Preparation method for ceftaroline fosamil

A technology of ceftaroline axetil and cephalosporin, which is applied in the field of preparation of ceftaroline axetil, can solve the problems of unfavorable industrial production, unavailable raw materials, and many by-products, and achieve the effects of low cost, improved purity, and few side reactions

Active Publication Date: 2015-06-24
SHANDONG LUOXIN PARMACEUTICAL GROUP STOCK CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0015] Although these synthetic methods have short synthetic routes, there is no supply in the market of the compound of formula V, and the raw materials are not easy to get, and environmentally unfriendly reagents such as phosphorus pentachloride have been used in a large amount in the reaction, which is unfavorable for suitability for industrialized production; also because (Z) -2-(5-dichlorophosphoramido-1,2,4-thia

Method used

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  • Preparation method for ceftaroline fosamil
  • Preparation method for ceftaroline fosamil
  • Preparation method for ceftaroline fosamil

Examples

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Embodiment 1

[0037] 1） 7β-[(phenylacetyl)amino]-3-[4-pyridyl-2-thiazolylthio]-3-cephem-4-carboxylic acid benzhydryl ester (formula IC ) preparation

[0038] At a temperature of 20-25°C, add 2000mL of dehydrated dimethylformamide into a dry reaction vessel, add 80g of thionyl chloride at room temperature, control the temperature at 30°C, stir for 1 hour, and then add 222g of 7-phenylacetyl Amino-3-hydroxy-3-cephalosporin-4-carboxylic acid benzhydryl ester (formula Ia, 0.4mol, industrial grade, content ≥ 90%), control the temperature at 25°C, stir for 8 hours, add 15 liters of ice water, filter the separated solid, rinse with a small amount of water, and suction filter to obtain about 228g of 7-phenylacetyl Amino-3-chloro-3-cephalosporin-4-carboxylic acid diphenylmethyl ester filter cake (formula Ib , the measured moisture is 15.8%, the equivalent dry weight is 192g, 0.36mol), and the molar yield is 90%.

[0039] 221.5g 7-phenylacetamido-3-chloro-3-cephalosporin-4-carboxylic acid diph...

Embodiment 2

[0050] 1） 7β-[(phenylacetyl)amino]-3-[4-pyridyl-2-thiazolylthio]-3-cephem-4-carboxylic acid benzhydryl ester (formula IC ) preparation

[0051] At a temperature of 20-25°C, add 2800mL of dehydrated dimethylformamide into a dry reaction vessel, add 120g of thionyl chloride at room temperature, control the temperature at 30°C, stir for 1 hour, and then add 278g of 7-phenylacetyl Amino-3-hydroxy-3-cephalosporin-4-carboxylic acid benzhydryl ester (formula Ia , 0.5mol, industrial grade, content ≥ 90%), control the temperature at 25°C, stir for 8 hours, add 15 liters of ice water, filter the separated solid, rinse with a small amount of water, and suction filter to obtain about 295g of 7-benzene Acetylamino-3-chloro-3-cephalosporin-4-carboxylic acid benzhydryl ester filter cake (formula Ib , the measured moisture is 18.0%, the equivalent dry weight is 242g, 0.455mol, and the molar yield is 91%).

[0052] The above-mentioned 7-phenylacetamido-3-chloro-3-cephalosporin-4-carboxyl...

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Abstract

The invention relates to a synthetic method for ceftaroline fosamil. According to the synthetic method, 7-phenylacetamide-3-hydroxy-3-cephalosporin-4-carboxylate-diphenylmethyl is selected as a raw material to be chloridized and reacts with 4-(4-pyridyl)-1,3-thiazole-2-thiol sodium salt at a C-3 site to obtain a thioether compound, p-cresol and immobilized penicillinase are adopted for removing carboxyl and amino protecting groups respectively, the thioether compound and the acylated AE-active ester are subjected to C-7 site condensation reaction, and crystallization in acetic acid is performed after hydrolyzation to prepare the ceftaroline fosamil successfully. The preparation method has the advantages that use of toxic and harmful substances such as trifluoroacetic acid and phosphorus pentachloride is avoided, reaction conditions are moderate, side reactions are few, technology is simple, yield and product purity are high, cost is low, raw materials are cheap and easy to obtain, and the preparation method is applicable to industrial production.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a preparation method of ceftaroline axetil. Background technique [0002] Ceftaroline fosamil was developed by Japan's Takeda Pharmaceutical Company, the US Forest Laboratories (Cerexa) company obtained market authorization, and was approved for marketing by the US Food and Drug Administration on October 29, 2010. The trade name of the drug is Teflaro, which is a prodrug of ceftaroline (ie, N-phosphorylated ceftaroline), and belongs to the fifth generation of cephalosporin antibiotics. The drug is indicated for the treatment of community-acquired bacterial enteritis (CABP) and acute bacterial skin and skin tissue infections (ABSSSI), including methicillin-resistant Staphylococcus aureus (MRSA), in adults. [0003] The Chinese chemical name of ceftaroline axetil: ( 6 R, 7R ) -7 -{( 2 Z ) -2 -(ethoxyimino)-2-[ 5-(phosphoramido)1,2,4- Thiadiazol-3-yl]-acetylamino}-3-{[4-(1-methyl-4-p...

Claims

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Application Information

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IPC IPC(8): C07F9/6561
CPCY02P20/55
Inventor 李明杰刘明霞李志滨韩后良
Owner SHANDONG LUOXIN PARMACEUTICAL GROUP STOCK CO LTD
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