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A kind of synthetic method of (s)-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile

A synthetic method, the technology of chloroacetyl group, applied in the direction of organic chemistry, etc., can solve the problems of easy moisture absorption, slow reaction speed, inconvenient preparation, storage and feeding, etc., and achieve low water absorption, prolonged reaction time and convenient preparation. Effect

Inactive Publication Date: 2016-06-29
HEBEI UNIVERSITY OF SCIENCE AND TECHNOLOGY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The reaction condition is a heterogeneous reaction, and in order to prevent the hydrolysis of the raw material chloroacetyl chloride, the reaction needs to be carried out at 5°C, resulting in a slow reaction rate. In the examples, it takes 3 to 18 hours to complete the reaction
Additional raw materials ( S )-2-cyanopyrrolidine hydrochloride is extremely hygroscopic and inconvenient for preparation, storage and feeding

Method used

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  • A kind of synthetic method of (s)-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile
  • A kind of synthetic method of (s)-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile
  • A kind of synthetic method of (s)-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] Take a reaction bottle, add ( S )-2-cyanopyrrolidine p-toluenesulfonate (40g, 0.15mol) and dichloromethane (200mL), cooled to -10°C, added triethylamine (0.15mol) dropwise, and stirred to obtain a clear solution; Chloroacetyl chloride (0.225mol) was added dropwise to the clarified solution, and the temperature was controlled at -5°C. After the dropwise addition was completed, the stirring was continued until the reaction was complete, and 100mL of water was added to quench the reaction, due to ( S )-2-cyanopyrrolidine p-toluenesulfonate reacts with triethylamine to generate pyrrolidine-2-carbonitrile, and the pyrrolidine-2-carbonitrile is detected in real time by thin layer chromatography. When pyrrolidine-2 -The disappearance of the color development of formonitrile means that the reaction is complete; after standing still and quenching, the solution is separated, the water phase is removed, and the organic phase is saturated with NaHCO 3 The solution was washed 2 tim...

Embodiment 2

[0050] Take a reaction bottle, add ( S )-2-cyanopyrrolidine p-toluenesulfonate (40g, 0.15mol), dichloromethane (400mL), cooled to -5°C, added dropwise triethylamine (0.3mol), and stirred to obtain a clear solution. Chloroacetyl chloride (0.3mol) is then added dropwise to the clear solution, the temperature is controlled below 0°C, after the dropwise addition is complete, continue to stir until the reaction is complete, and add 100mL of water to quench the reaction; Aqueous phase, organic phase with saturated NaHCO 3 The solution was washed 2 times, each time saturated with NaHCO 3 The volume of the solution was 100mL; after washing, let stand to separate the liquid, remove the water phase, dry the washed organic phase with anhydrous magnesium sulfate, and concentrate to obtain 22.5 g of white solid, with a yield of 86.7%. Detected by nuclear magnetic resonance, the resulting white solid is ( S )-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile, the purity determined by HPLC met...

Embodiment 3

[0052] Take a reaction bottle, add ( S )-2-cyanopyrrolidine p-toluenesulfonate (40g, 0.15mol), dichloromethane (400mL), cooled to 10°C, added dropwise triethylamine (0.45mol), and stirred to obtain a clear solution. Chloroacetyl chloride (0.45mol) is then added dropwise to the clear solution, the temperature is controlled below 10°C, after the dropwise addition is complete, continue to stir until the reaction is complete, and add 100mL of water to quench the reaction; Aqueous phase, organic phase with saturated NaHCO 3 The solution was washed 2 times, each time saturated with NaHCO 3 The volume of the solution was 100 mL; after washing, it was left standing to separate the liquid, the water phase was removed, the washed organic phase was dried with anhydrous magnesium sulfate, and concentrated to obtain 23 g of white solid, with a yield of 88.6%. Detected by nuclear magnetic resonance, the resulting white solid is ( S )-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile, the puri...

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Abstract

The invention discloses a ( S )-1-(2-chloroacetyl) pyrrolidine-2-carbonitrile synthetic method, with ( S )-2-cyanopyrrolidine tosylate as raw material, in the presence of an aprotic organic solvent and an organic base, reacted with chloroacetyl chloride to synthesize ( S )-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile; the aprotic organic solvent is dichloromethane or chloroform, and the organic base is triethylamine or diisopropylethylamine. The invention has the advantages of low cost, high yield, high purity, simple operation and time saving, and is beneficial to industrialized production.

Description

technical field [0001] The present invention relates to a kind of synthetic method of vildagliptin intermediate, specifically relate to ( S )-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile synthetic method. Background technique [0002] Vildagliptin (chemical name: (2 S )-1-[[(3-Hydroxy-1-adamantyl)amino]acetyl]pyrrolidine-2-carbonitrile, Vildagliptin) has the following structure: [0003] [0004] Vildagliptin is an oral hypoglycemic drug belonging to the cyanopyrrolidine class of DPP-4 inhibitors. The drug was developed by Novartis and was approved by the European Commission for marketing in September 2007. It has a very obvious hypoglycemic effect when used alone or in combination with metformin and insulin, and it is safe to take, well tolerated, and less adverse reactions and many other advantages. [0005] ( S )-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile is a key intermediate in the synthesis of vildagliptin. World patents WO0034241; WO0196295; WO2004092127 di...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D207/16
CPCC07D207/16
Inventor 张勇高子彬杨金路
Owner HEBEI UNIVERSITY OF SCIENCE AND TECHNOLOGY
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