Method for preparing montelukast sodium salts

一种孟鲁司特钠、胺盐的技术，应用在钠有机化合物、呼吸系统疾病、有机化学等方向，能够解决正丁基锂存在危险性、总收率降低、昂贵试剂等问题，达到简化偶联和水解反应、提高效率、高收率的效果

Inactive Publication Date: 2011-08-24
LG LIFE SCI LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] However, according to the method of the U.S. patent, n-butyllithium should be used as a base in the process of preparing 1-(mercaptomethyllithium) cyclopropane acetate lithium salt, so due to the following disadvantages: n-butyllithium is dangerous when handled expensive reagents, so an improved method is needed
Disadvantageously, the process results in a reduced overall yield

Method used

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  • Method for preparing montelukast sodium salts
  • Method for preparing montelukast sodium salts
  • Method for preparing montelukast sodium salts

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0052] Preparation of 2-(2-(3(S)-(3-(7-chloro-2-quinolyl)-vinyl)phenyl)-3-methylsulfonyloxypropyl)phenyl-2-propane Alcohol (2)

[0053] 2-(2-(3(S)-(3-(7-chloro-2-quinolyl)-vinyl)phenyl)-3-hydroxypropyl)phenyl-2-propanol (20.0g ) was dissolved in 70 ml of tetrahydrofuran, the temperature of the reactor was lowered to 0° C., and diisopropylethylamine (8.43 ml) was slowly added dropwise thereto. The internal temperature of the reactor was lowered to -25°C, methanesulfonyl chloride (5.54 g) was slowly added dropwise under nitrogen, and the reaction mixture was stirred at -25°C for one hour. After completion of the reaction, 200 ml of acetonitrile was slowly added dropwise at an internal reactor temperature below -20°C. The resulting solid was filtered using a cryofilter under nitrogen, washed with 100 ml of acetonitrile cooled below 0°C and dried to give 21.7 g of the title compound as a pale yellow solid.

[0054] 1 H NMR (400MHz, CDCl 3 ): δ8.12(m, 2H), 7.75(m, 3H), 7.66(d,...

Embodiment 2

[0056] Preparation of [R-(E)]-1-[[[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methyl ethyl)phenyl]propyl]thio]methyl]cyclopropaneacetic acid (4)

[0057] Methyl 1-(mercaptomethyl)cyclopropaneacetate (1.37 g) was dissolved in 15 ml tetrahydrofuran and the internal reactor temperature was cooled to -15°C. Sodium bistrimethylsilylamide (2M solution in tetrahydrofuran, 4.8 ml) was added dropwise to the reaction mixture under nitrogen, followed by stirring at -15°C for one hour. At this reaction temperature, the compound (4.0 g) prepared in Example 1 was added thereto, followed by stirring for 7 hours. After the coupling reaction was completed, the internal reactor temperature was raised to room temperature, and a 10% lithium hydroxide aqueous solution (12 g) was added thereto. The internal reactor temperature was raised to 50°C and reacted at this temperature for 10 hours. After the reaction was completed, the reaction solution was cooled to room temperature,...

Embodiment 3～8

[0059] The reaction was carried out in the same manner as in Example 2 except for changing the types of solvent and base. The results thus obtained are shown in Table 1 below.

[0060] Table 1

[0061]

solvent

alkali

Yield (%)

Example 3

Tetrahydrofuran

Sodium Bistrimethylsilylamide (95%)

84.7

Example 4

Tetrahydrofuran

Lithium bistrimethylsilylamide (95%)

68.7

Example 5

Tetrahydrofuran

Potassium Bistrimethylsilylamide (95%)

84.5

Example 6

dimethylformamide

Sodium Bistrimethylsilylamide (95%)

82.1

[0062] Example 7

dimethylformamide

Lithium bistrimethylsilylamide (95%)

83.5

Example 8

3-Methyltetrahydrofuran

Potassium Bistrimethylsilylamide (95%)

66.4

[0063] * 95%: the purity of the reactant

[0064] As can be seen from above Table 1, according to the method of the present invention, by using bistrimethylsilylamino alka...

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PUM

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Abstract

The present invention provides a method for preparing montelukast sodium salts of chemical formula 1 in the Description. The method of the present invention comprises the steps of: coupling the methanesulfonyl of chemical formula 2 and the compound of chemical formula 3 in the presence of bis(trimethylsilyl)amide alkali metal salts, adding an alkali metal base, and heating and hydrolyzing the resultant material to produce the compound of chemical formula 4; enabling a reaction between the compound of chemical formula 4 and 4-tert-butylcyclohexylamine and refining the resultant to produce the amine salts of chemical formula 5; and converting the amine salts into sodium salts.

Description

technical field [0001] The invention relates to a method for preparing montelukast sodium salt. More preferably, the present invention relates to a method for preparing montelukast sodium salt, the method comprising: in the presence of a bistrimethylsilylamino alkali metal salt, combining a methylsulfonyl compound of the following formula 2 with The compound of the following formula 3 is coupled, and an alkali metal base is added thereto, and the mixture is hydrolyzed by heating to prepare the compound of the following formula 4, the compound of the formula 4 is reacted with 4-tert-butylcyclohexylamine, and then Purification is performed to prepare the amine salt of formula 5, and the amine salt of formula 5 is converted to the sodium salt. Background technique [0002] Montelukast sodium salt is a substance showing the efficacy of Singulair (from Korean MSD), which is commonly used in the treatment of asthma and symptoms associated with allergic rhinitis, in Pharmacologic...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D215/18
CPCC07D215/18A61P11/02A61P11/06A61P37/08C07F1/04
Inventor 李仁相李锡柱姜哉银
Owner LG LIFE SCI LTD
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