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Synthesis method of (S)-1-(2-chloracetyl) pyrrolidine-2-formonitrile

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

Inactive Publication Date: 2014-09-10
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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  • Synthesis method of (S)-1-(2-chloracetyl) pyrrolidine-2-formonitrile
  • Synthesis method of (S)-1-(2-chloracetyl) pyrrolidine-2-formonitrile
  • Synthesis method of (S)-1-(2-chloracetyl) pyrrolidine-2-formonitrile

Examples

Experimental program
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Effect test

Embodiment 1

[0048] Take a reaction bottle, add ( S )-2-cyanopyrrolidine p-toluenesulfonate (40 g, 0.15 mol) and dichloromethane (200 mL), cooled to -10°C, added triethylamine (0.15 mol) dropwise, and stirred to obtain a clear solution; Chloroacetyl chloride (0.225 mol) was added dropwise to the resulting clear solution, and the temperature was controlled at -5°C. After the addition was complete, stirring was continued until the reaction was complete, and 100 mL 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 times...

Embodiment 2

[0050] Take a reaction bottle, add ( S )-2-cyanopyrrolidine p-toluenesulfonate (40 g, 0.15 mol), dichloromethane (400 mL), cooled to -5°C, added triethylamine (0.3 mol) dropwise, and stirred to obtain a clear solution. Chloroacetyl chloride (0.3 mol) was then added dropwise to the clear solution, and the temperature was controlled below 0°C. After the dropwise addition, stirring was continued until the reaction was complete, and 100 mL of water was added to quench the reaction; The aqueous phase was removed and the organic phase was washed 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, let stand to separate the liquid, remove the aqueous 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...

Embodiment 3

[0052] Take a reaction bottle, add ( S )-2-cyanopyrrolidine p-toluenesulfonate (40 g, 0.15 mol), dichloromethane (400 mL), cooled to 10°C, added triethylamine (0.45 mol) dropwise, and stirred to obtain a clear solution. Chloroacetyl chloride (0.45 mol) was then added dropwise to the clear solution, and the temperature was controlled below 10°C. After the dropwise addition, stirring was continued until the reaction was complete, and 100 mL of water was added to quench the reaction; The aqueous phase was removed and the organic phase was washed 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, let stand to separate the liquid, remove the aqueous phase, dry the washed organic phase with anhydrous magnesium sulfate, and concentrate 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)pyrrolidin...

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Abstract

The invention discloses a synthesis method of (S)-1-(2-chloracetyl) pyrrolidine-2-formonitrile. (S)-2-nitrilepyrrolidinetosylate is taken as a raw material and reacts with chloroacetyl chloride in the presence of an aprotic organic solvent and an organic alkali to synthesize the (S)-1-(2-chloracetyl) pyrrolidine-2-formonitrile, wherein the aprotic organic solvent is dichloromethane or chloroform, and the organic alkali is triethylamine or diisopropylethylamine. The synthesis method has the advantages of low cost, high yield, high purity, simple and convenient operation and time saving, and is advantageous for industrial 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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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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