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Preparation method of alogliptin

A compound and organic solvent technology, applied in the field of drugs for the treatment of type 2 diabetes, can solve the problems of high price and difficult application of 3-methyl-6-chlorouracil, and achieve low raw material cost, controllable reaction and simple operation Effect

Inactive Publication Date: 2015-03-25
SHANGHAI TIANCI BIOLOGICAL VALLEY BIOLOGICAL ENG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The starting material 3-methyl-6-chlorouracil in this method is expensive and difficult to apply in industrial production

Method used

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  • Preparation method of alogliptin
  • Preparation method of alogliptin
  • Preparation method of alogliptin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0084] (1) Preparation of 1-methylbarbituric acid (compound of formula III)

[0085] 0.74kg of N-methylurea was added to 5L of glacial acetic acid, the temperature was controlled at 0 to 30°C, 1.4kg of dimethyl malonate was added, heated to 90°C and kept warm until the reaction was complete, acetic acid was recovered under reduced pressure, 3L of 95% ethanol was added, and the mixture was analyzed. Crystallization to obtain 1-methylbarbituric acid (compound of formula III) yellow solid 1.29kg, yield 91%, melting point 130~133℃, 1 H NMR (DMSO-d 6 , 300 MHz): δ=11.31(s, 1H), 3.56(s, 2H), 3.03(s, 3H) ppm.

[0086] (2) Preparation of 1-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-ylmethanesulfonate formula (IV)

[0087] 1kg of 1-methylbarbituric acid (compound of formula III) was dissolved in 5L of dichloromethane, added DIPEA 1kg, temperature controlled at 0~30°C, 0.9kg of methanesulfonyl chloride was added dropwise, the temperature was controlled until the reaction was compl...

Embodiment 2

[0095] (1) Preparation of 1-methylbarbituric acid (compound of formula III)

[0096] 0.74kg of N-methylurea was added to 3L of glacial acetic acid, the temperature was controlled at 0 to 30°C, 1.1kg of malonic acid and 2kg of acetic anhydride were added, heated to 90°C and incubated until the reaction was complete, acetic acid was recovered under reduced pressure, and 3L of 95% ethanol was added. , crystallization to obtain 1-methylbarbituric acid (compound of formula III) yellow solid 1.32kg, yield 93%, melting point 132~135℃, 1 H NMR (DMSO-d 6 ,300MHz):δ=11.31(s,1H),3.56(s,2H),3.03(s,3H)ppm.

[0097] (2) Preparation of 1-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl p-toluenesulfonate (compound of formula IV)

[0098] 1kg of 1-methylbarbituric acid (compound of formula III) was dissolved in 3L of pyridine, the temperature was controlled at 0~30°C, 1.5kg of p-toluenesulfonyl chloride was added, the temperature was controlled until the reaction was complete, and the reac...

Embodiment 3

[0106] (1) Preparation of 1-methylbarbituric acid (compound of formula III)

[0107] 0.74kg of N-methylurea was added to 3L of absolute ethanol, the temperature was controlled at 0~30°C, 1.6kg of diethyl malonate was added, heated to reflux, incubated until the reaction was complete, cooled to 0~5°C, and crystallized to obtain 1-Methylbarbituric acid (compound of formula III) yellow solid 1.35kg, yield 95%, melting point 131~133℃, 1 H NMR (DMSO-d 6 ,300MHz):δ=11.31(s,1H),3.56(s,2H),3.03(s,3H)ppm.

[0108] (2) Preparation of 1-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl trifluoromethanesulfonate (compound of formula IV)

[0109] 0.1kg of 1-methylbarbituric acid (compound of formula III), dissolved in 0.5L of 2-methyltetrahydrofuran, temperature controlled at 0~30℃, added with 0.1kg of triethylamine, and added dropwise with 0.2kg of trifluoromethanesulfonic anhydride , control the temperature until the reaction is complete, add the reaction solution to 0.5L ice water, s...

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Abstract

The invention relates to a preparation method of alogliptin. The preparation method comprises the following steps: performing cyclization by taking N-methylurea which is low in price and easy to obtain as a raw material to obtain a compound shown in the formula III, introducing a leaving group to obtain a compound shown in the formula IV, reacting with a compound shown in the formula V to obtain a compound shown in the formula VI, then performing reaction on the compound shown in the formula VI and (R)-3-Boc aminopiperidine to obtain a compound shown in the formula VII, and performing deprotection on the compound shown in the formula VII to form a salt, thereby obtaining alogliptin or the salt thereof. Compared with a traditional method, the method has the advantages of low cost, easiness in control of reaction, simple post-treatment operation and the like, and is suitable for industrial production of alogliptin or the salt thereof.

Description

technical field [0001] The invention relates to the field of chemical medicine and medicine, in particular to a drug aloritine for treating type II diabetes: 2-[[6-[(3R)-3-amino-1-piperidinyl]-3,4- Preparation method of dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidinyl]methyl]benzonitrile or its salt. Background technique [0002] Diabetes is considered to be one of the major threats to human mortality in the 21st century. As early as 2006, the World Health Organization (WHO) estimated that there are 180 million people with diabetes worldwide, and by 2030 this number will double. The main harm of diabetes is to damage the heart, blood vessels, eyes, kidneys and nerves, and the complications caused by diabetes caused about 1.1 million deaths in 2005. WHO predicts that diabetes-related deaths will increase by more than 50% over the next 10 years, thus creating a significant societal burden. [0003] Diabetes is divided into two categories according to the etiology: type I and typ...

Claims

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Application Information

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IPC IPC(8): C07D401/04
CPCC07D401/04
Inventor 李新涓子李健之汪迅李勇刚池王胄沈小良刘海高艳吕兴红
Owner SHANGHAI TIANCI BIOLOGICAL VALLEY BIOLOGICAL ENG
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