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Synthesis method of montelukast sodium intermediate

A technology of montelukast sodium and its synthetic method, which is applied in the field of drug synthesis, can solve the problems of being unsuitable for industrial production, harsh reaction conditions, and long production cycle, and achieve the effects of low cost, short process route, and easy operation and production

Inactive Publication Date: 2020-10-30
SHANDONG BESTCOMM PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0011] The synthesis route is long (7 steps in total), the reaction conditions are harsh, and the yield is low, so the cost is high, the production cycle is long, and it is not suitable for industrial production

Method used

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  • Synthesis method of montelukast sodium intermediate
  • Synthesis method of montelukast sodium intermediate
  • Synthesis method of montelukast sodium intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] Embodiment 1: the synthesis of formula (II) compound

[0036]

[0037] 3-Bromobenzyl bromide (97.8g, 391.4mmol) and triphenylphosphine (102.7g, 391.4mmol) were dissolved in DMF (500mL), heated to 120°C, stirred for 2h, cooled to 0°C and stirred for 30min, added Sodium methoxide (42.3g, 782mmol) was stirred for 30min, then the compound of formula (IV) (50g, 260.9mmol) was slowly added, the temperature was gradually raised to room temperature, and the mixture was reacted for 1h. TLC detected that the reaction of the raw materials was complete. Pour the reaction solution into 1L of 1mol / L dilute hydrochloric acid, add 1L of ethyl acetate for extraction, wash the organic phase with saturated sodium bicarbonate solution and brine successively, collect the organic phase, dry, decolorize, and concentrate under reduced pressure. The concentrated solution was added into ice water, stirred for 30 min, the solid gradually precipitated out, filtered, rinsed with aqueous sodium ...

Embodiment 2

[0038] Embodiment 2: the synthesis of formula (II) compound

[0039]

[0040] 3-Bromobenzyl bromide (65.2g, 260.9mmol) and triphenylphosphine (68.4g, 260.9mmol) were dissolved in THF (500mL), heated to 60°C, stirred for 12h, cooled to 0°C and stirred for 30min, added Potassium tert-butoxide (35.1g, 313.1mmol) was stirred for 30min, then the compound of formula (IV) (50g, 260.9mmol) was slowly added, the temperature was gradually raised to room temperature, and the mixture was reacted for 2h. The reaction of the raw materials was detected by TLC. Pour the reaction solution into 1L of 1mol / L dilute hydrochloric acid, add 1L of ethyl acetate for extraction, wash the organic phase with saturated sodium bicarbonate solution and brine successively, collect the organic phase, dry, decolorize, and concentrate under reduced pressure. The concentrated solution was added into ice water, stirred for 30 min, the solid precipitated out, filtered, washed with aqueous sodium bicarbonate ...

Embodiment 3

[0041] Embodiment 3: the synthesis of formula (II) compound

[0042]

[0043] 3-Bromobenzyl bromide (71.7g, 287.0mmol) and triethylphosphine (33.9g, 287.0mmol) were dissolved in toluene (500mL), heated to 100°C, stirred for 6h, cooled to 0°C and stirred for 30min, added Sodium hydride (17.2g, 430mmol) was stirred for 30min, then the compound of formula (IV) (50g, 260.9mmol) was slowly added, and the temperature was gradually raised to room temperature, and the mixture was reacted for 2h. TLC detected that the reaction of the raw materials was complete. Pour the reaction solution into 1L of 1mol / L dilute hydrochloric acid, add 1L of ethyl acetate for extraction, wash the organic phase with saturated sodium bicarbonate solution and brine successively, collect the organic phase, dry, decolorize, and concentrate under reduced pressure. The concentrated solution was added into ice water, stirred for 30 min, the solid precipitated out, filtered, washed with aqueous sodium bicar...

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Abstract

The invention provides a synthesis method of a montelukast sodium intermediate. The synthesis method comprises the following steps: (1) carrying out Witting reaction on a compound (IV) and 3-bromobenzyl bromide to obtain a compound (II); and (2) carrying out a coupling reaction on the compound (II) and a compound (III) under the action of a palladium catalyst to obtain the compound (I). The synthesis method is short in step, mild in condition, easyand convenient to operate, beneficial to reducing the process cost and capable of realizing industrial production.

Description

[0001] 1. Technical field [0002] The invention belongs to the technical field of medicine synthesis, and in particular relates to a synthesis method of a montelukast sodium intermediate. [0003] 2. Background technology [0004] Montelukast Sodium (Montelukast Sodium) is an anti-asthma drug developed by Merck of the United States. It was approved by the U.S. Food and Drug Administration (FDA) on February 20, 1998. Its trade name is Singulair (Singulair). ). As a selective leukotriene receptor antagonist, montelukast sodium can selectively bind to leukotriene receptors in the respiratory tract, and is a highly effective, low-toxic, safe anti-inflammatory and anti-allergic drug for asthma. [0005] The chemical name of montelukast sodium is: 1-[[[(1R)-1-[3-[(1E)-2-(7-chloro-2-quinoline)vinyl]phenyl]-3- Sodium [2-(1-hydroxy-1-methylethyl)phenyl]propyl]thio]methyl]cyclopropaneacetate, its chemical structure is as follows. [0006] [0007] The compound of formula (I) is an...

Claims

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Application Information

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IPC IPC(8): C07D215/18
CPCC07D215/18
Inventor 甄宜战周化印赵显栋陈敬金张志强
Owner SHANDONG BESTCOMM PHARMA CO LTD
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