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Preparation method of 3-hydroxymethyl-7beta-phenylacetyl-3-cephalo-4-diphenylmethyl carboxylate

A technology of diphenylmethyl carboxylate and phenylacetamido, applied in the field of preparation of 3-hydroxymethyl-7β-phenylacetamido-3-cephalosporin-4-carboxylate Product process operation, high production cost, low yield and other problems, to achieve the effect of simple operation, improved purity and high yield

Inactive Publication Date: 2011-07-13
ZHEJIANG UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

There are also literatures that try to prepare the intermediate 3-hydroxymethyl-7β-phenylacetylamino-3-cephalosporin-4 by using 7-ACA as the starting material, first acetylating the 7-position aminophenyl, and then removing the 3-position acetyl group by alkaline hydrolysis -Carboxylic acid, but after acidification of the alkaline hydrolysis reaction mixture, the lactone product of 3-hydroxymethyl-7β-phenylacetamido-3-cephalosporin-4-carboxylic acid is mainly obtained, and the lactone cannot be recombined with benzhydryl Esterification reaction of nitrogen methane (Eur.J.Med.Chem.2002, 37, 323-332)
In short, the existing reported processes have disadvantages such as low yield, high production cost, easy generation of by-products and complicated process operations in phenylacetylation.

Method used

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  • Preparation method of 3-hydroxymethyl-7beta-phenylacetyl-3-cephalo-4-diphenylmethyl carboxylate

Examples

Experimental program
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Effect test

Embodiment 1

[0020] Preparation of 3-hydroxymethyl-7β-phenylacetamido-3-cephalosporin-4-carboxylic acid (2): Add 35.0g (0.33mol) Na in a 1000ml four-necked flask successively 2 CO 3, 500ml of water and 400ml of acetone, and cooled to -5 ~ 0 ℃. Add 81.7g 7-ACA (0.30mol) under stirring, and stir for 10min to make it uniform. At this temperature, a solution of 50.1 g (0.33 mol) of phenylacetyl chloride dissolved in 100 ml of acetone was added dropwise within 2.5 to 3 hours. After the dropwise addition was completed, the reaction was continued with stirring at the same temperature for 1 hour. After the reaction was complete, 500 ml of ethyl acetate was added, and 210 ml of hydrochloric acid solution with a mass concentration of 10% was added dropwise to make the pH of the reaction solution 3.0 to 3.5. The ethyl acetate layer was separated, the aqueous layer was extracted with 200 ml ethyl acetate, the organic phases were combined, washed with 300 ml saturated NaCl solution, and dried over an...

Embodiment 2

[0022] Preparation of 3-hydroxymethyl-7β-phenylacetamido-3-cephalosporin-4-carboxylic acid (2): except replacing Na with triethylamine 2 CO 3 Except, other operating conditions were the same as in Example 1, and 99.5 g of white solid was obtained with a yield of 85.0% and a purity of 98.0%.

Embodiment 3

[0024] Preparation of 3-hydroxymethyl-7β-phenylacetamido-3-cephalosporin-4-carboxylic acid (2): except replacing NaOH with NaOH 2 CO 3 Except that other operating conditions were the same as in Example 1, 95.4 g of white solid was obtained with a yield of 81.5% and a purity of 97.2%.

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Abstract

The invention provides a preparation method of 3-hydroxymethyl-7beta-phenylacetyl-3-cephalo-4-diphenylmethyl carboxylate. The invention uses 7-ACA as starting material and uses the technical route of acetylation of first 7-amino phenylacetyling and then removal of 3-acetylation by hydrolysing via alkali to prepare intermediate 3-hydroxymethyl-7beta-3-cephalo-4-carboxylate, avoiding generation of 3-O-phenylacetyl side products without protecting process and deprotecting process. During the preparation process of 4-diphenylmethyl-acrylation of intermediate, the ethyl acetate solution of diphenylmethyldiazomethane is directly added into the mixed solution after the hydrolysis reaction and the hydrochloric acid is dripped to accelerate the esterification reaction, avoiding the generation of lactone of 3-hydroxymethyl-7beta-3-cephalo-4-carboxylate and promoting the generation of methyl-esterification of diphenyl. The target product is washed by reflowing in acetone and the purity thereof isgreater than 99%. The invention has the advantages of simple operation, moderate reaction conditions, high yield, high purity of the product, etc.

Description

(1) Technical field [0001] The invention relates to a preparation method of 3-hydroxymethyl-7β-phenylacetamido-3-cephalosporin-4-carboxylic acid diphenylmethyl ester. (2) Background technology [0002] 3-Hydroxymethyl-7β-phenylacetamido-3-cephalosporin-4-carboxylic acid diphenylmethyl ester (1) is an important intermediate for the preparation of cephalosporins, and is widely used in the synthesis of cephalosporins. Its 3-hydroxymethyl group can be used in the synthesis of drugs such as cefotaxime and cefdinir through halogenation to obtain 3-halomethyl-7β-phenylacetamido-3-cephalosporin-4-carboxylic acid diphenylmethyl ester (EP 0162394 A2, JP 04066584 A); Or the 3-hydroxymethyl group can be used for the synthesis of drugs such as Ceftobiprole (WO 96 / 35692, WO 01 / 90111 A1). Compound 1 is also a key intermediate for the research and development of new cephalosporins. [0003] Bibliographical reports prepare the method for 1 mainly: 7-amino cephalosporanenoic acid (7-ACA) i...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D501/30C07D501/06
Inventor 孙楠俞克平胡信全莫卫民顾士崇
Owner ZHEJIANG UNIV OF TECH