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Preparing method for vildagliptin

A technology of amides and organic solvents, applied in the field of preparation of medicinal compounds, to achieve the effects of saving reaction raw materials and solvents, high purity and high yield

Active Publication Date: 2016-11-16
NORTHEAST PHARMA GRP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But above-mentioned method all can not fundamentally suppress the generation of impurity IV and reduce the consumption of 3-amino-1-adamantanol

Method used

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  • Preparing method for vildagliptin
  • Preparing method for vildagliptin
  • Preparing method for vildagliptin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] The impact of different molar ratios of raw materials on the reaction yield:

[0025] (1) Add 80.0g N,N-dimethylformamide, (S)-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile, 3-amino-1-adamantanol to a 250mL reaction flask , triethylamine, the selection of different molar ratios of the raw materials is shown in Table 1, and the reaction solution was obtained by stirring and reacting at 20° C. to 30° C. for 20 hours;

[0026] (2) Extraction: Distill the reaction solution under reduced pressure at 60-70°C, lower the temperature to below 30°C, add 120.0g of dichloromethane and 60.0g of half-saturated aqueous ammonium chloride solution, add 40ml of saturated aqueous sodium bicarbonate solution, and stir The layers were placed, and the dichloromethane layer was washed once with 50.0 g of water to obtain an organic phase extract;

[0027] (3) Drying: Add 8g of anhydrous magnesium sulfate to the organic phase extract and dry for 1-2 hours, filter, concentrate under reduced pres...

Embodiment 2

[0032] The influence of adopting different organic bases on the reaction yield:

[0033] (1) Add 80.0g N,N-dimethylformamide, 13.8g (0.08mmol) (S)-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile, 13.4g to a 250mL reaction flask (0.08mmol) 3-amino-1-adamantanol, 0.08mmol organic base, the selection of the organic base is shown in Table 2, and it was incubated at 20°C to 30°C and stirred for 20 hours to obtain a reaction solution;

[0034] (2) Extraction: Distill the reaction solution under reduced pressure at 60-70°C, lower the temperature to below 30°C, add 120.0g of dichloromethane and 60.0g of half-saturated aqueous ammonium chloride solution, add 40ml of saturated aqueous sodium bicarbonate solution, and stir The layers were placed, and the dichloromethane layer was washed once with 50.0 g of water to obtain an organic phase extract;

[0035] (3) Drying: Add 8g of anhydrous magnesium sulfate to the organic phase extract and dry for 1-2 hours, filter, concentrate under reduced...

Embodiment 3

[0040] The influence of adopting different organic solvents on the reaction yield:

[0041] (1) Add 80.0g organic solvent, 13.8g (0.08mmol) (S)-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile, 13.4g (0.08mmol) 3-amino - 1-adamantanol, 8.1g (0.08mmol) triethylamine, see Table 3 for the selection of the organic solvent, keep warm at 20°C to 30°C and stir for 20 hours to obtain a reaction solution;

[0042] (2) Extraction: Distill the reaction solution under reduced pressure at 60-70°C, lower the temperature to below 30°C, add 120.0g of dichloromethane and 60.0g of half-saturated aqueous ammonium chloride solution, add 40ml of saturated aqueous sodium bicarbonate solution, and stir The layers were placed, and the dichloromethane layer was washed once with 50.0 g of water to obtain an organic phase extract;

[0043] (3) Drying: Add 8g of anhydrous magnesium sulfate to the organic phase extract and dry for 1-2 hours, filter, concentrate under reduced pressure, and concentrate until n...

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Abstract

The invention relates to a preparing method for vildagliptin and belongs to the field of compound preparation. The method comprises the following steps that under an amide organic solvent system and the existence of alkali, 3-amino-1-adamantanol and (S)-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile are subjected to an alkylation reaction, and a reaction solution is obtained; then, the reaction solution is subjected to posttreatment, and vildagliptin is obtained. The method has the advantages that reaction raw materials and a solvent are saved, the yield is high, purity is high, the content of dipolymer impurities is low, the medicinal requirement is met, operation is simple, the reaction time is short, posttreatment is easy, and industrialization is promoted.

Description

technical field [0001] The invention belongs to the field of preparation of medicinal compounds, in particular to a preparation method of vildagliptin. Background technique [0002] In 2007, Novartis' Vildagliptin (trade name: Galvus), chemical name (s)-1-[(3-hydroxy-l-adamantyl)amino]acetyl-2-cyano-pyrrole Alkane, as a DPP-4 inhibitor, is used for the treatment of diabetes and has been approved by the European Commission. In 2011, it approved the import of vildagliptin tablets and compound preparations of vildagliptin and metformin in China. Vildagliptin is the only drug of the same type that can be used in combination with hypoglycemic drugs such as metformin and thiazolidinone. The drug has shown a good therapeutic effect in the treatment of diabetes and has occupied a huge market share in the world. [0003] In the synthesis of vildagliptin, at present, there are literatures reporting its synthesis method, but there are certain defects. [0004] The invention patent "...

Claims

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Application Information

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IPC IPC(8): C07D207/16
CPCC07D207/16
Inventor 沈思思刘九知杨璐陶芳
Owner NORTHEAST PHARMA GRP
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