Preparation method for vildagliptin

A synthesis method and cyano technology, applied in the direction of organic chemistry and the like, can solve the problems of high price, low product purity, cumbersome vildagliptin reaction route, etc., and achieve a short reaction route, improve product purity, and high yield. Effect

Active Publication Date: 2019-08-06
THE SECOND PEOPLES HOSPITAL OF SHENZHEN
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0008] The technical problem to be solved in the present invention is aimed at the problems in the prior art that the reaction route of vildagliptin is relatively cumbersome, the reaction raw material (S)-2-cyano-pyrrolidine is expensive, and the product purity is not high.

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  • Preparation method for vildagliptin
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  • Preparation method for vildagliptin

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preparation example Construction

[0022] The invention discloses a preparation method of vildagliptin, and those skilled in the art can learn from the content of this article and appropriately improve the process parameters to realize it. It needs to be pointed out that all similar replacements and modifications are obvious to those skilled in the art, and they are all considered to be included in the present invention, and relevant personnel can obviously make changes without departing from the content, spirit and scope of the present invention. Changes or appropriate changes and combinations are made to the content described herein to realize and apply the technology of the present invention.

[0023] In the present invention, unless otherwise specified, the scientific and technical terms used herein have the meanings commonly understood by those skilled in the art.

Embodiment 1

[0025] Embodiment 1: the preparation of (S)-2-cyano-pyrrolidine

[0026]

[0027] In 150mL tetrahydrofuran, add 8.25g (48mmol) butenedioic acid diethyl ester and 12.11g (50mmol) (S)-N-Boc-3-amino-3-cyano-propionic acid ethyl ester, in 0.20g ( In the presence of 0.6mmol) catalyst palladium trifluoroacetate, 0.15g (0.8mmol) 2-tert-butylimidazothiazole chiral ligand (L1) and 17.01g (85mmol) copper acetate, feed air and stir at 50°C for 3 Hours, TLC to monitor the reaction process, after the reaction is complete, add water to separate the layers, dry the organic phase with anhydrous magnesium sulfate overnight, concentrate under reduced pressure, dissolve 50mL of toluene, add 4.37g of solid sodium hydroxide, seal the tube and heat to 180°C under nitrogen protection, React for 10 hours, cool to room temperature, filter, remove the solvent under reduced pressure, and obtain compound (S)-N-Boc-2-cyano-pyrrolidine 8.93g (45.5mmol) through column chromatography, the yield is 95%, e...

Embodiment 2

[0029] Embodiment 2: the preparation of (S)-2-cyano-pyrrolidine

[0030] In 120mL tetrahydrofuran, add 5.16g (30mmol) butenedioic acid diethyl ester and 7.99g (33mmol) (S)-N-Boc-3-amino-3-cyano-propionic acid ethyl ester, in 0.17g ( In the presence of 0.5mmol) catalyst palladium trifluoroacetate, 0.33g (0.6mmol) 2-tert-butylimidazothiazole chiral ligand (L1) and 13.98g (70mmol) copper acetate, feed air, and stir at 40°C for 5 Hours, TLC monitors the reaction process, after the reaction is complete, add water to separate the layers, dry the organic phase with anhydrous magnesium sulfate overnight, concentrate under reduced pressure, dissolve 50mL of toluene, add 4.31g of solid sodium hydroxide, seal the tube and heat to 180°C under nitrogen protection, React for 10 hours, cool to room temperature, filter, remove the solvent under reduced pressure, and obtain compound (S)-N-Boc-2-cyano-pyrrolidine 5.63g (28.7mmol) through column chromatography with a yield of 96%. e.e. >99.9%. ...

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Abstract

The invention provides a preparation method for vildagliptin. Through the presence of imidazo thiazole as a chiral ligand and a palladium catalyst, a vildagliptin product with high yield and high purity can be obtained by taking diethyl fumarate and amino protected (S)-3-amino-cyano-ethyl propanoate as initial raw materials through steps such as cyclization, deprotection and coupling; and the preparation method is short in reaction route, high in yield and less in by-product, so that production costs can be reduced, and industrial production can be realized.

Description

technical field [0001] The application relates to a preparation method of vildagliptin, a medicine for treating diabetes, and belongs to the field of western medicine synthesis. Background technique [0002] In recent years, the incidence of diabetes has increased year by year, and diabetes has become another non-communicable disease that seriously threatens human health after cardiovascular diseases and malignant tumors. The type II incidence of diabetes accounts for 90%, and the pathogenesis of type II diabetes is mainly caused by the human body's resistance to insulin and insulin and cell function defects. Clinically used drugs for the treatment of type II diabetes mainly include insulin secretion promoters, sulfonylureas, meglitinides, insulin sensitizers, insulin and insulin receptor agonists and dipeptidyl peptidase-4 inhibitors . [0003] Vildagliptin, chemically named (2S)-1-[[(3-hydroxy-1-adamantyl)amino]acetyl)]-2-cyano-pyrrolidine, was developed by Novartis A p...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/16
CPCC07D207/16
Inventor 谭回李维平
Owner THE SECOND PEOPLES HOSPITAL OF SHENZHEN
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