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Improvement method of cefalexin synthesis process

A technology of cephalexin and synthesis process, applied in the direction of organic chemistry and the like, can solve the problems of many impurities in the product, complicated reaction process, difficult purification of the product, etc., and achieves the effects of not easy side reactions, high yield, and removal of impurities.

Inactive Publication Date: 2014-11-05
孙丽华
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0014] On the basis of in-depth research on the prior art, the inventor aimed at the complex reaction process in the prior art, and carried out under the harsh conditions of low temperature and anhydrous, the product has many impurities, and the product is difficult to purify. Improvement, the reaction uses 7-ADCA as a raw material through carboxyl protection, and then undergoes condensation reaction with α-aminophenylacetyl chloride or its hydrochloride, and obtains cephalexin through post-hydrolysis treatment;

Method used

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  • Improvement method of cefalexin synthesis process
  • Improvement method of cefalexin synthesis process
  • Improvement method of cefalexin synthesis process

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] a. Carboxyl protection of 7-ADCA

[0040] Weigh 69g (0.322mol) of 7-ADCA and 1200ml of dichloromethane into a 2L three-necked reaction flask, add 91.5ml of triethylamine under stirring, add 90ml (0.7mol) of trimethylchlorosilane dropwise at 20°C, and react at 20°C After 0.5h, the silyl compound (II) of 7-ADCA was obtained, and the temperature was lowered to -5°C for later use.

[0041] b. Preparation of cephalexin

[0042] Add 60g (0.354mol) of α-aminophenylacetyl chloride, 1500ml of dichloromethane, and 8.5g (0.07mol) of 4-dimethylaminopyridine (DMAP) into the reaction flask, stir and cool down to -5°C, and slowly add step 7-ADCA silyl compound (II) dichloromethane solution, heat and stir at -5°C for 2.5 hours, then add 6ml of triethylamine, continue stirring and reacting for 1.5 hours, take samples for measurement, the residual amount of 7-ADCA in the reaction solution should not exceed 2% is the end point of the reaction.

[0043] Then add 600ml of deionized water...

Embodiment 2

[0048] a. Carboxyl protection of 7-ADCA

[0049] Weigh 69g (0.322mol) of 7-ADCA and 1500ml of dichloromethane into a 2L three-necked reaction flask, add DMF110ml under stirring, add 95ml of 2-(trimethylsilyl)ethoxymethyl chloride dropwise at 20°C, and add at 20°C After reacting for 0.5h, the silyl compound (II) of 7-ADCA was obtained, and the temperature was lowered to -5°C for later use.

[0050] b. Preparation of cephalexin

[0051] Add 60g (0.354mol) of α-aminophenylacetyl chloride, 1500ml of dichloromethane, and 9g of 4-dimethylaminopyridine (DMAP) into the reaction flask, stir and cool down to -10°C, and slowly add the silane of step 7-ADCA dropwise Compound (II) dichloromethane solution, heat and stir at -5°C for 2.5 hours, then add 8.5ml of ethylenediamine, continue to stir and react for 1.5 hours, take samples for measurement, and take the 7-ADCA residue in the reaction solution as not more than 2%. end.

[0052] Then add 650ml of deionized water and concentrated hy...

Embodiment 3

[0056] a. Carboxyl protection of 7-ADCA

[0057] Weigh 69g (0.322mol) of 7-ADCA and 1500ml of chloroform into a 2L three-necked reaction flask, add 110ml of trimethylamine under stirring, add 100ml of tert-butyldiphenylchlorosilane (TbDPSCl) dropwise at 20°C, and react at 20°C After 0.5h, the silyl compound (II) of 7-ADCA was obtained, and the temperature was lowered to -5°C for later use.

[0058] b. Preparation of cephalexin

[0059] Add 72.5g (0.35mol) of α-aminophenylacetyl chloride hydrochloride, 1500ml of chloroform, and 10g of 4-dimethylaminopyridine (DMAP) into the reaction flask, stir and cool down to -10°C, and slowly add step 7 -ADCA silyl compound (II) trichloromethane solution, heat and stir at -5°C for 2.5 hours, then add 8.5ml triethylamine, continue stirring and reacting for 1.5 hours, take samples for measurement, the residual amount of 7-ADCA in the reaction solution should not exceed 2% is the end point of the reaction.

[0060] Then add 720ml of deionize...

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Abstract

The invention belongs to the field of pharmaceutical synthesis, and particularly relates to an improvement method of a beta-lactam antibiotic cefalexin synthesis process. According to the method, a 7-ADCA (amino desacetoxy cephalosporanic acid) is taken as a raw material, the method comprises the steps that the 7-ADCA is subjected to silane protection of carboxyl, and then the 7-ADCA has a condensation reaction with alpha-amino benzeneacetyl chloride or hydrochlorides thereof under the catalysis of 4-dimethylaminopyridine; the obtained object is subjected to hydrolyzed aftertreatment so as to obtain cefalexin; and after the cefalexin is treated by using an organic solvent and subjected to alkali adjustment treatment, an appropriate pH value of the cefalexin is controlled by using a hydrochloric acid, so that cefalexin crystals with an extremely high purity are obtained. The method has the advantages that the method is simple in operation, mild in reaction condition and has small possibility of causing side effects, and can effectively remove impurities and prepare 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] Cephalexin (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 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 action...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D501/22C07D501/04C07D501/12
CPCC07D501/22C07D501/04C07D501/12
Inventor 孙丽华
Owner 孙丽华
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