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A kind of preparation method of cefcapene hydrochloride intermediate bcn

A technology of cefcapene hydrochloride and intermediates, applied in organic chemistry and other fields, can solve the problems of long industrial routes and low purity

Active Publication Date: 2020-08-14
湖北凌晟药业股份有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0002] Cefcapene pivoxil hydrochloride is the fourth generation of oral cephalosporin antibiotics. Cefcapene pivoxil hydrochloride intermediate (BCN) is a key intermediate for the synthesis of cefcapene pivoxil hydrochloride and is also a precursor raw material, hereinafter referred to as BCN. The core D-7-ACA and the side chain BAPA are prepared by the mixed anhydride preparation reaction and the subsequent treatment process. After BCN is modified, various cefcapene hydrochloride analogues can also be obtained. The existing BCN synthesis methods generally have low purity. The lack of long industrial routes

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  • A kind of preparation method of cefcapene hydrochloride intermediate bcn
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  • A kind of preparation method of cefcapene hydrochloride intermediate bcn

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preparation example Construction

[0023] The invention provides a kind of preparation method of cefcapene hydrochloride intermediate BCN, comprising the following steps:

[0024] In a nitrogen atmosphere, 3-deacetyl-7-aminocephalosporanic acid is mixed with tetramethylguanidine and an organic solvent for a salt-forming reaction to obtain D-7-ACA-MG salt;

[0025] In a nitrogen atmosphere, mix (Z)-2-(2-tert-butoxycarbonylaminothiazol-4-yl)-2-pentenoic acid, mixed anhydride reagent, methylene chloride and amines for mixed anhydride acylation Reaction to obtain mixed anhydride BAPA-MS;

[0026] Mixing the D-7-ACA-MG salt with the mixed anhydride BAPA-MS for condensation reaction to obtain a condensation product;

[0027] The condensation product, chlorosulfonyl isocyanate and dichloromethane are mixed for carbamylation reaction and then hydrolyzed in a mixed solution of ethyl acetate and water to obtain a BCN precursor;

[0028] The BCN precursor is mixed with diisopropylamine for salt formation and crystalliza...

Embodiment 1

[0064] Synthesis of D-7-ACA-MG Salt

[0065] Under the protection of nitrogen, in a dry and clean R0205 reactor, add 400kg of dichloromethane, 45kg of D-7-ACA (3-deacetyl-7-aminocephalosporanic acid), cool down to 5°C, and add dropwise within 30 minutes Tetramethylguanidine 22.5kg, after dripping, stir until dissolved, and the reactor is cooled to -5°C for subsequent use;

[0066] Synthesis of Mixed Anhydride BAPA-MS

[0067] Under nitrogen protection, in a dry and clean R0204 reactor, add 58.3kg of BAPA and 550kg of dichloromethane, start stirring, cool to -15°C, add 22.39kg of methanesulfonyl chloride and 39.56kg of diisopropylamine, and heat up to 0 ℃ heat preservation and stirring for 2 hours, cool down to -25 ℃ for later use;

[0068] condensation reaction

[0069] Quickly press the D-7-ACA-MG salt solution prepared in the R0205 reactor into the R0204 reactor. -MG salt <1.0%, determined by peak area normalization method), after the liquid phase control results come ou...

Embodiment 2

[0085] Synthesis of D-7-ACA-MG Salt

[0086] Under the protection of nitrogen, in a dry and clean R0205 reaction kettle, add 400kg of dichloromethane, 45kg of D-7-ACA (3-deacetyl-7-aminocephalosporanic acid), cool down to 0°C, and add dropwise within 30 minutes Tetramethylguanidine 22.5kg, after dripping, stir until dissolved, and the reactor is cooled to 1°C for subsequent use;

[0087] Synthesis of Mixed Anhydride BAPA-MS

[0088] Under nitrogen protection, in a dry and clean R0204 reactor, add 58.3kg of BAPA and 550kg of dichloromethane, start stirring, cool to 1°C, add 23.57kg of methanesulfonyl chloride and 39.56kg of diisopropylamine, and heat up to 0°C after adding Insulate and stir for 2 hours, cool down to -23°C for later use;

[0089] condensation reaction

[0090] Quickly press the D-7-ACA-MG salt solution prepared in the R0205 reactor into the R0204 reactor. -MG salt <1.0%, determined by peak area normalization method), after the liquid phase control results co...

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Abstract

The invention provides a preparation method of cefcapene pivoxil hydrochloride intermediate BCN, and belongs to the technical field of organic synthesis. Mixed anhydride BAPA prepared by a mixed anhydride preparation reaction and D-7-ACA-MG salt can be subjected to a condensation reaction, and the cefcapene pivoxil hydrochloride intermediate BCN is obtained by carbamoylation reaction and salt formation crystallization. The preparation method has short process route, high product purity and low cost, and is suitable for industrial production. Data of the embodiment shows that the prepared cefcapene pivoxil hydrochloride intermediate BCN can have purity as high as 98.84% and yield as high as 91.99%.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis, in particular to a preparation method of cefcapene hydrochloride intermediate BCN. Background technique [0002] Cefcapene pivoxil hydrochloride is the fourth generation of oral cephalosporin antibiotics. Cefcapene pivoxil hydrochloride intermediate (BCN) is a key intermediate for the synthesis of cefcapene pivoxil hydrochloride and is also a precursor raw material, hereinafter referred to as BCN. The core D-7-ACA and the side chain BAPA are prepared by the mixed anhydride preparation reaction and the subsequent treatment process. After BCN is modified, various cefcapene hydrochloride analogues can also be obtained. The existing BCN synthesis methods generally have low purity. The lack of long industrial routes. As the prior art discloses the synthesis of thiazole acetic acid (BAPA) through reactions such as condensation, cyclization, and introduction of protecting groups of 4-chloroac...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D501/04C07D501/34
CPCC07D501/04C07D501/34
Inventor 金联明门万辉何健邹菁
Owner 湖北凌晟药业股份有限公司
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