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Method for preparing beta-lactam derivative through enzymatic reaction

A technology of enzymatic reaction and synthesis method, applied in the direction of fermentation, etc., can solve the problems of harsh reaction conditions, complicated operation, high toxicity of reagents, etc., and achieve the effect of mild reaction conditions, friendly environment and simple operation

Active Publication Date: 2013-10-30
CHONGQING SHENGHUAXI PHARMA CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0018] In view of the above-mentioned problems, the present invention aims to avoid the defects of high reagent toxicity, harsh reaction conditions, complicated operation, high cost and heavy environmental load in the existing preparation process of the compound of formula 1, and the immobilized deacetylation of the compound of formula 2 is provided. Base esterase (CE enzyme) prepares the method for formula one compound:

Method used

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  • Method for preparing beta-lactam derivative through enzymatic reaction
  • Method for preparing beta-lactam derivative through enzymatic reaction
  • Method for preparing beta-lactam derivative through enzymatic reaction

Examples

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reference example 1

[0025] Reference Example 1: 7β-[(Z)-2-(2-tert-butoxycarbonylaminothiazol-4-yl)-2-butenoyl]amino-3-acetoxymethyl-3-cephem-4- Synthesis of carboxylic acid (Formula 2) (refer to US4500716)

[0026] Add 142g (0.5mol) of (Z)-2-(2-tert-butoxycarbonylaminothiazol-4-yl)-2-butenoic acid and 76mL (0.55mol) of triethylamine into dichloromethane (400mL) and cool down To -50°C, 40mL (0.52mol) of methanesulfonyl chloride was added dropwise, the temperature was controlled between -50°C to -40°C, and the drop was completed, and stirred at -50°C to -40°C for 5h. Then, add 163g (0.6mol) of 7-ACA (0.6mol) and 180mL (1.3mol) of triethylamine in dichloromethane (400mL) dropwise to the reaction solution, and control the temperature between -50°C and -40°C. ℃~-40℃ for 3h. Acidify with dilute hydrochloric acid and extract with ethyl acetate. The extract was washed with brine and dilute sodium bicarbonate water, dried, concentrated, and solidified to obtain 7β-[(Z)-2-(2-tert-butoxycarbonylaminothia...

Embodiment 1

[0027] Example 1: 7β-[(Z)-2-(2-tert-butoxycarbonylaminothiazol-4-yl)-2-butenoyl]amino-3-hydroxymethyl-3-cephem-4-carboxy Synthesis of acid (Formula 1)

[0028] Add 40g (72.4mmol) of compound formula 2 into 240mL of purified water to make the concentration of formula 2 300mM, adjust the pH to 7.8 with 25% ammonia water to completely dissolve the compound of formula 2, add immobilized deacetylesterase 2KU, and react at 25°C for 6h . After suction filtration, the pH of the filtrate was adjusted to 2-5 with dilute hydrochloric acid, and a white solid was precipitated. After suction filtration and drying, 34.6 g of Compound 1 was obtained, with a yield of 94%.

Embodiment 2

[0029] Example 2: 7β-[(Z)-2-(2-tert-butoxycarbonylaminothiazol-4-yl)-2-butenoyl]amino-3-hydroxymethyl-3-cephem-4-carboxy Synthesis of acid (Formula 1)

[0030] Add 40g (72.4mmol) of compound formula 2 into 60mL of purified water and 60mL of acetone to make the concentration of formula 2 600mM, adjust the pH to 7 with 25% ammonia water to completely dissolve the compound of formula 2, add immobilized deacetylesterase 1KU, 15 ℃ reaction 10h. After suction filtration, the pH of the filtrate was adjusted to 3-4 with dilute hydrochloric acid, and a white solid was precipitated, which was filtered by suction and dried to obtain 33.2 g of Compound 1 with a yield of 90%.

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Abstract

The invention relates to a method for preparing beta-lactam derivative through enzymatic reaction. The method for preparing beat-lactam derivative through enzymatic reaction comprises the step of synthesizing a compound shown in a formula I by virtue of an enzymatic reaction, and the compound can be used for preparing antibacterial cefcapene pivoxil, wherein R is the conventional amino protection groups like a t-butyloxycarboryl group. A biological enzyme catalyst used in the enzymatic reaction is immobilized deacetyl esterase, and the method for synthesizing the compound shown in the formula I has the advantages of mild conditions, low cost and environmental friendliness, and is easy to operate.

Description

technical field [0001] The invention relates to a method for preparing beta-lactam derivatives by enzymatic reaction, and the derivatives can be used to prepare antibacterial drug cefcapene pivoxil. Background technique [0002] Cefcapene pivoxil is the fourth-generation oral cephalosporin antibiotic, developed by Shionogi Co., Ltd., Japan, and listed in 1997. Its chemical structure is as follows: [0003] [0004] It has a strong antibacterial effect on a variety of bacteria, stronger antibacterial activity than the existing oral cephalosporins, and a lower dosage. [0005] There are many reports on the process route of cefcapene pivoxil in early patents and literature. The representative patent WO2008 / 155615 once disclosed the synthesis method of cefcapene pivoxil. -Acylation reaction of N atom, carbamylation reaction of 3-hydroxyl group, and esterification reaction of 4-carboxyl group to prepare cefcapene axetil. The preparation route is as follows: [0006] [0...

Claims

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Application Information

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IPC IPC(8): C12P35/00
Inventor 贾春荣刘军王宗玉辛涛
Owner CHONGQING SHENGHUAXI PHARMA CO LTD
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