Preparation method of alogliptin benzoate

Abstract

The invention discloses a preparation method of alogliptin benzoate. The preparation method of alogliptin benzoate comprises the following steps of, firstly, reacting 3-methyl-6-chlorouracil with 2-cyanobenzyl bromide to obtain 2-(6-chloro-3-methyl-2, 4-dioxo-3, 4-dihydro-2H-pyrimidine-1-methyl)-benzonitrile; secondly, reacting 2-(6-chloro-3-methyl-2, 4-dioxo-3, 4-dihydro-2H-pyrimidine-1-methyl)-benzonitrile with (R)-3-aminoperidine dihydrochloride to obtain alogliptin; thirdly, salifying alogliptin with benzoic acid to obtain alogliptin benzoate. According to the preparation method of alogliptin benzoate, condensation reaction in the first step is implemented in dichloromethane solvent and under reflux conditions, thereby being mild in conditions and capable of achieving a yield higher than 90%; condensation reaction in the second step is implement in water or water-methylbenzene mixed solution to avoid production of disubstituted impurities and achieving high product purity.

Description

technical field [0001] The invention belongs to the technical field of medicine preparation, and in particular relates to a preparation method of alogliptin benzoate, a medicine for treating type 2 diabetes. Background technique [0002] The chemical name of alogliptin benzoate is: 2-({6-[(3R)-3-aminopiperidin-1-yl]-3-methyl-2,4-dioxo-3,4- Dihydropyrimidin-1(2H)-yl}methyl)-benzonitrile monobenzoate is a dipeptidyl peptidase IV (DPP-IV) inhibitor developed by Takeda Pharmaceutical Co., Ltd., Japan. Approved by the FDA for the treatment of type 2 diabetes, CFDA also approved its imported preparations for domestic sales in 2013. [0003] At present, there are four main routes for the synthesis of alogliptin benzoate: [0004] (1) Route A: using 6-chlorouracil as the starting material, it is prepared by four-step reaction, firstly conducts condensation reaction with 2-cyanobenzyl bromide, then conducts methylation reaction with methyl iodide, and then reacts with (R) -3-amino...

AI Technical Summary

Problems solved by technology

[0011] Since there are two active amino groups in (R)-3-aminopiperidine dihydrochloride, it is very easy to produce double-substituted impurities, which is why routes B and D do not hesitate to use higher-priced substituted (R)-3-amino groups. The reason for the reaction of piperidine, and a large number of experiments have shown that: the above-mentioned second-step condensation reaction in alcoholic solvents is easy to generate disubstituted impurities and is difficult to remove by purification, resulting in lower purity of the final product