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Preparation method of vildagliptin dimer impurities

A dimer and impurity technology, applied in the field of vildagliptin dimer impurity preparation, to achieve the effect of mild reaction conditions, high purity, and high impurity yield

Inactive Publication Date: 2017-11-24
合肥创新医药技术有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

At present, there is no report in the art about the relevant preparation process of the above-mentioned impurities

Method used

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  • Preparation method of vildagliptin dimer impurities
  • Preparation method of vildagliptin dimer impurities
  • Preparation method of vildagliptin dimer impurities

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] A kind of preparation method of vildagliptin dimer impurity that the present invention proposes, the steps are as follows:

[0031] Potassium carbonate, catalyst and vildagliptin were dissolved in tetrahydrofuran, the molar ratio of vildagliptin and potassium carbonate was 1:2, vildagliptin intermediate (S)-N-chloroacetyl-2-cyano The base pyrrolidine is dissolved in tetrahydrofuran, and is added dropwise in the vildagliptin solution, and the mol ratio of vildagliptin and vildagliptin intermediate (S)-N-chloroacetyl-2-cyanopyrrolidine is 1:2, the dropwise addition was completed, refluxed for 20 hours, filtered, and the filtrate was concentrated to dryness to obtain the crude product of the target product, which was purified.

Embodiment 2

[0033] A kind of preparation method of vildagliptin dimer impurity that the present invention proposes, the steps are as follows:

[0034] Potassium carbonate, catalyst and vildagliptin were dissolved in tetrahydrofuran, the molar ratio of vildagliptin and potassium carbonate was 1:4, vildagliptin intermediate (S)-N-chloroacetyl-2-cyano The base pyrrolidine is dissolved in tetrahydrofuran, and is added dropwise in the vildagliptin solution, and the mol ratio of vildagliptin and vildagliptin intermediate (S)-N-chloroacetyl-2-cyanopyrrolidine is 1:3.5, the dropwise addition was completed, refluxed for 22 hours, filtered, the filtrate was concentrated to dryness, and the crude product of the target product was obtained; the crude product of the target product was dissolved in saturated saline, extracted with ethyl acetate, the ethyl acetate layer was separated, and dichloro Extract with methane, separate the water layer, combine the dichloromethane layers, wash with saturated bri...

Embodiment 3

[0036] A kind of preparation method of vildagliptin dimer impurity that the present invention proposes, the steps are as follows:

[0037] Potassium carbonate, catalyst and vildagliptin were dissolved in tetrahydrofuran, the molar ratio of vildagliptin and potassium carbonate was 1:5, vildagliptin intermediate (S)-N-chloroacetyl-2-cyano The base pyrrolidine is dissolved in tetrahydrofuran, and is added dropwise in the vildagliptin solution, and the mol ratio of vildagliptin and vildagliptin intermediate (S)-N-chloroacetyl-2-cyanopyrrolidine is 1:4, the dropwise addition was completed, refluxed for 26 hours, filtered, the filtrate was concentrated to dryness, and the crude product of the target product was obtained; the crude product of the target product was dissolved in saturated saline, extracted with ethyl acetate, the ethyl acetate layer was separated, and dichloride was added Extract with methane, separate the water layer, combine the dichloromethane layers, wash with sat...

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Abstract

The invention discloses a preparation method of vildagliptin dimer impurities and relates to the technical field of chemical medicine. The preparation method comprises steps as follows: vildagliptin and a vildagliptin intermediate (S)-N-chloracety-2-cyanopyrrolidine react under the action of a catalyst under an alkaline condition, and a target product is prepared. According to the preparation method, raw materials are easy to obtain, the preparation process is simple, reaction conditions are mild, prepared vildagliptin impurities are high in yield and purity, have the yield reaching 87.0% and the purity reaching 98.5% and can be used for qualitative and quantatative analysis of impurities in production of vildagliptin, accordingly, the quality of vildagliptin can be controlled better, and the medicine safety can be improved.

Description

technical field [0001] The invention relates to the technical field of medicine and chemical industry, in particular to a preparation method of vildagliptin dimer impurities. Background technique [0002] Vildagliptin is a dipeptidylase type IV (DDP-IV) inhibitor developed by Novartis, which can be used to treat type 2 diabetes. It was approved for marketing by the European Union in September 2007, and was launched in China in 2011. Vildagliptin, the chemical name is 1-[2-(3-hydroxyadamantan-1-ylamino)acetyl]pyrrolidine-2(S)-carbonitrile, and its chemical structure is as follows: [0003] [0004] In the quality standard of vildagliptin, its process impurities are as follows: [0005] 1. Vildagliptin amide impurity, its structural formula is as follows: [0006] [0007] 2. Vildagliptin dimer impurity, its structural formula is as follows: [0008] [0009] 3. Vildagliptin R-isomer impurity: 1-[2-(3-hydroxyadamantan-1-ylamino)acetyl]pyrrolidine-2(R)-carbonitrile...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/16
Inventor 曹明成刘宏亮年帅
Owner 合肥创新医药技术有限公司
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