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Purpose of compound for preparing Sitagliptin and Sitagliptin preparation method

A technology for sitagliptin and a compound, which is applied in the field of preparing sitagliptin and achieves the effects of large yield, high amino conversion efficiency and easy operation

Active Publication Date: 2017-10-24
WUHAN HESHENG TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] However, the synthetic method of sitagliptin still needs to be further improved

Method used

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  • Purpose of compound for preparing Sitagliptin and Sitagliptin preparation method
  • Purpose of compound for preparing Sitagliptin and Sitagliptin preparation method
  • Purpose of compound for preparing Sitagliptin and Sitagliptin preparation method

Examples

Experimental program
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Effect test

Embodiment 1

[0032] The preparation of embodiment 1 transaminase

[0033] In the following examples, the transaminase is derived from the modified enzyme of the transaminase derived from Arthrobacter by Codexis, and the preparation method of the transaminase is as follows:

[0034] The target gene encoding transaminase (synthesized by Wuhan Tianyi Huiyuan Company) was inserted into the expression plasmid pRSFDuet-1 to obtain a recombinant expression plasmid. The recombinant expression plasmid was transformed into E.coliBL21(DE3) competent cells, and the transformation liquid was spread on the LB plate containing kanamycin, and cultured upside down at 37°C overnight. The resulting recombinant E.coli BL21 (DE3) was inoculated into the LB medium containing kanamycin (the LB medium contains 10g / L protein, 5g / L yeast extract and 10g / LNaCl, pH7.0), Shake culture at 37°C overnight, and insert into 500ml LB medium (the medium is contained in a 2000ml Erlenmeyer flask) according to the inoculum si...

Embodiment 2

[0035] Example 2 Transaminase to the transamination reaction of 3-carbonyl-4-(2,4,5-trifluorophenyl) hydroxyethyl butyrate

[0036] Add 1.1ml 1.83M isopropylamine aqueous solution (pH=8.5), 0.5ml crude transaminase solution, 0.4ml 250mM / L 3-carbonyl-4-(2,4,5-trifluorophenyl) into a 10ml single-necked flask The dimethyl sulfoxide (DMSO) solution of hydroxyethyl butyrate was reacted with magnetic stirring at 45°C for 24 hours, and the conversion rate of the amino group was greater than 99% as determined by high performance liquid chromatography (HPLC). After the reaction, adjust the pH to 11.0, and extract twice with 10 mL of ethyl acetate, combine the extracts, add anhydrous sodium sulfate to dry overnight, remove the solvent by rotary evaporation, and distill under reduced pressure to obtain 25 mg of (R)-3- Amino-4-(2,4,5-trifluorophenyl)-butyric acid hydroxyethyl ester, yield 90.5%, purity>95%, optical purity>98%.

Embodiment 3

[0037] Example 3 The transamination reaction of transaminase to 3-carbonyl-4-(2,4,5-trifluorophenyl) hydroxypropyl butyrate

[0038] Add 1.1ml 1.83M isopropylamine aqueous solution (pH=8.5), 0.5ml crude transaminase solution, 0.4ml 250mM / L 3-carbonyl-4-(2,4,5-trifluorophenyl) into a 10ml single-necked flask The dimethyl sulfoxide (DMSO) solution of hydroxypropyl butyrate was reacted with magnetic stirring at 45° C. for 24 hours, and the conversion rate of amino groups was determined by high performance liquid chromatography (HPLC) to be greater than 99%. After the reaction, adjust the pH to 11.0, and extract twice with 10 mL of ethyl acetate, combine the extracts, add anhydrous sodium sulfate to dry overnight, remove the solvent by rotary evaporation, and distill under reduced pressure to obtain 25 mg of (R)-3- Amino-4-(2,4,5-trifluorophenyl)-butyric acid hydroxypropyl ester, yield 90.5%, purity>95%, optical purity>98%.

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Abstract

The invention provides a compound shown by a formula I, a purpose of a stereoisomer, a geometrical isomer, a tautomer, an oxynitride, a hydrate, a solvate, a metabolite, a pharmacologically acceptable salt or prodrug of the compound in Sitagliptin preparation, and a Sitagliptin preparation method. The formula I is shown in the description, wherein R1 is a substitutional group containing the hydroxyl group. The compound shown by the formula I or the stereoisomer, the geometrical isomer, the tautomer, the oxynitride, the hydrate, the solvate, the metabolite, the pharmacologically acceptable salt or the prodrug of the compound shown by the formula I has high water solubility, and is used for obtaining a chiral amino intermediate to further obtain the Sitagliptin. Compared with the prior art, the compound has the advantages that the amino group conversion rate is greatly improved; the yield of the Sitagliptin is also greatly improved.

Description

technical field [0001] The invention relates to the field of medicine, in particular, the invention relates to the application of the compound in preparing sitagliptin and the method for preparing sitagliptin. Background technique [0002] Diabetes mellitus is a metabolic disease that occurs due to changes in insulin secretion, leading to insulin deficiency and weakened action, or decreased insulin activity, or under the combined influence of the two. It is characterized by high blood sugar and accompanied by protein, sugar and fat metabolism. disorder. Diabetes and its complications are the third most harmful to human health after cardiovascular diseases and tumors, becoming an important disease that endangers human health. The International Diabetes Federation predicts that by 2030, the total number of people suffering from diabetes will exceed 435 million. my country has become the world's fastest growing diabetes prevalence nation One, there are currently about 40 mil...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04C12P13/04
CPCC07D487/04C12P13/04
Inventor 侯安伟刘然
Owner WUHAN HESHENG TECH CO LTD
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