Unlock instant, AI-driven research and patent intelligence for your innovation.

Continuous preparation method of vildagliptin key intermediate

An intermediate and key technology, which is applied in the field of synthesis of vildagliptin's key intermediate - 1-pyrrolidine-2-carbonitrile, can solve problems such as lack of industrial conditions, complicated process, and yield loss, and achieve The yield and quality advantages are obvious, the process operation is simple, and the effect of avoiding safety risks

Pending Publication Date: 2022-03-11
河北合佳医药科技集团股份有限公司
View PDF5 Cites 0 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, this route still uses expensive L-prolineamide as a starting material, and the subsequent deprotection process uses methanesulfonic acid, and sulfonic acids are genotoxic impurities, which will lead to potential genotoxic residues in the final product. risk, detrimental to the safety of the drug
If it is calculated by L-proline, the process is more complicated, and multiple product crystallization and purification have caused a large amount of yield loss, which does not meet the conditions for industrialization
[0013] At present, a high-yield, high-quality, low-cost and industrialized (s)-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile synthesis process needs to be developed urgently

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Continuous preparation method of vildagliptin key intermediate
  • Continuous preparation method of vildagliptin key intermediate
  • Continuous preparation method of vildagliptin key intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] Under the protection of nitrogen, add 100ml of dichloromethane, 23g of L-proline, and 8.8g of sodium hydroxide to the round bottom flask successively, stir and control the temperature to 10-15°C, add 48g of di-tert-butyl dicarbonate dropwise until the system is dissolved , continue to control the temperature at 10-15°C and add 26g of ethyl chloroformate dropwise, add dropwise 42g of 25% ammonia water under rapid stirring, continue to react for 4 hours after the system dissolves, add concentrated hydrochloric acid to adjust the system to neutral, separate the organic phase and use Dry over sodium sulfate and evaporate the solvent to obtain 37.7 g of colorless oily boc-L-prolineamide.

[0039] Add 100ml of dimethylformamide to the obtained boc-L-proline amide, add 14.8g of cyanuric chloride at room temperature, after a large amount of precipitation in the system, continue the reaction for 2h, cool down to 0-10°C and add sodium bicarbonate to neutralize the system, Filter ...

Embodiment 2

[0041]Under the protection of nitrogen, add 100ml of dichloromethane, 23g of L-proline, and 22.3g of triethylamine to the round-bottomed flask successively, stir and control the temperature to 5-10°C, and add 48g of di-tert-butyl dicarbonate dropwise until the system is dissolved. , continue to control the temperature at 10-15°C and add 26g of ethyl chloroformate dropwise, add dropwise 42g of 25% ammonia water under rapid stirring, continue to react for 4 hours after the system dissolves, add concentrated hydrochloric acid to adjust the system to neutral, separate the organic phase and use Dry over sodium sulfate and evaporate the solvent to obtain 37.7 g of colorless oily boc-L-prolineamide.

[0042] Add 100ml of dimethylformamide to the obtained boc-L-proline amide, add 14.8g of cyanuric chloride at room temperature, after a large amount of precipitation in the system, continue the reaction for 2h, cool down to 0-10°C and add sodium bicarbonate to neutralize the system, Filt...

Embodiment 3

[0044] Under the protection of nitrogen, add 100ml of dichloromethane, 23g of L-proline, and 8.8g of sodium hydroxide to the round bottom flask successively, stir and control the temperature to 10-15°C, add 48g of di-tert-butyl dicarbonate dropwise until the system is dissolved , continue to control the temperature at 10-15°C and add 22.3g of ethyl chloroformate dropwise, add dropwise 42g of 25% ammonia water under rapid stirring, continue to react for 3 hours after the system dissolves, add concentrated hydrochloric acid to adjust the system to neutral, separate the organic phase for use Dry over anhydrous sodium sulfate and evaporate the solvent to obtain 37.7 g of colorless oily boc-L-prolineamide.

[0045] Add 100ml of dimethylformamide to the obtained boc-L-proline amide, add 14.8g of cyanuric chloride at room temperature, after a large amount of precipitation in the system, continue the reaction for 2h, cool down to 0-10°C and add sodium bicarbonate to neutralize the syst...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

No PUM Login to View More

Abstract

The invention discloses a continuous preparation method of a vildagliptin key intermediate (s)-1-(2-chloracetyl) pyrrolidine-2-formonitrile, and belongs to the technical field of organic synthesis. The preparation method comprises the following steps: preparing Boc-L-prolinamide from L-proline as a starting raw material by using a one-pot method, carrying out a dehydration reaction on Boc-L-prolinamide and cyanuric chloride, adding a solvent and thionyl chloride to carry out deprotection salifying crystallization so as to obtain (s)-pyrrolidine-2-formonitrile hydrochloride, and finally adding chloroacetyl chloride to carry out a reaction so as to obtain (s)-1-(2-chloracetyl) pyrrolidine-2-formonitrile. According to the method, a one-pot method and a continuous preparation method are combined, an intermediate crystallization step is omitted, the yield is up to 60% or above, the purity is up to 99.7%, and the whole reaction process is simple, easy to operate and suitable for industrial production.

Description

technical field [0001] The invention relates to a synthesis method of (s)-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile, a key intermediate of vildagliptin, and belongs to the technical field of organic synthesis. Background technique [0002] Vildagliptin (Vildagliptin), the chemical formula is (2S)-1-{2-[((3-hydroxy-1-adamantyl)amino]acetyl}-pyrrolidine-2carbonitrile, the clinical drug is oral administration Difetopeptidase-Ⅳ (DPP-Ⅳ) of the drug, originally researched by Swiss Novartis Pharmaceutical Co., Ltd., was approved to be marketed in the European Union in 2008 for the treatment of type 2 diabetes. (s)-1-(2-chloroacetyl Base) pyrrolidine-2-carbonitrile (1) is a key intermediate for the synthesis of vildagliptin, and its structural formula is as follows: [0003] [0004] The current synthetic route of this intermediate is mainly divided into two categories: [0005] The first type of process route, represented by the original research patents WO2000034241 and WO...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/16
CPCC07D207/16
Inventor 刘振强王丽霞刘新元梁丙辰马爱华
Owner 河北合佳医药科技集团股份有限公司