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Method for preparing substituted (S)-pyrrolidine-2-formonitrile and vildagliptin

A technology of pyrrolidine and nitrile, which is applied in the field of medicine, can solve the problems of product residue, high price, and difficult operation, and achieve the effects of environmental protection, increased yield, and reduced cost

Active Publication Date: 2016-08-24
HYBIO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] In the prior art, trifluoroacetic anhydride is mostly used, but its price is relatively high, and there is a large exotherm in the process of quenching the reaction, the operation is difficult, the purity of the product is easily affected, and the yield is also low
Although the price of cyanuric chloride is relatively low, the industrial production of cyanuric chloride generally adopts two kinds of highly toxic substances, sodium cyanide or hydrocyanic acid, as raw materials. The environmental friendliness of cyanuric chloride is poor, and it is easy to Residues in the product affect the purity of the product

Method used

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  • Method for preparing substituted (S)-pyrrolidine-2-formonitrile and vildagliptin
  • Method for preparing substituted (S)-pyrrolidine-2-formonitrile and vildagliptin
  • Method for preparing substituted (S)-pyrrolidine-2-formonitrile and vildagliptin

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0060] Method A

[0061] Synthesis of (S)-1-(2-chloroacetyl)pyrrolidine-2-carboxamide

[0062] Compound S-proline amide (11.2g, 100mmol) was added to compound chloroacetyl chloride (11.5g, 100mmol) tetrahydrofuran (200mL) solution pre-cooled to 0°C, the solution was kept at 0°C and stirred for 30 minutes, potassium carbonate (27.3 g, 200 mmol) was added into the mixed solution, and the resulting mixed solution was stirred at 0° C. for 1 hour, and then the reaction solution was warmed up to room temperature and stirred for 3 hours.

[0063] The end of the reaction was detected by TLC. After the compound S-prolinamide completely disappeared, the reaction system was filtered, the filter cake was washed with tetrahydrofuran (50 mL), and the filtrates were combined. The solvent was rotary evaporated to dryness, and the residual oil was dissolved in ethyl acetate. The obtained ethyl acetate solution was washed with water (50 mL×2), and dried over anhydrous sodium sulfate for 2 hou...

Embodiment 2

[0065] Method B

[0066] Synthesis of (S)-1-(2-bromoacetyl)pyrrolidine-2-carboxamide

[0067] Compound S-prolinamide (11.2g, 100mmol) was added to bromoacetyl bromide (20.0g, 100mmol) tetrahydrofuran (200mL) solution pre-cooled to 0°C, and the solution was stirred at 0°C for 30 minutes, potassium carbonate (27.3g, 200 mmol) was added into the mixed solution, and the resulting mixed solution was stirred at 0° C. for 1 hour, and then the reaction solution was warmed up to room temperature and stirred for 3 hours.

[0068] The end of the reaction was detected by TLC. After compound 2 disappeared completely, the reaction system was filtered, the filter cake was washed with tetrahydrofuran (50 mL), and the filtrates were combined. The solvent was rotary evaporated to dryness, and the residual oil was dissolved in ethyl acetate. The obtained ethyl acetate solution was washed with water (50 mL×2), and dried over anhydrous sodium sulfate for 2 hours. After removing the desiccant, i...

Embodiment 3

[0070] Method C

[0071] Synthesis of (S)-1-(2-bromoacetyl)pyrrolidine-2-carboxamide

[0072] Compound S-prolinamide (11.2g, 100mmol) was added to a solution of bromoacetyl chloride (15.6g, 100mmol) tetrahydrofuran (200mL) precooled to 0°C, and the solution was stirred at 0°C for 30 minutes. Potassium carbonate (27.3g, 200 mmol) was added into the mixed solution, and the resulting mixed solution was stirred at 0° C. for 1 hour, and then the reaction solution was warmed up to room temperature and stirred for 3 hours.

[0073] The end of the reaction was detected by TLC. After compound 2 completely disappeared, the reaction system was filtered, the filter cake was washed with tetrahydrofuran (50 mL), and the filtrates were combined. The solvent was rotary evaporated to dryness, and the residual oil was dissolved in ethyl acetate. The obtained ethyl acetate solution was washed with water (50 mL×2), and dried over anhydrous sodium sulfate for 2 hours. After removing the desicca...

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Abstract

The invention provides a method for preparing (S)-1-(2-halogenated acetyl)pyrrolidine-2-formonitrile as shown in the formula (I). Optionally in the presence of a diluent, (S)-1-(2-halogenated acetyl)pyrrolidine-2-formamide and a dehydrating agent propanephosphonic acid cyclic anhydride (T3P) react with each other. The invention also provides a method for preparing vildagliptin by using S-prolinamide involving the above reaction. The method for preparing the compound as shown in the formula (I) has the following advantages: use of expensive trifluoroacetic anhydride is not required, yield is increased, and cost is reduced; use of cyanuric chloride prepared from highly toxic raw materials is not required, and the reaction is more environmentally friendly; and an improved method for preparing vildagliptin is then obtained. In the formula (I) and formula (II), X1 is halogen.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a method for (S)-1-(2-haloacetyl)pyrrolidine-2-carbonitrile and a method for preparing vildagliptin. Background technique [0002] Vildagliptin is a dipeptidylase type IV (DDP-IV) inhibitor, which can be used to treat type II diabetes. It is a selective, competitive and reversible DPP-IV inhibitor. Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like polypeptide (GLP-I) are important hormones for maintaining glucose concentration in the body, and both have incretin-stimulating effects. In patients with type II diabetes, the insulin-stimulating function of GIP is impaired, and only GLP-1 can play a role in stimulating insulin secretion. It promotes the secretion of insulin by acting on the receptors on the islet B cell membrane. GLP-I also inhibits glucagon secretion and gastric emptying to increase satiety (appetite suppression). DPP-IV binds to pr...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/16
Inventor 刘飞孟方奕华刘建马亚平袁建成
Owner HYBIO PHARMA
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