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Method for preparing (S)-(+)-2,2-dimethyl cyclopropane methanoic acid by biological resolution in ionic liquid cosolvent

A technology of ethyl dimethylcyclopropanecarboxylate and dimethylcyclopropane, which is applied in the field of biological separation and preparation-2, can solve the problems of easy agglomeration, high viscosity and low solubility, and achieves good stability , good dispersibility, the effect of improving solubility

Active Publication Date: 2014-05-14
ZHEJIANG UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

When the surfactant AOT is added during the reaction, because AOT is a white waxy solid at room temperature, its solubility in water is not high (1.5g / 100g water, 25°C), and it has a high viscosity, causing lipase Novozym435 It is easy to agglomerate after the conversion reaction, which is not conducive to the recovery and reuse of the enzyme. In addition, due to the strong electrostatic and hydrophobic interactions between the enzyme and AOT molecules, the enzyme molecules adsorbed on the macroporous adsorption resin will fall off during the enzyme recovery and washing. inactivation, thereby reducing the stability of the enzyme

Method used

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  • Method for preparing (S)-(+)-2,2-dimethyl cyclopropane methanoic acid by biological resolution in ionic liquid cosolvent
  • Method for preparing (S)-(+)-2,2-dimethyl cyclopropane methanoic acid by biological resolution in ionic liquid cosolvent
  • Method for preparing (S)-(+)-2,2-dimethyl cyclopropane methanoic acid by biological resolution in ionic liquid cosolvent

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Experimental program
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Effect test

Embodiment 1

[0025] Embodiment 1: Add hydrophilic ionic liquid 1-butyl-3-methylimidazolium trifluoromethanesulfonate ([Bmim]OTF) to increase substrate solubility, improve the substrate concentration and enzyme-catalyzed resolution of the reaction Reaction efficiency of ethyl 2,2-dimethylcyclopropanecarboxylate.

[0026] Dissolve 0.1ml of [Bmim]OTF in 9.9ml of pH 7.2, 1mol / L phosphate buffer, add 65mmol of substrate ethyl 2,2-dimethylcyclopropanecarboxylate, add 160mg of lipase Novozym 435, Enzymatically catalyzed reactions were carried out in 50ml Erlenmeyer flasks. The reaction temperature was 30° C., the rotation speed of the shaker was 200 r / min, and the reaction was performed for 24 hours. After the reaction, extract with twice the volume of ethyl acetate, set the volume to 20ml, and perform gas chromatography analysis. The concentration of the product obtained is 2.8g / L, the ee value of the product is 97.8%, and the yield is 38.1%.

Embodiment 2～7

[0028] With reference to the method of Example 1, the reaction of the aqueous phase system under the same conditions is used as a contrast (i.e. the reaction medium is 10ml of pH 7.2, 1mol / L phosphate buffer), to investigate the effect of different types of hydrophilic ionic liquids on 2,2- The impact of ethyl dimethylcyclopropane formate bioresolution, the results are shown in Table 1:

[0029] Table 1

[0030]

[0031]

[0032] Conclusion: The above hydrophilic ionic liquids can effectively improve the bioresolution of ethyl 2,2-dimethylcyclopropanecarboxylate catalyzed by lipase Novozym 435. A preferred hydrophilic ionic liquid is 1-butyl-3-methylimidazolium triflate ([Bmim]OTF).

Embodiment 8～15

[0034] With reference to the method of Example 1, change the volume fraction of [Bmim]OTF in the reaction system, investigate the impact of the volume fraction of [Bmim]OTF on 2,2-dimethylcyclopropane ethyl formate bioresolution, the results are shown in the table 2:

[0035] Table 2

[0036]

[0037] Conclusion: The volume fraction of [Bmim]OTF is better in the range of 1-10%, and the optimal volume fraction is 6%.

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Abstract

The invention provides a method for preparing (S)-(+)-2,2-dimethyl cyclopropane methanoic acid by biological resolution in a water-ionic liquid cosolvent system. The method comprises the following steps of: performing biological catalytic asymmetric hydrolysis reaction by taking racemic 2,2-dimethyl cyclopropane ethyl formate as a substrate and lipase Novozym 435 as a biocatalyst at the temperature of 30 DEG C at a speed of 200 revolutions / minute in the water-ionic liquid cosolvent system which is formed by mixing a phosphate buffer solution of which the pH value is between 6.0 and 7.8 and a hydrophilic ionic liquid for 24 to 56 hours, and after reacting, separating and purifying a reaction solution to obtain the (S)-(+)-2,2-dimethyl cyclopropane methanoic acid. According to the method, a biological resolution effect of catalyzing the 2,2-dimethyl cyclopropane ethyl formate by the lipase Novozym 435 can be improved effectively by a reaction system containing the hydrophilic ionic liquid cosolvent; and by solubilizing the substrate, the concentration of the reacted substrate is improved from 65 mmol / L during water-phase conversion to 100 mmol / L, the yield is up to 47.1 percent, and the reaction time is shortened to 52 hours from 64 hours during the water-phase conversion.

Description

(1) Technical field [0001] The invention relates to a method for preparing (S)-(+)-2,2-dimethylcyclopropanecarboxylic acid by biological resolution in a water-ionic liquid co-solvent system. (2) Background technology [0002] S-(+)-2,2-Dimethylcyclopropanecarboxylic acid is an important chiral intermediate in the synthesis of cilastatin. Cilsatatin (cilsatatin), the chemical name is (+)-(Z)-7-[(2R)-(2-amino-2-carboxyethyl)sulfur]-2-[(1S)-(2, 2-Dimethylcyclopropanecarboxamido)]-2-heptenoic acid is the first renal dehydrodipeptidase inhibitor used clinically, and it is an antibacterial drug compounded with imipenem——Tai can It is a broad-spectrum β-lactam antibiotic developed by Merck in 1979 and first listed in Germany in 1985. As an inhibitor of renal dehydropeptidase, cilastatin can effectively prevent renal dehydropeptidase from degrading imipenem in vivo and enhance the antibacterial activity of imipenem. The preparation of optically pure 2,2-dimethylcyclopropanecar...

Claims

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Application Information

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IPC IPC(8): C12P41/00C12P7/40C12P7/62
CPCY02P20/54
Inventor 王普黄金何军邀任峰
Owner ZHEJIANG UNIV OF TECH
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