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Method for enzymatically synthesizing beta-lactam antibiotic in mixed system of water and organic medium

A lactam and medium technology, applied in the field of enzyme-catalyzed synthesis of β-lactam antibiotics, can solve the problems of increased yield, difficult control of acyl donor side chains and product hydrolysis, and improved yield, reduced deprivation ability, and side effects. The effect of response inhibition

Inactive Publication Date: 2010-04-07
ZHEJIANG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0012] However, due to the large amount of water contained in the reaction system, the hydrolysis of the acyl donor side chain and the product is still difficult to control during the reaction, and the yield needs to be further improved.

Method used

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  • Method for enzymatically synthesizing beta-lactam antibiotic in mixed system of water and organic medium
  • Method for enzymatically synthesizing beta-lactam antibiotic in mixed system of water and organic medium
  • Method for enzymatically synthesizing beta-lactam antibiotic in mixed system of water and organic medium

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045] Example 1 Enzyme-catalyzed synthesis of amoxicillin in tert-amyl alcohol containing 2% water

[0046] With 2.16 grams of 6-APA (10mmol) and 3.6 grams of D-hydroxyphenylglycine methyl ester (20mmol) (general formula (C) compound, wherein R1 is p-hydroxyphenyl, R3 is methoxy, abbreviated D-HPGM ) into 98ml of analytically pure tert-amyl alcohol through molecular sieve removal of water. Then, add 2ml of water to the reaction system, place the reaction mixture in a constant temperature incubator and vibrate for 5 minutes to make each substance well dispersed, add 0.1g / ml of penicillin G acylase, and react at 10°C for 12 hours , 88% of the amoxicillin productive rate determined by liquid chromatography, the molar ratio selectivity of the synthetic product of amoxicillin and the hydrolyzate of D-hydroxyphenylglycine methyl ester is 1.6 (compared with, for the aqueous medium under common conditions is around 0.6).

Embodiment 2

[0047] Example 2 Enzyme-catalyzed synthesis of amoxicillin in tert-amyl alcohol containing 10% water

[0048] 2.16 g of 6-APA (10 mmol) and 3.6 g of D-HPGM (20 mmol) were added to 90 ml of analytically pure tert-amyl alcohol which was dewatered by molecular sieves. Then, add 10ml of water to the reaction system, place the reaction mixture in a constant temperature incubator and vibrate for 5 minutes to make each substance well dispersed, add 0.1g / ml of penicillin G acylase, and react at 10°C for 8 hours , liquid chromatographic determination of amoxicillin productive rate 83%, the molar ratio selectivity of the synthetic product of amoxicillin and the hydrolyzate of D-hydroxyphenylglycine methyl ester is 1.4 (compared with, for the aqueous medium under common conditions is around 0.6).

Embodiment 3

[0049] Example 3 Enzyme-catalyzed synthesis of ampicillin in ethyl acetate containing 2% water

[0050] 2.16 grams of 6-APA (10mmol) and 3.3 grams of D-phenylglycine methyl ester (20mmol) (general formula (C) compound, wherein R1 is phenyl, R3 is methoxyl, abbreviated D-PGM) is added to 98ml Pure ethyl acetate (<0.1% water content) was analyzed. Then, add 2ml of pH6.5 phosphate buffer solution to the reaction system, place the reaction mixture in a constant temperature incubator and shake for 5 minutes, add 0.1g / ml of penicillin G acylase, and react at 10°C for 8 hours , liquid chromatographic determination of ampicillin yield 93%, ampicillin synthesis product and the molar ratio selectivity of the hydrolysis product of D-phenylglycine is 2.0 (compared with about 1.2 for the aqueous medium under common conditions).

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Abstract

The present invention discloses a method for preparing beta-lactam antibiotics by utilizing enzymatic synthesis process in water / organic medium mixed system. Said method includes the following steps:mixing beta-lactam nuclear parent, acylation reagent, water and organic solvent, then adding penicillin acylase and making reaction for 1-48hr at -10-45deg.C.

Description

technical field [0001] The invention relates to a preparation method of β-lactam antibiotics, in particular to a method for catalyzing the synthesis of β-lactam antibiotics in a water / organic medium mixed system containing a small amount of water. Background technique [0002] At present, industrial semi-synthetic β-lactam antibiotics such as ampicillin, amoxicillin, cefaclor, cephalexin and cefadroxil are prepared by chemical methods, and the reaction process involves the protection of the side chain and the activation of the carboxyl group , condensation reaction, and side chain deprotection steps, so there are many chemical reaction steps in the production process, the discharge of three wastes is large, and the environmental pollution is serious. [0003] In recent years, there have been many reports in the literature on the preparation of β-lactam antibiotics by enzymatic methods. The advantages of using the enzymatic method to prepare β-lactam antibiotics are that the...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C12P35/04C12P37/04
Inventor 吴起林贤福潘绳彬陈志春
Owner ZHEJIANG UNIV
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