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Process for the preparation of alogliptin

一种化合物、衍生物的技术，应用在制备阿格列汀及其类似物领域，能够解决分离等问题，达到方法安全、有成本效益的效果

Inactive Publication Date: 2012-02-22
MAPI PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method also has the problem of separation of mixed solvents (toluene, NMP, diisopropylethylamine)

Method used

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  • Process for the preparation of alogliptin
  • Process for the preparation of alogliptin
  • Process for the preparation of alogliptin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0147] Preparation of (R)-2-((6-(3-aminopiperidine -1-yl)-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)benzonitrile (alogliptin) (Scheme 3):

[0148]

[0149] Option 3

[0150] Preparation of 1-(2-isocyanobenzyl)-3-methylurea

[0151] 2-Cyanobenzylamine hydrochloride (90 g) and dichloromethane (800 ml) were placed in a round bottom (RB) flask. Methyl isocyanate (45.6 g) was added at 5°C. Triethylamine (81 g) in dichloromethane (300 ml) was added at the same temperature and stirred at room temperature for 16 h. Water (1 L) was added and stirred for 30 min. The solid obtained was collected by filtration and dried in an oven at 50 °C for 12 h. The yield was 85%, and the purity was 99.8%.

[0152]Preparation of 1-(2-isocyanobenzyl)-3-methylpyrimidine-2,4,6(1H,3H,5H)-trione

[0153] a) To a stirred solution of 0.11 mol of sodium ethanolate in 80 ml of absolute ethanol was added 0.1 mol of 1-(2-isocyanobenzyl)-3-methylurea and 0.1 mol of diethylmalonate. The mi...

Embodiment 2

[0171] Preparation of (R)-2-((6-(3-aminopiperidine) via 6-amino-1-(2-isocyanobenzyl)-3-methylpyrimidine-2,4(1H,3H)-dione -1-yl)-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)benzonitrile (alogliptin) (Scheme 4).

[0172]

[0173] Option 4

[0174] Preparation of 6-amino-1-(2-isocyanobenzyl)-3-methylpyrimidine-2,4(1H,3H)-dione

[0175] a) 1-(2-isocyanobenzyl)-3-methylurea (0.2mol) and cyanoacetic acid (0.22mol) were dissolved in acetic anhydride (400ml), and the mixture was heated to 80°C for 2h. The acetic anhydride was evaporated under reduced pressure and water (200ml) was added. The mixture was cooled to 0-5°C, 2N NaOH solution (220ml) was added and stirring was continued for 2h. The solid obtained was filtered off, washed with cold methanol and dried under vacuum. The yield of 6-amino-1-(2-isocyanobenzyl)-3-methylpyrimidine-2,4(1H,3H)-dione was 72%.

[0176] b) Under nitrogen atmosphere, 1-(2-isocyanobenzyl)-3-methylurea (98.4g) and cyanoacetic acid (80.0...

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Abstract

The present invention is based on the discovery of a process for preparing pyrimidin- dione compounds, especially alogliptin and its derivatives, which comprises the reaction of a urea derivative of formula (VIII) with a malonic acid or its derivatives to form intermediates of formulae (VII) or (VII-A), which are subsequently converted to a compound of formula (II) upon introduction of a leaving group X. Compound (II) then reacts with an amine to form compound (I), which is optionally converted to its salts of formula (IV).

Description

field of invention [0001] The invention relates to a method for preparing alogliptin (alogliptin) and its analogs, which are inhibitors of dipeptidyl peptidase-4 (DPP-4) and are used for treating type II diabetes. Background of the invention [0002] Diabetes affects millions of people worldwide and is considered one of the major threats to human mortality in the 21st century. In 2006, the World Health Organization (WHO) estimated that more than 180 million people worldwide had diabetes, a number that was predicted to double by 2030. Over time, uncontrolled diabetes can damage body systems, including the heart, blood vessels, eyes, kidneys and nerves. According to WHO, approximately 1.1 million people died from diabetes in 2005, and diabetes-related deaths are expected to increase by more than 50% in the next decade. Worldwide, the socioeconomic burden of diabetes is substantial. [0003] There are two main types of diabetes, designated Type I and Type II, with Type II di...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A01N43/54
CPCA61K31/513A61P3/10A61P19/02A61P43/00C07C275/24C07C275/50C07D239/545C07D239/62C07D403/04
Inventor E·马罗姆M·米垂斯基S·如博诺夫
Owner MAPI PHARMA
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