Preparation method of (S)-(+)-2,2-dimethylcyclopropanecarboxylic acid by biocatalysis

A technology of ethyl dimethylcyclopropanecarboxylate and dimethylcyclopropane is applied in the field of biocatalytic preparation of (S)-(+)-2,2-dimethylcyclopropanecarboxylic acid, and can solve the problem of low yield, Problems such as many process steps, to achieve the effects of high catalytic efficiency, reduced optical purity, and no by-products

Inactive Publication Date: 2009-12-09
ZHEJIANG UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This route is environmentally friendly and low in cost, but there are many process steps and the yield is very low

Method used

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  • Preparation method of (S)-(+)-2,2-dimethylcyclopropanecarboxylic acid by biocatalysis
  • Preparation method of (S)-(+)-2,2-dimethylcyclopropanecarboxylic acid by biocatalysis
  • Preparation method of (S)-(+)-2,2-dimethylcyclopropanecarboxylic acid by biocatalysis

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Experimental program
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Embodiment 1

[0036] Embodiment 1: the preparation of (S)-(+)-2,2-dimethylcyclopropanecarboxylic acid

[0037] Take three parts of 150mg Novozym 435 lipase in parallel and place in 25ml Erlenmeyer flasks, add 10ml pH of 7.0 phosphate buffer respectively, then add 0.25mmol substrate 2,2-dimethylcyclopropane ethyl carboxylate for different Symmetrical hydrolysis reaction. The reaction conditions are: the rotating speed of the shaker is 200r / min, the transformation temperature is 30°C, and the transformation time is 40h. After the reaction finishes, combine three parts of reaction solutions, get 10ml reaction solution and extract twice with equal volume ethyl acetate, settle to 20ml, analyze with gas chromatography, as figure 2 shown. The calculation of the yield adopts the internal standard method, and the e.e. value and yield of the product are 94.65% and 38.36%, respectively. The remaining reaction solution was separated as follows: adjust the pH of the reaction solution to 9.0 with a N...

Embodiment 2～7

[0039] With reference to the method for embodiment 1, add the substrate of different concentrations listed in table 1, other conditions are identical, shaker speed 200r / min, investigate the influence of substrate concentration on asymmetric hydrolysis reaction, substrate concentration in table 1 is every Add the millimoles of ethyl 2,2-dimethylcyclopropanecarboxylate to 1 liter of phosphate buffer, the enzyme concentration is the number of grams of Novozym 435 lipase added per 1 liter of phosphate buffer, and the pH is the initial pH of the phosphate buffer , the conversion time in the table is the reaction time, and the conversion temperature is the reaction temperature. After the reaction finished, the reaction solution was extracted twice with equal volume of ethyl acetate and then settled to 20ml, and analyzed by gas chromatography, the results are shown in Table 1:

[0040] Table 1

[0041]

Embodiment 8～14

[0043] With reference to the method of Example 1, the concentration of adding Novozym 435 lipase in the reaction system is different, specifically as listed in Table 2, other conditions are the same, the shaking table speed is 200r / min, and the effect of enzyme concentration on 2,2-dimethylcyclo The impact of propane ethyl formate asymmetric hydrolysis reaction, the substrate concentration in table 2 is the millimole of 2,2-dimethylcyclopropane ethyl carboxylate per 1 liter of phosphate buffer, and the enzyme concentration is per 1 liter of phosphate buffer Add the grams of Novozym 435 lipase to the solution, and the pH is the initial pH of the phosphate buffer. After the reaction finished, the reaction solution was extracted twice with equal volume of ethyl acetate and then settled to 20ml, and analyzed by gas chromatography, the results are shown in Table 2:

[0044] Table 2

[0045]

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Abstract

The invention discloses a novel preparation method of (S)-(+)-2,2-dimethylcyclopropanecarboxylic acid by biocatalysis. The method uses ethyl 2,2-dimethylcyclopropanecarboxylate as substrate and Novozym 435 lipase as biological catalyst, then biological catalyst asymmetric hydrolysis reaction is carried out on the mixture at a temperature of 25-45 DEG C and at pH ranging from 6.0-8.0 in a water phase reaction system, after the reaction is completed, the reaction solution is isolated to obtain (S)-(+)-2,2-dimethylcyclopropanecarboxylic acid. The asymmetric hydrolysis reaction utilizes Novozym 435 lipase to catalyze ethyl 2,2-dimethylcyclopropanecarboxylate, therefore, the enzyme specificity is strong, the catalytic efficiency is high, no side product is generated, and the optical purity and yield of the product are both higher than those of the product obtained by chemical methods.

Description

(1) Technical field [0001] The invention relates to a lipase enzymatic method to catalyze the asymmetric hydrolysis of ethyl 2,2-dimethylcyclopropane formate to synthesize cilastatin key chiral intermediate (S)-(+)-2,2-dimethyl Cyclopropanecarboxylic acid method. (2) Background technology [0002] S-(+)-2,2-Dimethylcyclopropanecarboxylic acid is an important chiral intermediate in the synthesis of cilastatin. Cilsatatin (Cilsatatin) chemical name: (+)-(Z)-7-[(2R)-(2-amino-2-carboxyethyl)sulfur]-2-[(1S)-(2,2 -Dimethylcyclopropanecarboxamido)]-2-heptenoic acid, the first renal dehydrodipeptidase inhibitor to be used clinically. Tienam, a composite agent made of cilastatin and carbapenem antibiotic imipenem (Imipenem), has both strong broad-spectrum antibacterial activity and β-lactamase inhibitory effect. Ram-positive bacteria, Gram-negative bacteria, aerobic bacteria and anaerobic bacteria all have strong antibacterial effects, and are especially suitable for the treatment...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12P7/40
Inventor 王普何军邀祝加男
Owner ZHEJIANG UNIV OF TECH
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