Preparation method of high-purity vildagliptin

Abstract

The invention discloses a preparation method of high-purity vildagliptin, which comprises the following steps: carrying out nucleophilic substitution reaction on an intermediate (2S)-1-(2-chloracetyl)-2-pyrrolidine formonitrile and 3-amino-1-adamantanol in a certain reaction solvent by using potassium iodide as a catalyst and potassium carbonate as an acid-binding agent, carrying out after-treatment to obtain grease, and carrying out solvent crystallization to obtain a vildagliptin crude product; and refining the vildagliptin crude product by using a purified solvent to obtain the refined product. The synthesis method by controlling the vildagliptin crude product obtains favorable technical effects, and can obviously lower the impurity content in the vildagliptin crude product. A refinement technique different from the documents is adopted, and isopropanol and 2-butanone impurity removal is performed to obtain favorable technical effects, thereby obviously lowering the content of the main impurity 3-amino-1-adamantanol and vildagliptin bis-substituted impurity in the vildagliptin crude product. The vildagliptin purity detected by HPLC (high performance liquid chromatography) and GC (gas chromatography) is up to 99.8% or above, and the contents of the two impurities are respectively lower than 0.1%.

Description

field of invention [0001] The invention belongs to the field of organic chemistry, and in particular relates to a preparation process of high-purity vildagliptin. Background technique [0002] Vildagliptin is a highly selective substrate-like enzyme inhibitor that more thoroughly inhibits DPP-4 enzyme activity and can obtain more active GLP-1 compared with competitive inhibitors (such as sitagliptin) . Vildagliptin is covalently bound to the catalytic site of DPP-4, acting quickly and slowly dissociated, so it can quickly and persistently increase the level of active GLP-1 in the body, effectively covering the mealtime and fasting periods, and is more conducive to the patient's HbA1c level reaching the standard. Due to the unique mechanism of action of vildagliptin, its hypoglycemic effect is significant, and it is glucose concentration-dependent hypoglycemic, so it is less hypoglycemic, does not increase body weight, and is safer. Vildagliptin simultaneously improves α an...

AI Technical Summary

Problems solved by technology

[0008] The advantage of the L-proline route is that the price of L-proline is low, and the disadvantage is that the first step in the synthesis step is due to the poor solubility of L-proline, and the yield of acetylation is not high.

In the second step, the carboxylic acid is converted into an amide, and the condensing agent DCC is required. The reaction operation described in the literature requires strict anhydrous operation, and will produce DCU, a by-product that is difficult to remove. It is reported in the literature that the purification process requires column chromatography.

In WO2011012322A2, the method of 2-butanone cannot make the residual amount of 3-amino-1-adamantanol less than 0.1%. During the research, it was also found that 2-butanone has a good effect on removing vildagliptin double-substituted impurities , while the removal effect on 3-amino-1-adamantanol was not obvious

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