Synthetic method of antibiotic cefoxitin

A cefoxitin and synthesis method technology, applied in antibacterial drugs, organic chemistry, etc., can solve the problems of cefoxitin acid synthesis technology, such as difficulty, no application value, and difficult industrial production, so as to shorten the production cycle and product yield The effect of high efficiency and elimination of wastewater discharge

Active Publication Date: 2009-10-14
国药集团致君(苏州)制药有限公司
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Problems solved by technology

[0005] The synthetic method of bibliographical report cefoxitin is all to be raw material with 7-ACA or carboxyl-protected 7-ACA at present; Also have bibliographical use cephamycin C as raw material, because raw material is difficult to obtain, and reaction route is long, yield is low, High cost, difficult to industrialized production, so no application value
[0006] The synthesis technology of cefoxitin acid is relatively difficult. Although there has been some progress in domestic research on its synthesis technology, the cost is still high and the quality is not good

Method used

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preparation example Construction

[0014] The synthetic method of antibiotic cefoxitin comprises following processing steps:

[0015] (1) Dissolve 7-ACA in an organic solvent, add alkali, drop thiopheneacetyl chloride for acylation to obtain cephalothinic acid, the temperature of the acylation reaction is -20 to 50°C, and the optimum temperature is -10 ~25°C;

[0016] (2), without purification, the cephalotinic acid obtained in step (1) is directly methoxylated under the action of tert-butyl hypochlorite and sodium methylate to obtain the methoxyl group introduced at the 7-position Intermediate A, under the action of cyclohexylamine, intermediate A can obtain 7-α-methoxycefalotin cyclohexylamine salt; the reaction temperature of intermediate A and cyclohexylamine is 20-50°C, and the optimum temperature is 35°C ~45°C;

[0017] (3), the 7-alpha-methoxycefalotin cyclohexylamine salt obtained in step (2) is reacted with benzathine diacetate under solid alkaloid catalysis to obtain 7-alpha-methoxy -3-Desacetoxy c...

Embodiment 1

[0027] The synthesis of embodiment 1 cephalothin acid

[0028] In the flask, add 40g of 7-aminocephalosporanic acid (7-ACA), 17.2g of triethylamine, and 240mL of dichloromethane, control the temperature at 0-10°C, add 27.2g of thiopheneacetyl chloride dropwise under stirring, and dropwise add complete.

[0029] Then keep the temperature and react for 5 hours. After the reaction is finished, filter to remove the solid, and the filter cake is washed with 100 mL of dichloromethane. Combine the filtrate and lotion, and evaporate to dryness to obtain 56 g of cephalothinic acid, with a yield of 1.4%. In actual production, the combined filtrate and washings can be directly used in the next reaction.

[0030] Synthesis of 7-α-Methoxycefalotin Cyclohexylamine Salt

[0031] In the flask, add 60 g of cephalothinic acid, 200 mL of tetrahydrofuran, and 500 mL of dichloromethane, and stir for 10 min to completely dissolve the cephalothinic acid. Cool to -85°C with liquid nitrogen, and a...

Embodiment 2

[0038] The synthesis of embodiment 2 cephalothinic acid

[0039] In the flask, add 40g of 7-aminocephalosporanic acid (7-ACA), 30.2g of N,N-dimethylaminopyridine, 250mL of ethyl acetate, control the temperature at 0-10°C, and add 27.2g of thiopheneacetyl chloride dropwise under stirring (0.17mol), the dropwise addition was completed in three hours.

[0040] Then keep the temperature and react for 5 hours. After the reaction is finished, filter to remove the solid, and the filter cake is washed with 100 mL of ethyl acetate. Combine the filtrate and lotion, and evaporate to dryness to obtain 52 g of cephalothinic acid, with a yield of 1.3%. In actual production, the combined filtrate and washings can be directly used in the next reaction.

[0041] Synthesis of 7-α-Methoxycefalotin Cyclohexylamine Salt

[0042] In the flask, add 60 g of cephalotinic acid, 200 mL of DMF, and 500 mL of dichloromethane, and stir for 10 min to completely dissolve the cephalothinic acid. Cool to -...

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Abstract

The invention relates to a synthetic method of antibiotic cefoxitin. 7-ACA is taken as a starting material and firstly reacts with thiopheneacetyl chloride, cephalothin acid is obtained by separation; the cephalothin acid is not purified, and the methoxylation is directly carried out on the cephalothin acid to obtain an intermediate A which introduces methoxy on the position of 7, the intermediate A obtains 7-alpha-methoxy cephalothin cyclohexylamine salt under the action of cyclohexylamine; the 7-alpha-methoxy cephalothin cyclohexylamine salt reacts with benzathine diacetate under the catalysation of solid alkaloid to obtain 7-alpha-methoxy-3-deacetoxy cephalothin benzathine salt; and the carbamylation is carried out under the action of chlorosulfonyl isocyanate to obtain the cefoxitin. The synthetic method has the advantages that compared with the prior art, the synthetic method simplifies the operation process, has high product yield, reduces the production cycle, eliminates the discharge of waste water containing organic solvent and reduces the production cost. The product quality is stable, and the synthetic method is applicable to the large-scale industrial production.

Description

technical field [0001] The invention relates to a method for synthesizing cephalosporin antibiotic cefoxitin, belonging to the technical field of antibiotic drug preparation. Background technique [0002] Cefoxitin (Cefoxitin), the second-generation cephalosporin antibiotic developed by Merck Company of the United States, has a balanced antibacterial spectrum and is similar to the second-generation cephalosporin, but because its structure contains a 7α-methoxy group, it greatly reduces It is stable to β-lactamase, and its drug resistance problem is much smaller than that of other second-generation cephalosporin products. At present, cefoxitin, which is different from the first and third generation cephalosporins, has once again attracted people's attention due to the increasing drug resistance of bacteria. [0003] Cefoxitin chemical name: (6R, 7S)-3-carbamoyloxymethyl-7-oxy-8-oxo-7-[2-(2-thiazolyl)acetamido]-5 -Thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid. Its che...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D501/57C07D501/04A61P31/04
Inventor 史利军黄凯赵是熙
Owner 国药集团致君(苏州)制药有限公司
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