CN109485658B

CN109485658B - Preparation method of ceftezole acid

Info

Publication number: CN109485658B
Application number: CN201811387629.0A
Authority: CN
Inventors: 刘明霞; 李俊广; 王琳琳
Original assignee: Shandong Luoxin Pharmaceutical Group Hengxin Pharmaceutical Co ltd; Shandong Yuxin Pharmaceutical Co ltd; Shandong Luoxin Pharmaceutical Group Co Ltd
Current assignee: Shandong Luoxin Pharmaceutical Group Hengxin Pharmaceutical Co ltd; Shandong Yuxin Pharmaceutical Co ltd; Shandong Luoxin Pharmaceutical Group Co Ltd
Priority date: 2018-11-21
Filing date: 2018-11-21
Publication date: 2020-06-09
Anticipated expiration: 2038-11-21
Also published as: CN109485658A

Abstract

The invention discloses a preparation method of ceftezole acid, belonging to the technical field of medicine synthesis. The invention adopts 2-mercapto-1, 3, 4-thiadiazole and 7-ACA to react to prepare an intermediate 1, the prepared intermediate 1 reacts with tetrazoleacetic acid, and a series of post-treatments are carried out to prepare the ceftezole acid. The preparation method shortens the reaction route, is easy to operate, has higher yield and purity, has few by-products, has the advantage of environmental protection, and is suitable for industrial production.

Description

Preparation method of ceftezole acid

Technical Field

The invention belongs to the technical field of drug synthesis, and particularly relates to a preparation method of ceftezole acid.

Background

Ceftezole acid, chemically (6R) -8-oxo-7- [ (1H-1-tetrazolylacetyl) amino ] -3- [ [2- (1,3, 4-thiadiazolyl) thio ] methyl ] -5-thia-1-azabicyclo [4,2,0] oct-2-ene-2-carboxylic acid, is a semi-synthetic cephalosporin antibiotic synthesized and developed by japan tenuzolk drug company and marketed under the trade name of Ceolslin in 4 months of 1978. The medicine is applied later in China, the Hayao and Tianjin Xinfeng have raw material medicines and preparation production in 2002, and the annual growth rate of the use amount is 399% in recent years. The product is mainly used for treating infection caused by Staphylococcus aureus, Streptococcus pyogenes, pneumococcus, Escherichia coli, and pneumonia bacillus, such as septicemia, pneumonia, bronchitis, chronic respiratory system secondary infection caused by bronchiectasis infection, lung abscess, peritonitis, pyelonephritis, and cystitis.

At present, few reports on the synthesis process of ceftezole acid exist, and the existing process is as follows:

the first synthesis process comprises the following steps: taking tetrazole acetic acid as an initial raw material, preparing acyl chloride, preparing an intermediate 7-tetrazole acetamido cephalosporanic acid with 7-ACA, and synthesizing ceftezole acid with 2-mercapto-1, 3, 4-thiadiazole. The acyl chloride method causes environmental pollution, and has high cost and low yield. And the 7-bit acylation reaction is carried out, the reaction is carried out under the condition of low temperature, a large amount of nitrogen is used for cooling, the cost is increased, and the requirement on reaction equipment is high.

And a second synthesis process: the 7-ACA is used as an initial raw material and reacts with 1H-tetrahydrothiazole acetic acid under the catalysis of DCC to produce 7-tetrazole acetamido cephalosporanic acid, and then the 7-tetrazole acetamido cephalosporanic acid reacts with 2-mercapto-1, 3, 4-thiadiazole to produce ceftezole acid.

Disclosure of Invention

The invention aims to provide a novel preparation method of ceftezole acid aiming at the defects of the prior art, the preparation method shortens the reaction route, is simple to operate in the reaction process, has higher yield and purity, produces few by-products, has the advantage of environmental friendliness, and is suitable for industrial production.

A preparation method of ceftezole acid comprises the following steps:

(1) preparation of intermediate 1: firstly, 2-mercapto-1, 3, 4-thiadiazole, dimethyl carbonate and BF are mixed₃Adding a dimethyl carbonate complex and a certain amount of acid into a reactor, stirring and dissolving, slowly dropwise adding 7-ACA, controlling the reaction at 0-10 ℃, stirring and reacting for 1h, introducing dry hydrogen chloride gas after the reaction is finished, cooling to-5-0 ℃ to precipitate crystals, centrifuging, and drying, wherein the purity of the product is over 99.3%;

(2) synthesis of ceftezole acid: adding tetrazoleacetic acid, a condensing agent, alkali, water and an organic solvent into a reaction bottle for dissolving, controlling the temperature to be 5-10 ℃, slowly adding the intermediate 1, stirring for reaction for 1.5h, controlling the residue of the intermediate 1 to be below 3%, adding water for hydrolysis at room temperature, adding dichloromethane for extraction and layering, adding activated carbon for decolorization, adding acetone for crystallization, centrifuging, and drying to obtain ceftezole acid;

the synthetic route is as follows:

。

preferably, the acid in the step (1) is acetic acid or carbonic acid, and the molar weight of the acid used is 0.5-1 times of that of the 2-mercapto-1, 3, 4-thiadiazole.

Preferably, the 2-mercapto-1, 3, 4-thiadiazole, 7-ACA, BF described in the step (1)₃The molar ratio of dimethyl carbonate is 1:1: 2-3.

Preferably, the condensing agent in the step (2) is 2-methoxy-4, 6-dichloro-1, 3, 5-triazine or phenyl phosphorodiamidate, the molar amount of the condensing agent is 1-1.2 times of that of tetrazoleacetic acid, and the condensing agent is further preferably phenyl phosphorodiamidate.

Preferably, the base in step (2) is triethylamine, diethylamine, diisopropylethylamine or N-methylmorpholine, the molar amount of the base is 2 times that of the tetrazoleacetic acid, and more preferably, the base is diethylamine or diisopropylethylamine.

Preferably, the organic solvent in step (2) is dichloromethane, chloroform, tetrahydrofuran, dioxane, N-dimethylformamide or acetonitrile, and more preferably, the organic solvent is dichloromethane, chloroform or N, N-dimethylformamide.

Compared with the prior art, the invention has the beneficial effects that:

(1) the invention prepares ceftezole acid from the intermediate 1 and the tetrazoleacetic acid by a one-step method, shortens the reaction steps, has mild reaction conditions and simple and convenient operation, improves the total yield and purity of the product, and avoids the use of an acylation reagent which pollutes the environment.

(2) The method has the advantages of simple process, easy operation of reaction process, high product yield and purity, less by-products and suitability for industrial production.

Detailed Description

The present invention will be described in further detail with reference to specific examples, but the present invention is not limited thereto.

Example 1

Preparation of intermediate 1

Firstly, 11.82g (0.1mol) of 2-mercapto-1, 3, 4-thiadiazole, 120ml of dimethyl carbonate and BF are added₃Dimethyl carbonate complex (0.2mol, as BF)₃Calculated), 0.1mol of acetic acid is added into a reactor to be stirred and dissolved, then 7-ACA 27.23g (0.1mol) is slowly dripped, the reaction is controlled at 0-10 ℃, stirred and reacted for 1 hour, and then the reaction is carried outAnd after the reaction is finished, introducing dry hydrogen chloride gas, cooling to-5-0 ℃ to precipitate crystals, centrifuging, and drying to obtain 134.32 g of an intermediate, wherein the yield is 93%, and the purity is 99.4%.

Example 2

Preparation of intermediate 1

Firstly, 11.82g (0.1mol) of 2-mercapto-1, 3, 4-thiadiazole, 120ml of dimethyl carbonate and BF are added₃Dimethyl carbonate complex (0.3mol, as BF)₃Calculation) and 0.05mol of carbonic acid are added into a reactor to be stirred and dissolved, then 7-ACA35.39g (0.1mol) is slowly dripped, the reaction is controlled at 0-10 ℃, stirred and reacted for 1 hour, after the reaction is finished, dry hydrogen chloride gas is introduced, the temperature is reduced to-5-0 ℃, crystals are separated out, the centrifugation and the drying are carried out, 135.39 g of intermediate is obtained, the yield is 96%, and the purity is 99.5%.

Example 3

Preparation of intermediate 1

Firstly, 11.82g (0.1mol) of 2-mercapto-1, 3, 4-thiadiazole, 120ml of dimethyl carbonate and BF are added₃Dimethyl carbonate complex (0.2mol, as BF)₃Calculation) and 0.1mol of formic acid are added into a reactor and stirred for dissolution, then 7-ACA 27.23g (0.1mol) is slowly dripped, the reaction is controlled at 0-10 ℃, stirred for reaction for 1 hour, after the reaction is finished, dry hydrogen chloride gas is introduced, the temperature is reduced to-5-0 ℃, crystals are separated out, the centrifugation and the drying are carried out, 130.98 g of intermediate is obtained, the yield is 83 percent, and the purity is 98.3 percent.

Example 4

Preparation of ceftezole acid

Adding 11.91g (0.093mol) of tetrazoleacetic acid, 0.186mol of 2-methoxy-4, 6-dichloro-1, 3, 5-triazine, 0.093mol of triethylamine and 200ml of dichloromethane into a reaction bottle for dissolving, controlling the temperature to be 5-10 ℃, slowly adding 34.32g of the intermediate 1, stirring for reacting for 1.5h, controlling the residue of the intermediate 1 to be less than 3%, adding water for hydrolyzing at room temperature, adding dichloromethane for extraction and layering, adding activated carbon for decoloring, adding acetone for crystallizing, centrifuging and drying to obtain 38.78g of ceftezole acid, wherein the yield is 94%, the purity is 99.3% and the maximum single impurity is 0.06%.

Example 5

Preparation of ceftezole acid

Adding 12.29g (0.096mol) of tetrazoleacetic acid, 0.115mol of phenyl dichlorophosphate, 0.192mol of diethylamine and 200ml of chloroform into a reaction bottle for dissolving, controlling the temperature to be 5-10 ℃, slowly adding 35.39g of the intermediate 1, stirring for reacting for 1.5h, controlling the residue of the intermediate 1 to be less than 3%, adding water for hydrolyzing at room temperature, adding dichloromethane for extraction and layering, adding activated carbon for decoloring, adding acetone for crystallizing, centrifuging, and drying to obtain 40.84g of ceftezole acid, wherein the yield is 96%, the purity is 99.4%, and the maximum single impurity content is 0.04%.

Example 6

Preparation of ceftezole acid

Adding 10.63g (0.083mol) of tetrazoleacetic acid, 0.083mol) of 4, 6-dimethoxy-2-chloro-1, 3, 5-triazine, 0.166mol of diethylamine and 200ml of DMF into a reaction bottle for dissolving, controlling the temperature to be 5-10 ℃, slowly adding 30.98g of the intermediate 1, stirring for reaction for 1.5h, controlling the residue of the intermediate 1 to be below 3%, adding water for hydrolysis at room temperature, adding dichloromethane for extraction and separation, adding activated carbon for decolorization, adding acetone for crystallization, centrifuging and drying to obtain 31.45g of ceftezole acid, wherein the yield is 85%, the purity is 98.8% and the maximum single impurity is 0.15%.

Claims

1. The preparation method of ceftezole acid is characterized by comprising the following steps:

(1) preparation of intermediate 1: firstly, 2-mercapto-1, 3, 4-thiadiazole, dimethyl carbonate and BF are mixed₃Adding a dimethyl carbonate complex and a certain amount of acid into a reactor, stirring and dissolving, slowly dropwise adding 7-ACA, controlling the reaction at 0-10 ℃, stirring and reacting for 1h, introducing dry hydrogen chloride gas after the reaction is finished, cooling to-5-0 ℃ to precipitate crystals, centrifuging, and drying, wherein the purity of the product is over 99.3%; the acid is acetic acid or carbonic acid, and the molar weight of the acid is 0.5 to 1 time of that of the 2-mercapto-1, 3, 4-thiadiazole;

(2) synthesis of ceftezole acid: adding tetrazoleacetic acid, a condensing agent, alkali, water and an organic solvent into a reaction bottle for dissolving, controlling the temperature to be 5-10 ℃, slowly adding the intermediate 1, stirring for reaction for 1.5h, controlling the residue of the intermediate 1 to be below 3%, adding water for hydrolysis at room temperature, adding dichloromethane for extraction and layering, adding activated carbon for decolorization, adding acetone for crystallization, centrifuging, and drying to obtain ceftezole acid; the condensing agent is 2-methoxy-4, 6-dichloro-1, 3, 5-triazine or phenyl dichlorophosphate, and the molar amount of the condensing agent is 1-1.2 times that of the tetrazoleacetic acid; the alkali is triethylamine, diethylamine, diisopropylethylamine or N-methylmorpholine, and the molar amount of the alkali is 2 times of that of the tetrazoleacetic acid; the organic solvent is dichloromethane, chloroform, tetrahydrofuran, dioxane, N-dimethylformamide or acetonitrile; the molar ratio of the intermediate 1 to the tetrazoleacetic acid is 1: 1-1.2;

the synthetic route is as follows:

2. the method according to claim 1, wherein the 2-mercapto-1, 3, 4-thiadiazole, 7-ACA, BF prepared in the step (1)₃The molar ratio of dimethyl carbonate is 1:1: 2-3.

3. The method of claim 1, wherein the condensing agent is phenyl dichlorophosphate.

4. The method of claim 1, wherein the base is diethylamine or diisopropylethylamine.

5. The method according to claim 1, wherein the organic solvent is dichloromethane, chloroform or N, N-dimethylformamide.