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Method for synthesizing (s)-1-(2,6-dichloro-3-fluoro-phenyl)ethanol catalyzed by immobilized double enzymes

A fluoroacetophenone and double-enzyme technology, which is applied in the field of immobilized double-enzyme catalyzed synthesis of 1-ethanol, can solve the problems that the catalyst, that is, the free enzyme is unstable and inconvenient, the optical purity of the product needs to be improved, and the catalyst consumption is large, etc. The effect of low cost, high product yield and simple recovery

Active Publication Date: 2021-02-09
HANGZHOU NORMAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0012] Using the above method to synthesize the product, because the free enzyme is used in the synthesis process, the activity of the enzyme lasts for a short time, so the amount of catalyst used is relatively large and wasteful; the catalyst, that is, the instability of the free enzyme during transportation is also a big problem. ; In addition, the optical purity of the obtained product also needs to be improved

Method used

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  • Method for synthesizing (s)-1-(2,6-dichloro-3-fluoro-phenyl)ethanol catalyzed by immobilized double enzymes
  • Method for synthesizing (s)-1-(2,6-dichloro-3-fluoro-phenyl)ethanol catalyzed by immobilized double enzymes
  • Method for synthesizing (s)-1-(2,6-dichloro-3-fluoro-phenyl)ethanol catalyzed by immobilized double enzymes

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] Weigh 4mg of 2,6-dichloro-3-fluoroacetophenone and 5mg of coenzyme NADP + , dissolved in the reaction solvent, the reaction solvent is 90% potassium phosphate buffer and 10% isopropanol. Then add calcium phosphate enzyme crystals to the reaction solvent, the enzyme crystals contain 3 mg of aldehyde ketone reductase and 1 mg of alcohol dehydrogenase, place the reaction container in a shaking table at 40 ° C for 12 hours, and filter after the reaction is over. The filter residue is washed with a washing solvent to obtain a filtrate, and then water and n-heptane are added to the filtrate for extraction to obtain an organic layer and an aqueous layer. The washing solvent is the same as the extraction solvent, and the organic layer is dried by adding anhydrous magnesium sulfate, and filtered , heated and spin-dried under reduced pressure to obtain a solid. The product was analyzed by chiral HPLC, and the conversion rate was 95%, and its optical purity was 100% ee.

[0043]...

Embodiment 2

[0046] Weigh 10mg of 2,6-dichloro-3-fluoroacetophenone and 10mg of coenzyme NADP + , dissolved in the reaction solvent, the reaction solvent is 90% potassium phosphate buffer and 10% isopropanol. Then add calcium phosphate enzyme crystals to the reaction solvent, the enzyme crystals contain 10 mg of aldehyde ketone reductase and 3 mg of alcohol dehydrogenase, and place the reaction container in a shaker at 30°C for 12 hours of shaking; after the reaction, filter, The filter residue is washed with a washing solvent to obtain a filtrate, and then water and n-heptane are added to the filtrate for extraction to obtain an organic layer and an aqueous layer. The washing solvent is the same as the extraction solvent, and the organic layer is dried by adding anhydrous magnesium sulfate, and filtered , heated and spin-dried under reduced pressure to obtain a solid. The product was analyzed by chiral HPLC, and the conversion rate was 32%, and its optical purity was 100% ee.

Embodiment 3

[0048] Weigh 10mg of 2,6-dichloro-3-fluoroacetophenone and 10mg of coenzyme NADP + , dissolved in the reaction solvent, the reaction solvent is 90% potassium phosphate buffer and 10% isopropanol. Then add calcium phosphate enzyme crystals to the reaction solvent, the enzyme crystals contain 10 mg of aldehyde ketone reductase and 3 mg of alcohol dehydrogenase, and place the reaction container in a shaker at 40°C for 12 hours of shaking reaction; after the reaction, filter, The filter residue is washed with a washing solvent to obtain a filtrate, and then water and n-heptane are added to the filtrate for extraction to obtain an organic layer and an aqueous layer. The washing solvent is the same as the extraction solvent, and the organic layer is dried by adding anhydrous magnesium sulfate, and filtered , heated and spin-dried under reduced pressure to obtain a solid. The product was analyzed by chiral HPLC, and the conversion rate was 79%, and its optical purity was 100% ee.

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Abstract

The invention relates to a method for the synthesis of (S)-1-(2,6-dichloro-3-fluoro-phenyl)ethanol catalyzed by an immobilized double enzyme, which uses 2,6-dichloro-3-fluorophenyl Ketones as substrates in calcium phosphate-enzyme crystals and coenzyme NADP + Under the synergistic catalysis of , react with the reaction solvent at 30-60°C to obtain the optically pure product (S)-1-(2,6-dichloro-3-fluoro-phenyl)ethanol. The method of the invention has low cost, the enzyme crystal is convenient for catalytic separation and repeated utilization, the yield of the target product can reach 95%, and the ee can reach 100%. The method is environmentally friendly and energy-saving, and is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of synthesis of crizotinib pharmaceutical intermediates, in particular to a method for synthesizing (S)-1-(2,6-dichloro-3-fluoro-phenyl)ethanol catalyzed by immobilized double enzymes method. Background technique [0002] Enzyme is a kind of protein with special three-dimensional spatial conformation produced by biological cells and having catalytic activity. As we all know, biocatalysis, as a kind of green catalysis, has attracted people's attention because of its environmental protection, energy saving and high efficiency. However, enzymes are the most commonly used in biocatalysis and are often used as resolution catalysts. As a kind of biocatalyst, the reaction catalyzed by enzyme has the advantages of strong specificity (enzyme catalysis has regioselectivity and stereoselectivity), high catalytic efficiency, and can be operated under isothermal conditions of normal temperature and pressure. But at th...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C12P7/22C12N11/18C12N11/14
CPCC12N9/0006C12N11/14C12N11/18C12P7/22C12Y101/01002
Inventor 王安明章鹏飞陈鑫鑫沈超
Owner HANGZHOU NORMAL UNIVERSITY