Industrial production method of Alogliptin benzoate raw material medicine

Abstract

The invention discloses an industrial production method of Alogliptin benzoate raw material medicine. According to the method, ethanol / water mixed solvents are used as crystallization solvents; the ethanol / water mixed solvents and Alogliptin benzoate crude products are heated and flow back to a state that the solution is clear; the temperature is lowered, and crystal seeds are added; the gradient temperature reduction crystal separation is carried out; centrifugation and drying are carried out, and the Alogliptin benzoate raw material medicine is obtained. The adopted mixed solvents have low toxicity, and a better environment-friendly effect can be achieved. Compared with the method in the prior art, the industrial production method provided by the invention has the advantages that the solvent use type is reduced, the process is simple, the yield is high, and the production cost is reduced; through the method, the purity of the obtained Alogliptin benzoate finished product is at least 99.8 percent, the single impurity content is lower than or equal to 0.05 percent, the ethanol residue is low (lower than or equal to 0.1 percent) and is much lower than the limit of 0.5 percent of medical raw material medicine; impurities X generated by the reaction between phthalic acid and Alogliptin can be removed.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to an industrial production method of alogliptin benzoate bulk drug. Background technique [0002] Alogliptin Benzoate, the chemical name is 2-[[6-[(3R)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2, 4-dioxo-1(2H)-pyrimidinyl] methyl] benzonitrile benzoate, the structure is shown in formula (I), [0003] [0004] It is a DPP-IV inhibitor developed by Takeda Pharmaceutical. It can promote the insulin secretion related to glucose concentration by increasing the plasma concentration of GLP-1 in the body, maintain the level of glucagon-like-1 peptide and glucose-dependent insulinotropic peptide in the body, increase the secretion of insulin, and thus play a role in reducing blood pressure. Sugar curative effect. [0005] Chinese patent 201310106584.6 discloses a crystal compound of alogliptin benzoate, which is refined with methanol and ethyl acetate in the synthesis process, an...

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Problems solved by technology

[0005] Chinese patent 201310106584.6 discloses a crystal compound of alogliptin benzoate, which is refined with methanol and ethyl acetate in the synthesis process, and the yield is only 65%; Chinese patent 201410236391.7 discloses a crystal form of alogliptin benzoate A refining method, in which the crude product of alogliptin benzoate is crystallized in methanol in the presence of benzoic acid to obtain the fine product of alogliptin benzoate; Chinese patent 201410388488.X discloses a polymorphic form of alogliptin benzoate The preparation method of crystals uses methanol and methyl tert-butyl ether as recrystallization solvents; the methanol used in the above patents is a second-class solvent with high toxicity and is not suitable for the final step of refined production of raw materials. The price of methyl tert-butyl ether Expensive, high production costs

[0006] Chinese patent 201310195299.6 discloses a batch production process of alogliptin benzoate with high polymorphic content. Firstly, the benzoic acid is refined with water, and then one or both of tetrahydrofuran, ethyl acetate, acetonitrile, and methanol are purified. The above mixture is salt-formed and precipitated, and the solvent is preferably dehydrated alcohol; this method needs to refine the benzoic acid first, increase the process, and simultaneously have high requirements for the purity of alogliptin, requiring ≥99.5%. In actual production, it is necessary to increase the purification steps of alogliptin, which is not conducive to production

[0009] At the same time, it was also found that whether it is refined with methanol or absolute ethanol, solvent molecules will be included in the alogliptin benzoate molecules, resulting in high solvent residues of alogliptin benzoate, which cannot meet the requirements of pharmaceutical raw materials. need

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