Synthetic method of vildagliptin intermediate

A synthesis process, pyrrolidine technology, applied in the direction of organic chemistry, etc., can solve the problems of cumbersome operation, high price, high reaction cost, separation and purification, etc., achieve the effects of reducing workload, easy operation, and avoiding production of by-products

Active Publication Date: 2014-05-21
ZHANG JIA GANG VINSCE BIO PHARM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Among them, the price of L-prolinamide is relatively high, the cost of reaction with trifluoric anhydride and thionyl chloride is relatively high, and the product intermediate is separated and purified, and the operation is cumbersome.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0014] Add 20.0g of L-proline in the 250ml reaction bottle, and then add 100ml of tetrahydrofuran. While stirring, 30ml of chloroacetyl chloride was added dropwise. After the dropwise addition was completed, the mixture was stirred at room temperature for 4 h. Reactions were monitored with TLC plates. After the reaction is complete, add 40 ml of distilled water and continue to stir for 20 min. After stirring, add 100ml of ethyl acetate and 60ml of distilled water into the reaction solution. Then pour into a separatory funnel, let it stand, and collect the organic layer. The aqueous layer was extracted twice with 200 ml ethyl acetate. The organic layers were combined and dried by adding anhydrous sodium sulfate for 20 h. After drying, the organic solvent was evaporated, and the oil weighed 28g. Add 320ml of tetrahydrofuran, 48g of di-tert-butyl dicarbonate, and 128g of ammonium bicarbonate, and stir. When a white turbid liquid appeared, add 8ml of pyridine, and then stirre...

Embodiment 2

[0016] Add 40.0g of L-proline in the 500ml reaction bottle, and then add 200ml of tetrahydrofuran. While stirring, 60ml of chloroacetyl chloride was added dropwise. After the dropwise addition was completed, the mixture was stirred at room temperature for 4 h. Reactions were monitored with TLC plates. After the reaction is complete, add 40 ml of distilled water and continue to stir for 20 min. After stirring, add 200ml of ethyl acetate and 120ml of distilled water into the reaction solution. Then pour into a separatory funnel, let it stand, and collect the organic layer. The aqueous layer was extracted twice with 400 ml of ethyl acetate. The organic layers were combined and dried by adding anhydrous sodium sulfate for 20 h. After drying, the organic solvent was evaporated, and the oil weighed 55g. Add 640ml of tetrahydrofuran, 96g of di-tert-butyl dicarbonate, and 256g of ammonium bicarbonate, and stir. When a white turbid solution appeared, add 16ml of pyridine, and then...

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PUM

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Abstract

The invention belongs to the technical field of organic synthesis, and particularly relates to a synthetic method of an important vildagliptin intermediate (S)-1-(2-chloracetyl) pyrrolidine-2-methyl cyanogens. The synthetic method has the advantages that the intermediate is not separated in a reaction process, the workload is reduced, the operation is easy; di-tert-butyl dicarbonate ester is used as a condensing agent of amide, so that the production cost is reduced, and POCl3 is used as a dehydrating condensation agent, so that the reaction yield is increased.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis, and specifically relates to a synthesis method of (S)-1-(2-chloroacetyl)pyrrolidine-2-cyanide, an important intermediate of vildagliptin. Background technique [0002] Diabetes mellitus is a group of metabolic diseases characterized by hyperglycemia due to defects in insulin secretion and / or insulin action. Sustained high blood sugar and long-term metabolic disorders can lead to damage, dysfunction and failure of tissues and organs throughout the body, especially the eyes, kidneys, cardiovascular and nervous systems. Severe cases can cause acute complications such as dehydration, electrolyte disturbance and acid-base imbalance, ketoacidosis and hyperosmolar coma. According to the latest data from the International Diabetes Federation, there are currently 382 million people with diabetes in the world, and it is estimated that by 2035, the total number of people suffering from diabetes w...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/16
CPCC07D207/16
Inventor 彭学东张梅赵金召陈晓龙
Owner ZHANG JIA GANG VINSCE BIO PHARM
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