Mass production process of polycrystalline high-content benzoic acid alogliptin

Abstract

The invention relates to a mass production process of polycrystalline high-content benzoic acid alogliptin. According to the process, the products do not need to be refined and the qualified products conforming to the pharmaceutical production demand can be obtained directly. The process comprises the following steps: putting 5kg of the benzoic acid into a 200L reaction kettle; adding 100L of pure water; stirring, heating and refluxing for 1 hour; centrifuging after the reaction liquid is decreased to 50 to 60 DEG C; filtering into a filter cake in a pressing manner by using a plate-and-frame filter press and performing the forced air drying at the temperature of 60 to 65 DEG C for 10 to 12 hours, thereby obtaining 2.41kg of a white needle-shaped crystal benzoic acid refined product; putting 3.11kg of alogliptin and 1.13kg of the white needle-shaped crystal benzoic acid refined product into the reaction kettle; adding 15L of a solvent; heating and dissolving; heating until refluxing for 2 to 3 hours; stopping the heating until separating out white solids; naturally cooling to the room temperature; stirring and separating out a crystal for 10 to 12 hours; centrifuging; washing the obtained solid by using 1L of the solvent; and performing the forced air drying for 8 to 10 hours at the temperature of 40 to 45 DEG C, thereby obtaining 3.82kg of the finished polycrystalline high-content benzoic acid alogliptin product.

Description

【Technical field】 [0001] The invention relates to a batch production process of polymorphic high-content alogliptin benzoate. The product does not need to be further refined, and qualified products meeting the requirements of pharmaceutical production can be directly obtained. 【Background technique】 [0002] Alogliptin is a selective serine protease dipeptidyl peptidase IV (DPP IV) inhibitor, through the control of glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP, also known as It is the incretin activity of gastric inhibitory peptide), which can effectively maintain blood sugar homeostasis (glucose homeostasis, glucose homeostasis). Therefore, it has been proposed as a powerful drug in the treatment of type 2 diabetes. The benzoate salt of alogliptin (SYR-322) has shown encouraging antidiabetic efficacy. [0003] Alogliptin is chemically named 2-[6-[3(R)-aminopiperidin-1-yl]-3-methyl-2,4-dioxo-1,2,3,4-tetrahydro Pyrimidin-1-ylmethyl]b...

AI Technical Summary

Problems solved by technology

[0014] Starting with 6-chloro-3-methyluracil, although impurities are avoided However, when introducing the (R)-3-aminopiperidine substituent group, (R)-3-aminopiperidine dihydrochloride is also used as a raw material, so that this step reaction also inevitably produces some 3- Amino substituted product And it is difficult to remove, which will eventually affect the purity of the finished product

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