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Preparation method of sitagliptin

A technology of sitagliptin and trifluorophenyl, applied in the field of compound preparation, can solve the problems of low optical purity ee%, waste of resources and high cost, and achieve the effects of high purity, mild process conditions and high EE value

Active Publication Date: 2012-10-03
SUZHOU XINKAI BIOLOGICAL MEDICINE TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The optical purity ee% of the product of chiral induction and asymmetric hydrogenation is low, and further purification is required to increase the ee%, so there is a waste of resources, while half of the isomers cannot be used in the chemical resolution method, the yield is low, and the cost is high

Method used

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  • Preparation method of sitagliptin
  • Preparation method of sitagliptin
  • Preparation method of sitagliptin

Examples

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Embodiment 1

[0065] Add oxalyl chloride to the dichloromethane solution of 2,4,5-trifluorophenylacetic acid, stir for 2 hours, slowly add this solution dropwise to the dichloromethane solution of Meldrum's acid and sym-collidine, and react at zero temperature 3-6 hours. Hydrochloric acid was added to quench the reaction, and the layers were separated. Sodium hydroxide solution was added to the organic layer, the layers were separated, the organic phase was discarded, the aqueous phase was acidified with hydrochloric acid, and filtered to obtain a yellow solid. Dissolve the yellow solid in methanol, heat and reflux for 3-6 hours, and cool to obtain the methanol solution of the first step product.

[0066] Add ammonium acetate to the methanol solution of the first step product, heat and reflux for 20 hours, cool, concentrate under pressure, add ethyl acetate after the methanol is removed, cool, separate the ammonium acetate slurry layer, wash once with water, and distill ethyl acetate under...

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Abstract

The invention discloses a preparation method of sitagliptin, comprising the following steps: reacting 2, 4, 5-trifluoro-phenylacetic acid with malonic cyclo (sub) isopropyl ester; reacting 3-oxo-4-(2, 4, 5-trifluorophenyl) methyl butyrate with ammonium acetate; reacting 3-amino-4-(2, 4, 5-trifluorophenyl) methyl crotonate with hydrogen; performing hydrolysis reaction to (R)-3-amino-4-(2, 4, 5-trifluorophenyl) methyl butyrate; and reacting (R)-3-amino-4-(2, 4, 5-trifluorophenyl) butyric acid with 3-(trifluoromethyl)-5, 6, 7, 8-tetrahydro-[1, 2, 4] triazol [4, 3-a] pyrazine hydrochloride to obtain sitagliptin. According to the invention, EE value greater than 90% is obtained through high-efficiency catalytic hydrogenation; sitagliptin is prepared by only five steps; yield is higher; technical conditions are mild; operations are simple; cost is low; and yield and purity of products are high.

Description

technical field [0001] The invention relates to a preparation method of a compound, in particular to a preparation method of sitagliptin. Background technique [0002] Sitagliptin is a dipeptidyl peptidase-IV inhibitor drug used to treat type 2 diabetes. It controls the blood sugar level of diabetic patients by improving the ability of diabetic patients' own pancreatic β cells to produce insulin and increasing the secretion of insulin when blood sugar rises. And it is well tolerated, does not gain weight, and does not risk hypoglycemia. [0003] At present, there are many methods for synthesizing sitagliptin at home and abroad, involving chiral induction and asymmetric hydrogenation: the steps are of different lengths, as few as four or five steps, as many as more than ten steps. The optical purity ee% of the product of chiral induction and asymmetric hydrogenation is low, and further purification is required to increase the ee%, so there is a waste of resources, while hal...

Claims

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Application Information

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IPC IPC(8): C07D487/04
Inventor 张松林
Owner SUZHOU XINKAI BIOLOGICAL MEDICINE TECH
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