KR800000086B1 - Process for preparing 7-(l-substituted-acetamido)-3-cephem-4-carboxylic acid derivatives - Google Patents

Abstract

Title compds. (I; R1 = H, hydroxyalkylthio, heterocyclic thio, R2 = lower alkyl, lower alkylthioalkyl, acylalkyl, acylaminoalkyl, lower alkenyl, aralkenyl, lower alkinyl, R3 = H, lower alkyl, aryl, X = S, sulfinyl, sulfonyl) were prepd. by reacting 7-amino-3-substituted-3-cephem-4-carboxylic acid(II) and α-substituted-acetic acid(III). Thus, acylation of 6.6g 7-amino-3-(1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid with 2.76g methyl-thioacetic acid gave 2.5g I.

Description

Method for preparing 7- (α-substituted-acetamido) -3-cepm-4-carboxylic acid derivatives

The present invention relates to novel 7- (α-substituted-acetamido-3-sappem-4-carboxylic acids and derivatives thereof in their carboxyl groups and those having pharmacologically acceptable and antimicrobial (antibacterial) activity. It relates to a method for preparing salts.

7- (α-substituted-acetamido) -3-cepem-4-carboxylic acid derivatives of the novel substance of the present invention may be represented by the following general formula (I).

(Ⅰ)

(Ⅰ)

In the general formula (I)

R ₁ is hydrogen, hydroxy (lower) alkylthio or heterocyclicthio, which heterocyclicthio may be substituted by loweralkyl or alkanoyloxy (lower) alkyl,

R ₂ is lower alkyl, lower alkylthio (lower) alkyl, asyl (lower) alkyl, asyl amino (lower) alkyl, lower alkenyl, ar (lower) alkenyl, or lower alkynyl,

R ₃ is hydrogen, lower alkyl or aryl,

X is sulfur, sulfinyl or sulfonyl,

R ₂ is not lower alkyl when R ₁ is hydrogen.

As used herein, the term "lower" used in connection with moieties derived from alkanes, alkenes or alkyls such as alkyl, alkenyl or alkynyl, etc., unless otherwise specified, has a carbon number of 1 in a group. It is understood that it is in the range from 6 to 6. Each group (group) mentioned above is as follows.

Suitable examples of hydroxy (lower) alkylthio include, for example, 2-hydroxyethylthio, 2-hydroxypropylthio 3-hydroxypropylthio, 2-hydroxybutylthio, hydroxy butylthio, 2-hydroxypentyl Means a group having 1 to 6 carbon atoms in one group, such as thio, 3-hydroxypentylthio, 2-hydroxyhexylthio, 3-hydroxyhexylthio, 5-hydroxy hexylthio, or the like, Preference is given to having 1 to 4 carbon atoms and more preferred to those having 2 to 3 carbon atoms.

By heterocyclic thio is meant an unsaturated monocyclic heterocyclic thio group containing at least one heteroatom selected from oxygen, sulfur, nitrogen or the like. Suitable examples of heterocyclic thio include unsaturated 5-membered ring heteromonocyclics in which a sulfur atom and a nitrogen atom 1-3 are bonded. Specific examples thereof include thiazolyl and thiadiazolyl (eg, 1,2). , 4-thiadiazolyl, 1,3,4-thiadiazolyl or 1,2,5-thiadiazolyl) and the like, as the unsaturated 5-membered heteromonocyclic linking an oxygen atom and a nitrogen atom 1-3, specific examples For example, oxazolyl, oxdiazolyl (for example, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl), and the like, and nitrogen atoms Unsaturated 5-membered cyclic heterocyclic cyclic 2-4 may be mentioned. Specific examples thereof include triazolyl (eg 4H-1,2,4-triazolyl or 2H-1,2,3-triazolyl). ), Tetrazolyl (e.g., 1H- tetrazolyl or 2H- tetrazolyl), and the like, and these heterocyclic groups Lower alkyl having 1 to 4 carbon atoms which may be optionally substituted (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, cyclopentyl, pentyl, cyclohexyl or hexyl) is preferred. Or alkanoyloxy (lower) alkyl (e.g. formyloxymethyl, acetoxymethyl, acetoxyethyl, acetoxypropyl, propionyloxymethyl, butyryloxymethyl, isobutyryloxymethyl, isobutyryloxyethyl Isobutylyloxypropyl, hexanoyloxymethyl, pivaloyl oxymethyl, lauroyloxymethyl, lauroyloxyethyl, lauroyloxypropyl, palmitoyloxymethyl, palmitoyloxyethyl or stearoyloxy Methyl) and the like and are preferably substituted with lower alkanoyloxy (lower) alkyl and higher alkanoyloxy (lower) alkyl having 2-24 carbon atoms, and more preferably an alkanoyloxy group having 5-17 carbon atoms. this The group to substitution by selecting any one from among optionally.

Suitable examples of lower alkyl include those having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl or the like, preferably 1- It has four.

Suitable examples of lower alkylthio (lower) alkyls are those in which one group has 2-12 carbon atoms, and the lower alkyl groups described above are for example methylthio, ethylthio, propylthio, isopropylthio, butylthio, t- And those substituted with butylthio, pentylthio, hexylthio or similar groups, preferably those having 2-6 carbon atoms, and more preferably those having 2-3 carbon atoms.

Suitable examples of asyl (lower) alkyls include lower alkanoyl (lower) alkyls having 2 to 12 carbon atoms, in which the lower alkyl described above is lower alkanoyl (e.g. formyl, acetyl, propy). Oyl or butyryl), or an aroyl (lower) alkyl having 7 to 14 carbon atoms in one group, for example benzoyl (lower) alkyl, the lower alkyl being aroyl (e.g. Heterocyclic-carbonyl (lower) alkyl substituted with benzoyl, toluoyl or xylyl) and having 6 to 12 carbon atoms in the group, the lower alkyl being heterocyclic-carbonyl (e.g. nico Thinoyl, furoyl or denoyl), or the like.

Suitable examples of the acylamino (lower) alkyl are lower alkanoylamino lower alkyls having 2 to 12 carbon atoms, wherein the lower alkyls described above are alkanoylamino (e.g. formamido, acetamido, propionamido or butylamido). And lower alkyls such as benzamido or toluamido, such as aroylamino (lower) alkyl, for example benzamido (lower) alkyl, substituted with And heterocyclic-carbonylamino (lower) alkyl having 6 to 12 carbon atoms, and the lower alkyl of the above is heterocyclocyclic-carbonylamino (e.g. nicotinamido, puramido or thiophene). Carboxamido) or the like.

Suitable examples of lower alkenyl include vinyl, 1-propenyl, allyl, isopropenyl, 2-butenyl, 3-pentenyl, 1-cyclohexenyl, 1,3-cyclohexadienyl or the like. Likewise, one group has 2-6 carbon atoms, preferably 2-4 carbon atoms, and more preferably 2-3 carbon atoms.

Suitable examples of ar (lower) alkenyl include those having 8 to 9 carbon atoms in one group, such as styryl, cinnamil, or the like.

Suitable examples of hypopolar alkynyl include 2-4 carbon atoms in one group, such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, or the like. To have.

Suitable examples of aryls are those having 6-10 carbon atoms in one group, preferably 6-8 carbon atoms, such as phenyl, tolyl, xylyl, mesityl, cumenyl, naphthyl or the like .

Suitable derivatives in the carboxyl group include esters, amides and acid anhydrides, and good esters such as methyl esters, trichloroethyl esters, pivaloyloxymethyl esters, 1-cyclopropylethyl esters, acetoxymethyl Esters, methoxymethyl esters, acetonyl esters or phenacyl esters).

Suitable examples of pharmacologically acceptable salts include inorganic metal salts such as alkali metal salts (e.g. sodium or potassium), alkali metal salts (e.g. calcium or magnesium salts), trimethylamine, triethylamine, dicyclohexylamine Or salts with organic salts such as the like.

The preparation method of compound (I) which is the object of the present invention is prepared by various methods described below and one typical method thereof.

Representative methods for the preparation of compound (I) as a target are represented by the following reaction series.

(Ⅲ)

(Ⅲ)

(Ⅰ)

(Ⅰ)

In the above scheme, R ₁ , R ₂ , R ₃ and X are as described above.

The present reaction is carried out with 7-amino-3-substituted-3-cepem-4-carboxylic acid (II) or derivatives thereof at their carboxyl groups or their salts with carboxyl groups or salts thereof, α-substituted acetic acid (III) or derivatives thereof. The reaction proceeds by reacting with.

Suitable derivatives in the carboxyl group of compound (II) can be seen by referring to any one of various examples of compound (I).

Suitable reactive derivatives in the carboxyl group of compound (III) include, for example, acid halides, acid anhydrides, activated amides, activated esters, and the like. Acid chlorides, acid azides, dialkylphosphonic acids, phenylphosphonic acids , Diphenylphosphoric acid, dibenzylphosphoric acid, halogenated phosphoric acid, dialkylphosphorous acid, sulfurous acid, thiosulfic acid, sulfuric acid, alkylcarbonic acid, aliphatic carboxylic acid (e.g., pibaric acid, pentanoic acid, 2-iso) Acid anhydrides mixed with an acid, such as pentanoic acid, 2-ethylbutyric acid or trichloroacetic acid), aromatic carboxylic acids (e.g., benzoic acid) or symmetric acid anhydrides; and acid amides containing imidazole , 4-substituted imidazole, dimethylpyrazole, triazole, or ester (e.g. cyanomethyl ester, methoxymethyl ester, vinyl ester, propargyl ester, P-nitrophenyl ester, 2,4- Nitro phenyl ester, trichlorophenyl ester, pentachlorophenyl ester, methanesulfonylphenyl ester, phenylazophenyl ester, phenylthioester, P-nitrophenyl thioester, P-cresylthioester, carboxymethyl thioester, pyranyl Esters, pyridyl esters, piperidyl esters, 8-quinolylthioesters or N, N-dimethylhydroxyl amines, 1-hydroxy-2- (1H) -pyridone N-hydroxy succinimides or N- Hydroxyphthalimide) or the like. Suitable reactive derivatives are those which are optionally selected from them depending on the kind of the α-substituted acetic acid used substantially.

In this reaction, in order to manufacture the silyl derivative in the amino group and carboxyl group of compound (II), a silyl compound (for example, chlorotrimethylsilane or bistrimethylsilyl acetate) is reacted with compound (II) beforehand, This is reacted with compound (III) to produce compound (I), which is the target product, and this method is also included in the scope of the present reaction. Derivatives in the carboxyl group of compound (II) can be converted into their free form during the reaction, which is also included in the scope of the present reaction.

The reaction is usually carried out in solvents such as acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, dimethylformamide, pyridine or other organic solvents that do not adversely affect the reaction. Proceed.

The hydrophilic solvent in these solvents can be used as a water mixture.

In proceeding with this reaction, when α-substituted acetic acid (III) is used in the form or salt of the free acid, the reaction is N, N'-dicyclohexylcarbodiimide, N-cyclohexyl-N'-morpholino -Ethylcarbodiimide, N-cyclohexyl-N '-(4-diethyl aminocyclohexyl) carbodiimide, N, N'-diethyl carbodiimide, N, N'-diisopropyl carbodiimide, N-ethyl-N '-(3-dimethyl (aminopropyl) carbodiimide, N, N'-carbonyldi (2-methyl-imidazole), pentamethyleneketene-N-cyclohexylimine, diphenylketene- N-cyclohexylimine, alkoxyacetylene, 1-alkoxy-1-chloroethylene, trialkylphosphite, ethylpolyphosphate, isopropylpolyphosphate, phosphorusoxychloride, phosphorus chloride, thionyl chloride, oxaling chloride , Triphenylphosphine, 2-ethyl-7-hydroxy benz isoxazorium salt, 2-ethyl-5- (m-sulfope Preference is given to proceeding in the presence of a condensing agent such as) -isooxazoriumhydrooxide intramolecular salt, (chloromethylene) dimethylammonium chloride or the like.The salt of compound (II) is an alkali in its carboxy group. Salts in carboxyl groups, such as salts of organic bases such as metal salts (e.g. sodium or potassium salts), alkaline metal salts (e.g. calcium or magnesium salts), trimethylamine, dicyclohexylamine or the like, and acids (E.g., salts in amino groups such as hydrochloric acid, sulfuric acid, acetic acid, tartaric acid, maleic acid, benzenesulfonic acid or toluene sulfonic acid), and salts of compound (III) are alkali metal salts thereof (e.g. Sodium or potassium salts), alkaline metal salts (e.g. calcium or magnesium salts), trimethylamine, dicyclohexylamine or similar organic salts .

The reaction is preferably carried out in the presence of alkali bicarbonates, trialkylamines, N, N-dialkylbenzylamines, pyridine or similar bases.

When the base or the condensing agent is a liquid, it also acts as a solvent. The reaction temperature is not limited and the reaction usually proceeds under cooling or at room temperature. The reaction product is isolated by a conventional known method.

The starting compound (II) and the target compound (I) are both highly unstable compounds and easily decomposed during the reaction, and therefore, it is preferable to perform the production reaction and isolation of the product under mild conditions.

The following examples illustrate the invention.

Example A

2.76 g of methylthioacetic acid and dimethylformamide (a few drops) are added to thionyl chloride and the mixture is stirred at room temperature. Excess thionylchloride is evaporated off under reduced pressure and the residue is dissolved in 30 ml of dried acetone.

Separately, 6.60 g of 7-amino-3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cepem-4-carboxylic acid and 6.0 g of sodium bicarbonate were mixed with 90 ml of water and 70 ml of acetone. Dissolve in a solvent.

To the solution is added dropwise the solution obtained above at -5 ° to 0 ° C and the mixture is stirred at room temperature for 2 hours. 300 ml of water is added to the reaction mixture, and the mixture is washed with 200 ml of ethyl acetate. The liquid layer was separated, adjusted to pH 2 with 1N-HCl, and extracted with 300 ml of ethyl acetate. The liquid layer was extracted twice with 100 ml of ethyl acetate again. The ethyl acetate extracts are combined together, washed three times with water and dried over magnesium sulfate.

The solvent is evaporated from the solution. A small amount of ethyl acetate was added to the residue and the mixture was left to stand to give 7-methyl thioacetamido-3- (1,3,4-thiadiazol-2-yl-) thio methyl-3-cepem-4- 2.5 g of brown powder of carboxylic acid was obtained.

The powder was dissolved in sodium bicarbonate liquid solution. The solution was treated with activated carbon powder, acidified with 1N-HCl and extracted with ethyl acetate. The extract is dried and the solvent is evaporated from the solution under reduced pressure to give 1.2 g of a yellow powder of a pure compound having a melting point of 128-131 ° C. (decomposition).

Example B

2.6 g of methylthio acetic acid and 3 drops of dimethylformamide were added to 6 ml of thionyl chloride, and the mixture was stirred at 40 ° C for 2 hours. Excess thionylchloride was evaporated off the mixture and 70 ml of acetone were added to the residue. 75 ml of a mixed solution of 6.8 g of 7-amino-3- (1-methyl-1N-tetrazol-5-yl) thiomethyl-3-cepem-4-carboxylic acid with 5.9 g of sodium bicarbonate and 50 ml of aceron Dissolved in. To this solution was added dropwise the acetone solution obtained above under cooling and the mixture was stirred for 2 hours. The reaction mixture is concentrated under reduced pressure. The acetic acid is added to the residue and the mixture is washed with ethyl acetate. The aqueous solution was acidified with 10% HCl and extracted with ethyl acetate. The extract is washed with water, treated with activated carbon powder, dried and concentrated under reduced pressure.

Ethyl acetate was added to the residue, and the precipitated crystals were collected by filtration and washed with ether. 7-methyl thioacetamido-3- (1-methyl-1H-tetrazol-5-yl) having a melting point of 81-84 ° C. 4.8 g of) -thiomethyl-3-cepem-4-carboxylic acid is obtained.

Example C

3.44 g of 7-amino-3- (5-methyl-1,3,4-thiadiazol-2-yl) -thiomethyl-3-cepem-4-carboxylic acid was mixed with 12 g of triethylamine and 15 ml of acetone. It was dissolved in a mixed solution of 15 ml of water and the solution was cooled to 0 deg. 1.59 g of unidirectional methylthioacetic acid is added to 80 ml of tetrahydrofuran and refluxed, then evaporated over lithium aluminum hydride and the mixture is stirred under cooling (-20--18 ° C.) with a coolant consisting of dry ice and acetone. 1.6 g of triethylamine and 2.0 g of isobutyl chloroformate are added to this solution. The solution obtained immediately at 0 ° C. is added to the dimixture while stirring the mixture vigorously. The mixture is stirred for 1 hour and the solvent is evaporated off the mixture at a temperature below 40 ° C. and under reduced pressure. 30 ml of water is added to the residue, the mixture is adjusted to pH 8 and washed with ethyl acetate. 150 ml of ethyl acetate is added to the aqueous layer and the solution is adjusted to 2N-HCl-pH2.

The precipitate is filtered off and the ethyl acetate layer is separated. The remaining correction liquid layer is extracted with 50 ml of ethyl acetate twice, and the extract is added to the ethyl acetate layer obtained above. The ethyl acetate solution was washed twice with water, washed twice with a quartz solution saturated with sodium chloride and dried over magnesium sulfate. The solution was concentrated under reduced pressure to give a tan 7-methylthioacetamido-3- (5-methyl-1,3-thiadiazol-2-yl) thiomethyl-3 having a melting point of 167-168 ° C. (decomposition). 1.9 g of cefem-4-carboxylic acid are obtained.

Example D

7-amino-3- (3-methyl-1,2,4-thiadiazol-5-yl) thiomethyl-3-cepem-4-carboxylic acid 3.45 g, triethylamine 1.20 g, acetone 17.5 ml A mixture of 17.5 ml of water and 2.12 g of methylthioacetic acid, 2.74 g of isobutyl chloro formate, 2.03 g of trimethylamine, and 80 ml of tetrahydrofuran are added at 0 ° C. When the mixture was treated in the same manner as described in Example (C), yellow powder 7-methylthioacetamido-3- (3-methyl-1,2,4- having a melting point of 179-180 占 폚 (decomposition). 3.5 g of thiadiazol-5-yl) thiomethyl-3-cepem-4-carboxylic acid is obtained.

Example E

7.6 g of 7-amino-3- (5-methyl-1,3,4-thiadiazol-2-yl) -thiomethyl-3-cepem-4-carboxylic acid and 3.0 g of mesylacetic acid were used as starting materials. use. The reaction and work-up were carried out in the same manner as described in Example (A), whereby 7-mesyl acetamide-3- (5-methyl-1,3,4-thiadiazole-2 having a melting point of 155 to 161 占 폚. 1.1 g of -yl) thiomethyl-3-cepem-4-carboxylic acid is obtained.

Example F

3.3 g of allylthio acetic acid are added to 6 ml of thionylchloride containing 3 drops of dimethyl formamide. The mixture is left to bubble and warmed to 50 ° C. for 30 minutes. Excess thionyl chloride is evaporated off the reaction mixture and the residue is dissolved in 70 ml of dried acetone.

Aqueous solution of 7.6 g of 7-amino-3- (5-methyl-1,3,4-thiadiazol-2-yl) thiomethyl-3-cepem-4-carboxylic acid with 5.9 g of sodium bicarbonate (75 ml) is added to 50 ml of acetone. To this solution is added dropwise the solution obtained under cooling and the mixture is stirred for 2 hours. The reaction mixture is concentrated, ice water is added to the residue and washed with ethyl acetate. The aqueous solution is acidified with 10% HCl and extracted with ethyl acetate. The extract was washed with water and dried and the solvent was evaporated under reduced pressure. Melting point: 156-158 ° C. (decomposition) Phosphorous 7-allylthioacetamido-3- (5-methyl-1,3,4-thiadiazole-2- 5.6 g of 1) thiomethyl-3-cepem-4-carboxylic acid are obtained.

Example G

7-amino-3- (3-methyl-1,2,4-thiadiazol-5-yl) thiomethyl-3-cepem-4-carboxylic acid 2.58 g, triethylamine 1.0 g, acetone 15 ml, A mixture of 15 ml of water, 1.65 g of allylthioacetic acid, 1.70 g of isobutyl chloroformate, 1.4 g of triethylamine, and 60 ml of tetrahydrofuran were reacted in the same manner as described in Example (C), and then Take care. The precipitated crystals were recrystallized from a mixture of ethyl acetate, ether and acetonitrile to give a colorless 7-allylthioacetamido-3- (3-methyl-1,2,4-thia) having a melting point of 114-115 占 폚. Diazol-5-yl) thiomethyl-3-cepem-4-carboxylic acid 1.6 g is obtained.

Example H

7-amino-3- (3-methyl-1,2,4-thiadiazol-5-yl) thiomethyl-3-cepem-4-carboxylic acid 2.58 g, triethylamine 1.0 g, water 15 ml, a A mixture of 15 ml of cetone and 1.65 g of 2-propynylthio acetic acid, 1.70 g of isobutyl chloroformate, 1.4 g of triethylamine, and 60 ml of tetrahydrofuran were reacted in the same manner as described in Example (C). And post-treatment, 7- (2-propynyl) thioacetamido-3- (3-methyl-1,2,4-thiadiazol-5-yl) thiomethyl-3-cepem-4-car Obtain an acid.

The material thus obtained is recrystallized from a mixture of ethyl acetate and ether to give 1.75 g of a tan crystal of pure target compound having a melting point of 127-129 ° C.

Example I

1.48 g of allylthiol is added to a solution of 1.04 g of sodium methoxide in 30 ml of dry methanol, and 2.15 g of α-bromophenylacetic acid is added to the solution while stirring under nitrogen atmosphere, and the mixture is stirred at room temperature for 3 hours. A large amount of metanium is distilled off under reduced pressure, and the residue is dissolved in water and washed with ethyl acetate. The aqueous layer was acidified with 2N hydrochloric acid and extracted three times with 100 ml of ethyl acetate.

The extract is washed with water and dried over magnesium sulfate. Ethyl acetate was evaporated under reduced pressure to give a viscous oil, and oil was left to obtain 1.8 g of 2-allylthio-2-phenylacetic acid having a melting point of 58-65 占 폚.

7-amino-3- (5-methyl-1,3,4-thiadiazol-2-yl) thiomethyl-3-cepem-4-carboxylic acid 3.44 g, triethylamine 1.1 g, water 10 ml, a A mixture of 10 ml of cetone and 2.0 g of 2-allylthio-2-phenyl acetic acid obtained above, 1.3 g of isobutylchloroformemade, 1.1 g of trimethyl amine, and 50 ml of tetrahydrofuran were prepared as described in Example (C). Reaction and work up in the same manner. 7- (2-allylthio-2-phenylacetamido) -3- (5-methyl-1,3,4-thiadia, melting point: 89-94 ° C. (decomposition). Zol-2-yl) White granular crystals of 2.0 g of thiomethyl-3-cepem-4-carboxylic acid are obtained.

Example J

Using 7-amino-3- (4-methyl-4H-1,2,4-triazol-3-yl) -thiomethyl-3-cepem-4-carboxylic acid and methylthioacetic acid as starting materials, Reaction and post-treatment were carried out in the same manner as described in Example (A), and 7-methylthio acetamido-3- (4-methyl-4H-1,2, having a melting point of 154-159 占 폚 (decomposition) 4-triazol-3-yl) thiomethyl-3-shepam-4-carboxylic acid is obtained.

Example K

3.4 g of 7-amino-3- (5-methyl-thiadiazol-2-yl) -thiomethyl-3-cepam-4-carboxylic acid was added 35 ml of acetone-water (1: 1) and triethylamine 3.0. It is added to a mixture of g and dissolved in a cooled state to 0-5 ° C. A solution of 2.0 g of isopropylthio acetyl chloride dissolved in 10 ml of dry acetone was added dropwise to the above solution for 20 minutes under stirring at the same temperature. During the addition the pH of the solution is adjusted to 7-8 with triethylamine.

The mixture is stirred at the same temperature for 30 minutes and then the reaction mixture is raised to room temperature.

After evaporating a portion of acetone at 40 ° C. under reduced pressure, the mixture is washed with 50 ml of ethyl acetate. 80 ml of ethyl acetate is added to the aqueous liquid layer and the mixture is gradually adjusted to pH 1.8 with 1N hydrochloric acid.

The unreacted 7-amido-3- (5-methyl-1,3,4-thiadiazol-2-yl) thiomethyl-3-cefe-4-carboxylic acid precipitated was removed by filtration and acetic acid. The ethyl layer is separated. The aqueous liquid layer is further extracted with 70 ml of ethyl acetate and the ethyl acetate layers are combined. The extract is washed three times with 30 ml of saturated aqueous sodium chloride solution and dried over magnesium sulfate.

When the solvent is removed under reduced pressure, 7-isopropylthioacetamido-3- (5-methyl-1,3,4-thiadiazol-2-yl) thiomethyl-3-cepem having a melting point of 156-157 占 폚. 2.8 g of colorless crystals of 4-carboxylic acid precipitate.

Example L

Prepare a solution of 3.25 g of t-butylthio acetyl chloride in 10 ml of acetone, and separately prepare 7-amino-3- (5-methyl-1,3 in a mixture of 20 ml of acetone, 30 ml of water and 4.1 g of triethylamine. , 4-thiadiazol-2-yl) 5.16 g of thiomethyl-3-cepem-4-carboxylic acid was prepared, and the latter was cooled to -5 to 0 DEG C and added electronically for 5 minutes with stirring. The mixture is stirred at the same temperature for 30 minutes and further stirred at room temperature for 30 minutes.

The reaction mixture was washed twice with 30 ml of benzene and 150 ml of ethyl acetate was added to the aqueous layer. The mixture was adjusted to pH 2 with 10% hydrochloric acid to precipitate unreacted 7-amino-3- (5-methyl-1,3,4-thiadiazol-2-yl) thiomethyl-3-cepem-4- 0.75 g of carboxylic acids are filtered off.

The ethyl acetate layer was separated and the correction liquid layer was further extracted twice with 50 ml of ethyl acetate. The ethyl acetate layers were combined, washed three times with 30 ml of water, washed three times with saturated aqueous sodium chloride solution and dried over magnesium sulfate.

When the solvent was removed, 7-t-Butylthioacetamido-3- (5-methyl-1,3,4-thiadiazol-2-yl) thiomethyl-3 having a melting point of 154-155 ° C. (decomposition) 4.6 g of cefem-4-carboxylic acid are obtained.

Example M

A solution of 2.1 g of 2-methylthio-2-methylacetyl chloride dissolved in 10 ml of dry acetone was added to a mixture of 35 ml of acetone-water (1: 1) and 4.0 g of trimethylamine in 7-amino-3- (5-methyl). -1,3,4-thiadiazol-2-yl) To a solution of 3.4 g of thiomethyl-3-cepem-4-carboxylic acid was cooled to -5-0 ° C and added for 5 minutes while stirring. The mixture is stirred at the same temperature for 10 minutes and at room temperature for 20 minutes. A portion of acetone is evaporated off at 35 ° C. under reduced pressure and the residue is washed with 50 ml of ethyl acetate.

50 ml of ethyl acetate is added to the aqueous layer and the mixture is adjusted to pH 2.2 with 1N hydrochloric acid. 0.35 g of unreacted 7-amino-3- (5-methyl-1,3,4-thiadiazol-2-yl) thiomethyl-3-cepem-4-carboxylic acid precipitated was filtered off The ethyl layer is separated.

The aqueous liquid layer was further extracted with 50 ml of ethyl acetate, and both ethyl acetate layers were combined.

The solution is washed four times with 20 ml of water and saturated aqueous sodium chloride solution and dried over magnesium sulfate. Removal of the solvent under reduced pressure afforded 7- (2-methylthio-2-methylacetamido) -3- (5-methyl-1,3,4-thiadiazol-2-yl) thiomethyl-3-cepem. 2.7 g of 4-carboxylic acid crystals are obtained.

The crystals were recrystallized from a mixture of ethanol and water (5: 1) to obtain 1.95 g of the target compound having a melting point of 171-172 占 폚.

Example N

The following compounds are obtained by employing the same method as in Examples (A)-(M) by using the corresponding starting materials.

(1) 7-methylthioacetamido-3- (5-isobutylyloxymethyl--1,3,4-thiadiazol-2-yl) thiomethyl-3-cepem-4-carboxylic acid (Oil) and its sodium salt, [melting point: 200.5-202 ° C (decomposition)]

(2) 7-methylthioacetamido-3- (5-palmitoyloxymethyl-1,3,4-thiadiazol-2-yl) thiomethyl-3-cepem-4-carboxylic acid (powder ) And their sodium salts, [melting point: 145-150 ° C. (decomposition)]

Example O

3.96 g of allylthio acetic acid are dissolved in a mixed solvent of 3.4 g of triethylamine and 15 ml of methylene chloride.

4.22 g of benzoyl chloride is added dropwise to this solution at -15--2 < 0 > C and the mixture is stirred at the same temperature for 20 minutes. One-way, 4.28 g of 7-amino-3-methyl-3-cepem-4-carboxylic acid and 2.42 g of triethylamine are dissolved in a mixed solvent of 22.5 ml of acetone and 22.5 ml of water. The solution obtained above is added to this solution at -10 ° C, and the mixture is stirred for 10 minutes at the same degree of silver. The reaction mixture was washed with 200 ml of benzene, the liquid layer was adjusted to pH 5-6 with 1N hydrochloric acid, and the precipitate was filtered off. Adjust the filtrate to pH 4 and wash three times with ether. The liquid layer was adjusted to pH 1 with 1N hydrochloric acid and extracted three times with ethyl acetate. The extracts were washed with water, dried over magnesium sulfate, and ethyl acetate was evaporated from the solution. 1.7 g of colorless powder 7-allylthioacetamido-3-methyl-3-cepem-4-carboxylic acid having a melting point of 118-119 ° C was obtained. Get

Example P

5.04 g of benzoylmethyl thioacetic acid is added to 6 ml of thionyl chloride containing 3 drops of dimethylformamide, and the mixture is allowed to stand at room temperature until bubbling, followed by warming at 50 ° C for 30 minutes. Excess thionyl chloride is evaporated from the reaction mixture and the residue is dissolved in 70 ml of dried acetone.

One-way, 75 ml of dissolved aqueous solution of 4.3 g of 7-amino-3-methyl-3-cepem-4-carboxylic acid and 5.9 g of sodium carbonate are added to 50 ml of acetone. To the mixture is added dropwise the solution obtained above under cooling and the mixture is stirred for 2 hours. The reaction mixture is concentrated, ice water is added to the residue and washed with ethyl acetate. The aqueous solution is acidified with 10% hydrochloric acid and then extracted with ethyl acetate. The extract was washed with water and the solvent was evaporated under reduced pressure to give 0.9 g of 7-benzoyl methylthio acetamido-3-methyl-3-cepem-4-carboxylic acid having a melting point of 120-124 ° C.

Example Q

7.6 g of metcaptoacetic acid and 8.0 g of chloromethyl methylsulfide were added dropwise to an aqueous solution containing 10.2 g of caustic potassium under a nitrogen atmosphere and stirring at 5 ° C. The mixture is stirred at rt for 22 h. The reaction mixture is washed with ether, acidified with concentrated hydrochloric acid and extracted with chloroform. The extract is washed with saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent is evaporated off to obtain 4.4 g of methylthiomethylthioacetic acid as a colorless oil (oil).

[IR spectrum: 2680, 2570, 1710, 1420, 1295, 1200, 1130cm-1 NMR spectrum (CDCl ₃ , δ), 2.17 (3H, s), 3.40 (2H, s), 3.80 (2H, s), 10.37 (1H, s)]

2.14 g of 7-amino-3-methyl-3-cepem-4-carboxylic acid is dissolved in 40 ml of an aqueous solution containing 1.11 g of triethylamine at 0 ° C. Separately 1.67 g of methylthiomethylthioacetic acid obtained above are dissolved in 60 ml of dried (anhydrous) tetrahydrofuran and the solution is cooled to -17 to -15 ° C. 1.11 g of triethylamine and 1.5 g of isobutyl chloroformate are added to the solution. To this mixture is added dropwise a solution obtained at 0-5 ° C. above, and the mixture is stirred at room temperature for 1 hour. Next, tetrahydrofuran is distilled off under reduced pressure, and ethyl acetate is added to the residue. The mixture is acidified with dropwise addition of concentrated hydrochloric acid under stirring. Aliquot the ethyl acetate layer, dry over magnesium sulfate and distill off the solvent. The oily residue was washed with diisopropyl ether, ethyl acetate and ether to give a yellow powder and a melting point of 7-methylthiomethylthioacetamido-3-methyl-3-cepem having a melting point of 140 캜 (decomposition). 0.65 g of 4-carboxylic acid is obtained.

Example R

A mixture of 1.01 g of metcaptoacetic acid, 1.5 g of benzamido methanol and 100 mg of P-toluenesulfonic acid was refluxed at 120 ° C. for 2 hours on an oil bed. The reaction mixture is dissolved in ethyl acetate and dried. Raising the solvent under reduced pressure yields an oily product of 1.6 g of benzamido methylthio acetic acid. [IR Spectrum (Film) 3450, 2650, 1730, 1640, 1580, 1535, 1490, 1375, 2550, 1275, 1245, 1150, 1045, 720, 696cm ^l , NMR spectrum (CDCl ₃ , δ) 3.40 (2H, s ), 4.66 (2H, d, J = 6 Hz) 7.25-7.56 (2H, m), 7.67-7.93 (3H, m), 11.9 (1H, s)]. 4.3 g of 7-amino-3-methyl-3-cepem-4-carboxylic acid is dissolved in a mixture of 2.02 g of triethylamine, 20 ml of acetone and 20 ml of water and the mixture is cooled to 0 ° C. Separately, 6.75 g of benzamido methyl thioacetic acid obtained above was added to 100 ml of refluxed tetrahydrofuran, evaporated over lithium aluminum hydride and the mixture was stirred while cooling (-20-18 ° C.) with dry ice and acetone. . To the mixture are added 3.04 g of triethylamine and 4.1 g of isobutyl chloroformate. The mixture is stirred vigorously and the solution obtained above is added to the mixture immediately at 0 ° C.

The mixture is stirred for 1 hour and then the solvent is distilled off under reduced pressure at a temperature below 40 ° C. 30 ml of water is added to the residue, the mixture is adjusted to pH 8 and washed with ethyl acetate. 150 ml of ethyl acetate is added to the aqueous solution and the aqueous layer is adjusted to pH 2 with 2N hydrochloric acid. The precipitate is filtered off and the ethyl acetate layer is separated. The residual liquid layer was extracted twice with 50 ml of ethyl acetate and the extract was added to the ethyl acetate layer obtained above. The solution was washed twice with water, washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and concentrated under reduced pressure. 7-benzamido methylthio acetamido-3-methyl-3- having a melting point of 95-97 ° C. 4.4 g of cefem-4-carboxylic acid are obtained.

Example S

2.14 g of 7-amino-3-methyl-3-cepem-4-carboxylic acid is dissolved in a mixed solution of 1.2 g of triethylamine, 15 ml of water and 15 ml of acetone, and the solution is cooled to -10 ° C.

One-way, 1.95 g of 2-propynylthioacetic acid is dissolved in 70 ml of dried tetrahydrofuran. To the solution, 1.8 g of triethylamine and 2.05 g of isobutylchloroformate are added at -20 ° C, and the mixture is stirred. The solution obtained above is added immediately to the mixture while stirring at -10 ° C. The mixture is stirred at room temperature for 30 minutes and then concentrated under reduced pressure. 150 ml of ethyl acetate is added to the concentrated residue, acidified with diluted hydrochloric acid, and the ethyl acetate is separated. The extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and the solvent was evaporated. The melting point was 7- (2-propynyl) thioacetamido-3-methyl-3-cepem having a melting point of 133 ° C (decomposition). 1.0 g of 4-carboxylic acids are obtained.

Example T

2.14 g of 7-aminol3-methyl-3-cepem-4-carboxylic acid is dissolved in a mixture of 1.1 g of triethylamine, 10 ml of water and 10 ml of acetone. The solution was added immediately to a solution of 3.1 g of 2-allylthio-2-phenylacetic acid, 2.0 g of isobutylchloroformate, 1.6 g of triethylamine and 60 ml of terahydrofuran at 0 ° C. and the mixture was kept at room temperature for 2 hours. Stir while. The precipitate was filtered off, 20 ml of water was added to the filtrate concentrated under reduced pressure at 40 ° C., and 150 ml of ethyl acetate was added to the aqueous solution. The mixture is adjusted to pH 2 with 2N hydrochloric acid. The liquid layer is separated and extracted twice with 50 ml of ethyl acetate. The ethyl acetate extract was added to the ethyl acetate solution obtained above, washed with water, washed twice with a saturated aqueous solution of sodium chloride, and then dried over magnesium sulfate. Ethyl acetate was distilled off from the solution under reduced pressure, and the residue was treated with a mixture of ethyl acetate and ether, and the melting point was 7- (2-allylthio-2-phenylacetamido) -3-methyl having a melting point of 68-73 占 폚. 1.2 g of 3-cefe-4-carboxylic acid are obtained.

Example U

1.7 g of 7-amino-3-methyl-3-cepem-4-carboxylic acid is dissolved in a mixture of 1.0 g of triethylamine, 15 ml of water and 15 ml of acetone. On one hand, 1.9 g of Cis-styryl thioacetic acid is dissolved in 60 ml of dried tetrahydrofuran. While stirring the solution vigorously, 1.3 g of triethylamine and 1.4 g of isobutyl chloroformate are added at -20 ° C, and the mixture is stirred for 3 minutes. The solution obtained at -10 ° C described above is added immediately to the mixture with vigorous stirring and the mixture is stirred at room temperature for 1 hour. The reaction mixture is concentrated at 40 ° C. under reduced pressure and the residue is washed with ethyl acetate. Ethyl acetate is added to the residue and the mixture is adjusted to pH 2 with 10% hydrochloric acid at 5 ° C. The ethyl acetate layer is separated and the remaining aqueous solution layer is extracted with ethyl acetate. The extract is added to the ethyl acetate layer obtained above, washed with water and dried over magnesium sulfate. The solvent is distilled off from the solution under reduced pressure. When yellow oily residue was treated with diisopropyl ether and ethyl acetate, it was 7- (Cis-styrylthioacetamido) -3-methyl-3-cepem-4- having a melting point of 142-l46 占 폚 (decomposition). 1.0 g of carboxylic acid is obtained.

Example V

The following compounds are obtained using the corresponding starting materials in the same manner as described in Examples (A) to (M) or (O) to (U).

(1) 7-methylthioacetamido-3- (2-hydroxyethyl) -thiomethyl-3-cepem-4-carboxylic acid, melting point: 134-138 ° C (decomposition)

(2) 7-allylthioacetamido-3- (2-hydroxyethyl) -thiomethyl-3-cepem-4-carboxylic acid, hygroscopic component powder [IR spectrum (Nujol) 3350, 1780, 1720, 1665 , 1525cm ^-1 ]

Example W

To a solution of 10 ml of 2-methylthio-2-phenylacetic acid in 100 ml of methylene chloride and 5 ml of acetic acid, 6.5 mg of sodium tungstate and 6 ml of hydrogen peroxide were added at 0 ° C. The resulting mixture is kept stirring at 3 ° C. until the starting material is gone.

Water is added to the reaction mixture and methylene chloride is distilled off. The residue is made strongly acidic, and after adding sodium chloride, it is extracted four times with ethyl acetate. The extract is dried over magnesium sulfate and the solvent is distilled off. Recrystallization of the residue from methylene chloride yields 7 g of 2-methanesulfinyl-2-phenylacetic acid having a melting point of 123-126 ° C. Thus, 198 mg of 2-methane sulfinyl-2-phenylacetic acid and 100 mg of triethylamine are dissolved in 5 ml of methylene chloride. This solution was added dropwise to a solution of 5 ml of methylene chloride and 136 mg of isobutylchloroformate for 10 minutes while being cooled to -65 to -60 ° C. The resulting mixture was stirred for 30 minutes and then 344 mg of 7-amino-3- (5-methyl-1,3,4-thiadiazol-2-yl) thiomethyl-3-cepem-4-carboxylic acid and its A solution obtained by dissolving a 2-molecular equivalent of bistri methyl silyl acetamide in 5 ml of methylene chloride is gradually added dropwise at -65 to -60 占 폚. The resulting mixture is stirred for 2 hours. The reaction mixture is added to 10 ml of aqueous sodium bicarbonate solution, the aqueous layer is separated with a separatory nipple, and extracted in small portions with ethyl acetate to be neutralized with 10% hydrochloric acid. The extract is dried over magnesium sulfate and the solvent is distilled off. Ether is added to the residue to make it powdered. The powder thus obtained was collected by filtration and dried to obtain 7- (2-methanesulfinyl-2-phenylacetamido) -3- (5-methyl-1,3,4 having a melting point of 110-130 ° C. 110 mg of -thiadiazol-2-yl) thiomethyl-3-cepem-4-carboxylic acid is obtained.

스펙트럼(D₂O+NaHCO₃,δ) 2.51(S,3H), 2.72(S,3H), 3.75, 3.42(AB-q,2H, J=17Hz), 4.00(d,1H, J=13Hz), 4.50(d,1H, J =13Hz), 5.10(d,1H, J =4.5Hz), 5.68(d,1H, J =4.5Hz)]IR spectrum (Nujol) 3300, 1785, 1715, 1680 cm ^-1 , NMR

Spectrum (D ₂ O + NaHCO ₃ , δ) 2.51 (S, 3H), 2.72 (S, 3H), 3.75, 3.42 (AB-q, 2H, J = 17 Hz), 4.00 (d, 1H, J = 13 Hz) , 4.50 (d, 1H, J = 13 Hz), 5.10 (d, 1H, J = 4.5 Hz), 5.68 (d, 1H, J = 4.5 Hz)]

Example X

According to the same method as in Examples (A)-(M), (O)-(U) or (W),

7-Methanesulfinylacetamido-3- (5-methyl-1,3,4-thiadiazol-2-yl) thiomethyl-3-cepem-4-carboxyl with melting point 117-119 ° C. (decomposition) Acids were obtained using 7-amino-3- (5-methyl-1,3,4-thiadiazol-2-yl) thiomethyl-3-cepem-4-carboxylic acid and methanesulfinyl acetic acid as starting materials Lose.

Claims (1)

7-amino-3-substituted-3-cepem-4-carboxylic acid or a derivative thereof in a carboxyl group thereof, a salt thereof and a-substituted-acetic acid or a compound represented by general formula (III), or 7- (α-substituted-acet) characterized by producing a compound of the general formula (I) or derivatives or salts thereof in the carboxyl group by reacting with derivatives or active derivatives or salts thereof in the carboxyl group. Amido) -3-cepem-4-carboxylic acid and preparation method of derivatives

(Ⅱ)

(Ⅲ)

(Ⅱ) In the above formula, R ₁ is a hydrogen atom, hydroxy (lower) alkylthio or heterocyclic thio, heterocyclic thio may be optionally substituted with lower alkyl or alkanoyloxy (lower) alkyl, R ₂ is lower alkyl, lower alkylthio (lower) alkyl, asyl (lower) alkyl, asylamino (lower) alkyl, lower alkenyl, ar (lower) alkenyl or lower alkynyl, and the like. R ₃ is a hydrogen atom, lower alkyl or aryl and X is sulfur, sulfinyl or sulfonyl. Provided that when R ₁ is hydrogen R ₂ is not lower alkyl Derivatives of the substances of general formula (III) include their active derivatives.