Chiral resolution method of isobutyrate compound

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

Active Publication Date: 2021-06-22
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

[0043] In a 10mL reaction bottle, add 0.1g of substrate ester into 5mL of 0.3M potassium phosphate buffer solution, adjust the pH to 7.0-7.5, add 0.005-0.1g of hydrolase (lyophilized powder preparation or enzyme solution, see Table 1 for details) 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 hydrolysis system. Take 100 μL of the hydrolyzed system and use 900 μL of 50% acetonitrile to stop the reaction. After fully shaking and mixing, centrifuge at 8000 rpm for 1 min to obtain the supernatant aqueous phase and organic solid phase. After the supernatant aqueous phase is dried with nitrogen, it is dissolved in ethanol, and the conversion rate and Chirality, 100 kinds of hydrolases were screened for the following substrates (these 100 kinds of hydrolases were all from commercial enzymes, the known sequences reported in the literature were artificia...

Embodiment 2

[0049] (1) Feeding: Into a 100mL reaction bottle, add 0.5g of hydrolase Thermomyces.sp, 30mL tris-hydrochloric acid buffer solution (300mM, pH=9.0), stir, and dissolve the enzyme in tris - In hydrochloric acid buffer;

[0050] (2) Add substrate: add 1g of main raw material to the above-mentioned reaction bottle Stir, the system pH=9.0;

[0051] (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;

[0052] (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 use Adjust the pH to 2~3 with 0.5M hydrochloric acid, the product precipitates, control the temperature of the product to concentrate at 40~45°C, filter to obtain the product After testing, its purity...

Embodiment 3

[0054] (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 of ethyl acetate

[0055] (2) Add substrate: add 1g of main raw material to the above reaction bottle Stir and maintain the pH of the system to 7.5 with 1N NaOH;

[0056] (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;

[0057] (4) Post-treatment: Take 100 μL of the system and terminate the reaction with 900 μL of 50% acetonitrile. After fully shaking and mixing, centrifuge at 8000 rpm for 1 min. After drying the supernatant liquid phase with nitrogen, dissolve it in ethanol. The conversion rate detected by HPLC is 45.67 %, 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, pyrimidone, 4-hydroxyquinoline, quinazoline and quinazolinone, R2 is selected from substituted or unsubstituted alkyl and aryl, and the chiral resolution method comprises the following steps: S1, carrying out hydrolysis treatment on a racemic isobutyrate compound by adopting hydrolase to obtain a hydrolyzed system, wherein the hydrolase is derived from Thermomyces sp.Rhizomucor miehei, Bacillus sp.; and S2, separating the acid in the hydrolyzed system from the isobutyrate compound which is not hydrolyzed. The hydrolase used in the method has the advantages of good stability, good enantiomer selectivity, mild reaction conditions, low cost and simple operation.

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 isobutyric aci...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12P41/00C12P7/62
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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