus obtained were identical with those of the compound produced in Example 1.

Example 6 A 529 mg quantity of p-methoxybenzyl 2-[3-phenylacetamido-4-(2-benzothiazolyldithio)-2-azetidinon-1 -yIj- 3-methyl-3-butenoate and 157 mg of benzenesulfonyl cyanide were dissolved in 5 ml of ethyl acetate. To the solution was added 0.5 ml of water and the mixture was reacted with heating at 80"C for 1 hour. The reaction mixture was cooled to room temperature and was washed with water, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, giving p-methoxybenzyl 2-(3-phenylaceta mido-4-benzenesu Ifonyith io-2-azetidinon-1 -yl)-3-methyl-3-butenoate in a yield of 88%. The NMR spectrum data of the compound thus obtained were identical with those of the compound prepared in Example 1.

Example 7 A 478 mg quantity of p-methoxybenzyl 2-[3-phenylacetamido-4-(2-benzothiazolyldithio)-2-azetidinon-1 -ylj- 3-methyl-3-butenoate and 155 mg of benzene sulfonyl cyanide were dissolved in 5 ml of chloroform. To the solution was added 0.25 ml of water and the mixture was reacted with heating for 1.5 hours while refluxing the chloroform. The reaction mixture was cooled to room temperature, washed with water, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, giving p-methoxybenzyl 2-(3-phenylacetamido-4-benzenesulfonylthio-2-azetidi non-I -yl)- 3-methyl-3-butenoate in a yield of 89%. The NMR spectrum data of the compound thus obtained were identical with those of the compound produced in Example 1.

Example 8 A 542 mg quantity of p-methoxybenzyl 2-[3-phenylacetamido-4-(2-benzothiazolyidithio)-2-azetidinon-1-yl]- 3-methyl-3-butenoate and 176 mg of benzenesulfonyl cyanide were dissolved in 5 ml of water and the mixture was reacted with heating at 67"C for 1.5 hours. The acetonitrile was distilled off under reduced pressure and the residue was dissolved in 10 ml of benzene. The benzene solution was washed with water, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, giving p-methoxybenzyl 2-(3-phenylacetamido-4-benzenesu lfonylthio-2-azetidinon-1 -yl )3-methyl-3-butenoate in a yield of 93%. The NMR spectrum data of the compound thus obtained were identical with those of the compound produced in Example 1.

Example 9 A 290 mg quantity of p-methoxybenzyl 2-[3-phenylacetamido-4-(2-benzothiazolyldithio)-2-azetidinon-1-yl]- 3-methyl-3-butenoate and 94 mg of benzenesulfonyl cyanide were dissolved in 3 ml of acetone. To the solution was added 3 mg of sodium benzenesulfinate and the mixture was reacted at room temperature for 2 hours. The acetone was distilled off under reduced pressure and the residue was purified by silica gel column chromatography, giving p-methoxybenzyl 2-(3-phenylacetamido-4-benzenesulfonylthio-2 azetidinon-1-yl)-3-methyl-3-butenoate in a yield of 96%. The NMR spectrum data of the compound thus obtained were identical with those of the compound produced in Example 1.

Example 10 A 345 mg quantity of p-methoxybenzyl 2-[3-phenylacetamido-4-(2-benzothiazolyldithio)-2-azetidinon-1 -ylj- 3-methyl-3-butenoate and 112 mg of benzenesulfonyl cyanide were dissolved in 3.5 ml of acetone. To the solution was added 5 mg of benzenesulfinic acid and the mixture was reacted with heating for 8 hours while refluxing the acetone. The acetone was distilled off under reduced pressure and the residue was purified by silica gel column chromatography, giving p-methoxybenzyl 2-(3-phenylacetamido-4-benzenesulfonylthio-2 azetidinon-1-yl)-3-methyl-3-butenoate in a yield of 86%. The NMR spectrum data of the compound thus obtained were identical with those of the compound produced in Example 1.

Example ii A 343 mg quantity of p-methoxybenzyl 2-[3-phenylacetamido-4-(2-benzothiazolyidithio)-2-azetidinon-1-yl]- 3-methyl-3-butenoate and 111 mg of benzenesulfonyl cyanide were dissolved in 3.5 ml of ethyl acetate. To the solution was added 5 mg of 2-mercaptobenzothiazole and the mixture was reacted with heating for 8 hours while refluxing the ethyl acetate. The ethyl acetate was distilled off under reduced pressure and the residue was purified by silica gel column chromatography, giving p-methoxybenzyl 2-(3-phenylacetamido-4 benzenesulfonylthio-2-azetidinon-1-yl)-3-methyl-3-butenoate in a yield of 80%. The NMR spectrum data of the compound thus obtained were identical with those of the compound produced in Example 1.

Example 12 A 400 mg quantity of p-methoxybenzyl 2-[3-phenylacetamido-4-(2-benzothiazolyidithio)-2-azetidinon-1-yl]- 3-methyl-3-butenoate and 130 mg of benzenesulfonyl cyanide were dissolved in 4 ml of tetrahydrofuran. To the solution was added 3 mg of sodium hydroxide and the mixture was reacted at room temperature for 2 hours. The tetrahydrofuran was distilled off under reduced pressure and the residue was dissolved in 10 ml of benzene. The benzene solution was washed with water, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, giving p-methoxybenzyl 2-(3-phenylacetamido-4-benzenesulfonylthio-2-azetidinon-1 -yl)-3-methyl-3-butenoate in a yield of 91%.The NMR spectrum data of the compound thus obtained were identical with those of the compound produced in Example 1.

Example 13 A 453 mg quantity of p-methoxybenzyl 2-[3-phenylacetamido-4-(2-benzothiazolyldithio)-2-azetidinon-1-yI]- 3-methyl-3-butenoate and 147 mg of benzenesulfonyl cyanide were dissolved in 4.5 ml of tetrahydrofuran.

To the solution was added 20ps1 of a 28% methanol solution of sodium methoxide and the mixture was reacted at room temperature for 50 minutes. The tetrahydrofuran was distilled off under reduced pressure and the residue was dissolved in 10 ml of benzene. The benzene solution was washed with water, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, giving p-methoxybenzyl 2-(3-phenylacetamido-4-benzenesulfonylthio-2-azetidinon-1-yl)- 3-methyl-yl-3-butenoate in a yield of 93%. The NMR spectrum data of the compound thus obtained were identical with those of the compound produced in Example 1.

Example 14 A 290 mg quantity of p-methoxybenzyl 2-[3-phenylacetamido-4-(2-benzothiazolyldithio)-2-azetidinon-1 -yl]- 3-methyl-3-butenoate and 94 mg of benzenesulfonyl cyanide were dissolved in 3 ml of tetrahydrofuran. To the solution was added 3 ml of sodium salt of 2-mercaptobenzothiazole and the mixture was reacted at room temperature for 2 hours. The tetrahydrofuran was distilled off under reduced pressure and the residue was purified by silica gel column chromatography, giving p-methoxybenzyl 2-(3-phenylacetamido-4 benzenesulfonylthio-2-azetidinon-1 -yI)-3-methyl-3-butenoate in a yield of 91%. The NMR spectrum data of the compound thus obtained were identical with those of the compound produced in Example 1.

Example 15 A 316 mg quantity of p-methoxybenzyl 2-F3-phenylacetamidoA-(2-benzothiazolyldithio)-2-azeridinon-1 -ylj- 3-methyl-3-butenoate and 102 mg of benzenesulfonyl cyanide were dissolved in 3 ml of tetrahydrofuran. To the solution was added 5 ml of aniline salt of 2-mercaptobenzothiazole and the mixture was reacted at room temperature for 10 hours. The tetrahydrofuran was distilled off under reduced pressure and the residue was purified by silica gel column chromatography, giving p-methoxybenzyl 2-(3-phenylacetamido-4 benzenesulfonylthio-2-azetidinon-1-yl)-3-methyl-3-butenoate in a yield of 85%. The NMR spectrum data of the compound thus obtained were identical with those of the compound produced in Example 1.

Example- 16 A 316 mg quantity of p-methoxybenzyl 2-[3-phenylacetamido-4-(2-benzothiazolyldithio)-2-azetidinon-1 -ylj- 3-methyl-3-butenoate and 102 mg of benzenesulfonyl cyanide were dissolved in a solvent mixture of 1.5 ml of ethyl acetate and 1.5 ml of methanol. The mixture was reacted with heating for 2 hours while refluxing the solvent. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography, giving p-methoxybenzyl 2-(3-phenylacetamido-4-benzenesulfonylthio-2azetidinon-1 -yl)-3-methyl-3-butenoate in a yield of 82%. The NMR spectrum data of the compound thus obtained were identical with those of the compound produced in Example 1.

Example 17

A 250 mg quantity of benzyl 2-[3-phenoxyacetamido-4-(5-methoxybenzothiazol-2-yldithio)-2-azetidinon-1 - yl]-3-methyl-3-butenoate and 79 mg of benzenesulfonyl cyanide were dissolved in 2.5 ml of acetone. To the solution was added 3 mg of sodium benzenesulfinate and the mixture was reacted at room temperature for 2 hours. The same subsequent procedure as in Example 9 was followed, producing benzyl 2-(3 phenoxyacetamido-4-benzenesulfonylthio-2-azetidinon-1 -yl)-3-methoxy-3-butenoate in a yield of 93%. The NMR spectrum data of the compound thus obtained were identical with those of the desired compound.

Table 5 below shows the NMR spectrum data thereof.

Example 18

A 255 mg quantity of benzyl 2-[3-phenoxyacetamido-4-(5-methylthiadiazol-2-yldithio)-2-azetidinon-1-yIj-3 methyl-3-butenoate and 90 mg of benzenesulfonyl cyanide were dissolved in 2.5 ml of acetone. To the solution was added 3 mg of sodium benzenesulfinate and the mixture was reacted at room temperature for 2 hours. The same subsequent procedure as in Example 9 was followed, producing benzyl 2-(3 phenoxyacetamido-4-benzenesu lfonylthio-2-azetidinon-1 -yI )-3-methyl-3-butenoate in a yield of 85%. The NMR spectrum data of the compound thus obtained were identical with those of the compound produced in Example 17.

Example 19

A 480 mg quantity of methyl 2-[3-phenylacetamido-4-(2-benzothiazolyldithio)-2-azetidinon-1 -yl]-3-methyl3-butenoate and 203 mg of ptoluenesulfonyl cyanide were dissolved in 5 ml of acetone. To the solution was added 3 mg of sodium toluenesulfinate and the mixture was reacted at room temperature for 2 hours. The same subsequent procedure as in Example 9 was followed, producing methyl 2-[3-phenylacetamido-4-(p toluenesulfonylthio)-2-azetidinon-1-ylj-3-methyl-3-butenoate in a yield of 96%. The NMR spectrum data of the compound thus obtained were identical with those of the desired compound. Table 5 below shows the NMR spectrum data of the compound.

Example 20

A 210 mg quantity of 3,4,5-trimethoxybenzyl 2-[3-phenoxyacetamido-4-(2-benzothiazoiyidithio)-2- azetidinon-1-yl]-3-methyl-3-butenoate and 61 mg of benzenesulfonyl cyanide were dissolved in 2.5 ml of acetone. To the solution was added 3 mg of sodium benzenesulfinate and the mixture was reacted at room temperature for 2 hours. The same subsequent procedure as in Example 9 was followed, producing 3,4,5-trimethoxybenzyl 2-(3-phenoxyacetamido-4-benzenesulfonylthio-2-azetidi non-i -yl)-3-methyl-3- butenoate in a yield of 95%. The NMR spectrum data of the compound thus obtained were identical with those of the desired compound. Table 5 shows the NMR spectrum data of the compound.

Example 21

A 340 mg quantity of p-methoxybenzyl 2-[3-phenoxyacetamido-4-(2-benzothiazolyldithio)-2-azetidinon-1 - yl]-3-methyl-3-butenoate and 107 mg of benzenesulfonyl cyanide were dissolved in 3.5 ml of acetone. To the solution was added 3 mg of sodium benzenesulfinate and the mixture was reacted at room temperature for 2 hours. The same subsequent procedure as in Example 9 was followed, producing p-methoxybenzyl 2-(3-phenoxyacetamido-4-benzenesulfonylthio-2-azetidinon-1 -yl)-3-methyl-3-butenoate in a yield of 90%.

The NMR spectrum data of the compound thus obtained which are shown below in Table 5 were identical with those of the desired compound.

Example 22

A 362 mg quantity of benzyl 2-[3-phenoxyacetamidoA-(6-nitrnbenzothiazol-2-yldkhio)-2-azetidinon-1 -yl]3-methyl-3-butenoate and 112 mg of benzenesulfonyl cyanide were dissolved in 3.5 ml of acetone. To the solution was added 3 mg of sodium benzenesulfinate and the mixture was reacted at room temperature for 2 hours. The same subsequent procedure as in Example 9 was followed, producing benzyl 2-(3 phenoxyacetamido-4-benzenesu Ifonylthio-2-azetidinon-1 -yI)-3-methyl-3-butenoate in a yield of 81%. The NMR spectrum data of the compound thus obtained were identical with those of the compound produced in Example 17.

Example 23

A 268 mg quantity of 3,4,5-trimethoxy-2,6-dichlorobenzyl 2-[3-phenoxyacetamido-4-(4 methylbenzothiazol-2-yidithio)-2-azetidinon-1-yl]-3-methyl-3-butenoate and 69 mg of benzenesulfonyl cyanide were dissolved in 3 ml of acetone. To the solution was added 3 mg of sodium benzenesulfinate and the mixture was reacted at room temperature for 2 hours. The same subsequent procedure as in Example 9 was followed, producing 3,4,5-trimethoxy-2,6-dich lorobenzyl 2-(3-phenoxyacetamido-4 benzenesulfonylthio-2-azetidinon-1-yl)-3-methyl-3-butenoate in a yield of 85%. The NMR spectrum data of the compound thus obtained were identical with those of the desired compound. The NMR spectrum data are shown below in Table 5.

Example 24

A 412 mg quantity of p-bromophenacyl 2-[3-phenoxyacetamido-4-(6-methyl benzothiazol-2-yldithio)-2- azetidinon-1-yl]-3-methyl-3-butenoate and 114 mg of benzenesulfonyl cyanide were dissolved in 4 ml of acetone. To the solution was added 3 mg of sodium benzenesulfinate and the mixture was reacted at room temperature for 2 hours. The same subsequent procedure as in Example 9 was followed, producing p-bromophenacyl 2-(3-phenoxyacetamido-4-benzenesu lfonylthio-2-azetidinon-1 -yl)-3-methyl-3-butenoate in a yield of 94%. The NMR spectrum data of the compound thus obtained were identical with those of the desired compound. Table 5 below shows the NMR spectrum data thereof.

Example 27

A 372 mg quantity of 94luorenyl 2-[3-phenoxyacetamido-4-(2-benzothiazolyidithio)-2-azetidinon-1-yl]-3-methyl-3-butenoate and 110 mg of benzenesulfonyl cyanide were dissolved in 4 ml of acetone. To the solution was added 3 mg of sodium benzenesulfinate and the mixture was reacted at room temperature for 2 hours. The same subsequent procedure as in Example 9 was followed, producing 94luorenyl 2-(3phenoxyacetamido-4-benzenesu lfonylthio-2-azetidinon-1 -yl)-3-methyl.3-butenoate in a yield of 85%. The NMR spectrum data of the compound thus obtained which are shown below in Table 5 were identical with those of the desired compound.

Example 28

A 289 mg quantity of 9-fluorenyl 2-[3-phenylacetamido-4-(2-benzothiazo lyldithio)-2-azetidinon-1 -yl]-3-methyl-3-butenoate and 87 mg of benzenesulfonyl cyanide were dissolved in 3 ml of acetone. To the solution was added 3 mg of sodium benzenesulfinate and the mixture was reacted at room temperature for 2 hours. The same subsequent procedure as in Example 9 was followed, producing 9-fluorenyl 2-(3-phenylacetamido-4-benzenesulfonylthio-2-azetidinon-1-yl)-3-methyl-3-butenoate in a yield of 90%. The NMR spectrum data of the compound thus obtained which are shown below in Table 5 were identical with those of the desired compound.

Example 25

A 294 mg quantity of methoxyethoxymethyl 2-[3-phenoxyacetamido-4-(2-benzothiazolyldithio)-2- azetidinon-1-yl]-3-methyl-3-butenoate and 102 mg of benzenesulfonyl cyanide were dissolved in 3 ml of acetone. To the solution was added 3 mg of sodium benzenesulfinate and the mixture was reacted at room temperature for 2 hours. The same subsequent procedure as in Example 9 was followed, producing methoxyethoxymethyl 2-(3-phenoxyacetamido-4-benzenesulfonylthio-2-azetidinon-1 -yl )-3-methyl-3butenoate in a yield of 78%. The NMR spectrum data of the compound thus obtained which are indicated below in Table 5 were identical with those of the desired compound.

Example 26

A 305 mg quantity of methoxymethyl 2-[3-phenoxyacetamido-4-(2-benzothiazolyldithio)-2-azetidinon-1 -yl]-3-methyl-3-butenoate and 109 mg of benzenesulfonyl cyanide were dissolved in 3 ml of acetone. To the solution was added 3 mg of sodium benzenesulfinate and the mixture was reacted at room temperature for 2 hours. The same subsequent procedure as in Example 9 was followed, producting methoxymethyl 2-(3-phenoxyacetamido-4-benzenesulfonylthio-2-azetidinon-1-yl)-3-methyl-3-butenoate in a yield of 75%.

Example 29

A 250 mg quantity of p-nitrobenzyl 2-[3-phenylacetamido-4-(2-benzothiazolyl dith io)-2-azetidinon-1 -yl]-3-methyl-3-butenoate and 79 mg of benzenesulfonyl cyanide were dissolved in 2.5 ml of acetone. To the solution was added 3 mg of sodium benzenesulfinate and the mixture was reacted at room temperature for 2 hours. The same subsequent procedure as in Example 9 was followed, producing p-nitrobenzyl 2-(3-phenylacetamido-4-benzenesulfonylthio-2-azetidinon-1 -yl)-3-methyl-3-butenoate in a yield of 94%. The NMR spectrum data of the compound thus obtained which are shown below in Table 5 were identical with those of the desired compound.

Example 30

A 310 mg quantity of o-nitrobenzyl 2-[3-phenylacetamido-4-(2-benzothiazolyldithio)-2-azetidinon-1-yl]-3-methyl-3-butenoate and 98 mg of benzenesulfonyl cyanide were dissolved in 3 ml of acetone. To the solution was added 3 mg of sodium benzenesulfinate and the mixture was reacted at room temperature for 2 hours. The same subsequent procedure as in Example 9 was followed, producing o-nitorbenzyl 2-(3-phenylacetamido-4-benzenesulfonylthio-2-azetidinon-1 -yl)-3-methyl-3-butenoate in a yield of 93%. The NMR spectrum data of the compound thus obtained which are shown below in Table 5 were identical with those of the desired compound.

Example 31

A352 mg quantity of 1-methoxycarbonyl-2-oxopropyl 2-[3-phenoxyacetamido-4-(2-benzothiazolyldithio)-2-azetidinon-1 -yl]-3-methyl-3-butenoate and 112 mg of benzenesulfonyl cyanide were dissolved in 3.5 mi of acetone. To the solution was added 3 mg of sodium benzenesulfinate and the mixture was reacted at room temperature for 2 hours. The same subsequent procedure as in Example 9 was followed, producing 1-methoxycarbonyl-2-oxopropyl 2-(3-phenoxyacetamido-4-benzensulfonylthio-2-azetidinon-1 -yl)-3-methyl-3-buteonate in a yield of 90%. The NMR spectrum data of the compound thus obtained which are shown below in Table 5 were identical with those of the desired compound.

Example 32

A 180 mg quantity of methyl 2-[3-phenylacetamido-4-(2-benzothiazolyldithio)-2-azetidinon-1 -yl]-3-methyl-3-butenoate and 85 mg of p-chlorobenzenesulfonyl cyanide were dissolved in 2 ml of acetone. To the solution was added 3 mg of sodium p-chlorobenzenesulfinate and the mixture was reacted at room temperature for 2 hours. The same subsequent procedure as in Example 9 was followed, producing methyl 2-[3-phenylacetamido-4-(p-chlorobenzenesulfonysthio)-2-azetidinon-1-yl]-3-methyl-3-butenoate in a yield of 86%. The NMR spectrum data of the compound thus obtained which are shown below in Table 5 were identical with those of the desired compound.

Example 33

A203 mg quantity of methyl 2-[3-phenylacetamido-4-(2-benzothiazolyidithio)-2-azetidinone-1-yl]-3-methyl-3-butenoate and 101 mg of p-nitrobenzensulfonyl cyanide were dissolved in 2 ml of acetone. To the solution was added 3 mg of sodium p-nitrobenzenesulfinate and the mixture was reacted at room temperature for 2 hours. The same subsequent procedure as in Example 9 was followed, producing methyl 2-[3-phenylacetamido-4-(p-nitrobenzenesulfonylthio)-2-azetidinone-1 -yl]-3-methyl-3-butenoate in a yield of 72%. The NMR spectrum data of the compound thus obtained which are shown below in Table 5 were identical with those of the desired compound.

Example 34

A 231 mg quantity of methyl 2-[3-phenylacetamido-4(2-benzothiazolyldithio)-2-azetidinon-1 -yl]-3-methyl-3-butenoate and 115 mg of o-nitrobenzenesulfonyl cyanide were dissolved in 2.5 ml of acetone. To the solution was added 3 mg of sodium benzenesulfinate and the mixture was reacted at room temperature for 2 hours. The same subsequent general procedure as in Example 9 was followed, producing methyl 2-[3-phenylacetamido-4-(o-nitrobenzenesulfonylthio)-2-azetidinon-1 -yl]-3-methyl-3-butenoate in a yield of 70%. The NMR spectrum data of the compound thus obtained were identical with those of the desired compound. Table 5 below shows the data thereof.

Example 35

A 308 mg quantity of benzyl 2-[3-phenylacetamido-4-(2-benzothiazolyidithio)-2-azetidinon-1-yl]3-methyl-3-butenoate and 133 mg of p-nitrobenzenesulfonyl cyanide were dissolved in 3 ml of acetone. To the solution was added 0.3 ml of water and the mixture was reacted with heating for 2 hours while refluxing the acetone. The same subsequent general procedure as in Example 5 was followed, producing benzyl 2-[3-phenylacetamido-4-(p-nitrobenzenesulfonylthio-2-azetidinon-1 -yl]-3-methyl-3-buteonate in a yield of 77%. The NMR spectrum data of the compound thus obtained which are shown below in Table 5 were identical with those of the desired compound.

Example 36

A 189 mg quantity of benzyl 2-[3-phenylacetamido-4-(2-benzothiazolyldithio)-2-azetidinon-1 -ylj-3-methyl-3-butenoate and 76 mg of p-methoxybenzenesulfonyl cyanide were dissolved in 2 ml of acetone. To the solution was added 0.2 ml of water and the mixture was reacted with heating for 2 hours while refluxing the acetone. The same subsequent general procedure as in Example 5 was followed: producing benzyl 2-[3-phenylacetamidoA-(p-methoxybenzenesulfonylthio)-2-azetidinon-1 -ylj-3-methyl-3-butenoate in a yield of 93%. The NMR spectrum data of the compound thus obtained which are shown below in Table 5 were identical with those of the desired compound.

Example 37

A315 mg quantity of p-nitrobenzyl 2-[3-methoxy-3-phenylacetamido-4-(2-benzothiazolyidithio)-2-azetidinon-1-yl]-3-methyl-3-butenoate and 95 mg of benzenesulfonyl cyanide were dissolved in 3 ml of acetone. To the solution was added 3 mg of sodium benzenesulfinate and the mixture was reacted at room temperature for 2 hours. The same subsequent general procedure as in Example 9 was followed, producing p-nitrobenzyl 2-(3-methoxy-3-phenylacetamido-4-benzenesulfonylthio-2-azetidinon-1 -yl)-3-methyl-3-butenoate in yield of 88%. The NMR spectrum data of the compound thus obtained which are shown below in Table 5 were identical with those of the desired compound.

Examples 38 to 40 The general procedure of Example 5 was repeated, producing the compounds as shown below in Table 3.

The NMR spectrum data of these compounds are listed below in Table 5.

TABLE 3

Ex.Na R7 ' R9 R4 R3 Yield Cli (%) 38 H f CII3 Cm/3 5 94 PhCH2CNH- COoCH2CC3 39 " N Cm!3 0 95 40 ', H Coil3 4 > 78 Example 41

A 13.2 g quantity of p-methoxybenzyl 2-[3-phenylacetamido-4-(2-benzothiazolyldithio)-2-azetidinon-1 -yl]-3-methyl-3-butenoate and 7.0 g of 2-benzothiazolyl benzenethiosulfonate was dissolved in 130 ml of acetone. To the solution were added 26 ml of water and then 20 mg of sodium benzenesulfinate and the mixture was stirred at room temperature for 3 hours. The precipitated 2-benzothiazolyl disulfide crystals were filtered and the filtrate was concentrated under reduced pressure.The residue was dissolved in benzene, washed with water and dried. The benzene was distilled off to give p-methoxybenzyl 2-(3-phenylacetamido-4-benzenesulfonyfthio-2-azetidinon-1 -yl)-3-methoyl-3-butenoate. The compound thus obtained was purified by silica gel column chromatography, affording p-methoxybenzyl 2-(3-phenylacetamido-4-benzenesulfonylthio-2-azetidinon-1-yl)-3-methyl-3-butenoate in a yield of 93%. The NMR spectrum data of the compound were identical with those of the desired compound. Table 5 shows the NMR spectrum data of the compound.

Example 42

A 13.2 g quantity of p-methoxybenzyl 2-[3-phenylacetamido-4-(2-benzothiazolyldithio)-2-azetidinon-1 -yl]-3-methyl-3-butenoate and 7.0 g of 2-benzothiazolyl benezenethiosulfonate was dissolved in 130 ml of acetone. To the solution was added 26 ml of water and then 20 mg of sodium 2-benzothiazolyl thiolate and the mixture was stirred at room temperature for 3 hours. The precipitated 2-benzothiazolyl disulfide crystals were filtered and the filtrate was concentrated under reduced pressure. The residue was treated in the same manner as in Example 41, giving p-methoxybenzyl 2-(3-phenylacetamido-4-benzenesulfonylthio-2-azetidinon-1-yl)-3-methyl-3-butenoate in a yield of 91%. The NMR spectrum data of the compound were identical with those of the compound obtained in Example 41.

Example 43

A 263 mg quantity of benzyl 2-[3.phenoxyacetamido-4-(S-methoxybenzothiazol-2-yldithio)-2-azetidinon-1 -ylj-3-methyl-3-butenoate and 147 mg of 5-methoxybenzothiazol-2.yl benzenethiosulfonatewere dissolved in 2.5 ml of acetone. To the solution were added 0.5 ml of water and then 2 mg of sodium benzenesulfinate and the mixture was stirred at room temperature for 3 hours. The precipitated 5-methoxybenzothiazol-2-yl disulfide crystals were filtered and the filtrate was concentrated under reduced pressure. The residue was treated in the same manner as in Example 41, giving benzyl 2-(3-phenoxyacetamido-4-benzenesulfonylthio-2-azetidinon-1-yl)-3-methyl-3-butenoate in a yield of 96%.

The NMR spectrum data of the compound were identical with those of the desired compound. Table 5 shows the NMR spectrum data of the compound.

Example 44

A 500 mg quantity of benzyl 2-[3-phenoxyacetamido-4-(5-methylthiadiazol-2-yidithio)-2-azetidinon-1-yl]-3-methyl-3-butenoate and 251 mg of 5-methylthiadiazol-2-yl benzenethiosulfonate were dissolved in 5 ml of acetone. To the solution were added 1 ml of water and then 5 mg of sodium benzenesulfinate and the mixture was stirred at room temperature for 3 hours. The precipitated 5-methylthiadiazol-2-yl disulfide crystals were filtered and the filtrate was concentrated under reduced pressure. The residue was treated in the same manner as in Example 41, giving benzyl 2-(3-phenoxyacetamido-4-benzenesulfonylthio-2-azetidinon-1-yl)-3-methyl-3-butenoate in a yield of 89%.

The NMR spectrum data of the compound thus obtained were identical with those of the compound produced in Example 43.

Example 45

A 500 mg quantity of methyl 2-E3-phenylacetamido-4-(2-benzothiazolyidithio)-2-azetidinon-1-yl-3-methyl-3-butenoate and 314 mg of 2-benzothiazolyl p-toluenethiosulfonate were dissolved in 5 ml of acetone. To the solution were added 1 ml of water and then 2 mg of sodium p-toluenesulfinate and the mixture was stirred at room temperature for 3 hours. The precipitated 2-benzothizaolyl disulfide crystals were filtered and the filtrate was concentrated under reduced pressure. The residue was treated in the same manner as in Example 41, giving methyl 2-[3-phenylacetamido-4-(p4oluenesulfonylthio)-2-azetidinon-1 -yl]-3-methyl-3-butenoate in a yield of 95%.

Example 46

A 500 mg quantity of p-methoxybenzyl 2-[3-phenylacetamido-4-(2-benzothiazolyidithio)-2-azetidinon-1-yl]-3-methyl-3-butenoate and 260 mg of 2-benzothiazolyl benzenethiosulfonate were dissolved in 5 ml of acetone. To the solution was added 2 mg of sodium benzenesulfinate and the mixture was stirred at room temperature for 12 hours. The precipitated 2-benzothiazolyl disulfide crystals were filtered and the filtrate was concentrated under reduced pressure.

The residue was purified by silica gel column chromatography, giving p-methoxybenzyl 2-(3-phenylacetam ido-4-benzenesulfonylthio-2-azetidinon-1 -yl)-3-methyl-3-butenoate in a yield of 90%. The NMR spectrum data of the compound were identical with those of the compound produced in Example 41.

Example 47 The same procedure as in Example 46 was repeated with the exception of using chloroform in place of acetone as a solvent, producing p-methoxybenzyl 2-(3-phenylacetamido-4-benzenesulfonylthio-2-azetidinon-1-yl)-3-methyl-3-butenoate in a yield of 86%. The NMR spectrum data of the compound thus obtained were identical with those of the compound produced in Example 41.

Example 48 The same procedure as in Example 46 was repeated with the exception of using benzene in place of acetone as a solvent, producing p-methoxybenzyl 2-(3-phenylacetamido-4-benzenesulfonylthio-2-azetidinon-1 -yl)-3-methyl-3-butenoate in a yield of 82%. The NMR spectrum data of the compound thus obtained were identical with those of the compound produced in Example 41.

Example 49 The same procedure as in Example 46 was repeated with the exception of using acetonitrile in place of acetone as a solvent, producing p-methoxybenzyl 2-(3-phenylacetamido-4-benzenesulfonylthio-2-azetidinon-1-yl)-3-methyi-3-butenoate in a yield of 91%. The NMR spectrum data of the compound thus obtained were identical with those of the compound produced in Example 41.

Example 50 The same procedure as in Example 46 was repeated with the exception of using ethyl acetate in place of acetone as a solvent, producing p-methoxybenzyl 2-(3-phenylacetamido-4-benzenesulfonylthio-2-azetidinon-1 -yl)-3-methyl-3-butenoate in a yield of 85%. The NMR spectrum data of the compound thus obtained were identical with those of the compound produced in Example 41.

Example 51 The same procedure as in Example 46 was repeated with the exception of using nitromethane in place of acetone as a solvent, producing p-methoxybenzyl 2-(3-phenylacetamido-4-benzenesulfonylthio-2-azetidinon-1-yl)-3-methyl-3-butenoate in a yield of 90%. The NMR spectrum data of the compound thus obtained were identical with those of the compound produced in Example 41.

Example 52 The same procedure as in Example 46 was repeated with the exception of using dioxane in place of acetone as a solvent, producing p-methoxybenzyl 2-(3-phenylacetamido-4-benzenesu lfonylthio-2-azetidinon-2-yl)-3-methyl-3-butenoate in a yield of 82%. The NMR spectrum data of the compound thus obtained were identical with those of the compound produced in Example 41.

Example 53 The same procedure as in Example 46 was repeated with the exception of using tetrahydrofuran in place of acetone as a solvent, producing p-methoxybenzyl 2-(3-phenylacetamido-4-benzenesulfonylthio-2-azetidinon-1 -yl)-3-methyl-3-butenoate in a yield of 67%. The NMR spectrum data of the compound thus obtained were identical with those of the compound produced in Example 41.

Example 54 A 500 mg quantity of p-methoxybenzyl 2-[3-phenylacetamido-4-(2-benzothiazolyidithio)-2-azetidinon-1-yl]-3-methyl-3-butenoate and 260 mg of 2-benzothiazolyl benzenethiosulfonate were placed into a 260 mg reactor in which 10 ml of isopropyl alcohol was then introduced. The mixture was stirred at room temperature for 12 hours during which the reactants did not completely dissolved, remaining as suspended. The insolubles were filtered off and washed with 10 ml of acetone. The washing and the filtrate were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, producing p-methoxybenzyl 2-(3-phenylacetam ido-4-benzenesulfonylthio-2-azetidinon-1 -yl)-3-methyl-3-butenoate in a yield of 95%.The NMR spectrum data of the compound thus obtained were identical with those of the compound produced in Example 41.

Example 55 The same procedure as in Example 54 was repeated with the exception of using methanol in place of isopropyl alcohol as a solvent, producing p-methoxybenzyl 2-(3-phenylacetamido-4-benzenesulfonylthio-2-azetidinon-1 -yl)-3-methyl-3-butenoate in a yield of 92%. The NMR spectrum data of the compound thus obtained were identical with those of the compound produced in Example 41.

Example 56

A 200 mg quantity of 3,4,5-trimethoxybenzyl 2-[3-phenoxyacetamido-4-(2-benzothiazolyldithio)-2-azetidinon-1 -yl]-3-methyl-3-butenoate and 97 mg of 2-benzothiazolyl benzenethiosulfonate were dissolved in 3 ml of acetone. To the solution were added 0.3 ml of water and then 2 mg of potassium 2-benzothiazolyl thiolate. The mixture was stirred at room temperature for 3 hours. The precipitated 2-benzothiazolyl disulfide crystals were filtered and the filtrate was concentrated under reduce pressure. The residue was treated in the same manner as in Example 41, giving 3,4,5-trimethoxybenzyl 2-(3-phenoxyacetamido-4-benzenesulfonylthio-2-azetidinon-1 -yl)-3-methyl-3-butenoate in a yield of 92%.

The NMR spectrum data of the compound thus obtained were identical with those of the desired compound.

Table 5 below indicates the data thereof.

Example 57

A 1.0 g quantity of p-methoxybenzyl 2-[3-phenoxyacetamido-4-(2-benzothiazolyidithio)-2-azetidinon-1-yl]-3-methyl-3-butenoate and 488 mg of 2-benzothiazolyl benzenethiosulfonate were dissolved in 10 ml of acetone. To the solution were added 2 ml of water and then 5 mg of sodium 2-benzothiazolyl thiolate. The mixture was stirred at room temperature for 3 hours. The precipitated 2-benzothiazolyl disulfide crystals were filtered and the filtrate was concentrated under reduced pressure. The residue was treated in the same manner as in Example 41, giving p-methoxybenzyl 2-(3-phenoxyacetamido-4-benzenesulfonylthio-2.azetidit1on-1 -yl)-3-methyl-3-butenoate in a yield of 96%. The NMR spectrum data of the compound thus obtained were identical with those of the desired compound.Table 5 below indicates the data thereof.

Example 58

A 198 mg quantity ofbenzyl 2-[3-phenoxyacetamido-4-(6-nitrobenzothiazol-2-yidithio)-2-azetidinon-1-yl]-3-methyl-3-butenoate and 113 mg of 6-nitrobenzothiazol-2-yl benzenethiosulfonate were dissolved in 2.5 ml of acetone. To the solution were added 0.5 ml of water and then 3 mg of sodium benesulfinate. The mixture was stirred at room temperature for 8 hours. The precipitated 6-nitrobenzothiazol-2-yl disulfide crystals were filtered and the filtrate was concentrated under reduced pressure. The residue was treated in the same manner as in Example 41, giving benzyl 2-(3-phenoxyacetamido-4-benzenesulfonylthio-2-azetidinon-1-yl)-3-methyl-3-butenoate in a yield of 79%.

Example 59

A 1.03 g quantity of 3,4,5-trimethoxy-2,6-dichlorobenzyl 2-[3-phenoxyacetam ido-4-(4-methylbenzothiazol-2-yldithio)-2-azetidinon-1 -yl]-3-methyl-3-butenoate and 448 mg of 4-methylbenzothiazol-2-yl benzenethiosulfonate were dissolved in 10 ml of acetone. To the solution were added 2 ml of water and then 8 mg of sodium benzenesulfinate. The mixture was stirred at room temperature for 5 hours. The precipitated 4-methylbenzothiazol-2-yl disulfide crystals were filtered and the filtrate was concentrated under reduced pressure. The residue was treated in the same manner as in Example 41, giving 3,4,5-trimethoxy-2,6-dichlorobenzyl 2-(3-phenoxyacetamido-4-benzenesulfonylthio-2-azetidinon-1 -yl)-3-methyl-3-butenoate in a yield of 86%.

Table 5 below indicates the data thereof.

Example 60

A 1.23 g quantity of p-bromophenacyl 2-[3-phenoxyacetamido-4-(6-methylbenzothiazol-2-yldithio)-2-azetidinon-1 -ylj3-methyl-3-butenoate and 572 mg of 6-methylbenzothiazol-2-yl benzenethiosulfonate were dissolved in 10 ml of acetone. To the solution were added 2 ml of water and then 3 mg of sodium benzenesulfinate. The mixture was stirred at room temperature for 5 hours. The precipitated 6-methylbenzothiazol-2-yl disulfide crystals were filtered and the filtrate was concentrated under reduced pressure. The residue was treated in the same manner as in Example 41, giving p-bromophenacyl 2-(3-phenoxyacetamido-4-benzenesu lfonnylthio-2-azetidinon-1 -yl)-3-methyl-3-butenoate in a yield of 94%.

Table 5 below shows the data thereof.

Example 61

^-u/ mg quantity OT metnoxyetnoxymetnyi 2-[3-phenoxyacetamido-4-(2-benzothiazolyldith io)-2-azetidinon-1 -yl]-3-methyl-3-butenoate and 164 mg of 2-benzothiazolyl benzenethiosulfonate were dissolved in 4 ml of acetone. To the solution were added 0.8 ml of water and then 1 mg of sodium benesulfinate. The mixture was stirred at room temperature for 1.5 hours.

The precipitated 2-benzothiazolyl disulfide crystals were filtered and the filtrate was concentrated under reduced pressure. The residue was treated in the same manner as in Example 41, giving methoxyethoxy 2-(3-phenoxyacetamido-4-benzenesulfonylthio-2-azetidinon-1 -yl )-3-methyl-3-butenoate in a yield of 83%.

Table 5 below indicates the data thereof.

Example 62

A 329 mg quantity of methoxymethyl 2-[3-phenoxyacetamido-4-(2-benzothiazolyl-2-ylditio)-2-azetidinon-1 -yl]-3-methyl-3-butenoate and 190 mg of 2-benzothiazolyl benzenethiosulfonate were dissolved in 5 ml of acetone. To the solution were added 1 ml of water and then 3 mg of sodium benzenesulfinate. The mixture was stirred at room temperature for 4 hours. The precipitated 2-benzothiazolyl disulfide crystals were filtered and the filtrate was concentrated under reduced pressure. The residue was treated in the same manner as in Example 41, giving methoxymethyl 2-(3-phenoxyacetamido-4-benzenesulfonylthio-2-azetidinon-1 -yl )-3-methyl-3-butenoate in a yield of 72%. The NMR spectrum data of the compound thus obtained were identical with those of the desired compound. Table 5 below shows the data thereof.

Example 63

A 1.15 g quantity of 9-fluorenyl 2-[3-phenoxyacetamido-4-(2-benzothiazolyldithio)-2-azetidinon-1 -ylj-3-methyl-3-butenoate and 545 mg of 2-benzothiazolyl benzenethiosulfonate were dissolved in 20 ml of acetone, To the solution were added 4 ml of water and then 10 mg of sodium benzenesulfinate. The mixture was stirred at room temperature for 2 hours. The precipitated 2-benzothiazolyl disulfide crystals were filtered and the filtrate was concentrated under reduced pressure. The residue was treated in the same manner as in Example 41, giving 9-fluorenyl 2-(3-phenoxyacetamido-4-benzenesulfonylthío-2-azetidinon-1-yl)-3-methyl-3-butenoate in a yield of 93%.

Table 5 below indicates the data thereof.

Example 64

A7.16 g quantity of 94luoroenyl 2-[3-phenylacetamido-4-(2-benzothiazolyidithio)-2-azetidinon-1-yl]-3-methyl-3-butenoate and 3.86 g of 2-benzothiazolyl benzenethiosulfonate were dissolved in 100 ml of acetone. To the solution were added 20 ml of water and then 10 mg of sodium benzenesulfinate. The mixture was stirred at room temperature for 1 hour. The precipitated 2-benzothiazolyl disulfide crystals were filtered and the filtrate was concentrated under reduced pressure. The residue was treated in the same manner as in Example 41, giving 9-fluoroenyl 2-(3-phenylacetamido-4-benzenesulfonylthio-2-azetidinon-1 -yl)-3-methyl-3-butenoate in a yield of 89%. The NMR spectrum data of the compound thus obtained were identical with those of the desired compound.

Table 5 below indicates the data thereof.

Example 65

A 500 mg quantity of p-nitrobenzyl 2-[3-phenylacetamido-4-(2-benzothiazolyidithio)-2-azetidinon-1-yl]-3-methyl-3-butenoate and 254 mg of 2-benzothiazolyl benzenethiosulfonate were dissolved in 5 mi of acetone. To the solution were added 1 ml of water and then 2 mg of sodium benzenesulfonate. The mixture was stirred at room temperature for 3 hours.

The precipitated 2-benzothiazolyl disulfide crystals were filtered and the filtrate was concentrated under reduced pressure. The residue was treated in the same manner as in Example 41, giving p-nitrobenzyl Z-(3-phenylacetamido-4-benzenesulfonylthio-2-azetidinon-1-yl)-3-methyl-3-butenoate in a yield of 91%. The NMR spectrum data of the compound thus obtained were identical with those of the desired compound.

Table 5 below indicates the data thereof.

Example 66

A 500 mg quantity of o-nitrobenzyl 2-[3-phenylacetamido-4-(2-benzothiazolyldithio)-2-azetidinon-1-ylI-3-methyl-3-butenoate and 254 mg of 2-benzothiazolyl benzenethiosulfonate were dissolved in 5 ml of acetone. To the solution were added 1 ml of water and then 2 mg of sodium benzenesulfinate. The mixture was stirred at room temperature for 3 hours.

The precipitated 2-benzothiazolyl disulfide crystals were filtered and the filtrate was concentrated under reduced pressure. The residue was treated in the same manner as in Example 41, giving o-nitrobenzyl 2-(3-phenylacetamido-4-benzenesulfonylthio-2-azetidinon-1-yl)-3-methyl-3-butenoate in a yield of 91%. The NMR spectrum data of the compound thus obtained were identical with those of the desired compound.

Table 5 below indicates the data thereof.

Example 67

A 500 mg quantity of 1-methoxywarbonyl-2-oxopropyl 2-[3-phenoxyacetamido-4-(2-benzothiazolyldithio)-2-azetidinon-1 -yl]3-methyl-3-butenoate and 263 mg of 2-benzothiazolyl benzenethiosulfonate were dissolved in 5 ml of acetone. To the solution were added 1 ml of water and then 2 mg of sodium benzenesulfinate. The mixture was stirred at room temperature for 3 hours.

The precipitated 2-benzothiazolyl disulfide crystals were filtered and the filtrate was concentrated under reduced pressure. The residue was treated in the same manner as in Example 41, giving 1 -methoxywarbonyl-2-oxopropyl 2-(3-phenoxyacetamido-4-benzenesu lfonylthio-2-azetidinon-1 -yI)-3-methyl-3-butenoate in a yield of 87%.

Table 5 below indicates the data thereof.

Example 68

A 500 mg quantity of methyl 2-[3-phenylacetamido-4-(2-benzothiazolyldithio)-2-azetidinon-1 -yl]-3-methyl-3-butenoate and 334 mg of 2-benzothiazolyl p-chlorobenzenethiosulfonate were dissolved in 5 ml of acetone. To the solution were added 1 ml of water and then 3 mg of sodium 2-benzothiazolyl thiolate. The mixture was stirred at room temperature for 3 hours. The precipitated 2-benzothiazolyl disulfide crystals were filtered and the filtrate was concentrated under reduced pressure. The residue was treated in the same manner as in Example 41, giving methyl 2-[3-phenylacetamido-4-(p-chlorobenzenesulfonylthio)-2-azetidinon-1-yl]-3-methyl-3-butenoate in a yield of 72%. The NMR spectrum data of the compound thus obtained were identical with those of the desired compound. Table 5 belows indicates the data thereof.

Example 69

A 500 mg quantity of methyl 2-[3-phenylacetamido-4-(2-benzothiazolyidithio)-2-azetidinon-1-yl]-3-methyl-3-butenoate and 344 mg of 2-benzothiazolyl p-nitrobenzenethiosulfonate were dissolved in 5 ml of acetone. To the solution were added 1 ml of water and then 3 mg of sodium 2-benzothiazolyl thiolate. The mixture was stirred at room temperature for3 hours. The precipitated 2-benzothiazolyl disulfide crystals were filtered and the filtrate was concentrated under reduced pressure. The residue was treated in the same manner as in Example 41, giving methyl 2-[3-phenylacetamido-4-(p-nitrobenzenesulfonylthio)-2-azetidinon-1-yl]-3-methyl-3-butenoate in a yield of 58%. The NMR spectrum data of the compound thus obtained were identical with those of the desired compound. Table 5 below indicates the data thereof.

Example 70

A 500 mg quantity of methyl 2-[3-phenylacetamido-4(2-benzothiazolyldithio)-2-azeridinon-1 -yl]-3-methyl-3-butenoate and 344 mg of 2-benzothiazolyl o-nitrobenzenethiosulfonate were dissolved in 5 ml of acetone. To the solution were added 1 ml of water and then 3 mg of sodium 2-benzothiazolyl thiolate. The mixture was stirred at room temperature for 3 hours. The precipitated 2-benzothiazolyl disulfide crystals were filtered and the filtrate was concentrated under reduced pressure. The residue was treated in the same manner as in Example 41, giving methyl 2-[3-phenylacetamido-4-(o-nitrobenzenesulfonylthio)-2-azetidinon-1 -ylj-3-methyl-3-butenoate in a yield of 75%. The NMR spectrum data of the compound thus obtained were identical with those of the desired compound.Table 5 below indicates the data thereof.

Example 71

A 500 mg quantity of benzyl 2--phenylacetamido-4-(2-benzothiaz:olyldithio)-2-azeridinon-1 -yl]-3-methyl-3-butenoate and 314 mg of 2-benzothiazolyl p-nitrobenzenethiosulfonate were dissolved in 5 ml of acetone. To the solution were added 1 ml of water and then 3 mg of sodium 2-benzothiazolyl thiolate. The mixture was stirred at room temperature for 3 hours. The precipitated 2-benzothiazolyl disulfide crystals were filtered and the filtrate was concentrated under reduced pressure. The residue was treated in the same manner as in Example 41, giving benzyl 2-[3-phenylacetamido-4-( p-nitrobenzenesu If onyithio)-2-azetidinon-1 -yl]3-methyl-3-butenoate in a yield of 70%. The N MR spectrum data of the compound thus obtained were identical with those of the desired compound.Table 5 below indicates the data thereof.

Example 72

A 500 mg quantity of benzyl 2[3-phenylacetamido-4-(2-benzothiazolyldithio)-2-azetidinon-1 -ylj-3-methyl-3-butenoate and 300 mg of 2-benzothiazolyl p-methoxybenzenethiosulfonate were dissolved in 5 ml of acetone. To the solution were added 1 ml of water and then 3 mg of sodium 2-benzothiazolyl thiolate. The mixture was stirred at room temperature for 3 hours. The precipitated 2-benzothiazolyl disulfide crystals were filtered and the filtrate was concentrated under reduced pressure. The residue was treated in the same manner as in Example 41, giving benzyl 2-[3-phenylacetamido-4-(p-methoxybenzenesu lfonylthio)-2-azetidinon-1 -yl]-3-methyl-3-butenoate in a yield of 88%. The NMR spectrum data of the compound thus obtained were identical with those of the desired compound.Table 5 below indicates the data thereof.

Example 73

A 200 mg quantity of p-nitrobenzyl 2-[3-methoxy-3-phenylacetamido-4-(2-benzothiazolyldithio)-2-azetidinon-1 -yl]-3-methyl-3-butenoate and 102 mg of 2-benzothiazolyl benzenethiosulfonate were dissolved in 3 ml of acetone. To the solution were added 0.3 ml of water and then 1 mg of sodium benzenesulfinate. The mixture was stirred at room temperature for 3 hours. The precipitated 2-benzothiazolyl disulfide crystals were filtered and the filtrate was concentrated under reduced pressure. The residue was treated in the same manner as in Example 41, giving p-nitrobenzyl 2-[3-methoxy-3-phenylacetamido-4-(2-benzothiazolylthio)-2-azetidinon-1 -yl]-3-methyl-3-butenoate in a yield of 90%. The NMR spectrum data of the compound thus obtained were identical with those of the desired compound.Table 5 below indicates the data thereof.

Examples 74 to 76 The compounds as shown below in Table 4 were produced by following the general procedure of Example 41. Table 5 below lists the NMR spectrum data of the compounds thus obtained.

TABLE 4

Ex No. R7 R2 R9 R4 R3 Yield Cl!3 (%) 74 H 0 Ns)D!) $ CH3 CH3 PhCH2CNH- COOCII,CCe, 75 " " " CH3 e 96 76 U ,, H 3 t Example 77 The same procedure as in Example 41 was repeated with the exception of using 17 mg of benzenesulfinic acid in place of 20 mg of sodium benzenesulfinate as a catalyst, producing p-methoxybenzyl-2-(3-phenylacetamido-4-benzenesulfonylthio-2-azetidinon-I -yl)-3-methyl-3-betenoate in a yield of 87%. The NMR spectrum data of the compound thus obtained were identical with those of the compound produced in Example 41.

Example 78 The same procedure as in Example 41 was repeated with the exception of using 20 mg of benzothiazole thiol in place of 20 mg of sodium benzenesulfinate as a catalyst, producing p-methoxybenzyl-2-(3-phenylacetamido-4-benzenesu lfonylthio-2-azetidinon-1 -yl)-3-methyl-3-butenoate in a yield of 91%. The NMR spectrum data of the compound thus obtained were identical with those of the compound produced in Example 41.

TABLE 5

R1 R2 ))NSSO2R3 o NR4 R7 R2 R4 R3 NMR6CDCt > 8,J=Hz) 1.71(s,3H),3.54(s, 2H), 3.78(s, 3H), 4.45(s, 1 H), 4.69(s, 0 Cr1 1 H), 4.72(bs, 1 H), H || IH- 5.02(s, Ph lH),5.06(dd, PhCH2CNH- cooClf2 < 1 H, 5=4.0 and 6.5), S.70(d, I H, J=4.0), 5.90(d, 1 H, J =6.5), 6.82(d, 2H, J=7.0), 7.00-7.85(m, 12H) 1.78(s, 3H), 4.37 and 4.42(ABq, 2H, J=12.0), CFI2 4.55(s,1H),4.79(s, O || 1H),4.82(bs, lH), H Ii < CFIs Ph 5.14(s,2H),5.27(dd, PhOCH2CNH- 1 H, J=4.0 and 7.0), COOCFI2Ph 5.87(d, 1 H,J=4.0), 6.75-7.90(m,16H) 1.74(s, 3H), 2.40(s, 3H), 3.50(s, 2H), CFI2 3.71(s, 3H), 4.64(s, O 1 H), 4.70(s, 1 H), 4.89 H Ii wCFI3 /\ eCH3 (5, lH),5.05(dd, lH, PhCH2CNH- I J=5 and 8), 5.78(d, 1 H, COOT!3 J=5),6.52(d,H,J=8), 7.22(s, 5H), 7.30(d, 2H, J=9), 7.68(d, 2H, J=9) 1.79(s, 3H), 3.85(s, 9H), 4.35 and 4.41 CH, (ABq, 2H, 5=12.5), O Il 4.62(s,1H),4.80(s, H || I CT!3 OCFI3 Ph 1H), 4.84(bs, 1H), PhOCH2CNH- I -( 5.08(s, 2H), 5.26(dd.

COOCT!21 OCFI3 lH, 5=4 and 7), 5.84 t (d, 1 H, J--4), 6.54(s, 3 2H), 6.75-7.90(m, 11 H) 1.76(s, 3H), 3.77(s, 3H), 4.34 and 4.40 CH2 (ABq,2H,J=12), 4.53(s, 1 H), 4.76(s, Cut!3 1 Zit ,, lH), 4.79(bs, lH), 5.07(s, 5.07(s, 2H), 5.27(dd, COOT!2 SOCH3 1 H,J=4and6.5), 5.86(d,1H,J=4), 6.65-7.90(m 15H) TABLE 5 (continued)

Rf R2 R4 R3 NMR(CDCta,8,J=Hz) 1.76(s, 3H), 3.89(s, CH2 6H), 3.94(s, 3H), 4.36 and 4.41 (ABq, O tCFI3 2H,J=12),4.60(s, H CL OCT!3 Ph 1 H), Ph 4.78(bs, 1 H), PhOCH2CNH- COOT!2 / < OCEI 4.80(s, 1 H), 5.24(dd, 2 \ 1 H, 3 and 6.5), 5.38 OCN3 (s, 2H), 5.88(s, 2H), 6.75-7.90(m,llH) 1.85(s, 3H), 4.38 and CH 4.44 (ABq, 2H, J = 12), 2 4.90 (5, 1 H), 4.96(s, tCFI3 2H), 5.28 and 5.34 0 ,, (ABq,2H,J=12), ll < 5.35(dd,1H,J=4and COOCT!2C ~ Br 6.5), 5.85(d, lH,J=4), 6.75-7.95(m,15H) 1.82(s, 3H), 3.36(s, 3H), 3.40-3.65(m, 2H), CIT2 3.65-3.90 (m, 2H), 4.36 O CII and 4.41 (ABq, 2H, J=12), H ii { 3 Ph 4.69 (s, 1H), 4.79 (s PhOCH2CNH- COON OCH2CH2 1H),4.94(bs,1H),5.15 5.60 (m, 3H), 5.90 (d, lH, J=4), oCH3 6.75-8.00 (m, 11H) 1.85 (s,3H), 3.46 (s, 3H), 4.41 and 4.46 (ABq, 2H,J=12),4.71 (5, lH), 4.82 4.82(s, lH),4.95 (bs, lH), ,II CII, 5.10-5.40 (m, 3H), CIT3 5.91 (d,lH,J=4.7), COOCH2OCH3 6.80-8.00(m,1H) 1.78 (s, 3H), 4.39 and C!!2 4.44(ABq, 2H, J=12), 4.76(s, 1H), 4.85 (s, 1H), O \ < 4.88 (bs, 1H), H ti Ph 5.34(dd, lH,J=4.7 PhOCH2CNH- and 8.2), 5.87 (d, 1H, 6.80-7.90 (m, 19H) COOt 6.80-7.90(m,19H) 1.76 (s, 3H), 3.57 (s, 2H), 4.71 (s,1H), 4.82 (5, 1 H), 4.84(s, 1 H), O 5.16(dd,1H,J= 4.7 and 8.1), 5.76 (d, PhCH2CNH- n ,, ', 1H,J=4.7),6.50(d,1 H,J=8.1),6.74(s, 1 H), 7.05-7.90 (m, 18H) 1.78 (s, 3H), 3.56(s, 2H), 4.57 (s, 1H), 476 (s, 1 H), 4.88 (bs, 1 H), il 5.11(dd,1H,J=4and H II Y > CH3 Ph 7), 5.23 (5, 2H), 5.72 PhCH2CNH- (d, 1 H, J =4)6.06 (d, COOCIT2NO2 1 H, J=7), 7.00-8.00 (m, 12H),8.19 (d,2H,J=7) TABLE 5 (continued)

R7 R2 R4 RS NMR{CDCtab,J=Hz) t 1.78(s, 3H), 3.56 (s, CH2 2H), 4.60 (s, 1 H), t , , 4.76(s, 1 H), 4.87 (bs, Cut!3 Lah),5.12 (dd, lH,J= " D | 4 and 6.5), 5.53 (s,2 COOCH2 H), 5.64 (d, 1 H, J=4), - 6.20 (d, 1H,J=6.5), NO2 7.10-8.20 (m, 14H) 1.84 3H), 2.35 (s, 3H), 3.83 (s, 3H), 4.38 Il and 4A5 (ABq, 2H,J= O 9\ CH 11), 4.80-5.05 (m, 3 H [t | Ph H),S.38(dd, lH,J=4 PhOCH2CNH- COOCH- COUCH, and 7), 5.55(s, lah), 1 S.85(d,lH,J'=4.0), CO2 CT!3 6.75-8.00 (m, 11 H) 1.78 (s, 3H), 3.51 (bs, 2H), 3.70 (s, 3H), 4.61 CH2 (bs, 1 H), 4.76 (s, 1H), O 4.86 (bs, 1 H), 5.06 (dd, " ffi\Ct -CL 1H, 5=5 and 8). 5.83 PhCH2CNH- (d, 1 H, J=5), 7.14 (d, COOCH, 1H, 5=8), 7.23 (s, 5H), 7.43 (d, 2H, J'=8), 7.81 (d 2H, J=8) 1.80 (s, 3H), 3.52 (bs, 2H), 3.70 (s, 3H), 4.55 CH2 (bs, lH),4.79 (s, lah), H 11 > 4.87 (bs, 1 H), 5.03 (dd, H Ii > CH3 nN 2 1 H, 5=5 and 8), 5.87 PhCH2CNH- CT!3 2 H, J =5), 6.73 (d, COOT!3 1 H, J 7.22(s,5 H), 7.94 (d, 2H, J=9), 8.24 (d, J=9) 1.80 (s, 3H), 3.48 (bs, 2H),3.70 (s,3H), 4.64 (bs, 1 H), 4.80 (s, 1 1 H),4.88 (bs, 1 H), " ff " )=/ 5.13 (dd, 1H,J=5 and NO2 8)6.06 (d, 1 H, J =5), 6.88 (d, lH,J=8),7.17 (s, 5H), 7.60-8.20 (m, 4H) 1.75 (s, 3H), 3.50 (s, 2H), 4.76 (bs, 1 H), 4.84 (s, 1H), 4.92 (bs, - lH),5.10(dd, 1H,J= 0 II 2 n 5and8),5.12(s,2H), H Ir ci -NO, 5.92 (d, 1H,J=5), PhCH2CNH- 3 \=/ 6.91 (d,lH,J=8), PhCH2CNH COOCH2Ph 7.20 (s, 5H), 7.30 (s, 5H), 7.87 (d, 2H, J= 9),8.18 (d,2H,J=9) TABLE 5 (continued)

R1 R2 R4 R3 NMR(CDC56,J=Hzl 1.75 (s, 3H), 3.50 (s, 2H), 3.79 (s, 3H), 4.65 (bs, lah),4.77 (s, lah), 4.85 (bs, 1H), 5.12 (dd, nOCH3 1 H, J=5 and 8),5.13 - (s, 2H), 5.73 (d, lH, J=5), 6.63 (d, lH, J= 8), 6.87 (d, 2H, J=9), 7.20 (5, sH), 7.29 (s, 5H), 7.67 (d, 2H, J=9) 1.79 (s, 3H), 3.46 (s, 3H), 3.61 (s, 2H), CH2 4.57 (s, 1 H), (s, 1 1 H), 4.88 (bs, 1 H), CH3O- PhCH2CNH- CH, C3 Ph 5.23 (s, 2H), 5.29 (s, jl 1 < 1 6.00 (bs, 1H) O COOCT!2/CNO2 7.10-7.90 (m, 12H), 8.17 (d, 2H,J=9) CH 1.91(s, 3H), 2.15(s, 3H), O 3 3.60 (s, 2H), 4.60-4.80 (m, Ir /\ , 3H), 5.83 (d, lH, J=SHz), H CIT '3 7.20 (m, 8H), 7.66 (d, 2H, J= 9Hz) PhCH2CNH- 3 3 CooCfl2CCe3 1.90 (s,3H),2.13 (s,3H), 3.50 (s,2H),3.75 (s, 3H), 4.60-4.80 (m, 3H), 5.85 (d, " " tB CH 1H,J=4.SHz),6.84(d,2H, 3 \=/ J=7Hz),7.20 (m, 6H), 7.77 (d, 2H, J=7Hz) 2.50 (s, 3H), 3.63 (s, 2H), H ff H CH3 4 5.20-5.50 (m, 2H), 7.20 3 7.80(m,11H)

Claims

1. A process for preparing an azetidinone derivative represented by the formula

wherein R1 is hydrogen, halogen, or lower alkoxy, R2 is hydrogen, halogen, lower alkoxy, amino or a group

(in which R5 is substituted or unsubstituted phenyl, substituted or unsubstituted phenylmethyl, substituted or unsubstituted phenoxymethyl, or substituted or unsubstituted benzoyl), or R1 and R2, when taken together,, are carbon, R3 is substituted or unsubstituted phenyl, and R4 is hydrogen, optionally substituted hydrocarbon residue or acyl, silyl, sulfonyl or phosphonyl derived from inorganic acid or organic acid, the process comprising reacting a dithioazetidinone derivative represented by the formula

wherein R1, R2 and R4 are as defined above and R9 is substituted or unsubstituted, nitro-containing aromatic heterocyclic residue with a compound represented by the formula R3SO2R10 (Vll) wherein R3 Is as defined above and R10 is hydrogen, a group -CN or a group SR9 (in which R9 is as defined above).

2. A process as defined in claim 1 in which R1 in the dithioazetidinone derivative of the formula (VI) is hydrogen, F, Cl, Br, I or C1-C4 alkoxy, R2 is hydrogen, F, Cl, Br, I, C1-C4 alkoxy, amino or a group

(in which R5 is phenyl, phenyl having 1 to 3 substituents, e.g., C1-C4 alkyl, F, CI, Br, I, C1-C4 alkoxy or nitro on the phenyl ring, phenylmethyl, phenylmethyl having 1 to 3 substituents, e.g., C1-C4 alkyl, F, Cl, Br, I, C1-C4 alkoxy or nitro on the phenyl ring, phenylmethyl having methylene substituted with halogen, hydroxy, hydroxyimino, C1-C4 alkoxyimino or amino, phenoxymethyl, phenoxymethyl having 1 to 3 substituents, e.g., C1C4 alkyl, F, CI, Br, I, C1-C4 alkoxy or nitro on the phenyl ring, benzoyI, or benzoyl having 1 to 3 substituents, e.g., C1-C4 alkyl, F, CI, Br, I, Ca-C4 alkoxy or nitro on the phenyl ring), or R1 and R2 are carbonyl when taken together, R4 iS hydrogen, or one of the following groups

(in which R6 is hydrogen or carboxy protecting group, and Z1 and Z2 are the same or different and represent halogen, sulfur-containing group, oxygen-containing group or nitrogen-containing group), and R9 is said heterocyclic residue selected from the class consisting of thiazol-2-yl, thiadiazol-2-yl, benzothiazol-2-yI, benzoxazol-2-yl, benzimidazol-2-yl, pyrimidin-2-yl and 2-pyridyl, or said heterocyclic residue having 1 to 3 substituents, e.g., C1-C4 alkyl, phenyl, C1-C4 alkoxy, nitro or halogen.

3. A process âs defined in claim 1 in which R3 in the compound of the formula (VII) is phenyl or phenyl having 1 to 3 substituents, e.g., C7-C4 alkyl, F, Cl, Br, I, C1-C4 alkoxy or nitro on the phenyl ring.

4. A process as defined in any one of claims 1 to 3 in which R10 in the compound of the formula (VII) is hydrogen.

5. A process as defined in any one of claims 1 to 3 in which R10 in the compound of the formula (VII) is a group -CN.

6. A process as defined in any one of claims 1 to 3 in which RIO in the compound of the formula (VII) is -SR9 (wherein R9 is as defined above).

7. A process as defined in any one of claims 1 to 6 in which about 1 to about 5 moles of the compound of the formula (VII) is used per mole of the compound of formula (Vl).

8. A process as defined in claim 5 or 6 in which the reaction system contains as a catalyst at least one compound selected from a sulfinic acid represented by the formula R3So2H (Vlla) (wherein R3 is as defined above) or a salt thereof, a thiol represented by the formula RsSH (veil) (wherein R9 is as defined above) or a salt thereof and a nucleophilic compounds capable of producing R3 SOz (wherein R3 is as defined above) when reacted with the compound of the formula (Vllb) or (Vllc).

9. A process as defined in claim 8 in which a catalyst is used in an amount of about 0.0001 to about 0.1 mole per mole of the compound of the formula (VI).

10. A process as defined in any one of claims 1 to 9 in which the reaction is conducted at a temperature ranging from -20 C to the temperature at which the solvent used is refluxed.