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A kind of preparation method of montelukast sodium and its intermediate

A technology of montelukast sodium and montelukast acid, which is applied in the field of synthesis of montelukast sodium and its intermediates, can solve the problems of low overall yield and increase purification procedures, and achieve mild and easy-to-control reaction conditions , Simple process operation, good stability

Active Publication Date: 2016-02-03
LUNAN PHARMA GROUP CORPORATION
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Therefore, this method requires the addition of complicated purification procedures, resulting in an overall yield of only 20% or less

Method used

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  • A kind of preparation method of montelukast sodium and its intermediate
  • A kind of preparation method of montelukast sodium and its intermediate
  • A kind of preparation method of montelukast sodium and its intermediate

Examples

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Comparison scheme
Effect test

Embodiment 1

[0039] Example 1 Preparation of compound 2-(3-(3-(2-(7-chloro-2-quinolyl) vinyl) phenyl)-3-oxopropyl) phenyl)-2-propoxy) Tetrahydropyran (Intermediate 2)

[0040] According to the patent CN101638381, the total yield is 41%.

Embodiment 2

[0041] Example 2 Preparation of Compound 2-(3(S)-(3-(2-(7-chloro-2-quinolyl)vinyl)phenyl)-3-hydroxypropyl)phenyl)-2-propane oxy)tetrahydropyran (Intermediate 3)

[0042] Dissolve 115.0g (0.359mol) of (-)-diisopine pinocampyl chloride borane in 480ml of THF, and cool the solution to -15°C; dissolve 129.1g (0.239mol) of Intermediate 2 in 560ml of THF, Add this solution dropwise to the above-mentioned (-)-diisopinepinene chloroborane solution at -15°C to obtain a red solution. After dropping, slowly raise the temperature to 15°C while stirring, and react at this temperature for 6 hours. Poured into ice water, the reaction solution precipitated a solid precipitate, suction filtered, washed the solid twice with water and once with ethyl acetate; added the solid to 1.9L of 6% diethanolamine aqueous solution, then added 4L of dichloromethane, stirred for 10 Minutes later, the liquid was separated, and the aqueous phase was extracted once more with dichloromethane, and the dichlorome...

Embodiment 3

[0043] Example 3 Preparation of compound 2-(3(S)-(3-(2-(7-chloro-2-quinolyl)vinyl)phenyl)-3-methylsulfonylpropyl)phenyl)-2 -propoxy)tetrahydropyran (intermediate 4)

[0044] Dissolve 43.0g (79.4mmol) of intermediate 3 in 800ml of dichloromethane, and cool to -10°C while stirring; add 11.82g (103mmol) of methanesulfonyl chloride and 15.4g (119mmol) of triethylamine into the reaction solution , continue to stir at -10°C for 30 minutes, then slowly heat up to 0°C, and react for another 1h. After the reaction is complete, add 400ml of saturated sodium bicarbonate solution, stir for 10 minutes and then separate the liquids. The aqueous phase is extracted with dichloromethane (200ml× 2), combined extracts, anhydrous Na 2 SO 4 Drying; filtering, concentration, the residue was washed twice with toluene, and dried to obtain 45.1 g of the product with a yield of 91.7%, and the HPLC showed that the purity was 95.5%.

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Abstract

The invention relates to a method suitable for preparing montelukast sodium and intermediate 2-(3(S)-(3-(2-(7-chlorine-2-quinolyl) vinyl) phenyl)-3-hydroxypropyl) phenyl)-2-propoxy) tetrahydropyrane (intermediate 3) of the montelukast sodium in a large scale. According to the method, 7-chloroquinaldine and 3-cyanobenzaldehyde are used as starting raw materials, 2-(3-(3-(2-(7-chlorine-2-quinolyl) vinyl) phenyl)-3-oxopropyl) phenyl)-2-propoxy) tetrahydropyrane (intermediate 2) is obtained by six steps of reaction, then intermediate 3 with ee more than 99% and yield more than 90% is obtained by chiral reduction, and the montelukast sodium with high optical purity and high chemical purity is obtained by the intermediate 3 through four steps of reaction.

Description

technical field [0001] The invention belongs to the field of pharmaceutical chemical synthesis, and in particular relates to a synthesis method of montelukast sodium and an intermediate thereof. Background technique [0002] The chemical name of Montelukast Sodium is: 1-(((1-(R)-(3-(2-(7-chloro-2-quinolyl)-vinyl)phenyl)-3 -(2-Hydroxy-1-methylethyl)phenyl)propyl)thio))methyl)sodium cyclopropylacetate, the structural formula is as follows: [0003] [0004] It is a new type of high selectivity LTD developed by Merck Company of the United States 4 The receptor antagonist, trade name Singular, was first launched in Finland and Mexico in February 1998, in the United Kingdom and the United States in April and October of the same year, and then in Canada, Italy, Spain, Sweden, and Switzerland , Germany, France and other 71 countries listed. This medicine is listed as Selective Leukotriene LTD 4 Receptor antagonist, can interact with leukotrienes LTD in the airway 4 Selectiv...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D215/18C07D405/12
CPCY02P20/55
Inventor 王红波赵桂芳张生
Owner LUNAN PHARMA GROUP CORPORATION
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