KR810001136B1 - Process for preparing 3-acyloxy methyl-2-cephem compounds - Google Patents

Abstract

Cephem compds. (I; R = V; R2 = C2-4 alkenylene, 1,2-phenylene; R1 = carboxylic protecting group; R4 = C1-4 alkyl) were prepd. by the reaction of II and III(X = cl, OH) or IV. Thus, 500 mg P-nitrobenzyl-7-phenoxyacetamido-3-methylenecepham-4-carboxylate-1-oxide was reacted with 5 ml Ac2O and one drop of acetyl chloride at 130-140oC for 2.75 hr to give p-nitrobenzyl-7-phenoxyacetamido-3-acetoxymethyl-2-cephem-4-carboxylate.

Description

Method for preparing 3-acyloxymethyl-2-cepem compound

The present invention relates to a process for the preparation of 3-acyloxymethyl-Δ ² -cepem of formula (I) which is useful as an intermediate for the preparation of the antibiotic cephalosporin.

In the above structural formula

R ₁ is a carboxylic acid protecting group,

R ₄ is C ₁ -C ₄ alkyl,

R is (1) an imide group of the following structural formula,

Wherein R ₂ is C ₂ -C ₄ alkenylene or 1,2-phenylene.

(2) amido groups of the following structural formulas,

Where R ₃ is

(a) hydrogen, C ₁ -C ₃ alkyl, halomethyl, benzyloxy, 4-nitro benzyloxy, 2,2,2-trichloro ethoxy, 4-methoxy-benzyloxy, 3- (2-chlorophenyl ) -5-methylisoxazol-4-yl,

(b) a group R 'wherein R' is phenyl or phenyl substituted with 1 to 2 halogen, nitro, cyano, trifluoromethyl, C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy,

(c) a group of formula R'-CH _2-, wherein R 'is as defined above and m is 0 or 1,

-의 기(여기서 R＂는 전술한 R', 2-티에닐, 또는 3-티에닐이고 R'은 전술한 바와 같다), 또는(d) Structural formula R ＂-

A group of-wherein R 'is R', 2-thienyl, or 3-thienyl and R 'is as described above, or

(e) groups of the formula R'-CH _2-

Wherein R 'is 2-thienyl, 3-thienyl, 2-furyl, 3-furyl-2-thiazolyl, 5-tetrazolyl, 1-tetrazolyl or 4-isoxazolyl), or

(3) It is an imidazolidinyl group of the following structural formula.

here

R 'is as described above

U is nitroso or acetyl.

Cephalosporin antibiotics having an acyloxymethyl group at the C ₃ carbon atom of the cefe nucleus are known in the art. References: US Pat. Nos. 3,270,009, 3,278,531,5,5 32,694, 3,705,897, 3,728,342, 3,795,672].

New methods of producing such cephalosporins are constantly being studied. The present invention relates to a process for preparing 3-acyloxymethylΔ ² -cefem compound, which can be easily converted to the aforementioned 3-acyloxymethyl cephalosporin antibiotic using known techniques.

Recently, 3-exomethylenecepam esters of the following structural formula have been described in the following documents. [Reference: J. Ory, Chauvette et al. Chem., 38 2994 (1973) and US Pat. No. 3,792,995]

Corresponding sulfoxides of formula (II) to be described below are used as starting materials in the present invention and can be readily prepared from the corresponding 3-exomethylene cepam esters by known methods. For example, the corresponding sulfoxide can be prepared by reacting 3-exomethylene sepam acid or ester with peracid such as m-chloroperbenzoic acid, peracetic acid and the like. 3-exo double bonds of the starting material are inert under sulfoxide formation conditions and therefore sulfoxides are prepared by selective oxidation of sulfides.

Snowpoxite S. The tertiary starting materials are preferably prepared by the methods described in the following references [see: pending U.S. Patents 536,273 and 536,280 (filed Dec. 24, 1974) to S. Kukulza] , Peniclanic acid ester sulfoxide was reacted with N-chlorohalogenation agent in anhydrous inert solvent at about 70 to 100 ° C. to obtain azetidi sulfinyl chloride which was converted to Lewis acid Friedel-Craft type catalyst in anhydrous inert organic solvent. The ring is closed by reaction with to prepare 3-exo methylenecepam sulfoxide ester.

As mentioned above, 3-exo methylene cefamsulfoxide ester is the starting material of the present invention, and the sulfoxide ester is the aforementioned 3-acyloxymethyl cephalosporin (3-acyloxymethyl-Δ ³ -cefem compound). It can be converted to the corresponding 3-acyloxymethyl-Δ ² 3-cefem useful as an intermediate in the preparation of.

The compounds of the present invention are prepared by reacting 3-exomethylenecepam sulfoxide of formula (II) with a mixture of the following formula (III) acylates and their corresponding anhydrides (following formula (IV)) at 70 ° to 130 ° C. .

In the above structural formula

R, R ₁ and R ₄ are as described above,

X is chloro or hydroxy.

In structural formulas (I) and (II), R ₁ is a carboxylic acid protecting group, preferably a group which can be removed by a hydrogenation reaction. Preferred carboxyl protecting groups are 2,2,2-trihalomethyl, benzyl, P-nitrobenzyl, Succinimidomethyl, phthalimidomethyl, P-methoxybenzyl C ₂ -C ₆ alkanoyloxymethyl, dimethylallyl, phenacyl, or P-halofenacyl, where halo is chlorine, bromine or iodine.

Specific examples of preferred carboxylic acid protecting groups are 2,2,2-trichloroethyl, 2,2,2-tribromoethyl, benzyl, P-nitrobenzyl, succinimido methyl, phthalimidomethyl, P-methoxybenzyl, Acetoxymethyl, pivaloyloxymethyl, propionoxymethyl, phenacyl, P-chlorophenacyl and P-bromo phenacyl.

More preferred carboxylic acid protecting groups are benzyl, P-nitrobenzyl, P-methoxybenzyl, 2,2,2-trichloroethyl, phenacyl, P-chloro phenacyl and P-bromophenacyl.

Most preferred carboxylic acid protecting groups are P-nitrobenzyl and 2,2,2-trichloroethyl.

-NH로 정의된다.The R group at the 7-position of the ₃ -exomethylenecepam sulfoxide of formula (II) and 3-acyloxymethyl-Δ ² -cepem product of formula (II)

Defined as -NH.

Specific examples of R ₃ groups are hydrogen, methyl, ethyl, n-propyl, isopropyl, chloromethyl, bromomethyl, benzyloxy, 4-nitrobenzyloxy, 2,2,2-trichloroethoxy, 4-meth Oxybenzyloxy, phenyl 2-chlorophenyl, 3,4-dichlorophenyl, 3-chloro-4-fluorophenyl, 4-nitrophenyl, 2-cyanophenyl, 4-trifluoromethylphenyl, 3-methylphenyl, 2 -Ethylphenyl, 4-n-propylphenyl, 4-tert-butylphenyl, 2-methoxyphenyl, 4-ethoxyphenyl, 3-isopropyloxyphenyl, 4-isobutyloxyphenyl, benzyl, 3-bro Mobenzyl, 2,5-dichlorobenzyl, 4-chloro acetoxybenzyl, 2-nitrobenzyl, 3-cyanobenzyl, 4-trifluoromethylbenzyl, 3-methylbenzyl, 4-n-butylbenzyl, 2- Methoxybenzyl, 3-isopropoxybenzyl, phenoxymethyl, 3-urido phenoxymethyl, 4-fluorophenoxymethyl, 3-chloro-4fluorophenoxymethyl, 2,5-dichlorophenoxymethyl, 3-isopropoxy phenoxymethyl, 4-ethylphenoxymethyl, 4-chloro Oxymethyl, 3-nitrophenoxymethyl, 4-cyanophenoxymethyl, 2-trifluoromethyl phenoxymethyl, 3-methylphenoxymethyl, 4-n-propylphenoxymethyl, 4-n-butylphenoxy Methyl, 3-methoxyphenoxymethyl, 4-ethoxyphenoxymethyl, α- (benzyloxycarbonyl) -thien-2-yl methyl, α- (4-nitrobenzyloxy carbonyl) -thiene-2 -Ylmethyl, α- (benzyloxycarbonyl) -thien-3-ylmethyl, α- (acetoxymethoxycarbonyl) -thien-2-ylmethyl, α- (benzyloxycarbonyl) benzyl, α- (4-nitrobenzyloxycarbonyl) benzyl, α- (4-methoxybenzyloxycarbonyl) benzyl, α- (2,2,2-trichloroethoxycarbonyl) benzyl, α- (P-chlorophene Acyloxycarbonyl) -4-bromobenzyl, α- (benzyloxycarbonyl) -3-chlorobenzyl, α- (4-nitrobenzyloxycarbonyl) 4-fluorobenzyl, α- (4-nitrobenzyloxy Carbonyl) -3-methoxybenzyl, α- (4-methoxybenzyloxycarbonyl) -4-isopropoxybenzyl, α-benzyloxycarbonyl-3-nitrobenzyl, α (4-nitrobenzyloxyca Carbonyl) -2-cyanobenzyl, (Pα bromophenacyloxycarbonyl) -4-trifluoromethylbenzyl, α- (4-nitrobenzyloxycarbonyl) -4-methylbenzyl, α-benzyloxycarbonyl 3-n-butylbenzyl, α- (benzyloxycarbonyl) -4-methoxybenzyl, α- (4-nitrobenzyloxycarbonyl) -3-isopropoxybenzyl, thien-2-ylmethyl, thiene 3-ylmethyl, fur-3-ylmethyl, fur-3-ylmethyl, thiazol-2-ylmethyl, tetrazol-5-ylmethyl, tetrazol-1-ylmethyl, isoxazol-4-yl Methyl and 3- (2-chlorophenyl) -5-methylisoxazol-4-yl and the like.

The group -COOR ₁ appears in the definition of the group of the compound according to the invention, meaning "protected carboxy group".

“Protected carboxy” refers to a carboxyl group protected with one of the carboxylic acid protecting groups generally used to protect or block the carboxylic acid functionality of the compound during a reaction or series of reactions involving other functional groups of the compound. Such protected carboxyl groups can readily separate the corresponding carboxylic acids by hydrocracking methods. Carboxylic acid protecting groups include benzyl, 4-methoxybenzyl C ₂ -C ₆ alkanoyl oxymethyl, 4-nitrobenzyl, phenacyl, halofenacyl, dimethylallyl, 2,2,2-trichloroethyl and succinimidomethyl . The nature of such ester forming groups is not a problem as long as the ester formed is stable under the reaction conditions of the process of the invention. Moreover, other known carboxy protectors are described in the following documents. [Protective groups inorganic chemistry of E. Haslem, Chapter 5].

Preferred R ₁ groups in the rough definition of “protected carboxy” are benzyl, 4-methoxybenzyl, 4-nitrobenzyl, 2,2,2-trichloroethyl, phenacyl, and P-halofenacyl.

Of course, carboxy protectors cannot be described completely.

The action of this group is to protect reactive functional groups during the preparation of the desired product. Later they can be removed without destroying the rest of the rich.

Most of the protecting groups are well known in the art and their use is equally adapted to the method of the present invention.

The process of the present invention can also be carried out with human 3-exomethylenecepam sulfoxide of formula (II) wherein R is a cyclic imido group of the following formula.

This cyclic imido group is formed by R ₂ together with the nitrogen-carbonyl bond to which it is bonded, and reacts the 7-amino group of 7-amido-3-exomethylenecepam ester with dicarboxylic acid or anhydride thereof or reactive variant thereof. The resulting derivative is then formed by reacting a C ₁ -C ₄ alkylhalo formate such as ethylchloroformate in the presence of an organic base. R ₂ is C ₂ -C ₄ alkenylene or 1,2-phenylene and can be thought of as a residue of the dicarboxylic acid and thus the cyclic imide can be prepared from dicarboxylic acid, anhydride thereof, or a suitable reaction variant thereof.

For example, cyclic imides are prepared from maleic acid, methylmaleic acid, phthalic acid or anhydrides thereof and similar or related compounds.

Further examples of this type of cyclic anhydride are described in the following documents. See, Journol of Organic Chemistry, Vol. 26, pp 3365-1961.

In addition, the R groups of the structural formulas (I) and (II) may be imidazolidinyl groups of the following structural formulas.

In the above formula

U is nitroso or acetyl

R 'is phenyl or phenyl substituted with 1 to 2 halogen, nitro, cyano, trifluoromethyl, C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy groups.

Such groups include 2,2-dimethyl-3-nitroso-5-oxo-4- (substituted-imidazolidin-1-yl or 2,2-dimethyl-3-acetyl-5-oxo-4- ( Substituted) -imidazolidin-1-yl groups and typically the 4-substituents (R ′) in the imidazolidinyl structure include phenyl, 3-bromophenyl, 2-chlorophenyl, 4-fluorophenyl, 3- Iodophenyl, 3-chloro-4-fluorophenyl, 2-chloro-4-bromophenyl, 4-nitrophenyl, 2-cyanophenyl, 3-trifluoromethylphenyl, 4-methylphenyl, 3-ethylphenyl, 4-isopropylphenyl, 4-t-butylphenyl, 3-methoxyphenyl, 2-ethoxyphenyl, 4-n-propoxyphenyl, 3-isopropoxyphenyl or 4-isobutoxyphenyl.

3-exomethylene cepam sulfoxide of formula (II), wherein R used as starting material is the imidazolidinyl group described above, reacts exomethylene cepam or its corresponding free acid of formula (V) with acetone under suitable basic conditions To obtain a stable N-nitroso or N-acetyl derivative wherein R is an imidazolidinyl group as described above by obtaining an unstable intermediate of the following formula (VI) and cooling it under acidic conditions with sodium nitrite or acetic anhydride. This is oxidized in a known manner to give the sulfoxide of the corresponding structural formula (II).

See J. Org. Chem, 37 (1972) 2765 by Gottstein and Helvetica Chimica Acta 55 (1972) 388 by Hoisler.

As is known in the penicillin and cephalosporin arts, the starting material 3-exo-methylenecepam sulfoxide of the formula (II) is neither naturally occurring penicillin source such as penicillin G and / or penicillin V. It can be easily prepared from.

6-Amino penicillic acid (6-APA) can be prepared by isolating acyl functional groups using conventional techniques in one of the naturally occurring penicillins.

Any of the starting materials of formula II can be prepared by conventional techniques and from 6-APA. For example, 6-APA can be converted to the desired ester by esterifying a 3-carboxyl functional group using several typical esterification methods.

Moreover, any of the groups defined in R can be prepared by acylating the amino group of 6-APA. This can be accomplished by reacting 6-APA with the activated form of the acid of the intended acyl group. Such activated forms include the corresponding acid halides, anhydrides thereof or activated esters such as pentachlorophenyl esters.

Similarly, penicillin can be converted to sulfoxide by oxidation under various known conditions, such as, for example, treatment with m-chloroterbenzoic acid or sodium periodate.

This conversion reaction, separation from 6-APA, esterification and oxidation reactions are carried out in a family of continuity with structural modifications. In some cases, all conversion reactions can be carried out using known techniques, conditions and reagents.

Once the penicillin sulfoxide ester of the following structural formula is obtained, it is obtained from an N-chloro halogenating agent (e.g., N-chloro) at 75 ° to 130 ° C in the presence of an anhydrous inert solvent such as 1, 1,2-trichloroethane or toluene. Treated with succinimide or N-chlorophthalimide to obtain azetidi of the following formula (sul), which is reacted with a Friedel craft type catalyst in the presence of an anhydrous inert organic solvent effective for cyclization A 3-exomethylenecepam sulfoxide ester of formula (II) is obtained, which is a starting material of the invention.

Lewis acid Friedel Kraft catalysts useful for the ring reaction of azetidinone sulfinyl chloride include ditin, zinc chloride, zinc bromide, titanium tetrachloride and zirconium chloride, with tin tin chloride being particularly preferred. This cyclization reaction is carried out at about 20 ° to 85 ° C. with an inert solvent, preferably an aromatic hydrocarbon such as benzene, toluene, or xylene, or halogen substitution such as methylene 1,2-dichloroethane or 1,1,2-trichloroethane. In the presence of an aprotic organic solvent, such as an aliphatic hydrocarbon.

In the preparation of starting materials useful in the present invention, the P-nitrobenzyl 6-phenoxyacetamido penicilamate sulfoxide solution dissolved in anhydrous toluene is treated with 1.1 molar equivalents of N-chlorosuccinimide and the reaction mixture is about 90 minutes. Reflux. The reaction mixture containing chloride intermediate) is cooled to about 50 ° C. and 1.1 molar equivalents of anhydrous ditin chloride are added. The resulting mixture was stirred at room temperature for about 90 minutes, then water and ethyl acetate were added to the reaction mixture and the organic layer was separated. The organic layer containing the product was washed sequentially with acetic acid, sodium bicarbonate solution and brine, and the washed organic layer was dehydrated and evaporated to P-nitrobenzyl 7-phenoxy acetamido-3-exomethylenecepam-4-carboxylate-1. To obtain an oxide.

Preferred among the 3-exo methylenecepam sulfoxide esters of formula (II) used as starting materials in the preparation of the present invention are compounds of the formula

In the above structural formula

m is 0 or 1

R ₁ is a carboxylic acid protecting group.

Correspondingly, among the 3-acyloxymethyl-Δ ² -cepemester products of formula (I) obtained according to the present invention, compounds of the following formula are preferred.

In the above structural formula,

m is 0 or 1

R ₁ is a carboxylic acid protecting group,

R ₄ is C ₁ -C ₄ alkyl, preferably methyl.

Another preferred among the 3-exo methylene cefesulfoxide esters of formula (II) used in the preparation of the present invention is a compound of the formula

In the above structural formula

R ₁ is a carboxylic acid protecting group.

Correspondingly, the 3-acyloxymethyl-Δ ² -cepemester of structure (I) produced from the above-mentioned preferred compounds has the following structure.

In the above structural formula,

R ₁ is a carboxylic acid protecting group,

R ₄ is C ₁ -C ₄ alkyl, preferably methyl.

Converting 3-exomethylenecepam sulfoxide to the corresponding 3-acyloxymethyl-Δ ² -cepem converts 3-exomethylene cepam sulfoxide to the following structural formula (III) acyl compound and the corresponding next structural formula (III) anhydride. It can be made by reaction with.

In the above structural formula

X is chloro or hydroxy,

R ₄ is C ₁ -C ₄ alkyl.

Acyl compounds used include acetyl chloride, floppyonyl chloride, n-butyryl chloride, isobutyryl chloride, valeryl chloride, trimethylacetyl chloride, α-methylbutyryl chloride, β-methylbutyryl chloride, acetic acid, propionic acid, n Butyric acid, isobutyric acid, valeric acid, trimethylacetic acid, α-methylbutyric acid and β-methylbutyric acid.

As described above, each acyl compound is used in admixture with its corresponding symmetric acid anhydride.

For example, to obtain 3-propionoxymethyl-Δ ² -cepemester as a product, a mixture of propionyl chloride and propionic anhydride or a mixture of propionic and propionic anhydrides is used.

In the preparation of the invention it is preferred to use a mixture of acetyl chloride and acetic anhydride, or a mixture of acetic acid and acetic anhydride, whereby 3-acetoxy methyl-Δ ² -cepem ester is produced as product.

When the present invention is carried out using an acyl compound wherein X is chlorine, 3-exomethylene sefam sulfoxide of formula (III) is mixed with a mixture of acyl chloride of the selected formula (III) and the corresponding anhydride of formula (IV). do.

Generally, the molar ratio of acyl chloride: 3-exomethylene sefamsulfoxide is from about 1:30 to about 3: 2 and preferably from about 1:20 to about 1: 1.

When the present invention is carried out using an acyl compound wherein X is chlorine, 3-exomethylene sefam sulfoxide of formula (III) is mixed with a mixture of acyl chloride of the selected formula (III) and the corresponding anhydride of formula (IV). do.

Generally the molar ratio of acyl chloride: 3-exomethylenecepam sulfoxide is from about 1:30 to about 3: 2 and preferably from about 1:20 to about 1: 1.

In addition, the corresponding anhydride used uses a molar excess of at least 1 molar equivalent, preferably about 10 times, relative to the amount of 3-exomethylene sefamceroxide. Larger amounts can be used without loss, but there is no advantage in the present invention.

When carrying out the present invention using an acyl compound wherein X is hydroxy, 3-exomethylene sepam sulfoxide is mixed with a mixture of the selected carboxylic acid and its corresponding anhydrous anhydride.

Generally, the water ratio of carboxylic acid: anhydride is about 1:12 to about 35: 1, preferably about 2: 5 to 7: 1. Generally, about 1 to 40 mmoles of anhydride and about 2 to 65 mmoles of acid are used for each millimole of 3-exomethylene sepam sulfoxide.

Acylation mixtures can be used in excess and without damage, but have no advantage.

Thus, the acid-anhydride mixture preferably contains about 2 to 250 millimoles of anhydride and about 4 to 400 millimoles of acid per millimolar of 3-exomethylenecepam sulfoxide.

Typically, 3-exomethylene sepam sulfoxide is added to a mixture of the prepared acyl compound and its corresponding anhydride, and the resulting mixture is then heated at about 70 ° C. to 130 ° C. for a sufficient time to yield 3-acyloxy of the desired formula (I). Obtain the methyl-Δ ² -cefem compound.

The time required to achieve the reaction is wide but typically takes about 2 to 80 hours, preferably about 4 to 6 hours.

In addition to acyl mixtures, inert organic solvents can be used in addition to acylated mixtures, especially when acyl chloride is used.

However, this is not essential and in no way contributes to reactive odors.

Inert organic solvents include aromatic hydrocarbons such as benzene, toluene and ethylenebenzene; Chlorinated hydrocarbons such as chlorobenzene, carbon tetrachloride and 1,1,2-trichloroethane:

Esters such as ethyl acetate, butyl acetate and ethyl propionate can be used.

The resulting 3-acyloxymethyl-Δ ³ -cepem product is recovered by evaporation of excess material and purification of the resulting residue by conventional methods such as chromatographic separation, filtration, crystallization recrystallization and other known methods.

Examples of conversions that can be made according to the method of the present invention are as follows.

P-nitrobenzyl 7-maleimido-3-methylenecepam-4-carboxylate-1-oxide to P-nitrobenzyl 7-maleimido-3-acetoxy-methyl-2-cefe-4-carboxylate,

2,2,2-richloroethyl 7-phthalimido-3-methylenecepam-4-carboxylate 1-oxide to 2,2,2-trichloroethyl 7-phthalimido-3-propionoxymethyl 2-cefe-4-carboxylate,

Benzyl-7-formamido-3-methylenecepam-4-carboxylate 1-oxide to benzyl 7-formamido-3-butyrooxymethyl-2-cefe-4-carboxylate,

2,2,2-trichloroethyl 7-acetamido-3-methylenecepam-4-carboxylate-1-oxide to 2,2,2, -trichloroethyl 7-acetamido-3-acetoxymethyl- 2-cefe-4-carboxylate,

P-nitrobenzyl 7-butyramido-3-methylenecepam-4-carboxylate-1-oxide to P-nitrobenzyl 7-butyramido-3-acetoxymethyl-2-cefe-4-carboxylate in,

P-methoxybenzyl 7-chloroacetamido-3-methyllemcepam 4-carboxylate-1-oxide to P-methoxybenzyl 7-chloroacetamido-3-propionoxymethyl-2-cefem- 4-carboxylate,

P-nitrobenzyl 7- (4'-nitrobenzyloxycarboxamido) -3-methylenecepam-4-carboxylate-1-oxide to P-nitrobenzyl 7- (4'-nitrobenzyloxycarboxamido ) -3-isobutyricoxymethyl-2-cepem-4-carboxylate,

P-Chlorophenacyl-7-benzyloxycarboxamido-3-methylenecepam-4-carboxylate-1-oxide to P-chlorophenacyl 7-benzyloxycarboxamido-3-valeroxymethyl-2- With cefe-4-carboxylate,

Succinimidomethyl 7- (benzyloxycarboxamido) -3-methylenecepam-4-carboxylate 1-oxide to succinimidomethyl 7- (benzyloxy carboxamido) -3 acetoxymethyl-2-cef 4-carboxylate,

2,2,2-trichloroethyl 7- (2 ', 2', 2'-trichloroethoxy-carboxamido) -3-methylenecepam-4-carboxylate-1-oxide , 2-trichloroethyl 7- (2 ', 2', 2'-trichloroethoxycarboxamido) -3-propionoxymethyl-2-cepem-4-carboxylate,

Acetoxymethyl 7- (4'-methoxybenzyloxycarboxamido) 3-methylenecepam 4-carboxylate-1-oxide to acetoxymethyl 7- (4'-methoxybenzyloxycarboxamido)- 3-acetoxymethyl-2-cepem-4-carboxylate,

Benzyl 7-phenoxyacetamido-3-methylenecepam-4-carboxylate-1-oxide to benzyl 7-phenoxyacetamido-3-acetoxymethyl 2-cefe-4-carboxylate,

Phthalimidomethyl 7-benzamido-3-methylenecepam-4-carboxylate-1-oxide to phthalimidomethyl 7-benzamido-3-α-methylbutyroxymethyl-2-cefe-4-carboxylate ;

Phenacyl 7- (4'-chlorobenzamido) -3-methylenecepam-4-carboxylate-1-oxide with penacyl 7- (4'-chlorobenzamido) -3-acetoxymethyl-2- With cefe-4-carboxylate,

P-Chlorophenacyl 7- (3'-bromobenzamido) -3-methylenecepam-4-carboxylate-1-oxide to P-chlorophenacyl 7- (3'-bromobenzamido)- 3-acetoxymethyl-2-cepem-4-carboxylate,

Fivaloyloxymethyl 7- (4'-nitrobenzamido) -3-methylenecepam-4-carboxylate 1-oxide was converted to pivaloyloxymethyl 7- (4'-nitrobenzamido) -3-pro Pionoxymethyl-2-cefe-4-carboxylate,

Acetoxymethyl 7- (2'-cyanobenzamino) -3-methylenecepam-4-carboxylate-1-oxide to acetoxymethyl 7- (2'-cyanobenzamido) -3-acetoxymethyl 2-cefe-4-carboxylate,

Succinimidomethyl 7- (4'-trifluoromethylbenzamido) 3-methylenecepam-4-carboxylate-1-oxide to succinimidomethyl 7- (4'-trifluoromethylbenzamido) -3- β-methylbutyroxymethyl-2-cepem-4-carboxylate,

Phthalimidomethyl 7- (3'-methylbenzamido) -3-methylenecepam-4-carboxylate-1-oxide-phthalamidomethyl-7- (3'-methylbenzamido) -3-acet Methoxymethyl-2-cefe-4-carboxylate lot.

2,2,2-ribromoethyl 7- (2'-methoxybenzamido) -3-methylenecepam-4-carboxylate-1-oxide was added to 2,2,2-trimomomoethyl 7- (2 '-Methoxybenzamido) -3-valeroxymethyl-2-cepem-4-carboxylate;

Propionoxymethyl 7-phenylacetamido-3-methylenecepam-4-carboxylate-1-oxide to propionoxymethyl 7-phenylacetamido-3-acetoxymethyl-2-cefe-4- With carboxylate,

P-nitrobenzyl 7- (2'-thienylacetamido) -3-methylenecepam-4-carboxylate-1-oxide to P-nitrobenzyl 7- (2'-thienylacetamido) -3- With propionoxymethyl-2-cepem-4-carboxylate,

P-methoxybenzyl 7-phenylacetamido-3-methylenecepam-4-carboxylate-1-oxide to P-methoxybenzyl 7-phenyl acetamido-3-butyroxymethyl-2-cefe-4 With carboxylate,

2,2,2-trichloroethyl 7-phenoxyacetamido-3-methylenecepam-4-carboxylate 1-oxide to 2,2,2-trichloroethyl 7-phenoxyacetamido-3-ace With toxetyl-2-cepem-4-carboxylate,

P-nitrobenzyl 7- (2 ', 5'-dichlorophenylacetamido) -3-methyllemcepam-4-carboxylate-1-oxide to P-nitrobenzyl 7- (2', 4 ',-dichloro Phenylacetamido) -3-acetoxymethyl-2-cepem-4-carboxylate,

Benzyl 7- (3'-brophenoxyacetamido) -3-methylenecepam-4-carboxylate-1-oxide to benzyl 7- (3'-bromoacetamido) -3-isobutyroxymethyl 2-cefe-4-carboxylate;

P-bromophenacyl 7- (4'-chlorophenylacetamido) -3-methylenecepam-4-carboxylate-1-oxide to P-bromophenacyl 7- (4'-chlorophenylacetamido)- 3-acetoxymethyl-2-cepem-4-carboxylate,

Pivaloyloxymethyl 7- (3'-chlorophenoxyacetamido) -3-methylenecepam-4-carboxylate-1-oxide with pivaloyloxymethyl 7- (3'-chlorophenoxyacetamido ) -3-acetoxymethyl-2-cepem-4-carboxylate,

P-nitrobenzyl 7- (4'-nitrophenylacetamido) -3-methylenecepam-4-carboxylate-1-oxide to P-nitrobenzyl-7 (4'-nitrophenylacetamido) -3- With propionoxymethyl-2-cepem-4-carboxylate,

P-methoxybenzyl 7- (4'-nitrophenoxyacetamido) -3-methylenecepam-4-carboxylate-1-oxide to P-methoxybenzyl 7- (4'-nitrophenoxyacetamido ) -3-acetoxymethyl-2-cepem-4-carboxylate,

P-nitrobenzyl 7- (3'-cyanophenylacetamido) -3-methylenecepam-4-carboxylate-1-oxide to P-nitrobenzyl 7- (3'-cyanophenylacetamido)- 3-butyricoxymethyl-2-cepem-4-carboxylate,

P-bromophenacyl 7- (2'-cyanophenoxyacetamido) -3-methylene sefam-4-carboxylate-1-oxide was converted into P-bromophenacyl 7- (2'-cyanophenoxyacetyl) Amido) -3-acetoxymethyl-2-cepam-4-carboxylate,

Propionoxymethyl 7- (4'-trifluoromethylphenylacetamido) -3-methylenecepam-4-carboxylate-1-oxide with propionoxymethyl 7- (4'-trifluoromethylphenylacetami Fig. 3)-Acetoxymethyl-2- cefe-4-carboxylate,

2,2,2-tribromoteryl 7- (3'-trifluoromethylphenoxy acetamido) -3-methylenecepam-4-carboxylate-1-oxide to 2,2,2-tribromomethyl 7- (3'-trifluoromethyloxysetamido) -3-propionoxymethyl-4-shepam carboxylate,

2,2,2-trichloroethyl 7- (2'-ethylphenylacetamido) -3-methylenecepam-4-carboxylate-1-oxide was added to 2,2,2-trichloroethyl 7- (2 ' Ethylphenylacetamido) -3-acetoxymethyl-2-cepem-4-carboxylate,

Acetoxymethyl 7- (4'-isopropylphenoxyacetamido) -3-methylenecepam-4-carboxylate-1-oxide to acetoxymethyl 7- (4'-isopropylphenoxyacetamido) 3-butyricoxymethyl-2-cepem-4-carboxylate,

Benzyl 7- (3'-ethoxyphenylacetamido) -3-methylenecepam-4-carboxylate-1-oxide to benzyl 7- (3'-ethoxyphenyl acetamido) -3-isobutyroxymethyl 2--2-fem-4-carboxylate,

P-nitrobenzyl 7- (4'-isopropoxyphenoxyacetamido) -3-methylenecepam-4-carboxylate 1-oxide was converted into P-nitrobenzyl 7- (4'-isopropoxyphenoxyacetamido Fig. 3)-valeleroxymethyl-2-cefe-4-carboxylate,

P-nitrobenzyl 7- (α-2,2,2-trichloroethoxycarbonylphenyl acet amido) -3-methylenecepam-4-carboxylate-1-oxide P-nitrobenzyl 7- (α- 2,2,2-trichloroethoxycarbonylphenyl acet amido) -3-α-methylbutyroxymethyl-2-cefe-4-carboxylate.

P-methoxybenzyl 7- (α-phenacyloxycarbonylphenylacetamido) -3-methylenecepam-4-carboxylate-1-oxide to P-methoxybenzyl 7- (α-phenacyloxycarbonyl Phenylacetamido) -3-acetoxymethyl-2-cepem-4-carboxylate,

Benzyl 7- (2-thienyl-α-benzyloxycarbonylacetamido) -3-methylenecepam-4-carboxylate-1-oxide with benzyl 7- (2-thienyl-α-benzyloxycarbonylacet Amido) -3-β-methyl butyroxymethyl-2-cefe-4-carboxylate,

2,2,2-trichloroethyl 7- (α-P-nitrobenzyloxycarbonyl phenylacetamido) -3-methylenecepam-4-carboxylate-1-oxide to 2,2,2-trichloroethyl With 7- (α P-nitrobenzyloxycarbonyl phenylacetamido) -3-acetoxymethyl-2-cepem-4-carboxylate,

P-nitrobenzyl 7- (α-benzyloxycarbonylphenylacetamido) -3-methylenecepam-4-carboxylate-1-oxide to P-nitrobenzyl 7- (α-benzyloxycarbonylphenyl acetamido ) -3-acetoxymethyl-2-cepem-4-carboxylate,

P-methoxybenzyl 7- (α-4-methoxybenzyloxycarbonylacetamido) -3-methylenecepam-4-carboxylate-1-oxide to P-methoxybenzyl 7- (α-4-meth Oxybenzyloxycarbonylphenylacetamido) -3-propionoxymethyl-2-cefe-4-carboxylate.

P-nitrobenzyl 7- (2'-thienyl-α-P-nitrobenzyloxycarbonylacetamido) -3-methylenecepam-4-carboxylate-1-oxide to P-nitrobenzyl-7- (2 '-Thienyl-α-P-nitrobenzyloxycarbonylacetamido) -3-acetoxymethyl-2-cepem-4-carboxylate,

P-nitrobenzyl 7- (2'-thienylacetamido) -3-methylenecepam-4-carboxylate-1-oxide to P-nitrobenzyl 7- (2'-thienylacetamido) -3- Acetoxymethyl-2-cepem-4-carboxylate,

Benzyl 7- (3'-dienylacetamido) -3-methylenecepam-4-carboxylate-1-oxide to benzyl 7- (3'-thienylacetamido) -3-acetoxymethyl-2- With cefe-4-carboxylate,

P-methoxybenzyl 7- (2'-putylacetamido) -3-methylenecepam-4-carboxylate 1-oxide was converted into P-methoxybenzyl 7- (2'-furylacetamido) -3-pro Pionoxymethyl-2-cepem-4-carboxylate,

P-Chlorophenacyl7- (3'-furylacetamido) -3-methylenecepam-4-carboxylate-1-oxide was converted into P-chlorophenacyl 7- (3'-furylacetamido) -3- With butyroxymethyl-2-cepem-4-carboxylate,

Succinimidomethyl 7- (2'-thiazolylacetamido) -3-cetylenecepam-4-carboxylate-1-oxide with succinimidemethyl 7- (2'-thiazolylacetamido) -3- With valericoxymethyl-2-cepem-4-carboxylate,

P-nitrobenzyl 7- (5'-tetrazolylacetamido) -3-methylenecepam-4-carboxylate-1-oxide to P-nitrobenzyl 7- (5'-tetrazolylacetamido) -3- with α-methylbutyroxymethyl-2-cepem-4-carboxylate

P-nitrobenzyl 7- (1'-tetrazolylacetamido) -3-methylenecepam-4-carboxylate-1-oxide to P-nitrobenzyl 7- (1'-tetrazolylacetamido) -3- Acetoxymethyl-2-cepem-4-carboxylate,

P-methoxybenzyl 7- (4'-isoxazolylacetamido) -3-methylenecepam-4-carboxylate-1-oxide to P-methoxybenzyl 7- (4'-isoxazolylacetamido ) -3-acetoxymethyl-2-cepem-4-carboxylate.

Benzyl-7- [3- (2′-chlorophenyl) -5'-methylisoxazole-4'-ylcarboxamido] -3methylenecepam-4-carboxylate-1-oxide with benzyl 7- [3 '-(2'-chlorophenyl) -5'-methylisoxazol-4'-yl] carboxamido-3-β-methylbutyroxymethyl-2-cefe-4-carboxylate,

P-nitrobenzyl 7- (2 ', 2'-dimethyl-3'-acetyl-5'-oxo-4'-phenylimidazolidin-1'-yl) -3-methylenecepam-4-carboxylate- P-nitrobenzyl 7- (2 ', 2'-dimethyl-3'-acetyl-5'-oxo-4'-phenylimidazolidin-1'-yl) -3-acetoxymethyl- 2-cefe-4-carboxylate,

Benzyl 6- [2 ', 2'-dimethyl-3'-nitroso-5'-oxo-4'-(4'-chlorophenyl) -imidazolidin-1'-yl] -3-methylenecepam- 4-carboxylate-1-oxide was benzyl 7- [2 ', 2'-dimethyl-3'-nitroso-5'-oxo-4'-(4'-chlorophenyl) -imidazolidine-1 ' -Yl] -3'-acetoxymethyl-2-cepem-4-carboxylate.

The 3-acyloxymethyl-Δ ² -cepemester of formula (I) is useful as an intermediate in the preparation of antibiotically active cephalosporins. Treatment of the Δ ² -cepem product with the method described in US Pat. No. 3,705,897 yields the corresponding Δ ³ -cepemester. The described method is a method for preparing the 3-halomethyl-Δ ² -cefmem compounds in particular directly, but is also sufficiently applied to the preparation of 3-acyloxymethyl-Δ ² -cefem esters.

The method described in the above-mentioned US patent includes the use of an oxidant to oxidize the [Delta] ² -Sefem compound to produce cefesulfoxide.

Isomerization of the double bond takes place from the Δ ² position to the Δ ³ position for at least a portion of the oxidized product. The isomerized product of the double bond of sulfoxide is completed by treatment with tertiary amine. Treatment of the resulting Δ ³ -cepemsulfoxide with various defined reducing agents is reduced to the corresponding sulfites. When this method is applied to the product of formula (I) prepared in the present invention, 3-acyloxymethyl-Δ ³ -cepemester is obtained.

In this respect, it can be seen that, in addition to the Δ ² -cepem product of structural formula (I) obtained in the present invention, generally a trace amount of the corresponding Δ ³ -cepemp compound is produced. Of course the two products can be easily separated by conventional techniques as described above. However, the purpose of producing the Δ ² -cepem compound does not need to be separated as it includes the final conversion to the Δ ³ -cepem antibiotic compound.

Treatment of the mixture of Δ ² -cepem and Δ ³ -cepem prepared in the present invention under the above-described conditions yields the desired Δ ³ -cepem compound. Simply oxidizing the Δ ³ -cefem present as an impurity in the starting material is sulfoxide and reducing it to sulfide to recover the required product.

The corresponding Δ ³ -cefem acid exhibits antimicrobial activity. Such compounds are obtained by separating ester functional groups. Deesterification can be achieved in several ways, depending on the nature of the protecting group: (1) treatment with acids such as trifluoroacetic acid, formic acid or hydrochloric acid, (2) zinc and acids (e.g. formic acid, Acetic acid, hydrochloric acid), or (3) hydrogenation on a suspension or carrier such as barium sulfate, carbon or alumina in the presence of palladium, platinum, rhodium, or a compound thereof. In addition, the resulting 3-acyloxymethyl-Δ ³ -cefemic acid can be separated from the amido or imido groups at the 7 position to obtain a free 7-amino group, followed by reacylation to obtain various known chemical compounds of cephalosporin antibiotics. have. Separation and reacylation methods are well known in the cephalosporin art.

Thus, the methods of the present invention make various known cephalosporin antibiotics described below useful:

Sodium salt of 7- (2-thienylacetamido) -3-acetoxymethyl-3-cepem-4-carboxylic acid (cephalotin); 7- (α-aminophenylacetamido) -3-acetoxymethyl-3-cepem-4-carboxylic acid) cephaloclysin); And sodium salt of 7-cyanoacetamido-3-acetoxymethyl-3-cepem-4-carboxylic acid (sephacetyl).

The following examples illustrate the invention in detail. However, this does not limit the scope of the invention.

Example 1

To 5 ml of pure acetic anhydride 500 mg (1 mmol) of P-nitrobenzyl 7-phenoxyacetamido-3-methylenecepam-4-carboxylate-oxide are added followed by one drop of acetylchloride to the resulting mixture. . The mixture is refluxed and cooled at 130 to 140 ° C. for 2.75 hours, then ethyl acetate is added and the mixture is washed with aqueous sodium bicarbonate solution followed by water. The resulting organic layer is separated and evaporated to yield a foamy P-nitrobenzyl 7-phenoxyacetamido-3-acetoxymethyl-2-cefe-4-carboxylate.

nmro (CDCL ₃ ): 2.00 (S, 3H, acetoxy); 4.53 (S, 2H, -OCH ₂ NH-); 4.70 (d, 1H, J = 4.5 Hz, C ₆ -H); 5.73 (d, 2H, J = 4.5 Hz, C ₇ -H); 5.13 (bs, 1 H, C ₄ -H); 6.50 (bs ₁ H, C ₂ H); 5.20, 5.33 (2S, 1H <+ 1H, -CH ₂ O); 6.75-7.30 (m, 5H, phenoxy); 7.50, 8.13 (2d, 2H + 2H, AB, J = 9 Hz, nitrobenzylcarboxylate)

Example 2

500 ml (1 mmol) of P-nitrobenzyl 7-phenoxyacetamido-3-methylenecepam-4-carboxylate-1-oxide was added to 10 ml of benzene, and 2 ml of acetic anhydride and 2 drops of acetyl chloride were added to the resulting slurry. Was added and the resulting mixture was refluxed at 85 ° C. for 15 hours and treated as in Example 1 to give P-nitrobenzyl 7-phenoxy acetamide-3-acetoxymethyl-2-cem-4-carboxylate.

Example 3

500 ml of P-nitrobenzyl 7-phenoxyacetamido-3-methylenecepam-4-carboxylate-1-oxide are added to 10 ml of anhydrous toluene and 2 ml of acetic anhydride and two acetyl chlorides are added to the resulting slurry. The mixture was refluxed at 110 ° to 112 ° C. for 18 hours and the resulting reaction mixture was treated in the same manner as in Example 1 to give P-nitrobenzyl-7-phenoxyacetamido-3-acetoxymethyl-2-cepem-4-carboxylate and Trace amounts of compatible Δ ³ isomers are obtained.

Example 4

500 ml of P-nitrobenzyl 7-phenoxyacetamido-3-phenylenecepam-4-carboxylate-1-oxide was added to 10 ml of anhydrous toluene, and 2 ml of acetic anhydride and 0.0071 ml (sepam sulfoxide) were added to the resulting mixture. 1 equivalent of acetyl chloride was added and the resulting mixture was refluxed at 111 ° C. for 5 hours to almost completely convert methylenecepam sulfoxide to P-nitrobenzyl 7-phenoxyacetamido-3-acetoxymethyl-2 -Cefem-4-carboxylate and small amounts of the corresponding Δ ³ isomers are obtained.

Example 5

To a mixture of 33 ml of acetic acid and 66 ml of acetic anhydride, 6 g (12 mmol) of P-nitrobenzyl-7-phenoxyacetamido-3-methylenecepam-4-carboxylate-1-oxide were added and the mixture was subjected to slow nitrogen. Maintain in air and reflux at about 126 ° C., then measure thinness chromatography on silica gel plate using a mixture of benzene and ethyl acetate (1: 1) to measure adaptability. The reaction was completed in about 2.5 hours, after which the resulting red solution was evaporated to black tar. The resulting residue is dissolved in about 50 ml of ethyl acetate and the ethyl acetate solution is washed three times with 50 ml of saturated sodium bicarbonate solution each time and once with 50 ml of saturated sodium chloride solution. The ethyl acetate layer was dehydrated in magnesium sulfate, treated with activated charcoal, filtered through silica gel, and the filtrate was evaporated to afford P-nitrobenzyl 7-phenoxyacetamido-3-acetoxymethyl-2-cefe-4-carboxylate. 5.8 g (89%) of a mixture of P-nitrobenzyl 7-phenoxyacetamido-3-acetoxymethyl-3-cepem-4-carboxylate (3: 1) (89%) are obtained in a pale yellow foam.

nmr (3: 1 mixture of Δ ² and Δ ³ )

σ (CDCL ₃ ) 6.5 (broad S, 0.75 △ ² -CH ₂ ), 5.8 (dd, 1, C ₇ -H), 4.6 (S, 2, C ₇ -methylene), 3.6 (broad S, 0.5, △ _{^{3 -C 2), 2.1-2.2 (ss}} , 3, △ 3 -C 3, acetoxy).

EXAMPLES 6-10

The reaction of Example 5 was repeated under several conditions as follows.

Example 11

To 5 ml of acetic anhydride and 20 ml of acetic acid was added 600 mg of 2,2,2-trichloroethyl 7- (P-nitrobenzyloxycarbonylamino) -3-methylenecepam-4-carboxylate-1-oxide The resulting mixture is stirred at 110 ° C. for 6 hours, then the reaction mixture is cooled and the solvent is evaporated. The resulting residue is taken up in ethyl acetate and the ethyl acetate solution is washed with saturated aqueous sodium bicarbonate solution. The organic layer was dehydrated over magnesium sulfate and evaporated and the residue was chromatographed on silica gel to give 2,2,2-trichloroethyl 7- (P-nitrobenzyloxycarbonylamino) -3-acetoxymethyl-2-cefem- 100 mg of a 6: 1 mixture of 4-carboxylate and 2,2,2-trichloroethyl 7- (P-nitrobenzyloxycarbonylamino) -3-acetoxymethyl-3-sepe-4-carboxylate are obtained. .

nmr (6: 1 mixture of Δ ² and Δ ³ )

sigma (CDCL ₃ ): 6.45 (broad S, 0.83, Δ ² -C ₂ ), 4.75 (S, 2, trichloroethyl), 4.65 (broad S, 1.66, Δ ² -C ₃ ), 3.5 (broad S, 0.34, Δ ³ -C ₂ ), 2.10-2.15 (broad S, 3, Δ ² and Δ ³ C ₃ ′ -acetoxy).

Example 12

To a mixture of 5 ml of acetic anhydride and 20 ml of acetic acid was added 600 mg of P-nitrobenzyl-7- (2-thienylacetamido) -3-methylenecepam-4-carboxylate-1-oxide and the resulting mixture was 110 After stirring for 4 hours at 占 폚, the mixture is cooled, evaporated, and the resulting residue is dissolved in ethyl acetate. The ethyl acetate solution was washed with aqueous sodium bicarbonate solution, dehydrated on magnesium sulfate, the solvent was evaporated and the residue was chromatographed on silica gel to give 110 mg of P-nitrobenzyl 7- (2-thienylacetamido) -3-acetoxy Obtain methyl-2-cefe-4-carboxylate.

nm r sigma (CDCL ₃ ): 6.4 (broad S, 1, Δ ² -C ₂ ), 5.6 (dd, 1, C ₇ -H); 4.6 (broad S, 2, C ₃ '-methylene), 3.8 (S, 2, C ₇ -methylene), 2.05 (S, 3, C ₃ ' -acetoxy).

Example 13

600 mg of P-nitrobenzyl 7-phenoxyacetamido-3-methylenecefe-4-carboxylate-1-oxide was added to a mixture of 5 ml of propionic anhydride and 20 ml of propionic acid, followed by stirring at 130 ° C. for 6 hours. The mixture is cooled and the solvent is removed in vacuo. The resulting residue was dissolved in 150 ml of ethyl acetate, the ethyl acetate solution was washed with saturated aqueous sodium bicarbonate solution, the ethyl acetate layer was separated, dehydrated on magnesium sulfate, the solvent was evaporated, and the residue was chromatographed on silica gel. 166 mg of P-nitrobenzyl 7-phenoxyacetamido-3-propionyloxymethyl-2-cefe-4-carboxylate are obtained.

nmrσ (CDCL ₃ ): 6.45 (broad S, 1, △ ² -C ₂ ), 5.7 (dd, 1, C ₇ -H), 2.3 (p, 2, methylene of propionoxy) 1.1 (t, 3 , Methyl propionoxy)

Example 14

P-nitrobenzyl 7-phenylacetamido-3-methylenecefe-4-carboxylate-1-oxide is added to the mixture of acetic anhydride and acetic acid at once. The mixture is heated, stirred for some time, cooled, evaporated and dried. The residue is taken up in ethyl acetate and the product is purified as in the above-described example to give P-nitrobenzyl 7-phenylacetamido-3-acetoxymethyl-2-cefe-4-carboxylate.

Formulation Method 1

To 170 ml of methylene chloride is added 5.65 g of P-nitrobenzyl 7-phenoxyacetamido-3-acetoxymethyl-2-cefe-4-carboxylate and 20 ml of isopropyl alcohol and the mixture is cooled to about 0 ° C. . A solution of 2.12 g of 85% industrial P-chloroperbenzoic acid was added dropwise to 55 ml of methylene chloride, and the reaction was measured by thin layer chromatography. After 45 minutes the methylene chloride mixture is washed three times with 100 ml aqueous sodium chloride solution and the methylene chloride layer is dehydrated on magnesium sulfate and treated with activated carbon. The methylene chloride solution was cooled in an ice bath, petroleum ether was slowly added and crystallized to give 4.39 g (76-g) of P-nitrobenzyl 7-phenoxyacetamido-3-racetoxymethyl-3-sepe-4-carboxylate-1-oxide. %) Is obtained. Fusion: 187 to 188 ℃

Analysis: C ₂₅ H ₂₃ N ₃ O ₁₀ S

Theoretic: C 53.83% H 4.16 N 7.54 O 28.70 S 5.75

Found: 53.67 3.89 7.29 28.45 5.38

Preparation method 2

To 75 ml of N, N-dimethylformamide (DMF) was added 2.70 g of the product obtained in Preparation 1, the resulting mixture was cooled to -80 ° C and 1.6 ml of phosphorus trichloride was added at once. The resulting mixture is stirred at −80 ° C. for only 10 minutes and warmed to −0 ° C. using an ice water bath. After stirring for 25 minutes, the resulting orange solution was poured into ice, the precipitate formed was filtered off, washed with water and dried to obtain 2.35 (89.5%) of P-nitrobenzyl 7-phenoxyacetamido-3-acetoxymethyl-3- Cefem-4-carboxylate is obtained.

nmrσ (CDCL ₃ -DMSO 1: 1): 2.03 (S, 3H, Acetoxy), 3.50 (6S, 2H, -S-CH _2- ), 4.53 (S, 2H, -O-CH ₂ -NH-) , 4.90 (d, 1H, J = 4.5 Hz, C ₇ -H) 5.90 (d, 1H, J = 4.5 Hz, C ₇ -H), 5.20, 5.30 (2S, 1H + 1H, acetoxymethyl), 5.33 (S, 2H, nitrobenzyl), 6.77-7.40 (m, 5H, phenoxy), 7.53, 8.17, (2d, 2H + 2H, AB, J-9 Hz, nitrobenzylcarboxylate).

Claims (1)

3-exomethylenecepam sulfoxide of the following formula (II) is reacted with the acyl compound of the following formula (III) and its corresponding anhydride (formula (IV)) at about 70 to 130 ° C. To prepare compounds of

In the above structural formula X is chloro or hydroxy R ₄ is C ₁ -C ₄ alkyl R ₁ is a carboxylic acid protecting group R is (1) an imide group of the following structural formula,

Wherein R ₂ is C ₂ -C ₄ alkenylene or 1,2-phenylene (2) amido groups of the following structural formulas,

Wherein R ₃ is (a) hydrogen, C ₁ -C ₃ alkyl, halomethylbenzyloxy, 4-nitrobenzyloxy, 2,2,2-trichloroethoxy, -4-methoxybenzyloxy, or 3- (2-chlorophenyl) -5-methylisoxazol-4-yl, (b) a group R 'wherein R' is phenyl or phenyl substituted with 1 to 2 halogen, nitro, cyano, trifluoromethyl, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy (c) a group of the formula R '-(o) m-CH _2- Where R 'is as described above and m is 0 or 1 (d) Structural Formula R ''-

Flag of Wherein R '' is R ', 2-thienyl or 3-thienyl as described above and R ₁ is as described above, (e) the structural formula R '"- CH ₂ - of the group (wherein R'" is 2-thienyl, 3-thienyl, 2-furyl, 3-furyl 2-thiazolyl, 5-tetrazolyl, 1-tetrazolyl Or 4-isoxazolyl), or (3) imidazolidinyl group of the following structural formula

(Wherein R 'is as described above and U is nitroso or acetyl.)