Preparation method of Vildagliptin intermediate

A technology for intermediates and preparation steps, which is applied in the field of preparation of vildagliptin intermediates, can solve the problems of low yield, unfriendly environment, and a large amount of solvents, and achieve the goals of reducing energy consumption, shortening reaction time, and increasing yield Effect

Inactive Publication Date: 2018-08-24
NANAN CHUANGPEI ELECTRONICS TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] The technical problem to be solved by the present invention: for vildagliptin intermediate 1-(2-chloroacetyl) proline, all need to carry out high-temperature reflux reaction under solvent conditions, the reaction requires a large amount of solvent, the consumption is serious, and it is not environmentally friendly Friendly, low yield problem, a preparation method of vildagliptin intermediate is provided

Method used

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  • Preparation method of Vildagliptin intermediate
  • Preparation method of Vildagliptin intermediate
  • Preparation method of Vildagliptin intermediate

Examples

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example 1

[0019] With a molar ratio of 1:10, weigh L-proline and chloroacetyl chloride, add them into a three-necked flask, and stir and mix at room temperature; after stirring and mixing for 5 minutes, add triethylamine, triethylamine and L- The molar ratio of proline is 2:1, stirred and reacted at room temperature for 3h, recovered excess chloroacetyl chloride by distillation under reduced pressure after the reaction, poured the reaction solution into ethyl acetate and distilled water, stirred and mixed, let stand to separate layers, collected organic layer, and distilled under reduced pressure to recover ethyl acetate to obtain vildagliptin intermediate 1-(2-chloroacetyl)proline, with a melting point of 112.3°C, a purity of 99.89%, and a yield of 92.5%.

example 2

[0021] Weigh L-proline and chloroacetyl chloride at a molar ratio of 1:12, add them to a three-necked flask, and stir and mix at room temperature; after stirring and mixing for 7 minutes, add sodium acetate, sodium acetate and L-proline to the three-necked flask The molar ratio is 2.5:1, stirred and reacted at room temperature for 4h, after the reaction, the excess chloroacetyl chloride was recovered by distillation under reduced pressure, the reaction solution was poured into ethyl acetate and distilled water, stirred and mixed, and allowed to stand for layering, and the organic layer was collected. Ethyl acetate was recovered by pressure distillation to obtain vildagliptin intermediate 1-(2-chloroacetyl)proline, with a melting point of 112.7°C, a purity of 99.92%, and a yield of 93.0%.

example 3

[0023] With a molar ratio of 1:15, weigh L-proline and chloroacetyl chloride, add them to a three-necked flask, and stir and mix at room temperature; after stirring and mixing for 10 minutes, add 4-dimethylaminopyridine, 4-dimethylaminopyridine, and 4-dimethylaminopyridine to the three-necked flask The molar ratio of aminopyridine and L-proline is 3:1. Stir the reaction at room temperature for 5 hours. After the reaction, distill under reduced pressure to recover excess chloroacetyl chloride. Pour the reaction solution into ethyl acetate and distilled water, stir and mix, and then let stand Separate layers, collect the organic layer, and recover ethyl acetate by distillation under reduced pressure to obtain vildagliptin intermediate 1-(2-chloroacetyl)proline, with a melting point of 113.1° C., a purity of 99.92%, and a yield of 94.8%.

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Abstract

The invention belongs to the field of medicine intermediates, and particularly relates to a preparation method of a Vildagliptin intermediate. The preparation method is characterized in that L-prolineand chloroacetyl chloride are used as raw materials to react; in the reaction process, the adding of other solvents is not needed, so that the introducing of other impurities is avoided, and the purity is improved; by adding an acid-binding agent, the hydrochloric acid produced in the reaction is timely neutralized, so that the reaction time is shortened; the yield rate is increased, the productis easy to purify, and the safety and reliability are realized. Compared with the prior art, the preparation method has the advantages that the adding of a large amount of solvent is not needed, the reaction can be performed at room temperature, the energy consumption is decreased, and the environment-friendly effect is realized.

Description

technical field [0001] The invention belongs to the field of pharmaceutical intermediates, and in particular relates to a preparation method of a vildagliptin intermediate. 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 significantl...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/16
CPCC07D207/16
Inventor 王玉环
Owner NANAN CHUANGPEI ELECTRONICS TECH CO LTD
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