Improved industrialization technology for preparing Vildagliptin

A process and technology of acylation reaction, applied in the field of medicine, to achieve good tolerance, shorten the reaction time, and improve the effect of the preparation method

Inactive Publication Date: 2015-12-16
BEIJING KCODE PHARMA R &D CO LTD
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  • Summary
  • Abstract
  • Description
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  • Application Information

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Problems solved by technology

Secondly, vildagliptin was dissolved in vildagliptin by isopropanol in the preparation method of vildagliptin calcium chloride trihydrate (1:1:3) complex, but isopropanol was not used in this process

Method used

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  • Improved industrialization technology for preparing Vildagliptin
  • Improved industrialization technology for preparing Vildagliptin
  • Improved industrialization technology for preparing Vildagliptin

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Embodiment Construction

[0021] The present invention will be described in more detail below with examples, but it cannot be considered that the present invention is limited to this example.

[0022] (1) Acylation reaction

[0023] Add wg-11400g and tetrahydrofuran 40g into the reaction kettle and stir to dissolve at room temperature. After stirring for 15 minutes, add 2000g of triethylamine dropwise (the temperature does not change much during the dropwise addition), and cool down to -2°C to -10°C after dropping. Add 1700g of chloroacetyl chloride dropwise at temperature -10°C~-5°C (white fumes are generated when dropping); after dropping, keep warm for 1 hour (the residual wg-1 detected by HPLC is less than 5%; after the reaction, the reaction solution is light purple mixed suspension). The molar yield is between 60% and 78%.

[0024] (2) Dehydration reaction

[0025] Cool the wg-2 solution obtained in the previous step to below 0°C, and add TFAA5200g dropwise at 0°C~-5°C (white smoke is generate...

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Abstract

The invention discloses a novel preparation method of Vildagliptin. The preparation method comprises that L-prolinamide as a raw material, chloroacetyl chloride and tetrahydrofuran undergo an acylation reaction, the reaction product is subjected to suction filtration, the filtrate and trifluoroacetic anhydride directly undergo a dehydration reaction without filtrate separation purification to produce (-)-(2S)-1-chloroacetylpyrrolidine-2-carbonitrile (II), the refined (-)-(2S)-1-chloroacetylpyrrolidine-2-carbonitrile, 3-amino-1-adamantanol (III), potassium carbonate and potassium iodide undergo a reaction to produce (-)-(2S)-1-[[(3-hydroxytricyclo[3.3.1.1[3,7]]dec-1-yl)amino]acetyl]pyrrolidine-2-carbonitrile (I) in acetone, and the (-)-(2S)-1-[[(3-hydroxytricyclo[3.3.1.1[3,7]]dec-1-yl)amino]acetyl]pyrrolidine-2-carbonitrile (I) is refined by calcium double salt, ethyl acetate and butanone to form pure Vildagliptin (compound wg-0). The improved synthesis technology has the advantages of less reaction steps, operation simpleness, after-treatment simpleness, low employee cost, equipment cost and time cost, high yield, high product quality and industrialization feasibility.

Description

technical field [0001] The invention belongs to the technical field of medicine, and relates to an improved industrial process for a compound named vildagliptin (wg-0). The Chinese chemical name of vildagliptin is (-)-(2S)-1-[[(3- Hydroxytricyclo[3.3.1.1[3,7]]decane-1-yl)amino]acetylpyrrolidine-2-carbonitrile. The structural formula is: [0002] [0003] Vildagliptin is produced through a key intermediate (-)-(2S)-1-chloroacetylpyrrolidine-2-carbonitrile (II, referred to as wg-3) and 1-aminoadamantan-3-ol (III ) from a nucleophilic substitution reaction. Background technique [0004] Vildagliptin is a diabetes drug that is already on the market in China. There are also many studies on vildagliptin, and there are also patents and articles related to synthesis and purification. But in the process of industrialization, these patents or documents all have such or such problems, mainly the purity of (-)-(2S)-1-chloroacetylpyrrolidine-2-carbonitrile (wg-3) is low, and Too ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/16
CPCC07D207/16
Inventor 寇国通
Owner BEIJING KCODE PHARMA R &D CO LTD
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