CS209825B2 - Method of preparation of the 2-chlorsulfinylazetidin-4-ons - Google Patents

Abstract

2-Chlorosulfinyl azetidin-4-one (I; R = remaining group of carboxylic acid; R1 = protecting group of carboxylic acid) were prepd. by reaction of penicillin sulphoxide ester (II) with N-chloro-halogenating agent in inert org. inert solvent at 75-175≰C. The improvement comprises carrying ont reaction in presence of organic solvent insol, weakly basic crosslinked poly 4-(vinylphridine) polymer in wt. ratio of polymer to II of 1:1-1:5. The polymer is crosslinked to 1-10% with e.g. divinyl benzene, N,N'-methylene-bisacrylamide, trimethacrylate or divinylsulphon.

Description

The invention relates to an improved process for the preparation of 2-chlorosulfinylazetidin-4-ones from penicillin sulfoxide esters.

According to the invention, a production method is possible

2-chlorosulfinylazetidin-4-one of formula I

(I) in which denotes

R is a carboxyl group residue a

R1 is a carboxylic acid protecting group consisting of the reaction of a penicillin sulfoxide ester of formula II

wherein R and R 1 are as defined above in an inert organic solvent with an N-chloro halogenated compound, characterized in that the reaction is carried out in the presence of a cross-linked polyvinylpyridine polymer containing between about 1 percent to 10 percent crosslinking, at a temperature ranging from 75 to 175 ° C, at a weight ratio of polymer to penicillin sulfoxides of from 1: 1 to 1.5.

The process of the invention involves the use of a slightly basic, organic solvent insoluble cross-linked polyvinylpyridine209825 polymer to obtain 2-chlorosulfinylazetidin-4-one. The vinylpyridine copolymer causes rapid removal of hydrogen chloride from the heterogeneous reaction medium and thus prevents the development of by-products. Further, the acid-bound vinyl pyridine crosslinked polymer is readily removed from the reaction mixture by filtration or other suitable means.

These 2-chlorosulfinylazetidin-4-ones are useful intermediates in the process described by Kukolja (U.S. Pat. No. 4,052,387) for the preparation of sulfoxides of 3-exomethylenecepham-4-carboxylic acid esters. The improved process of the present invention and the cyclization of 2-chlorosulfinylazetidinones can be illustrated by the following scheme.

(III)

In the preceding reaction scheme, R is an organic radical, for example benzyl or phenoxymethyl, and R 1 is a carboxyl protecting group. The sulphoxide group of the penicillin sulphoxide ester used as starting material may have either the or the β configuration (R or S).

These 2-chlorosulfinylazetidin-4-ones prepared according to the improved process of the invention, as well as other substances, have been previously described. U.S. Pat. No. 6,960,851, issued June 1, 1976 to Kukolja et al. disclose 3-imido-substituted-2-chlorosulfinylazetidin-4-ones in which the amino group of azetidinone is diacetylated with a dicarboxylic acid derivative and the conversion of 3-iridoidazetidinones yields 3-methylcephems (desacetoxycephalosporins). In U.S. Patent No. 3,843,682, Oct. 22, 1974, to Kukolja et al. also discloses 3-imido-2-chlorosulfinylazetidin-4-ones. Later, Kukolja, in U.S. Patent No. 4,081,440, March 28, 1978, discloses 3-amido-2-chlorosulfinylazetidin-4-ones in which the 3-amino group is monoacetyl. Also disclosed herein is a process for the preparation of 3-amidoazetidinones by N treatment

-chlorohalogenating agents to penicillin sulfoxide esters.

In U.S. Pat. No. 4,052,387, Oct. 4, 1977, Kukolja discloses a process for preparing 3-exomethylenencephamsulfoxides by cyclizing 3-amido-2-chlorosulfinylazetidin-4-ones with a Friedel-Crafts catalyst or a cation exchange reagent.

Further, Ta-Sen-Chou discloses in U.S. Patent No. 4,075,203, Feb. 21, 1978, an improved process for the preparation of 3-exomethylenencephem derivatives which involves the use of a combination of alkylene oxide and calcium oxide in the preparation phase of 3-amino-2-chlorosulfinylazetidine- 4-onu.

The invention provides yet another improvement in the two-step process for the preparation of 3-exomethylencephamsulfoxides from penicillin sulfoxide esters via 2-chlorosulfinylazetidin-4-ones as intermediates. The improvement of the invention involves the use of a slightly basic, organic solvent-insoluble polymer of polyvinylpyridine, cross-linked, for example with divinylbenzene, as a hydrogen chloride acceptor in the first stage of production to form an intermediate,

2-chlorosulfinylazetidin-4-one.

These 3-exomethylencephamsulfoxides are valuable intermediates for cephalosporan antibiotics. For example, they can be converted by ozonolysis of the 3-exomethylene group to the esters of 3-hydroxy-3-cephemesulfoxides. These may be halogenated to form the corresponding

The 3-halo-3-cephem-esters, or these 3-hydroxy-compounds, may be reacted with a diazolalkanane, for example diazomethane, to give the corresponding 3-methoxy-3-cephemesulfoxide esters. The sulfoxide forms of these compounds can be reduced by known methods, for example, as described in U.S. Patent No. 3,641,014 to Murphy et al., But particularly by the method described by Hattfield in U.S. Patent No. 4,044,002, August 23, 1977. Deesterification

The 3-halo- or 3-methoxyesters provide antibiotics. For example, 3-methoxysubstituted cephalosporin antibiotics are described by Chauvett in US Patent Nos. 3,917,587 and 3,917,588, while 3-halogen substituted cephalosporin antibiotics are described by Chauvette in US Patent Nos. 4,064,343, 3,962,227 and 3,925,372.

According to the present invention, the 6-acylamido-2,2-dimethylpenam-4-carboxylic acid sulfoxide ester of formula II

wherein R is a carboxylic acid moiety and R 1 carboxylic acid protecting group is reacted in an inert organic solvent, preferably at a temperature between about 75 ° C to 175 ° C in a substantially anhydrous medium with an N-chloro halogenated reagent in the presence of] to form a similarly substituted 2-chlorosulfinylazetidin-4-one of the following Formula I

del-Crafts catalyst causing cyclization of this 2-chlorosulfinylazetidinone to 3-exomethylencepham.

The starting material, penicillin sulphoxide, can have either a or β configuration (R or S). The preparation of penicillin sulfoxides is well known, for example penicillin-3-sulfoxides can be prepared by reacting penicillin with organic peracids such as perbenzoic acid, peracetic acid, or preferably m-chloroperbenzoic acid, or with inorganic oxidants such as sodium periodate. The penicillin sulfoxides are preferably prepared by reacting penicillin with ozone in an inert solvent followed by separation of the mixture of formed α and β sulfoxides. The preparation of penicillin-α-sulfoxides is described by Spry in U.S. Patent No. 3,691,188.

As mentioned above, the reaction of the penicillin sulfoxide ester is carried out in an inert organic solvent under substantially anhydrous conditions. The term "inert organic solvent" means an aprotic organic solvent that does not react appreciably with either the N-chloro halogenating agent or 2-chlorosulfinylazetidinone under the conditions of this process. Suitable inert organic solvents are those having a boiling point at least as high as the reaction temperature and include aromatic hydrocarbons such as benzene, toluene, ethyl carbonene, cumene, xylenes, tetralin and the like; halogenated hydrocarbons such as carbon tetrachloride, chloroform, 1,1,2-trichloroethane, ethylenedibromide and the like halogenated hydrocarbon solvents; aromatic ethers such as anisole, phenetol, diphenyl ether and the like. Preferred organic solvents for this process are benzene, toluene and xylenes. Preference is given to using reagent grade solvents and suitably dried, for example by binary distillation or molecular sieve distillation, or by conventional drying agents such as calcium chloride, magnesium sulfate, sodium sulfate and the like.

The temperature at which the process is carried out with a given solvent can be increased by carrying out the process at elevated pressure, for example at about 70 kPa to about 175 kPa.

The N-chlorogenating agents used in the process of the invention are represented by the compounds of the following general formula

R 2, N-Cl, R 5 in which is

R? hydrogen, chlorine, alkyl of 1 to 3 carbon atoms, cyclohexyl, phenyl, or phenyl substituted with chlorine, bromine, methyl or nitro; and

R 3 is a substituent R 4 - X - in which R 1 is an alkyl of 1 to 3 carbon atoms, the cyclo copolymer is filtered off from the reaction mixture and the 2-chlorosulphinylazetidinone is isolated, or the filtrate can be treated with Frie 2 O → 5 hexyl, phenyl, or phenyl substituted with chlorine, bromine, methylene, or nitro; and X represents a group

O — N — C,

Cl o

-C, o

—O — c— or —SO2—; or R 2 and R 3 together with the nitrogen atom to which they are attached form a heterocyclic group of the formula

wherein Y is o-phenylene or - (CHaJn) wherein n is 2 or 3;

wherein Y is as defined above.

The above definition includes several types of preferred N-chlorinated compounds that can be used in the preparation of sulfinyl chlorides. These N-chlorinated compounds include a) ureas, b) amides, cj urethanes, dj sulfonamides, e) sulfimides and f) imides.

Preferred N-chlorinated urea derivatives that can be used in the process of this invention have the general formula

chlorine, bromine, methyl or nitro.

Examples of these ureas are:

N, N-dichloro-N-methylurea, N, N-dichloro-N-ethyl-N-cyclohexylurea, Ν, Ν-dichloro-N-phenylurea,

N, N ^, -dichloro-N, N ^, -diphenylurea _r

N, N’-dichloro-N- (p-tolyl) urea

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

N, N’-dichloro-N, NMicyclOhexylurea,

N, N'-dichloro-N-isopropyl-N '- (p-tolyl urea,

N, N'-dichloro-N-phenyl-N'-propylureaLa,

N, N '-dichloro-N-cyclohexyl-N' - (p-nitrophenyl) urea,

N, N, N’-trichloro-N-methylurea,

N, N, N'-trichloro-N-phenyl urea _r and the like.

Preferred N-chlorinated amides which can be used in the process of Part ^{1 of the} invention have the general formula

O Rz

II /

R4 — c — n \

Cl in which R 2 and R 4 are as defined above.

Examples of these amides are: N-chloroacetamide, N-chloropropionamide, N-chloro-N-methylacetamide, Ν, Ν-dichloroacetamide, N-chloro-N-cyclohexylacetamide, N-chloro-N-ethylbenzamide, N-chloro-p-chlorobenzamide , N-chloro-p-toluamide, N-chloro-N-phenylpropionamide, N-chloro-N- (m-bromophenyl) butyramide, N-chlorhexahydrobenzamide, N, 2,4-trichloroacetanilide and the like.

Preferred N-chlorinated urethanes that can be used in the preparation of the sulfinyl chlorides of this invention have the general formula

O R2

R4 — O — C — N \

Cl in which R 2 and R 4 are as defined above.

Examples of such urethanes are methyl N, N-dichlorocarbamate, ethyl N, N-dichlorocarbamate-phenyl N, N-dichlorocarbamate, cyclohexyl-Ν, dichl-dichlorocarbamate, methyl-N-chlorocarbaxate, ethyl-N-chlorocarbamate, ethyl- N-cyclohexyl-N-chlorocarbamate, phenyl-N-chlorocarbamate, phenyl-N-phenyl-N-chlorocarbamate, p-tolyl-N-chlorocarbamate, m-chlorophenyl-N-methyl-N-chlorocarbamate, cyclohexyl-N-cyclohexyl- N-chlorocarbamate, isopropyl-Np-tolyl-N-chlorocarbamate, phenyl-N-propyl-N-chlorocarbamate, cyclohexyl-Np-nitrophenyl-N-chlorocarbamate and the like.

in which it means

R 2 is hydrogen, chloro, C 1 -C 3 alkyl, cyclohexyl, phenyl, or chloro, bromo, methyl, or nitro substituted phenyl; and

R 4 represents alkyl of 1 to 3 carbon atoms, cyclohexyl, phenyl, or phenyl substituted with 209825

Preferred N-chlorinated sulfonamides that can be used to prepare the sulfinyl chlorides of this invention have the general formula. R2

R4-SO2-N-Cl wherein R2 and R4 are as defined above.

Examples of such sulfonamides that may be used as halogenating agents are Ν, Ν-dichlorobenzenesulfonamide, N, N-dichloromethanesulfonamide, N, N-dichlorocyclohexanesulfonamide, N, N-dichloro-p-toluenesulfonamide, N-chloromethanesulfonamide, N-cyclohexyl-N -chlorobenzenesulfonamide, N-cyclohexyl-N-chloroethanesulfonamide, N-chlorobenzenesulfonamide, N-phenyl-N-chlorobenzenesulfonamide, N-chloro-p-toluenesulfonamide, N-ethyl-N-chloro-m-nitrobenzenesulfonamide, N-ethyl-N-chloro -m-nitrobenzenesulfonamide, N-methyl-N-chloro-m-chlorobenzenesulfonamide, N-methyl-N-chloro-p-toluenesulfonamide, N-cyclohexyl-N-chlorocyclohexanesulfonamide, Np-tolyl-N-chlorisopropanesulfonamide, N-propyl-N -chlorobenzenesulfonamide, Np-nitrophenyl-N-chlorocyclohexanesulfonamide, and the like.

Another preferred type of N-chloro halogenating agent that can be used in the preparation of sulfinyl chlorides is the sulfimide of formula

wherein Y is o-phenylene, -CH 2 -CH 2 - or -CH 2 -CH 2 -CH 2.

These compounds include o-sulfobenzoic acid N-chloroimide, j-sulfopropionic acid N-chloroimide and χ-sulfobutyric acid N-chloroimide.

Particularly preferred N-chloro halogenating agents for the preparation of the sulfinyl chlorides of the present invention are the N-chloroimides of the formula:

II

The agents used in the process of the invention are commercially available and any of them can be prepared by generally known procedures. Typical literature sources detailing the preparation of N-chloro halogenating agents are Bachand et al. J. Org. Chem. 39, (1974) pp. 3136-3138; Theilacker et al., Liebigs Ann. Chem. 703, (1967) pp. 34-36; and Houben-Weyl, Methoden der Organischen Chemie, Volume V / 3, pp. 796-810.

The N-Cl 2 -haloxygenating agents which have a preferred use in the process of the invention are N-chloroimides, especially N-chlorosuccinimide or N-chlorophthalimide, and in particular N-chlorophthalimide.

The cross-linked polyvinylpyridine polymers used in the process of the invention are weakly basic resins that are insoluble in inert organic solvents - and especially in the reaction medium used in the present invention. These polymers contain from about 1% to about 10% crosslinking.

The cross-linked polyvinylpyridine polymer is prepared by polymerizing vinyl monomer monomer in the presence of a crosslinking agent. As used herein, the term "vinylpyridine" means 4-vinylpyridine, 3-vinylpyridine, 2-vinylpyridine and methylated vinylpyridines such as 2-methyl-4-fluoropyridine and 3-methyl-4-vinylpyridine. The preferred monomer is 4-vinylpyridine. These polyvinylpyridines can be crosslinked by many known crosslinking agents. Examples of crosslinking agents are difunctional substances such as vinylaromates, for example -divinylbenzene, acrylamides, for example N, N'-methylenebisacrylamide -____________..............

o ................................

[CH2 [NH — C — CH = CH2] 2]

Ν, Ν '-decamethylenebisacrylamide and Ν, dialΝ-diallylacrylamide; esters of acrylates and methacrylates such as ethylenediacrylate, ethylenedimethyl acrylate and triethylene glycol dimethacrylate; allyl esters of aromatic and aliphatic dicarboxylic acids such as dialkyl phthalate, diallyl malonate and diallyl succinate; and other diffuse vinyl and allyl derivatives such as divinylsulfone and N, N'-di.allylpiperazine; trifunctional crosslinking agents, for example 1,1,1-trimethylolpropantrimethacrylate

O or II [CH 3 CH 2 -C (O-C-C (CH 3) = CH 2) 3],

1,2-Dimethyl-1-triethacrylate, 1,1,1-trimethylolethane triacrylate, 1,11-trimethylol ethane trimethacrylate, 1,3,5-Sriacryloylhexahydro-s-thiaziazine, 1,3,5-trimethacryl-ethylhexahydro-tris-trisyclohexane triaHylisocyanurate; and tetrafunctional cross-linking agents, such as ptatrytritetyl tetramethacrylate, pentaerythritol tetrametacrylate, tallyallyl oxytethane, and tetraallvlp / iro m m l ltate.

wherein Y is o-phenylene, -CH 2 -CH 2 - or -CH 2 -CH 2 -CH 2 -.

These compounds include N-chlorophthalimide, N-chlorosuccinimide and N-chlorglutarimide.

Many of these N-chloro halogenation or 209825

A preferred crosslinker is dlvinylbenzene. Other preferred materials are methylenebisacrylamide and methylenebismethacrylamide of the formulas below

OO. II .II

CH = CH — C — NiH — CH2 — NH — C — CH = CH2

0o

IIII

CH2 = C-C-NH-CH2-NH-C-C = CH2

CH5CH3

The vinylpyridine monomer may also be crosslinked with. divinylpyrrolidine or methylated divinylpyridine, for example 2-methyl-4,6-divinylpyridine. Obviously, they can be. other known or preparable crosslinkers are used to prepare the cross-linked polyvinylpyridium polymer used in the process of the invention.

Preferred crosslinked polymers of the present invention are poly (4- ⁽ vii) ^, 11- (4-pyridine)) divinylbenzene (containing about 2-5% crosslinking), poly- (4-vinylpyridine) -N, N '. -methylene-bisacrylamide and poly- (4-vinylpyridine) -N, N'-methylene-bismetacrylamide.

Polyvinylpyridine polymers are conveniently prepared by heating vinylpyridine in the presence of azobisisobromotromiril and crosslinker in an aqueous solvent system. A suitable aqueous system that can be used is saline and diisobutyl ketone. The saline solution promotes polymerization in the organic phase and thus ensures more complete polymerization.

The polymerization can also be carried out as described by Hallensleben and Wurm. Angew. Chem. - Int. Ed. Engl. 15, 163 (1976), which reported the preparation of poly- (4-vinylpyridine J) divinylbenzene.

Alternatively, these crosslinked polymers can be prepared in water by a emulsion polymerization method with a surfactant such as polyvinyl alcohol or polyethylene oxide. The macroreticular beads of crosslinked polymers can be prepared by known methods, for example as described in U.S. Patent 3,816,355.

The crosslinkers described herein are commercially available and can be prepared by known methods.

It is apparent from chemical practice that, while the polymers formed by the various crosslinkers are functional equivalents in the process,. the individual crosslinked polymers may have certain advantageous properties not manifest in others. For example, certain polymers may be regenerated and reused several times, while others resist less regeneration and reuse.

Furthermore, some of the crosslinked polymers are easier to get rid of the free impurities accompanying their preparation than others. Similarly, some polymers - are more expensive than others. Also, for a given feedstock, a smaller amount of one polymer may be sufficient than a number of other polymers.

The preferred cross-linking range of the polymers is between about 2% - and 5%. The desired cross-linking range is obtained by using a suitable amount of cross-linking material in the polymerization of the polymer. Polypyridine, which has the desired degree of crosslinking, rapidly absorbs the hydrogen chloride formed during the reaction with the penicillin sulfoxide N-chloro halogenating agent. Furthermore, the acid is rapidly and completely removed from the reaction system because the polymer is insoluble in the reaction medium. This rapid removal of the acidic by-product prevents its reaction with the unreacted starting material and thus prevents the by-reactions from forming undesirable by-products.

Crosslinked polyvinylpyrrolidine can be used in various forms. For example, it may be in the form of a fine powder or small spheres or in the form of macroporous spheres. The preferred form of the copolymer has a large specific surface area which is a measure of the accessibility of the basic polymer moieties to the acid. Accordingly, the lower the average particle size, the higher the specific surface area and the greater accessibility of the basic groups. Likewise, the copolymer in the form of macroporous beads has a large specific surface area including an inner surface with an accompanying high occurrence of basic groups in the copolymer. For copolymers in the form of relatively uniform shapes, for example spheres, such as macroreticular spheres, a size between about 20 x 10 ^-6 and 120 x 10 ^-6 m diameter is preferred. The irregularly shaped copolymers, which can be obtained by crushing the copolymerized resin in a hammer mill, obtain a preferred particle size by collecting a proportion passed through a sieve of about 120 mesh.

The copolymer having a degree of crosslinking in the range of about 1 to 10% exhibits a characteristic swelling in the organic solvents used in the process. A copolymer having a higher degree of crosslinking swells less and the degree of swelling decreases with increasing degree of crosslinking. The increased volume of the copolymer due to the swelling allows a significant increase in the hydrogen chloride access to the basic groups of the polymer. Copolymers that are more than 10% crosslinked swell much less than those that are less than 10% crosslinked, or - within the preferred range and although they do not dissolve in organic solvents, are not effective for binding hydrogen chloride. .

The use of a crosslinked copolymer of preferred particle size allows the process of the invention to be carried out at higher concentrations than prior processes in which alkylene oxide and calcium oxide were used as acid binders (Ta-Sen Chou, U.S. Pat. For example, at concentrations 3 or 4 times higher than those permitted in the prior art, the yields of the product are the same or higher than in these processes.

In carrying out the process of the present invention, the N-Ghalalhalogenant may be used in molar excess relative to the penicillin sulfoxide ester. Generally, however, between about 1 mol and 1.5 mol of N-chloro halogenating agent per mole of penicillin sulfoxide ester is used. The preferred molar ratio of N-chloro halogenating agent is between about 1.0 to 1.1 to 1.5 moles per mole of penicillin sulfoxide.

A preferred weight ratio of the amount of polymer used to the amount of penicillin sulfoxide ester is about 1: 1 and 1: 5, more preferably the ratio is about 1: 2 and 1: 3.

The highest yields of 2-chlorosulfinylazetidinon-4-one according to the invention are obtained when the concentration of penicillin sulfoxide ester in an inert solvent is between about 20 mg / ml to about 45 mg / ml. Penicillin sulfoxide has low solubility in inert aprotic solvents such as benzene or toluene but is slightly more soluble in halogenated hydrocarbon solvents. However, the product, 2-chlorosulfinylazetidinone, is completely soluble in the inert solvent used in the process.

One aspect of the improved process of the invention, the use of a cross-linked polymer having an average particle size in the preferred range, allows the process to be carried out at higher concentrations of penicillin sulfoxide than possible by the prior art. Using a crosslinked polymer having a preferred particle size and a penicillin sulfoxide concentration of between about 50 mg / ml and 85 mg / ml achieves the same yields as those performed at lower concentrations.

The penicillin sulfoxide esters that can be used in the process of the invention are represented by the above general formula (II), wherein R is an organic carboxylic acid residue and R 1 is a -carboxylic acid protecting group. Expression

The "R-C-" of Formula II may be any carboxylic acid derived acyl group that is stable under the described conditions of the process of the invention. For example, the N-acyl group represented by the foregoing expression in Formula II may be any of the well-known N-acyl groups used in the preparation of the cephalosporan antibiotics described in the literature that do not chlorinate with the N-chloro halogenating agent or do not react with tin tetrachloride itself. in the second step of the process for the preparation of 3-exomethylencephamsulfoxide.

The penicillin sulfoxide esters which can be used in the process of the present invention are those compounds of formula (II) wherein R is hydrogen, alkyl of 1 to 3 carbon atoms, halomethyl or cyanomethyl; or R is. R ', wherein R' is phenyl or phenyl substituted with 1 or 2 substituents selected from the group consisting of alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, halogen, protected hydroxy, nitro, cyano and trifluoromethyl; or R is a group of the formula R "-O" wherein R "- is thermal butyl 2,2,2-trichloroethyl, benzyl, 4-nitrobenzyl or 4-methoxybenzyl; or -R represents a radical of formula R '' - (Z) n 'CH2', in which R '' has the meaning of the above substituent R ', 2-thienyl, 3-thienyl, 2-phenyl, 3-phenyl or

1,4-cyclohexadienyl; n is 0 or - 1 and - Z is O or S with the restriction that - if n is 1 R '' means R '; or R represents a substituted aralkyl group of the general formula

R ’” - CH—,

Q in which R '' is as defined above- and Q is protected hydroxy or protected amino; and R 1 represents a protected carboxyl group.

In the above definition of penicillin sulfoxides, the term "alkyl of 1 to 3 carbon atoms" refers to methyl, ethyl, n-propyl and isopropyl, the term "halomethyl" refers to chloromethyl and bromomethyl.

Examples of substituted phenyl groups expressing the term "R" as defined above are 4-methylphenyl, 3-ethylphenyl, 2,4-dimethylphenyl, 4-n-propylphenyl, 4-tertiary butylphenyl, 2-methoxyphenyl, 4-ethoxyphenyl, 3-isopropoxyphenyl , 4-isobutyloxyphenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 3-chloro-4-fluorophenyl, 4-nitrophenyl,

2-cyanophenyl, 4-trifluoromethylphenyl and the like mono or di-substituted phenyl and hydroxy-protected phenyl groups such as 3-formyloxyphenyl, 4-trityloxyphenyl, 4-benzyloxyphenyl, 3-nitrobenzyloxyphenyl, 4-chloroacetoxyphenyl and the like, protected-hydroxy-substituted groups .

Examples of groups expressing the term "R - (Z) _n --CH 2 -" as defined above are phenoxymethyl, 4-fluorophenoxymethyl, 3-benzyloxyphenoxymethyl, 4-benzhydryloxyphenoxymethyl,

3-trityloxyphenoxymethyl, 4-nitrobenzyloxyphenoxymethyl, 4-trimethylsilyloxyphenoxymethyl,

3-nitrophenoxymethyl, 4-cyanophenoxymethyl,

4-trifluoromethylphenoxymethyl, 4-n-propylphenoxymethyl, 3-methoxyphenoxymethyl, 4-ethoxyphenoxymethyl, 3,3-dimethylphenoxymethyl,

3,4-dichlorophenoxymethyl, 2-fluorophenoxymethyl, phenylthiomethyl, 4-trimethylsilyloxyphenylthiomethyl, 3-nitrophenylthiomethyl, 4-cyanophenylthiomethyl, 4-trifluoromethylphenylthiomethyl, 2-chlorophenylthiomethyl, 3,4-dichloro209825 phenylthiomethyl, 4-trifluoromethylthiomethyl, 4-trifluoromethylthiomethyl, -dimethylphenylthiomethyl, 4-benzhydryloxyphenylthiomethyl,

3-trityloxyphenylthiomethyl, 2-thienylmethyl, 2-furylmethyl and 3-furylmethyl.

Examples of groups defined by the above formula wherein R is substituted aralkyl of formula

R ’” - CH- (Q1-, are:

α- (benzhy dryloxy) -thien-2-ylmethyl, α- (4-nitrobenzyloxy) -thien-2-ylmethyl, α- (tert-butyloxycarbamido) -thien-2-ylmethyl, α-formyloxybenzyl, α-benzyloxybenzyl , α-tertiary butylcarbamidobenzyl, N- (2,2,2-trichloroethoxycarbamido) -benzyl, ca- (trimethylsilyloxy) -4-bromobenzyl, N- (benzhydryloxycarbamido) -3-chlorobenzyl, N- [benzhydryloxy] -furan-2 -ylmethyl, α- (tertiary butyloxycarbamido) -furan-2-ylmethyl, car (4-nitrobenzyloxy) -2-cyanobenzyl, ca- (benzyloxycarbamido) -4-methoxybenzyl, and α- (trimethylsilylamino) benzyl.

In the above formula, R 1 is a carboxylic acid protecting group. Such groups are esters forming groups commonly used in the chemistry of cephalosporin antibiotics to block or protect the C 6 carboxyl group of a molecule during the reaction or sequence of reactions of other groups of the molecule. These protecting groups can be readily removed by cleavage under acid hydrolysis or hydrogenolysis conditions. Examples of such carboxylic acid protecting groups are tert-butyl, haloalkyl ester groups such as trihaloalkyl, for example 2,2,2-trichloroethyl and monohaloalkyl such as 2-iodoethyl; benzyl ester type protecting groups such as benzyl, 4-methoxybenzyl,

4-nitrobenzyl and 3,5-dimethoxybenzyl; diarylalkyl protecting groups such as diphenylmethyl and ^4,4 -dimethoxydifenylmethyl; and other known protecting groups such as phenylacyl, p-chlorophenacyl and the succinimidomethyl ester forming group. These R 1 protecting groups in the improved process of the invention only act as carboxylic acid protecting groups and are not critical in this process. Other generally known carboxylic acid protecting groups may be used, for example those described by E. Haslam in Protective Groups in Organic Chemistry, JFW McOmie, ed., Plenum Press, NY, 1973, Chapter 5. Preferred ester groups represented by the term R 1 in the process of this invention is tert-butyl, diphenylmethyl, p-methoxybenzyl and p-nitrobenzyl. The p-nitrobenzyl ester is a particularly preferred carboxylic acid protecting group.

The term "protected hydroxy" in the above formula refers to commonly used hydroxy protecting groups which are readily removable. Such groups include, for example, formyloxy, acetoxy, chloroacetoxy, benzyloxy, p-nitrobenzyloxy, trityloxy and trimethylsilyloxy. Like the carboxylic acid protecting groups described above, the hydroxy protecting groups only act as blocking groups to prevent unnecessary side reactions during the process of the invention. The nature of these groups therefore does not play an essential role in avoiding unnecessary side reactions during the process of the invention. Such groups are therefore not essential to the process of the invention and other groups well known to those skilled in the art, such as those described in C., may be used in addition to the above groups.

D. Rees in "Protecting Groups in Organic Chemistry, see Chapter 3 above."

The term "protected amino group" used in the above definition of preferred trainings in the process of the invention refers to a substituted amino group in which the substituent is one of the commonly used blocking or protecting groups used in the chemistry of cephalosporins and penicillins. For example, an amino protecting group is a group that is readily removable after the process of the invention under acidic or alkaline hydrolysis or hydrogeinolysis conditions. Examples of such groups include urethane-forming groups with an amino group, for example, tert-butyloxycarbonyl, benzyloxycarbonyl, substituted beinzyloxycarbonyl, such as p-methoxybenzyloxycarbonyl, and p-nitrobenzyloxycarbonyl, trihalkoxycarbonyl, trihalkoxycarbonyl, trihalkoxycarbonyl, trihalkoxycarbonyl, protecting groups such as enamine formed with methyl or ethyl acetoacetate and similar known amino protecting groups. Other examples of commonly used amino protecting groups are described in J. W. Barton in Protective Groups in Organic Chemistry, supra, Chapter 2.

A preferred group of penicillin derivative starting materials in the process of the invention are those represented by formula II wherein R is benzyl, phenoxymethyl, or 2-thienylmethyl and wherein R 1 is benzyl or substituted benzyl, for example p-nitrobenzyl or p-methoxybenzyl.

The cross-linked polyviinylpyridine polymer acts excellently in the process of the invention. The success of the reaction depends in part on the rapid removal of the hydrogen chloride produced by the reaction. Although the polymer is insoluble in the organic solvent used, it rapidly binds hydrogen chloride and, due to its insolubility, typically swells efficiently to remove the acid from the medium for the reaction medium. Furthermore, the copolymer is weakly basic and thus does not cause decomposition of the product, 2-chlorosulfinylazetidinoin, which occurs when strongly basic hydrogen chloride acceptors are used.

The insolubility of the described cross-linked copolymer is one of its important properties for another reason. Other weakly basic compounds commonly used as acid acceptors that are at least partially soluble in the reaction medium are ineffective acceptors in the process of the invention. For example, little or no product is obtained by the prior art if pyridine or. quinoline replaces alkylene oxide, or a combination of alkylene oxide and calcium oxide (T. S. Chou, U.S. Pat. No. 4,075,203). Further, a soluble polyvinylpyridine polymer that is not crosslinked is ineffective in the reaction.

The following Table I shows the yields of 3-exomethylencepham-4-carboxylic acid sulphoxide obtained under the conditions of the preparation of the intermediate, 2-chlorosulphinyllaltidinone, in the presence of poly (4-vinylpyridine) with varying percent crosslinking with the preferred crosslinking agent divinylbenzene.

Table I

Effect of crosslinking on the yield of 3-exomethylenencephamsulfoxide ¹

Percentage of ² crosslinks Polymer Weight / Weight of penicillin % Yield 2 1/2 59.5 2 2/5 43.4 3 1/2 63.5 4,5 1/2 63.3 30 1/2 0

¹ In all cases, 50 g of p-mtrorenzyl 6-fenoxyаcetamido-2,2-dimethylpenam-3-carboxylate-l-oxide with N-chlorophthalimide in the presence of said weight ratio of copolymer in 1800 ml of toluene previously dried by azeotropic distillation. Unisolated 2-chlorosulphinyl-aztidinone was converted into tin (II) chloride to 3-exomethylencephamsulfoxide.

Poly (4-vinylpyridine) crosslinked with divinylrenzene

As can be seen from Table I, when the degree of crosslinking is high, such as 30%, the product yield is. little or none. A high percentage of crosslinking reduces the degree of swelling of the resin, making the base sites in the polymer less accessible to hydrogen chloride.

As mentioned above, the use of a cross-linked polyvinylpyridine polymer allows the preparation of 2-chlorosulfinylazetidinones at higher concentrations than previously possible under optimal conditions. Crosslinked polymer. in the form of spheres with a particle size between approximately ²⁰ x ^{10 6} m 120. ^10-6 m or particles of about 120 to 140 mesh is the preferred form of the polymer because it allows the process to be carried out with three to four times the amount of penicillin sulfoxide ester in one. of the solvent before the amounts applicable in the foregoing processes. A higher concentration thus allows greater throughput in the two-step production of the 3-exomethylenecephamsulfoxide ester. This higher throughput is of considerable economic importance in the industrial production of the 3-exomethyleneencephamsulfoxide ester.

Crosslinked polyvinylpyridine polymers can be regenerated with a base and reused in the process of the invention. As mentioned above, upon completion of the process, the insoluble polymer is separated from the 2-chlorosulfinyl aztidinone in solution. The polymer is boiled with acetone to remove co-precipitated byproducts, in particular insoluble imides and amides formed from N-chlorimide and N-chloramide chlorinating agents, and then filtered. The polymer is then suspended in water and the suspension is treated with a base such as 1N sodium hydroxide to a pH between 8 and 9.5. When the pH remains constant, the polymer is formed. It is filtered, washed with water and acetone and then dried, for example, under vacuum. Prior to reuse, the recovered polymer may be further dried by azeotropic distillation in a suitable solvent such as benzene or toluene.

Examples of the 2-chlorosulfinylazetidinones of formula (I) above are benzyl-B-methyl-4- [2-chloasulfonyl-4-oxo-3-thenylacetido-1-azetidinyl) -3-mercurenoate, p-nitrobenzyl-3-methyl-2- ( 2-Chloasulfinyl-4-oxo-3-phenylacetamido-1-azetidinyl] -3-butenoate,

2,2,2-β-β-β-β-π-2β- (2--2- [2-chlorosulfinyl-4- [4- (azetidinyl) -3] -butenoate, p 4-Methyl-4- (2-chlorosulfinyl-4-oxo-3-butyr-4-yl) -3-butenoate;

Я9 tert-butyl 3-methyl-2- (2-chlorosulfinyl-4-oxo-3-benzamido-1-azetidinyl) -3-butenoate, p-nitrobenzyl-3-methyl-2- [2-chlorosulfinyl, -4-Oxo-3- (2'-thienylacetamido) -1-azetidinyl] -3-butanenoate, p-nitrobenzyl-3-methyl-2- (2-chlorosulinyl) 1-4-oxo-3-lenoxyacetamido-1 -azetidinyl) -3-butenoate, p-nitrobenzyl-3-methyl-2- (2-chloro-vinyl-4-oxo-3-phenoxyactamido-1-azetidinyl) -3-butenoate,

2,2,2-Trichldimethyl-3-methylyl-2- [2-chlorosulphinyl-4 (fdXf (3-dramamido-1-piperidinyl)) β-butenoate,

2,2,2-Trichloro-3-methyl-2- [2-chloro-ynyl-4-oxo-3- (thienylacetamido) -1-azetidinyl] -3-butenoate; endxyacetamido-1-azetidinyl) -3-butenedate, benzhydryl-3-methyl-2- (2-chlorosulphinyl-4-oxo-3-cyanoacetamido-1-azetidinyl) -3-butenoate, p-nitrobenzyl-3-methyl-2f (2-Chloroullinyl) -4-oxo-3- (d-lermyloo-phenylacetamido-1-azetidinyl) -3-butenedate, p-nitrober-2-yl-3-methyl-4- [2- (2-chloroullinyl) -4-o] .o-3- (α-t-butyloxycarbonylaminophenyl acetamido) -1-3β-tert-butyl] -3-bute ^; benzoatryl-3-methyl-2- [2-chloro-quinoline 1-4fdxd-3f (α-t-t) utyloxycarbonylamino-1,14f-cyclohexadienylacetamido] -1H-azetidinyl] -3-butenoate, tert-butyl-3fmethylf2f [fdχd-3f] (4-Chloro-phenylthioactamido) -1-azetidinyl] -3-butenoate and p-nitrobenzyl-3-methyl-2f [2-chlorosullinyl-4-oxo-3- (3'-thienylacetamido) -1-azetidinyl] -3-butenoate.

The preferred penicillinsulloxides described above provide the following fused 2-chlorosullinylazetidinones according to the invention, wherein R in formula I is benzyl, lenoxymethyl or 2-thienylmethyl and R 1 is benzyl or a substituted benzyl group, especially p-nitrobenzyl and p-methoxybenzyl.

In a preferred embodiment of the process of the invention, the p-nitrobenzyl-d-eenoxyacetamido-2,2-dimethylpenam-3-carboxylate-1-oxide is reacted with N-chlorophthalimide in 'dried toluene' at reflux temperature in the presence of a (4-vinylpyridine) divinylbenzene copolymer. The heterogeneous reaction mixture is heated to reflux temperature with stirring for 1 hour and 40 minutes and then cooled to about 10 ° C. the insoluble copolymer was removed and the l-filtrate containing 2-chlorosullinylazetidin-4-one was treated with tin tetrachloride to cause cyclization to the 3-exomethyl-ethylamsulloxide ester as described below.

when the above embodiment of the process of the invention is carried out at an "elevated" pressure, for example from about 35 kPa to -do. The reaction temperature is increased to about 135 ° C and the reaction time is reduced to about one third of the time required for the reaction at reflux and atmospheric pressure.

In another preferred embodiment of the process of the invention, the p-nitrobenzyl O-leoxyoxyacetamido-2,2-dimethylpenam-3-carboxylate-1-oxide is reacted with N-chloro-thalimide in dry toluene at reflux temperature.

in the presence of poly [4-vinylpyridine] -methylenebisacrylamide with about 10% crosslinking. The heterogeneous reaction mixture is heated at reflux with stirring for about 2 hours and then cooled to about 15 ° C. The mixture is filtered to remove the polymer and the alpha-imide and the azetidinone sulfinyl chloride-containing filtrate is treated with tin (II) chloride to give the 3-exomethylenealamsuloxide ester as described below. This embodiment can be carried out at elevated pressure.

As mentioned above, the 2-chlorosullinylazetidinone prepared by the process of the invention can be converted without isolation to the 3-oxomethylteccelamsulloxide ester described by Kukolja in U.S. Patent 4,052,387. 3-methylethyleneslamsulloxide. The improved procedure is performed as follows.

After reaction of the penicillin sulfoxide ester. with an N-chlorbalogenating agent in the presence of cross-linked polyvinylpyridine and '2-' formation

The insoluble polymer from the reaction medium and without isolation of the intermediate is further treated with first an oxo-ligand forming agent which is further de-defined and then with tin tetrachloride. If the addition of tin tetrachloride in the presence of oxo-ligand-forming substances a solid complex forms in the refractory mixture. According to this improved process, the insoluble complex formed by the reaction of suleinyl chloride and tin chloride described by Kukoljou in U.S. Patent No. 4,052,387 is stabilized by oxo-ligand formed in the presence of oxo-ligand forming agents. The stabilized complex is stirred for about 3 hours to 20 hours and washed with a hydrocarbon solvent. This mixture is then added slowly to the substance containing a hydroxy group, for example methylphenol or ethanol, to decompose the complex and to form the 3-exomethylphenylamide ester.

The oxo-11gand 'forming materials, the liters may be used in the process, are alkyl and cycloalkyl209825 ethers such as dimethyl ether, diethyl ether, di-n-propyl ether, di-n-but-butyl ether and the like; cycloalkyl ethers such as tetrahydrofuran and tetrahydropyran and the like; ketones and cyclic ketones such as acetone, diethylketone, methylethylketone, methyl-n-propylketone, methylisopropylketone, methylisobutylketone and the like; cyclic ketones, such as cyclobutanone, cyclopentanone, cyclohexanone, cycloheptanone and the like, including alkyl-substituted cycloalkyl ketones, for example methyl-substituted cyclohexanones and methyl-substituted cyclopentanones; trialkyl and triarylphosphine oxides such as tri-lower alkylphosphine oxides, for example trimethylphosphine oxide, triethylphosphine oxide, tri- (n-propyl) phosphine oxide, tri- (n-butyl) phosphine oxide and the like; tricycloalkylphosphine oxides such as tricyclohexylphosphine oxide and the like; triaryl phosphine oxide, for example triphenyl phosphine oxide and the like.

. Preferred oxo-ligand forming agents are diethyl ether, acetone and diethyl ketone.

As mentioned previously, it is preferred to add the oxodigand-forming agent to the 2-chlorosulfinylazetidin-4-one solution prior to the addition of tin (II) chloride. Alternatively, the eye-ligand-forming agent may be added simultaneously with tin (II) chloride.

Generally, the solution of 2-chlorosulfinylazetidinone is cooled to about 0 ° C to about 15 ° C before addition of the oxoligand-tin chloride forming agent. Thereafter, the reaction is allowed to proceed with stirring at room temperature for about 3 to 20 hours to safely terminate the cyclization to the 3-exomethyl-encephamsulfoxide ester. Complex formed by 2-chloj sulfinylazetidinonemchloi ^ ^1, l · dem cíničitýn-o'xoliganden is then separated from the solution for example by filtration, centrifugation or other conventional means, washed with an inert hydrocarbon solvent such as pentane, hexane or toluene. The stable complex can be stored for later use, or furthermore is preferably distributed as follows ^r. The solid complex was slowly added to an excess of the hydroxy-containing material to give the 3-exomethyl ester, lecefamsulfoxide. Substances containing hydroxy? a group suitable for decomposition is lower alcohols such as methanol and ethanol.

The structure of the 2-chlorosulfinylazetidinone-tin tetrachloride-oxoligand complex has not been established. However, it appears that one molecule of the oxoligand substance forms a coordination bond with at least one central tin atom of the complex. It should be noted that tin (II) chloride may form a coordinating bond with the oxygen atom of the sulfinyl group as well as with the oxygen atoms of the amide group in position. 3 of the azetidinone and perhaps with an oxygen atom of the carbonyl group of the ester group.

The oxoligand-forming compound is added in an amount corresponding to between about 1 to about 1 mole per mole of 2-chlorosulfmylazetidinone and preferably between about 0.8 and about 1.2 mole per mole, while tin tetrachloride is used in an amount corresponding to between about 2 and about 3 moles per mole. one mole of 2-chlorosulfinylazetidinone.

The complex consisting of 2-chlorosulfinylazetidinone-tin tetrachloride-oxoligand is usually strongly colored, depending on the particular sulfinyl chloride used in the process, and can range from red through orange-red to brown.

As previously noted, the oxo-ligand-stabilized complex is more stable than the complex formed by the 2-chlorosulfmylazetidinone-tin chloride formed by the prior art method of Kukolji, U.S. Patent No. 4,052,387. The oxygen ligand renders the complex more stable by avoiding the possible coordination bond. Changes in the complex before completion of the cyclization reaction and formation of the 3-exomethylencephamsulfoxide ester. Accordingly, the oxygen ligand complex of the invention allows higher product yields. Further, when the oxygen ligand is present in the complex, the complex is generally obtained in solid form, whereas without the oxygen ligand the complex is often obtained less. pure because it precipitates as a rubbery substance that makes it difficult to handle rather than as a solid.

· When carrying out the improved process of the invention, certain penicillin sulfoxides are preferred as starting materials · that the resulting esters of _{3-exomethylencefansulfo:} χidů are preferred intermediates in the preparation of antibiotics.

Examples of preferred starting materials are:

p-nitrobenzyl-6-phenoxyacetamido-2,2-dimethylpenam-3-carboxylate-1-oxide, p-nitrobenzyl-5-phenylacetoacetate-2,2-dimethylpenam-3-carboxylate-loxide and p-nitrobenzyl-6- (2 (thienylacetamido) -2,2-dimethylpenam-3-carboxylate-1-oxide.

Examples of the appropriately substituted 2-chlorosulfinylazetidinones prepared in this process with the preferred penicillin sulfoxides are:

p-nitrobenzyl-3-methyl-2- (2-chlorosulfinyl-4-oxo-3-phenoxyacetamido-1-azetidrinyl) -3-butenoate, p-mtrobenzyl-3-methyl-2- (2-chlorosulfinyl-4) - oxo-3-phenylacetamide 4 - [(L-azeidide) -3-butenoate ^; (thienylacetanido) -1-azetidinyl] -3-butenoate.

Examples of preferred 3-exomethylencephamsulfoxide esters prepared from preferred penicillin sulfoxide esters are:

p-nitrobenzyl-7-phenoxyacetamido-3-exomethylencepham-4-carboxylate-1-oxide, p-nitrobenzyl-7-phenylacetamido-3-exomethylencepham-4-carboxylate-1-oxide and p-nitrobenzyl-7- [2'- thienylacetamido) -3-exomethylencepham-4-carboxylate-1-oxide.

As previously noted, the sulfoxide configuration in the starting penicillin sulfoxide ester may be either a or β, or a mixture of the two. The configuration of the sulfoxide in the 3-exomethylemcefam ester is β.

A particularly preferred embodiment of the invention is illustrated in the following reaction scheme in which p-nitrobenzyl-6-phenoxyacetamido-2,2-dimethylpenam-3-carboxylate-1-oxide is reacted in essentially anhydrous toluene with N-chlorophthalimide in the presence of a poly (4). -vinylpyridine) crosslinked with about 2 percent divinylbenzene with an average particle size of about 50.10 ^-6 m to give the correspondingly substituted 2-chlorosulfinylazetidinone ester. The insoluble polymer and phthalimide were separated from the reaction medium and the filtrate was cooled. About 1 molar equivalent of diethyl ether was added to the cooled filtrate followed by tin (II) chloride to form an orange-red complex containing the ester ligand. Then the complex is stirred at room temperature for about 10 hours, filtered, washed with hexane and added to a large excess of methanol to form a suspension of p-nitrobenzyl-7-phenoxyacetamido-3-exomethylencephene, m-4-carboxylate- l (S-oxide.

СН _Ъ

coo-chtoluen

N-chlorine (talimicl no ₂

o-ch ₂ -conh poles (4-vinylpyridine) у 2 ^l J-diviuylbeiuen

O

«S-Cl

.COOCH no ₂

SnCLfi

Methyl alcohol complex

COO-CH, # Vwo ₂

O

The following examples further illustrate the process of the invention without limiting it. · Unless otherwise stated, penicillin sulfoxides are in the β configuration.

She said dl

Preparation of a (4-vinylpyridine) divinylbenzene copolymer

In a 2 liter three - necked round bottom flask with. 100 ml of water and 4.8 g of polyvinyl alcohol are added and the solution is heated to 80 ° C under nitrogen. K. a solution of 50 g of 4-vinylpyridine and 3.0 g of dlvinylbenzene in 100 ml of toluene is added rapidly with stirring to the hot solution, then 2 g of azobisisobutyronitrile are added. The copolymer immediately forms and the suspension is stirred vigorously for about 16 hours at 80 ° C.

The copolymer is separated from the reaction mixture by filtration through a cloth and washed thoroughly with water, acetone, diethyl ether, methylene chloride and finally methanol. Swelling occurs with washing with diethyl ether, methylene chloride and methanol. The copolymer resin is dried under vacuum to give 45.05 g of dry resin.

The resin is finally crushed and the fraction passing through a 60 mesh screen is collected. The nitrogen content determined by combustion is 12.35 ·%.

EXAMPLE 2 liters of reagent grade toluene are subjected to binary distillation to obtain and remove 200 ml of liquid with a Dean-Starke aqueous trap. Discontinue the heating and add 50 g of 4-vinylpyridinedivinylbenzene copolymer (about 2% crosslinking), then add

100.3 g of p-nitrobenzyl-6-phenoxyacetamido-2,3-dimethylpenam-3-carboxylate-1-oxide and 38.4 g of N-chlorophthalimide. The slurry was heated to reflux for 100 minutes and then cooled to 10 ° C and stirred for 10 minutes. Progress of the reaction was monitored by NMR, which showed the formation of sulfinyl chloride and in about 90% yield. The reaction mixture was quenched. The filtrate was cooled in an ice bath.

The presence of sulfinyl chloride: p-nitrobenzyl 3-methyl-2- (2-chlorosulfinyl-4-oxo-3-phenoxyacetamido-1-azetidinyl) -3-butenoate is confirmed by NMR data.

NMR (CDCl3):

δ 1.93 (s, 3H, vinyl methyl), and 4.33 (s, 2H, phenoxy methyl) δ. 5.03 - 5.13 (m, 3H, CH2 --CH2 --CH3) - 5.30 (s, 2H, ester methylene) - 5.57 (d, 1H, J = 4.5 cps, C- 2H in j = act S 6.30 (q, 1H, J = 4.5 cps and 9.0 cps, C-3H in f-actam) δ 6.8 - 7.0 (m, 5H, side aromatic chain) δ 7.20 - 8.23 (2d, 4H, J - 9.0 cps, aromatic ester) δ 7.82 (bs, 1H, NH)

18.28 ml of diethyl ether is added to the cooled filtrate, then 50 ml of tin (II) chloride are added. The pale orange-red complex was stirred at ice bath temperature for 30 minutes and then at room temperature for about 16 hours, filtered and washed with hexane (400 mL). The complex is slowly added to 600. ml of methanol with stirring. The suspension was stirred at 0 ° C for 4 hours. An off-white precipitate of the product, p-nitrobenzyl-7-phenoxyacetamido-3-exomethylencepham-4-car-. 1-oxide boxylate is filtered off, washed with 100 ml of methanol and dried in vacuo. Crystalline product obtained in 76.2% yield. it is almost white and melts from about 194.5 to about 195 ° C.

The foregoing example illustrates an embodiment wherein the concentration of penicillin sulfoxide to solvent is about 50 g per 1800 mL, the maximum concentration at which the former method yielded the best yield. The following examples in tabular form illustrate the process of the invention using the triple concentration used in Example 2 with a copolymer having a preferred average particle size.

Example Penicillin (g) Size ¹ Yield Yield Number Toluene (mT) Particles (m ~ ⁶ ) in% 2 in% 3

3 15/175 40 84 71.1 4 15/175 70 87 73.0 5 15/175 100 ALIGN! 88 73.9

¹ poles (4-vinylpyridine) divinylbenzene in the form of spheres yield p-nitrobenzyl-α-methyl-β- (2-fluorosulfinyl-4-ol); The amount of p-m-benzobenzyl-7-phenoxyacetamido-3-exomethylencepham-4-carboxylate-1-oxide in the form of a percentage of (R, R, R), R, R, R, R, R, R, R, R, R and R are as percentages. 'O'9'8 2 '5

EXAMPLE 6 p-Nitrobenzyl-7- (-4-methylphenoxyacetamido) -3-exomethylenecepham-4-carboxylate-1-oxide ml of toluene was subjected to binary distillation while separating 8 ml of liquid with a Dean-Starke trap. The toluene was cooled and 0.67 g of poly (4-vinylpyridine) divinylbenzyl copolymer (about 2% crosslinking), 2 grams, p-nitrobenzyl-6- (4-methylphenoxyacetamido) -2,2-dimethylpenam-3 was added. The mixture was heated at reflux for 100 minutes, cooled in an ice bath, and the α-phthalimide copolymer was filtered off to the yellow filtrate containing p-nitrober. 2-yl-3-methyl-2- (2-chlorosulfinyl-4- (oxo-3-p-methyllenoxyacetamido-: 1-azididinyl) -3-buttnoate (NMR identical to sulfinyl chloride prepared in Examples 2-5) with the exception of the signal (δ 2.28, s, 3H] caused by the presence of a methyl group in the para- position of the phenoxyacetamide side-chain] 0.36 ml of dlethylether- - and - then - 1 ml of tin (II) chloride are added. the yellow-brown complex is stirred - for 1 hour at 0 ° C and then overnight at room temperature and filtered. The complex, when added to methanol, decomposes and a slurry of insoluble product is formed. The slurry was stirred for 4 hours at 0 ° C. Filtered - washed with methanol and dried under vacuum at room temperature to give 0.61 grams of p-nitrobenzyl 7- (4-methylphenoxyacetamido) -3-ethoxymethylencepham-4-carboxylate. Melting point ^: about 172-174 DEG C. The NMR spectrum of the product in DMSO-d6 gives the following signals (delta): 2.23 (s, 3H, methyl 4-methylbenzyl), 5.05 ( d, 1H, J = 4.5 cps, - C & H], 5.28 (s, 2H, p-nitrobenzylmethylHer), -5.37 - (s, 1H, Cl-H], 5.50 and 5 .70 (2s, 2H, .dbd.CH2 .alpha.), 5.80 (q, 1H, J = 4.5, 10 cps, C @ 7 -H], .delta., 73- and 7.03 - - - ( 2d, 4H, J = 9 cps, 4-methylbenzyl aromatic H-1, and 7.40 and 8.17 (2d, 4 H, 1 H - - = - -9 ^; cps, p-nitrobenzyl aromatic H) ].

EXAMPLE 7 p-Nitro-benzyl-7-phenylacetamide-3-exomethylenecepham-4-carboxylate-1-oxide

30-0 ml of reagent grade toluene is binary distilled to obtain and remove 30 ml of liquid with a Dean-Starke water trap. Discontinue the heating and add 2.50 g of vinylpyridinvinylbenzene copolymer (about 2% crosslinking) and heat the polymer slurry to reflux for a few minutes to remove the water, discontinue heating and add 7.28-g (0.015 M). p-nitrobenzyl-6-phenylacttamido-2,2-dimethylptamine-3-carboxylate-1-oxide and 2.88 g of N-chlorophthalimide The mixture was heated at reflux for 100 minutes, then cooled to 10 ° C and filtered 3-neck round bottom flasks placed on an ice bath The product of this reaction is p-nitrobenzyl-3-methyl-2- (2-chloro-4-oxo-3-phenylacetamido-1-azetidinyl) -3-butenoate in about 78% yield The identity of the sulfinyl chloride was confirmed by NMR data:

NMR - (CDCl3):

δ 1.80 (s, 3H, vinyl methyl) δ 3.57 (s, 2H, CH2J side chain

1 δ 5.0 - 5.13 (m, 3H, CH 2 CH - CH -) δ 5.20 (s, 2H, CH 2 ester) δ 5.43 (d, 1H, J = 4.5 cps C- 2H - v / Maktam] δ 6.42 (q, 1H, J = 4.5 and -9 cps -C-3H in β-lactam) δ 7.13 (s, 5H, sidecharomatic chain)

7.4 and 8.18 (2d, 4H, J = -8 cps, aromatic ester)

To the reaction mixture was added 1.37 ml (0; 0T3 M) diethyl ether and 3.75 ml (0.032 M) tin (II) chloride to give a brown insoluble complex, which was stirred for 30 minutes on ice. The chocolate-brown complex is filtered off, washed with 60 ml of hexane and slowly added to 45 ml of methanianol to form a suspension of the product, p-nitrobenzyl-7-. Phenylacetamido-3-thiomethylencepham-4-carboxylate-1-oxide The suspension of the product was stirred at an ice bath temperature for 4 hours, filtered, washed with 15 ml of methanol and dried under vacuum to give 4.3 g (59%). 3% yield] of a dry product melting from about 2-8.5 to about -208.5 degrees Celsius to recrystallize from -acetone.

Example8

2.2.2-Trichloroethyl 7-phenoxyacetamido-3-exomethylencepham-4-carboxylate-1-oxide

800 ml of toluene are subjected to a binary distillation under a Dean-Starke water separator to remove 80 ml of liquid from the separator. Heating is discontinued - 6.68 g of poly (4-vinylpyridine) divinylbenzene containing about 2% crosslinking, 20 g are added to hot toluene.

2,2.2-Trichloroethyl-6) -phenoxyacetamido-2,2-dimethyl-methyl-3-carboxylate-1-oxide and 7.74 g of N-chlorophthalimide. The suspension was heated to reflux for 100 minutes and then cooled in an ice bath for about 20 minutes. The cold suspension was freed of copolymer and phthalimide by filtration and the filtrate was cooled in an ice bath. The formation of sulfinyl chloride, 2,2,2-trichloroethyl 3-methyl-2- (2-chlorosulfinyl-4-oxo-3-phenoxyacetamido-1-azetidinyl) -3-butenoate, in about 83% yield, was confirmed by NMR data.

NMR (CDCl3):

δ 1.95 (s, 3Ή, vinyl methyl) δ 4.52 (s, 2H, O CH 2 -) δ 4.66 (d, -2H, J = 2 cps, —CH 2 CC 13)

20918 25 δ 5.07 - 5.33 (m, ZN, CH2 — C — CH-) δ 5.53 (d, 1H, J 4.5 cps, C-2H in / L-lactam) δ 6.28 (q , 1H, J 4.5 and 10 cps, C-3H in, β'-lactam) δ 6.83-7.47 (m, 5H, C 6 H 8 -O-) δ 8.06 (1H, d, J = 10 cps NH)

To the cold filtrate was added 3.66 mL of diethyl ether and 10 mL of tin (II) chloride was added with stirring. After stirring for about one hour, the complex begins to precipitate. The dark complex suspension was stirred overnight at room temperature, filtered and washed with 80 mL hexane. The resulting yellow-brown sand complex was added to 120 mL of methanol and the mixture was cooled in an ice bath. If the product does not precipitate after stirring for about four hours, the amount of methanol is reduced to 1/3 of the original volume by evaporation. The concentrate was dissolved in ethyl acetate and the solution was washed with 2 x 5% aqueous sodium bicarbonate and water and dried over magnesium sulfate. The dried solution was evaporated to dryness to give 15.62 g of crude product, 2,2,2-trichloroethyl-7-phenoxyacetamido-3-exomethylencepham-4-carboxylate-1-oxide as a brown foam.

The product is suspended in 60 ml of methanol and the suspension is heated to about 50 ° C to form a solution. Upon cooling to room temperature, the product crystallized. The crystalline precipitate was filtered off and dried to give 1.9 g of product melting at about 143.5-144 degrees Celsius.

NMR (CDCl3):

3.75 (q, 2H, J = 4 and 18 cps, C2H)

4.58 (s, 2H, phenoxyacetyl methylene)

4.83 (d, 2H, J = 1.5 cps, trichloroethyl CH2)

4.95 (d, 1H, J = 4.5cps, CgH)

6.06 (q, 1H, J = 4.5 and 11 cps, C7H)

5.53 (s, 1H, C 4 H)

5.42 and 5.87 [2s, —CH2)

8.16 (d, 1H, J = 11 cps, NH) and

6.83-7.50 ^: (m, 5H, aromatic H) delta.

The following is an example in which penicillin α-sulfoxide is used as the starting material.

Example 9 liter of reagent grade benzene was azeotropically dried using a Dean-Starke water trap to separate and remove 100 ml of liquid during distillation. Remove the benzene heating and add 16.7 g of poly (4-vinylpyridine) divinylbenzene copolymer (about 2% crosslinking), 19.2 g of N-chlorophthalimide and 50.12 g of p-nitrobenzyl-6-phenoxyacetamido-2,2- dimethylpenam-3-carboxylate-1α-oxide. The mixture was heated to reflux for 120 minutes. The pale yellow suspension was cooled to 10 ° C and stirred for 10 minutes, and then insoluble polymer and phthalimide were filtered off. Sulfinyl chloride is produced in about 93% yield and is completely identical to the sulfinyl chloride of Example 2 by NMR spectrum.

9.14 ml of diethyl ether is added to the pale yellow filtrate, then 25 ml of tin (II) chloride are added. The almost colorless complex was stirred for 30 minutes at about 60 ° C and overnight at room temperature. The granular complex becomes light orange, filtered, washed with 200 ml of hexane, and dried to a slightly colored free-flowing powder. The complex is slowly added to 300 ml of methanol, immediately forming a thick suspension of the product, p-nitrobenzyl-7-phenoxyacetamido-3-exomethylencepham-4-carboxylate-1/3-oxide. The suspension was stirred for 4 hours at 0C, filtered, washed with 50 ml of methanol and dried in vacuo to give 39.9 g (79.9% yield) of product as very fine crystals melting at about 197-198 ° C ^Q

The following example uses (4-vinylpyridin-divinylbenzene) poles with about 4.5% crosslinking.

EXAMPLE 10 liters of reagent grade toluene were dried by binary distillation for 3 hours to remove 400 mL of toluene and water separated in a Dean-Starke trap. The distillation is discontinued and 50.0 g of copolymer (about 4.5% crosslinking), 100.3 g of p-mtrobenzyl-6-phenoxyacetamido-2,2-dimethylpenam-3-carboxylate-1-oxide and 45.68 g are added. Of N-chlorophthalimide. The mixture was heated at reflux for 100 minutes and then cooled to 0-5 ° C and filtered into 35 mL of cold toluene containing 50 mL of tin (II) chloride. The bright red-orange complex is stirred overnight without discoloration. The complex is filtered off, washed with pentane and 500 ml of methanol are added. The resulting slurry was stirred at about 0-5 ° C for 6.5 hours. The slurry was filtered and the product, p-nitrobenzyl 7-phenoxyacetamido-3-exomethylencepham-4-carboxylate, washed with diethyl ether and dried to give 63.2 g (63.3% yield).

Example 11

Regeneration of a (4-vinylpyridine) divinylbenzene copolymer

The mixture of copolymer and phthalimide separated from the reaction, in which 35.1 g of copolymer is used, is stirred in 500 ml of acetone. Heat the slurry to a boiling point on a steam bath and filter while hot. Phthalimide is soluble in hot acetone and separated from the copolymer by filtration in solution. The copolymer was then stirred in 200 ml of water and the pH of the slurry was adjusted to 9.5 IN with sodium hydroxide (about 42 ml was added). The copolymer is filtered and washed with water until the pH of the wash water is neutral. The copolymer was further washed with acetone to remove water and dried under vacuum at 50 ° C. Dry regenerated

The 32 copolymer weighed 34.3 g corresponding to 97.7% recovery.

The following is an example of a process in which a regenerated polymer is used, previously used three times and regenerated after each use by the method described in the previous example.

Example 12

460 ml of reagent grade toluene was binary distilled to separate 30 ml of liquid in a Rean-Starke trap. The toluene heating is removed and 12.0 g of regenerated copolymer is added. To remove water, the suspension is further refluxed using a DeanStarke trap and heating is discontinued. 36.0 g of p-nitrobenzyl-6-phenoxyacetamido-2,2-dimethylpenam-3-carboxylate-1-oxide and 13.8 g of N-chlorophthalimide are added to the warm suspension. The reaction mixture was heated to reflux for 100 minutes with stirring. The brown suspension is cooled to 10 ° C, filtered off and the filtrate is placed in an ice bath. To the cold filtrate was gradually added 6.6 mL of diethyl ether and 18 mL of tin (II) chloride. The dark orange complex formed was stirred at ice bath temperature for 30 minutes and then at room temperature for about 16 hours, filtered and washed with hexane (150 mL). The washed complex was slowly added to 215 mL of methanol to give a slurry of the product, p-nitrobenzyl-7-phenoxyacetamido-3-exomethylencepham-4-carboxylate-1-oxide. The slurry was stirred at ice bath temperature for 4 hours, filtered, washed with 50 mL of methanol and dried in vacuo to give 25.7 g of an off-white product melting at about 195 ° C.

Example 13

Preparation of 4-vinylpyridine-N, N'-methylenebisacrylamide

A 1 liter three-necked round-bottom flask equipped with a heating mantle, nitrogen inlet, stirrer, thermometer and reflux condenser was charged with 200 mL deionized water and 75 g of sodium chloride. The solution was stirred under nitrogen for 30 minutes at room temperature and a solution of 30.0 g of 4-vinylpyridine, 3.0 g of Ν, Ν-methyleneblsacrylamide and 0.2 grams of azobisisobutyronitrile in 90 ml of diisobutyl ketone was added. The temperature of the reaction solution is raised to between about 65 and 70 ° C with rapid stirring (200 rpm). After about 30 minutes a precipitate formed.

The reaction mixture was stirred and heated for about 18 hours, and the polymer that precipitated was further treated as follows: First, it was distilled off by azeotropic distillation using a Dean-Starke separator with diisobutyl ketone and after cooling the mixture to room temperature 500 ml of methanol were added. The suspension is vigorously stirred for about 15 minutes to form a polymer dispersion and to break down large particles. The suspension is poured into 500 ml of water and the pH adjusted to less than 2 with hydrochloric acid. The acidified suspension was stirred for 30 minutes and then filtered through a Buchner funnel through syringe. The polymer was washed with three liter portions of water and the decantation was separated in the first and second washes. After a third wash, the pH of the suspension is adjusted to 8.0-8.5 by addition of ammonium hydroxide and the polymer is filtered off. The polymer was washed again with three 1 L portions of water and decanted. The resulting polymer was washed with methanol (500 mL) for 15 minutes, filtered and dried.

Following the polymerization conditions and using the same amounts of 4-vinylpyridine and azobisisobutyronitrile used in Example 13, the following crosslinked (4-vinylpyridine) polymers (PVP) polymers were prepared with the indicated amount of crosslinking agent proposed.

13a PVP-1,1,1-trimethylolpropantrimethacrylate is prepared with 3.0 g of 1,1,1-trimethylolpropantrimethacrylate.

13b PVP-ethylenediacrylate is prepared with 1.5 g of ethylenediacrylate.

13c PVP-triethylene glycol dimethacrylate is prepared with 1.5 g of triethylene glycol dimethacrylate.

13d PVP-dialkyl malonate is prepared with 1.5 g of diallyl malonate.

The crosslinked polymers used in the process of the invention, such as those described in Examples 13a to 13d, are thoroughly washed prior to use as described in Example 13.

Example 1 a d 1 4

Method with (4-vinylpyridine) -methylene-bisacrylamide

In a one-liter three-necked round-bottomed flask equipped with stirring, a Dean-Starke trap and a reflux condenser was charged 250 ml of toluene and 6.3 g of (4-vinylpyridine) -N, N´-methylenebisacrylamide,

O

II

CHafNH — C — CH = CH2 - (10% crosslinking). The mixture was heated to reflux until all water was separated in a separator. The heating was discontinued and 18.79 g of p-nitrobenzyl-6-phenoxyacetamido-2,2-dimethylpenam-3-carboxylate-1-oxide and 8.48 g of N-chlorophthalimide were added rapidly to the hot mixture. About 50 ml of dry toluene are used to flush out the ester and the chloro compound. The reaction mixture is then heated to reflux for 100 minutes and then cooled to between about 5 and about 10 ° C. Cold reaction mixture containing chlorosulfinylase. The tidinone is filtered into a dry flask to separate the polymer and phthalimide and the filter cake is washed with dry toluene. The cold temperature of the chlorosulfinyl compound-containing filtrate is maintained at about 5-10 ° C and 3.43 mL of diethyl ether is added. 9.38 ml of tin (II) chloride are then quickly added and the mixture is stirred in the cold. 30 minutes and then. about 18 hours at room temperature. The reddish complex is filtered off, dried on the filter, washed with hexane and dried. The dry solid complex was added to 113 ml of methanol and the suspension was stirred at ice bath temperature for 4 hours until the product crystallized.

The product suspension is filtered and the product is washed with methanol and dried. 13.6 g of product, p-nitrobenzyl-7-phenoxy, acetamido-3-exomethylenecepham-4-carboxylate-1-oxide, melting at about 193 to about 195 ° C (72.5% yield), are obtained. The purity of the product as determined by HPLC is 92.5%.

Example 15

Process with poly (4-vinylpyridine) trimethylolpropane trimethyl acrylate

The procedures and conditions described in the previous examples were repeated using the same amount of solvent, starting material, chlorinating agent, tin tetrachloride and diethyl ether except that 6.3 g of poly (4-vinylpyridine) trimethylol propane trimethyl acrylate was used,

O

II

CH3CH2 — C (O — C — C = CH2) 3,

AND

CH ........

(3% crosslinking) instead of poly (4-vinylpyridine) methylenebisacrylamide. The tin (II) chloride complex is isolated and the product isolated using the above procedures. This is obtained

12.44 g (63.3 percent yield) of p-nitrobenzyl-7-phenoxyacetamido-3-exomethylencepham-4-carboxylate-1-oxide.

Example 16

Process with poly (4-vinylpyridine) methyldivinylpyridine

In the same manner and under the same conditions as in Example 14, it is dried by azeotropic distillation of 500 ml of toluene and 12.5 g of poly (4-vinylpyridinomethyldivinylpyridine (about 2% crosslinking). 2-dimethylpenam-3-carboxylate-1-oxide and 16.95 g of N-chlorophthalimide to the dry mixture and heated to reflux for 100 minutes to form azetidinone sulfinyl chloride. The reaction mixture was filtered to remove polymer and phthalimide. The filtrate was treated with 18.75 ml of tin (II) chloride and 6.85 ml of diethyl ether. The complex formed was stirred overnight at room temperature, filtered and dried. 0.9 g (61.33% yield) of p-nitrobenzyl 7-phenoxyacetamido-3-exomethylencepham-4-carboxylate-1-oxide melting at about 191.5 ° to about 193.5 ° C.

Crosslinked sweats (4-vilylpyridine) methyldivinylpyridine polymer used in this example. was thoroughly washed before use as described in Example 13.

The procedures of Examples 10, 12, 14, 15 and 16 were followed by NMR to confirm formation. sulfinyl chloride in situ, as in Example 2. The yields obtained in these examples for sulfinyl chloride are shown below.

Claims (4)

A process for the preparation of 2-chlorosulfinylazetidin-4-one of formula I CH, ^Z ^ СN ₃ (I) in which is R carboxylic acid residue a R 1 is a carboxylic acid protecting group which comprises reaction in an inert solvent environment under substantially anhydrous conditions of the penicillin sulfoxide ester of formula (II) in which R and R 1 are as defined above with an N-chloro halogenating agent, characterized in that in the presence of a cross-linked polyvinyl pyridine polymer containing between about 1 percent to 10 percent crosslinking, at a temperature in the range of from 75 to 175 ° C, by weight, a polymer to penicillin sulfoxide ratio of from 1: 1 to 1.5. 2. A process according to claim 1, wherein the cross-linked polyvinylpyrtidine is cross-linked poly (4-vinylpyridine). 3. A process according to claim 2, wherein poly (4-vinylpyridine) crosslinked with divinylbenzene, methylene bisacrylamide or methylene bisismethacrylamide is used. and 4. A process according to claim 3, wherein a polymer cross-linked with 2 to 5% by weight of divinylbenzene is used.