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Preparation method of alogliptin benzoate with high yield

A benzoic acid, high-yield technology, applied in the field of pharmaceutical preparation, can solve the problems of increasing other impurity risks, increasing reaction steps, increasing costs, etc., and achieves the effects of simplified quality control inspection means, less impurities, and high total yield

Pending Publication Date: 2022-02-18
XIAN XINTONG PHARM RES CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The disadvantage of this method is that the de-tert-butoxycarbonyl protecting group should be considered in the later stage, which not only increases the cost, but also increases the reaction steps, thus increasing the risk of introducing other impurities

Method used

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  • Preparation method of alogliptin benzoate with high yield
  • Preparation method of alogliptin benzoate with high yield
  • Preparation method of alogliptin benzoate with high yield

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Example 1: Preparation Intermediate 2- (6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl - methyl) -4-fluorobenzene Methitrile

[0031]

[0032] N, N-dimethylformamide 20g, 6-chloro-3-methyl uracil 5.1 g, 2-cyano-3-methyl uracil 5.1 g, 2-cyano-3-methyl uracil, N-diisopropylamine 4g, heating To 45-75 ° C, the reaction time is 2 to 8 h. Cooling, adding 55 kg, stirring temperature 10 to 20 ° C, filtration to obtain solid, dried to give 8.5 g of product, yield 95%.

Embodiment 2

[0033] Example 2: Preparation of agellatine hydrochloride

[0034]

[0035] 50 g of acetonitrile 50g, intermediate I 8.3 g, (R) -3-amino piperidiniol, 18g, 18 g of sodium hydrogencaridin, temperature rise to acetonitrile, refluxed to acetonitrile, refluxed to 20 ~ 8 hours, cool down to 20- 30 ° C, filtration, filtrate was added to the reaction bottle to cool down to 0 to 10 ° C, and concentrated hydrochloric acid, filtered, dried to give a white solid 10.2 g, yield 90%.

Embodiment 3

[0036] Example 3: Preparation of benzoic acid Agelipine

[0037]

[0038] Agelipatine hydrochloride 10g and purified water 80 g were added to the reaction flask, and pH to 7.0 to 9.5 were adjusted with sodium bicarbonate. The organic phase was separated, and the aqueous phase was added to methylenechloromethane to extract Agelipine. The organic phase was evaporated.

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Abstract

The invention discloses a preparation method of alogliptin benzoate with high yield. The preparation method comprises the following steps: (1) carrying out a reaction on 6-chloro-3-methyl uracil and 2-cyanobenzyl bromide to obtain 2-((6-chloro-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)benzonitrile; (2) enabling the 2-((6-chloro-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)benzonitrile to react with R-3-aminopiperidine dihydrochloride so as to obtain alogliptin hydrochloride; and (3) subjecting the alogliptin hydrochloride to reacting with benzoic acid to obtain alogliptin benzoate. The method has the advantages of no ultrahigh temperature and high pressure requirements in the reaction, no highly toxic materials, fewer impurities and higher total yield.

Description

Technical field [0001] The present invention relates to the field of drug preparation, and Preparation method of 3,4-dihydropyrimidine-1 (2H) - group) methyl] benzonitrile benzoic acid. Background technique [0002] Agellatin, Chemical Nomination: (R) -2 - [(6- (3-aminopiperidine-1-yl) -3-methyl-2,4-dioxide-3,4- Dihydropyrimidine-1 (2H) -yl) methyl] benzylbenzoic acid, molecular formula: C 18 Hide 21 N 5 O 2 C 7 Hide 6 O 2 , Molecular weight: 461.51, the chemical structure formula is as follows: [0003] [0004] Diabetes is a global disease. At present, global patients have reached 285 million. There are also nearly 93 million in diabetic patients in my country, accounting for 1 / 3 of global diabetes, including 90% of patients with type 2 diabetes. Looking for effective blood glucose control drugs, reducing complications and death have always been the goal of research and development of global diabetes treatment. [0005] In April 2010, the Agrest is approved by Japan's Hoheng ...

Claims

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Application Information

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IPC IPC(8): C07D401/04C07C51/41C07C63/08
CPCC07D401/04C07C51/412C07C63/08
Inventor 张青郭维博东丽丽罗晶柳小秦
Owner XIAN XINTONG PHARM RES CO LTD
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