KR810001265B1 - Method for preparing alkyl oxime derivative of 7-amino thiazolyl acetamide sephalosporan acid - Google Patents

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Description

Method for preparing alkyl oxime derivative of 7-amino thiazolyl acetamide sephalosporan acid

The present invention relates to a new process for the preparation of cephalosporane derivatives. It is represented by the new alkyloxime structural formula (I) of 7-amino thiazolyl acetamide-cephalos foronic acid derivative | guide_body dealt with in this invention.

In the above structure, R is selected from the group consisting of alkyl having 1-5 carbon atoms, cycloalkyl having 3-5 carbon atoms, and -CH ₂ -SR 'groups, wherein R' is acyl of alkanes having 2-4 carbon atoms, 1 -Methyl-tetra-zolyl, and 2-methyl-1,3,4-thiadiazolyl. R ₁ is selected from hydrogen and a group which can be easily released by acid hydrolysis or hydrogenolysis, R ₂ is a group consisting of alkyl having 1-4 carbons, alkenyl and alkynyl having 2-4 carbons Is selected.

A is selected from the group consisting of hydrogen, an alkali metal cation, an alkali metal or magnesium equivalent, an organic amine base cation, and esters that are easily removable by acid hydrolysis or hydrogenolysis. In this case, when R ₁ dihydrogen, A is not an ester group easily removable by acid hydrolysis or hydrogenolysis.

The wavy line means that OR ₂ can be in either of two possible isomeric positions, syn or anti.

Examples of acids for the acyl group of R ₁ include acetic acid, propionic acid, n-butyl acid, and dizobutyl acid.

Alkyl and cycloalkyl groups for R ₁ include methyl, ethyl, propyl, izopropyl, butyl, izobutyl, tert-butyl, pentyl, cyclopropyl, cyclobutyl and cyclopentyl.

Groups that can be easily released by hydrolysis with acid or hydrolysis as R ₁ are already well known in cephalosporan chemistry. Examples of these include tert-butoxy carbonyl, trityl, benzyl, dibenzyl, trichloroethyl, carbobenzyloxy, formyl, trichloroethoxy carbonanyl, or 2-tetra hydropyranyl groups. have.

Among the alkyl, alkenyl, and alkynyl groups in R ₂ are methyl, ethyl, propyl, isopropyl, butyl secondary-butyl, tert-butyl, vinyl, propenyl, butenyl, ethynyl, or propargyl. have.

Examples of A include sodium, potassium, lithium, calcium or magnesium, and trimethylamine, triethylamine, methylamine, propylamine, N, N-dimethyl ethanolamine, tri (hydroxymethyl) -aminomethane, arginine or lysine and the like. The same organic base, and the group which can be easily released by acid hydrolysis or hydrogenolysis such as benzhydryl, tertiary butyl, benzyl, P-methoxy benzyl and the like.

The compound of formula (I) may exist as a syn isomer such as formula (IS) or as an anti-antibody such as formula (IA).

Among them, syn-type compounds such as structural formula (IS) are common. Common ones of the compounds of formula (I) are those in which A is hydrogen, an alkali metal cation, an organic amine cation, or an alkali equivalent of metal or magnesium. Common groups of A which can be easily released by acid hydrolysis or hydrogenolysis are benzylhydryl, tert-butyl, benzyl, P-methoxy benzyl and trichloroethyl.

Common groups of R ₁ that can be easily released by acid hydrolysis or hydrogenolysis are tert-butyoxy carbonyl, trityl, dibenzyl, trichloroethyl and carbobenzyl oxy.

In addition, among the compounds of the formula (I),

R is -CH ₂ -S-R ', wherein R' is acyl, 1-methyl-tetrazolyl, or 2-methyl-1,3,4-thiadiazolyl of alkanoic acid having 2-4 carbon atoms Phosphorus compounds,

R is an alkyl having 1-5 carbons and cycloalkyl having 3-5 carbons,

R ₁ is hydrogen or trityl, R ₂ is methyl, R is -CH ₂ -S-R ', wherein R' is acetyl, 2-methyl-1,3,4-thiadiazolyl or 1-methyl- Tetrazolyl and A is hydrogen,

R ₁ is hydrogen, R ₂ is methyl, R is -CH ₂ -SR ¹ , wherein R ¹ is acetyl, 2-methyl-1,3,4-thiadiazolyl or 1-methyl-tetrazolyl and A is hydrogen , A compound which is an alkali metal, an organic amine or an equivalent of an alkaline earth metal or magnesium, a compound in which R ₁ is hydrogen or trityl, R ₂ is methyl, R is methyl or isopropyl, A is hydrogen, and R ₁ is hydrogen, R ₂ is methyl, R is -CH ₂ -SR ¹ , wherein R ¹ is acyl of alkanoic acid having 2-4 carbon atoms, and A is hydrogen or an alkali metal.

Particularly common among the compounds of formula (I) include

7- [2- (2-amino 4-thiazolyl) 2-methoxyiminoacetylamino] -3-[(1-methyltetrazool-5-yl) -thiomethyl] cepa-3-m 4-carboxyl mountain,

7-[(2- (2-amino 4-thiazolyl) 2-methoxy-aminoacetyl)} amino] -3-[(2-methyl 1,3,4-dithiazool-5-yl) -thio Methyl] sepha-3-em 4-carboxylic acid,

3-acetyl thiomethyl 7-[{2-amino-4-thiazolyl) 2-methoxyiminoacetyl} -amino] -sepha-3-em 4-carboxylic acid,

7-[{2- (2-amino 4-thiazolyl) 2-methoxyiminoacetyl} amino] -3-isopropyl-cepa-3-em 4-carboxylic acid,

7-[{2- (2-amino 4-thiazolyl) -2-menoxyiminoacetyl} amino] -3- (1-methyltetrazol-5-yl) -thiomethyl sefa-3-em 4-cara Syn isomer of cycloxyl acid,

7-[{2- (2-amino 4-thiazolyl) 2-methoxyiminoacetyl} -amino] 3- (2-methyl 1,3,4-thiadiazol 5-yl) thiomethyl sepa-3- Syn isomer of M 4-carboxylic acid.

3-acetyl thiomethyl 7-[{2- (2-amino 4-thiazolyl) 2-methoxyiminoacetyl} -amino] syn isomer of Sepha-3-M 4-carboxylic acid.

Syn-isomer of 7-[{2- (2-amino 4-thiazolyl) 2-methoxyiminoacetyl} amino] -3-isopropyl sefa-3-em 4-carboxylic acid,

7-[{2- (2-amino 4-thiazolyl) 2-methoxyiminoacetyl} amino] syn isomer of 3-methyl sepha-3-em 4-carboxylic acid.

3-acetyl thiomethyl obtained according to the method described in Example 6

7-[{2- (2-amino 4-thiazolyl) 2-methoxyaminoacetyl} amino] sepha-3-em 4-carboxylic acid,

7-[{2- (2-amino 4-thiazolyl) 2-methoxyiminoacetyl} amino] -3-[(2-methyl-1,3,4-thiadiazol 5-yl) -thiomethyl] Sodium salt of syn isomer of cepha-3-m-4-carboxylic acid,

7-[{2- (2-amino 4-thiazolyl) -2-methoxyiminoacetyl} amino] -3-[(1-methyltetrazol-5-yl) -thiomethyl] -cepha-3-em Sodium salt of the syn isomer of 4-carboxylic acid,

Sodium salt of syn isomer of 3-acetyl thiomethyl 7-[{2-amino 4-thiazolyl) -2-methoxyiminoacetyl} -amino] -sepha-3-em 4-carboxylic acid,

Crystalline sodium salt of syn isomer of 3-acetyl thiomethyl 7-[{2- (2-amino 4-thiazolyl) -2-methoxyiminoacetyl} -amino] -sepha-3-m 4-carboxylic acid There is.

The products of formula (I) may be present in the same form as above or in the form of the following formula (Ib).

R, R ₁ , R ₂ and A are as described above. According to the present invention, a process for preparing a compound such as Structural Formula (I) is obtained by reacting a compound of Structural Formula (II) with a compound of Structural Formula (III) to obtain a compound of Structural Formula (I ′). Treatment with a hydrogenolysis agent yields a compound of formula (I '), which is then chlorinated to obtain the corresponding alkali metal, magnesium, alkaline earth metal, or organic amine salt.

In the above, A 'is selected from a group or hydrogen which can be easily released by acid hydrolysis or hydrogenolysis, and R ₁ ' is selected from a group which can be easily released by acid hydrolysis or hydrogenolysis.

In a more general method of the present process, a compound of formula (II) may be prepared by reacting an acid functional derivative of formula (II) such as chloric acid or acid anhydride, or an anhydride formed by reaction of an acid with dizopropyl chloroformate or dicyclohexyl carbodiimide. There is a way to react.

In addition to other alkali chloroformate salts, dialkyl carbodiimides, or other dicycloalkyl carbodiimides, anhydrides or other dicycloalkyl carbodiimides formed by the reaction of acids with acid azides, acidamides, or hydrides. Also useful are oxy succinimide, acid esters formed with P-nitrophenol or 2,4-dinitrophenol or other acid derivatives such as acid azide and acid amide, and other acid halides.

Conversion of a compound, such as formula (I '), to a compound of formula (I') is a group in which R ₁ 'is readily removable by acid hydrolysis, and A' is a group easily removable by hydrogen or acid hydrolysis. In the case of an acid hydrolysis agent.

When R ₁ ′ is a group that can be easily released by hydrogenolysis and A ′ is a group that can be easily released by hydrogen or hydrogenolysis, the compound of formula (I ′) can be treated with a hydrogenolysis agent have.

When one of R ₁ 'or A' is a group that can be easily released by acid hydrolysis and the other is a group that can be easily released by hydrogenolysis, the compound of formula (I ') Can be treated with an agent.

The acid hydrolysis agent used in the reaction with the compound of formula (I ′) is formic acid, trifluorotoacetic acid, acetic acid and the like. These can be used as aqueous solutions or anhydrides.

Zinc-acetic acid systems may also be useful.

If R ₁ ', which is a leaving group, is trityl or tert-butoxy carbonanyl, and A' is benzyl hydride, tert-butyl, or P-methoxy benzyl, the acid hydrolysis agent may be trifluoroacetic anhydride or an aqueous solution. Formic acid or acetic acid in the phase is suitable.

When R <_1>'andA' are trichloroethyl, the thing of zinc-acetic acid series is preferable.

When R ₁ 'is dibenzyl or carbo benzyloxy, or R ₁ ' and A 'is benzyl, hydrogen in the presence of a catalyst is suitable as the hydrogenolysis agent.

Compounds such as the formula (I ') or (I') may be used to convert the acid to sodium hydroxide, inorganic bases such as potassium hydroxide or sodium bicarbonate, or substituted or unsubstituted aliphatic carboxylic acids (e.g. diethylacetic acid, ethyl hexanoic acid). , Acetic acid) can be chlorided by known methods.

Such chloride may also be formed by reaction with an organic base such as triethylamine or diethylamine.

In the preparation of such salts, free acids or sorbates of free acids can be used as starting materials, and the reaction is usually carried out in the presence of one or more bases such as water, ether, methanol, ethanol and acetone. Crystalline salts are usually obtained by reacting salts of aliphatic carboxylic acids, usually sodium acetate with free acid.

In the preparation of such sodium salts the reaction takes place in a suitable organic solvent such as methanol containing a small amount of water.

It is an object of the present invention to provide a process for the preparation of compounds of formula (I) in which the -OR ₂ group is in the syn position, in particular when the product of formula (III) has an -OR ₂ group in the syn position.

In one variation of the process according to the invention for preparing compounds of formula (I '), salts of compounds such as formula (I'), wherein R ₁ ′ is a group that can be easily released by acid hydrolysis, are treated with an acid so that A salt of a compound of formula (I '), which forms a compound of formula (I') or is a group in which R ₁ 'is easily removable by hydrogenolysis, is treated with a hydrogenolysis agent to form a salt of a compound of formula (I'). .

Acid hydrolysis agents used in the process are usually formic acid, but acetic acid and trifluoro acid are also useful. The acid can be used in the form of anhydride or aqueous solution.

Hydrolysis agents are usually hydrogen in the presence of a hydrogenation catalyst.

In another variation of the process of the invention according to the preparation of the compound of formula (I '), the compound of formula (II) is treated with an acid of formula (III _A ) to obtain a compound of formula (VI), which is subjected to acid hydrolysis. Treatment with a zener or hydrolysis agent.

Acid and the reaction of formula (Ⅱ) compound and formula (Ⅲ _A) is performed under the same conditions as in the compound and the acid in the reaction of formula (Ⅲ) of formula (Ⅱ) mentioned earlier. The reaction with thiourea and the compound of formula VI is carried out under neutral or acidic conditions and this kind of reaction is carried out by Masaki [JACS, Vol. 90 (1968), p. 4508].

In the process according to the present invention for obtaining the compound of formula (I _A ), a compound of formula (IV) is reacted with a compound of formula (V) to obtain a compound of formula (I _A ) and chlorided to obtain A ₁ ′. And a compound of formula (I _A ) wherein the compound is an alkali metal, alkaline earth metal, magnesium, or an organic amine base.

The reaction between the compound of formula (IV) and the compound of formula (V) is preferably carried out in a water-acetone mixture, but can also be reacted in a mixture of water-dioxane, water-tetrahydrofuran, or water-ethyl alcohol. .

This reaction is usually done in the presence of a buffer such as a mixture of acidic sodium phosphate-sodium bicarbonate to keep the pH slightly acidic.

Another object of the present invention is to prepare a compound of formula (I _A ) in which -OR ₂ group is in syn position, and for this purpose, a compound of formula (IV) in which OR ₂ group is in syn position is used.

The new antibiotic composition according to the present invention contains at least one suitable amount of the compound of formula (I).

The composition according to the invention thus has a high antimicrobial activity and is particularly effective against gram positive bacteria such as Staphylocococci or Streptococci, and gram negative bacteria, in particular Coliform. It is effective against bacteria, Klebsiella, Salmonella and Proteus.

Therefore, these compositions can be used pharmaceutically and also contain highly active pathogens, such as staphylococcal infections, in particular staphylococcal calcecaemia, malignant staphylococcal infections of the face and skin, piodellimatis, septicemia It is very effective in treating pain, anthrax, cellulitis, cellulitis, solitary disease, early or late malignant influenza staphylococcal infection, bronchial pneumonia and tuberculous purulent purpura.

Such pharmaceutically usable compositions can be used as a medicament prescribed for coribacillus cis fungus, or for their complications or complications of other diseases caused by Proteus, Krebsila, Salmonella or Gram-negative bacteria. Can be used effectively.

Among the compositions according to the invention are those wherein A is hydrogen, an alkali metal of the cation, an organic amine or alkaline earth metal of the cation, or magnesium. Common groups of A which can be easily decomposed by acid hydrolysis or hydrogenolysis are benzylhydryl, tert-butyl, benzyl, para-methoxy benzyl and ethyl trichloride. Tertiary-butoxy carbonanyl, trityl, dibenzyl, trichloroethyl and carbobenzyl jade are common as R ₁ which can be easily decomposed by acid hydrolysis or hydrogenolysis.

In addition to the general ancestors according to the present invention,

R is -CH ₂ -S-R 'wherein R' is an acyl of alkanoic acid having 2-4 carbon atoms, 1-methyl-tetrazolyl, or 2-methyl-1,3,4-thiadiazolyl Phosphorus composition,

A composition wherein R is alkyl having 1-5 carbons or cycloalkyl having 3-5 carbons,

R ₁ is hydrogen or trityl, R ₂ is methyl, R is -CH ₂ -S-R 'and A is hydrogen, wherein R' is acetyl, 2-methyl-1,3,4-thiadiazolyl or 1- The composition is methyl-tetrazolyl,

R ₁ is hydrogen, R ₂ is methyl, R is -CH ₂ -S-R 'and A is hydrogen, an alkali metal, an organic amine, alkaline earth metals, or magnesium; and R' is acetyl, 2-methyl A composition that is -1,3,4-thiadiazolyl or 1-methyl-tetrazolyl

A composition wherein R ₁ is hydrogen or trityl, R ₂ is methyl, R is methyl or isopropyl, and A is hydrogen,

And R ₁ is hydrogen, R ₂ is methyl, R is -CH ₂ -S-R ', A is hydrogen or an alkali metal, and R' is acyl of alkanoic acid having 2-4 carbon atoms.

Particularly common are the above compositions wherein the OR ₂ group in formula (I) is syn position.

Common ones of the above compositions include 7-[{2- (2-amino 4-thiazolyl) 2-methoxy imino acetyl} amino] -3-[(1-methyl tetrazol 5-yl) thiomethyl] Sepha 3-M 4-carboxylic acid,

7-[{2- (2-amino 4-thiazolyl) -2-methoxy imino acetyl} amino] -3-[(2-methyl 1,3,4-thiadiazol 5-yl) -thiomethyl -Cepha-3-em 4-carboxylic acid,

3-acetylthio methyl 7-[{2- (2-amino 4-thiazolyl) 2-methoxy imino acetyl} amino] -sepha-3-em 4-carboxylic acid,

7-[{2- (2-amino 4-thiazolyl) 2-methoxy imino acetyl} amino] -3-isopropyl-cepa-3-em 4-carboxylic acid, 7-[{2- (2 -Amino 4-thiazolyl) 2-methoxy imino acetyl} -amino] -3-methyl-cepa-3-em 4-carboxylic acid,

7-[{2- (2-amino 4-thiazolyl) -2-methoxy imino acetyl} amino] 3-[(1-methyl tetrazol 5-yl) thiomethyl] -cepa-3-m 4- Geometric isomers of carboxylic acids, 7-[{2- (2-amino 4-thiazolyl) 2-methoxy imino acetyl} amino] -3-[(2-methyl-1,3,4-thiadiazole 5-yl) -thiomethyl] -cepa-3-m 4-cockamic acid,

Geometric isomer of 3-acetyl thiomethyl 7-[{2- (2-amino 4-thiazolyl) 2-methoxy imino acetyl} -amino] -sepha-3-em 4-carboxylic acid,

Geometric isomers of 7-[{2- (2-amino 4-thiazolyl) 2-methoxy imino acetyl} -amino] -3-isopropyl sefa-3-em 4-carboxylic acid,

Geometric isomer of 7-[{2- (2-amino 4-thiazolyl) -2-methoxy imino acetyl) -amino] -3-methyl sepha-3-em 4-carboxylic acid,

Obtained according to the method described in Example 6

3-acetyl thiomethyl-7-[{2- (amino 4-thiazolyl) -2-methoxy imino acetyl} amino] -sepha-3-em 4-carboxylic acid,

7-[{2- (amino 4-thiazolyl) -2-methoxy imino acetyl} amino] -3-[(2-methyl 1,3,4-thiadiazol 5-yl) thio methyl] cepha- Sodium salt of the isomer of 3-M 4-carboxylic acid,

7-[{2- (amino 4-thiazolyl) -2-methoxy imino acetyl} amino] 3-[(1-methyl tetrazol-5-yl) -thiomethyl] cepa-3-m 4-cara Sodium salts of geometric isomers of acids,

Sodium salt of the geometric isomer of 3-acetyl thiomethyl 7-[{2- (amino 4-thiazolyl) -2-methoxy imino acetyl} amino] -sepha-3-em 4-carboxylic acid,

And crystalline sodium salts of the geometric isomers of 3-acetyl thiomethyl 7-[{2- (amino 4-thiazolyl) -2-methoxy imino acetyl} amino] -sepha-3-em 4-carboxylic acid have.

Such compositions may be used by oral or rectal or injection methods for skin diseases or mucus secretion that occur locally at home or school.

They can also be used in liquid or solid form, which can be used in various pharmaceutical forms that are generally available to the human body.

For example, it can be used simply, dragee, or compressed into tablets, into gelatin capsules, in the form of granules, powdered medicines, injectables, etc., or in the form of plasters, creams or gels.

These actives are absorbed in the excipients associated with conventional pharmaceutical preparations, which include talc, gum arabic, lactose, starch, magnesium stearate, cocoa, butter, liquid or non-liquid additives, animal and vegetable fats and oils, and paraffin derivatives. , Glycols, various wetting agents, dispersants, emulsifiers and the like.

The dosage of the composition according to the present invention varies in the range depending on the type and extent of the disease and is in the range of 5-80 mg / kg depending on the compound and the method of administration.

The new intermediate product obtained in the present invention has the following structure.

Compounds of formula II wherein R is —CH ₂ —S—R ′ may be prepared by substitution reactions starting with 7-amino-cephalosporonic acid.

The compound of formula (III) is treated with a base such as the following formula (B) and thiourea and treated with a base to obtain a compound of formula (C), which can be easily released by acid hydrolysis or hydrogenolysis. Treatment with a functional derivative yields a compound of formula (D), which is then treated with a base and an acid to obtain a compound of formula (II).

The reaction between thiourea and the compound of formula (B) to obtain the compound of formula (II) in syn form is carried out in a water-soluble solvent such as water-soluble acetone or ethanol or at room temperature, and the reaction time is 1-3 hours. It is enough. Compounds of formula (B) are described in J. of Med. Chem. Vol. 16 (1973), p.978 /, obtained by reacting diazomethane or alkylhalogen compounds or sulfates with ethyl γ-chloro-alpha-oxyimino-acetylacetate.

Compounds of formula (IV) are obtained by reacting an acid of the following structure with 7-aminocephalospotanic acid and treating its product with an acid hydrolysing agent or a hydrogenolysis agent.

In the same manner, a compound such as syn-form (IV) can be obtained by reacting a compound such as syn-form (III) with 7-amino cephalosporonic acid.

The compounds of formula (Ⅲ _A) is obtained by treatment of the compound and that after the reaction product of a chloroacetyl group, the structural formula (C) a derivative of a base with an acid.

The following examples are intended to illustrate the present invention in detail, and the present invention is not limited to these examples.

Example 1

7-[{2- (2-Tyrylylamino 4-thiazolyl) 2-methoxy imino acetyl} -amino] -3-[(2-methyl 1,3,4-thiadiazolol-5-yl) Thiomethyl] -sepha-3-em 4-carboxylic acid.

2.5 g of sodium salt of 2- (2-trityl amino 4-thiazolyl) 2-methoxy amino acid was mixed with a mixed solution of methylene chloride 40 cm ³ and 2 N hydrochloric acid 5 cm ³ , transferred to another container, washed with water and dried. Then concentrate. This is again dissolved in 30 cm ³ of dried tetrahydrofuran. 0.7 g of dicyclohexylcarbodiimide was added thereto, followed by stirring at room temperature for 45 minutes, followed by vacuum filtration to form di-cyclohexyl urea, followed by cooling to -5 ° C and 7-amino-3-[( 2-methyl-1,3,4-thiadiazol 5-yl) -thiomethyl] -sepha-3-em 4-carboxylic acid 0.895 g, water 10 cm ³ , and triethylamine 0.9 cm ³ (first 0 ° C.) Add a solution of cooled) to. Then, it was left at room temperature for about 1 hour and 30 minutes, after which tetrahydrofuran was removed, methylene chloride 40cm ³ was added, washed with dilute hydrochloric acid, washed with water and concentrated to dryness.

After dissolving the glass object obtained here dioxane 8cm ³ was added dropwise to saturated sodium bicarbonate solution 3cm ³ was stirred for 30 minutes and the filtered and washed with ether, and then recovering the starting material, 0.554g of the sodium salt form and dioxane After removal, methylene chloride is added, washed with diluted hydrochloric acid 1, and then washed with water and concentrated to dryness to the expected dryness. It is triturated by adding ether, vacuum filtered and washed to obtain 1.9 g of crude product.

The crude product was added to 5 cm ³ of ethyl acetate, stirred, ether 5 cm ³ was added thereto, stirred, and then vacuum filtered and washed.

It is then dissolved in methylene chloride 2 cm ³ to give 1.47 g of partially purified product which is then precipitated with ether 25 cm ³ . Vacuum filtration followed by washing yields 1.4 g of the desired product.

Thus obtained 7-[{2- (2-tritylamino 4-thiazolyl) 2-methoxy imino acetyl} amino] 3-[(2-methyl 1,3,4-thiadiazol 5-yl ) Thiomethyl] Sepha-3-M 4-carboxylic acid has a syn form.

The sodium salt of 2- (2-tritylamino 4-thiazolyl) 2-methoxy imino acetic acid is syn form, but when used as a starting material in Example 1 above, it is prepared as follows.

Step A: ethylγ-chloro α-methoxy imino acetylacetate

Ethyl α- γ- chloro-oxy-diamino into acetyl acetate 22.5g methylene chloride 100cm ³ and this is a pure solution of diazomethane (21.6g / ℓ) 275cm ³ while being stirred slowly and then placed in an ice bath.

It is left for 5 minutes and then some alumina is used to remove excess diazomethane. After concentration, it is purified by eluting silica with methylene chloride. This gives 11.93 g of the desired product.

Step B: ethyl 2- (2-amino 4-thiazolyl) 2-methoxy imino acetate

First, 1 g of ethylγ-chloro α-oxymino acetyl acetate is mixed with a solution of ³ cm ³ of anhydrous ethanol and 0.42 g of solid thiourea.

After stirring at room temperature for about 2 hours, the mixture was diluted with 60 cm ³ of ether to obtain crystals of chloride. The mixture was vacuum filtered with stirring, washed and dried to give 685 mg of hydrogen chloride.

It is dissolved in 4 cm ³ of water at 50 ° C. and potassium acetate is added until the pH is 6 to obtain crystals of amine. These cooled, vacuum filtered, washed with water and dried gives 270 mg of the desired product. The melting point of this product is 161 占 폚.

The compound thus obtained has a syn form.

NMR (CDCI ₃ 60MHZ) ppm: 40

(N-OCH ₃ ) 6.7 (protons of thiazole rings).

Step C: ethyl 2- (2-tritylamino 4-thiazolyl) 2-methoxy imino acetate

4.6 g of the compound obtained according to the previous step was dissolved in 92 cm ³ of methylene chloride at 30 ° C., cooled to −10 ° C., and 2.9 cm ³ of tritylamine was added, followed by cooling to −35 ° C. again. Leave for about 15 minutes, add 6.1 g of trityl chloride, and leave until it reaches room temperature. The time required is about 2 hours 30 minutes. The above is washed with water and then with 0.5N hydrochloric acid and sodium acetate dissolved in water. It was concentrated again to dryness, and then concentrated by adding ether, dissolving it in methanol, and adding water and ether again to obtain a crystalline compound, which was vacuum filtered and washed with ether to obtain 6.15 g of the desired compound. The melting point of this compound is 120 ° C.

The above compound has a geometrically symmetrical arrangement.

Step D: Sodium salt of 2- (2-tritylamino 4-thiazolyl) 2-methoxy imino acetic acid

After dissolving 7.01 g of the ester obtained in step B in 35 cm ³ of dioxane, it was heated to 110 ° C. in an oil bath and after about 5 minutes, 2N sodium hydroxide was added and stirred under reflux for 30 minutes to obtain sodium salt crystals. It is cooled, filtered off, added with ether, washed with dioxane to give 5.767 g of crystal salt. Concentration of the mother liquor gave 1.017 g of crystal salt, from which 6.784 g of sodium salt could be obtained.

The compound has a geometrically symmetric configuration.

Example 2

7-[{2- (2-amino 4-thiazolyl) -2-methoxy imino acetyl} amino] -3-[(2-methyl 1,3,4-thiadiazol 5-yl) -thiomethyl Sepha-3-M 4-carboxylic acid

1.4 g of the compound obtained in Example 1 was taken, and stirred with 50% of liquid formic acid 5 cm ³ at 57 ° C. for 15 minutes, water 5 cm ³ was added thereto, cooled to room temperature, vacuum filtered, and ethanol 5 cm ³ was added thereto. To dry.

The concentrated dry matter in ethanol 5cm ³ was finely crushed and then vacuum filtered and washed with ethanol and ether to give 0.687 mg of crude product.

After the above compound was dissolved in water 7cm ³ and triethylamine 0.2cm ³ by vacuum filtration and washed with 50% formic acid acidified throwing 0.2cm ^3.

It is stirred, vacuum filtered and washed with alcohol and ether to give 0.275 g of compound.

Analysis: C ₁₇ H ₁₇ O ₅ N ₇ S ₄ (0.5 Ethanol)

Theoretic: C% 39.25, H% 3.66, N% 17.80, S% 23.28

Found: 39.3 3.5 17.9 23.1

The compound obtained here has a geometrically symmetrical arrangement.

NMR spectrum (DMSO, 60MHZ) ppm: 3.85 (N-OCH ₃ ) 6.76 (proton of thiazole ring)

Example 3

7-[{2- (2-tritylamino 4-thiazolyl) -2-methoxy imino acetyl} amino] -3-[(1-methyl tetrazol 5-yl) thiomethyl] -cepha-3- M 4-carboxylic acid

The crude product obtained in Example 1 and 2.33 g of 2- (2-tritylamino 4-thiazolyl) -2-methoxy imino acetic acid are dissolved in 30 cm ³ of methylene chloride. 0.7 g of dicyclohexyl carbodiimide is added to this, and it is left to stand for 50 minutes through an inert gas at normal temperature. Vacuum filtration of this resulted in the formation of dicyclohexylurea, which was cooled to -5 [deg.] C. and then added again to 7-amino 3-[(1-methyl tetrazol 5-yl) thiomethyl] -cepha-3-M 4-cara. to a solution of the acid and 0.854g of methylene chloride 10cm ³⁾ and triethylamine (0.75cm ^3.

After this, so the room temperature was added acetic 1cm ³ vacuum filtration after 10 minutes and concentrated after drying as a water wash was added to the hydrochloric acid and dioxane 8cm ³ and 2.5cm ³ of saturated sodium bicarbonate solution again. The sodium of the first acid obtained by vacuum filtration is obtained and washed with a mixture of ether and ether-dioxane 1: 1.

On the other hand, after dioxane is released, methylene chloride is added, washed with water added with hydrochloric acid, dried and concentrated. To this was added pulverized ether, concentrated in vacuo and washed with ether to obtain 2.29 g of crude product.

The crude product was again stirred in ethanol for 1 hour at 10 ° C., then vacuum filtered and washed with ether to give 1.42 g of the desired compound.

This compound has a geometrically symmetrical arrangement.

Example 4

7-[{2- (2-amino 4-thiazolyl) 2-methoxy imino acetyl} -amino] -3-[(1-methyltetrazool 5-yl) thiomethyl] -cepa-3-m 4 Carboxylic acid

1.4 g of the compound obtained in Example 3 was added to 5 cm ³ of 50% liquid formic acid, and left at 55 ° C between aqueous solutions. 15 minutes, then water 5cm ³ was added and cooling vacuum filtered, and then the concentrate was added ethanol 5cm ³ to the filtrate was added the alcohol 5cm ³ crushing, vacuum filtered and dried after methylene chloride-ether 1: the dough subjected to 1 mixture of After vacuum filtration and washing, 0.557 g of raw fish is obtained.

Analysis: C ₁₆ H ₁₇ O ₃ N ₉ S ₃ (0.5 Ethanol)

Theoretic: C% 38.19, H% 3.77, N% 23.58, S% 18.00

Found: 38.1 3.9 22.5 17.7

The compound obtained here has a geometrically symmetrical arrangement.

NMR spectrum (DMSO, 60MHZ) p.p.m:

3.83 (N-OCH ₃ ) 6.73 (protons of thiazole rings)

Example 5

3-acetyl thiomethyl 7-[{2- (2-tritylamino 4-thiazolyl) -2-methoxy imino acetyl} -amino] -cepa-3-m-4-carboxylic acid

40cm ³ of methylene chloride and 2N hydrochloric acid 6.5cm ³ 2- (2- trityl-amino-4-thiazolyl) -2-methoxy- imino] - If the dissolved sodium salt 3.1g of acetic acid as the starting material in Example 1 You can get a mountain equivalent to that. This acid is dissolved in methylene chloride 30 cm ³ , 0.82 g of dicyclohexyl carbodiimide is added, stirred in an aqueous solution for 1 and a half hours, and then cooled. Vacuum filtration of this resulted in the formation of dicyclohexyl urea, which was cooled to −5 ° C., whereupon 1.1 g of 7-amino 3-acetyl thiomethyl sepa-3-em 4-carboxylic acid, 13 cm ³ of methylene chloride, and triethyl were added. A solution of 0.9 cm ³ of amine (at 0 ° C.) is added.

The solution was brought to room temperature again, 1 cm ³ of acetic acid was added, and the water-repellent substance was vacuum filtered, washed with water slightly added with hydrochloric acid, washed again with water and concentrated. Then, a precipitate in dioxane was added and 3.5 cm ³ of saturated sodium bicarbonate was added. Vacuum filtration. Washing it with a dioxane-ether mixture first gives 0.64 g of acid salt sodium salt. On the other hand was placed in a release-dioxane, methylene chloride was added to 30cm ³ of hydrochloric acid in water (10cm ³ water and 2 HCl 10cm ³⁾ wash with.

It is triturated again with ether 25cm ³ and washed by vacuum filtration to obtain 1.89 g of crude product.

This was dissolved in ³ cm ³ of ethyl acetate and recrystallized twice by adding ether 25 cm ³ to obtain 0.89 g of compound.

The compound obtained here has a geometrically symmetrical arrangement.

In Example 5, the starting material of 7-amino 3-acetyl thiomethyl sepha-3-em 4-carboxylic acid was as follows.

To 5.44 g of 7-amino cephalosporranic acid, 50 cm ³ of water containing 1% hydroquinol is added via inert gas.

1.7 g of sodium bicarbonate was added with stirring, and when the dissolution was completed, 3 g of potassium thioacetate was added thereto. After stirring for 3 hours at 60 ° C, the mixture was cooled and acidified by adding acetic acid.

Stirring is performed at room temperature, followed by vacuum filtration, washing and drying to obtain the desired product.

Example 6

8-acetyl thiomethyl 7-[{2- (2-amino 4-thiazolyl) 2-methoxy-imino acetyl} -amino] -cepha-3-M 4-carboxylic acid

50% of liquid formic acid 5 cm ³ is added thereto while the compound obtained in Example 5 is stirred at 55 ° C. for 15 minutes in an aqueous solution. Again, 5 cm ³ of water was added thereto, cooled to room temperature, vacuum filtered, and 5 cm ³ of alcohol was added again, followed by filtration, concentration, and drying.

After adding 5 cm ³ of alcohol and pulverizing, 440 mg of product was obtained, which was dissolved in 50% of liquid acetone 6 cm ³ and vacuum filtered to obtain 0.265 g of pure product.

Analysis: C ₁₆ H ₁₇ O ₆ N ₅ S ₃ (0.25 CH ₃ COCH ₃ )

Theoretic: C% 41.39, H% 3.83, N% 14.41, S% 19.78

Found: 41.2 3.8 14.4 19.8

The compound obtained here has a geometrically symmetrical arrangement.

NMR spectrum (DMSO 60MHZ) 3.83 (N-OCH ₃ ): 6.73 (protons of thiazole rings).

Example 7

Tert-butyl 7-[{2- (2-tritylamino 4-thiazolyl) 2-methoxy-imino acetyl} -amino] -3-isopropyl sefa-3-m-4-carboxylate

1.65 g of the sodium salt of [2-tritylamino 4-thiazolyl) 2-methoxy imino] -acetic acid are acidified as in Example 1.

Its residue is dissolved in methylene chloride 25 cm ³ .

0.71 g of dicyclohexyl carbodiimide was added thereto, and 0.965 g of tert-butyl ester 7-amino 3-isoflophyl cepha-3-M 4-carboxylic acid was added thereto while stirring for 10 minutes in an aqueous solution of ice water. do. Agitation vacuum filtration and then be continued for 2 hours at room temperature, dicyclohexyl urea, and wash with water 10cm ³ including after washing with water containing 2N hydrochloric acid 10cm ³ 2cm ^3, again with saturated sodium bicarbonate solution 5cm ^3. It is dried and concentrated to give a dry product.

Its residue is dissolved in ether, vacuum filtered and washed again with dizopropyl ether to give 1.66 g of product.

This compound has a geometrically symmetrical arrangement.

Example 8

7-[{2- (2-amino 4-thiazolyl) 2-methoxy imino acetyl} -amino] -3-isopropyl sefa-3-em 4-carboxylic acid.

1.66 g of the compound obtained in Example 7 is stirred with trifluoro acetic acid 6 cm ³ at room temperature for 15 minutes. To this was added 60 cm ³ of dizopropyl ether, followed by vacuum filtration and washing with dizopropyl ether to obtain 0.825 g of a compound in the form of a salt of trifluoroacetic acid.

This compound was dissolved again in water and 6cm ³ O seteun 4cm ³ to release the acetone was added to pyridine 0.2cm ^3. This gives 0.232 g of the product.

The filtrate was concentrated and ³ cm ³ of water was added to give 0.194 g of product, from which a total of 0.426 g of product was obtained. This compound 7 [{2- (2-amino-4-thiazolyl) -2-methoxy imino acetyl} -amino] -3-isopropyl-cepa-3-m-4-carboxylic acid is also geometrically symmetrical Has a layout.

Analysis: C ₁₆ H ₁₉ O ₅ N ₅ S ₂ (0.25CH ₃ COCH ₃ )

Theoretic: C% 46.23, H% 4.88, N% 15.41, S% 14.10

Found: 46.1 4.7 15.5 14.1

NMR spectrum (DMSO 60MHZ) ppm: 3.83 (N-OCH ₃ ): 6.78 (protons of a azole ring).

Example 9

Tert-butyl-7-[{2- (2-tritylamino 4-thiazolyl) 2-methoxy imino acetyl} amino] -3-methyl sepa-3-m 4-carboxylic acid

In the same manner as in Example 1, 2.3 g of 2-[(2-tritylamino 4-thiazoylyl) 2-methoxy imino] -sodium acetate was reacted to obtain a free acid, which was returned to 30 cm ³ of methylene chloride. After dissolution, 1.1 g of dicyclohexyl carbodiimide was added thereto, and after 5 minutes, 1.35 g of tert-butyl 7-amino desacetocececephalosporane acid was added thereto. The mixture was stirred for 2 hours, vacuum filtered, the filtrate was washed with water acidified with hydrochloric acid, washed again with water and finally with a solution saturated with sodium bicarbonate, then concentrated to dryness, and then triturated by adding ether. Vacuum filtration concentrated to dryness yields 2.8 g of pure product.

This compound has a geometrically symmetrical arrangement.

Example 10

7-[{2- (2-amino 4-thiazolyl) 2-methoxy imino acetyl} amino] -3-methyl sepha-3-em 4-carboxylic acid.

To 2.3 g of the compound obtained in Example 9, 8 cm ³ of trifluoroacetic acid is added. The mixture was added with 80 cm ³ of dizopropyl ether while shaking at room temperature for 15 minutes, stirred, vacuum filtered, and washed with dizopropyl ether to obtain 1.12 g of a product in the form of a salt of trifluoroacetic acid. This was again dissolved in 10 cm ³ of ethanol at 40 ° C. and pyridine 0.2 cm ³ was added to obtain complete crystals.

The mixture is cooled to 10 ° C., then vacuum filtered and washed with ethanol and ether to give 0.531 g of pure product.

Analysis: C ₁₄ H ₁₅ O ₅ N ₅ S ₂ (0.25EtOH)

Theoretic value: C% 42.6 H% 4.06 N% 17.13 S% 15.68

Found: 42.2 3.9 16.6 15.5

The compound obtained here has a geometrically symmetrical arrangement.

NMR spectrum (DMSO 60 MHz) ppm: 3.85 (NOCH ₃ ); 6.68 (protons of thiazole ring).

Example 11

-7 [{2- (2-tritylamino 4-thiazolyl) 2-methoxy imino acetyl} -amino] -3- (1-methyltetrazool 5-yl) -thiomethyl sepa-3-m- 2.7 g of carboxylic acid 3-acetoxymethyl-7-[{2-tritylamino 4-thiazolyl) -2-methoxy iminoacetyl} -amino] -cepha-3-m 4-carboxylic acid and mono sodium phosphate 0.624g, jungtan sodium 1.51g, 1- methyl-5-tetrazol 1.32g bots, captopril, and then left overnight the mixture of 40cm ³ of water and 20ml of acetone in 48 ℃ left to stand for one hour at 60 ℃ again. Purification was carried out purely to give a compound having the geometrically symmetrical arrangement as in Example 3.

Example 12

7 [{2- (2-amino-4 thiazolyl) -2-methoxyimino acetyl} -amino] -3-[(1-methyl-tetrazol-5-yl) -thiomethyl] -cepa-3- M-4 carboxylic acid

Step A: 3-Acetoxyoxytyl-7-[{2- (2-tritylamino-4-thiazolyl) -2-methoxyaminoacetyl} -amino] -cepha-3-m-4-carboxylic acid

A mixture of 3.06 g of sodium 2- (2-tritylamino-4-thiazolyl) -2-methoxyiminoacetate, 65 cm ^{3 of} methylene chloride and 6.5 cm ³ of dihydrochloric acid is washed with water and concentrated to dryness to obtain an acidified product. This acidate is dissolved in dry methylene chloride 30 cm ³ and 0.78 g of dicyclohexylcarbodiimide is added thereto. The mixture is stirred at room temperature for 1 hour and then vacuum filtered. Thereby cephalostatin spokes is added a solution of 1.01g of acid in a mixture of methylene chloride and triethylamine 0.9cm 13cm ^{3 3} in the filtrate of the above-cooling his filtrate to -10 ℃ and 7-amino.

The temperature is reduced to room temperature and 1 cm ³ of acetic acid is added thereto.

The mixture is vacuum filtered, washed with water containing hydrochloric acid, washed again with water and evaporated to dryness to obtain a dry product.

In its glass object into a 10cm ^3-dioxane and water, then adding the 1cm ³ of water saturated with sodium bicarbonate 3cm ³ herein. The mixture is stirred, vacuum filtered, washed and concentrated to give a dry product. It was added and the methylene chloride to its glass objects then washed with a mixed solution of water and 1N hydrochloric acid 10cm ³ 5cm ^3. The mixture is poured and the organic is washed with water and evaporated to yield a dry matter. The residue was triturated with ether to obtain 1.747 g of a crude product dissolved in ethyl acetate, which was then precipitated with ether again to give pure 3-acetoxymethyl-7-[{2- (2-amino 4- with a geometrically symmetrical arrangement. 1.255 g of thiazolyl) -2-methoxyimino acetyl} -amino] -cepa-3-m-4-carboxylic acid are obtained.

Step B: 3-acetoxy methyl 7-[{2- (2-amino 4-thiazolyl) -2-methoxyimino acetyl} -amino] -cepha-3-em 4-carboxylic acid.

A mixture of 0.975 g of the compound obtained in Step A and 50% of the liquid formic acid 4 cm ³ was stirred at 55 ° C. for 10 minutes, and thereto was added 4 cm ³ of water, followed by vacuum filtration, and the filtrate was evaporated under reduced pressure to obtain a dried product; The residue was triturated with ethanol 2 cm ³ , vacuum filtered again and washed with ethanol to obtain pure 3-acetoxymethyl-7 [{2- (2-amino-4-thiazolyl) -2-methoxyiminoacetyl}-. Amino] -sepha-3-em-4-carboxylic acid 0.42 g is obtained.

The compound obtained here has a batch of geometric isomers.

):2 중 스펙트럼선 9.58, J-8HZ(-(ONH); 6.76(티아졸 환의 양자).NMR spectrum (DMSO, 60MHZ) ppm 2.03 (

): Double spectral line 9.58, J-8HZ (-(ONH); 6.76 (protons of thiazole ring).

Step C: 7-[{2- (2-Amino-4-thiazolyl) -2-methoxyiminoacetyl} -amino] -3-[(1-methyltetrazol-5-yl) -thiomethyl]- Sepha-3-m-4-carboxylic acid.

1.7 g of the mixture of step B, 0.624 g of monosodium phosphate, 0.51 g of sodium bicarbonate, 1.32 g of 1-methyl-5-mercapto-thiazole, and a mixture of 40 cm ³ of water and 20 cm ³ of acetone were left at 48 ° C. overnight. After 1 hour at 60 ℃ to obtain a compound having the same geometrically symmetric arrangement as in Example 1.

Example 13

7 [{2- (2-tritylamino 4-thiazolyl) 2-methoxy imino acetyl} -amino] -3-methyl-cepa-3-em 4-carboxylic acid.

To 2.44 g of a non-isomer of 2- (2-tritylamino 4-thiazolyl) 2-methoxyimino-acetic acid, 25 cm ³ of tetrahydrofuran is added while passing through an argon stream. Again a solution of 0.5 cm ³ of N-methyl morpholine is added thereto. After cooling to −15 ° C., 0.71 cm ³ of dizobutylchloroformate is added and it is stirred at 15 ° C. for 5 minutes.

After cooling the above solution to -30 ° C, 1.07 g of 7-amino desacetoxy cephalosporranic acid was dissolved in 8 cm ³ of saturated sodium bicarbonate solution and cooled to 0 ° C.

This was stirred for 1 hour and 30 minutes in argon gas and the temperature was returned to room temperature again. The mixture was concentrated under reduced pressure, and thereto was added methylene chloride, washed with 1N hydrochloric acid, and extracted with water mixed with methylene chloride. The organic layer was dried and concentrated under reduced pressure to obtain 3.45 g of a product.

When using the non-isomer of 2- (2-tritylamino 4-thiazolyl) 2-methoxyimino-acetic acid as a starting material in Example 13, it is carried out as follows.

Step A: Ethyl 2- (2-amino 4-thiazolyl) 2- (methoxyimino) acetate non isomer

2N sodium hydroxide 330cm ^{3 was added} to 116 g of ethyl 4-chloro 2-oxyiminoacetoacetate, 360cm ³ of anhydrous acetone, and 66cm ³ of methyl sulfate, and stirred for 105 minutes, followed by stirring for 105 minutes, followed by Thiourea 45.6 add g. The mixture was again heated to 53 ° C. for 25 minutes, acetone was distilled off, and 180 cm ³ of dizopropyl ether was added thereto, stirred, and 41.32 g of potassium carbonate was added thereto. Filtration of this mixture afforded 21.1 g of a compound of geometric isomers. Pour this filtrate separately and re-extract it with 100 cm ³ of dizopropyl ether, dry the organic layer, filter under vacuum, add 13 cm ³ of 1N hydrochloric acid-ethanol to obtain hydrochloride crystals, vacuum filter it, and wash and dry with dizopropyl ether. 32 g of product, which is a geometric isomer, can be obtained.

55.85 g of the above hydrochloride is dissolved again in 275 cm ³ of methanol containing 20% water and cooled to reflux to form crystals. The mixture was diluted with ether 550 cm ³ , stirred for 30 minutes, washed with a mixture of methanol and ether in a ratio of 2/3: 1/3, and evaporated to give 34.85 g of pure chloride, an asymmetric geometric isomer.

Hydrogen chloride 29.3g, 110cm ³ of water, then the methylene chloride was stirred with 10% sodium bicarbonate, mixtures of 110cm ³ of 110cm ³ and the liquid phase separated off and extracted again with methylene chloride, the organic phase was dried and evaporated to re-extract solution to obtain a dry product thereof, glass objects Ether was added, stirred, vacuum filtered and the mixture was washed again with ether and dried to give 20.4 g of pure compound. The melting point of this compound is 115 ° C.

NMR spectrum (CDCI ₃ , 60MHZ) ppm 4.08 (NOCH ₃ ): 7.5 (protons of thiazole ring).

Step: Non-Isomer of ethyl 2- [2-triylamino-4-thiazolyl] -2- [methoxy imino) -acetate

15.1 g of trityl chloride was added to the mixture of 11.45 g of the compound obtained in step A), dried methylformamide 23 cm ³ , dried methylene chloride 45 cm ³ and triethylamine 7 cm ³ for 20 minutes, and stirred with 50 cm ³ of hydrochloric acid. While adding.

This mixed solution is separated and the liquid phase is extracted again with methylene chloride.

The organic phase extract was washed with water, reextracted, dried and vacuum filtered to evaporate the filtrate. The ratio of the product ethyl-2- (2-tritylamino-4-thiazolyl) -2-methoxy imino-acetate was Obtain 30.1 g of isomers.

Step C: Non-Isomer of 2- [2-tritylamino 4-thiazolyl] -2-methoxyimino acetic acid

25 cm ³ of 2N caustic soda was added to a mixture of 30.1 g of compound B of step B and 5 cm ³ of caustic soda in 150 cm ^{3 of} dioxane, and stirred for 1 hour to generate sodium salt for 15 minutes.

The mixture is vacuum filtered, washed with 1-1 dioxane-ether mixture, triturated with ether and dried to yield 18.4 g of sodium salt. This methylene chloride 250cm ^3, was added to a mixed solution of water 100cm ³ with 2N hydrochloric acid to separate 50cm ³ After stirring for 10 minutes.

The liquid solution re-extracted with methylene chloride is washed twice with water, re-extracted, dried and vacuum filtered. The filtrate is evaporated, added to ether, triturated, vacuum filtered and finally washed again with ether to give 13.85 g of dry product. The melting point of this compound is 220 ° C.

NMR spectrum (CDCI ₃ , 60MHZ) ppm; 4.2 (OCH ₂ ): 7.32 (protons of thiazole).

Example 14

Of diethyl amine salt of 7-[{2- (2-tritylamino 4-thiazolyl) -2-methoxy imino acetyl} -amino] -3-methyl-cepa-3-m-4-carboxylic acid Non-isomer

The acid obtained in Example 13 was dissolved in about 7 cm ^{3 in} dioxane while stirring in the presence of argon gas, and 0.65 cm ³ of diethylamine was added thereto at room temperature. When crystals are formed slowly, the mixed solution is stirred again at room temperature for 20 minutes and vacuum filtered to obtain crystalline salt of diethylamine. The solid was washed twice with 2 cm ³ of dioxane, diluted with dioxane and then added 110 cm ³ of isopropyl ether to form crystals. The mixture was stirred slowly for 1 hour, filtered, washed with isopropyl ether and dried. Di of 7 [{2- (2-tritylamino-4-thiazolyl) -2-methoxyiminoacetyl} amino] -3-methyl-cepa-3-m-4-carboxylic acid, which is a particularly pure salt of 1.94 1.94 g of non-isomers of ethyl amine salt are obtained.

Example 15

7-[{2- (2-amino 4-thiazolyl) -2-methoxyimino acetyl} -amino] -3-methyl sepha-3-em 4-carboxylic acid, non isomer

The diethylamine salt obtained in Example 14 was dissolved in 50 cm ³ of methylene chloride, washed twice with 25 cm ³ of 1N hydrochloric acid, and once with 25 cm ³ of water. The aqueous phase was extracted with methylene chloride and the organic layer was dried and concentrated under reduced pressure to afford 7-[{2- (1-tritylamino 4-thiazolyl) -2-methoxyimino acetyl} -amino] -3-methyl sepa. 1.72 g of non-isomers of 3-M 4-carboxylic acid are obtained.

The above compound was added to 8.5 cm ³ of 50% liquid formic acid in the presence of argon, put in an oil bath, stirred at 60 ° C. for 20 minutes, vacuum filtered, washed with liquid formic acid, washed again with water, and ethanol 10 cm ³ in liquid solution. The solution was dried at a very low pressure and washed three times with a 1: 1 ethanol-water mixture to give 5 cm ³ of ethanol.

Ether was added to the dried product obtained by concentrating the compound, stirred vacuum filtration, washed with ethanol, washed with ether and dried again to obtain compound 7 [{2- (2-amino-4-thiazolyl) -2-methoxy iminoacetyl } -Amino] -3-mg-cepa-3-m-4-carboxylic acid non-isomer 400 mg is obtained.

NMR spectrum (DMSO, 60MHZ) ppm; 3.96 (N-OCH ₃ ): 7.48 (protons of thiazole rings)

Analysis: C ₁₄ H ₁₅ O ₅ H ₅ S ₂ (0.5H ₂ O)

Theoretic: C% 41.1, H% 3.9, N% 17.2, S 15.7

Found: 40.9 3.9 17.5 15.7

Example 16

Non-isomer of 3-acetylthiomethyl 7-[{2- (2-tritylamino 4-thiazolyl) -2-methoxy imino acetyl} -amino] -cepha-3-m 4-carboxylic acid

2.22 g of a non-isomer of 2- (2-tritylamino 4-thiazolyl) -2-methoxy imino acetic acid in the presence of argon, 20 cm ³ of dry tetrahydroplan, 15 cm ³ of methylene chloride, and 0.5-methyl-morpholine 0.55 The cm ³ mixture was cooled to -20 ° C, isobutyl chloroformate 0.65 cm ³ was added, stirred and cooled to -35 ° C, and then 7-amino-3-acetylthiomethyl sepa- ^3- acetylthiomethyl sepa-3- M. 4-Carr acid, methylene chloride, 1.44g 25cm ³ and anhydrous triethylamine 1.4cm ³ - was added to the mixed solution, then the solvent removed by air drying, it 7cm 1N hydrochloric acid and ³ N hydrochloric acid (i.e., 1 N 1N hydrochloric acid) after the addition of 7cm ³ was vacuum filtered to separate his filtrate the organic phase solution to extract the aqueous solution, and the remaining methylene chloride is back washed by water, dried, vacuum filtered and evaporated to his filtrate dried compound 4.58 get g

Example 17

Non-isomer of 3-acetylthiomethyl 7-[{2- (2-amino 4-thiazolyl) 2-methoxy imino acetyl} -amino] -sepha-3-em 4-carboxylic acid

A mixture of 4.85, g of the compound obtained in Example 16 and 30 cm ³ of formic acid at a concentration of 50% was heated to 55 ° C. for 20 minutes to form triphenyl calbinol, and the crystals were separated, cooled, diluted with water and stirred. After vacuum filtration, washing and drying to give 1.257 g of triphenyl carbinol.

The filtrate is evaporated under reduced pressure and the resulting crystals and mixture are stirred for half an hour and vacuum filtered to wash and dry the resulting solids to separate 1.68 g of crude product.

The 1.68 grams of the compound obtained above was dissolved in 4 cm ³ of 1N solution of sodium bicarbonate, vacuum filtered to insoluble materials, washed with water, and then filtered through 0.24 cm ³ of acetic acid to be washed with water, followed by drying, to obtain 426 mg of pure compound. do.

0.15 cm ³ of formic acid was added to the filtrate, which was then filtered to separate the crystalline substance and washed with water to obtain 505 mg of pure compound. Melting point is 190 ℃ in the dough state.

Analysis: C ₁₆ H ₁₇ O ₆ N ₅ S ₃

Theoretic: C% 40.76, N% 14.85, S% 20.40.

Actual value: 41.76. 14.4 19.2

NMR spectrum (DMSO, 60MHZ) ppm: 3.95 (N-OCH ³ ): 7.45 (protons of thiazole rings).

Example 18

Geometric isomer of 3-acetyl thiomethyl 7-[-{2- (2-amino 4-thiazolyl) -2-methoxyiminoacetyl} -amino] cepha-M 4-carboxylic acid

4.55 g of geometric isomers of 3-acetoxy methyl 7-[{2- (2-amino 4-thiazolyl) -2-methoxyiminoacetyl {-amino] cepha-M 4-carboxylic acid and 1.7 g of potassium thioacetate , A mixed solution of 2 g of dehydrated monoatomic sodium phosphate, 1.05 g of sodium bicarbonate, and 20 cm ³ of distilled water was heated at 70 ° C. for 1 hour and 30 minutes, acidified with 2 cm ³ of formic acid, and 60 cm ^{3 of} methyl acetate (insoluble components removed by vacuum drying). Extract 4 times.

The organic solution was washed with water and evaporated to obtain a dried product. The residue was again dissolved in 20 cm ³ of acetone containing 10% water, 0.5 g of activated carbon was added thereto, stirred for 5 minutes, and then the resulting filtrate was vacuum filtered. The filtrate obtained by washing with acetone containing 10% of water is evaporated to obtain a dried product, washed with anhydrous alcohol, vacuum filtered, washed with alcohol and washed with ether again to obtain 1.9 g of pure compound.

NMR spectrum (DMSO, 60MHZ) ppm: 3.85 (N-OCH ₃ ): 6.75 (protons of thiazole ring)

The compound obtained here is the same as the compound of Example 6.

Example 19

7-[{2- (2-amino 4-thiazolyl) 2-methoxyimino acetyl} -amino] -3-[(2-methyl 1,3,4-thiadiazol 5-yl) -thiomethyl] Geometric Isomers of the Sodium Salt of Sepha-3-M4-carboxylic Acid

An aqueous solution of sodium bicarbonate was added to a mixed solution of 5 cm ³ of acetone and 2.3 g of the Syn isomer in Example 2 to maintain a pH of 7, and 0.4 g of the active product was added thereto, followed by stirring for 5 minutes and vacuum filtration. To 1-1 (acetone-water) mixture and add 50 cm ³ of ethanol. The mixture was evaporated under reduced pressure at 30 DEG C to obtain a dried product, which was put in ethanol 5 cm ³ and the crystals were ground and vacuum filtered.

This product is washed with ethanol and again with ether, to give 1.3 g of pure compound.

Sodium analysis: 4.18% theory, 4.70% found

Example 20

7-[{2- (2-amino 4-thiazolyl) 2-methoxy imino acetyl} -amino] -3-[(1-methyl tetrazol-5-yl) -thiomethyl] -cepa-3- M 4-carboxylic acid, sodium salt of Syn isomer

7-[{2- (2-amino 4-thiazolyl) 2-methoxyimino acetyl} -amino] -3-[(1-methyl tetrazol-5-yl) -thiomethyl]-obtained in Example 4 A filtrate 1: 1 (ethanol-water) obtained by stirring a mixed solution of 3.55 g of the geometric isomer of Sepha-3-M 4-carboxylic acid, 7 cm 3 of methanol, and 7 cm 3 of an aqueous 1N sodium bicarbonate solution at room temperature for 5 minutes, followed by vacuum filtration. ) Wash twice with a mixture, add 85 cm 3 of ethanol to make sodium salt, add 170 cm 3 of ether, stir for 10 minutes, and vacuum filter the resulting filtrate to wash with 1-1 (ether-ethanol) mixture, and then add ether Washed and dried to afford 3.26 g of compound.

The crude product obtained here is purified as follows.

The compound obtained above is again dissolved in 40 cm 3 of water, its pH is adjusted to 6.8-7 with 0.6 cm 3 of acetic acid, diluted with ethanol and the solvent is evaporated under 35 ° C. under reduced pressure.

Its residue is again dissolved in ethanol to remove moisture and then dried and dissolved in 16 cm 3 of methanol diluted with 160 cm 3 of acetone to obtain its crystal salt.

The mixture is stirred for 5 minutes, vacuum filtered and the solid product is washed with acetone and with ether to give 2.3 g of compound.

The intrinsic rotation of the above compounds is as follows.

-13.5°±1°(물 속에서 농도는 1%)

-13.5 ° ± 1 ° (1% concentration in water)

Na analysis: Theoretical value: 4.31%, Found: 4.8%

Example 21

Geometric isomer of the sodium salt of 3-acetyl thiomethyl 7-[{2- (2-amino 4-thiazolyl) -2-methoxyimino acetyl} -amino] sepha-3-m 4-carboxylic acid

4.5 g of Syn isomer of the compound obtained in Example 6, a mixed solution of 9 cm 3 of ethanol and 1N aqueous sodium bicarbonate solution were stirred at room temperature for 5 minutes, and the resulting filtrate was washed with a 1: 1 ethanol-water mixture, followed by excitation. 110 cm 3 of ethanol was added to the solution, followed by stirring to precipitate sodium salt crystals. It was again diluted with 220 cm 3 of ethyl ether, stirred and vacuum filtered, washed with a 1: 1 ethanol-ether mixture and washed with ether again, and the obtained compound was dissolved in 40 cm 3 of water and acetic acid was added to adjust the pH to 6.8. Let 7 be at. The mixture is diluted with 100 cm 3 of ethanol, and the solvent is evaporated under reduced pressure at 35 ° C or lower.

The concentrate obtained here is triturated twice with 50 cm 3 of ethanol and evaporated to give a dry product. The residue was again dissolved in 15 cm 3 of methanol, filtered and diluted with 150 cm 3 of acetone to form sodium salt, stirred for 5 minutes, vacuum filtered, washed with acetone and then dried under reduced pressure to give 1.8 g of compound. Get

The intrinsic rotation of this compound is as follows.

=-31°±2°(물속에서 농도는 0.6%)

= -31 ° ± 2 ° (concentration in water is 0.6%)

Na analysis: 4.65% theoretical, 4.9% found

Example 22

Microcrystalline sodium of 3-acetyl thiomethyl-7-[{2- (2-amino-4-thiazolyl) -2-methoxyiminoacetyl} -amino] -cepa-3-m-4-carboxylate Syn isomer of salt

A mixed solution of 471.5 mg of the Syn isomer obtained in Example 6 and 1.5 cm 3 of anhydrous sodium acetate 1N solution dissolved in anhydrous methanol was added while stirring 0.5 cm 3 of ethanol, and 2 cm 3 of ethanol was added to the filtrate obtained by vacuum filtration to form sodium salt. Let's do it.

Again the mixture was vacuum filtered, washed with methanol and dried at 45 ° C. in a drier under reduced pressure to yield 0.25 g of anhydrous compound.

Na analysis: Theoretical value: 4.66%: Measured value: 4.6%

Example 23

Geometric isomers of 3-acetyl thiomethyl 7-[{2-amino-4-thiazolyl) 2-methoxy imino acetyl} -amino] -cepha-3-em-4-carboxylic acid

Step A): Geometric Isomers of Ethyl-2 (2-chloroacetamido 4-thiazolyl) 2-methoxyimino Acetate

A mixed solution of 45.8 g of an isomer of ethyl 2- (2-amino 4-thiazolyl) -2-methoxy imino acetate was dissolved in 200 cm 3 of methylene chloride, dried and distilled to remove 2 cm 3 of solvent, followed by cooling. .

50 cm 3 of pyratin was added thereto, and 41 g of anhydrous monochloroacetic acid was added thereto, followed by slowly heating until dissolved.

After leaving for 6 hours at 20 ° C. in the presence of nitrogen, 5 cm 3 of water was added thereto, stirred, and poured into 300 cm 3 of cooled 2N hydrochloric acid. The mixture was separated, and a liquid solution was extracted with methylene chloride. The organic solution was extracted by washing with water or sodium bicarbonate, washed with water, dried, and the concentrate obtained by treating with activated carbon was added to 300 cm 3 of zoflofil ether. To obtain crystals, and the mixture is concentrated to obtain a dough.

After cooling the mixture, the vacuum filtered product was washed with zoflophyll ether and dried to give 45.4 g of compound. The melting point of the compound was 113 ° C. Melting point = 113 degrees Celsius.

Purification of the compound obtained here can be obtained by recrystallization with a mixture of methylene chloride-isopropyl ether.

NMR (CDCI ₃ , 60 MHz)

(a) Center of the triplet spectrum 1.38p.p.m. J = 7 Hz

(b) Single line spectrum 4.33p.p.m

(c) The center of the four main line spectral line 4.44p.p.m. J = 7 Hz

(d) Single line spectrum 4.33 p.p.m.

(e) Single line spectrum 7.27 p.p.m.

(f) Disconnection Spectrum 9.95p.p.m.

Step B: Geometric Isomers of 2- (2-Chloroacetamide 4-thiazolyl) -2-methoxy imino acetic acid

30 cm 3 of pure caustic soda solution was added to a mixed solution of 46 g of the compound obtained in Step A and 230 cm 3 of anhydrous ethanol in 29 ° C. and in the presence of nitrogen to dissolve, and then sodium salts were precipitated in crystalline form. After 16 hours the mixture is vacuum filtered and washed. The sodium salt obtained here is dissolved in water, cooled, and added to 100 cm 3 of 2N hydrochloric acid, saturated with caustic soda, and extracted with ethyl acetate containing 10% ethanol. The organic phase extract is dried, treated with activated carbon and distilled under reduced pressure. Water is added together with benzene and the residue is added to methylene chloride to dry distill the solution and again to methylene chloride. The solution is cooled, vacuum filtered and washed to dry to give 34 5 g of compound. Melting point = 200 ° C., purification of this compound is obtained by recrystallization with acetone-isopropyl ether.

Analysis: C ₈ H ₈ O ₄ N ₃ CIS = 277.68 (Molecular Weight)

Theoretic: C% 34.60 H% 2.90 N% 15.13 CI% 12.77 S% 11.55

Found: 34.8 2.8 14.8 12.6 11.5

NMR Spectrum (DMSO, 6MHz)

(a) Single line spectrum 3.92 p.m. (d) Single line spectrum 7.58 p.p.m.

(b) Single line spectrum 4.38 p.p.m. (e) Single line spectrum 12.6p.p.m.

(c) disconnection spectrum about 5p.p.m.

Step C: Geometric of 3-acetyl thiomethyl-7-[{2-chloroacetamino-4-thiazolyl) -2-methoxy imino acetyl} -amino] -cepa-3-m-4-carboxylic acid Isomers

A mixture of 15.3 g of isomer of 2- (2-chloroacet amido-thiazolyl) -2-methoxy iminoacetic acid and 80 cm 3 of methylene chloride at 0 ° C in the presence of 3.8 cm 3 of thionyl chloride and 26 cm 3 of methylene chloride After adding to the mixture, the mixture was left at 0 ° C. for 15 minutes and tritylamine 7 cm 3 was added thereto.

A mixture of 14.4 g of 7-amino-3-acetylthio methyl-cepha-3-m-4-carboxylic acid and 100 cm 3 of methylene chloride and 14 cm 3 of tritylamine was added to the above mixture in the presence of 0 ° C. nitrogen, and then 20 After raising the temperature to ℃ ℃ stirred for 1 hour and obtained by evaporation under reduced pressure, 30-35 ℃.

The dry matter is placed in 25 cm 3 of water, and then the solution is passed through activated carbon. 50 cm 3 of 2N hydrochloric acid was added thereto, vacuum filtered, and the crude product obtained by washing with water was mixed with 80 cm 3 of ethanol, and 7 cm 3 of tritylamine and 15 cm 3 of 4N sulfuric acid were added with stirring at 5 ° C. It was left for 15 minutes, then vacuum filtered, washed with ethanol, washed again with ether and dried under reduced pressure to obtain the required compound.

Step D: 3-Acetylthiomethyl-7-[{2- (2-amino-4-thiazolyl) -2-methoxyiminoacetyl} -amino] -cepa-3-m-4-carboxylic acid

1 g of potassium bicarbonate at 20 ° C. is added to 5.48 g of the compound of Step C and a mixture of 10.6 cm 3 of water and 912 mg of thiourea, dissolved, and stirred for 6 hours in the presence of 20 ° C. nitrogen. After about an hour and a half, mucus precipitates, adding 30 cm3 of water and 3 cm3 of formic acid. It was cooled to 5 ° C., vacuum filtered, washed with water containing 10% formic acid, dissolved in 30 cm 3 of aqueous triethylamine solution at 5 ° C. and 3 cm 3 of formic acid were added. The mixed solution was vacuum filtered and the brown mucus obtained by washing with an aqueous formic acid solution was removed, and the liquid layer was separated and passed through activated charcoal to obtain a clear yellow solution. The solution was saturated with ammonium sulfide, vacuum filtered and the precipitate was washed with water and again vacuum filtered to give a precipitate. The precipitate obtained by saturating the mother liquor with ammonium sulfide and the mixed liquor under vacuum filtration three times is referred to as B. Combine the points A and B into ethanol, stir well at 20 ℃ for 1 hour and then leave for 16 hours at 0 ℃. The solid obtained by vacuum filtration of this mixture was washed with ether and dried under reduced pressure to obtain the same compound as in Example 6,18.

Example 24

7-[{2 (2-amino-4-thiazolyl) -2-methoxyiminoacetel} -amino-3 [1-methyl-tyrazol-5-yl) -thiomethyl] -cepha-3-em -4-carboxylic acid, or 3-acetyl thiomethyl-7 [{2- (2-amino-4-thiazolyl) -2-methoxyimino acetyl} -amino] -cepa-3-m-4-cara Acid or any of 3-acetylthiomethyl-7 [{2- (2-amino-4-thiazolyl) -2-methoxyiminoacetyl} -amino] cepha-3-m-4-carboxylate About 5 cm <3> of injection is obtained with 500 mg and sufficient sterile liquid excipient.

Example 25

7-[{2 (2-amino-4-thiazolyl) -2-methoxyimino acetyl} -amino-3 [(1-methyl-tetrazol-5-yl) -thiomethyl] -cepha-3-em -4-carboxylic acid, or 3-acetyl thiomethyl-7-[{2-2 (-amino-4-thiazolyl) -2-methoxyiminoacetyl} -amino] -cepha-3-m-4- Take 250 mg of one of the carboxylic acids and combine with sufficient excipient to obtain 400 mg of gelatin capsules.

(Pharmacological data)

A. Vitro Acitivity

The method used here is a method of diluting the liquid medium in a tube with an amount of sterile nutrient medium of increasing test compound.

When each tube is incubated with bacteria at 24-48 h at 37 ° C. in an oven, the increased inhibitory action is controlled by determining the minimum inhibitory concentration (MIC in μg / cm 3), the results of which are shown in the following table.

Compound of Example 2

Compound of Example 4

Compound of Example 21

Experimental Infection of Escherichia coli ((T) O ₂₆ B ₆ )

Compounds The compounds of Examples 6 and 10 were examined by experimentally infecting Escherichia coli in 10 rats weighing approximately 2 g.

E. coli (T) O ₂₆ B ₆ from the Pasteur Institute diluted in distilled water at a ratio of 1 / 5.5 was intraperitoneally injected into rats 24 hours old and the test compound was subcutaneously injected or infected for 1 hour or 5 hours. 24 hours are administered to inject dead cells after 8 days. The results are shown in the following table.

Experimental Infection of C. Clevezilla pneumoniae

The effects exhibited by the compounds of Examples 4 and 6 were studied by experimentally infecting mice with Klebsil pneumoniae. Ten rats weighing 21 grams are intraperitoneally injected with 0.5 cm ³ of Klebsilar pneumoniae 52.145 diluted to a 1/100 ratio with distilled water. After infection, the compounds were pia dosed every 30 minutes, 4 hours, 8 hours, 24 hours, and 32 hours to examine the number of rats that died after 10 days. The lesson is presented next.

D. Experimental Infections of Crevsila Pneumoniae

Mice were experimentally infected with clebosila pneumoniae to account for the effect of Example 19 and nearly the compounds. Ten days after 24 hours, 10 rats of 21.5 g were intraperitoneally injected with 0.5 cm ³ of Klebsilar pneumoniae diluted in a 1/1000 ratio with distilled water and subcutaneously administered at 1, 5 or 24 hour intervals. The number of rats killed in the The results are presented below.

Claims (1)

A process for preparing a compound of formula (I), wherein the compound of formula (II) is reacted with a compound of formula (III) or a reactive derivative thereof.

Wherein R is C ₁ -C ₅ alkyl, C ₃ -C ₅ cycloalkyl or -CH ₂ -SR ', wherein R' is acyl, 1-methyltetrazolyl of alkanoic acid having C ₂ -C ₄ or 2-methyl-1, 3, 4-thiadiazolyl group) and R ₁ is hydrogen or a group that can be easily removed by acid hydrolysis or hydrogenolysis and R ₁ 'is an acid hydrolysis or hydrogenolysis. Is a group that can be easily removed by R ₂ is C ₁ to C ₄ alkyl, C ₂ to C ₄ alkynyl or alkenyl and A is hydrogen, an alkali metal cation or an equivalent alkaline earth metal, magnesium or organic amine A base cation or an ester group that can be easily removed by acid hydrolysis or plasticization, wherein when R ₁ is hydrogen, A is not an ester group that can be easily removed by hydrolysis or hydrogenolysis. This means that the wave line OR ₂ can exist in either of two possible isomers, syn or anti, and A 'is a group that can be easily removed by hydrogen or acid hydrolysis or hydrogenolysis.