Method for synthesizing (S)-1-1(2,6-dichloro-3-fluorine-phenyl) ethanol through immobilized bienzyme catalysis

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: 2018-07-17
HANGZHOU NORMAL UNIVERSITY
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  • Abstract
  • Description
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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)-1-1(2,6-dichloro-3-fluorine-phenyl) ethanol through immobilized bienzyme catalysis
  • Method for synthesizing (S)-1-1(2,6-dichloro-3-fluorine-phenyl) ethanol through immobilized bienzyme catalysis
  • Method for synthesizing (S)-1-1(2,6-dichloro-3-fluorine-phenyl) ethanol through immobilized bienzyme catalysis

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Experimental program
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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 synthesizing (S)-1-1(2,6-dichloro-3-fluorine-phenyl) ethanol through immobilized bienzyme catalysis. 2,6-dichloro-3-fluoroacetophenone is used as a substrate, andreacts with a reaction solvent at 30 to 60 DEG C under the synergetic catalysis action of calcium phosphate-enzyme crystal and coenzyme NADP+ to prepare an optical pure product (S)-1-1(2,6-dichloro-3-fluorine-phenyl) ethanol. The method disclosed by the invention is low in cost; the enzyme crystal is convenient for catalytic separation and repeated use; the target product yield can be up to 95 percent, and ee can be up to 100 percent; the method is environmentally friendly, can save energy and reduce consumption, 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 Applications(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
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