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Preparation method of intermediate of medicine vildagliptin for treating type 2 diabetes

A technology for diabetes medicines and intermediates, applied in the field of preparation of intermediates, can solve the problems of unfriendly environment, high price and high equipment requirements, and achieve the effects of avoiding competitive side reactions, mild conditions and high yields

Inactive Publication Date: 2018-04-24
临沂齐泽医药技术有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] In the above method, chiral L-proline is used as a raw material, reacted with chloroethyl chloride, and carboxylic acid esterification forms a competing reaction, reducing the yield
In addition, in this method, the carboxylic acid is condensed to obtain an amide and then dehydrated to obtain a cyano group. The widespread use of trifluoroacetic anhydride, cyanuric chloride, etc. has problems such as expensive, high equipment requirements, and unfriendly to the environment.
[0007] CN105884669A discloses a preparation method of vildagliptin. In this method, L-proline is firstly reacted to form an amide compound, which avoids the side reaction of acid chloride esterification. However, the dehydrating agent used in this reaction uses propyl phosphoric anhydride, which has limited sources and is expensive. , is acidic and has certain corrosiveness, and the yield of this method is not high

Method used

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  • Preparation method of intermediate of medicine vildagliptin for treating type 2 diabetes
  • Preparation method of intermediate of medicine vildagliptin for treating type 2 diabetes
  • Preparation method of intermediate of medicine vildagliptin for treating type 2 diabetes

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Effect test

Embodiment 1

[0034] The preparation of the compound shown in formula I

[0035] In the presence of nitrogen, mix (S)-2-carboxypyrrolidine 12.66g (110mmol) with N-hydroxyphthalimide 16.31g (100mmol), DCC 24.74g (120mmol), DMAP 1.22g (10mmol) Stir the reaction in dichloromethane at 0°C for 12 hours for condensation reaction, monitor the completion of the reaction by TLC, filter, and concentrate the filtrate under reduced pressure, and column chromatography to obtain 24 g of the compound represented by formula I, with a yield of 92.3% and a purity of 99.31%.

[0036] 1 HNMR (400MHz, CDCl 3 ), δ7.76~7.71(m,2H), 7.32~7.27(m,2H), 3.81~3.76(m,.1H), 3.64(s,1H), 3.14~3.10(m,2H), 2.14~ 2.02(m,4H).

Embodiment 2

[0038] The preparation of the compound shown in formula I

[0039] In the presence of nitrogen, mix (S)-2-carboxypyrrolidine 12.66g (110mmol) with N-hydroxyphthalimide 16.31g (100mmol), DCC 26.8g (130mmol), DMAP 3.67g (30mmol) Stir the reaction in dichloromethane at 5°C for 15 hours for condensation reaction, monitor the completion of the reaction by TLC, filter the filtrate, concentrate under reduced pressure, and column chromatography to obtain 24.26 g of the compound represented by formula I, with a yield of 93.2% and a purity of 99.17%.

Embodiment 3

[0041] The preparation of the compound shown in formula I

[0042] In the presence of nitrogen, mix (S)-2-carboxypyrrolidine 13.82g (120mmol) with N-hydroxyphthalimide 16.31g (100mmol), DCC 24.74g (120mmol), DMAP 2.44g (20mmol) Stir the reaction in dichloromethane at 10°C for 12 hours for condensation reaction, monitor the completion of the reaction by TLC, filter, and concentrate the filtrate under reduced pressure, and column chromatography to obtain 23.71 g of the compound represented by formula I, with a yield of 91.1% and a purity of 99.07%.

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Abstract

The invention discloses a preparation method of an intermediate of a medicine vildagliptin for treating type 2 diabetes. The preparation method comprises the steps that 1, 2-carboxyl pyrrolidine and N-phthalimide are subjected to condensation to obtain a compound shown as the formula I which is shown in the description; 2, in the presence of tris(2-phenylpyridine)iridium, silver bromide and a compound shown as the formula II, the compound shown as the formula I and trimethylsilyl cyanide are subjected to heating reaction to obtain (S)-2-cyanopyrrolidine; 3, the (S)-2-cyanopyrrolidine is reacted with chloroacetyl chloride to obtain the vildagliptin intermediate (S)-1-(2-chloracetyl)-2-cyanopyrrolidine. According to the preparation method, the adopted raw materials are wider in resource, thereaction is high in selectivity and yield, the chiral target compound is obtained, the conditions are mild, and the method is easy to implement.

Description

technical field [0001] The invention belongs to the technical field of medicine preparation, and relates to a preparation method of an intermediate of vildagliptin, a medicine for treating type II diabetes. Background technique [0002] Vildagliptin, a DPP-IV inhibitor developed by Novartis, was approved in the European Union in 2008 for the treatment of type 2 diabetes. The chemical name is (S)-1-[2-(3-hydroxyl Adamantane-1-ylamino)acetyl]-2-cyanopyrrolidine, the specific structure is as follows: [0003] [0004] Extensive research has been done on the preparation of vildagliptin and its intermediates in this field, for example, WO2006100181, US20080167479, etc. These methods are mainly carried out through the following routes: [0005] [0006] In the above method, chiral L-proline is used as a raw material to react with chloroethyl chloride, and carboxylic acid esterification forms a competing reaction, which reduces the yield. In addition, in this method, the ca...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/16
CPCC07D207/16
Inventor 师敬利孙益东
Owner 临沂齐泽医药技术有限公司