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Method for preparing chiral 3R, 5S-dihydroxyl compound by nonaqueous phase

A technology of bishydroxy compounds and chiral compounds, which is applied in the field of asymmetric preparation of chiral pharmaceutical intermediates by biocatalysis, can solve the problems of low substrate concentration, difficulty in meeting optical purity requirements of products, and low total yield. Simple, good application prospect, process controllable effect

Active Publication Date: 2010-11-10
金隆科技集团有限公司
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  • Abstract
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  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

This technology allows for better yields from certain chemical compounds by utilizing two different types of reaction systems - one involves reacting an organolithium derivative (C2H5) or another molecule called dihydrocortisone oxime; this second type also includes other substances like enzymatic processes that help convert these starting materials into desired products. By combining both techniques together, there are benefits over existing methods such as reducing waste generated during production while improving productivity at large scales.

Problems solved by technology

This patented technical problem addressed in this patent relates to finding ways to efficiently produce various types of molecules with specific structures called quaternized hydrogenated imidazolidine bases or guaimides from certain sugars while minimizing waste materials generated during their manufacturing process.

Method used

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  • Method for preparing chiral 3R, 5S-dihydroxyl compound by nonaqueous phase
  • Method for preparing chiral 3R, 5S-dihydroxyl compound by nonaqueous phase
  • Method for preparing chiral 3R, 5S-dihydroxyl compound by nonaqueous phase

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Effect test

Embodiment 1

[0035] A method for preparing 3R, 5S-dihydroxy-6-benzyloxy-ethylhexanoate, comprising the following steps: in a 1ml reaction system, sequentially add 9.5-140mg of sodium formate, 3,5-dicarbonyl-6- Benzyloxy-ethyl hexanoate 10~150mg, 0.1M (pH=6.0) potassium phosphate buffer, NAD + 20μl (0.5mM), formate dehydrogenase 27.2mg (4U / ml), double carbonyl reductase supernatant 65μl (6U / ml), and finally add n-hexane 500μl; react at room temperature and shaking speed of 200rpm for 18 hours, After the reaction was stopped, the samples were separated and purified, and the samples were subjected to high-performance liquid chromatography to analyze the conversion rate of the substrate and the optical purity of the product.

[0036] When the substrate concentration is less than or equal to 100g / L, the conversion rate is greater than 99%, and the conversion rate at 125g / L is 95.1%, and the ee and de of the product 3R, 5S-dihydroxy-6-benzyloxy-ethyl hexanoate The values ​​are all higher than 9...

Embodiment 2

[0041] A method for preparing 3R, 5S-dihydroxy-6-benzyloxy-ethylhexanoate, comprising the steps of: adding 9.5 mg of sodium formate and 3,5-dicarbonyl-6-benzyl to a reaction system of 1 ml successively Oxy-ethylhexanoate 10mg, 0.1M (pH=6.0) potassium phosphate buffer, NAD + 20μl (0.5mM), formate dehydrogenase 27.2mg (4U / ml), double carbonyl reductase supernatant 65μl (6U / ml), and finally add n-hexane 500μl; react at 40°C and shaking speed 200rpm for 18 hours After the reaction is stopped, separation and purification are carried out, and the sample is subjected to high performance liquid chromatography to analyze the conversion rate of the substrate and the optical purity of the product.

[0042] The substrate conversion rate was 76.4%, and the ee and de values ​​of the product 3R, 5S-dihydroxy-6-benzyloxy-ethylhexanoate were both higher than 99.5%.

Embodiment 3

[0044] A method for preparing 3R, 5S-dihydroxy-6-benzyloxy-ethyl hexanoate, comprising the steps of: in a reaction system of 1ml, adding sodium formate 140mg (2M), 3,5-dicarbonyl- 6-Benzyloxy-ethylhexanoate 10g / L, 0.1M (pH=6.0) potassium phosphate buffer, NAD + 20μl (0.5mM), formate dehydrogenase 27.2mg (4U / ml), double carbonyl reductase supernatant 65μl (6U / ml), finally add ethanol 100-400μl, react at room temperature and shaking speed 200rpm for 18 hours , after the reaction was stopped, separation and purification were carried out, and the sample was analyzed by high performance liquid chromatography for substrate conversion rate and product optical purity.

[0045] When the ethanol content is 20% (v / v), the conversion rate is 95.0%, and the conversion rate is 3.3% at 30%, the ee and de values ​​of the product 3R, 5S-dihydroxy-6-benzyloxy-ethyl hexanoate Both are higher than 99.5%.

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Abstract

The invention belongs to the field of asymmetrically preparing chiral medicine intermediates in a biocatalysis method, and particularly relates to a method for preparing 3R, 5S-dyhydroxy-6-benzyloxy-ethyl hexanoate with single optical purity via reduction by taking 3, 5- dicarbonyl-6-benzyloxy-ethyl hexanoate as a substrate and taking double carbonyl reductase as a biocatalyst. The method comprises the following steps: (1) adding the substrate, the double carbonyl reductase and a coenzyme cyclic regeneration system mediated by formate dehydrogenase in a reaction liquid, and oscillating for reaction for at least 1 hour, wherein the reaction liquid is the mixed solution of an organic solvent and a buffer solution; and (2) separating and purifying the product obtained in step (1) to obtain a single optical isomer 3R, 5S- dihydroxyl compound. The invention adopts the double carbonyl reductase and is simultaneously combined with the nonaqueous phase solvent system and the coenzyme regeneration system to synthesize the 3R, 5S-dyhydroxy-6-benzyloxy-ethyl hexanoate via catalysis, the optical purity ee and de values are both larger than 99.5%, the concentration of the substrate reaches 150g/L, and the method has wide practical value.

Description

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Claims

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Application Information

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Owner 金隆科技集团有限公司
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