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A kind of preparation method of ceftaroline axetil

A technology of ceftaroline axetil and cephem, 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: 2017-01-04
SHANDONG LUOXIN PHARMA GRP CO LTD
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  • Summary
  • 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-thiadiazol-3-yl)-2-ethoxyimino acetyl chloride has stronger activity of dichlorophosphate, can be react with primary amines under neutral conditions, so that the obtained compound 3-[4-(1-methyl-4-pyridinium)-2-thiazolylthio]-7β-[2-(5-phosphonamido- 1,2,4-thiadiazol-3-yl)-2(Z)-ethoxyiminoacetamido]-3-cephem-4-carboxylic acid has more by-products, which leads to a decrease in yield, Not conducive to industrial production

Method used

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  • A kind of preparation method of ceftaroline axetil
  • A kind of preparation method of ceftaroline axetil
  • A kind of preparation method of ceftaroline axetil

Examples

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Effect test

Embodiment 1

[0037] 1) Preparation of 7β-[(phenylacetyl)amino]-3-[4-pyridyl-2-thiazolylthio]-3-cephem-4-carboxylic acid benzhydryl ester (Formula Ic)

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

[0039] Suspend 221.5g of 7-phenylacetamido-3-chloro-3-cephalosporin-4-carboxylic acid benzhydryl ester filte...

Embodiment 2

[0050] 1) Preparation of 7β-[(phenylacetyl)amino]-3-[4-pyridyl-2-thiazolylthio]-3-cephem-4-carboxylic acid benzhydryl ester (Formula Ic)

[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, technical grade, content ≥ 90%), control the temperature at 25°C, stir for 8 hours, add 15 liters of ice water , the separated solid is filtered, rinsed with a small amount of clear water, and suction filtered to obtain about 295g of 7-phenylacetamido-3-chloro-3-cephalosporin-4-carboxylic acid diphenylmethyl ester filter cake (formula Ib, measure 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-carb...

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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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Patent Type & Authority Patents(China)
IPC IPC(8): C07F9/6561
CPCY02P20/55
Inventor 李明杰刘明霞李志滨韩后良
Owner SHANDONG LUOXIN PHARMA GRP CO LTD
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