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Chiral resolution method of isobutyrate compound

A technology of chiral resolution and isobutyrate, which is applied in fermentation and other directions, can solve the problems of high cost and complicated operation of chiral resolution, and achieve the effect of easy availability of raw materials and catalysts, simple operation and good stability

Inactive Publication Date: 2021-02-12
ASYMCHEM LIFE SCI TIANJIN
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] The main purpose of the present invention is to provide a chiral resolution method for isobutyrate compounds, so as to solve the problems of high cost and complicated operation of chiral resolution of isobutyrate compounds in the prior art

Method used

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  • Chiral resolution method of isobutyrate compound
  • Chiral resolution method of isobutyrate compound
  • Chiral resolution method of isobutyrate compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] In a 10 mL reaction bottle, add 0.1 g of substrate ester into 5 mL of 0.3 M potassium phosphate buffer solution, adjust the pH to 7.0~7.5, add 0.005~0.1 g of hydrolase (lyophilized powder preparation or enzyme solution, see Table 1) Form a hydrolysis reaction system, control the pH of the hydrolysis reaction system to 7.0~7.5, stir at a constant temperature of 30°C±3°C for a certain period of time, and obtain a hydrolyzed system. Take 100 μL of the hydrolyzed system and stop the reaction with 900 μL of 50% acetonitrile, shake and mix well, and centrifuge at 8000 rpm for 1 min to obtain the supernatant aqueous phase and organic solid phase, which are dried with nitrogen, dissolved in ethanol, and detected by HPLC According to the efficiency and chirality, 100 kinds of hydrolases were screened for the following substrates (these 100 kinds of hydrolases are all from commercial enzymes, artificially synthesized from known sequences reported in literature or obtained by artif...

Embodiment 2

[0047] (1) Feeding: Add 0.5 g of hydrolase Thermomyces.sp, 30 mL of tris-hydrochloric acid buffer (300 mM, pH=9.0) into a 100 mL reaction bottle, stir, and dissolve the enzyme in tris In aminomethane-hydrochloric acid buffer;

[0048] (2) Substrate addition: add 1 g of the main raw material to the above reaction bottle , stirring, the system pH=9.0;

[0049] (3) Reaction: The system was reacted at 30°C, stirred for 24 hours, and the pH of the system was maintained to 9.0 with 1N NaOH;

[0050] (4) Post-treatment: Add 20 mL of acetonitrile to the system after the reaction, stir for 30 minutes, and then filter through a diatomaceous earth pad. Adjust the pH of the obtained organic phase system to 8~9 with sodium bicarbonate solution, add 20 mL of ethyl acetate for extraction three times, and water The pH of the phase was adjusted to 2~3 with 0.5 M hydrochloric acid, and the product was precipitated, and the temperature of the product was controlled at 40~45°C to concentrate a...

Embodiment 3

[0052] (1) Feeding: Add 0.05 g of hydrolase Thermomyces.sp, 25 mL of potassium phosphate buffer (100 mM, pH=7.5) into a 100 mL reaction bottle, stir, and dissolve the enzyme in potassium phosphate buffer; add 2.5 mL ethyl acetate

[0053] (2) Substrate addition: add 1 g of the main raw material to the above reaction flask , stirred, and maintained the pH of the system to 7.5 with 1N NaOH;

[0054] (3) Reaction: The system was reacted at 40°C, stirred for 120 hours, and the pH of the system was maintained to 7.5 with 1N NaOH;

[0055] (4) Post-treatment: Take 100 μL of the system and stop the reaction with 900 μL of 50% acetonitrile. After fully shaking and mixing, centrifuge at 8,000 rpm for 1 min. After drying the supernatant liquid phase with nitrogen, dissolve it in ethanol, and detect the conversion rate by HPLC. is 45.67%, and the product is The e.e. value was 99.5%.

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Abstract

The invention provides a chiral resolution method of an isobutyrate compound. The isobutyrate compound is a racemic isobutyrate compound and has the following structural general formula, R1 is selected from any one of the following substituted or unsubstituted groups: pyridine, pyrazole, pyrimidinone, 4hydroxyquinoline, quinazoline and quinazolinone, and R2 is selected from substituted or unsubstituted alkyl and aryl. According to the method, a racemic isobutyrate compound is subjected to hydrolysis treatment by adopting hydrolase to obtain a hydrolyzed system, and the hydrolase is from Thermomyces sp., Rhizomucor miehei and Bacillus sp.; and step S2, separating acid in the hydrolyzed system from the unhydrolyzed isobutyrate compound. The hydrolase used in the method is good in stability,good in enantiomer selectivity, mild in reaction condition, low in cost and simple to operate.

Description

technical field [0001] The invention relates to the technical field of chiral resolution, in particular to a chiral resolution method for isobutyrate compounds. Background technique [0002] The vast majority of drugs are composed of chiral molecules, and two chiral molecules may have significantly different biological activities. The drug molecule must match the geometric structure of the receptor (substance that reacts) in order to have the desired drug effect. Therefore, often only one of the two isomers is effective, and the other is ineffective or even harmful. Heterocyclic substituted isobutyrate derivatives are a class of compounds with a relatively simple structure and a wide range of uses. Some of their compounds are intermediates of many new drugs in the current experimental and clinical stages. [0003] The literature (Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 3, p. 668 - 672) reported the chemical synthesis method of chiral pyrazole isobutyri...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12P17/12C12P17/10C12P41/00
CPCC12P41/005C12P41/001C12P7/62
Inventor 洪浩詹姆斯·盖吉肖毅陈轶晖张娜李艳君龚天保黄鑫朱柳杨李响崔毅李招
Owner ASYMCHEM LIFE SCI TIANJIN
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