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Method for enzymatically synthesizing beta-lactam antibiotic in organic solvent

An organic solvent and lactam technology, which is applied in the field of preparation of beta-lactam antibiotics, can solve the problems of difficulty in controlling the hydrolysis of acyl donor side chains and products, and increase the yield, and achieves the improvement of the yield, the reduction of by-products, the realization of The effect of recycling

Inactive Publication Date: 2008-02-27
ZHEJIANG UNIV
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  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] 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 organic solvent
  • Method for enzymatically synthesizing beta-lactam antibiotic in organic solvent
  • Method for enzymatically synthesizing beta-lactam antibiotic in organic solvent

Examples

Experimental program
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Effect test

Embodiment 1

[0048] Embodiment 1 Enzyme-catalyzed synthesis of ampicillin in anhydrous ethyl acetate

[0049] With 2.16 grams of 6-aminopenicillanic acid (10mmol) (general formula (III) compound, abbreviated 6-APA) and 3.3 grams of D-phenylglycine methyl ester (20mmol) (general formula (V) compound, wherein R is Phenyl, R3 is methoxy, abbreviated as D-PGM) was added to ethyl acetate which was dehydrated by molecular sieve to form a mixture with a total volume of 100ml. Then, the mixture of the reaction was placed in a constant temperature incubator to vibrate for 5 minutes, and the penicillin G acylase of 10.0 grams (1180 IU) was added, and reacted for 12 hours at 15° C., and the conversion rate of the antibiotic nucleus reached 90% as determined by liquid chromatography. The ampicillin yield was 88%, and the molar ratio selectivity of the synthetic product of ampicillin and the hydrolyzed product of D-phenylglycine was 2.5 (compared with about 1.2 for the reaction in aqueous medium under ...

Embodiment 2

[0050] Example 2 Enzyme-catalyzed synthesis of amoxicillin in anhydrous tert-amyl alcohol

[0051] With 2.16 grams of 6-APA (10mmol) and 3.6 grams of D-hydroxyphenylglycine methyl ester (20mmol) (general formula (V) compound, wherein R1 is p-hydroxyphenyl, R3 is methoxy, abbreviated D-HPGM ) was added to tert-amyl alcohol which was dehydrated by molecular sieve to form a mixture with a total volume of 100ml. Then, place the reaction mixture in a constant temperature incubator and vibrate for 5 minutes so that each substance is well dispersed, add 20.0 grams (2360 IU) of penicillin G acylase, react at 15°C for 20 hours, and determine the antibiotic mother by liquid chromatography. The nuclear conversion rate reaches 86%, the amoxicillin productive rate is 85%, and the molar ratio selectivity of the synthetic product of amoxicillin and the hydrolysis product of D-p-hydroxyphenylglycine methyl ester is 1.8 (by comparison, for water under normal conditions It is about 0.6 when re...

Embodiment 3

[0052] Example 3 Enzyme-catalyzed synthesis of amoxicillin in isopropanol-n-octane mixed solvent

[0053] 2.16 g of 6-APA (10 mmol) and 5.4 g of D-HPGM (30 mmol) were added to isopropanol-n-octane (50 / 50) through molecular sieves to form a mixture with a total volume of 100 ml. The reaction mixture was placed in a constant temperature incubator and shaken for 5 minutes so that each substance was well dispersed. Add the penicillin G acylase of 20.0 grams (2360IU), react at 15 ℃ for 20 hours, the liquid phase chromatographic determination antibiotic mother nucleus conversion rate reaches 94%, amoxicillin productive rate 92%, the synthetic product of amoxicillin and D - The molar ratio selectivity of the hydrolyzed product of p-hydroxyphenylglycine methyl ester is 1.5 (compared to about 0.6 for the reaction in aqueous medium under ordinary conditions).

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Abstract

The present invention discloses a method for preparing beta-lactam antibiotics by utilizing enzymatic synthesis process in organic solvent. Said method includes the following steps: mixing beta-lactam nuclear parent, acylation reagent and organic solvent, adding penicillin acylase, then making reaction for 1-36hr at -10-45deg.C, the concentration of penicillin acylase in reaction system is 30-300U IU / ml. Said invention, can greatly raise yield of beta-lactam antibiotics.

Description

technical field [0001] The present invention relates to the preparation method of β-lactam antibiotic. In particular, it relates to a method for enzymatically synthesizing β-lactam antibiotics in an organic solvent. 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 reaction steps are simple, the...

Claims

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Application Information

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IPC IPC(8): C12P35/04C12P37/04C12R1/01C12R1/02C12R1/11C12R1/185
Inventor 林贤福陈春秀吴起德水
Owner ZHEJIANG UNIV
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