A kind of preparation method of vildagliptin

A technology of solvent and cyanuric chloride, which is applied in the field of preparation of vildagliptin, can solve the problems that by-product formation is not easy to control, and product purity cannot be guaranteed, so as to reduce the content of by-products, reduce energy consumption, and reduce by-products. The effect of product formation

Active Publication Date: 2019-09-03
HEBEI MEDICAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0015] The above various routes, the ubiquitous problem is that the formation of by-products is not easy to control, and the purity of the final product cannot be guaranteed

Method used

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  • A kind of preparation method of vildagliptin
  • A kind of preparation method of vildagliptin
  • A kind of preparation method of vildagliptin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] Synthesis of Vildagliptin Intermediate-1

[0054] Add 100g of L-prolineamide and 300ml of N,N-dimethylformamide into a 1L reaction bottle, control the temperature to 0-10°C under stirring, add 80.8g of cyanuric chloride slowly in batches, Insulation reaction 2h. The reaction solution was poured into 600ml of purified water, adjusted to pH 9-10 with saturated aqueous sodium carbonate solution, and extracted three times with ethyl acetate, 600ml each time. Combine the organic phases, wash with 500ml of saturated aqueous sodium bicarbonate solution, add 50g of anhydrous sodium sulfate, and stir at 20-30°C for 1h. Filter, wash the filter cake with 100ml of ethyl acetate, concentrate the filtrate to dryness under reduced pressure to obtain an oil, add 300ml of ethyl acetate, adjust the pH to 2~3 with 30% hydrogen chloride ethanol solution, cool down to 0~10°C, stir and crystallize for 2h . After filtering, the filter cake was washed with 100 ml of ethyl acetate, and the f...

Embodiment 2

[0062] Synthesis of Vildagliptin Intermediate-1

[0063] Add 100g of L-prolineamide and 300ml of N,N-dimethylacetamide into a 1L reaction bottle, control the temperature to 0-10°C under stirring, add 50.9g of cyanuric chloride slowly in batches, Insulation reaction 2h. The reaction solution was poured into 600ml of purified water, adjusted to pH 9-10 with saturated aqueous sodium carbonate solution, and extracted three times with dichloromethane, 600ml each time. Combine the organic phases, wash with 500ml of saturated aqueous sodium bicarbonate solution, add 50g of anhydrous sodium sulfate, and stir at 20-30°C for 1h. Filter, wash the filter cake with 100ml of dichloromethane, concentrate the filtrate to dryness under reduced pressure to obtain an oil, add 300ml of ethyl acetate, adjust the pH to 2~3 with 20% hydrogen chloride ethanol solution, cool down to 0~10°C, stir and crystallize for 2h . After filtering, the filter cake was washed with 100 ml of ethyl acetate, and t...

Embodiment 3

[0070] Synthesis of Vildagliptin Intermediate-1

[0071] Add 100g of L-prolineamide and 300ml of dimethyl sulfoxide into a 1L reaction flask, control the temperature to 0-10°C under stirring, slowly add 80.8g of cyanuric chloride in batches, and keep the reaction at 0-10°C for 2 hours. Pour the reaction solution into 600ml of purified water, adjust the pH to 9-10 with saturated aqueous sodium carbonate solution, and extract with toluene three times, 600ml each time. Combine the organic phases, wash with 500ml of saturated aqueous sodium bicarbonate solution, add 50g of anhydrous sodium sulfate, and stir at 20-30°C for 1h. Filter, wash the filter cake with 100ml of toluene, concentrate the filtrate to dryness under reduced pressure to obtain an oil, add 300ml of toluene, adjust the pH to 2~3 with 40% hydrogen chloride ethanol solution, cool down to 0~10°C, stir and crystallize for 2h. After filtration, the filter cake was washed with 100ml of toluene, and the filter cake was v...

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Abstract

The present invention relates to a preparation method of vildagliptin, comprising using L-prolineamide as a raw material, dehydrating with cyanuric chloride to generate (S)-2-cyanopyrrolidine; (S)-2-pyrrolidine The reaction of cyanopyrrolidine and hydrogen chloride to form a salt gives Intermediate ‑1; Intermediate ‑1 reacts with chloroacetic acid under the conditions that EDCI is the condensation agent, HOBt is the catalyst, and DIEA is the acid-binding agent to obtain Intermediate ‑2; Intermediate ‑ 2 react with 3-amino-1-adamantanol to obtain vildagliptin, which is filtered, concentrated, crystallized, and then filtered to obtain the crude product of vildagliptin; after refining with acetone, the finished product of vildagliptin is obtained, and the present invention creates A new route, which can reduce the generation of by-products in each step, reduce the content of by-product vildagliptin disubstituted and 3-amino-1-adamantanol in the product to less than 0.1%, effectively improve the vildagliptin The yield and purity of Tin are high, the raw materials are easy to obtain, and the conditions are mild, so it is suitable for large-scale industrial production.

Description

technical field [0001] The invention relates to a preparation method of vildagliptin. Background technique [0002] Vildagliptin, English name Vildagliptin, chemical name: (S)-1-[[(3-hydroxy-1-adamantyl)amino]acetyl]-2-cyanotetrahydropyrrolidine. It is a class of substituted pyrrolidine compounds developed by Novartis, Switzerland, and is a selective, competitive and reversible dipeptidylase IV (DPP-IV) inhibitor. The drug inhibits the activity of the enzyme by combining with DPP-IV to form a DPP-IV complex, increasing the concentration of GLP-1 (glucagon-like peptide-1), promoting the production of insulin by islet B cells, and reducing pancreatic hyperplasia. Glucagon concentration, thereby lowering blood sugar, and no significant effect on body weight. It can be used to treat type 2 diabetes. Whether it is used alone or in combination with other antidiabetic drugs, it can significantly reduce the level of glycosylated hemoglobin. It has good tolerance and no significant...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D207/16
Inventor 张恺薛娜石晓伟陈兴贺王亚博律涛
Owner HEBEI MEDICAL UNIVERSITY
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