Repaglinide substantially free of dimer impurity

A dimer and impurity technology, applied in the field of preparation of repaglinide, can solve the problems of high reagent cost and low product yield

Inactive Publication Date: 2010-07-07
ACTAVIS GRP PTC EHF
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  • Summary
  • Abstract
  • Description
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  • Application Information

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Problems solved by technology

The method used in the '924 patent also has some disadvantages such as high cost of reagents, low product yield, additional purification steps required

Method used

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  • Repaglinide substantially free of dimer impurity
  • Repaglinide substantially free of dimer impurity
  • Repaglinide substantially free of dimer impurity

Examples

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preparation example Construction

[0110] According to another aspect of the present invention, the preparation method of the dimer impurity of formula IIa is provided, it comprises:

[0111] In the presence of a dehydrating agent selected from boric acid or boric acid derivatives and in a suitable solvent, (S)-3-methyl-1-(2-piperidinylphenyl)-1-butan having a structure of formula III The amine or its salt is reacted with 3-ethoxy-4-ethoxycarbonylphenylacetic acid or its salt having the structure of formula VI to produce IIa compound 2-ethoxy-N-[(1S)-3- Methyl-1-[2-(1-piperidinyl)phenyl]butyl]-4-[2-[[(1S)-3-methyl-1-[2-(1-piperidinyl) phenyl]butyl]amino]-2-oxoethyl]benzamide.

[0112]

[0113] Exemplary boronic acid derivatives include, but are not limited to: aryl or substituted arylboronic acids, such as phenylboronic acid, 2-chlorophenylboronic acid, 2-nitrophenylboronic acid, 3-nitrophenylboronic acid, 4- Nitrophenylboronic acid, 2-carboxyphenylboronic acid, 2-chloro-4-carboxyphenylboronic acid, 2-chlo...

Embodiment 1

[0181] Preparation method of pure repaglinide substantially free of dimer impurities

[0182] Crude repaglinide (15 g, dimer impurity content: 0.35%) was dissolved in toluene (90 mL) at 60-65°C. Cyclohexane (15 mL) was then added to the hot solution at 60-65°C. The solution was cooled slowly at 25-30°C and stirred for 1-2 hours. The precipitated product was filtered, washed with cyclohexane (30 ml), and then vacuum-dried at 50-55° C. for 6 hours to obtain 12.5 g of pure repaglinide (yield: 83.3%; dimerization as measured by HPLC). Bulk impurity content: 0.06%).

Embodiment 2

[0184] 2-Ethoxy-N-[(1S)-3-methyl-1-[2-(1-piperidinyl)phenyl]butyl]-4-[2-[[(1S)-3- Preparation of methyl-1-[2-(1-piperidinyl)phenyl]butyl]amino]-2-oxoethyl]benzamide (dimer impurity)

[0185]In a round bottom flask equipped with a Dean Stark condenser, (S)-3-methyl-1-(2-piperidinylphenyl)-1-butylamine (2.0 g, 0.00813 mol) was dissolved in toluene ( 50 mL), then 3-ethoxy-4-ethoxycarbonylphenylacetic acid (0.91 g, 0.00406 mol) and phenylboronic acid (0.099 g, 0.000813 mol) were added. The reaction mixture was refluxed for 16-18 hours. The reaction mixture was then cooled to 25-30°C and then filtered. The toluene layer was washed with water and 1% sodium bicarbonate solution. Then the toluene was distilled off completely. To the resulting residue was added hexane (20 mL) to precipitate a solid and stirred for 1 hour. The resulting solid was filtered and washed with hexane (10 mL). The crude product was purified by column chromatography to prepare 2-ethoxy-N-[(1S)-3-methyl-1-...

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Abstract

The present invention provides highly pure repaglinide substantially free of dimer impurity, and process for the preparation thereof. The present invention also relates to 2- ethoxy-N-[(1S)-3-methyl-1-[2-(1-piperidinyl)phenyl]butyl]-4-[2-[[(1S)-3-methyl-1-[2-(1- piperidinyl)phenyl]butyl]amino]-2-oxoethyl]benzamide, an impurity of repaglinide, and a process for preparing and isolating thereof. The present invention further relates to pharmaceutical compositions comprising solid particles of pure repaglinide substantially free of dimer impurity or pharmaceutically acceptable salts thereof, wherein 90 volume- percent of the particles (D90) have a size of less than about 400 microns. The present invention also provides an optical resolution method of racemic 3-methyl-1-(2- piperidino-phenyl)-1-butylamine and use thereof for the preparation of repaglinide.

Description

[0001] Cross References to Related Applications [0002] This application claims priority from Indian Provisional Applications Nos. 1160 / CHE / 2007 and 1515 / CHE / 2007 filed on June 6, 2007 and July 16, 2007 respectively, which are incorporated herein by reference. technical field [0003] The invention provides high-purity repaglinide substantially free of dimer impurities and a preparation method thereof. The present invention also relates to the impurity 2-ethoxy-N-[(1S)-3-methyl-1-[2-(1-piperidinyl)phenyl]butyl]-4-[ 2-[[(1S)-3-methyl-1-[2-(1-piperidinyl)phenyl]butyl]amino]-2-oxoethyl]benzamide, and methods for its preparation and isolation . The present invention also relates to a pharmaceutical composition comprising solid particles of pure repaglinide or a pharmaceutically acceptable salt thereof substantially free of dimer impurities, wherein 90% by volume of the particles (D 90 ) has a particle size of less than about 400 microns. The present invention also provides an...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D295/135
CPCC07D295/135A61P3/10
Inventor 索尼·塞巴斯蒂安沙希达·维恩卡他·巴拉拉马穆蒂·卡提卡雷迪尼廷·萨拉德钱德拉·普拉德汉乔恩·瓦尔盖尔森
Owner ACTAVIS GRP PTC EHF
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