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Preparation method of cefalexin

A technology of cephalexin and aminobenzene, which is applied in the field of improving the synthesis process of β-lactam antibiotic cephalexin, can solve the problems of difficult product purification, harsh reaction conditions, and high activity of mixed anhydrides, and achieve production cost reduction, mild reaction conditions, The effect of less side effects

Pending Publication Date: 2020-04-24
刘思思
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method requires the protection and deprotection of the 7-ADCA carboxyl group. In the process of deprotection by hydrolysis, it is easy to cause the hydrolysis of cephalexin, thereby reducing the product yield. The reaction conditions are harsh and cumbersome group protection and deprotection steps are required. , the mixed anhydride method has the advantage of fast reaction speed, but because the activity of the mixed anhydride is very high and extremely unstable, the reaction is required to be carried out under low temperature and anhydrous conditions, and the product is also prone to racemization, and the product purity cannot meet the requirements of the preparation
[0009] Patent CN201410046595.4 discloses a method for preparing cephalexin. The method is to feed L-phenylglycine ester derivatives and 7-ADCA according to a molar ratio of 1.15-1.6:1, and then feed 7-ADCA 1-2 times Add the catalyst penicillin acylase to carry out the acylation reaction, and give the gene sequence encoding the penicillin acylase, which overcomes the reverse reaction in the process of enzyme condensation reaction to a certain extent, reduces the use of side chains, avoids In order to avoid excessive consumption of side chains, but there are still many impurities in the product, and it is difficult to purify the target product
[0010] Patent CN104130272 discloses a method for preparing cephalexin. The method is to silylate and protect the carboxyl group of 7-ADCA, and then condense with α-aminophenylacetyl chloride or its hydrochloride under the catalysis of 4-dimethylaminopyridine Reaction, obtain cephalexin by post-hydrolysis treatment, then after organic solvent and alkali adjustment treatment, control the suitable pH value with hydrochloric acid, obtain the extremely high purity cephalexin crystal, this method is easy to operate, and the purity of cephalexin is high, but it Acyl chloride and DMAP are used, the acid chloride is highly polluting and unstable to the environment, and the reaction yield cannot be effectively controlled

Method used

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  • Preparation method of cefalexin

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] a Carboxyl protection of 7-ADCA

[0029] Weigh 70g (0.327mol) of 7-ADCA and 350ml of dichloromethane into a 1L three-necked flask, add 99g (0.98mol) of triethylamine under stirring, and dropwise add 35.5g (0.327mol) of trimethylchlorosilane at 20°C, React at 20°C for 1 hour to obtain the silyl compound of 7-ADCA, and cool down to -5°C.

[0030] b Preparation of cephalexin

[0031] Add 61.3g (0.327mol) of α-aminophenylacetic acid hydrochloride and 600ml of dichloromethane into a 2L three-necked flask, then add 66g (0.653mol) of triethylamine and 78.2g (0.653mol) of trifluoroacetic acid succinimide ), and react at a temperature of 15° C. for 3 h. After the reaction is completed, the active ester reaction liquid is obtained by suction filtration. At -5° C., the carboxyl protection reaction liquid of 7-ADCA is added dropwise, and the reaction is kept for 3 h.

[0032] Add 300ml of water to the reaction solution, adjust the pH to 2 with concentrated hydrochloric acid, reac...

Embodiment 2

[0036] a Carboxyl protection of 7-ADCA

[0037] Weigh 70g (0.327mol) of 7-ADCA and 350ml of dichloromethane into a 1L three-necked flask, add 99g (0.98mol) of triethylamine under stirring, and dropwise add 35.5g (0.327mol) of trimethylchlorosilane at 20°C, React at 20°C for 1 hour to obtain the silyl compound of 7-ADCA, and cool down to -5°C.

[0038] b Preparation of cephalexin

[0039] Add 61.3g (0.327mol) of α-aminophenylacetic acid hydrochloride and 600ml of dichloromethane into a 2L three-necked flask, then add 66g (0.653mol) of triethylamine and 78.2g (0.653mol) of trifluoroacetic acid succinimide ), and react at a temperature of 15° C. for 3 h. After the reaction is completed, the active ester reaction liquid is obtained by suction filtration. At -5° C., the carboxyl protection reaction liquid of 7-ADCA is added dropwise, and the reaction is kept for 3 h.

[0040] Add 300ml of water to the reaction solution, adjust the pH to 1 with concentrated hydrochloric acid, reac...

Embodiment 3

[0044] a Carboxyl protection of 7-ADCA

[0045] Weigh 70g (0.327mol) of 7-ADCA and 350ml of dichloromethane into a 1L three-necked flask, add 99g (0.98mol) of triethylamine under stirring, and dropwise add 35.5g (0.327mol) of trimethylchlorosilane at 20°C, React at 20°C for 1 hour to obtain the silyl compound of 7-ADCA, and cool down to -5°C.

[0046] b Preparation of cephalexin

[0047] Add 61.3g (0.327mol) of α-aminophenylacetic acid hydrochloride and 600ml of dichloromethane into a 2L three-necked flask, then add 66g (0.653mol) of triethylamine and 78.2g (0.653mol) of trifluoroacetic acid succinimide ), and react at a temperature of 15° C. for 3 h. After the reaction is completed, the active ester reaction liquid is obtained by suction filtration. At -5° C., the carboxyl protection reaction liquid of 7-ADCA is added dropwise, and the reaction is kept for 3 h.

[0048] Add 300ml of water to the reaction solution, adjust the pH to 3 with concentrated hydrochloric acid, reac...

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Abstract

The invention belongs to the field of medicine synthesis, in particular to an improved method of a beta-lactam antibiotic cefalexin synthesis process. According to the method, 7-ADCA is used as a rawmaterial and is protected by carboxyl silane; after activation with alpha-aminophenylacetic acid hydrochloride and trifluoroacetic acid succinimide, condensation reaction is carried out; cefalexin isobtained through hydrolysis after-treatment, the proper pH value is controlled through hydrochloric acid after organic solvent and alkali adjustment treatment, and cefalexin crystals with extremely high purity are obtained. The method has the advantages of being easy and convenient to operate, mild in reaction condition, not prone to causing side reaction and capable of effectively removing impurities and preparing high-purity cefalexin.

Description

technical field [0001] The invention belongs to the technical field of medicine synthesis, and in particular relates to an improved synthesis process of β-lactam antibiotic cephalexin. Background technique [0002] Cefalexin (Cefalexin IV, Cefalexin, 1), chemical name: (6R, 7R)-3-methyl-7-[(R)-2-amino-2-phenylacetamido]-8-oxo- 5-thia-1-azabicyclo[4,2,0]oct-2-ene-2-carboxylic acid-hydrate, the structural formula is as follows: [0003] [0004] It is the first generation of oral cephalosporin developed by Eli Lilly in 1967 and put on the market in 1970. It has broad-spectrum antibacterial effect and has antibacterial effect on Gram-positive bacteria and Gram-negative bacteria. Its mechanism of action is By inhibiting the synthesis of the cell wall, the contents of the cell expand to rupture and dissolve, thereby achieving a bactericidal effect. Because of its good oral absorption, low toxicity, wide antibacterial spectrum, and to a certain extent, it can tolerate the acti...

Claims

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Application Information

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IPC IPC(8): C07D501/22C07D501/06C07D501/04C07D501/12
CPCC07D501/04C07D501/06C07D501/12C07D501/22
Inventor 刘思思
Owner 刘思思