KR810001817B1 - Process for preparing sulfinylchloride from penicillin sulfoxide - Google Patents

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Description

Process for preparing sulfinylchloride from penicillin sulfoxide

The present invention relates to an improved process for the preparation of the sulfinyl chlorides of the general formula (I) which are useful as intermediates.

의 그룹이다.In the above general formula, R ₁ is a protecting group of carboxylic acid, R is a) hydrogen, C ₁ -C ₃ alkyl, halomethyl, cyanomethyl, benzyloxy, 4-nitrobenzyloxy, tert-butyloxy 2,2, 2-trichloroethoxy, 4-methoxybenzyloxy, 3- (2-chlorophenyl) -5-methylisoxazol-4-yl; Or b) phenyl or phenyl substituted with one or two halogens, protected hydroxy, hanit, roscia, norifluoromethyl, C ₁ -C ₄ alkyl, or C ₁ -C ₄ alkoxy R ', or c) R' is equal to R 'or 1,4-cyclohexadienyl, 2-thienyl, or 3-thienyl; m is 0 or 1, Q is oxygen or sulfur and when m is 1, R 'is a group of formula R'-() wherein R 'is R'; d) wherein R 'is as above and R ₂ is protected hydroxy or protected imino.

Is a group.

The present invention provides an improved preparation of 2-chloro-sullinylazetidine-4- silver intermediate by reacting with an N-chlorohalogenating agent in the presence of alkylene oxide and calcium oxide at a temperature of 75 ° C to 135 ° C for a penicillin sulfoxide ester. It is about a method. Intermediate obtained by separating all of the conversion products of alkylene oxide, calcium oxide, and alkali oxide and calcium oxide can be cyclized in the presence of a Friedel-Craft catalyst to prepare 3-exemethylenecepam sulfoxide.

Recently issued US Pat. No. 3,843,682 discloses 3-methyl-2- (2-chlorosulfinyl-4-oxo-3-, also commanded as 2-chlorosulfinyl-3-imido-azetidin-4-one. A method for preparing imido-1-azetidinyl) 3-butenoate ester is described. This compound is prepared by reacting the corresponding penicillin sulfoxide ester with sulfuryl chloride at 75 ° C. to 120 ° C. Since this method is limited only when using 6-imido penicillin sulfoxide ester as starting material, only 3-imido-substituted-2-chlorosulfinylazetidin-4-one is prepared by this method. There is no publication on the use or possibility of the use of 6-amido penicillin sulfoxide esters, including readily obtainable penicillin sulfoxide derivatives of natural penicillin G and / or penicillin V.

The product obtained when proceeding with the reaction described in US Pat. No. 3,843,682 using a ester to 6-amido penicillin sulfoxide as starting material is free of 2-closulfinylazetidin-4- silver product or Or at most a complex mixture containing traces beyond the detectable level by conventional assays. Therefore, this previously described method has obvious drawbacks because it requires the absence of amide hydrogen at position 6 of the starting material penicillin sulfoxide.

Belgian patent 837540, issued June 23, 1976, describes a process for preparing intermediates that are sulfinyl chlorides from 6-amido penicillin sulfoxide esters. This method is to treat penicillin sulfoxide with N-chlorohalogenating agent at 575 ° to 135 ° C.

The degree of conversion of the 6-amido penicillin sulfide side to sulfinylchloride according to the reaction described above is now increased if the reaction scale is increased above the laboratory dose for research purposes, i.e. 50 g of the starting material penicillin sulfoxide. It has been clarified that the above use significantly reduces.

In the present invention, the conversion of 6-amido penicillin sulfoxide to the corresponding sulfinylchloride in large scale reaction (at least about 100 mmol) was found to be significantly increased when the reaction proceeded substantially in the presence of calcium oxide.

2-Chlorosulfinyl azetidin-4-one prepared by the method of the present invention can be ring-peptised to prepare 3-exomethylenecepam sulfoxide ester. The reaction for cyclization of 2-chlorosulfinylazetidine-4-wool with the corresponding 3-xomethylenecepamsulfoxide was carried out by the olefin portion of sulfinyl chloride and starting material azetidine-4-silver, induced by Friedel-Crafts catalysts. Intramolecular reactions are involved. This reaction is generally carried out using tin chloride as the Friedel-Craft catalyst.

The preparation of the present invention is carried out by the reaction of N-chlorohalogen in the presence of the epoxide compound of the following general formula (III) in an inert solvent under anhydrous conditions at a temperature of about 75 to 135 ° C The present invention relates to a method for preparing sulfinyl chloride of the general formula (I) by reacting with an agent, and to improving the reaction in the presence of calcium oxide.

Wherein R _X is hydrogen or methyl and R ₁ and R are as described.

The general formula of the amide functional group of sulfinyl chloride prepared by the process of the present invention is Among these amide functional groups, R is as follows.

의 그룹이다.a) hydrogen, C ₁ -C ₃ alkyl, halomethyl, cyanomethyl, benzyloxy, 4-nitrobenzyloxy, tert-butyloxy 2,2,2-trichloroethoxy, 4-methoxybenzyloxy, 3- (2-chlorophenyl) -5-methylisoxazol-4-yl, or b) phenyl or one or two halogens, protected hydroxy, nitro, cyano, trifluoromethyl, C ₁ -C R 'representing phenyl substituted with ₄ alkyl or C ₁ -C ₄ alkoxy or the like; Or c) R 'is R' or 1,4-cyclohexadienyl, 2-thienyl, or 3-thienyl; where m is 0 or 1, Q is oxygen or sulfur, and m is 1, R is R '

Is a group.

The R group is described in detail as follows. Hydrogen, methy, ethyl n-propyl, isopropyl, benzyloxy, t-butyloxy, 2,2,2-trichloroethoxy, 4-methoxy-benzyloxy, phenyl, 2-chlorophenyl, 3,4- Dichlorophenyl, 3-chloro-4-fluorophenyl, 3-formyloxyphenyl, 4-nitrophenyl, 2-cyanophenyl, 4-trifluoromethylphenyl, 3-methylphenyl, 2-ethylphenyl, 4-n- Propylphenyl, 4-t-butylphenyl, 2-methoxyphenyl, 4-ethoxyphenyl, 3-isopropyloxyphenyl, 4-isobutyloxyphenyl, 1,4-cyclo hexadienylmethyl, benzyl, 3- Bromobenzyl, 2,5-dichlorobenzyl, 4-chloroacetoxybenzyl, 2-nitrobenzyl, 3-cyanobenzyl, 4-trifluoromethylbenzyl, 3-methylbenzyl, 4-n-butylbenzyl, 2 -Methoxybenzyl, 3-isopropoxybenzyl, phenoxymethyl, 3-iodophenoxy, 4-fluorophenoxymethyl, 3-benzyloxyphenoxymethyl, 4-benzhydroxyphenoxymethyl, 3-tri Methyloxyphenoxymethyl, 4-nitrobenzyloxyphenoxymethyl, 4-trimethylsilyloxy Phenoxybenzyl, 3-nitrophenoxymethyl, 4-cyanophenoxymethyl, 2-trifluoromethylmethylphenoxymethyl, 3-methylphenoxymethyl, 4-n-propylphenoxymethyl, 4-n- Butylphenoxymethyl, 3-methoxyphenoxymethyl, 4-ethoxyphenoxymethyl, phenylthiomethyl, 3-iodomethylthiomethyl, 4-fluorophenylthiomethyl, 3-benzyloxyphenylthiomethyl, 4- Benzhydryloxyphenylthiomethyl, 3-trityloxyphenylthiomethyl, 4-nitro-benzyloxyphenoxythiomethyl, 4-trimethylsilyloxyphenylthiomethyl, 3-nitrophenylthiomethyl, 4-cyanophenylthio Methyl, 2-trifluoromethylphenylthiomethyl, 3-methylphenylthiomethyl, 4-n-propylphenylthiomethyl, 4-n-butylphenylthiomethyl, 3-methoxyphenylthiomethyl, 4-ethoxyphenylthiomethyl , α- (benzhydryloxy) -thien-2-ylmethyl, α- (4-nitrobenzyloxy) -thien-2-ylmethyl, α- (t-butyloxycarbonylamino) -thien-2- Monomethyl, α- (formyloxy) -thiene-3- Methyl, α- (benzyloxy) -thien-3-ylmethyl, α- (benzyloxycarbonylamino) -thien-3-ylmethyl, α- (chloroacetoxy) -thien-2-ylmethyl, α- (t-butyloxy) -thien-2-ylmethyl, α- (4-nitrobenzyloxycarbonylamino) -thien-2-ylmethyl, α-trityloxybenzyl, α- (4-methoxybenzyloxy ) Benzyl, α- (2,2,2-trichloroethoxycarbonylamino) benzyl, α- (trimethylsilyloxy) -4-bromobenzyl, α- (benzhydryloxycarbonylamino) -3- Clobenzyl, α- (trimethylsilylamino) -4-fluorobenzyl, α, 4-di (formyloxy) benzyl, α- (4-nitrobenzyloxycarbonylamino) -3-chloroacetoxybenzyl, α- (4-methoxybenzyloxycarbonylamino) -4-benzhydryloxybenzyl, α-benzyloxy-3-nitrobenzyl, α (4-nitrobenzyloxy) -2-cyanobenzyl, α- (t- Butoxycarbonylamino) -4-trifluoromethylbenzyl, α-formyloxy-4-methylbenzyl, α-benzyloxycarbonylamino-3-n-butylbenzyl, α- (benzyloxycarbonyla Mino) -4-methoxybenzyl, α-formoxy-3-isopropoxybenzyl, thien-2-ylmethyl, thien-3-ylmethyl or 3- (2-clophenoxy) -5-methylisox Four years old.

Particularly preferred among the groups defined by R are groups of the general formula. Particularly preferred among these is that R 'is 2-thienyl or phenyl.

If R 'is phenyl, it is more preferable that is oxygen when m is 1;

In the definition of group R the terms “protected amino” and “protected hydroxy” are used.

“Protected amino” lan-tert-butyloxycarbonyl, benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl-4-nitro-benzyloxycarbonyl, 2,2,2-trichloroethoxy herein Refers to an amino group substituted with one of the common amino blocking groups such as 1-carbomethoxy-2-propenyl or trimethylsilyl made from carbonyl, methylacetoacetate. Other typical amino protecting groups are described in J. W. Barton, Protective Groups in Orga-nic Chemistry J. F. W. Mcomie, Ed., Plenum Press, New York, N, Y. 1973 Chapter 2.

All such groups are also referred to herein as “protected amino”.

In this specification, a hydroxy such as hydroxyprotected formyloxy group, chloracetoxy group, benzyloxy group, benzhydryloxy group, trityloxy group, 4-nitrobezyloxy group or trimethylsilyloxy group An easily decomposable group created as a siloxane group. Other hydroxy protecting groups described in the literature (C. B. Reese, Protecting Groupsin Organic Chemistry, supra, Chapter 3) are also referred to herein as “protected hydroxy”.

In the general formula, R ₁ represents a carboxylic acid protecting group. As used herein, a “protected carboxycarb and a carboxylic acid protecting group” are typically used to subtract or protect the carboxylic acid functional group of a compound when undergoing a one-step reaction or several reaction steps involving other functional moieties of the compound. Refers to a carboxy group protected by one of the carboxylic acid protecting groups used. Such protected carboxy groups are those that are readily decomposed into the corresponding carboxylic acid by gasification or hydrocracking. Carboxylic protecting groups include C ₄ -C ₆ tert-alkyl, butyl, benzyl, 4-methoxybenzyl, C ₂ -C ₆ alkylnoyloxybenzyl, 2-omethyl, 4-nitrobenzyl, diphenylmethyl (benzhai Drill), phenacyl, p-halofenacyl, dimethylallyl, 2,2,2-trihaloethyl, succinimidomethyl or phthalimidomethyl, where halo represents chlorine, bromine or iodine. The nature of such ester forming groups does not matter as long as the resulting esters are stable under the reaction conditions in accordance with the inventive process. Furthermore, see E. Haslam, Protective Groups in Organic Chemistry JFW Mcomie, Ed., Plenum Press, New York, NY 1973, Chapter 5.

Other known carboxy protection groups, such as those described, are also included herein in “protected carboxy”.

Detailed examples of the carboxylic acid protecting group of the preferred sulfinyl chloride prepared by the production method of the present invention are as follows.

t-botyl, t-amyl, t-hexyl, 2,2,2-trichloroethyl, 2,2,2-tribromoethyl, 2-uretho, benzyl, p-nitropezyl, succinimidomethyl, phthal Imido, p-methoxybenzyl, benzhydryl, acetoxymethyl, pivaloyloxymethyl, pyrionoxymethyl, phenacyl, p-chlorophenacyl, p-bromophenacyl and the like.

Preferred carboxylic acid hydroxy, amino and carboxy groups are not limited thereto. It is to protect the highly reactive functional groups during the preparation of such their desired desired product. Next, they are removed without breaking down other parts of the molecule. Such protecting groups are well known in the literature and their uses are likewise applicable in the preparation of the invention. It is understood that all penicillin sulfoxides used as starting materials in the preparation of the present invention can be readily prepared from available penicillin sources such as natural penicillin G and / or penicillin V, which are common in the field of phenylcillin and cephalosporins. It is obvious to those with skill.

6-amino phenylsilic acid (6-APA) can be prepared by degrading 6-acyl functional groups from one of the natural penicillins described above by methods known in the art.

All known starting materials can be prepared from 6-APA by well known methods. For example, 6-APA can be converted to the desired ester by esterifying a 3-carboxyl functional group using a typical esterification method.

Furthermore, the amino group of 6-APA can be acylated to produce all groups defined by. This is accomplished by reacting 6-APA with the active form of the acid of the desired acyl group. Such active forms include the corresponding acid halides, anhydrides or active esters such as pentachlorophenyl esters.

Moreover, penicillin can be oxidized by treating penicillin with m-chloroperbenzoic acid or sodium periodate under a wide range of known conditions.

These conversion reactions, degradation to 6-APA, esterification, acylation and oxidation can be carried out in any order to match the desired structural modification order. In all cases all such conversion reactions can be achieved using reaction methods, conditions and reactants that are well understood and readily available to those of ordinary skill in the art.

Preferred among the penicillin sulfoxide esters used in the production method of the present invention are compounds of the following general formula (IV).

Wherein m is 0 or 1, preferably 1 and R ₁ is a carboxylic acid protecting group, preferably P-nitrobenzyl.

Likewise preferred sulfinyl chlorides prepared from these esters by the process of the invention are compounds of the general formula (V)

Wherein m is 0 or 1, preferably 1 and R ₁ is a carboxylic acid protecting group, preferably P-nitrobenzyl.

Other preferred penicillin sulfoxide esters for use in the present invention are compounds of the general formula (IV)

R ₁ in the general formula is a carboxylic acid protecting group, preferably P-nitrobenzyl.

Likewise other preferred sulfinyl chlorides prepared from these esters by the process of the present invention are compounds of formula (VII)

R ₁ in the general formula is a carboxylic acid protecting group, preferably P-nitrobenzyl.

The sulfinyl chloride prepared by the present method is prepared by the action of penicillin sulfoxide and an N-chloro halogenating agent at an elevated temperature.

N-chlorohalogenation agent is a by-product from the preparation of sulfinyl chloride and the nitrogen atom of the structural moiety of the reactant having an electron-withdrawing strength sufficient to produce a nitrogen-containing compound having the following characteristics: It means a reagent having at least one chlorine directly bonded to. The nitrogen-containing compound thus prepared corresponds to the first N-chlorohalogenating agent, but the chlorine atom is replaced by hydrogen. Secondly, this nitrogen-containing compound is inert to the sulfinylchloride product mainly due to the nature of the electron withdrawing site.

As for the N-chloro halogenating agent used for the manufacturing method of this invention, the following general formula (VIII) compound is preferable.

Wherein R ₄ is hydrogen, chlorine, C ₁ -C ₃ alkyl, cyclohexyl, phenyl or phenyl substituted with chlorine, bromine, methyl or nitro,

의 복소환그룹 또는

인 그룹이고 여기서 R₃는 0-페닐렌 또는 -(CH₂)n-이고 n은 2 또는 3이다.R ₄ and R ₅ together with the nitrogen atom to which they are attached

Heterocyclic group of or

Phosphorus group wherein R ₃ is 0-phenylene or-(CH ₂ ) n- and n is 2 or 3.

The various forms of preferred N-chloro compounds that can be used to prepare sulfinyl chloride are as defined above. Such N-chloro compounds include a) urea, b) amides, c) urethanes, d) sulfonamides, e) sulfoimides and f) imides.

Preferred N-chloro ureas usable in the present invention have the general formula (IX)

Wherein R ₄ is hydrogen, chlorine, C ₁ -C ₃ alkyl, cyclohexyl, phenyl or phenyl substituted with chlorine, bromine, methyl or nitro, R ₆ is C ₁ -C ₃ alkyl, cyclohexyl, phenyl or chlorine , Bromine, or phenyl substituted with nitro.

Examples of such ureas are as follows.

N, N'-dichloro-N-methylurea:

N / N'-dichloro-N-ethyl-N'-cyclohexylurea;

N, N'-dichloro-N-phenylurea: N, N'-dichloro-N, N'-diphenylurea: N, N'-dichloro-N- (P-tolyl) urea: N, N'-dichloro -N- (M-chlorophenyl) -N'-methylurea: N, N'-dichloro-N, N'-dicyclohexylurea: N, N'-dichloro-N-isopropyl-N '-(P -Tolyl) urea: N, N'-dichloro-N-phenyl-N'-propylurea: N, N'-dichloro-N-cyclohexyl-N '-(P-nitrophenyl) urea: N, N, N -Trichloro-N-methylurea: or N, NN'-trichloro-N-phenylurea.

Preferred N-chloroamides which can be used in the present invention are compounds of the following general formula (X).

In the above general formula

R ₄ and R ₆ are as described above.

Examples of such amides include N-chloroacetamide, N-clopropionamide, N-chloro-N-methylacetamide, N, N-dichloroacetamide, N-chloro-N-cyclohexylacetamide, N-chloro- NN-ethylbenzamide, N-chloro-P-chlorobenzamide, N-chloro-P-toluamide, N-chloro-N-phenylpropionamide, N-chloro-N (m-bromophenyl) butylamide , N-chlorohexahydro benzamide, or N, 2,4-trichloroacetanilide.

Preferred N-chloro urethanes which can be used for the preparation of the sulfinyl chlorides of the invention are compounds of the general formula (XI)

In the above general formula

R ₄ and R ₆ are as described above.

Examples of such amides include N-chloroacetamide, N-clopropionamide, N-chloro-N-methylacetamide, N, N-dichloroacetamide, N-chloro-N-cyclohexylacetamide, N-chloro- NN-ethylbenzamide, N-chloro-P-chlorobenzamide, N-chloro-P-toluamide, N-chloro-N-phenylpropionamide, N-chloro-N (m-bromophenyl) butylamide , N-chlorohexahydro benzamide, or N, 2,4-trichloroacetanilide.

In the above general formula

R ₄ and R ₆ are as described above.

Such urethanes include methyl N, N-dichlorocarbamate, ethyl N, N-dichlorocarbamate, phenyl, N, N-dichlorocarmate, cyclohexyl N, N-dichlorocarbamate, methyl N-chlorocarbamate, Ethyl-N-chlorocarbamate, ethyl N-cyclohexyl-N-chlorocarbamate, phenyl N-chlorocarbamate, phenyl N-phenyl-N-chlorocarbamate, P-tolyl N-chlorocarbamate, m-chloro Phenyl N-methyl-N-chlorocarbamate, cyclohexyl N-cyclohexyl-N-chlorocarbamate, isopropyl NP-tolyl-N-chloro carbamate, phenyl N-propyl-N-chlorocarbamate, or cyclohexyl NP-nitrophenyl-N-chlorocarbamate.

Preferred N-chlorosulfonamides which can be used for the preparation of the sulfinyl chlorides of the invention are compounds of the general formula (XII)

In the above general formula

R ₄ and R ₆ are as described above.

Examples of sulfonamides which can be used as the halogenating agent include N, N-dichlorobenzene-sulfonamide, N, N-dichloromethanesulfonamide, N, N-dichlorocyclohexanesulfonamide, N, N-dichloro-P-toluenesulfone Amide, N-chloromethanesulfonamide, N-cyclohexyl-N-chlorobenzenesulfonamide, N-cyclohexyl-N-chloroethanesulfonamide, N-chlorobenzenesulfonamide, N-phenyl-N-chlorobenzenesulfonamide , N-chloro-P-toluenesulfonamide, N-ethyl-N-chloro-m-nitrobenzenesulfonamide, N-methyl-N-chloro-m-chlorobenzenesulfonamide, N-methyl-N-chloro-P Toluenesulfonamide, N-cyclohexyl-N-chlorocyclohexanesulfonamide, NP-tolyl-N-chloroisopropanesulfonamide, N-propyl-N-chlorobenzenesulfonamide, or NP-nitrophenyl-N-chloro Cyclohexanesulfonamide.

A dunwook preferred N-chlorohalogenating agent that can be used to prepare sulfinyl chloride is the sulfimide of formula (XIII).

In the general formula, R ₃ is 0-phenylene, -CH ₂ -CH ₂ -or-CH ₂ -CH ₂ .

This compound includes N-chloroimide, β-sulfopropionic N-chloroimide and γ-sulfobutyric N-chloroimide of 0-sulfonbenzo.

Preferred N-chlorohalogenating agents used in the preparation of the sulfinyl chlorides of the present invention are N-chloroimides of the general formula (XIV).

In the general formula, R ₃ is 0-phenylene, -CH ₂ -CH ₂ -or-CH ₂ -CH ₂ .

This compound includes N-chlorophthalamide, N-chlorosuccinimide and N-chloroglutarimide.

Most of the N-chlorohalogenating agents used in the preparation of the present invention are commercially available, and all of them can be prepared by methods known in the chemical art.

Highly preferred N-chloro halogenating agents used in the preparation of the present invention are preferably N-chloroimide, in particular N-chlorosuccinimide or N-chlorophthalimide, especially N-chlorophthalimide.

The reaction of penicillin sulfoxide with N-chlorohalogen proceeds in the presence of the epoxide compound and calcium oxide. Generally at least 1 to 1.5 moles of halogenating agent is used with respect to 1 mole of penicillin linsulfoside ester. Larger amounts of halogenating agents may be used but there is no benefit. Therefore, the reaction is preferably used at a ratio of about 1.0 to 1.1 moles of halogenating agent per penicillin sulfoxide ester sunset. The resulting mixture is preferably dissolved in a suitable inert organic solvent and heated to 75-135 ° C. The reaction temperature is preferably 100 to 120 ° C, most preferably 102 to 110 ° C.

“Inert organic solvent” means an organic solvent that does not react with a reactant or product under sulfinyl chloride production conditions. Suitable inert solvents have a boiling point at least as high as the reaction temperature, for example aromatic hydrocarbons such as benzene, toluene, ethyl benzene or cumene, carbon tetrachloride, chlorobenzene, bromoform, bromobenzene, ethylene dichloride 1,1,2 Use toluene or 1,1,2-trichloroethane as halogenated hydrocarbons such as trichloroethane or ethylene dibromide, open chain hydrocarbons such as heptane, octane, nonane or mecan or any other suitable fluorinated solvent and the temperature is It was set as reaction temperature under reflux conditions.

What is needed for the manufacturing method of this invention is to advance reaction on anhydrous conditions. "Anhydrous condition" means that there is no water at all, and to avoid mixing in the reaction mixture of a substantial amount of water. This can be accomplished by any known method that can bring the reaction system to anhydrous state. Halogenating agents generally do not become a source of moisture in the reaction mixture because they react with water. The excess moisture in the reaction system is usually due to the moisture in the solvent used. Therefore, in general, the solvent is pretreated to remove residual moisture. The solvent can be effectively dehydrated to some extent anhydrous by contacting with a dehydrating agent which is combined with moisture prior to use in the reaction. Such dehydrating agents typically include anhydrous sodium sulfate, magnesium sulfate, sodium carbonate, calcium carbonate, calcium carbide, calcium chloride, calcium hydride, potassium sulfate, calcium oxide or molecular agents, especially solvents which are azeotropic with 3A and 4 moles. The solvent may be refluxed to remove moisture using known types of chemical devices, such as conventional Dean-stark traps or Barrett type moisture traps, which are capable of raising moisture when they are.

The starting material penicillin sulfoxide ester itself may also contain moisture. This can be removed by dehydration of the penicillin sulfoxide under vacuum in a typical drying method, for example in a low temperature oven at 50 ° C. or lower. Penicillin sulfoxide esters may also be added to the solvent to azeotrope the mixture to remove water.

Mixtures containing penicillin sulfoxide esters, N-chlorohalogenating agents, epoxide compounds and calcium oxide are generally heated to a defined range of temperature for 0.5 to 4 hours, preferably 1 to 2 hours, and then sulfinylchloride It can be separated from the reaction mixture. Although sulfinyl chloride can be separated from the reaction mixture, it is not necessary to separate it from the reaction mixture before proceeding to the next reaction. As pointed out above, sulfinyl chloride can be used as an intermediate to prepare 3-xomethylene sefam sulfoxide. It is not necessary at this time to separate the sulfinyl chloride itself, but the sulfinyl chloride reaction mixture must first be treated in the following manner before being used to prepare 3-exomethylene sefam sulfoxide.

In many cases, it is preferable to include a non-alaliic acid remover in the reaction mixture. It is advisable to add a small amount of hydrogen chloride which is detrimental to the reaction for some reason not yet identified, since it is released into the reaction system.

Non-alkaline acid scavengers are normally completely inert in the hydrogen chloride free reaction medium producing sulfinyl chloride, but are activated enough to react with hydrogen chloride, which may be produced, to remove hydrogen chloride from the medium half.

Typical non-alkaline acid scavengers include epoxy compounds such as ethylene oxide, propylene oxide, 1,2-epoxybutane, epichlorohydrin, or 1,2-epoxy-3-phenoxy-propane. These materials are nonalkylative but react with the acid in the reaction system to remove the acid.

The sulfinyl chloride production reaction is carried out in the presence of an epoxide compound which is a non-alkaline acid scavenger, especially in the presence of propylene oxide or 1,2-epoxybutane, when calcium oxide is added to the reaction mixture, the penicillin sulfoxide is the desired sulfinyl chloride. It has been found to be extremely advantageous in facilitating the transition to. This is particularly evident when the reaction scale is at a scale using starting materials with penicillin sulfoxide of at least 50 g.

It was found that conversion of the penicillin sulfoxide to sulfinyl chloride in the method of Belgian Patent No. 837040 significantly reduced with increasing reaction scale. The process of the present invention is therefore particularly particularly when the starting material is prepared with sulfinyl chloride using at least 50 g of penicillin sulfoxide.

The amount of the epoxide compound used in the preparation of sulfinyl chloride needs to be at least a sufficient amount to correspond to the amount of hydrogen chloride produced. Therefore, the epoxide compound does not require an excess, but usually uses 2 to 1 mole, particularly about 5 moles of epoxide per mole of penicillin sulfoxide. This excess can be used without causing adverse effects in the preparation of sulfinyl chloride. However, the presence of excess epoxide compounds is particularly severe when the mixture itself containing the product of sulfinyl chloride is used for conversion to the corresponding 3-exomethylenecepam sulfoxide. Therefore, it is highly desirable to separate not only excess epoxide as well as any product produced by reacting the epoxide compound with hydrogen chloride from the reaction mixture of sulfinyl chloride before the ring is closed using a Friedel-Craft catalyst. This can generally be achieved by distilling the reaction mixture under constant conditions for a period of time sufficient to remove excess epoxide.

As pointed out above, the present invention attempts to present the calcium oxide and the epoxide compound together when the penicillin sulfoxide is reacted with an N-chloro halogenating agent to produce sulfinyl chloride. The amount of calcium oxide is 100 to 500 g, preferably 200 to 250 g, of 1 mole of penicillin sulfoxide starting material. Calcium oxide is present throughout the production of sulfinyl chloride and also during the removal of excess epoxide compounds. It is then easily separated from the residual reaction mixture by filtration.

Typical preparations of sulfinyl chlorides according to the invention are carried out by mixing calcium oxide with molar equivalents of penicillin sulfoxide and N-chloro halogenating agent in a suitable solvent which has been dehydrated beforehand. Propylene oxide or 1,2-epoxybutane is then added and the resulting mixture is heated at the desired temperature for a defined period of time. Preferably the solvent used is one in which the temperature can be maintained by refluxing the reaction mixture with propylene oxide or 1,2-epoxybutane present. Toluene is such a suitable solvent. When the reaction time is completed, the reaction mixture is rapidly distilled to remove excess epoxide. The remaining mixture is cooled and filtered. The solvent is evaporated to yield the sulfinyl chloride product.

Sulfinyl chloride prepared by the present invention is as follows.

Tert-butyl 3-methyl-2- (2-chlorosulfinyl-4-oxo-3-phenylacetamido-1-azetidinyl) -3-bunoate; Tert-butyl 3-methyl-2- (2-chlorosulfinyl-4-oxo-3-phenylacetamido-1-azetidinyl) -3-bunoate; Benzyl 3-methyl-2- (2-chlorosulfinyl-4-oxo-3-pramide-1-azetidinyl) -3-bunoate; 2,2,2-trichloroethyl 3-methyl-2- (2-chlorosulfinyl-4-oxo-3-acetamido-1-azetidinyl) -3-bunoate; P-nitrobenzyl 3-methyl-2- (2-chlorosulfinyl-4-oxo-3-butylamido-1-azetidinyl) -3-bunoate; P-methoxybenzene 3-methyl-2- (2-chlorosulfinyl-4-oxo-3-chloroacetamido-1-azetidinyl) -3-bunoate; Benzhydryl 3-methyl-2- (2-chlorosulfinyl-4-oxo-3-cyano acetamido-1-azetidinyl) -3-bunoate; P-nitrobenzyl 3-methyl-2- [2-chlorosulfinyl-4-oxo-3- (4-nitrobenzyloxycarbamido) -1-azetidinyl] -3-bunoate; t-amyl 2-methyl-2- (2-chlorosulfinyl-4-oxo-3-chuckoxyoxycaramido-1-azetidinyl) -3-bunoate; t-hexyl 3-methyl-2- [2-chlorosulfinyl-4-oxo-3- (t-butyloxycarbamido) -1-azetidinyl] -3-bunoate; 2-iodoethyl 3-methyl-2- [2-chlorosulfinyl-4-oxo-3- (2 ', 2', 2'-trichloroethoxycarbamido) -1-azetidinyl] -3- Bunoate; Acetoxymethyl 3-methyl-2- [2-chlorosulfinyl-4-oxo-3- (4'-methoxybenzyloxycarbamido) -1-azetidinyl] -3-bunoate; Benzyl 3-methyl-2- [2-chlorosulfinyl-4-oxo-3- (2'-thienylacetamido) -1-azetidinyl] -3-bunoate; t-amyl 3-methyl-2- (2-chlorosulfinyl-4-oxo-3-benzamido-1-azetidinyl) -3-bunoate; Phenacyl 3-methyl-2- [2-chlorosulfinyl-4-oxo-3- (4'-chlorobenzamido) -1-azetidinyl] -3-bunoate; P-chlorophenacyl-3-methyl-2- [2-chlorosulfinyl-4-oxo-3- (3'-formyloxybenzamido) -1-azetidinyl] -3-bunoate; Pivaloyloxymethyl 3-methyl-2- [2-chlorosulfinyl-4-oxo-3- (4'-nitrobenzamido) -1-azetidinyl] -3-bunoate; Isopropyl 3-methyl-2- [2-chlorosulfinyl-4-oxo-3- (2'-cyanobenzamido) -1-azetidinyl] -3-bunoate; Succinimidoethyl 3-methyl-2- [2-chlorosulfinyl-4-oxo-3- (4'-trifluoromethylbenzamido) -1-azetidinyl] -3-bunoate; Phthalimidomethyl 3-methyl-2- [2-chlorosulfinyl-4-oxo-3- (3'-methylbenzamido) -1-azetidinyl] -3-bunoate; t-butyl 3-methyl-2- [2-chlorosulfinyl-4-oxo-3- (2'-methoxy benzamido) -1-azetidinyl] -3-bunoate; P-nitrobenzyl 3-methyl-2- [2-chlorosulfinyl-4-oxo-3- (1 ', 4'-cyclohexanedienylacetamido) -1-azetidinyl] -3-bunoate ; 2,2,2-trichloroethyl 3-methyl-2- [2-chlorosulfinyl-4-oxo-3- (2'-thienylacetamido) -1-azetidinyl] -3-bunoate ; P-methoxybenzyl 3-methyl-2- (2-chlorosulfinyl-4-oxo-3-phenyl acetamido-1-azetidinyl) -3-bunoate; 2,2,2-trichloroethyl 3-methyl-2- (2-chlorosulfinyl-4-oxo-3-phenoxyacetamido-1-azetidinyl) -3-bunoate; P-nitrobenzyl 3-methyl-2- [2-chlorosulfinyl-4-oxo-3- (2 ', 5'-thichlorophenylacetamido) -1-azetidinyl] -3-bunoate; Benzyl 3-methyl-2- [2-chlorosulfinyl-4-oxo-3- (3'-bromophenoxyacetamido) -1-azetidinyl] -3-bunoate; t-butyl 3-methyl-2- [2-chlorosulfinyl-4-oxo-3- (4'-chloroacetoxyphenylacetamido) -1-azetidinyl] -3-bunoate; Isobutyl 3-methyl-2- [2-chlorosulfinyl-4-oxo-3- (3'-formoxy phenoxyacetamido) -1-azetidinyl] -3-bunoate; P-nitrobenzyl 3-methyl-2- [2-chlorosulfinyl-4-oxo-3- (2'-nitrophenylacetamido) -1-azetidinyl] -3-bunoate; P-methoxybenzyl 3-methyl-2- [2-chlorosulfinyl-4-oxo-3- (4'-nitrophenoxyacetamido) -1-azetidinyl] -3-bunoate; Benzhydryl 3-methyl-2- [2-chlorosulfinyl-4-oxo-3- (3'-cyanophenylacetamido) -1-azetidinyl] -3-bunoate; P-bromophenacyl 3-methyl-2- [2-chlorosulfinyl-4-oxo-3- (2'-cyanophenoxyacetamido) -1-azetidinyl] -3-bunoate; Propionoxymethyl 3-methyl-2- [2-chlorosulfinyl-4-oxo-3- (4'-trifluoromethylphenylacetamido) -1-azetidinyl] -3-bunoate; 2,2,2-tribromoethyl 3-methyl-2- [2-chlorosulfinyl-4-oxo-3- (3'-trifluoromethylphenoxyacetamido) -1-azetidinyl] -3-bunoate; 2-iodoethyl 3-methyl-2- [2-chlorosulfinyl-4-oxo-3- (2'-ethylphenylacetamido) -1-azetidinyl] -3-bunoate; Acetoxymethyl 3-methyl-2- [2-chlorosulfinyl-4-oxo-3- (4'-isopropylphenoxyacetamido) -1-azetidinyl] -3-bunoate; t-butyl 3-methyl-2- [2-chlorosulfinyl-4-oxo-3- (3'-ethoxyphenylacetamido) -1-azetidinyl] -3-bunoate; P-nitrobenzyl 3-methyl-2- [2-chlorosulfinyl-4-oxo-3- (4'-isopropoxyphenoxyacetamido) -1-azetidinyl] -3-bunoate; P-nitrobenzyl 3-methyl-2- [2-chlorosulfinyl-4-oxo-3- (α-formyloxyphenylacetamido) -1-azetidinyl] -3-bunoate; P-methoxybenzyl 3-methyl-2- [2-chlorosulfinyl-4-oxo-3- (α-benzhydryloxyphenylacetamido) -1-azetidinyl] -3-bunoate; Zilbene 3-methyl-2- [2-chlorosulfinyl-4-oxo-3- (2-thienyl-α-benzyloxyacetamido) -1-azetidinyl] -3-bunoate; Benzhydryl 3-methyl-2- [2-chlorosulfinyl-4-oxo-3- (α-benzhydryloxyphenyl acetamido) -1-azetidinyl] -3-bunoate; P-nitrobenzyl 3-methyl-2- [2-chlorosulfinyl-4-oxo-3- (α-benzyloxycarbonylaminophenyl acetamido) -1-azetidinyl] -3-bunoate; t-butyl 3-methyl-2- [2-chlorosulfinyl-4-oxo-3- (α-t-butyloxycarbonylamidophenyl acetamido) -1-azetidinyl] -3-bunoate ; P-nitrobenzyl 3-methyl-2- [2-chlorosulfinyl-4-oxo-3- (2-thienyl-α-P-nitrobenzyloxycarbonylaminoacetamido) -1-azetidinyl] -3-bunoate; Benzyl 3-methyl-2- [2-chlorosulfinyl-4-oxo-3- (3'-thienylacetamido) -1-azetidinyl] -3-bunoate; P-methoxybenzyl 3-methyl-2- [2-chlorosulfinyl-4-oxo-3-phenylacetamido-1-azetidinyl] -3-bunoate; Benzhydryl 3-methyl-2- [2-chlorosulfinyl-4-oxo-3- (2 ', 5'-thichlorophenylthio acetamido) -1-azetidinyl] -3-bunoate; t-butyl 3-methyl-2- [2-chlorosulfinyl-4-oxo-3- (4'-chloroacetoxyphenylthio acetamido) -1-azetidinyl] -3-bunoate; P-nitrobenzyl 3-methyl-2- [2-chlorosulfinyl-4-oxo-3- (3'-nitrophenylthioacetamido) -1-azetidinyl] -3-bunoate; P-nitrobenzyl 3-methyl-2- [2-chlorosulfinyl-4-oxo-3- (2'-cyanophenylthioacetamido) -1-azetidinyl] -3-bunoate; P-methoxybenzyl 3-methyl-2- [2-chlorosulfinyl-4-oxo-3- (4'-trifluoromethylphenylthioacetamido) -1-azetidinyl] -3-bunoate; Benzyl 3-methyl-2-[[3-chlorosulfinyl-4-oxo-3- [3 '-(2'-chlorophenyl) -5'-methylisoxazole-4'-ylcarbamaido]- 1-azetidinyl]]-5-bunoate; Acetoxymethyl 3-methyl-2- [2-chlorosulfinyl-4-oxo-3- (3'-methylphenylthioacetamido) -1-azetidinyl] -3-bunoate; Or 2,2,2-trichloroethyl 3-methyl-2- [2-chlorosulfinyl-4-oxo-3- (4'-methoxyphenylthioacetamido) -1-azetidinyl] -3 -Buno Eight.

As indicated above, sulfinylchloride prepared by the present Baldo method is effective as an intermediate, and the sulfinyl chloride can be converted to the corresponding 3-exomethylenepepam sulfoxide by ring closure by a Friedel-Crafts catalyst such as stannous chloride. Can be.

Generally, the ring closure reaction is carried out in anhydrous inert organic solvent. Various secondary inert organic solvents can be used as the medium for the ring closure reaction. “Inert organic solvent” means an organic solvent that does not react with a reactant or product under ring closure conditions. The sulfinyl chloride starting material, like other acid chloride reagents, is susceptible to hydrolysis and is susceptible to attack by other protonic compounds such as alcohols and amines, so that moisture and these other protonic compounds should be absent from the reaction medium. Anhydrous aprotic solvents are therefore preferred. Although very small amounts of water such as those in commercially available anhydrous solvents are fine, this ring closure reaction is preferably carried out under anhydrous conditions. Suitable solvents include aromatic hydrocarbons such as benzene, toluene or xylene; Chlorobenzene, nitrobenzene, or nitro mesitylene; Halogenated aliphatic hydrocarbons such as chloroform, methylene chloride, carbon tetrachloride, 1,2-dichloroethane (ethylene chloride), 1,1,2-trichloroethane, 1,1-dibromo-2-chloroethane and others There are suitable solvents for Friedel-Kraft's type reactions such as carbon disulfide and nitro methane, which are known to those skilled in the art. Preferred solvents are aromatic hydrocarbons, in particular benzene, toluene and xylene, most preferably toluene; Halogenated aliphatic hydrocarbons, in particular methylene chloride and ethylene chloride.

All solvents used to prepare sulfinyl chloride can also be used to ring off azetidinone sulfinyl chloride. Thus sulfinyl chloride does not need to be separated from the resulting reaction mixture before proceeding with the ring closure reaction. However, when using this ring closure method, it is essential that the reaction mixture containing sulfinyl chloride starting material be treated before use to remove the first epoxide compound, followed by calcium oxide and all of its reaction products. This can be conveniently done by first distilling the reaction mixture to remove the low boiling epoxide and then filtering the half silver mixture to remove calcium oxide and other insolubles.

The filtrate thus obtained then uses ring closure with a Friedel-Crafts catalyst.

The ring closure of azetidinone sulfinyl chloride proceeds at a temperature of −20 ° C. to ± 100 ° C., preferably 10 ° C. to 60 ° C. and the optimum temperature of the ring closure reaction is determined by distillation of the Friedel-Crafts catalyst used. For example, when tin-tin is used, the ring closure proceeds at room temperature while other Friedel-Craft catalysts require higher temperatures.

To confirm completion of the ring closure, the catalyst is used at least one equivalent of Friedel-Craft per sunset of sulfinyl chloride starting material. Use of Friedel-Craft catalysts of less than one equivalent lowers the conversion of the product, leaving some unreacted sulfinyl chloride. Typically the amount of Friedel-Craft catalyst used is from just over one equivalent to about two equivalents per sulfinyl chloride sunset.

Preferably about 1.1 equivalents of catalyst are used per sulfinyl chloride sunset.

The reaction time is generally 15 minutes to 2 hours, and the reaction time varies to some extent depending on the type of reactant, the solvent used, and the temperature at which the reaction proceeds. Typically the reaction is complete after contacting the reactants at the desired temperature for 1 to 16 hours. The reaction mixture can be easily determined by completion of the ring closure reaction, for example by control chromatography.

3-exomethylenecepam sulfoxide prepared by the ring closure reaction of the sulfinyl chloride of the present invention can be isolated and purified by a conventional test method. Such methods include chromatographic separation, filtration, crystallization, and crystallization methods.

The ring closure product, 3-exomethylene sepam sulfoxide, is useful as an intermediate in the preparation of antibiotic compounds.

Exo methyllinecepam can be used to prepare novel sepime antibiotics of the following general formula (X V).

R ₇ in the formula is, for example, chlorine, bromine or methoxy.

Such chemical conversion of 3-exomethylenecepam compounds is published in the chemical literature (Robert R. Chauvette and Pamela A. Pennington, Journal of the American Chemical Society 96, 4986 (1974)).

In general, 3-exomethylcepam compounds are converted to 3-hydroxycefe by ozonation at low temperature, and treated with diazomethane in tetrahydrofuran containing 1 equivalent of triethylamine at room temperature. A oxy cefem derivative can be obtained. 3-halo cefem is derived from 3-hydroxycefe esters by treatment with a halogenating agent such as phosphorus trichloride or phosphorus tribromide in N, N-dimethylformamide.

Commercial cefeic acid has a strong antibacterial action. This can be obtained by decomposing the ester group. The deesterification reaction can be carried out by various known methods as follows depending on the nature of the protecting group.

1) treatment with an acid such as trifluoro acetic acid, hydrochloric acid or hydrochloric acid; Or 2) treating with zinc and an acid such as hydrochloric acid, acetic acid or hydrochloric acid; 3 or 3) hydrogenation in suspension in the presence of palladium, gold, rhodium or compounds thereof or on a reduced body such as barium sulfate, charcoal or alumina.

The present invention will be described in comparison with the following comparative examples. This is not intended to limit the scope of the invention by this embodiment for any reason.

Example 1

Preparation of P-nitrobenzyl 7-phenoxyacetamido-3-exo methylenecepam-7-carboxylate-1-oxide.

A. Reaction without using calcium oxide

Toluene (1.5 L) is azeotropic to remove 150 ml of material and dehydrated. Remove 50 ml more to transfer the reactants to the reactor. Stop heating and add 50 g of P-nitrobenzyl 6-phenoxy acetamido-2,2-dimethylphenam-3-carboxylate-1-oxide and 23 g of N-chlorophthalimide. A Dean-Stark moisture trap is attached to the device and a mixture of about 1: 1 calcium chloride and 14.3 g of magnesium oxide is added to the moisture trap.

The mixture is heated again and 45 ml of propylene oxide is added and the mixture is refluxed at < RTI ID = 0.0 > 102 C. < / RTI > The mixture is cleared after about 70 minutes. After 75 minutes, a sample of the reaction mixture was subjected to NMR, showing the presence of sulfinyl chloride intermediate on the spectrum. After 100 minutes, the water trap containing the calcium chloride and magnesium oxide mixture is replaced with a fresh water trap and the mixture is distilled off.

Raising the temperature of the reaction mixture to 110.5 ° C. for more than 35 minutes removes 315 ml of material. The mixture is then cooled to 10 ° C. over 20 minutes. The reaction mixture is filtered and the filtrate is added to a mixture of dichlorotin in 25 ml of toluene that has been cooled beforehand. The resulting mixture is stirred overnight until a red cake is produced.

The cake is filtered and extracted with 250 ml of acetone and 500 ml of ethyl acetate. The resulting extract is washed with 1 L of water and then with 500 ml of brine. The organic mixture is evaporated to reaction volume and cooled to crystallize. The resulting mixture is filtered and the solid is dried at room temperature in vacuo to yield 22.7 g (45.4%) of the title compound.

B. Reaction with Calcium Oxide

Toluene (2.0 L) is azeotropic to remove 200 ml of material and dehydrate. Also, 100 ml of toluene is removed for the purpose of transferring the reactants to the reaction system.

Stop heating and add 50 g of P-nitrobenzyl 6-phenoxyacetamido-2,2-dimethyl phenam-3-carboxylate-1-oxide, 22 g of N-chlorophthalimide and 22 g of calcium oxide . Heat and add 35 ml of propylene oxide at reflux to 103-104 ° C. The mixture is heated at 104 ° C. for 75 minutes and then 545 ml of material is removed by distillation at 110 ° C. for 30 minutes by raising the temperature of the reaction mixture. The resulting mixture is then cooled to 10 ° C. and filtered. The filtrate is added to a mixture of 50 ml of toluene previously cooled and 25 ml of ditin chloride. The resulting mixture is then stirred for 10 hours, forming a solid.

The solids were collected by filtration and extracted with 500 ml of ethyl acetate and 250 ml of acetone mixture. The extract is washed with 500 ml of water, evaporated to reaction volume and cooled overnight.

The title compound (28.55 g: 57%) is obtained.

Example 2

Preparation of P-nitrobenzyl 7-phenoxyacetamido-3-exo methylenecepam-4-carboxylate-1-oxide.

A. Reaction without using calcium oxide

Toluene (2.1 L) is distilled off to remove 160 ml of solvent and dehydrated. Remove 50 ml more to transfer the reactants to the reaction medium. 17.1 g (34 mmol) of P-nitrobenzyl 6-phenylacetamido-2,2-dimethylphenam-3-carboxylate-1-oxide 7.8 g (37.4 mmol) N-chlorophthalimide And 12 ml of propylene oxide are added. The mixture is refluxed at 103 ° C. for 100 minutes and then distilled to remove a total of 170 ml of material over about 30 minutes. The resulting mixture is cooled to 0-5 ° C. The resulting crystalline phthalimide by-product is then filtered off. The filtrate is added with a precooled mixture of ditin tin chloride in 8.5 ml of toluene. The mixture is stirred overnight until it is warmed to room temperature. The resulting solids are collected by filtration and washed thoroughly with toluene.

The solid is then extracted twice with 85 ml of acetone and 170 ml of water. The organic layer is separated, doubled in reaction volume and cooled to room temperature to crystallize. The title compound (4.0 g; 25%) is obtained.

B. Reaction with Calcium Oxide

The partial reaction is repeated except that the reaction mixture contains calcium oxide. Substances are used in the following amounts.

48.5 g (100 mmol) P-nitrobenzyl-6-phenylacetamido-2,2-dimethylphenyl-3-carboxylate-1-1-oxide, 48 g calcium oxide, 22 g N-chlorophthalamide and 35 ml Of propylene oxide.

The title compound (14.9 g: 32.6%) is obtained.

Example 3

Preparation of 2,2,2-trichloroethyl 7-phenoxy-acetamido-3-exomethylenecepam-4-carboxylate-1-oxide.

A. Reaction without calcium oxide

Toluene 2 is distilled off and dehydrated by removing 200 ml of material. 49.8 g (100 mmol) of 2,2,2-trichloroethyl 6-phenoxyacetamido-2,2-dimethylphenam-3-carboxylate-1-oxide with 20.4 g of N-chloro Deimide is added. Heat the mixture and add 35 ml of propylene oxide. The total mixture was refluxed at 103 ° C. for 100 minutes and the temperature was raised to 103-110 ° C. over 35 minutes to distill off 705 ml of the mixture. The mixture is cooled to 5-10 ° C. and then filtered. The filtrate is added to a precooled mixture of 50 ml of toluene and 25 ml of ditin chloride. The resulting mixture, which is red and free of solids, is stirred for 15 minutes until the color turns earthy brown and a small amount of solids is formed. The mixture is stirred overnight and then filtered to yield a cake that is light brown granular. The cake is dissolved in ethyl acetate. The ethyl acetate solution is washed twice with water. The organic layer is then evaporated to give a dense sample.

For example, methanol was added overnight to room temperature at room temperature, crystallization occurs. The mixture is filtered and washed with methanol to give 14.4 g (28.9%) of the title compound.

B. Reaction in the presence of calcium oxide

The partial reaction is repeated except that the reaction mixture contains 25 g of calcium oxide.

The title compound (18.6 g: 37.3%) is obtained.

Example 4

Preparation of P-nitrobenzyl 7-phenoxy acetamido-3-methylenecepam-4-carboxylate-1-oxide (stainless steel vessel, test plant scale).

A. Reaction without calcium oxide

76 liters of toluene are added to a 30 gallon stainless steel container. Toluene is distilled off to remove 19 L of material and dehydrated. In addition, 14 L of toluene is removed to obtain 43 L. Toluene under nitrogen gas was then cooled to 70 ° C. and 1.75 kg of P-nitrobenzyl 6-phenoxy acetamido-2,2-dimethyl phenam-3-carboxylate-1-oxide were added. Heat is added and 1,400 ml of propylene oxide is added when the temperature of the mixture reaches 85 ° C. Heating is continued and the mixture is refluxed at 102 ° C. A total of 700 g of N-chlorophthalamide is then added 87.5 g at approximately 7 minute intervals.

350 ml of propylene oxide is added before completing the addition of N-chlorophthalimide. 175 ml of propylene oxide is added over about 1 hour after the addition of N-chlorophthalimide is completed. The mixture is refluxed at 100 to 102 ° C. for 2.5 hours after the first N-chlorophthalimide addition. The 52.5 L mixture is cooled to about 61 ° C. and the mixture is concentrated to a volume of 38 L.

The mixture is then filtered and placed in a container containing 30 gallon glass-lined 875 ml of tin tin chloride and 13 liters of chloro pre-cooled to -2 ° C. The temperature is raised to + 14 ° C. and then cooled to 0-5 ° C. After that, the mixture is stirred overnight. The resulting red precipitate is filtered and the solids are dissolved in 8.75 L of acetone and 17.5 L of ethyl acetate mixture. The solution is washed with 17.5 L of water and then with 17.5 L of brine.

Isolate, concentrate to 15.5 L, cool to 0-5 [deg.] C. and stir overnight. The resulting mixture is then filtered and the combined solids are washed with 1.75 L of ethyl acetate and dried at 45-50 ° C. to give 389.6 g * 23.7%) of the title compound.

B. Reaction in the presence of calcium oxide

The reaction proceeds substantially under the conditions used in Part A, except that N-chlorophthalimide is added in one step and the reaction is carried out in a 75-cal styrene steel vessel, using the following amounts of material.

144 L toluene (2 distilled dewatered): 5.25 kg calcium oxide: 5.25 kg P-nitrobenzyl 6-phenoxyacetamido-2,2-dimethylphenyl-3-carboxylate-1-oxide: 2.415 g N-chlorophthalamide: 4.2 liters of propylene oxide: 2.625 ml of ditin chloride: 23.6 liters of acetone and 52.5 liters of ethyl acetate: 105 liters of mole.

This amount is used to obtain 2.47 g (47.4%) of the title compound under the conditions of Part A.

Example 5

Preparation of P-nitrobenzyl 7-phenoxy acetamido-3-methylenecepam-4-carboxylate-1-oxide (glass container, test plant scale).

A reaction without calcium oxide

56 liters of toluene are added to a 3-gallon glass lined vessel. Toluene is distilled twice to remove 9 L of distillate and dewater. The mixture is cooled to room temperature and filled with nitrogen gas. 17.5 liters of the remaining toluene are used as solvent for the N-chlorophthalamide reactant and 4.4 liters are used for washing the transfer vessel. Amido-2,2-dimethyl phenam-3-carboxylate-1-oxide is added. After reaching 90 ° C., 1,400 ml of propylene oxide was added. 700 g of N-chlorophthalamide in 17.5 L of toluene are added over 70 minutes.

While adding a solution of N-chlorophthalimide, 350 ml of propylene oxide is also added.

After completion of the N-chlorophthalimide addition, 75 ml of propylene oxide is added followed by 150 ml of propylene oxide. The mixture refluxed at 102-103 [deg.] C. is initially heated and refluxed for a total of 3 hours 40 minutes after the addition of N-chlorophthalimide is complete. The mixture is then cooled.

At 43 ° C., the mixture is concentrated in vacuo until the volume is reduced to 42 l. The mixture is then filtered and the filtrate is added to a 30 cal glass-lined container. 858 ml of stannic chloride is then added to the mixture and the reaction mixture is ringed at 14 ° to 17 °. The mixture is stirred overnight until a red precipitate forms. The precipitate is filtered off and washed with 4 liters of toluene. The red precipitate is then dissolved in 8.75 L of acetone. Ethyl acetate (17.5 L) and water (17.5 L) are then added. The resulting mixture is stirred and then separated. The organic layer is washed with a water of 1.75 L and then concentrated to 16 L. The concentrate is cooled to 0-5 [deg.] C. and stirred overnight.

The resulting mixture was filtered and the combined solids were stirred with 1 L of ethyl acetate and dried in vacuo at 40-45 ° C. to afford 70.16 g (4.1%) of the title compound.

B. Reaction in the presence of calcium oxide

400 liters of two dehydrated toluene are added to a 200 cal glass-lined vessel. Toluene is then added 14.6 kg of P-nitrobenzyl 6-phenoxyacetamido-2,2-dimethylphenam-3-carboxylate-1-oxide and 6.67 kg of N-chlorophthal imide. Heat the mixture to 100 ° C. and add 11.68 L of propylene oxide over 4 minutes.

The mixture is refluxed at 102-103 ° C. for 90 minutes and then concentrated over 45 minutes. 71 L of material is removed and the temperature is raised from 103 ° C to 110-111 ° C. The mixture is then cooled to about 95 ° C., filtered and added to 108 L of toluene 7.3 L of ditin tin chloride and cooled to −6 ° C. After filtration, 30 L of toluene was added to complete the transfer of the mixture. The mixture is then stirred at 17-20 [deg.] C. overnight. The resulting solids are collected by filtration and dissolved in 73 L of acetone. 146 L of ethyl acetate is then added to the acetone solution followed by 292 L of water. The mixture is stirred for 5 minutes and then separated. The organic layer is concentrated in vacuo to about 135 L, cooled to 0-5 [deg.] C. and left at that temperature overnight.

The resulting mixture is filtered, washed with 25 liters of ethyl acetate of combined solids and dried at 50 ° C. to yield 6.8 kg (46.9%) of the title compound.

Example 6

Preparation of P-nitrobenzyl 7-phenoxamido-3-methylenecepam-4-carboxylate-1-oxide

A reaction without calcium oxide

2 L of toluene is distilled off to remove 200 ml of material and dehydrated. Stop heating and add 50 g of P-nitrobenzyl 6-phenoxyacetamido-2,2-dimethylphenam-3-carboxylate-1-oxide and 23 g of N-chlorophthalamide. The mixture is refluxed at 108 ° C. for 78 minutes and then 440 ml of the mixture is distilled off over 22 minutes. The mixture is cooled to 10 ° C. and then filtered. The filtrate is added to a precooled mixture of 40 ml of toluene and 25 ml of ditin chloride. The resulting mixture is bright scarlet and has a particulate precipitate. The mixture is cooled in an empty bath, stirred for about one hour, then stirred at room temperature and refrigerated overnight to yield 22.8 g (45.6%) of the title compound.

B. Reaction in the presence of calcium oxide

The reaction of Part A is repeated except that 25 g of calcium oxide is contained in the reaction mixture.

The title compound (29.4 g: 59.1%) is obtained.

Example 7

Preparation of P-nitrobenzyl 7-phenoxamido-3-methylenecepam-4-carboxylate-1-oxide

A reaction without calcium oxide

2 L of toluene is distilled off to remove 200 ml of material and dehydrated. Stop heating and add 50 g of P-nitrobenzyl 6-phenoxyacetamido-2,2-dimethylphenam-3-carboxylate-1-oxide and 15.2 g of N-chlorosuccinimide. Heat the mixture and add 35 ml of propylene oxide. The total mixture was refluxed at 104 ° C. for 100 minutes and then 725 ml of the mixture was removed by raising the temperature to 103 to 110.5 ° C. and distilling for 35 minutes. The mixture is cooled to 10 ° C. and then filtered. The filtrate is added to a precooled mixture of 50 ml of toluene and 25 ml of ditin chloride. The mixture is stirred overnight and then stirred for 10 minutes at 5 to 10 ℃. The mixture is then filtered and the collected solids are dissolved in a mixture of 250 ml of acetone and 500 ml of ethyl acetate. The solution is washed with 500 ml of water and evaporated to reaction volume. Crystallization does not occur. A small amount of the title compound is added to the mixture as crystals and embedded. However, crystallization does not occur after the crystals are added and refrigerated for 3 days. The yield of the product is low and substantially below 20%.

B. Reaction in the presence of calcium oxide

The reaction of A is repeated except that 25g of calcium oxide is contained in the reaction mixture and 16.6g of N-chlorosuccinimide is used.

The title compound (23.35 g: 46.7%) is obtained.

Claims (1)

Next, the penicillin sulfoxide of the general formula (II) is reacted with an N-chloro halogenating agent in the presence of the epoxide calcium oxide of the following general formula (I) in an inert solvent at 75 ° to 135 ° C. under anhydrous conditions. Sulfinyl chloride of formula (I) is prepared.

In the above general formula, R _X is hydrogen or methyl, R ₁ is a carboxylic acid protecting group, R is a) hydrogen, C ₁ -C ₃ alkyl, halomethyl, cyanomethyl, benzyloxy, 4-nitrobenzyloxy, tertiary -Butyloxy 2,2,2-trichloroethoxy, 4-methoxybenzyloxy, 3- (2-chlorophenyl) -5-methylisoxazol-4-yl, or b) phenyl or one or two R 'group represents phenyl substituted with halogen, protected hydroxy, nitro, cyano, trifluoromethyl, C ₁ -C ₄ alkyl, or C ₁ -C ₄ alkoxy, or c) R' is R Is the same as' or 1,4-cyclohexadienyl, 2-thienyl or 3-thienyl, where m is 0 or 1, provided that when m is 1, R 'is R' and is oxygen or sulfur Is a group of-(), or; d) wherein R 'is as above and R ₂ is a protected hydroxy or protected amino group

Is a group.