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Process for the purification of Montelukast

A purification method, the technology of montelukast, applied in the field of preparation of high-purity montelukast, can solve the problems of long-term cycle, unfavorable economy, troublesome purification, etc., and achieve the effect of high yield and high yield

Inactive Publication Date: 2009-07-22
ESTEVE QUIMICA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Typically, montelukast and its pharmaceutically acceptable salts are obtained through complex synthetic manipulations, which result in the formation of several by-products due to competing side reactions
These methods require lengthy work-up to isolate montelukast and its intermediates and thus long time periods, which in turn makes the methods more costly and economically unfavorable
The purification of montelukast is known to be cumbersome and complicated, and it is difficult to obtain high-purity montelukast because montelukast and its precursors are unstable to oxygen and light that cause rapid degradation

Method used

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  • Process for the purification of Montelukast
  • Process for the purification of Montelukast
  • Process for the purification of Montelukast

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Example 1 : Preparation of montelukast acid

[0038] 143.6 g of sodium hydroxide was added to 102 g of (R, E)-2-(1-((1-(3-(2-(7-chloroquinolin-2-yl)vinyl)phenyl)-3 - (2-(2-Hydroxypropan-2-yl)phenyl)propylthio)methyl)cyclopropyl)acetonitrile in 407ml ethanol 96% (v / v) solution. The mixture was stirred at reflux temperature for 30 hours. After this period, the solvent was distilled off in vacuo (purification by HPLC: 61.5 area %; impurity i 2 : 1.84 area%; impurity i 5 : 3.70 area%; impurity i 6 : 1.42 area %). The mixture was partitioned between 1000 ml toluene and 1500 ml water at room temperature. The aqueous phase in which the inorganic salts were dissolved was discarded. The organic phase was mixed with 1500 ml of water and the mixture was heated to 60° C. and stirred for 15 minutes. At this point, the product dissolved in the aqueous layer. The pH of the aqueous layer was 12.5. Some impurities from the preparation process were dissolved in the organic la...

Embodiment 2

[0039] Example 2 : Crystals of montelukast acid

[0040] The toluene solution from the previous example was stirred at room temperature for 12 hours. After this time, a yellow suspension had formed. The resulting solid was filtered off, washed with toluene and dried under vacuum at 30 °C for 24 hours. 53 g of montelukast acid were recovered (purification by HPLC: 96 area %). Yield: 90%.

Embodiment 3

[0041] Example 3 : Purification of montelukast acid using toluene as extraction solvent

[0042] 45 ml of 0.5M aqueous NaOH was added to montelukast acid (impurity i 2 : 0.05 area%; impurity i 3 : 1.39 area%; impurity i 5 : 0.20 area%; impurity i 6 : 0.05 area %) and 30ml suspension of toluene. A bilayer solution was formed in which montelukast was dissolved as the sodium salt in the aqueous layer. After stirring at 40°C for 30 minutes, the organic layer was discarded. Wash with 30 ml of toluene two more times in sequence, each time adjusting the pH to 12.2-13.2. The resulting aqueous solution was acidified to pH 9.3 with 2M aqueous acetic acid and washed twice with 30 ml of toluene. Both extractions were performed at 60°C. Finally, another 30 ml portion of toluene was added to the aqueous solution and the mixture was acidified to pH 6.0 with 2M aqueous acetic acid at room temperature. The final organic layer was separated and kept as a solution of purified montelu...

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Abstract

It relates to a process for the purification of Montelukast, or pharmaceutically salts thereof, or solvates thereof, including stereoisomers or mixture thereof which comprises carrying out a specific set of selective solvent extractions of Montelukast or its impurities in a mixture of an organic solvent and water at specific ranges of pH and temperature which depend on the type of impurities to remove. In particular, it comprises at least one wash of an aqueous phase containing crude Montelukast in salt form with an organic solvent, at a pH comprised between 12.0 and 13.5; and optionally one or more washes of the resulting aqueous phase with an organic solvent at a pH comprised between 8.5 and 10.0. Montelukast is recovered by acidification at a pH comprised between 4.5 and 8.0 and solvent extraction, and is isolated either as acid or in salt form.

Description

[0001] The present invention relates to a method for preparing high-purity montelukast. Specifically, it relates to a method of purifying montelukast by selectively extracting montelukast or its impurities in a mixture of an organic solvent and water. Background technique [0002] Montelukast is 1-[[[(1R)-1-[3-[(1E)-2-(7-chloro-2-quinolinyl)vinyl]phenyl]-3-[2-( International Nonproprietary Name (INN) of 1-hydroxy-1-methylethyl)phenyl]propyl]sulfanyl]methyl]cyclopropaneacetic acid, CAS No. 158966-92-8. Montelukast sodium salt (CASNo 151767-02-1) is currently used in the treatment of asthma, inflammation, angina, cerebral spasm, glomerulonephritis, hepatitis, endotoxemia, uveitis and allograft rejection. [0003] The structure of montelukast sodium salt is formula (I): [0004] [0005] Different synthetic strategies are known for the preparation of montelukast and its salts. For example, EP480717 discloses certain substituted quinolone compounds including montelukast sodi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D215/18A61K31/4704
CPCC07D215/18A61K31/4704
Inventor Y·加桑斯古伦M·蒙萨尔瓦特吉拉古斯特拉P·塔拉维拉埃斯卡萨尼
Owner ESTEVE QUIMICA
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