FR2555578A1 - PROCESS FOR THE PREPARATION OF AZETIDINONE DERIVATIVES - Google Patents

Abstract

PROCESS FOR THE PREPARATION OF AZETIDINONE DERIVATIVES OF FORMULA: (CF DRAWING IN BOPI) WHERE R IS HYDROGEN, HALOGEN OR LOWER ALCOXY, R IS HYDROGEN, HALOGEN, LOWER ALCOXY, L ' AMINO OR AN NHCR GROUP (OR R IS PHENYL,

Description

2 5S78

  The present invention refers to a process for the preparation of

azetidinone derivatives.

  These derivatives prepared according to the method of the present invention correspond to the formula EtR1

R2 SSO R 3

O 4

  wherein R is hydrogen, halogen or lower alkoxy, R is hydrogen, halogen, lower alkoxy, amino or NHCR (where R is substituted or unsubstituted phenyl, IIO of substituted or unsubstituted phenylmethyl, substituted phenoxymethyl

  substituted or unsubstituted benzoyl), or R and R

  appears to be a carbonyl group, R is substituted or unsubstituted phenyl

  stituted and R is hydrogen, an optionally substituted hydrocarbon residue, or acyl, silyl, sulfonyl or phosphonyl derivative

a mineral or organic acid.

  The azetidinone derivatives of formula (I) are useful as intermediate stages for the synthesis of antibiotics of the type

  lactam and can be developed into a variety of antibiotic β-lactams.

  according to the choice of substituents. For example, a derivative of azene

  tidinone of formula (I) wherein R is the group COOR6 (where R is hydrogen or a protecting group for carboxyl),

  can be converted into a cephalosporin of formula (III) according to a

  assigned by Tetrahedron Letters, 23, 2187 (1982), represented by

the following equation.

O -2 - - N o COOR6 o COOR COOR6

(III)

  An azetidonone derivative of the formula (I) where R is hydrogen

  hydrogen, ethanol, sulphonyl or phosphonyl can be converted into

  different 1-lactams monocyclic antibiotics.

  Conventional methods for the preparation of derivatives

  Examples of azetidinone compounds of the formula (I) have been described, for example, in

  Japanese Patent Publication No. 129. 590/1975. This process comprises as indicated below in the equation of the reaction, the reaction of an azetidinone derivative of formula (IV) with a metal salt

  heavy sulfinic acid of formula (V) to obtain an azetidine derivative

  none of formula (Ib) 2 'R1 Mn + (- SO-R3) 2 R1 R2 SR7 2. n R2 SSO2R3

(V) 2

COOR6 COOR6

  (IV) b) (IV) (Ib) z55575 S-5? In the above reaction equation, R and R6 are as defined above, R1 is hydrogen, R2 is amino, or

  a group -NHR (where R is the acyl group), R is a heterocyclic group;

  aromatic clique, an aliphatic thio-acyl group, a thio-

  aromatic acyl, an aromatic aliphatic thio acyl group or an alicyclic thio acyl group, M is a heavy metal such as copper, silver, mercury, tin or the like and n is the valence of the heavy metal. However, the above process, carried out on an industrial scale,

  has the disadvantage of involving a heavy metal salt of sulfinic acid.

  that of formula (V) harmful or high price.

  The present invention is intended in particular to provide an economically advantageous process for the preparation of azetidinone derivatives of formula (I). Another object of the invention is to provide a process for the preparation of azetidinone derivatives of formula (I) without using a heavy metal salt of sulphinic acid which is harmful or of a high price. The object of the invention is also to provide a process for the preparation of azetidinone derivatives of formula (I) of high purity and

  with high efficiency in a simple process.

  These and other features of the present invention

  will be described in more detail in the following description.

  According to the present invention azetidinone derivatives of

  (I) can be prepared by reacting a dithio derivative

azetidinone of formula

R1

R SSR

(VI)

(+ R4

1 2 4 9

  in which R, R and R have the meaning given above and R is a heterocyclic aromatic residue containing nitro, substituted or unsubstituted, of formula

R SO R 0 (VII)

-4-

  o R has the meaning given above, R10 is hydrogen, a group

  pe -CN or a group -SR9 (o R9 has the meaning given above).

  Examples of halogen atoms represented by R in

  formulas (I) and (VI) are fluorine, bromine, chlorine, iodine and the like.

  lar. Examples of lower alkoxy groups represented by R are those having from 1 to 4 carbon atoms such as methoxy, ethoxy,

  propoxy, isopropoxy, butoxy, tert.-butoxy, etc.

  Examples of halogen atoms represented by R in

  formulas (I) and (VI) are fluorine, chlorine, bromine, iodine and the like.

  lar. Examples of lower alkoxy groups represented by R 2 include those having 1 to 4 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, butoxy and tert-butoxy, etc.

  examples of substituted phenyl groups represented by R are the phenol

  nyl substituted with 1 to 3 C 1 -C 4 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-dichlorophenyl

  dibromophenyl; phenyl substituted with 1 to 3 C1-C4 alkoxy groups

  such as 4-methoxyphenyl, 2,4-dimethoxyphenyl and 3,4,5-trimethylamine.

  thoxyphényle; phenyl substituted with 1 to 3 nitro groups such as 4-

  nitrophenyl and Z, 4-dinitrophenyl; etc. Examples of groups

  substituted phenylmethyl represented by R are substituted phenylmethyl

  killed by 1 to 3 C1-C4 alkyl groups on the phenyl ring such as tolyl-

  méthyrle; phenylmethyl substituted with 1 to 3 halogen atoms on the

  phenyl ring such as 4-chlorophenylmethyl, 2,4-dichlorophenyl-

  methyl, 2,4,6-trichlorophenylmethyl, 4-bromophenylmethyl and

  2,4-dibromophenylmethyl; phenylmethyl substituted with 1 to 3 groups

  C1-C4 alkoxy on the phenyl ring such as 4-methoxyphenylmethyl, 2,4-dimethoxyphenylmethyl and 3,4,5-trimethoxyphenylmethyl; phenylmethyl substituted with 1 to 3 nitro groups on the phenyl ring

  such as 4-nitrophenylmethyl and 2,4-dinitrophenylmethyl; phenyl

  methyl bearing methylene substituted with halogen, hydroxyl, hydroxy-imino, C 1 -C 4 alkoxy-imino, amino or the like

  such as phenyldichloromethyl, phenylhydroxymethyl, phenyl

-5 -

  hydroxy-iminomethyl, phenylmethoxy-iminomethyl, phenylamino-

  methyl and phenylacetoxymethyl; etc. Examples of substituted phenoxymethyl groups represented by R are phenoxymethyl substituted with 1 to 3 C 1 -C 4 alkyl groups on the phenyl ring, such as tolyloxymethyl; phenoxymethyl substituted with 1 to 3 halogen atoms

  gene on the phenyl ring such as 4-chlorophenoxymethyl, Z, 4-

  dichlorophenoxymethyl, 2,4,6-trichlorophenoxymethyl, 4-bromo-

  phenoxymethyl and 2,4-dibromophenoxymethyl; phenoxymethyl substituted with 1 to 3 C 1 -C 4 alkoxy groups on the phenyl ring as

  4-methoxyphenoxymethyl, 2,4-dimethoxyphenoxymethyl and 3,4,5-dimethylphenoxymethyl

  triméthoxyphénoxyméthyle; phenoxymethyl substituted with 1 to 3 groups

  nitro on the phenyl ring such as 4-nitrophenoxymethyl and 2,4-di-

  nitrophenoxymethyl, etc. Examples of substituted benzoyl groups represented by R are benzoyl substituted with 1 to 3 C 1 -C 4 alkyl groups on the phenyl ring such as toluoyl; substituted benzoyl

  by 1 to 3 halogen atoms on the phenyl ring such as 4-chlorobenzene

  zoyl, 2,4-dichlorobenzoyl, 2,4,6-trichlorobenzoyl, 4-bromo-

  benzoyl 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 as 4-nitro-

  benzoyl and 2,4-dinitrobenzoyl; etc ..

  Examples of substituted phenyl represented by R 3 in formulas (I) and (VII) are phenyl substituted with 1 to 3 C 1 -C 4 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-methoxy-

  phenyl, 2,4-dimethoxyphenyl and 4,4,5-trimethoxyphenyl; phenyl substituted with 1 to 3 nitro groups such as 4-nitrophenyl and

2,4-dinitrophenyl; etc ..

  The groups represented by R in formulas (I) and -6- (VI) are hydrogen, acyl, silyl, sulphonyl and phosphonyl derived from mineral or organic acids, and an optionally substituted hydrocarbon residue. Among these groups, the optionally substituted hydrocarbon residue is preferential. Examples of substituted hydrocarbon residues are the groups

Z Z2 Z2

COOR COOR and R

  o R is hydrogen or a protecting group for carboxyl.

  The wide variety of carboxyl protecting groups as described in the book by Theodora W. Greene: Protective Groups in Organic

  Synthesis ", chapter 5 can be used according to the present invention.

  Typical examples of these groups are phenyl-C 1 -C 4 alkyl

  optionally 1 to 3 substituents, for example C1-C4 alkoxy, halogen

  gene, methylenedioxy, C1-C4 alkyl or nitro on the phenyl ring

  such as benzyl, p-methoxybenzyl, trimethoxybenzyl, tri-

  methoxydichlorobenzyl, piperonyl, diphenylmethyl, bis (p-

  methoxyphenyl) methyl, ditolylmethyl, phenyl-p-methoxyphenyl-

  methyl, o (-p-methoxyphenylmethyl, trityl, o (-diphenylethyl,

  p-nitrobenzyl, o-nitrobenzyl and o, p-dinitrobenzyl; C1- alkyl

  C4 bearing at least one substituent selected from halogen, phenyl

  substituted with 1 to 3 C1-C4 alkoxy groups, benzoyl, benzoyl sub-

  with 1 to 3 halogen atoms on the phenyl ring, C1-C4 alkoxy, C1-C4 alkoxy substituted with 1 to 3 C 1 -C 4 alkoxy groups, benzyloxy, C1-C4 alkanoyl and 1-C4 alkoxy; C1-C4 alkoxycarbonyl, such as tert. butyl, trichloroethyl, 1-p-melocyphenyl-β-trichloroethyl, phenacyl,

  p-bromophenacyl, methoxymethyl, isopropoxymethyl, methyl

  thoxyethoxymethyl, benzyloxymethyl and 1-methoxycarbonyl-Z-

  oxopropyl; cumyl, fluorenyl; etc. Z1 and Z are the same or different and are each hydrogen, halogen, a group

  containing sulfur, a group containing oxygen, a group containing

  nitrogen or the like. Examples of represented substituents

L.1J ', VF ^

  By Z and Z are halogens such as bromine, chlorine and fluorine of sulfur-containing groups, for example C1-C4-thioalkyl such as methylthio and ethylthio, phenylthio optionally substituted by 1 to 5 nitro groups or halogen atoms on the phenyl ring such as phenylthio, p-nitrophenylthio and pentachlorophenylthio, 2-pyridyl-

  thio, 2-benzothiadiazolylthio, 1,3,4-thiadiazol-5-ylthio, 2-sub-

  1, 3, 4-thiadiazol-5-ylthio, 1, Z, 3,4-tetrazol-5-ylthio, the 1-sub-

  1, 2,3,4-tetrazol-5-ylthio, O-ethyldithiocarbonate, N, N-diethyl

  thyldithiocarbamate, phenylsulfonyl and p-methylsulfonyl; groups containing oxygen for example hydroxyl, C1-C4 alkoxy such as methoxy and ethoxy, acyl C1-C4-oxy such as acetoxy,

  benzoyloxy, nitrosoxy, nitriloxy, diphenylphosphonyloxy, methyl

  thanesulfonate, N-morphonyl and diphenylmethyloxy; groups

  containing nitrogen, for example di (C1-C4 alkyl) amino such as dimeric

  thylamino and piperidin-1-yl; etc ..

  Examples of the aromatic heteroaromatic hydrocarbon residue

  cyclic ring containing nitrogen, substituted or unsubstituted represented

  R9 in formula (VI) are those having optionally 1 to 3

  for example, C1-C4 alkyl, phenyl, C1-C4 alkoxy, nitro or halogen such as thiazol-2-yl, 4-methylthiazol-2-yl, methylmethyl-2-yl, yl, 4-phenylthiazol-2-yl, 5-phenylthiazole-

  2-yl, thiadiazol-2-yl, 5-methylthiadiazol-2-yl, 5-phenylthiadia;

  zole-2-yl, 5-methoxycarbonylthliadiazol-2-yl, benzothiazole-2-

  4-methylbenzothiazol-2-yl, yl, 6-methylbenzothiazol-2-yl, 5-methoxybenzothiazol-2-yl,

  6-nitrobenzothiazol-2-yl, 5-chlorobenzothiazol-2-yl, benzoate

  xazol-2-yl, 4-methylbenzoxazol-2-yl, 6-phenylbenzoxazole-2-

  yl, 5-methoxybenzoxazole-2-yl, 5-chlorobenzoxazol-2-yl,

  benzimidazol-2-yl, 5-methylbenzimidazol-2-yl, 6-chlorobenzo-

  imidazol-2-yl, pyrinmidin-2-yl, 5-methylpyrimidine-2-yl and

2-pyridyl, etc.

  The dithioazetidinone derivatives of formula (VI) used as one of the starting materials in the present invention are known

  and can be obtained by synthesis according to various methods. Professionals-

  Assayed synthetic drugs using penicillin have been described, for example, in Tetrahedron Letters, 3001 (1973), J. Amer. Chern. Soc., 86, 5307 (1964): Japanese Patent Application Laid-open No. 14665/1981; Japanese patent applications published under the numbers 29587/1982, 59896/1982, 183793/1982 and 183794/1982; and the Collection of Research Reports prepared for the 9th International Convention on the Heterocycle, page 300 (1983). The derivatives of formula (VI) can also be obtained by a combination of the methods described in these publications. These known methods are shown for example in the

diagram of reactions below.

t o R9SH

R2S 9 9 R 'SSR9

R2 aa / \ 4 or R9SSR9 R

  COOR6 ONR4

  Substitution ((VI) by chlorination 9

P (OCH3) 3 R SSR

5 R9SSR9IH30 + 5

R1 S N S

  (1) Triethylamine (2) Oxidation R NH 0 Y 6 electrolytic 0

COOR

1 2 4 5 6 9

  In the diagram above, R ,, R R R and R

  have the meaning given above.

  However, the dithioazetidinone derivatives of formula (VI) as used in the present invention are not limited to those

  can obtain according to these methods. An extensive range of dithio derivatives

  azetidinone of formula (VI) obtained by various methods including processes other than those indicated above may be used as

  starting material in the present invention.

  The compounds of formula (VII), i.e. the other starting material used according to the present invention, are also known. More specifically, the compounds of formula (VII) can be divided

  compounds of formulas (VIIa), (VIIb) and (VIIc), as indicated below.

  R 3 SO 2 H (VIIa) R SO CN (VIIb) R 3 SO SR 9 (VIIc) z

  oh R3 and R9 have the meaning given above.

  The compounds of formula (VIIb) can be formed by

  thesis, for example according to the method set forth in Tetrahedron Letter, 3351 (1969) or can be obtained in the reaction system of the present invention using the corresponding sulfonyl halide

and an alkaline cyanide.

  The compound of formula (VIIc) can be obtained by synthesis, for example according to the process described in US Pat. No. 3,788,063, expressed by the following equation: ## STR3 ## R9SS 9R9-2R9SCI2R3SO SR9 (VIIc)

2

  In this equation R and R9 have the sigzification given below.

  above. According to the present invention the dithioazetidinone derivative of formula (VI) is reacted with compound of Formula (VII), usually in a suitable solvent. The examples of solvents that can be used according to the present invention are very numerous.

- 10 -

  suffice that the solvent is capable of dissolving the compound of formula

  (VI) and that of formula (MI). Since these compounds do not have to

  thoroughly dissolved according to the present invention, even

  solvents dissolving these compounds only partially can be used.

  ployees. Possible solvents include organic solvents used alone or in combination with water. Examples of suitable organic solvents are ketones such as acetone, methyl ethyl ketone, diethyl ketone and methyl isobutyl ketone; esters as formates

  and acetates of methyl, ethyl and propyl, propionates of

  ethyl and ethyl; aromatic hydrocarbons such as benzene,

  toluene and xylene; halogenated hydrocarbons such as dichloromethane

  thane, dibromomethane, chloroform, bromoform, tetrachloro-

  carbon dioxide, dichloroethane, dibromoethane, and trichloro-

  ethane; ethers such as diethyl ether, dipropyl ether, dibutyl

  ether, tetrahydrofuran and dioxane; nitro alkanes such as

  nitromethane, nitroethane and nitropropane; nitriles like the

  cetonitrile, propionitrile, butyronitrile and valeronitrile; Sal-

  such as methanol, ethanol, propanol, isopropanol and butanol

  nol; etc. These organic solvents can be used alone or in

  at least two of these. The amount of solvent is usually

  between about 1 and about 400 times, preferably between about 1 and about 100 times, more preferably between about 1 and about 50 times

  the amount of the compound of formula (VI).

  The ratios between the compounds of formulas (VI) and (VII) used in the present invention are not especially limited and may be selected from widely separated limits. Usually from about 1 to about 5 moles of formula (VII) per mole of compound of formula (VI). It is appropriate to use as compound (VII),

  between about 1 and about 2 moles, preferably between about 1 and about

  1.5 moles of the compound of formula (VIIa), from about 1 to about 2 moles of the compound of formula (VIIb) or from about 1 to about 1.2 moles of the compound of formula (VIIc), all for 1 mole of composed of

formula (VI).

  The reaction according to the present invention can usually

  be carried out at a temperature between about -20 C and the temperature

  the temperature at which the solvent used boils at reflux. The preferred reaction temperature is from 0 to about 50 ° C using the compound (VIIa), from about 20 ° C to the reflux temperature of the solvent used for the compound (VIIc) and the compound (VII). The duration of the reaction according to the present invention varies depending on the reaction temperature, the types of compounds (VI) and (VII) and other conditions, but usually it is between about 0.1 and about 15

hours.

  In the case where the compound of formula (VIIa) is used as the compound of formula (VII), the reaction system does not need a catalyst. In the case where it is the compound (VIIb) or (VIIc) which is

  used as compound (VII) in the present invention, it is preferable

  to incorporate in the reaction system at least one type of catalytic

  lyseur chosen from a sulphinic acid of formula R SO H (VIIa) wherein Rt3 has the meaning given above or a salt thereof, a thiol of formula

R 9SH (VIII)

  o R9 has the meaning given above or one of its salts, and a compound

  nucleophile capable of giving R3SO water during its reaction.

  with the compound (VIIb) or (VIIc). The presence of the preceding catalyst

  dent in the reaction system results in producing the compound

  sought (I) with greater purity and higher yields.

  Examples of substituted or unsubstituted phenyl represent

  R3 in sulfinic acid (VIIa) are the same as those given by way of example above. Examples of the sulfinic acid (VIIa) as used above are benzenesulfinic acids,

  tolyl sulfinic, xylyl sulfinic, 4-chlorophenylsulfinic, 2,4dichloro

  phenylsulfinic, 2,4,6-trichlorophenylsulfinic, 4-bromophenylsulfinic

  2,4-dibromophenylsulfinic, 4-methoxyphenylsulfinic, 2,4-di-

2555 78

-12-

  methoxyphenylsulfinic, 3,4,5-trimethoxyphenylsulfinic, 4-nitrophened

  Examples of the sulfinic acid salt (VIIa) as used above are alkali metal salts such as lithium, sodium, potassium, and lerubidium, and the like. alkaline earth metal salts such as magnesium, calcium, strontium, and barium; ammonium salts, such as ammonium, tetra (C1-C4 alkyl) ammonium, for example tetramethylammonium,

  tetra-ethylammonium and trimethyl-ethylammonium, the pyridine salt

  dium, etc. Among these salts, an alkaline salt is preferably chosen. Preferred examples of alkaline salts are sodium benzenesulfinate,

  potassium benzenesulfinate, lithium benzenesulfinate, benzene

  rubidium zènesulfinate, sodium tolylsulfinate, potassium tolylsulfinate, sodium xylylsulfinate, 4-chlorophenylsulfinate

  sodium, potassium 4-chlorophenylsulfinate, 2,4-dichlorophenyl-

  sodium sulfinate, sodium 2,4,6-trichlorophenylsulfinate, 4-

  sodium bromophenyl sulfinate, sodium 2,4-dibromophenyl sulfinate, sodium 4-methoxyphenyl sulfinate, 4-methoxyphenyl sulfinate,

  potassium, sodium 2,4-dimethoxyphenylsulfinate, 3,4,5-trimethyl

  sodium thoxyphenylsulfinate, sodium 4-nitrophenylsulfinate, potassium 4nitrophenylsulfinate, 2,4-dinitrophenylsulfinate,

  sodium, 2,4-dinitrophenylsulfinate potassium, etc.

  Examples of the heterocyclic aromatic residue include

  nitro, substituted or unsubstituted, represented by R9 in the

  thiol (VIII) are the same as those given by way of examples above.

  Examples of the thiol (VIII) as used above are 2-thiazole-

  thiol, 2- (4-methyl) thiazolethiol, 2- (5-methyl) thiazolethiol,

  2- (4-phenyl) thiazolethiol, 2- (5-phenyl) thiazolethiol, 2-thiadiazole,

  thiol, 2- (5-methyl) thiadiazole-thiol, 2- (5-phenyl) thiadiazole-thiol, 2- (5-methoxycarbonyl) thiadiazole-thiol, 2-benzothiazole-thiol, 2- methyl benzothiazolethiol, 2- (6-methyl) benzothiazolethiol, 2- (5-methoxy) benzothiazolethiol, 2- (4-nitro) benzothiazolethiol,

  2- (6-nitro) benzothiazolethiol, Z- (5-chloro) benzothiazolethiol, 2-

  benzoxazole-thiol, 2- (4-methyl) benzoxazole-thiol, 2- (6-phenyl) -

  benzoxazole-thiol, 2- (5-methoxy) benzoxazole-thiol, 2- (5-chloro) -

  benzoxazole-thiol, Z-benzimidazole-thiol, Z- (6-methyl) benzimidazole

  zole-thiol, 2- (6-chloro) benzimidazole-thiol, 2-pyrimidine-thiol, 2- (5-methyl) pyrimidine-thiol, 2-pyridyl-thiol, etc. Examples of the thiol salt ( VIII) as used above,

  are the alkali metal salts such as lithium, sodium, potassium

  sium and rubidium, alkaline earth metal salts such as

  gnesium, calcium, strontium and barium, ammonium salts, such as ammonium, tetra (C1-C4 alkyl) ammonium, for example tetramethylamminonium, tetraethylammonium, pyridinium salt,

Among these salts, an alkaline salt is preferably chosen. Examples

  Preferred alkali metal salts are sodium thiazolethiolate,

  sodium 2- (4-methyl) thiazolethiolate, 2- (5-methyl) thiazole-

  sodium thiolate, sodium 2- (4-phenyl) thiazole thiolate, 2- (5-

  sodium phenyl) thiazole thiolate, sodium 2-thiadiazole thiolate,

  sodium 2- (5-methyl) thiadiazole thiolate, 2- (5-phenyl) thiadiazole;

  sodium thiolate, 2- (5-methoxycarbonyl) thiadiazole thiolate

  sodium 2-benzothiazolethiolate, 2- (6-methyl) benzoate

  sodium thiazole thiolate, 2- (5-methoxy) benzothiazole thiolate

  sodium, sodium 2- (4-nitro) benzothiazolethiolate, 2- (6-nitro) -

  sodium benzothiazole thiolate, 2- (5-chloro) benzothiazole thiolate

  sodium 2-benzoxazole-thiolate, 2- (4-methyl) benzoate

  sodium xazole thiolate, sodium 2- (6-phenyl) benzoxazole thiolate,

  sodium 2- (5-methoxy) benzoxazole thiolate, 2- (5-chloro) benzoate

  Sodium xazole-thiolate 2-benzoimidazole-sodium thiolate, the

  Sodium 2- (6-methyl) benzimidazole thiolate, 2- (6-chloro) benzimidine

  sodium azole thiolate, 2-pyrimidine sodium thiolate, 2-

  Sodium (5-methyl) pyrimidine thiolate, 2-pyridyl thiolate

  dium, potassium 2-benzothiazole thiolate, Z- (4-methyl) benzoate

  potassium thiazole thiolate, 2- (6-methyl) benzothiazole thiolate

  potassium, potassium 2- (6-nitro) benzothiazole thiolate, 2- (5-

  potassium methoxy) benzothiazole thiolate, 2- (5-methyl) thiadiazole

  potassium thiolate, lithium 2-benzothiazole thiolate, 2-

  rubidium benzothiazole thiolate, etc.

- 14-

  Examples of nucleophilic compounds that can be used

  are the water; alkali metal hydroxides such as lithium, sodium and potassium hydroxides; alcohols having 1 to 4 carbon atoms such as methanol, ethanol, propanol, isopropanol, butanol and their mineral or organic salts; phenols such as phenol

  cresol, p-methoxyphenol, p-nitrophenol and their inorganic salts

  organic or organic; thiols other than compounds (VIII) such as methanethiol, ethanethiol, propanethiol, thiophenol, thiocresol,

  p-nitrothiophenol and their mineral and organic salts; sulphate acids

  other than compounds (VIa) such as methanesulphonic

  neat, ethanesulfinic, propanesulfinic and their mineral and organic salts

  picnics; carboxylic acids such as acetic and propionic acids and their mineral and organic salts; etc. In the case where an alcohol having 1 to 4 carbon atoms is used as a solvent, a catalyst is not

  not necessary since the alcohol fulfills the function of a nu-

  cléophile. The reaction according to the present invention in the form of

  The reaction system comprising the catalyst indicated above is

  presented in the equation below.

R SSR9 R2 SSO R3

R2 R2 -... 2

NOT

0 SN - 4 0 RX

(VI) 3 9

R 33SO2e R9S (

R9SCN R3SO2CN

(IX) (VIIb) or or

309 93 9

R9SSR9 R3SO2SR (X) (VIIc) - 15 i 2 3 4 9 In the above equation, R, R2, R3 R and R have

the

meaning given above.

  In the case where at least one molecule of R SO G or R 9S is present in the reaction system, the catalytic reaction as represented above can occur between the compound (VI)

  and the compound (VIIb) or (VIIc), and leads to the compound (I).

  More specifically, when a sulfinic acid (VIIa) or a salt thereof is used as a catalyst, sulfinic acid (VIIa)

  or its salt is reacted with the compound (VI) to give a compound

  posed (I) and a thiol (VIII) or a salt thereof. The thiol (VIII) or its salt thus obtained is reacted with a compound (VIIb) or (VIIc), resulting in a compound (IX) or (X) respectively and recovering a sulfinic acid (VIIa) or a salt thereof . The compound (IX) or (X) is precipitated in the form of

  crystals because of its low solubility. The sulfinic acid (VIIa)

  or its salt is reacted with a compound (VI).

  In the case where a thiol (VIII) or its salt is used as a catalyst, the thiol (VIII) or its salt is reacted with a compound (VIIb) or (VIIc), giving a sulfinic acid (VIIa) or one of its salts, and a compound (ID or (X).) The compound (IX) or (X), having a low solubility, forms a deposit of crystals.The sulphinic acid (VIIa) or its salt is reacted with a compound (VI), giving a compound (I) and restoring a

thiol (VIII) or a salt thereof.

  In the case where a sulfinic acid (VIIa) or a salt thereof is used together with a thiol (VIII) or a salt thereof, the reactions

  previous events occur simultaneously.

  In the case where the catalyst is the nucleophilic compound

  mentioned above, the reaction proceeds in the same way as in the

  where the catalyst is sulfinic acid (VIIa) or its salt.

  Although the reaction can occur in a system containing only one molecule of catalyst, usually from about 0.0001 to about 0.1 mole, preferably from about 0.001 mole to about 0.1 mole.

  and about 0.05 moles of the catalyst per mole of compound (VI).

  After completion of the reaction, the azetidinone derivative (I) according to the present invention can be isolated from the reaction mixture at room temperature.

  using conventional methods such as filtration, centrifugation and

  The azetidinone derivative (I) thus obtained is essentially pure, but can easily be purified by rectification, distillation, extraction, etc.

  crystallization, by column chromatography or by

  if additional purification is required.

  According to the present invention, a desired compound (I) of high purity can be prepared in high yields without

  harmful or heavy-duty salts of heavy metals or sulfuric acid.

  finical, by performing simple operations. The present method

  Moreover, it has the following advantage. When a compound (VIIc) is used

  as the compound (VII), a compound (X) is formed as a secondary product.

  dary. But the compound (X) of high purity can be recovered in high yields by simple filtration and the recovered compound (X) is available as a starting material for the synthesis of the compound (VIIc)

  used as starting material according to the present invention.

  The invention will be described in more detail with the aid of the nonlimiting examples below, in which the symbol Ph denotes the group

phenyl.

o0 He Example 1

P I CH2 CNH

O + PhSO2H

COOCH2 _ <OCH,

O

PhCH2CNH O

SO2I + $ SH

c OOCH2-1 {% OCH.3

- 17 -

  1.0O g of 2- [3-phenylacetamido-4- (2-benzothiazolyldithio) -

  P-Methoxybenzyl 2-azetidin-1-yl-3-methyl-3-butenoate is

  under in 10 ml of acetone. To this solution is added 0, Z8 g of acid

  benzene-sulphinic acid and the mixture is reacted with stirring at

  room temperature for 4 hours. The acetone is distilled off under reduced pressure and the residue formed is purified by chromatography

  on a column of silica gel, giving 2- (3-phenylacetamido-4-benzene)

  sulfonylthio-2-azetidinone-1-yl) -3-methyl-3-butenoate

  zyle with a yield of 97%. The NMR spectrum of the compound thus obtained is identical to that of the desired compound. The NMR spectral data of the compound are shown in Table V.

Example 2

  2-3-Phenylacetamido-4- (2-benzothiazolyldithio) -Z-

  p-methoxybenzyl azetidinone-1-yl7-3-methyl-3-butenoate is reacted in the same manner as in Example 1 using the solvents

  listed in Table I below, giving 2- (3-phenylacetamido-4-

  benzenesulfonylthio-2-azetidinone-1-yl) -3-methyl-3-butenoate from p-

  methoxybenzyl with the yields reported in Table I below.

  The NMR spectral data of the compounds are identical to those of the

compound derived from Example 1.

Table I

  Solvent Yield (%) Acetone - water (20/1) 95 Acetonitrile 93 Tetrahydrofuran 98 Dioxanne 90 - 18-

Example 3

He PhCIJ2 CYXXi ss-neC ai P.'SO-H

0

C O CH2ó.VH

N O - He P; .CH CNHf

COOCH -1 \ -OCH3

o j -

  10 g of 2-phenylacetamido-4- (2,4-benzothiazolyldithio) -2-

  p-methoxybenzyl azetidinone - 1-yl-3-methyl-3-butenoate are dissolved

  in 100 ml of acetone. To this solution are added 2.8 g of benzene

  sulfinic and the mixture is reacted with stirring at room temperature.

  te for 4 hours. The reaction mixture is mixed with 0.91 g of

  30% aqueous solution of hydrogen peroxide and the reaction is carried out.

  The mixture is resuspended with stirring for one hour at room temperature.

  The precipitated 2-benzothiazolyl disulphide is filtered and the acetone is

  distilling the filtrate under reduced pressure. The residue is dissolved in benzene and the solution is washed several times with an aqueous solution of Na 2 S0 3 and with water and dried over anhydrous sodium sulfate. The benzene is distilled off under vacuum to give

  2- (3-phenylacetamrnido-4-benzenesulfonylthio-2-azetidinone-1-yl) -3-methyl-3-

  p-methoxybenzyl butenoate. The compound thus obtained is purified by recrystallization from benzene (yield 92% -). Spectral data

  NMR of the compound are identical to that of the compound obtained in Example 1.

-19-

Example 4

R1 RI

R2 _- SSR9 RS SSO02R3

[_R'SO H N,

0.vR4, "-S" -, v

  The compounds listed in Table II below are obtained

  naked by following the procedure of Example 1. The spectral data

  NMR of these compounds are identical to those of the compounds under consideration.

  The spectral data are shown in Table V.

Example 5

it N PhCH2CNH ss <+ PhSO2CN

N0

  COOCH 2-f -% OCH3 o i PhCH2CNH SSOZPh

> X. | T + N SCN

NES

COOCH2 \ - OCH3

  560 mg of 2- [3-phenylacetamido-4- (2-benzothiazolyldithio) -

  P-Methoxybenzyl 2-azetidin-1-yl] -3-methyl-3-butenoate and 302 mg of benzenesulfonyl cyanide are dissolved in 5 ml of acetone. At this

Table II

  R 'R2 R9 R4 3 Yield 0 Cil PhOCHa CN! I_. ## STR1 ## wherein: ## STR2 ## ## STR2 ## wherein ## STR2 ## wherein ## STR2 ## Table II (cont'd) R1 R2 R9] 3 Yield (': CH2Otltl Nu - TAJ CiH3 P h 94 PhOCH2 CNIIil2P cooc% {4oc: l Ctil S 0Cil ,, 90, COOCtl2 PHt CII3 dl1 c 3Il2J CC e 0 (1! Cil S $ vflS4CH, t CI3 "9 C0OCH12C (fJ $ éir t NU

Cooco-4 -

  Table II (continued) R1 R2 R9 R4 3 Yield C il

0 C13

C2

11P / JOCIIH3 '! 9 8

  C OOi * oc / G 's o () C} 129 "9 O1) t

NO *

N_ó) 2

  1 (/ 1-oo Table II (continued) R '> R2 R9 h1 43 Yield C (.Cil R3 2. 3 (C112

  IIPh () 'S12KNI-qSt (M.'il_ 1) h8i 1 ri ,.

1 '(2 (Z3_

  ## STR2 ## ## STR2 ## ## STR2 ## ## STR2 ## ## STR2 ## ## STR2 ## ## STR1 ## h 9 4 COOCil2-FO-NO2 e 1O 94 Cil 3. CIICtH

Vt ": 113 ', I, _" X) X-

COOC !! 2CC e3

1 C) 6 U

Uv. C! IOO u- 'IJI

- 25 -

  To the solution is added 0.5 ml of water and the mixture is reacted with heating for 1.5 hours by boiling the acetone under reflux. The acetone is distilled under reduced pressure and the residue is dissolved in 10 ml of benzene. The benzene solution is washed with water, dried over Na 2 SO 4 and concentrated under reduced pressure. The residue formed is purified by

  silica gel column chromatography, giving 2- (3-phenylacetate)

  p-Methoxybenzyl tamido-4-benzenesulfonylthio-2-a-zetidinone-1-yl) -3-methyl-3-butenoate in 95% yield. The NMR spectral data of the compound thus obtained are identical to those of the compound obtained

in example 1.

Example 6

  529 mg of 2- [3-phenylacetamido-4- (2-benzothiazolyldithio)]

  P-Methoxybenzyl 2-azetidin-1-yl] -3-methyl-3-butenoate and 157 mg

  benzenesulfonyl cyanide are dissolved in 5 mrl of ethyl acetate.

  0.5 ml of water is added to the solution and the mixture is reacted with heating.

  gh at 80 C for 1 hour. The reaction mixture is cooled to

  room temperature, washed with water, dried over Na 2 SO 4 and

  centered under reduced pressure. The residue is purified by chromatography

  on silica gel column, giving 2- (3-phenylacetamido-4-benzene)

  sulfonylthio-2-azetazinone-1-yl) -3-methyl-3-butenoate

  zyle with a yield of 88%. The NMR spectral data of the compound

  thus obtained are identical to those of the compound prepared in Example 1.

Example 7

  478 mg of 2- [3-phenylacetamido-4- (2-benzothiazolyldithio) -

  P-Methoxybenzyl 2-azetidin-1-yl] -7-methyl-3-butenoate and 155 mg

  of benzenesulphonyl cyanide are dissolved in 5 ml of chloroform.

  To the solution is added 0.25 ml of water and the mixture is reacted by heating for 1.5 h while boiling the chloroform under reflux. The reaction mixture is cooled to room temperature, washed with water, dried over Na2SO4 and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel, giving the

- 26 -

  Z - (3-phenylacetamido-4-benzenesulfonylthi) -2-azetidinone-1-yl-3-butene

  p-methoxybenzyl noate with a yield of 89%. The data

  NMR spectra of the compound thus obtained are identical to those of the

posed obtained in Example 1.

Example 8

  542 mg of 2-3-phenylacetamido-4- (2-benzothiazolyldithio) -

  P-methoxybenzyl 2-azetidin-1-yl] -3-methyl-3-butenoate and 176 mg of benzenesulfonyl cyanide are dissolved in 5 ml of acetonitrile. To this solution is added 0.25 ml of water and the mixture is reacted by heating at 67 ° C. for 1.5 hours. The acetonitrile is distilled off under reduced pressure and the residue is dissolved in 10 ml of benzene. The solution in benzene is washed with water, dried over Na 2 SO 4

  and concentrated under reduced pressure. The residue is purified by chromrnato

  silica gel column, giving 2- (3-phenylacetamido) -4-

  benzenesulfonylthio-2-azetidin-1-yl) -3-methyl-3-butenoate from p-

  thoxybenzyl with a yield of 93%. The NMR spectral data of the compound thus obtained are identical to those of the compound obtained in

Example 1

Example 9

  290 mg of 2-Z3-phenylacetamido-4- (2-benzothiazolyldithio) -

  P-methoxybenzyl 2-azetidin-1-yl] -3-methyl-3-butenoate and 94 mg of benzenesulfonyl cyanide are dissolved in 3 ml of acetone. To this solution are added 3 mg of sodium benzenesulfinate and the mixture is reacted at room temperature for 2 hours. The acetone is distilled off under reduced pressure and the residue is purified by

  silica gel column chromatography, giving 2- (3-phenyl)

  acetamido-4-benzenesulfonylthio-2-azetidinone-1-yl) -3-methyl-3-butene

  p-methoxybenzyl noate with a yield of 96%. The NMR spectral data of the compound thus obtained are identical to those of the

compound obtained in Example 1.

2S 55578

- 27 -

Example 10

  345 mg of 2- <3-phenylacetamido-4- (2-benzothiazolyidine)

  p-methoxybenzylthio) -2-azetidin-1-yl-3-methyl-3-butenoate and

  112 mg of benzenesulphonyl cyanide are dissolved in 3.5 ml of

  tone. To this solution is added 5 mg of benzenesulfinic acid and the mixture is reacted by heating for 8 hours by boiling the acetone under reflux. The acetone is distilled off under reduced pressure and the residue is purified by gel column chromatography.

  of silica, giving 2- (3-phenylacetamido-4-benzenesulfonylthio) -2-

  p-methoxybenzyl azetidin-1-y-3-methyl-3-butenoate in 86% yield. The spectral data of the compound thus obtained

  are identical to those of the compound obtained in Example 1.

Example 1 1

  343 mg of 2- [3-phenylacetamido-4- (2-benzothiazolyidine)

  p-methoxybenzylthio) -2-azetidin-1-yl] 3-methyl-3-butenoate and

  111 mg of benzenesulphonyl cyanide are dissolved in 3.5 ml of

  ethyl acetate. To this solution are added 5 mg of 2-mercaptobenzo

  thiazole and the mixture is reacted by heating for 8 hours by boiling the ethyl acetate under reflux. Ethyl acetate is discarded

  by distillation under reduced pressure and the residue is purified by chromatography

  silica gel columnography giving 2- (3-phenylacetamido)

  4-Benzenesulfonylthio -2-azetidinone-1-yl) -3-methyl-3-butenoate from p-

  methoxybenzyl with a yield of 80%. The NMR spectral data of the compound thus obtained are identical to those of the

Example 1

Example 12

  400 mg of 2-3-phenylacetamido-4- (2-benzothiazolyidine)

  p-methoxybenzyl thio) -2-azetidin-1-yl, -3-methyl-3-butenoate and

  mg of benzenesulfonyl cyanide are dissolved in 4 ml of tetra-

  hydrofuranne. To this solution are added 3 mg of sodium hydroxide

  and the mixture is reacted at room temperature for 2 hours.

  The tetrahydrofuran is distilled off under reduced pressure and the residue is dissolved in 10 ml of benzene. The benzene solution is

- 28 -

  washed with water, dried over Na 2 SO 4 and concentrated under reduced pressure. The residue is purified by gel column chromatography.

  silica, giving 2 - (3-phenylacetamido-4-benzenesulfonylthio-2 azetidin

  p-m ethoxybenzyl 3-methyl-3-butenoate) in 91% yield. The NMR spectral data of the compound thus obtained are identical.

  to those of the compound of Example 1.

Example 13

  453 mg of 2- (3-phenylacetamido-4- (2-benzothiazolyidine)

  p-methoxybenzyl thio) -2-azetidinone-1-yl-3-methyl-3-butenoate and 147 mg of benzenesulfonyl cyanide are dissolved in 4.5 ml of tetrahydrofuran. To the solution is added 20 μl of a 28% solution in methanol of sodium methoxide and the mixture is reacted at room temperature for 50 minutes. The tetrahydrofuran is distilled off under reduced pressure and the residue is dissolved in 10 ml of benzene. The benzene solution is washed with water, dried over Na 2 SO 4 and concentrated under reduced pressure. The residue is purified by

  silica gel column chromatography, giving Z- (3-phenylacetate)

  p-methoxybenzyl tamido -4-benzene sulfonylthio -2-azetidinone-1-yl) -3-methyl-3-butenoate in 93% yield. The NMR spectral data of the compound thus obtained are identical to those of the

Example 1

Example 14

  290 mg of 2- [3-phenylacetamido-4- (2-benzothiazolyidine)

  p-methoxybenzylthio) -2-azetidinone-1-yl-3-methyl-3-butenoate and

* 94 mg of benzenesulfonyl cyanide are dissolved in 3 ml of tetrahydro-

  furan. To this solution is added 3 ml of the sodium salt of 2-mercapto

  benzothiazole and the mixture is reacted at room temperature

  2 hours. Tetrahydrofuran is distilled off under vacuum and the

  residue is purified by column chromatography on silica gel,

  Z - (3-phenylacetamido-4-benzenesulfonylthio-2-azetidinone-1-yl) -

  P-methoxybenzyl 3-methyl-3-butenoate with a yield of 91%.

  The NMR spectral data of the compound thus obtained are identical to

  those of the compound obtained in Example 1.

2t55 5 7.

- 29 -

Example 15

  316 rng of 2- [3-phenylacetamido-4- (2-benzothiazolyldi)

  p-methoxybenzylthio) -2-azetidin-1-yl] -3-methyl-3-butenoate and

  102 mg of benzenesulfonyl cyanide are dissolved in 3 ml of tetra-

  hydrofuranne. To this solution is added 5 ml of the aniline salt of 2-mer.

  captobenzothiazole and the mixture is reacted at room temperature.

  biante for 10 hours. Tetrahydrofuran is distilled off

  under reduced pressure and the residue is purified by chromatography

  on silica gel column, giving 2- (3-phenylacetamido-4-benzene)

  sulfonylthio-2-azetidinone-1-yl) -3-methyl-3-butenoate

  zyle with a yield of 85%. The spectral data of this compound

  are identical to those of the compound of Example 1.

Example 16

  316 mg of 2- [3-phenylacetamido-4- (2-benzothiazolyidine)

  p-methoxybenzyl thio) -2-azetidinone-1-yl-3-methyl-3-butenoate and 102 mg of benzenesulfonyl cyanide are dissolved in a mixture of

  solvents consisting of 1.5 ml of ethyl acetate and 1.5 ml of methanol.

  The mixture is reacted by heating for Z hours by boiling.

  The solvent is refluxed. The solvent is distilled off under pressure.

  reduced and the residue is purified by column chromatography.

  silica gel, giving 2- (3-phenylacetamido-4-benzenesulfonylthio) -2-

  p-methoxybenzyl azetidinone-1-yl) -3-methyl-3-butenoate with a

  yield of 82%. The NMR spectral data of the compound thus obtained

  held are identical to those of the compound obtained according to Example 1.

Example 17

2o OCH PhOCH2CNH s 3 0

o2é + PhSO2CN -

  COOCH 2 P h - 30- I PhOCH2CNH SSO2Ph

CH30 N

+ SCN

COOCH 2 P h

  250 mg of 2- [3-phenoxyacetamido-4- (5-methoxybenzoate)

  benzyl thiazole -2-yldithio) -2-azetidinone - 1 -yl-3-methyl-3-butenoate

  and 79 mg of benzenesulfonyl cyanide are dissolved in 2.5 ml of

  tone. To this solution are added 3 mg of sodium benzenesulfinate and the mixture is reacted at room temperature for Z hours. We

  continue the treatment as in Example 9 giving 2- (3-phenoxy)

  acetamido-4-benzenesulfonylthio-2-azetidinone-1-yl) -3-methyl-3-butadiene

  benzyl noate with a yield of 93%. NMR spectral data

  of the compound thus obtained are identical to those of the desired compound.

  The NMR spectral data are shown in Table V below.

Example 18

  O PhOCH2CNH s <_N CH3 L | + PhSO2CN ON OOCH2Ph o It PhOCH2CNH SSO2Ph

<S SCN

CH3 +

N N

O h N - N CO2CHzPh

- 31 -

  255 mg of 2-3-phenoxyacetamido-4- (5-methylthiadiazole)

  Benzyl 2-yldithio) -2-azetidin-1-yl-3-methyl-3-butenoate and 90 mg of benzenesulfonyl cyanide are dissolved in 2.5 ml of acetone. To this solution are added 3 mg of sodium benzenesulfinate and the mixture is reacted at room temperature for 2 hours. We can

  followed the treatment as in Example 9, giving 2- (3-phenoxy)

  acetamido-4-benzenesulfonylthio-2-azetidinone-1-yl) -3-methyl-3-buty

  benzyl noate with a yield of 85%. The spectral data of the compound thus obtained are identical to those of the compound obtained in

Example 17.

Example 19

PhCH2 CNH _SS D / s

± CH3- - SO2CN

NOT

OI P hCH2 CNHLg SO Uj CH 3

- '* Nô + [SCN

COOCH 3

  480 mg of 2-3-phenylacetamido-4- (2-benzothiazolyidine)

  methyl thio) -2-azetidin-1-yl] -3-methyl-3-butenoate and 203 mg of p-toluenesulfonyl cyanide are dissolved in 5 ml of acetone. To this solution are added 3 mg of sodium toluenesulfinate and

  react the mixture at room temperature for 2 hours. We can

  followed the treatment as in Example 9, giving 2-phenylacetone

  methyl mido- 4- (p-toluene sulfonylthio) -2-azetidinone-1-yl-7-methyl-3-butenoate in 96% yield. The NMR spectral data of the compound thus obtained are identical to those of the desired compound. The

  NMR spectral data of the compound are shown in Table V below.

after.

- 32 -

Example 20

He PhOCH2CNH + h C + PhS02CN

COOCH 2 OC 3

C OCH3

P h -NéCOCH3 COOCH 2 - / OCli 3

3C: H.3

  210 mg of 2-L3-phenoxyacetamido-4- (2-benzothiazolyidine)

  3,4,5-trimethoxy-2-azetidin-1-yl-3-methyl-3-butenoate

  benzyl and 61 mg of benzenesulfonyl cyanide are dissolved in 2.5

  ml of acetone. To this solution is added 3 mg of benzene sulfinate of

  dium and the mixture is reacted at room temperature for Z h.

  The treatment is continued as in Example 9, giving the Z- (3-phenyl)

  noxyacetamido-4-benzenesulfonyltbio-2-azetidinone -yl) -3-methyl-3-

  3,4,5-trimethoxybenzyl butenoate with a yield of 95%. The NMR spectral data of the compound thus obtained are identical to those of the desired compound. The NMR spectral data of the compound are shown in Table V.

- 33 -

Example 21

O PhOCH 2 CNH S '

PhCHCN SSH + PhSO2CN -

PN

COOCH 2 - OCH 3

O He PhOCH2CNIi SS02Ph

+ SCN

0% N \

COOCHl2 OCHa

  340 mg of 2- [3-phenoxyacetamido-4- (2-benzothiazolyldithio) -

  P-Methoxybenzyl 2-azetidin-1-yl-3-methyl-3-butenoate and 107 mg of benzenesulfonyl cyanide are dissolved in 3.5 ml of acetone. AT

  this solution is added 3 mg of sodium benznesulfinate and the mixture

  Ge is reacted at room temperature for Z h. We can

  followed the treatment as in Example 9, giving 2- (3-phenoxy)

  acetamido-4-benzenesulfonylthio-2-azetidinone-1-yl) -3-methyl-3-butyl

  p-methoxybenzyl noate with a yield of 90%. The NMR spectral data of the compound thus obtained, which are recorded in

  Table V are identical to those of the desired compound.

- 34 -

Example 22

  N PhOCH2CNH SS an N PhSO2CN> O COOCH2Ph

0

It PhOCH2CNH SS02Ph N NO2 COOCH2Ph

  362 mg of 2-Z3-phenoxyacetamido-4- (6-nitrobenzothiazole)

  Benzyl 2-yldithio) -2-azetidin-1-yl] -3-methyl-3-butenoate and 112

  mg of benzenesulfonyl cyanide are dissolved in 3.5 ml of acetone.

  To this solution is added 3 mg of sodium benznesulfinate and

  react the mixture at room temperature for 2 hours. We can

  followed the procedure as in Example 9, giving 2- (3-phenoxyacetate)

  benzyl tamido-4-benzenesulfonylthio-2-azetidin-1-yl) -3-methyl-3-butenoate with a yield of 81%. NMR spectral data

  of the compound thus obtained are identical to those of the compound of the

17.

- 35 -

Example 23

O CH3

  it N PhOCH2CNH SSK t. t | / S + PhSO2CN> O N / ce OCH3

COOCH 2 OCH 3

  OCH3 or PhOCH2CNH SSO2Ph CH3

OCH3 + S S CN

XN C OCH3 S

COOCH 2 / OCH 3

C OCH 3

  Z68 mg of 2 -3-phenoxyacetamido-4- (4-methylbenzoate)

  thiiazol-2-ylthio) -Z-azetidinon-1-yl, 7-3-methyl-3-butenoate

  trimethoxy-2,6-dichlorobenzyl and 69 mg of benzenesulfonyl cyanide are dissolved in 3 ml of acetone. To this solution is added 3 mg of sodium benzenesulfinate and the reaction mixture is reacted with

  room temperature for 2 hours. We continue the com

  in example 9 giving 2- (3-phenoxyacetamido-4-benzenesulfonyl)

  thio-2-azetidinone-1-yl) -3-methyl-3-butenoate 3, 4, 5-trirneethoxy2, 6-

  dichlorobenzyl with a yield of 85%. Spectral data

  NMR of the compound thus obtained are identical to those of the

  sought. The NMR spectral data are shown in Table V,

hereinafter.

- 36 -

Example 24

oN PhOCH2CNH SS <

S.S <NI 'C

PhSO2CN.

O> N> o COOCH2 C - <(B r

O

he PhOCH2CNH SSO2Ph

N + 3S> -SCN

O O CH3

II COOCH2C B r

  412 mg of 2- [3-phenoxyacetamido-4- (6-methylbenzoate)

  thiazole-2-yldithio) -Z-azetidin-1-yl-7-3-methyl-3-butenoate from p-

  bromophenacyl and 114 mg of benzenesulfonyl cyanide are dissolved in 4 ml of acetone. To this solution is added 3 mg of benzenesulfinate

  of sodium and the mixture is reacted at room temperature

  2 hours. The treatment is continued as in Example 9

  giving 2- (3-phenoxyacetamido-4-benzenesulfonylthio-2-azetidinone

  P-bromophenacyl 1-yl) -3-methyl-3-butenoate with a yield of

  94%. The NMR spectral data of the compound thus obtained are identical.

  to those of the desired compound. NMR spectral data

  are shown in Table V below.

- 37 -

Example 25

PhOCH2CNH SS__D + PhSO2CN> P N o

COOCH 20OCH 2CH 2

OCH13

  i 0 o It P hOCH 2 CNH PhOCH2CNH SS02Ph

+ S S CN

COOCH2 OCH2 CH 2

OCH 3

  294 mg of 2- [3-Phenoxyacetamido-4- (2-benzothiazolyidine)

  thio) -2-azetidinone-1-y7-3-methyl-3-methoxyethoxymethyl-3-butenoate

  and 102 mg of benzenesulfonyl cyanide are dissolved in 3 ml of

  tone. To this solution are added 3 mg of sodium benzenesulfinate

  and the mixture is reacted at room temperature for 2 hours.

  The treatment is continued as in Example 9, giving the 2- (3-phenyl)

  noxyac etamido-4-benzenesulfonylthio-2-azetidinone-1-yl-3-methyl-3-

  methoxyethoxymethyl butenoate with a yield of 78%. The NMR spectral data of the compound thus obtained are shown on the table.

  V below are identical to those of the desired compound.

- 38 -

Example 26

O PhOCH2CNH S

+ PhSO2CN -

ol

COOCH2OCH3

O He PhOCH2CNH SSO2Ph

+ SCN

-ns

O COOCH2OCH3

  305 mg of 2- [3-phenoxyacetamido-4- (2-benzothiazolyldithio) -

  Methoxymethyl 2-azetidin-1-yl] -3-methyl-3-butenoate and 109 mg of benzenesulfonyl cyanide are dissolved in 3 ml of acetone. To this solution is added 3 mg of sodium benzenesulfinate and the mixture is reacted at room temperature for 2 hours. We continue

  as in Example 9, giving 2- (3-phenoxyacetaxrido-4-

  methylene benzene sulfonylthio-2-azetidinone-1-yl) -3-methyl-3-butenoate

  methyl with a yield of 75%. NMR spectral data from the

  posed, recorded in Table V below, are identical to

those of the desired compound.

- 39-

Example 27

O

  NNA OI 1 0 CoOt o2 PhOCH2CNH SS2Ph \ .. S $ 02Ph Co

  372 mg of 2-f3-phenoxyacetamido-4- (2-benzothiazolyidine)

  9-fluorenyl thio) -Z-azetidin-1-yl-3-methyl-3-butenoate and

  mg of benzenesulfonyl cyanide are dissolved in 4 ml of acetone.

  To this solution is added 3 mg of sodium benzenesulfinate and

  react the mixture at room temperature for 2 hours. We can

  followed the treatment as in Example 9, giving 2- (3-phenoxy)

  acetamido - 4-benzenesulfonylthio-2-azetiddinone-1-yl) -3-methyl-3-buten

  9-fluorenyl noate with a yield of 85%. Spectral data

  the NMR of the compound thus obtained, recorded in Table V below,

  are identical to those of the desired compound.

- 40 -

Example 28

O PhCH2CNH SS + 'PhSO2CN>

O

co-O Il PhCH2CNH SS02Ph

X N é +2> SCNI

O

  289 mg of 2- / 3-phenylacetamido-4- (2-benzothiazolyldithio) -

  9-fluorenyl 2-azetidin-1-yl-3-methyl-3-butenoate and 87 mg of benzenesulfonyl cyanide are dissolved in 3 ml of acetone. To this solution is added 3 mg of sodium benzenesulfinate and the mixture is reacted at room temperature for 2 hours. We continue

  as in Example 9, giving 2- (3-phenylacetamido-4-

  9-fluoro benzenesulfonylthio-2-azetidin-1-yl) -3-methyl-3-butenoate

  Renyl NMR with a yield of 90%. The spectral data of the compound thus obtained, which are recorded in Table V below, are identical

to those of the desired compound.

- 41 -

Example 29

  O PhCU2CNH SS <si + PhSO2CN> COOCH2-j-NO2 where it PhCH2CNH SS02Ph

XN '± SCN

0 '

COOCH 2-4 NO 2

  250 mg of 2- [3-phenylacetamido-4- (2-benzothiazolyidine)

  p-nitrobenzyl thio) -2-azetidin-1-yl] -3-methyl-3-butenoate and

  79 mg of benzenesulfonyl cyanide are dissolved in 2.5 ml of

  tone. To this solution is added 3 mg of sodium benzenesulfinate and

  the mixture is reacted at room temperature for 2 hours.

  The treatment is continued as in Example 9, giving 2- (3-

  phenylacetamido-4-benzenesulfonylthio-2-azetidinone-1-yl) methylmethyl

  P-nitrobenzyl 3-butenoate with a yield of 94%. The NMR spectral data of the compound thus obtained are recorded on the table.

  V below, are identical to those of the desired compound.

2 t55 5 7 8

- 42 -

Example 30

0

* It PhCH2CNHz / S S_ S S- (Se SN O - PhSO2CN

COOCH2-

NO2 NO It PhCH2CNH \ SS02Ph

, + SCN

COOCH2.

NO2

  -310 mg of 2- / 3-phenylacetamido-4- (2Z-benzothiazolyldithio) -

  O-nitrobenzyl 2-azetidin-1-yl-3-methyl-3-butenoate and 98 mg of benzenesulfonyl cyanide are dissolved in 3 ml of acetone. To this solution is added 3 mg of sodium benzenesulfinate and the mixture is reacted at room temperature for 2 hours. We continue

  treatment as in Example 9 giving 2- (3-phenylacetamido-4-

  benzene sulfonylthio-2-azetidinone-1-yl) -3-methyl-3-butenoate o-

  nitrobenzyl with a yield of 93%. The NMR spectral data of the compound thus obtained, shown in Table V below, are identical

to those of the desired compound.

- 43 -

Example 31

O

! 1 N

P hOCH 2 CNH S SCsX PhSO2CN> O

COOCH-COCH 3

UC02CH3

o0 PhOCH2CNH SSO2Ph> Nto + t 3f SCN

1 5 O

COO H-COCH3

C02CH3

  352 mg of Z- [3-phenoxyacetamido-4- (2-benzothiazolyldithio)]

  1-Methoxycarbonyl-2-oxo-2-azetidin-1-yl-3-methyl-3-butenoate

  propyl and 112 mg of benzenesulfonyl cyanide are dissolved in 3.5 ml of acetone. To this solution is added 3 mg of benzenesulfinate

  of sodium and the mixture is reacted at room temperature

  Z hours. The treatment is continued as in Example 9

  Z- (3-phenoxyacetamido-4-benzenesulfonylthio-2-azetidinone)

  3-methyl-3-butenoate of 1-methoxycarbonyl-2-oxo-propyl with a yield of 90%. The spectral data / compound thus obtained,

  reported in Table V, are identical to those of the desired compound.

- 44 -

Example 32

0

PhCH2 & NH SsS <1 + Ce-K -4so2cN N

COOCH 3

  o It PhCH2CNH SSO 3ce (>> (i5 + @J ^ - SCN

COOCH 3

  mg of 2- [3-phenylacetamido-4- (2-benzothiazolyidithio) -

  Methyl 2-azetidin-1-yl] -3-methyl-3-butenoate and 85 mg of p-chlorobenzenesulfonyl cyanide are dissolved in 2 ml of acetone. To this solution is added 3 mg of sodium p-chl orobenzenesulfinate and

  react the mixture at room temperature for 2 hours. We can

  followed the treatment as in Example 9 giving 2- [3-phenylacetate

  mido - 4- (p-chloroenzenesulfonylthio) -2-az etidinone -1-y173 methyl-3-

  methyl butenoate with a yield of 86%. The NMR spectral data of the compound thus obtained, recorded in Table V below, are

  identical to those of the desired compound.

- 45 -

Example 33

Q PhCH 2CNH S S-i X

I

  Nor + N02 - <3 S02CN o COOC-ia it PhCH2CNH S S 2 NO 2

+ SCN

/ SSO2-F- NO2S

COOCHs

  203 mg of 2-53-phenylacetamido-4- (2-benzothiazolyldithio) -

  Methyl 2-azetidin-1-yl-3-methyl-3-butenoate and 101 mg of cyano-

  The p-nitrobenzenesulfonyl compound is dissolved in 2 ml acetone. To this solution is added 3 mg of sodium p-nitrobenzenesulfinate and the mixture is reacted at room temperature for 2 hours. We

  continue the treatment as in Example 9 giving 2- (3-phenyl)

  acetarnido-4 - (p-nitrobenzene sulfonylthio) -2-azetidinone-1-yl73-nmethyl

  Methyl 3-butenoate with a yield of 72%. Spectrum data

  NMR spectra of the compound thus obtained, recorded in Table V below,

  are identical to those of the desired compound.

- 46 -

Example 34

O P h CH 2 CNI S 0X N s + NSO2C

COOCH 3

OO NO 2

PhCH2CNH SS2.

$ 0 + (SCXN

COOCH 3

  231 mg of 2 -3-phenylacetamido-4- (2-benzothiazolyidine)

  methyl thio) -Z-azetidin-1-yl-3-methyl-3-butenoate and 115 mg

  o-nitrobenzenesulfonyl cyanide is dissolved in 2.5 ml of acetone.

  To this solution is added 3 mg of sodium benzenesulfinate and

  react the mixture at room temperature for 2 hours. We can

  followed the treatment as in Example 9, giving Z- / 3-phenyl-

  acetamido -4- (o-nitrobenzene sulfonylthio) -2-azetidinone-1-yl-3-methyl-

  methyl-3-butenoate methyl with a yield of 70%. The NMR spectral data of the compound thus obtained are identical to those of the

  desired compound. The data are recorded in Table V below.

- 47 -

Example 35

  phcH2.CNH OI'1 q + NO2-V $ -SO2CNCOOCH2 P h

0

It PhCH2CNH SSO2-S NO x / SSO2NO 2 +

+ NSCN

COOCH2Ph

  308 mg of 2- [3-phenylacetamido-4- (2-benzothiazolyldithio)]

  Benzyl 2-azetidin-1-yl-3-methyl-3-butenoate and 133 mg of

  The p-nitrobenzenesulfonyl compound is dissolved in 3 ml of acetone. To this solution is added 0.3 ml of water and the mixture is reacted for Zh at the reflux temperature of acetone. We continue the treatment as

  in Example 5, giving Z- / 3-phenylacetamido-4-p-nitrobenzene-

  benzyl sulfonylthio-2-azetidin-1-yl-7-3-methyl-3-butenoate with a yield of 77%. The NMR spectral data of the compound thus obtained, recorded in Table V below, are identical to those of the

desired compound.

2555S78

- 48 -

Example 36

  PhCH2CNH S N C N Nickel + CH30-FtSO2CN>

10011+

  COOCH2 Ph PhCH2NH PhCH2NH SSO2- -OCH3 + t NtS> .SCN COOCH 2 P h

  189 mg of 2- [3-phenylacetamido-4- (2-benzothiazolyidine)

  benzyl thio) -2-azetidin-1-yl-3-methyl-3-butenoate and 76 mg of

  p-methoxybenzenesulfonyl cyanide are dissolved in 2 ml of acetone.

  To this solution is added 0.2 ml of water and the mixture is reacted with water.

  2 hours at the reflux temperature of acetone. We continue

  as in Example 5, giving 2- (3-phenylacetamido)

  4- (p-Methoxybenzene sulfonylthio) -Z-azetidinone-1-yl7-3-methyl-but-butene

  benzyl noate with a yield of 93%. The NMR spectral data of the compound thus obtained, recorded in Table V below, are

  identical to those of the desired compound.

-49 -

Example 37

  o OCH-3 ss / - / PhC 2CNH! S PhS2CN Due N ôs

COOCH 2_- NO2

O OCH3

He SSO2Ph

PhCH2CNHo + SSP -

yi N> s SCN

OOCH 2 NO 2

  315 mg of 2 -3-methoxy-3-phenylacetamrido-4- (2-b)

  zothiazolyldithio) -2-azetidinone -1-yl7- - 3-methyl-3-butenoate

  Benzyl and 95 mg of benzenesulfonyl cyanide are dissolved in 3 ml of acetone. To this solution is added 3 mg of sodium benzenesulfinate

  and the mixture is reacted at room temperature for 2 hours.

  The treatment is continued as in Example 9, giving 2- (3-

  methoxy-3-phenylacetamido-4-benzenesulfonylthio-2-azetidinone-yl)

  P-nitrobenzyl 3-methyl-3-butenoate with a yield of 88%. The NMR spectral data of the compound thus obtained, recorded on the table

  V below, are identical to those of the desired compound.

Examples 38 to 40

  The procedure of Example 5 is repeated, which allows

  get the compounds listed in Table III. Spectrum data

  The NMR trales of these compounds are shown in Table V.

R1 R

R SSR SS92 3

ANRL & + R3SQ2CN N

at I R4 R4

Table III

  Ex. No.R R2 R4 J3 Yield (%) CH3 o

38 H C CH3 CII3_ 94

  2 COOC112cc e3 il3 9 # v # 'CHl30- 95 39 3 if I8 Cil 78 J:

- 51 -

Example 41

  o PhCH2CVH SS3 PIzSO2S- \ (SNs / s PhiSO2iVa

COOCH2 OCH3

o PhCH2CNH SSO <$ S + <

O

COOCH - (OCH3

  13.2 g of 2 - [3-phenylacetamido-4- (2-benzothiazolyidine)

  thio) -2-azetidinone-1-yl] -3-methyl-3-methoxybenzyl-3-butenoate and 7.0 g of 2-benzothiazolyl benzenethiosulfonate are dissolved in ml of acetone. To this solution is added 26 ml of water and then 20 mg of sodium benzenesulfinate and the mixture is stirred at room temperature.

  ambient for 3 hours. 2-Benzothiazol disulfide crystals

  The precipitated precipitates are filtered and the filtrate is concentrated under reduced pressure.

  pick. The residue is dissolved in benzene, washed with water and separated

  ket. Benzene is distilled off to give 2- (3-phenyl)

  acetamido-4-benzenesulfonylthio-2-azetidinone-1-yl) -3-methyl-3-butene

  p-methoxybenzyl noate with a yield of 93%. The data

  NMR spectra of the compound are identical to those of the compound

  ket. The NMR spectral data of the compound are recorded

Bleau V. 2555Soe

- 52 -

Example 42

O0

It 1 1 PhCH2CNI SSO2Ph

COOCH2, OCH3

  13.2 g of 2 -3-phenylacetamido-4- (2-benzothiazolyidine)

  2-Benzothiazolyl p-methoxybenzyl thio) -Z-azetidin-1-yl-3-methyl-3-butenoate and 7.0 g of thiobenzenesulfonate are dissolved in 130 ml of acetone. AT

  this solution are added 26 ml of water and then 20 mg of 2-benzothiazolyl-

  sodium thiolate and the mixture is stirred at room temperature

  during 3 hours. The crystals of 2-benzothiazolyl disulfide preci

  The filtrates are filtered and the filtrate is concentrated under reduced pressure. The residue is treated in the same way as in Example 41, giving the

  2- (3-phenylacetamido-4-benzenesulfonylthio-2-azetidione-1-yl) -3-

  p-methoxybenzyl methyl-3-butenoate with a yield of 91%.

  NMR The spectral data of the compound are identical to those of the compound

in example 41.

- 53-

Example 43

o0

I G'NOCH CH3-

  $ 5 PGoC \ SPhS02S - '<O + Ph SO2Na COOCH2Ph

0

  It PhOCH2CA7I <S502Ph + (CHPO> COOCH2Ph

  263 mg of Z- [3-phenoxyacetamido-4- (5-methoxybenzothiazole)

  Benzyl benzyl zole -2-ylthio-2-azetidinone-1-yl7-3-methyl-3-butenoate and 147 mg of 5-methethoxy-benzothiazol-2-yl benzenethiosulfonate are dissolved in 2.5 ml of acetone. To this solution is added 0.5 ml of water and then 2 mg of sodium benznesulfinate and the mixture is stirred at room temperature for 3 hours. The precipitated methoxybenzothiazol-2-yl disulfide crystals are filtered and the filtrate is concentrated under reduced pressure. The residue is treated in the same way

  in example 41 giving 2- (3-phenoxyacetamido-4-benzenesulfonyl)

  benzyl nylthio-2-azetidin-1-yl) -3-methyl-3-butenoate with a

  96% yield. The NMR spectral data of the compound are

  to those of the desired compound. The NMR spectral data of the compound are shown in Table V.

- 54 -

Example 44

  It P hOCH2CNH 555F, CH3 2PhSo2S-5, - CH3

I N-N N-N

  O PhSO2VNa COOCH2Ph It PhOCH2CNH- SSO2Ph i__i / SSOaPh + (CHS r S 'k + k NN 2 COOCH2Ph

  500 mg of 2 -3-phenoxyacetamnido-4- (5-methylthiadiazole)

  Benzyl 2-yldithio) -2-azetidin-1-yl / 7-3-methyl-3-butenoate and 251 mg of 5-methylthiadiazol-2-yl benzenethiosulfonate are dissolved in 5 ml of acetone. To this solution is added 1 ml of water and then 5 mg of

  sodium benzenesulfinate and the mixture is stirred at room temperature.

  biante for 3 hours. Crystals of 5-methylthiadiazole disulfide

  2-yl precipitates are filtered and the filtrate is concentrated under pressure

  pick. The residue is treated in the same way as in Example 41, giving

  2- (3-Phenoxyacetamido) -4-benzenesulfonylthio-2-azetidinone-1 -

  benzyl yl) -3-methyl-3-butenoate with a yield of 89%. The 1RMN spectral data of the compound thus obtained are identical to those

  of the compound obtained in Example 43.

557

- 55 -

Example 45

o He

PICH2C CH- "2S

O Christmas CH3 "S02'Va

COOCH 3

  o0 It PhCH2C, VH P hCH2 C'k.I f SS02 MI CH3

O C + C

COOCH 3

  500 mg of 2- [3-phenylacetamido-4- (2-benzothiazolyidine)

  methyl thio) -2-azetidin-1-yl-3-methyl-3-butenoate and 314 mg of 2-benzothiazolyl ptoluenethiosulphonate are dissolved in 5 ml.

  of acetone. To this solution are added 1 ml of water and then 2 mg of ptoluene.

  sodium sulfinate and the mixture is stirred for 3 hours at room temperature.

  ambient temperature. Crystals of 2-benzothiazolyl disulfide precipitated

  The filtrates are filtered and the filtrate is concentrated under reduced pressure. The residue is treated in the same way as in Example 41, giving the

  2 -3-phenylacetamido-4- (p-toluenesulfonylthio) -2-azetidinone-1-yl

  Methyl 3-methyl-3-butenoate with a yield of 95%. The data

  NMR spectral data of the compound are shown in Table V.

- 56 -

Example 46

  o 1 PhCH2C-EW N 9'S4S <S PhSO2S S: o Jo iVoPls PhSO2Na COOCH2 -c OCH3 I PhCH2CNI SS02Ph - (0 +

COOCH2 _ OCH3

  500 mg of 2-13-phenylacetamido -4- (2-benzothiazolyldithio) -

  P-Methoxybenzyl 2-azetidin-1-yl7-3-methyl-3-butenoate and 260 mg of 2-benzothiazolyl 2-benzenethiosulfonate are dissolved in 5ml

  of acetone. To this solution are added 2 mg of benzene sulfinate of

  dium and the mixture is stirred for 12 hours at room temperature.

  The precipitated 2-benzothiazolyl disulfide crystals are filtered and the filtrate is concentrated under reduced pressure. The residue is purified by

  silica gel column chromatography, giving 2- (3-phenylacetate)

  tamido-4-benzenesulfonylthio-2-azetidinone-1-yl) -3-methyl-3-butenoate

  p-methoxybenzyl with a yield of 90%. Spectral data

  the NMR of the compound are identical to those of the compound obtained in

example 41.

- 57 -

Example 47

  The preparation of Example 46 is repeated with the difference

  that acetone is replaced by chloroform as a solvent,

  which makes it possible to obtain 2- (3-phenylacetamido-4-benzenesulphonylthio)

  P-methoxybenzyl 2-azetidinone-1-yl) -3-methyl-3-butenoate in 86% yield. The NMR spectral data of the compound as well

  obtained are identical to those of the compound obtained in Example 41.

Example 48

  The preparation of Example 46 is repeated except that acetone is replaced by benzene as a solvent, which allows

  to obtain 2- (3-phenylacetamido-4-benzenesulfonylthio-2-azetidinone

  P-methoxybenzyl 1-yl) -3-methyl-3-butenoate with a yield of

  82%. The NMR spectral data of the compound thus obtained are identical.

  to those of the compound obtained in Example 41.

Example 49

  The preparation of Example 46 is repeated except that

  tone is replaced by acetonitrile as solvent, which makes it possible

  hold 2 - (3-phenylacetamido-4-benzenesulfonylthio-2-azetidinone 1-yl) -

  P-methoxybenzyl 3-methyl-3-butenoate with a yield of 91%.

* The NMR spectral data of the compound thus obtained are identical

  to those of the compound obtained in Example 41.

Example 50

  The preparation of Example 46 is repeated except that

  tone is replaced as solvent by ethyl acetate, which allows

  to obtain 2 - (3-phenylacetamido-4-benzenesulfonylthio-2-azetidinone -

  P-methoxybenzyl 1-yl) -3-methyl-3-butenoate with a yield of

  85%. The NMR spectral data of the compound thus obtained are identical.

  those of the compound prepared according to Example 41.

- 58 -

Example 51

  The preparation of Example 46 is repeated except that

  tone is replaced as a solvent by nitromethane, which allows

  to obtain 2 - (3-phenylacetamido-4-benzenesulfonylthio-2-azetidinone

  P-methoxybenzyl 1-yl) -3-methyl-3-butenoate with a yield of

  %. The NMR spectral data of the compound thus obtained are identical.

  to those of the compound obtained according to Example 41.

Example 52

  The preparation of Example 46 is repeated except that

  tone is replaced by dioxane as solvent, which makes it possible

  hold 2 - (3-phenylacetamido-4-benzenesulfonylthio -2-azetidinone -1 -

  p-methoxybenzyl yl) -3-methyl-3-butenoate with a yield of

  82%. The NMR spectral data of the compound thus obtained are identical.

  to that of the compound of Example 41.

Example 53

  The preparation of Example 46 is repeated except that

  tone is replaced as solvent by tetrahydrofuran, which

  allows to obtain 2- (3-phenylacetamido-4-benzenesulfonylthio) -2-

  p-methoxybenzyl azetidinone-1-yl) -3-methyl-3-butenoate in a yield of 67%. The NMR spectral data of the compound as well

  obtained are identical to those of the compound of Example 41.

Example 54

  500 mg of 2- [3-phenylacetamido-4- (2-benzothiazolyidine)

  thio) -2-azethoxybenzyl ethanone-1-yl-3-methyl-3-butenoate and 260 mg of 2-benzothiazolyl benzenethiosulfonate are placed in a 260 mg reactor, into which is then introduced 10 ml of isopropyl alcohol. The mixture is stirred at room temperature for

  12 hours during which the reagents do not dissolve completely

  they remain in suspension. Insoluble products are isolated

- 59 -

  by filtration and washed with 10 ml of acetone. The washing liquid and the filtrate are combined and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel, giving the

  2- (3-phenylacetamido-4-benzenesulfonylthio-2-azetidinone-1-yl) - 3-

  p-methoxybenzyl methyl-3-butenoate with a yield of 95%. The NMR spectral data of the compound thus obtained are identical to

those of the compound of Example 41.

Example 55

  The preparation of Example 54 is repeated except that the alcohol

  Isopropyl is replaced as solvent by methanol, which allows

  to obtain 2- (3-phenylacetamido-4-benzenesulfonylthio-2-azetidine

  p-methoxybenzyl 3-methyl-3-butenoate) with a yield of

  92%. The NMR spectral data of the compound thus obtained

  are identical to those of the compound of Example 41.

Example 56

  o P H OCH2CWI PSS <'CN <OCHI3 (eS' SK

COOCH3 OC H

OCH 3

o He PhOCH2CN \ H / SSO2Ph OCH3

COOCH2 _ OCH3

OCH 3

- 60 -

  mg of 2 - [3-phenoxyacetamido-4- (2-benzothiazolyidine)

  thio) -2-azetidin-1-yl-3-methyl-3-butenoate 3, 4, 5-trimethoxy

  Benzyl and 97 mg of 2-benzothiazolyl benzenethiosulionate are dissolved in 3 ml of acetone. To this solution is added 0.3 ml of water and then 2 mg of potassium 2-benzothiazolylthiolate. The mixture is stirred at ambient temperature for 3 hours. The precipitated 2-benzothiazolyl disulfide crystals are filtered and the filtrate is concentrated under reduced pressure. The residue is treated in the same way as in

  Example 41, giving 2 - (3-phenoxyacetamido-4-benzenesulfonylthio)

  3, 4, 5-trimethoxybenzyl 2-azetidin-1-yl) -3-methyl-3-butenoate gave a 92% yield. The NMR spectral data of the compound

  thus obtained are identical to those of the desired compound. The data

  are shown in Table V below.

Example 57

I PhOCH2CVH N. Sa -WS PhSO2S S)

COOCH2 OCH3

o He PhOCH2CNVH

Y 3S02P + (

o

COOCH2 (J OCH3

30

- 61 -

  1.0 g of 2- [3-phenoxyacetamido-4- (2-benzothiazolyidine)

  p-Methoxybenzylthio-2-azetidin-1-yl-3-methyl-3-butenoate and 488 mg of 2-benzothiazolyl benzenethiosulfonate are dissolved in

  ml of acetone. To this solution is added 2 ml of water then 5 mg of 2-

  sodium benzothiazolyl thiolate. The mixture is stirred for 3 h at room temperature. 2-Benzothiazolyl disulfide crystals

  The precipitates are filtered and the filtrate is concentrated under reduced pressure.

  The residue is treated in the same way as in Example 41, giving the

  2- (3-phenoxyacetamido-4-benzenesulfonylthio-2-azetidinone-1-yl) - 3 -

  p-methoxybenzyl methyl-3-butenoate with a yield of 96%.

  The NMR spectral data of the compound thus obtained are identical to those of the desired compound. The data are recorded on the board

V below.

Example 58

  I PhOCHCi2CNINIPhSO2S (JJ has NO2 NO2 O PhSO2Na COOCH2Ph It PhOCH2CNH SSOPh (NO + \ O COOCH2Ph

  198 mg of 2- / 3-phenoxyacetamido-4- (6-nitrobenzothiazine)

  benzyl 2-azetidinone-1-yl-3-methyl-3-butenoate) and 113 mg of 6-nitrobenzothiazol-2-yl benzenethiosulfonate are dissolved in 2.5 ml of acetone. To this solution is added 0.5 ml of water

  then 3 mg of sodium benznesulfinate. The mixture is stirred at the temperature

- 62 -

  room temperature for 8 hours. Disulfide crystals of 6-nitro-

  Benzothiazol-2-yl precipitates are filtered and the filtrate is concentrated under

  reduced pressure. The residue is treated in the same way as in the example

  giving 41 2- (3-phenoxyacetamido-4-benzenesulfonylthio-2-azetyl)

  benzyl dinon-1-yl) -3-methyl-3-butenoate with a yield of 79%. The NMR spectral data of the compound thus obtained are identical to

  those of the compound obtained according to Example 43.

Example 59

  ## STR2 ##

{j ".,?> Cuz OCH3 ...

OCH3 PhSO2Na

COOCH2. = _ OCH3

Cú OCH3

  o PhOCH2CNf SSO2Ph CH3 0 Y R CZ OCH. eS 5 2

COOCH2 OCH3

C OC3

CZ OCH3

- 63 -

  1.03 g of Z- [3-phenoxyacetamido-4- (4-methylbenzothiazione)]

  zole-2-ylthio) -Z-azetidinone-1-yl-3-methyl-3-butenoate of 3, 4, 5

  trimethoxy-2,6-dichlorobenzyl and 448 mg of 4-methylbenzo-thiazol-2-yl benzenethiosulfonate are dissolved in 10 ml of acetone. To this solution is added 2 ml of water then mrg of. herzenesuifinate

  dium. The mixture is stirred at room temperature for 5 hours.

  The precipitated 4-methylbenzothiazol-2-yl disulfide crystals are filtered and the filtrate is concentrated under reduced pressure. The residue is

  treated in the same way as in Example 41, giving 2, 3-phenoxy-

  acetamido-4-benzenesulfonylthiourea-2-azetidinone-1-yl) -3-métPl71-3-buté-

  3, 4, 5-trimetoxy-2,6-dichlorobenzyl noate with a yield of

  86%. the NMR spectral data of the compound thus obtained are identi-

  those of the desired compound. The data are recorded in

Table V below.

- 64 -

Example 60

  It N L Ch 3 PhC F PfPh SOV2S a! 1 COOCH2C -r Br o il PhOCH2CNH -f \ SO2Ph

0 00

 J-- N \ CH3 Ya: he COOCH2C- Br

  1.23 g of 2- (3-phenoxyacetamido-4- (6-methylbenzothiazione)

  zole-2-yldithio -2-azetidinone-1-yl-3-methyl-3-butenoate of pbromo-

  phenyl and 572 mg of 6-methylbenzothiazole benzenethiosulfonate

  2-yl are dissolved in 10 ml of acetone. To this solution is added 2 nml of water and then 3 mg of sodium benzenesulfinate. The mixture is stirred at room temperature for 5 hours. The precipitated 6methylbenzothiazol-2-yl disulfide crystals are filtered and the filtrate is concentrated under reduced pressure. The residue is treated the same way

  that in example 41 giving 2-3-phenoxyacetamido-4-benzenesulfonate

  pbromophenacyl nylthio-2-azetidinone-1-yl) -3-methyl-3-butenoate with a yield of 94%. The NMR spectral data of the compound

  thus obtained are identical to those of the desired compound. The data

  are shown in Table V below.

2z 55578

- 65 -

Example 61

  307 mg of 2-Z3-phenoxyacetamido-4- (2-benzothiazolyldithio) -

  Methoxyethoxymethyl 2-azetidinone-1-yl-3-methyl-3-butenoate and P-1HCOCHI2C.H V-Ais PhSO2NVa I

COOCH2: OCH2CH2

  ooy O He PhOCH2CIH _15; CSSOPh + COOCH20CH2CHa I

OCH 3

  164 mg benzenethiosulfonate 2-benzothiazolyl are dissolved in 4 ml

  of acetone. To this solution is added 0.8 ml of water and then 1 mg of benzene.

  sodium sulfinate. The mixture is stirred at room temperature

  1.5 hours. The precipitated Z-benzothiazolyl disulfide crystals are filtered and the filtrate is concentrated under reduced pressure. The residue is treated

  in the same manner as in Example 41, giving 3- (3-phenoxyacetamido-4-benzenesulfonylthio-2-azetidin-1-yl) -3-methyl-3-butenoate

meth

  oxyethoxymethyl with a yield of 83%. Spectral data

  NMR of the compound thus obtained are identical to those of the

  sought. The data are recorded in Table V below.

- 66 -

Example 62

  o PhOCH2CNH N N JIJs) SS EPh S U-cfi o e PhSO2N.Va

COOCH20OCH3

  o PhOCH2CNH \ SSO2Ph + 0y 2Ph + cN3 zes)

COOCH20CH3

  329 mg of Z-EZ3-phenoxyacetamido-4- (2-benzothiazolyl)

  2-Benzenediazolyl benzenethiosulfonate 2-benzothiazolyl-2-azetidinone-1-yl-3-methyl-3-butenoate and 190 mg of benzenethiosulfonate are dissolved in 5 ml of acetone. To this solution are added 1 ml of water and then 3 mg of sodium benzenesulfinate. The mixture is stirred at the temperature

  ambient for 4 hours. 2-Benzothiazol disulfide crystals

  The precipitated precipitates are filtered and the filtrate is concentrated under reduced pressure.

  The residue is treated in the same way as in Example 41 giving the

  2- (3-Phenoxyacetamido-4-benzenesulfonylthio-2-azetidinone-1-yl) - 3 -

  Methoxymethyl methyl-3-butenoate with a yield of 72%. The NMR spectral data of the compound thus obtained are identical to those

  of the desired compound. The data are shown in Table V below.

after.

2555- 578

- 67 -

Example 63

  o PhOCH2CIVH N SSL </ Jk) PhSO2S N'S 1 I Q PhSO2Na COO 1 0 l PhOCH2CCVIt \, $ SO2Ph

  1.15 g of 2- [3-phenoxyacetamido-4- (2-benzothiazolyidine)

  9-fluorenyl thio) -2-azetidin-1-yl-3-methyl-3-butenoate and 545 mg of 2-benzothiazolyl benzenothiophosphate are dissolved in 20 ml of acetone. To this solution are added 4 ml of water and then 10 mg of

  sodium benzene sulfinate. The mixture is stirred at room temperature

  biante for 2 hours. 2-Benzothiazolyl disulfide crystals

  The precipitates are filtered and the filtrate is concentrated under reduced pressure.

  The residue is treated in the same way as in Example 41 giving the

  2- (3-Phenoxyacetamrnido-4-benzenesulfonylthio-2-azetidinone-1-yl) -3-

  9-fluorenyl methyl-3-butenoate with a yield of 93%. The data

  The NMR spectral results of the compound thus obtained are identical to those

  desired compound. The data are recorded in Table V below.

- 68 -

Example 64

  o PhCH2CNH o_, N. [0 X S - \ / PhSO2Na COO o It PhCH2CSSh \. _ / SS02Ph

FNFS + (LS \

COQ 7oo. (, I

  7.16 g of 2-r3-phenylacetamido-4- (2-benzothiazolyidine)

  9-flurenyl thio) -2-azetidin-1-yl-3-methyl-3-butenoate and 3.86 g of 2-benzothiazolyl benzenethiosulfonate are dissolved in 100 ml.

  of acetone. To this solution are added 20 ml of water and then 10 mg of benzene.

  sodium sulfinate. The mixture is stirred at room temperature for 1 h. The precipitated 2-benzothiazolyl disulfide crystals are filtered and the filtrate is concentrated under reduced pressure. The residue

  is treated in the same way as in Example 41, giving 2- (3-phenyl)

  tamido-4-benzenesulphonylthio-2-azetidinone-1-yl) -3-methyl-3-butenoic acid

  9-fluorenyl ester with a yield of 89%. Spectral data

  NMR of the compound thus obtained are identical to those of the compound

  ket. ' The data are recorded in Table V above.

- 69 -

Example 65

  o O It PhCH2CNH Y_ + V o <ss fflsIPhSO2S \, 0 N \ / \ PhSO2Na

COOCH2 NO2

He PhCH2CÀ; l2CSNph (

COOCH2 --NO

  500 mg of 2- [3-phenylacetamrnido-4- (2-benzothiazolyl)

  p-nitrobenzyl dithio) -2-azetidin-1-yl] -3-methyl-3-butenoate and 254 mg of 2-benzothiazolyl benznethiosulfonate are dissolved in ml of acetone. To this solution are added 1 ml of water and then 2 mg of sodium benzenesulfinate. The mixture is stirred at room temperature

  during 3 hours. Precise Z-benzothiazolyl disulfide crystals

  The filtrates are filtered and the filtrate is concentrated under reduced pressure. The residue is treated in the same way as in Example 41, giving the

  2 - (3-phenylacetamido-4-benzenesulfonylthio-2-azetidinone-1-yl) 3-methyl-

  p-nitrobenzyl hyl-3-butenoate with a yield of 91%. The data

  The NMR spectral results of the compound thus obtained are identical to those

  desired compound. The data are recorded in Table V below.

2S55578

- 70 -

Example 66

O PPhCH2CMIr PhSO2S N 'PhSO2Na

COOCH2

N02

  l O 2 It cPhCH2CoocH2 / SSOaPh + (C NO2

  500 mg of 2 -3-phenylacetamido-4- (2-benzothiazolyldithio)

  o-nitrobenzyl 2-azetidinone-1-yl-3-methyl-3-butenoate and 254 mg of 2-benzothiazolyl benzenethiosulphonate are dissolved in 5 ml of acetone. To this solution is added 1 ml of water and then 2 mg of sodium benzenesulfinate. The mixture is stirred at ambient temperature for 3 hours. The crystals of

  precipitated 2-benzothiazolyl disulfide are filtered and the filtrate is

  centered under reduced pressure. The residue is treated in the same way as

  in Example 41, giving 2- (3-phenylacetamido-4-benzenesulfonyl)

  o-nitrobenzyl thio-2-azetidinone-1-yl) -3-methyl-3-butenoate with a

  91% yield. The NMR spectral data of the compound thus obtained

  nude are identical to those of the desired compound. The data is

recorded in Table V below.

-71 -

Example 67

  o PhOCH2CNH N S 'kS PhS0C2! 3 COOCH - COCH3 h 2N I _ / SS02PhN

COOCH - COCH3

C02CH3

  500 mg of 2 - / - 3-phenoxyacetamido-4- (2-benzothiazolyl)

  1-methoxycarbonyl dithio-2-azetidin-1-yl] -methyl-3-butenoate

  2-oxopropyl and 263 mg of 2-benzothiazolyl benzenethiosulfonate are dissolved in 5 ml of acetone. To this solution are added 1 ml of water and then 2 mg of sodium benzenesulfinate. The mixture is stirred at ambient temperature for 3 hours. The precipitated 2-benzothiazolyl disulfide crystals are filtered and the filtrate is concentrated under

  reduced pressure. The residue is treated in the same way as in the example

  ple 41, giving 2- (3-phenoxyacetamido-4-benzenesulfonylthio-2-azene)

  tidinone-1-yl) -3-methyl-3-butenoate / 1-methoxy-carbonyl-2-oxopropyl with a yield of 87%. The NMR spectral data of the compound thus obtained are identical to those of the desired compound. The data

  are shown in Table V below.

- 72 -

Example 68

  o It PhCFI2C M I NI C ^ O "gS COOCH3 SNa PhCH2CNH z: s

Coochi.

  500 mg of 2 -3-phenylacetamido-4- (2-benzothiazolyl)

  methyl dithio) -2-azetidin-1-yl-3-methyl-3-butenoate and 334 mg of 2-benzothiazolyl p-chlorobenzenethiosulfonate are dissolved in

  5 ml of acetone. To this solution are added i mi of water then 3 mg of 2-

  sodium benzothiazolyl thiolate. The mixture is stirred at ambient temperature for 3 hours. The precipitated 2-benzothiazolyl disulfide crystals are filtered and the filtrate is concentrated under reduced pressure. The

  The residue is treated in the same way as in Example 41, giving the 2-

  [3-Phenylacetamido-4- (p-chlorobenzenesulfonylthio) -2-azetidinone-1-yl)

  Methyl 3-methyl-3-butenoate with a yield of 72%. The data

  The NMR spectral results of the compound thus obtained are identical to those

  desired compound. The data are recorded in Table V below.

- 73 -

Example 69

  o PhCH2CN Ie SS .. N N .... _ _S S COOCH3 C> - SiVa o, PhCH2CNTzSS 02 N 2

* 0

COOCH 3

  500 mg of 2- / 3-phenylacetamido-4- (2-benzothiazolyidine)

  methyl thio) -2-azetidin-1-yl-3-methyl-3-butenoate and 344 mg of 2-benzothiazolyl p-nitrobenzbethobenzonethiosulphonate are dissolved in 5 ml.

  of acetone. To this solution are added 1 ml of water and then 3 mg of 2-benzo

  sodium thiazolyl thiolate. The mixture is stirred at room temperature

  biante for 3 hours. 2-Benzothiazolyl disulfide crystals

  The precipitates are filtered and the filtrate is concentrated under reduced pressure.

  The residue is treated in the same way as in Example 41, giving

  2- [3-phenylacetamnido-4- (p-nitrobenzenesulfonylthio) -2-azetidinone-

  Methyl 1-yl7H-3-methyl-3-butenoate with a yield of 58%. The NMR spectral data of the compound thus obtained are identical to those

  of the desired compound. The data are shown in Table V below.

after.

-74

Example 70

O NVO2

P; hCHaC, -iN '

COOCH 3

0

I II NNO2 PhCH2CMfH S_ __ N

OSSO +, 8028

NOT

NCOOCH3

  500 mg of 2-3-phenylacetamido-4- (2-benzothiazolyl)

  Methyl dithio) -2-azetidin-1-ylf-3-methyl-3-butiinoate and 344 mg of 2-benzothiazol o-nitrobenzenethiosulfonate are dissolved in 5 ml.

  of acetone. To this solution is added 1 ml of water and then 3 mg of 2-benzo

  sodium thiazolylthiolate. The mixture is stirred at room temperature

  biarite for 3 h. The crystals of 2-benzothiazolyl disuluride preci

  are filtered and the flitrat is concentrated under reduced pressure. The re

  sidu is treated in the same úacon as in example 41, giving 2- [3-

  phenylacetamido-4- (o-nitrobenzene sulfonylthio) -2-azetidinone - 1 - 17 - 3 -

  methyl methyl 3-butenoate with a tendency of 75%. The data

  spectral 1tMN of the compound thus obtained are identical to those of the com-

  asked posture. The data are recorded in Table V below.

O

PhCH2CNI N0 +

COOCH 3

  500 mg of 2- [3-phenylacetamido -4- (2-benzothiazolyl) -2-

  Methyl dithio) -2-azetidin-1-yl] -3-methyl-3-butenoate and 344 mg of 2-benzothiazolyl o-nitrobenzenethiosulfonate are dissolved in 5 ml.

  of acetone. To this solution is added 1 ml of water and then 3 mg of 2-benzo

  sodium thiazolylthiolate. The mixture is stirred at room temperature

  biante for 3 hours. The crystals of 2-benzothiazolyl disulfide preci

  The filtrates are filtered and the filtrate is concentrated under reduced pressure. The re

  sidu is treated in the same way as in Example 41, giving 2Z [3-

  phenylacetamido -4- (o -nitrobenzene sulfonylthio) -2-azeticlinone-1lyl] -3 -

  methyl-3-butenoate methyl with a yield of 75%. The data

  NMR spectra of the compound thus obtained are identical to those of the

  asked posture. The data are recorded in Table V below.

- 75 -

Example 71

O

PhCH2CNH N.s, / -

  Air NO2 4 50S S 1 -COOCH2Ph SNa I PhCH2CNH S-02-N O2 + N. COOCH2Ph

  500 mg of 2 -3-phenylacetamido-4- (2-benzothiazolyl)

  benzyl dithio) -2-azetidin-1-yl-1-3-methyl-3-butenoate and 314 mg of 2-benzothiazolyl p-nitrobenzenethiosulfonate are dissolved in ml of acetone. To this solution is added 1 ml of water and then 3 mg of 2-benzene.

  sodium zothiazolyl thiolate. The mixture is stirred at room temperature

  biante for 3 hours. 2-Benzothiazolyl disulfide crystals

  The precipitates are filtered and the filtrate is concentrated under reduced pressure.

  The residue is treated in the same way as in Example 41, giving the

  2 -3-phenylacetamido-4- (p-nitrobenzene sulfonylthio) -2-azetidinoneone-y17-

  Benzyl 3-methyl-3-butenoate with a yield of 70%. The data

  NMR spectra of the compound thus obtained are identical to

  asked posture. The data are recorded in Table V below.

-76 -

Example 72

  ## EQU1 ## COOCH2Ph S o Ii PhCH2CNH SS 2 OCH3 (aN 1 5 COOCH2Ph

  500 mg of 2 -3-phenylacetamido-4- (2-benzothiazolyldithio) -

  Benzyl 2-azetidin-1-yl-3,7-methyl-3-butenoate and 300 mg of

  2-benzothiazolyl methoxybenzenethiosulfonate are dissolved in 5 ml

  of acetone. To this solution are added 1 mnl of water then 3 mag of Zbenzo-

  sodium thiazolyl thiolate. The mixture is stirred at room temperature

  biante for 3 hours. 2-Benzothiazolyl disulfide crystals

  The precipitates are filtered and the filtrate is concentrated under reduced pressure.

  The residue is treated in the same way as in Example 41, giving the

  2-r3-phenylacetamido-4- (p-methoxybenzenesulfonylthio) -2-azetidinone

  Benzyl 1-yl-3-methyl-3-butenoate with a yield of 88%. The NMR spectrum data of the compound thus obtained are identical to those

  of the desired compound. The data are shown in Table V below.

after.

5. -, '- - - i

- 77 -

Example 73

  PhCH2CNT! OCH13 N, .r Ph $ O2S S O + Ph SO2Na O II PhCH2 CNt OC 3 N PSOS PSSO2Ph + S2 0 PhSO2iV COOCH2 j NO! 0 It PhCH, 2CN, .v OCH3N

0 N J

COOCH; 2-0 NO 2

  mg of 2-f3-methoxy-3-phenylacetarnido-4- (2-benzo)

  thiazolyldithio) -2-azetidinone-1-yl-3-methyl-3-butenoate p-nitro-

  benzyl and 102 mg of 2-benzothiazolyl benzknethiosulfonate are dissolved in 3 ml. of acetone. To this solution are added 0, 30 ml of water

  then 1 mg of sodium benzenesulfinate. The mixture is stirred at the temperature

  room temperature for 3 hours. Disulfide crystals of 2-ben-

  precipitated zothiazolyl are filtered and the filtrate is concentrated under

  reduced. The residue is treated in the same way as in the example

  41, giving 2 -3-methoxy-3-phenylacetamido-4 - (2-benzothiazolylthio) -

  P-nitrobenzyl 2-azetidin-1-yl / 3-methyl-3-butenoate with a yield of

  90%. The NMR spectrum data of the compound thus obtained

  * 30 are identical to those of the desired compound. Data are considered

Table V below.

- 78 -

  Examples 74 to 76 The compounds listed in Table IV are obtained according to the method of preparation of Example 41. The NMR spectrum data

  compounds thus obtained are reported in Table V below.

R $ R9 R 'S $ 02R3

R2 R9SSO2R> R2

! R3 SQ02 O R

1 0 19 Ru R3 S02Na R

Table IV

  Ex. No. R1 R2 R9 R4 R3 Yield (%) o 7 4 Ci.l 3 PhCIH2CNH- 3 COOCil2CC e3

"/ CH30 96

S. 76 r vHCH3 0 -? 5 7 6 CH 75j 3U

2555 8

- 80 -

Example 77

  The preparation of Example 41 is repeated except that the mg of sodium benzenesulfinate used as a catalyst

  are replaced by 17 mg of benzenesulfinic acid, giving 2- (3-

  p-Methoxybenzyl phenylacetamido-4-benzenesulfonylthio-2-azetidinone-1-yl) -3-methyl-3-butenoate in 87% yield. The NMR spectrum data of the compound thus obtained are identical to those

of the compound of Example 41.

Example 78

  The preparation of Example 41 is repeated except that the mg of sodium benzenesulfinate used as a catalyst

  are replaced by Z0 mg benzothiazole-thiol, giving Z- (3-phenyl)

  Nylac Etamido-4-benzenesulfonylthio -2-azetidinone-1-yl) -3-methyl-3-

  p-methoxybenzyl butenoate with a yield of 91%. The data

  the NMR spectrum of the compound thus obtained are identical to those

composed of Example 41.

  (H; I ut) 58 '/ - () O' L (OOf: / 'HZ' P) g8'9

('9 = /' MI 'P) 06%

  ## EQU1 ## where ## STR1 ## where ## STR2 ## where ## STR2 ## where ## STR2 ## 1s q) iSt't (H i 1 ZtlD 0 s) 691 '(I' (s ',' L (Hi 'N) 8L' I '(l "s) p, 0' '(ni' S) IL 'I (ZI = [' '$ çoqoa) N'idú7 ZI

(JI) 8L% '(1I,?.

ú1.zOSS e.

  A nt..nn Ln tt tu.N (6 = 1 HlZ 'P) 89'L' (6 = 1 'IP) O'L' (H5 's) M'IL (= - ## EQU1 ## where ## EQU1 ## where ## EQU1 ## ## STR5 ## wherein R 1 is OH (OH) CO (OH); 's) The (Hz:' r) Ofi '' (H s) 01 '?. ## STR2 ## wherein Y is a hydrogen atom, or PP) LZ'5 '(HZ' s) bl '5qd leOd (H1! Sq) Zi',> (Hl S) 6L'17 '(11 1 ss) 55 17 (o'Z1 = f' 1Z 'bfV) '' a ú H H H ((((((((((((((((((H = p res res res res Tableau Tableau Tableau Tableau Tableau Tableau Tableau Tableau Tableau Tableau Tableau Tableau Tableau Tableau Tableau Tableau Tableau Tableau Tableau Tableau Tableau Tableau Tableau Tableau Tableau Tableau Tableau Tableau Tableau Tableau Tableau Tableau Tableau NMR (CDCl3, J = Hz) 1.79 (s, 3H), 3.85 (s, 91), 4.35 and 4.41 (ABq, 2H, J = 12.5), 11C. H2 4.62 (s, 1H), 4.80 (s, H PhOCH2e, I-Ph1H), 4.84 (bs, 11), CLI3 OCHI3 5.08 (s, 21H), 5.26 (dd , 1H, J = 4 and 7), 5.84 COOC 2 OCH 3 (cd, 11H, J 4), 6.54 (s, OCH 3 2H), 6.75-7.90 (m, 1H) 1.76 (s, 311), 3, .77 (s, 31I), 4.34 and 1.10 (ABq.211, J = 1 2), CEII2 4.53 (s, 1H), 4.76 (s). , CH3a ,, 1H), 4.79 (bs, 1H), I -5.07 (s.2I2H), 5.27 (dd, COOCH2CH-31I, J = 4 and 6.5), , 86 (d, 111, J = 4), 6.65 - 7, 90 (nm, 1 51) Table 1 (continued) R 1 R 2 R 4 R 3 NMR (CDCl 3 8, J = 11z 2) 1, 76 (s, 3H), 3.89 (s, 6H 1), 3.94 (s 3H),

OCH 4.36 and 4.41 (ABq.

  III 2H 4, J = 12), 4.60 (s, H 2 PiOC.I 2 CNN-CH 3 Ph 1 H), 4.78 (bs, 1H), OCH 3 4.80 (s, 1H), 5.24 (dd, I, J = 4 and 6.5), 5.38 (s, 211), 5.88 (s, 2t), and OCH 3, 6.75 - 7.90 (m, 1, 1). (s, 31), 4.38 and 4.44 (ABq 21. J = 1-2), CH 2 4.90 (s, IIf), 4.96 (s 21), 5.28 and 5.34 "CH 3 (ABq.211, J = 1-2), tI 5.35 (dd.1, J = 4 and COOCH2 Br 6.5), 5.85 (d, I II, J = 1), 6.75- 7.95 (m, 1511), and ## STR1 ## S-OI '' i! ú! HD / sq) 56'b 'QjI 4s) Z8'%) (tl 'sS) IL' 1 (I = '7l-ZH s) 917' '(IIú' s) 8 '1 <.0 (blVk 01 ## EQU1 ## where ## EQU1 ##

I 'P) 06' 'Qiu' u,) 09 '4-

  I '4' (QI 'sq) b76'bk' Q / I1 Hl119 II 100 s) 6L 'b' 1t 's) 69' V d C HHH 13tOtd H (Zi = f 'HZ' bV) 1 bl ' a% I1 9u% k '(/ Q,' ut) 06 'ú-59' ú Ha a (uig 'u) 5 9' ú-0b '' (1i S ') 9u' g '(ui g) ## EQU1 ## ## STR1 ## ## STR2 ## ## STR1 ## ## STR2 ## '(H i' s) L9 '(18 = -' H I 'P) 05'9' (L% '= f' I P) 9L5 '(1'8' # - IPO'DIdd

= ['(HI' PP) 91 '(MI

III P) L8 '' ('8I

  s) (1t 1 's) Z8'1 0 (H 1 1 s) ILq V' (HZ 4) L56C '(H1' s) 9I'I (Ips) A Co (1l6 1 'bed) 06'L - 08'9 (Hl 's) 9L'9' (The b = l HIl 'P) LS'9' (Z'H: 8aOO The 17 = ['Ill' PP) ú'd / H -rel : tDqd (It 'Sq) 88'b,' (HI I1 s) 58% '(H!' $) 9L'CHo 0 (i = I = / HZ / bUV) {717z1 o 6ú'b '(Hú' IH (ZH = ['' DCID) Nt, if I2 (8A) (I) (A1Ing) A neelqej.l Table V (contd) R 'R2 R4 R3 NMR (CDCZ2, - J) = Hz)

1.78 (s, 3H1), 3.56 (s.

  2H), 4.57 (s, 1H), C82 4.76 (sH), 4.88 (bs, 11) Il 5.11 (dd, IH.J = 4 and H PhCH2CNI Cf3 Ph7), 5.23 (s, 2H), 5.72 COOCHI 2 -NO 2 (d, 1H, J = 4), 6.06 (d,

NH, J = 7), 7.00-8.00

(m, 12H), 8.19 (d, .2H, J = 7).

1.78 (s, 3H), 3.56 (s.

  Cf12 2H), 4.60 (s, 1H), 4.76 (s, 11H), 4.87 (bs, CHCl 3 H), 5.12 (dd, I, H. F "% <4 and 6.5), 5.53 (2H), 5.64 (d, 111, J = 4), 6.20 (d 1H, J = 6.5), NO 2 7.10 - 8.20 (m, 1H) Cu Vi Ln U1 Table V (continued) R1 R2 R4 R3 NMR (CDCL3, J = Hz) I, 84 (s, 311), 2.35 (s, CH2 311), 3.83 (s.3H), 4.38 OL and 4.45 (ABq.2f, J = II> L CH3 1 1), 4.80-5.05 (m, 3H PhOCeH2CMA- I Ph -H), 5.38 (dd, IIH, J = 4 COOCI-COCW3 and 7), 5.55 (s.111), CO2CH3 5.85 (d, 111, J = 4.0), 6, 75-8.00 (m, III) 0.11, 78 (s, 31I), 3.51 (bs, 2H1), 3.70 (s, 311), 4.61 o CH2, (bs, 1H), 4.76 (s, 11), II 0. 4.86 (bs, 11), 5.06 (dd, ## STR1 ## = 5), 714 (d, COOCII3 1, I, J- = 8), 7.23 (s, 51), 7.43 (d, 211, J = 8), 7.81 (d, 211); ## EQU1 ## where R1 is R3 NMR (CDCl3 t8, J = Iz) 1.80 (s, 3H), 3.52 (bs, CH2 21H121), 70 (ss 311), 4.55 O1I 2 (bs, 1H), 4.79 (s, 111),

## STR1 ## 4.87 (bs, 1H) 5.03 (dd.

  ## STR1 ##, 5.87 COOCW13 (d, IH, J = 5), 6.73 (d, 1H, J = 8), 7. , 22 (s, 5H), 7.94 (d, 21I, J = 9), 8.24 (d 211, J = 9), 1.80 (s, 31), 3.48 (bs, 2H), , 3.70 (s, 311), 4.64 (bs, II), 4.80 (s, nI), 4.88 (bs, III), n = 5.13 (dd, 11. J = 5 and NO2 8), 6.06 (d, 1H, J = 5), O2 6.88 (d, II, J = 8), 7.17 (s, 51J), 7.60-8, 20 (zm, 411)% rl Ln cel Table V (continued) R 'R2 R4 R3 NMR (CDCZ3, J = Hz)

1.75 (s.31), 3.50 (s.

  CH 2 H), 4.76 (bs II), CH 2 O 4.84 (s, 1H), 4.92 (bs, CH 3 1H), 5.10 (dd) 1H 2 O. 8), 5.12 (ss 211), PhCI-I2CNH CO0CraPh 2 5.92 (d, I 1, .J = 5), 6.91 (d, 1H, J = 8), 7.20 (s), , 5H1), 7.30 (s, H), 7.87 (d 211 J = 9), 8.18 (d 21, J = 9) 1.75 (s, 311), 3.50 (s, 211), 3.79 (s, 311), 4.65 (bs, 11), 4.77 (s, II),

4.85 (bs 11), 5, 12 (idd.

  t IHI. J = 5 and 8), 5.13 (s, 211), 5.73 (d 1H, J = 5), 6.63 (d 1H.IJ = 8), 6.87 (d, 211, J = -9), 7.20 (s, 5H), 7.29 (s, H), 7.67 (d, 2H, J = 9).

_ _ .. 1

  (6- 'HZ i P) Li' 8 e (HZ I 't) 06'_ -01' L (aux ^ sq) g 'I = xo s' (Z'1 'Sq) fJ I9' ( ## STR1 ## wherein R1 HN2O1Yi - is 67, f ((Hg, s)), (O, H), (O) H [I1

s) 18 '{' I (HI 's) /.

  (Hu 's 19' 'H el s) 9>' ú '(HÉ' S) 6L 'I (ZH-lr = [' ôdas q ') Avq I Y1 "to 1 (> fro.s) A Table VI (cont.) R1 R2 R4 R3 NMR (CDC3,?,?,?) 1 91 (s. 31), 2, 15 ($, 311), CH3 3, 60 (s, 211) ), 4, 60-4, 80 (nl, VI 3 11), 5, 83 (d, 1 i1, J 51 /), HPC CNI- f CH3 CH3i 7, 20 (n, 81), 7, 66 (d , 261. J = 7, l) 5208 (a '21') = 1, ') P hCIIaCNH-9lira

2 COOCI12CC3 9)

  N 1, 90 (s, 311), 2, 13 (s, 311), 3, 50 (s, 211), 3, 75 (s, 31 1), 4, 60-4, 80 (m, 311); , 5, 85 (d, "iHI1, J-4, 511 $), 6, 84 (d, 211,

3 J-711J). 7, 20 (&quot; 611), 7, 77

  (d, 211, J-711,) 2, 50 (s, 311), 3, 63 (s, 211),

  CH3-) 5, 20-5, 50 ('", 211), 7, 20-

? 7, 80 (m, 1 jIH)

i._ J ..__.

- 93 -

Claims (10)

  1. Process for preparing azetidinone derivatives of formula R1 RC 2 (I) 0, NR4   wherein R is hydrogen, halogen or lower alkoxy.   R is hydrogen, halogen, lower alkoxy, or amino or NHCR (where R is substituted or unsubstituted phenyl).   substituted, substituted or unsubstituted phenylmethyl, phenoxymethyl   substituted or unsubstituted thyl or substituted or unsubstituted benzoyl),   or R and R together form a carbonyl group, R is   substituted or unsubstituted nyl and R is hydrogen, a hydrogen residue   optionally substituted hydrocarbon or acyl, silyl, sulpho   nyl or phosphonyl derived from a mineral or organic acid,   in that a dithioazetidinone derivative of formula 2 is reacted with R 'SSR' (VI) 0 - NR4   in which R, R and R have the meaning given above and R9 is an aromatic heterocyclic residue containing substituted or unsubstituted nitro, with a compound of formula R3SOR (VII)   R 1 has the meaning given above and R is hydrogen, a   -CN group or -SR9 group (o R9 has the meaning given above). - 94 -   2. Method according to claim 1, characterized in that   R in the dithioazetidinone derivative of formula (VI) is hydrogen   C1-C4 gene, fluorine, chlorine, bromine, iodine or alkoxy, R is hydrogen, fluorine, chlorine, bromine, iodine, C1-alkoxy. -C4, amino or an NHCR group (o R is phenyl, phenyl having from 1 to 3 substituents, chosen in particular from C1-C4 alkyl, fluorine, chlorine, bromine, iodine, C1-C4 alkoxy or nitro on the phenyl ring, phenylmethyl, phenylmethyl having from 1 to 3 substituents chosen in particular from C1-C4 alkyl, fluorine, chlorine, bromine, iodine, C1-C4 alkoxy or nitro on the phenyl ring, phenylmethyl of which the methylene group is substituted by halogen, hydroxyl, hydroxyimino, C1-C4-imino alkoxy   or amino, phenoxymethyl, phenoxymethyl having from 1 to 3 sub-   stituents chosen in particular from C1-C4 alkyl, fluorine, chlorine,   bromine, iodine, C1-C4 alkoxy or nitro on the phenyl nucleus, ben-   zoyl or benzoyl having from 1 to 3 substituents, chosen in particular from   C1-C4 alkyl, fluorine, chlorine, bromine, iodine, C1-C4 alkoxy or nitro on the phenyl nucleus), or R and R together form a carbonyl group, R4 is hydrogen or one of the following groups -> <; z> <2 z22 Z1 2 2Z 2 Z1 Z2Z COOR6, COOR   R is hydrogen or a carboxyl protecting group, and Z and Z are the same or different and are halogen, a sulfur-containing group, an oxygen-containing group or a group containing oxygen; nitrogen), and R9 is the heterocyclic residue selected from   thiazol-2-yl, thiadiazol-2-yl, benzothiazol-2-yl, benzoxazol - 95 -   zol-2-yl, benzimidazol-2-yl, pyrimidin-2-yl and 2-pyridin   dyl, or this heterocyclic residue has 1 to 3 substituents chosen in particular from C1-C4 alkyl, phenyl, C1-C4 alkoxy, nitro or halogen.   3. Process according to claim 1, characterized in that R in the compound of formula (VII) is phenyl or phenyl having from 1 to 3 substituents chosen in particular from C1-C4 alkyl, fluorine, chlorine, bromine, iodine, C1-C4 alkoxy or nitro on the phenyl nucleus.   4. Method according to any one of claims 1 to   3, characterized in that R0 in the compound of formula (VII) is hydrogen.   5. Method according to any one of claims 1 to   3, characterized in that R0 in the compound of formula (VII) is a -CN group.   6. Process according to any one of claims 1 to   3, characterized in that R0 in the compound of formula (VII) is a   group -SR9 (oh R9 has the meaning given above).   7. Method according to any one of claims 1 to   6, characterized in that from about 1 to about 5 moles is reacted   of compound of formula (VII) per mole of compound of formula (VI).   8. Process according to Claim 5 or 6, characterized in that the reaction system comprises as catalyst at least one compound chosen from sulfinic acids of formula R SO2H (VIIa) (where R has the meaning given above) or their salts. , thiols of formula R9SH (VIII)   (o R9 has the meaning given above) or their salts and the nucleophilic compounds capable of giving R SO2 (where R has the meaning given above) in the case where it is reacted with a data compound below. above) in the case where it is reacted with a compound of - 96- formula (VIIb) or (VIIc).   9. Process according to claim 8, characterized in that the catalyst is used in an amount of   between about 0.0001 and about 0.1 mole per compound of formula (VI).   10. Process according to any one of the claims   1 to 9, characterized in that the reaction is conducted at a temperature   between -20 C and the reflux temperature of the solvent.