Preparation method of alogliptin benzoate

A technology of benzoic acid and methyl, which is applied in the field of preparation of the drug alogliptin benzoate, can solve the problems of low product purity and difficult purification and removal of double-substituted impurities, achieve high product purity, avoid double-substituted impurities, and react The effect of mild conditions

Active Publication Date: 2018-04-24
CHANGZHOU SUNLIGHT PHARMA
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  • Abstract
  • Description
  • Claims
  • Application Information

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

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1）

[0046] The preparation method of the alogliptin benzoate of the present embodiment has the following steps:

[0047] ①Add 20.8g of dichloromethane, 3.21g of 6-chloro-3-methyluracil, 4.51g of 2-cyanobenzyl bromide and 5.16g of DIPEA to the reaction flask in sequence, heat up to reflux reaction (40-45°C), HPLC sampling control until 3-methyl-6-chlorouracil disappears to end the reaction.

[0048] After the reaction, cool the reaction system to 20-25°C, distill methylene chloride off under reduced pressure, add water and stir for 1 hour, then filter, rinse the filter cake with water, add absolute ethanol, control the temperature at 20-25°C, and stir for 1 hour Filter, rinse the filter cake with ethanol, and finally dry it under reduced pressure at a temperature of 60-70°C to obtain 5.28g of white crystalline solid 2-(6-chloro-3-methyl-2,4-dioxo- 3,4-dihydro-2H-pyrimidin-1-ylmethyl)-benzonitrile [hereafter referred to as intermediate], the yield is 95.8%.

[0049]②Add 5.28g of t...

Embodiment 2～ Embodiment 5）

[0054] Each embodiment is the preparation of intermediates, and the specific method is basically the same as step 1 of Example 1, the difference lies in the amount of 2-cyanobenzyl bromide and DIPEA, see Table 1 for details.

[0055] Table 1

[0056]

Embodiment 6～ Embodiment 9）

[0062] The steps ① of each embodiment are exactly the same as the steps ① of Example 1, and the steps ② and ③ of each embodiment are basically the same as the steps ② and ③ of Example 1, and the differences are shown in Table 3.

[0063] table 3

[0064]

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PUM

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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...

Claims

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Application Information

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IPC IPC(8): C07D401/04C07C63/06C07C51/41
CPCC07D401/04
Inventor 胡国宜胡锦平高永清王永成奚小金
Owner CHANGZHOU SUNLIGHT PHARMA
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