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An alogliptin purifying method

A technology of methylation and dioxo generation, applied in the direction of organic chemistry, can solve the problems of increased cost and operation difficulty, long preparation cycle and complicated operation steps

Active Publication Date: 2016-06-08
瀚晖制药有限公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0019] However, the steps of applying BOC protecting group and removing BOC protecting group are added in this method, which increases the cost and operational difficulty in large-scale industrial production.
Moreover, when the last step of benzoic acid is used as a deprotection reagent, due to its weak acidity, the oxygen of the carbamate cannot be effectively protonated, so the BOC protecting group cannot be removed smoothly, which affects the purity of the final product.
[0020] In summary, the methods for preparing high-purity alogliptin benzoate suitable for pharmaceutical use in the prior art basically have complicated operation steps, long preparation period, high production cost, and the use of various environmentally unfriendly organic solvents, which are not suitable for Defects such as industrialized mass production

Method used

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Examples

Experimental program
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Effect test

Embodiment 1

[0103]

[0104] AG-101 (580g, 2.11mol), (R)-3-aminopiperidine dihydrochloride (400.2g, 2.33mol), sodium bicarbonate (881.6g, 10.50mol) and absolute ethanol (5800ml ) into the three-necked flask of 10000ml, stir well. Raise the temperature to about 70-80°C for reaction, and the reaction is complete in about 5-6 hours (the content of AG-101 is less than 0.1% as monitored by HPLC).

[0105] The above reaction solution was cooled to about 0° C. to about 5° C., stirred for 2 hours, filtered, and the filter cake was washed with absolute ethanol (1160 ml) to obtain filtrate 1.

[0106] The filtrate 1 was concentrated to dryness under reduced pressure in a water bath at about 50°C, and the residue was added with absolute ethanol (580 ml) and stirred at room temperature for crystallization for about 5 hours (add 1 g of seed crystals if there was supersaturation). After a large amount of solids were precipitated, absolute ethanol (5220 ml) was added, and the mixture was stirred at r...

Embodiment 2

[0109] AG-101 (580g, 2.11mol), (R)-3-aminopiperidine dihydrochloride (400.2g, 2.33mol), sodium bicarbonate (881.6g, 10.50mol) and absolute ethanol (5800ml ) into the three-necked flask of 10000ml, stir well. Raise the temperature to about 70-80°C for reaction, and the reaction is complete in about 5-6 hours (the content of AG-101 is less than 0.1% as monitored by HPLC).

[0110] The above reaction solution was cooled to about 0° C. to about 5° C., stirred for about 2 hours, filtered, and the filter cake was washed with absolute ethanol (1160 ml) to obtain filtrate 1.

[0111] The filtrate 1 was concentrated to dryness under reduced pressure in a water bath at about 50°C, and the residue was added with absolute ethanol (5800ml), and stirred at room temperature for about 20 minutes to dissolve the solids, and some suspended solids were insoluble. Activated carbon (58 g) was added and stirred at room temperature for about 10 minutes. Filter under reduced pressure, and wash the ...

Embodiment 3

[0114] AG-101 (580g, 2.11mol), (R)-3-aminopiperidine dihydrochloride (400.2g, 2.33mol), sodium bicarbonate (881.6g, 10.50mol) and absolute ethanol (5800ml ) into the three-necked flask of 10000ml, stir well. Raise the temperature to about 70-80°C for reaction, and the reaction is complete in about 5-6 hours (the content of AG-101 is less than 0.1% as monitored by HPLC).

[0115] The above reaction solution was cooled to room temperature, 58 g of activated carbon was added thereto, stirred for 2 hours, filtered, and the filter cake was washed with absolute ethanol (1160 ml) to obtain filtrate 1.

[0116] The filtrate 1 was concentrated in a water bath at about 50°C to about 20% of the original volume under reduced pressure. A large amount of solids were precipitated, and absolute ethanol (4640ml) was added to dissolve them. Some suspended solids were insoluble, and then activated carbon (58g) was added at room temperature. Stir for about 10 minutes. Filter under reduced press...

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Abstract

The invention relates to an alogliptin purifying method through separating an alogliptin dimer impurity, and an alogliptin preparing method including the purifying method. The purifying method includes (1) providing an ethanol solution of 2-[6-[(3R)-aminopiperidin-1-yl]-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl-methyl]benzonitrile, (2) adsorbing the alogliptin dimer impurity through adsorption, and filtering, and (3) crystallizing the filtrate and separating to obtain crystals. The purifying method is characterized by being simple, convenient and efficient in operation, low in cost, environmental friendly, and outstanding in effects, and is suitable for industrial large-scale production.

Description

technical field [0001] The present invention relates to a method for purifying alogliptin, in particular to a method for purifying alogliptin by separating alogliptin dimer impurities, and a method for preparing alogliptin comprising the purification method. Background technique [0002] In recent years, the incidence of diabetes has shown a rising trend and is considered to be one of the major threats to human death 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] Among the numerous dia...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/04
Inventor 冯锋柴健俞旭峰杨建军梁江涛
Owner 瀚晖制药有限公司
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