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Process for preparing alcohol compounds with multiple chiral centers

An alcohol compound and compound technology, applied in the field of chiral compound synthesis, can solve the problem that chiral alcohol cannot obtain products with two or more chiral centers in one step, etc.

Active Publication Date: 2020-10-20
JILIN ASYMCHEM LAB CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The present invention aims to provide a method for preparing alcohol compounds with multiple chiral centers to solve the technical problem that the production of chiral alcohols in the prior art cannot obtain products with two or more chiral centers in one step

Method used

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  • Process for preparing alcohol compounds with multiple chiral centers
  • Process for preparing alcohol compounds with multiple chiral centers
  • Process for preparing alcohol compounds with multiple chiral centers

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] (1) Feeding: Add 30mg of the main raw material into a 10mL plastic bottle 100uL DMSO, 1.5mL phosphate buffer (100mmol / L, pH=7.0), the raw materials are evenly dispersed in the phosphate buffer;

[0034] (2) Ketoreductase: Add 1 mg coenzyme NAD+, 1.1 mg coenzyme NADP+, 130 mg D-glucose, 0.3 g ketoreductase main enzyme KRED and 5 mg glucose dehydrogenase GDH into a 10 mL plastic bottle, and the system pH=7.0;

[0035] (3) Reaction: The system was reacted at 30°C and stirred for 12 hours;

[0036] (4) Post-treatment: the system is extracted with 2 mL of ethyl acetate, left to separate liquids, and the product is detected by gas phase generation.

[0037]A total of 100 kinds of ketoreductases were screened (these 100 kinds of ketoreductases were all artificially synthesized from known sequences reported in the literature or the above sequences were artificially mutated), most of the reaction systems using the above ketoreductases left a large amount of raw materials , ...

Embodiment 2

[0041] (1) Feeding: Add 20g of the main raw material into the 2L reactor 500mL phosphate buffer (100mM, pH=6.0), the raw materials are evenly dispersed in the phosphate buffer;

[0042] (2) Ketoreductase: Add 0.15g of coenzyme NAD+, 54g of D-glucose, 40g of ketoreductase ACCR (SEQ ID NO: 1) and 2g of glucose dehydrogenase GDH into a 2L reaction kettle, and the system pH= 6.0;

[0043] (3) Reaction: The system was reacted at 25°C and stirred for 24 hours;

[0044] (4) post-processing: the system is filtered with 200g diatomaceous earth, extracted with 1.8L ethyl acetate, left to separate liquids, the organic phase is dried, filtered, concentrated to obtain crude product, purified by column chromatography to obtain 8.2g of higher purity product The purity is 95.0%, the yield is 41%, the ee value is 99.5%, and the de value is 99.2%.

Embodiment 3

[0046] (1) Feeding: Add 20g of the main raw material into the 2L reactor 150mL isopropanol, 1L phosphate buffer (100mM, pH=7.5), the raw materials are evenly dispersed in the phosphate buffer;

[0047] (2) Ketoreductase: Add 0.2 g of coenzyme NAD+ and 10 g of ketoreductase ACCR (SEQ ID NO: 1) into a 2L reaction kettle, and the system pH=7.5;

[0048] (3) Reaction: The system was reacted at 40°C and stirred for 16 hours;

[0049] (4) post-processing: the system is filtered with 200g of diatomaceous earth, extracted with 1.5L of ethyl acetate, left to separate liquids, the organic phase is dried, filtered, concentrated to obtain a crude product, and purified by column chromatography to obtain 9.2g of higher purity product The purity is 92.7%, the yield is 46%, the ee value is 98.7%, and the de value is 99%.

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Abstract

The invention discloses a method of preparing an alcoholic compound with a plurality of chiral centers. The method comprises the following steps of: allowing a substance with a formula as shown in thespecification to react in a reaction system by the action of ketoreductase to generate a product with a formula as shown in the specification, wherein R1 and R2 are methyl or ethyl; R3 is t-butyloxycarboryl or benzyloxycarbonyl; and n is equal to 0 or 1. With the adoption of the technical scheme, the ketoreductase takes a ketone compound as a raw material; chiral alcohol can be produced efficiently by a stereoselective reduction action; selective splitting can be performed; the chiral alcoholic compound with the chiral centers is obtained by one step; the method has the characteristics that asubstrate is relatively cheap and a product is high in purity; and the method is suitable for popularization in industrial production of the chiral alcohol.

Description

technical field [0001] The invention relates to the technical field of chiral compound synthesis, in particular to a method for preparing alcohol compounds with multiple chiral centers. Background technique [0002] Chiral alcohols are a class of optically active compounds with a hydroxyl group attached to the chiral carbon, and are widely used in the synthesis of chiral drugs and other chiral fine chemicals. The synthesis methods of chiral alcohols mainly include physical separation, resolution and asymmetric reduction. Among them, the chemical resolution often uses a resolving agent such as tartaric acid for multiple resolutions, and the chemical purity of the resulting product can reach more than 99%, but its disadvantage is that the resolution yield is extremely low, only less than 10%; in addition, chiral resolution The price of the agent is higher, which greatly increases the production cost; the operation is more complicated, and the post-processing does not take adv...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C12P7/02
Inventor 卢江平张娜李艳君贺晓晗刘文敬
Owner JILIN ASYMCHEM LAB CO LTD
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