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Preparation method for montelukast sodium intermediate

A technology of montelukast sodium and intermediates, which is applied in the field of pharmaceutical engineering and technology, can solve the problems such as recovery and reuse schemes that have not been reported in literature, and achieves stereoselectivity and yield increase, cost reduction, and mild reaction conditions. Effect

Active Publication Date: 2014-07-23
启东东岳药业有限公司 +1
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Wherein the recovery and reuse scheme of triethylamine hydroiodide has not been reported in the literature

Method used

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  • Preparation method for montelukast sodium intermediate
  • Preparation method for montelukast sodium intermediate
  • Preparation method for montelukast sodium intermediate

Examples

Experimental program
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Effect test

Embodiment 13-

[0031] The preparation of embodiment 13-[(2E)-2-(7-chloro-2-quinolyl) vinyl] benzaldehyde (formula II)

[0032] Under the protection of nitrogen, put 40g of 7-chloroquinaldine, 80g of isophthalaldehyde, 150g of acetic anhydride, and 102g of triethylamine into the three-necked flask successively, heat up to 100°C, keep the temperature for 8 hours, and detect 7-chloroquinaldine by TLC The response is complete. After the reaction was completed, 270 g of xylene was added and stirred while it was hot, cooled to 10° C. for crystallization for 2 hours, filtered, rinsed with xylene, and the yield was 95%.

Embodiment 21-

[0033] Preparation of Example 21-[3-[(2E)-2-(7-chloro-2-quinolyl)vinyl]phenyl]-2-propen-1-alcohol (Formula III)

[0034] Under the protection of nitrogen, put 12g of 3-[(2E)-2-(7-chloro-2-quinolyl)vinyl]benzaldehyde (Formula II) and 100mL of toluene into the three-necked flask successively, and slowly add 40g of it at 15°C The THF solution of vinylmagnesium chloride was added in about 0.5 hours, and the reaction temperature was controlled at 10°C to 15°C. After the addition, the reaction was kept for 3 hours, and the reaction was detected by TLC. Add the reaction solution to 200g of 10% ammonium acetate aqueous solution, add acetic acid to adjust the pH to 5-6, let stand to separate the phases, concentrate the organic phase, slowly add 35g of 95% ethanol to crystallize, keep warm at 10°C-15°C for 1 hour, and filter with suction The product was obtained with a yield of 91%.

Embodiment 32-3

[0035] Example 32-[3-[3-[(2E)-2-(7-chloro-2-quinolyl)vinyl]phenyl]-3-oxopropyl]benzoic acid methyl ester (Formula V) preparation of

[0036] Under nitrogen protection, drop into 1-[3-[(2E)-2-(7-chloro-2-quinolyl) vinyl] phenyl]-2-propen-1-ol (formula III ) 20g, methyl o-iodobenzoate 18.7g, triethylamine 8.3g, TEBA20g, palladium acetate 0.5g and xylene 200mL. The temperature was raised to 90° C. to 100° C., and the reaction was kept for 9 hours. TLC monitored that the reaction of the raw materials was complete. Cool down to 60°C, filter with suction, concentrate the filtrate under reduced pressure, add about 200mL of 95% ethanol, cool to about 20°C for crystallization for 2 hours, and filter with suction to obtain the product with a yield of 85%.

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Abstract

The invention discloses a preparation method for a montelukast sodium intermediate. The preparation method comprises the steps of reacting 7-chloroquinaldine with m-phthalaldehyde to generate a compound shown in formula II; reacting the compound shown in formula II with vinyl magnesium halide to generate a compound shown in formula III; reacting the compound shown in formula III with a compound shown in formula IV to generate a compound shown in formula V; carrying out a reduction reaction on the compound shown in formula V to generate a compound shown in formula VI; and reacting the compound shown in formula VI with methyl magnesium halide to generate a compound shown in formula I. According to the preparation method disclosed by the invention, production cost is further reduced, and a technological basis is laid for large-scale industrialized production for the intermediate.

Description

technical field [0001] The present invention relates to the field of pharmaceutical engineering and process technology, in particular to a montelukast sodium intermediate ((αS)-α-[3-[(1E)-2-(7-chloro-2-quinolinyl ) Vinyl] phenyl] -2-(1-hydroxyl-1-methylethyl) phenylpropanol, compound shown in formula I) new preparation process. Background technique [0002] Montelukast Sodium (Montelukast Sodium), the chemical name is [R-(E)]-1-[[[1-[3-[2-(7-chloro-2-quinolyl)vinyl]phenyl ]-3-[2-(1-Hydroxy-1-methylethyl) phenyl] propyl] thio] methyl] sodium cyclopropylacetate, developed by U.S. Merck, trade name "Singulair "(Singulair). It was launched in Finland and Mexico for the first time in February 1998, in the United Kingdom and the United States in April and October of the same year, and in China in 2002. This product is a selective leukotriene D4 receptor antagonist, which can selectively combine with leukotriene in the airway, block the action of allergic mediators, improve resp...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D215/18
CPCC07D215/18
Inventor 宋家良张程亮龙中柱刘星宇蔡水洪
Owner 启东东岳药业有限公司
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