A preparing method for alogliptin benzoate

A technology of benzoic acid and methyl group, applied in the field of preparation of improved processes, can solve the problems of low total yield, high industrialization cost, unfavorable recovery and mechanical application, etc., and achieves the effects of improving yield and purity, being easy to industrialize amplification, and being environmentally friendly in process.

Active Publication Date: 2018-01-05
CHANGZHOU NO 4 PHARMA FACTORY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] 2. DMF and DMSO are used as high-boiling solvents, which are not conducive to recycling
[0011] 3. The total yield is low, only 20-25%
[0016] 1. Adopting N-methylpyrrolidone (abbreviated as NMP) and toluene as the reaction solvent, a large amount of water needs to be added to precipitate the product during post-treatment, which brings limitations to industrial operations; in addition, the boiling point of NMP exceeds 200 ℃, which is not conducive to recycling, and the cost of industrialization is too high
Moreover, NMP and toluene are relatively toxic and are restricted in use
[0017] 2. The purity of the obtained product is not high
[0022] 1. The toluene reaction system is used, although the product can be precipitated from the solution, which brings convenience to the post-treatment. Compared with the patent WO2007035629A2, it has been improved to a certain extent, but toluene is highly toxic and its use is restricted, and the product precipitated from the toluene system The product is not ideal in terms of yield and quality
[0023] 2. The total yield of the method is still not high

Method used

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  • A preparing method for alogliptin benzoate
  • A preparing method for alogliptin benzoate
  • A preparing method for alogliptin benzoate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0059] Example 1 2-[(6-chloro-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)pyrimidinyl)methyl]benzonitrile (intermediate 1) preparation

[0060] In a 2L reactor with mechanical stirring and condenser, add 6-chloro-3-methyluracil (80g, 498.3mmol), 2-cyanobenzyl bromide (97.7g, 498.3mmol), ethyl acetate (600g ), diisopropylethylamine (128.8g, 996.6mmol) was reacted at about 70-75°C for 4 hours, cooled to 0-5°C, stirred for 5 hours, suction filtered, rinsed with a small amount of cold ethyl acetate, and obtained Add 800g of purified water to the wet product, stir wash at about 25°C for 20 minutes, filter with suction, and dry the wet product at 50°C to obtain 125.5g of off-white solid. Yield: 91.3%, HPLC purity: 99.76%.

Embodiment 2

[0061] Example 2 2-[(6-chloro-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)pyrimidinyl)methyl]benzonitrile (intermediate 1) preparation

[0062] In a 2L reactor with mechanical stirring and condenser, add 6-chloro-3-methyluracil (80g, 498.3mmol), 2-cyanobenzyl bromide (97.7g, 498.3mmol), propyl acetate (480g ), diisopropylethylamine (102g, 789.2mmol) was reacted at about 70-75°C for 4 hours, cooled to 5-10°C, stirred for 5 hours, filtered with suction, rinsed with a small amount of cold propyl acetate, and obtained wet Add 800g of purified water to the product, stir wash at about 25°C for 20 minutes, filter with suction, and dry the wet product at 50°C to obtain 128.1g of off-white solid. Yield: 93.2%, HPLC purity: 99.51%.

Embodiment 3

[0063] Example 3 2-[(6-chloro-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)pyrimidinyl)methyl]benzonitrile (intermediate 1) Scale up preparation

[0064] In a 200L reactor with mechanical stirring and condenser, add 6-chloro-3-methyluracil (8kg, 49.83mol), 2-cyanobenzyl bromide (10.58kg, 53.97mol), ethyl acetate (6.4 kg) and diisopropylethylamine (10.2kg, 78.92mol) were reacted at about 70-75°C for 4 hours, cooled to -5-0°C, stirred for 3 hours, filtered with suction, rinsed with a small amount of cold ethyl acetate , to obtain a wet product, add 800g of purified water, stir and wash at about 25°C for 20min under temperature control, filter with suction, and dry the wet product at 50°C to obtain 12.38kg of an off-white solid. Yield: 90.1%, HPLC purity: 99.91%. IR (cm -1 ): 3095, 2228, 1655, 1604, 1441, 1398, 1203, 1093, 981, 766 and 522. NMR 1 H-NMR (400MHz, CDCl 3 ): δH 7.75(1H,d,br), 7.63(1H,td), 7.44(1H,t), 7.24(1H,d), 6.01(1H,d), 5.51(2H,s), 3.38(3H ,s). ESI-MS(m / z):276[M+H...

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Abstract

The invention provides a preparing method for alogliptin benzoate, and particularly provides a method for preparing 2-[[6-[(3R)-3-aminopiperidin-1-yl]-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl]methyl]benzonitrile monobenzoate shown as a formula (I). The compound is a novel medicine treating diabetes mellitus type 2. The alogliptin benzoate (HPLC purity of which is greater than 99.95%) can be prepared in a high yield and high purity by the method, a process is simple and convenient to operate and the method is suitable for industrial production.

Description

technical field [0001] The invention provides a preparation method of a novel drug alogliptin benzoate for treating type 2 diabetes with an improved process. belongs to the field of medicinal chemistry. Background technique [0002] In the past 30 years, the prevalence of diabetes in my country has increased significantly, and the number of diabetic patients in China accounts for 1 / 3 of the total number of diabetic patients in the world. Diabetes and its chronic complications have become a major disease that threatens human health. [0003] Alogliptin benzoate (Alogliptin benzoate) is a serine protease dipeptidyl peptidase IV (DPP-4) inhibitor developed by Japan's Takeda Company, which can maintain glucagon-like peptide 1 (GLP-1) and glucose dependence in the body. Insulin-promoting polypeptide (GIP) level can promote the secretion of insulin, thereby exerting the hypoglycemic effect. [0004] Alogliptin significantly inhibits DPP-4 with high selectivity and delays the in...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/04C07C51/41C07C63/08
Inventor 沈征葛纪龙董秀忠杨京华屠永锐房燕冬毛秋霞王艳
Owner CHANGZHOU NO 4 PHARMA FACTORY
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