Efficient synthesis method of vildagliptin

A synthetic method and high-efficiency technology, applied in the direction of organic chemistry, etc., can solve the problems of main product purity and yield reduction, poor acid application effect, and increased production, so as to avoid adverse effects

Active Publication Date: 2015-09-30
烟台万润药业有限公司
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AI Technical Summary

Problems solved by technology

[0010] 1) The solubility of potassium carbonate in the organic solvent is extremely low, the reaction is two-phase, and the acid application effect is poor, resulting in the hydrogen chloride generated by the reaction consuming the raw material 3-aminoadamantanol to generate 3-aminoadamantanol hydrochloride, which affects the actual Ratio of reaction
Since one molecule of 3-aminoadamantanol can combine with two molecules of (S)-1-(2-chloroacetyl chloride)pyrrolidine-2-carbonitrile II to generate by-product I a , the consumption of 3-aminoadamantanol leads to the by-product I a The amount of production increases, the purity and yield of the main product decrease
[0011] 2) Vildagliptin I has low solubility in tetrahydrofuran and methyl ethyl ketone. In order to dissolve the product in the reaction solution, hot filtration at 65-70°C is required. The existence of a large excess of potassium carbonate will greatly affect the thermal filtration efficiency, thereby affecting Production equipment has higher requirements

Method used

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  • Efficient synthesis method of vildagliptin

Examples

Experimental program
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Effect test

Embodiment 1

[0039] Preparation of (S)-1-(2-chloroacetyl chloride)pyrrolidine-2-carbonitrile

[0040] In a 2L three-neck flask, add 100.0g (0.8772moL) L-prolinamide, 640g dichloromethane and 102.4g (1.0139moL) triethylamine in sequence to form a suspension, stir and cool down to -25°C, Add 116.0g (1.0265moL) chloroacetyl chloride dropwise into the solution, and control the dropping temperature ≤ -15°C; after the dropwise addition, stir and react at -25--15°C for 1h, take the sample and dissolve it in methanol, and TLC detects that the reaction is complete, and (S )-1-(2-chloroacetyl chloride) pyrrolidine-2-carboxamide suspension;

[0041](S)-1-(2-Chloroacetyl chloride)pyrrolidine-2-carboxamide suspension was warmed up to -5-5°C, without separation, 147.2g (2.0164moL) DMF ( N,N-Dimethylformamide) and 150.8g (0.9837moL) of phosphorus oxychloride, the dropwise addition was completed, and the temperature was kept at -5-5°C for 2 hours, the sample was dissolved and diluted with methanol, and t...

Embodiment 2

[0045] Preparation of (S)-1-(2-chloroacetyl chloride)pyrrolidine-2-carbonitrile

[0046] In a 2L three-neck flask, add 100.0g (0.8772moL) L-prolinamide, 640g ethyl acetate and 102.4g (1.0139moL) triethylamine in sequence, stir and cool down to -35°C, add dropwise 116.0g (1.0265moL) Chloroacetyl chloride, control the dropping temperature ≤ -25°C; after the dropwise addition, stir and react at -35--25°C for 1h, take the sample and dissolve it in methanol, TLC detects that the reaction is complete, and (S)-1-(2-chloroacetyl chloride is obtained ) pyrrolidine-2-carboxamide suspension;

[0047] (S)-1-(2-Chloroacetyl chloride)pyrrolidine-2-carboxamide suspension was warmed up to 10-20°C, without separation, 147.2g (2.0164moL) DMF and 150.8 g (0.9837moL) phosphorus oxychloride, after the dropwise addition, keep warm at 10-20°C for 2 hours, dissolve and dilute the sample with methanol, and TLC detects that the reaction is complete; add 700.0g of water to quench the reaction, separate...

Embodiment 3

[0051] Preparation of (S)-1-(2-chloroacetyl chloride)pyrrolidine-2-carbonitrile

[0052] In a 2L three-neck flask, add 100.0g (0.8772moL) L-prolinamide, 640g dichloromethane and 102.4g (1.0139moL) triethylamine in sequence to form a suspension, stir and cool down to -25°C, Add 116.0g (1.0265moL) chloroacetyl chloride dropwise into the solution, and control the dropping temperature ≤ -15°C; after the dropwise addition, stir and react at -25--15°C for 1h, take the sample and dissolve it in methanol, and TLC detects that the reaction is complete, and (S )-1-(2-chloroacetyl chloride) pyrrolidine-2-carboxamide suspension;

[0053] (S)-1-(2-Chloroacetyl chloride)pyrrolidine-2-carboxamide suspension was warmed up to -5-5°C, without separation, 147.2g (2.0164moL) DMF ( N,N-Dimethylformamide) and 150.8g (0.9837moL) of phosphorus oxychloride, the dropwise addition was completed, and the temperature was kept at -5-5°C for 2 hours, the sample was dissolved and diluted with methanol, and ...

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Abstract

The present invention relates to an efficient synthesis method of vildagliptin. According to the method, L-prolinamide is adopted as a raw material, N-chloro acetylation and amide dehydration are performed to generate an intermediate (S)-1-(2-chloroacetyl chloride)pyrrolidine-2-carbonitrile, and the (S)-1-(2-chloroacetyl chloride)pyrrolidine-2-carbonitrile and 3-amino adamantanol are subjected to condensation in acetonitrile in the presence of an organic base to obtain the target product vildagliptin. According to the present invention, the synthesis method operation only requires the separation of the one key intermediate, and the method has characteristics of simple and feasible operation, high efficiency, environmental protection, and easy industrial production achieving.

Description

technical field [0001] The invention relates to a high-efficiency synthesis method of vildagliptin, which belongs to the field of chemical synthesis. Background technique [0002] Vildagliptin, chemical name (S)-1-[[3-hydroxy-1-adamantylamine)amino]acetyl]-2-cyanopyrrolidine, structural formula as shown in I. It is a new oral hypoglycemic drug developed by Novartis, which was approved by the European Food and Drug Administration in 2008. Vildagliptin is an oral hypoglycemic drug belonging to type Ⅳ dipeptidyl peptidase (DPP-Ⅳ) inhibitors. Its mechanism of action is to inhibit the activity of this enzyme by combining with DPP-Ⅳ to form a complex. The concentration of blood glucose-like peptide Ⅰ (GLP-1) promotes the production of insulin by the pancreatic beta cells and at the same time reduces the concentration of glucagon, thereby reducing blood sugar. It has a very obvious hypoglycemic effect when used alone or in combination with metformin and insulin, and has many adva...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/16
CPCC07D207/16
Inventor 李忠郝宇孙宝佳林培森相龙明刘志刚
Owner 烟台万润药业有限公司
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