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Preparation method of (S)-1-(2-chloracetyl)pyrrolidine-2-carbonitrile

A technology of chloroacetyl and pyrrolidine, which is applied in the field of preparation of 1-pyrrolidine-2-carbonitrile, can solve the problems of difficult purification, high equipment requirements, and low yield, and achieve the protection of green resources, low raw material cost, Good product quality

Active Publication Date: 2015-01-07
NORTHEAST PHARMA GRP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

There are following defects in these two methods: (1) THF and trifluoroacetic anhydride are expensive, resulting in high cost; (2) trifluoroacetic anhydride is highly corrosive, and post-treatment operations are cumbersome, requiring high equipment; (3) trifluoroacetic anhydride is produced by decomposition Environmental protection treatment of fluoroacetic acid is under great pressure
⑷ Due to the production of a large number of by-product dimers, purification is difficult, resulting in low yield and poor purity
The above disadvantages limit the possibility of industrial production of this route

Method used

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  • Preparation method of (S)-1-(2-chloracetyl)pyrrolidine-2-carbonitrile

Examples

Experimental program
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Effect test

Embodiment 1

[0016] Preparation of (S)-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile:

[0017] Add 25g of L-prolinamide, 250ml of dichloromethane, and 25g of triethylamine into a 1000ml dry reaction flask to form a mixed solution. Cool the mixed solution to -20°C to -25°C, and dropwise add 26g of The mixture prepared by chloroacetyl chloride and 50ml of dichloromethane was added dropwise and kept at -20°C for 3 hours with stirring and reaction to obtain reaction solution 1 containing 1-chloroacetylpyrrolidine-2-carboxamide.

[0018] Raise the temperature of the above reaction solution 1 to 5°C, control the temperature of the reaction solution 1 to 5°C-15°C, add 45g of phosphorus oxychloride dropwise, after the dropwise addition, keep the reaction at 5°C-15°C for 1 hour to obtain the reaction solution two. Slowly add 100ml of water to the reaction solution 2, the internal temperature does not exceed 20°C, stir for 30 minutes, let stand to separate layers, extract the water layer with dichlo...

Embodiment 2

[0020] Preparation of (S)-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile:

[0021] Add 25g of L-prolinamide, 250ml of dichloromethane, and 35g of diisopropylethylamine into a 1000ml dry reaction flask to form a mixed solution, cool the mixed solution to -45°C to -50°C, and drop it into the reaction flask Add the mixed solution prepared by 30g of chloroacetyl chloride and 50ml of dichloromethane. After the dropwise addition, keep stirring at -50°C for 0.5 hours to obtain a reaction solution containing 1-chloroacetylpyrrolidine-2-carboxamide. .

[0022] Raise the temperature of the above reaction solution 1 to -5°C, control the temperature of the reaction solution 1 at -15°C to 5°C, add 40 g of phosphorus oxychloride dropwise, after the dropwise addition, keep the reaction at -5°C to 5°C for 0.5 hours, Obtain reaction solution 2. Slowly add 110ml of water to the reaction solution 2, the internal temperature does not exceed 20°C, stir for 30 minutes, let stand to separate layers,...

Embodiment 3

[0024] Preparation of (S)-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile:

[0025] Add 25g of L-prolinamide, 250ml of dichloromethane, and 31g of 4-dimethylaminopyridine into a 1000ml dry reaction flask to form a mixed solution. Cool the mixed solution to -30°C to -35°C, and dropwise add The mixture prepared from 30g of chloroacetyl chloride and 50ml of dichloromethane was added dropwise and kept at -30°C for 4 hours with stirring and reaction to obtain a reaction solution 1 containing 1-chloroacetylpyrrolidine-2-carboxamide.

[0026] The temperature of the above reaction solution 1 was raised to -5°C, the temperature of the reaction solution 1 was controlled at -5°C to 5°C, and 35 g of phosphorus oxychloride was added dropwise. Obtain reaction solution 2. Slowly add 120ml of water to the reaction solution 2, the internal temperature does not exceed 20°C, stir for 30 minutes, let stand to separate layers, extract the water layer with dichloromethane twice, each time the amount ...

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Abstract

The invention discloses a preparation method of (S)-1-(2-chloracetyl)pyrrolidine-2-carbonitrile, which is applied to the field of chemical synthesis. The preparation method comprises the following steps of (1) dropwise adding chloracetyl chloride into a mixed solution composed of L-prolinamide, organic alkali and dichloromethane, and reacting after finishing the dropwise adding operation to obtain a reaction solution I containing 1-chloroacetylpyrrolidine-2-carboxamide; and (2) enabling the reaction solution I to react with phosphorus oxychloride serving as a dehydrating agent to obtain (S)-1-(2-chloracetyl)pyrrolidine-2-carbonitrile. In the step (1), the temperature of the mixed solution I composed of L-prolinamide, organic alkali and dichloromethane ranges from 10 DEG C below zero to 60 DEG C, the temperature of reaction carried out after the dropwise adding operation is finished ranges from 50 DEG C below zero to 10 DEG C below zero, the reaction carried out after the dropwise adding operation is finished lasts for 0.5-4h, and the molar ratio of L-prolinamide to chloracetyl chloride is 1:(1.05-1.31). The preparation method is short in reaction step and simple in operation and has the advantages that the raw material cost is low, the yield is high, the product quality is good, little environment pollution can be caused, green resources can be favorably protected, the required equipment is simple, and the dosage of the used organic solvent is low.

Description

technical field [0001] The invention relates to a method for preparing (S)-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile in the technical field of pharmaceutical synthesis. Background technique [0002] On September 28, 2007, Novartis' new oral anti-diabetic drug Vildagliptin (trade name: Galvus) was approved by the European Commission for marketing. Vildagliptin (Vildagliptin) is an oral hypoglycemic drug belonging to the cyanopyrrolidine class of DPP-4 inhibitors. It has a very obvious hypoglycemic effect when used alone or in combination with metformin and insulin, and it is safe to take. Good acceptance, less adverse reactions and many other advantages. [0003] (S)-1-(2-Chloroacetyl)pyrrolidine-2-carbonitrile, the structural formula is attached figure 1 , is the key intermediate for the synthesis of vildagliptin. The preparation methods of Novartis’s original patent CN1329593A and Indian patent WO2011101861 are as follows: using chloroacetyl chloride and L-prolineamide...

Claims

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Application Information

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IPC IPC(8): C07D207/16
CPCC07D207/16
Inventor 刘九知杨璐孙德夫沈思思皮昌桥刘素娜陶芳王雅倩
Owner NORTHEAST PHARMA GRP
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