Preparation method of isomer impurities of vildagliptin

A technology for isomers and impurities, which is applied in the field of preparation of vildagliptin isomer impurities, to achieve the effects of improved safety, simple preparation process and easy operation

Inactive Publication Date: 2017-11-03
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 isomer impurities of vildagliptin
  • Preparation method of isomer impurities of vildagliptin
  • Preparation method of isomer impurities of vildagliptin

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Embodiment 1

[0039] The present invention provides a kind of preparation method of vildagliptin isomer impurity, the steps are as follows:

[0040] S1. Dissolve potassium carbonate and chloroacetyl chloride in tetrahydrofuran to obtain a chloroacetyl chloride solution; dissolve D-prolinamide (I) in tetrahydrofuran, add dropwise to the chloroacetyl chloride solution, and react at 20°C for 1.5h ; The reaction product (II) was obtained, filtered, the filtrate was taken, dried, trifluoroacetic anhydride was added to the filtrate, reacted at 20°C for 0.5h, and the solvent was spin-dried to obtain a crude product of the reaction product (Ⅲ), which was purified;

[0041] S2. Potassium carbonate and 3-amino-amantadinol were dissolved in tetrahydrofuran, catalyzed by potassium iodide, reacted with the reaction product (Ⅲ), kept at 50°C for 4.5 hours to cool down, filtered, and the filtrate was spin-dried to obtain the target Product (IV) crude, purified.

Embodiment 2

[0043] The present invention provides a kind of preparation method of vildagliptin isomer impurity, the steps are as follows:

[0044] S1. Dissolve potassium carbonate and chloroacetyl chloride in tetrahydrofuran, and the molar ratio of potassium carbonate and chloroacetyl chloride is 1.5:1 to obtain a chloroacetyl chloride solution; dissolve D-prolineamide (I) in tetrahydrofuran and add dropwise Into the chloroacetyl chloride solution, the molar ratio of D-prolineamide and chloroacetyl chloride is 1:1, react at 25°C for 1.5h; obtain the reaction product (II), filter, take the filtrate, dry, add to the filtrate Trifluoroacetic anhydride, the molar ratio of D-prolineamide and trifluoroacetic anhydride is 1:1.2, react at 25°C for 0.5h, and spin the solvent to obtain the crude product of reaction product (Ⅲ), which is purified;

[0045] S2. Potassium carbonate and 3-amino-amantadinol are dissolved in tetrahydrofuran, the molar ratio of potassium carbonate and 3-amino-adamantanel ...

Embodiment 3

[0047] The present invention provides a kind of preparation method of vildagliptin isomer impurity, the steps are as follows:

[0048] S1. Dissolve potassium carbonate and chloroacetyl chloride in tetrahydrofuran, and the molar ratio of potassium carbonate and chloroacetyl chloride is 2.5:1 to obtain a chloroacetyl chloride solution; dissolve D-prolineamide (I) in tetrahydrofuran and add dropwise Into the chloroacetyl chloride solution, the molar ratio of D-prolineamide and chloroacetyl chloride is 1:1.1, react at 25°C for 2.5h; get the reaction product (II), filter, take the filtrate, dry it, and add to the filtrate Trifluoroacetic anhydride, the molar ratio of D-proline amide and trifluoroacetic anhydride is 1:1.5, react at 25°C for 1.5h, and spin the solvent to obtain the crude product of reaction product (Ⅲ), and the crude product of reaction product (Ⅲ) Wash with saturated sodium bicarbonate solution to pH = 7-8, add ethyl acetate for extraction, collect the organic layer...

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Abstract

The invention discloses a preparation method of isomer impurities of vildagliptin, and relates to the technical fields of medicine and chemical industry. The preparation method comprises the steps: S1: enabling D-prolinamide (I) serving as a raw material to react with chloroacetyl chloride to obtain a reaction product (II), and then enabling the reaction product (II) to react with trifluoroacetic anhydride to obtain a reaction product (III); S2: enabling the reaction product (III) to react with 3-amino-1-adamantanol to generate a target product (IV). The preparation method disclosed by the invention has the advantages that the preparation process is simple, the operation is simple and convenient, reaction time is short, and the post-treatment purification is simple and effective, which is beneficial to industrialized production. The purity of manufactured impurities of the vildagliptin is high and is as high as 99.1% through HPLC (high-performance liquid chromatography) detection. By further studying the isomer impurities of the vildagliptin, the quality of the vildagliptin can be better controlled, and the drug safety is 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 isomer 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)-carbonitril...

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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