Vildagliptin preparation method

A technology of organic solvent and chloroacetyl group, applied in the field of preparation of pharmaceutical compounds, can solve problems such as the harm of fluoroboric acid, high price, etc., and achieve the effects of improving yield, improving yield, and being beneficial to the industrialization of the reaction

Inactive Publication Date: 2014-03-19
SHENYANG INSTITUTE OF CHEMICAL TECHNOLOGY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, fluoboric acid is harmful to the human body and the environment. In addition, the hydroxylation reagent required by this method needs to be prepared by itself and is expensive.

Method used

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preparation example Construction

[0038] The present invention provides a new preparation method of vildagliptin, the synthetic route is as follows:

[0039]

[0040] Wherein 1 is L-proline; 2 is (S)-1-(2-chloroacetyl)pyrrolidine-2-carboxylic acid; 3 is (S)-1-(2-chloroacetyl)pyrrolidine-2 -formamide; 4 is (S)-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile; 5 is 3-aminoadamantanol; 6 is 1-[[(3-hydroxy-1-adamant Alkyl)amino]acetyl]-2-cyano-(5)-tetrahydropyrrolidine (vildagliptin).

[0041] The preferred preparation method of the present invention comprises the following steps:

[0042] 1. Preparation of (S)-1-(2-chloroacetyl)pyrrolidine-2-carboxylic acid (2):

[0043] A certain amount of L-proline and THF are formed into a suspension, and a certain amount of chloroacetyl chloride is slowly added dropwise to the suspension. After the dropwise addition, reflux at 35°C for 2h, dilute with water, and continue to stir for 20min. After the reaction was completed, a certain amount of water was added, and the aqueo...

Embodiment 1

[0054] 1. Preparation of (S)-1-(2-chloroacetyl)pyrrolidine-2-carboxylic acid (2):

[0055] 4.8g (41.62mmol) L-proline and 45mL THF formed a suspension, and 4.7mL (62.43mmol) of chloroacetyl chloride was slowly added dropwise to the suspension. After the dropwise addition, reflux at 35°C for 2h, add 25ml of water to dilute, continue to stir for 20min, extract with 25mL of saturated saline and 50mL of ethyl acetate, extract the aqueous layer with 25*3mL of ethyl acetate, and dry over anhydrous magnesium sulfate. Suction filtration, rotary evaporation of the filtrate to obtain an oily liquid. Diethyl ether was recrystallized, cooled and filtered to obtain 7.21 g of a white solid with a yield of 91%.

Embodiment 2

[0057] 2. Preparation of (S)-1-(2-chloroacetyl)pyrrolidine-2-carboxamide (3):

[0058] (S)-1-(2-chloroacetyl)pyrrolidine-2-carboxylic acid 5g (0.026mol) was dissolved in 50mL of CH 2 Cl 2 Stirring in , DCC (5.4g, 0.026mol) was dissolved in 50mL CH 2 Cl 2 middle. CH of DCC 2 Cl 2 The solution was slowly added dropwise to the CH of formic acid 2 Cl 2 In the solution, it is expected to add dropwise for 1 hour, and after the dropwise addition, continue to react for 1 hour. Join NH 4 HCO 3 (20.6g, 0.26mol) continue reaction 1h, TLC detects developing agent (CH 2 Cl 2 : MeOH=20:1), after the reaction is complete, filter with CH 2 Cl 2 The filter residue was washed, the solution was concentrated, a small amount of ethyl acetate was added to recrystallize and cool the liquid, and the crude weight was 3.41 g by suction filtration, with a yield of 69%.

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Abstract

The invention provides a vildagliptin preparation method, and relates to a drug compound preparation method. According to the preparation method, L-proline is adopted as a raw material, and is subjected to reactions such as N-chloroacetylation, carbonyl amination and nitrile formation through amide dehydration to obtain an intermediate (S)-1-(2-chloroacetyl)pyrrolidine-2-formonitrile; and an amantadine hydrochloride is adopted as a raw material, and is subjected to mixing acid nitration and alkali hydrolysis to obtain the other intermediate 3-amino-adamantanol, and the two key intermediates are subjected to condensation to obtain the target product vildagliptin. The preparation method has characteristics of simpleness, easy performing, simple reaction operation, convenient time and environmental protection, and is suitable for industrial production.

Description

technical field [0001] The invention relates to a preparation method of a pharmaceutical compound, in particular to a preparation method of vildagliptin. Background technique [0002] Vildagliptin is a cyanopyrrolidine specific dipeptidyl peptidase Ⅳ (DPP-Ⅳ) inhibitor researched and developed by Novartis, which can effectively inhibit dipeptidyl peptidase Ⅳ and increase intestinal insulin-stimulating hormone pancreatic hyperactivity. The concentration of glucagon-like peptide-1 (GLP-1) in the body can significantly reduce the level of glycosylated hemoglobin, and achieve the purpose of treating type 2 diabetes. It has good tolerance and no significant adverse reactions. It is a good application Promising new drugs for diabetes. [0003] The chemical name of vildagliptin is 1-[[(3-hydroxy-1-adamantyl)amino]acetyl]-2-cyano-(5)-tetrahydropyrrolidine, and its structural formula is as follows: [0004] [0005] Patent WO00 / 34241 discloses the preparation method of vildag...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/16
CPCC07D207/16
Inventor 孟艳秋张宇丁一张萌
Owner SHENYANG INSTITUTE OF CHEMICAL TECHNOLOGY
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