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Process for making montelukast and intermediates therefor

a technology of montelukast and intermediates, which is applied in the direction of drug compositions, immunological disorders, organic chemistry, etc., can solve the problems of not being able to provide the compound (2) stereoselectively, and not being able to obtain the racemic produ

Inactive Publication Date: 2009-04-09
BENOVSKY PETR +6
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0016]A third aspect of the invention relates to a process of using the compound of formula (11), which comprises reacting a compound of formula (11)or an acid addition salt thereof with a methylmagnesium halide selected from methylmagnesium chloride, methylmagnesium bromide, methylmagnesium iodide, and combinations thereof, to form a compound of formula (4)The compound (11) can be used in an isolated and / or purified form. The compound of formula (4) can then be converted to montelukast and related compounds by various ways, especially by the following sequence:The conversion from (1a) to (1) assumes that R is not hydrogen and is, obviously unnecessary when R is hydrogen. The overall process has the advantage in providing suitable intermediate(s) that may be isolated in solid state and purified, and does not require the use of toxic hydrazine for the production process of making compound (4) from the compound (20).

Problems solved by technology

However, none of these other schemes were specifically applied to making montelukast.
But this process cannot provide the compound (2) stereoselectively in the R-configuration as suggested above, which is required for the montelukast synthesis.
Instead, only a racemic product may be obtained and no method has been suggested how to resolve the racemate into single enantiomers.

Method used

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  • Process for making montelukast and intermediates therefor
  • Process for making montelukast and intermediates therefor
  • Process for making montelukast and intermediates therefor

Examples

Experimental program
Comparison scheme
Effect test

example 1

Compound (11)

[0066]Step 1—Compound (20)

[0067]500 g of Methyl 2-((3S)-3-[2-(7-chloro-2-quinolinyl)-ethenyl]-phenyl)-3-hydroxypropyl)-benzoate monohydrate [Compound (18)] were placed into reactor and 3000 ml of toluene were added. The mixture of toluene / water was azeotropically distilled off (800 ml). Then the toluene solution was cooled to room temperature. The solution contained 480.11 g of anhydrous (18).

[0068]To the solution, 227.0 ml of triethylamine were added at room temperature and 110.2 ml of methanesulfonyl chloride were added dropwise so that reaction temperature did not exceed 40° C. Reaction mixture was subsequently stirred at 25-30° C. for 1 hour. Then 605 ml of triethylamine were added to the reaction mixture followed by addition of 156 ml of thioacetic acid at room temperature within 5 minutes. The reaction mixture was subsequently heated to 40-45° C. for 3.5 hours. 1000 ml of water were added to the reaction mixture and it was stirred for 15 minutes. The layers were s...

example 2

Compound (11)

[0074]Work under argon.

[0075]24.50 g of compound (20) were dissolved in 180 ml of anhydrous toluene (distilled from benzophenone / Na). Solution was cooled to 0-5° C. (dry ice / water bath). 41 ml of 3M MeMgCl in THF were added dropwise to the solution so that temperature did not exceed 5° C. (over 30 minutes). Reaction mixture was stirred and cooled to 0-5° C. No precipitation observed. Reaction was monitored by HPLC. Reaction mixture is turning cloudy—slight precipitation. Reaction was stopped after 3 h and 100 ml of water were slowly added with external cooling. Reaction mixture was subsequently acidified with 3 ml of glacial acetic acid to pH=4-5. Layers were separated and organic extract was dried over anhydrous magnesium sulfate. Mixture was filtered and solvent was evaporated to dryness (bath heated to 45° C.) giving 20.05 g) of crude thiolactone (11) base.

[0076]HPLC—after evaporation—80.69%

example 3

Compound (11a)

[0077]2.586 g of thiolactone (11) were dissolved in 18 ml of toluene at 40° C. Solution was cooled to room temperature and 7.1 ml of 1M aqueous HCl were added with stirring. Mixture was stirred for 2 h at room temperature. Precipitated solid material was separated by suction and washed with 5 ml of toluene and dried at room temperature.

[0078]HPLC: 95.43%

[0079]Yield: 1.43 g (63%)

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PUM

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Abstract

A process for making montelukast, a pharmaceutically useful compound of the following formula and salts thereof:using a compound of formula (11)is provided.

Description

[0001]This application is a Divisional of U.S. patent application Ser. No. 11 / 561,689, filed Nov. 20, 2006, the entire contents of which are incorporated herein by reference, which application claims the benefit of priority under 35 U.S.C. § 119(e) from U.S. provisional patent application Ser. No. 60 / 737,752, filed Nov. 18, 2005; Ser. No. 60 / 794,429, filed Apr. 24, 2006; and Ser. No. 60 / 824,382, filed Sep. 1, 2006, the entire contents of each provisional application being incorporated herein by reference.BACKGROUND OF THE INVENTION[0002]The present invention relates to the synthesis of montelukast, a pharmaceutical agent, as well as to intermediates and processes useful in the synthesis.[0003]Montelukast, chemically [R-(E)]-1-[[[1-[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]thio]methyl]cyclopropane acetic acid, has the following structure of formula (1):[0004]Montelukast monosodium salt (montelukast sodium) is commonly used for treatment ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07D215/18
CPCC07C309/75C07D409/10C07D215/18C07C2101/02C07C2601/02A61P11/06A61P37/08
Inventor BENOVSKY, PETRTHIJS, LAMBERTUSOVEREEM, ARJANNECASTULIK, JAKUBZHU, JIEBARTOS, PETRSKOUMAL, RADOMIR
Owner BENOVSKY PETR
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