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Preparation method for montelukast sodium intermediate

A technology of intermediates and solids, which is applied in the field of preparation of Montelus-Turner intermediates, can solve the problems of separation waste and unusable chiral alcohol, etc., and achieve the effect of green and environmental protection process

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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] In this method, the chiral alcohol of another configuration cannot be used for subsequent products, and a corresponding chiral resolving agent is required, and there is a large waste problem in the resolution process

Method used

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

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preparation example Construction

[0028] A kind of preparation method of montelukast sodium intermediate of the present invention comprises following reaction process:

[0029]

[0030] Described reaction process comprises the following steps:

[0031] In the first step, the raw material methyl 2-(3-(3-bromophenyl)-3-oxopropyl)benzoate (II) is provided.

preparation example

[0033] The preparation method of catalyst A comprises the following steps:

[0034] (1) After dissolving p-xylene with concentrated sulfuric acid at 0°C, add concentrated nitric acid dropwise, first react at this temperature for 1 hour, then raise the temperature to 100°C and continue the reaction for 2 hours. After the reaction is complete, introduce the reaction system into crushed ice , continue to stir to obtain a yellow solid;

[0035] (2) The yellow solid obtained in the step (1) was catalyzed by 10% Pd / C, stirred for 4 h under a hydrogen pressure of 1 atm, filtered off 10% Pd / C, and the reaction solution was concentrated to obtain a brownish-yellow oil;

[0036] (3) After dissolving the oil obtained in step (2) in dichloromethane, add it dropwise to Cbz-L-amino acid and CDI at 0°C, stir at room temperature for 2 hours, add water to quench, and wash the water layer with dichloromethane Extracted with methane, combined with dichloromethane, concentrated to give a light g...

Embodiment 1

[0041] A preparation method of montelukast sodium intermediate, comprising the following steps:

[0042] At first, in 100L autoclave, under the condition of communicating with argon gas, add raw material reactant 10kg methyl 2-(3-(3-bromophenyl)-3-oxopropyl group) methyl benzoate ( II), then add 60kg of toluene as a solvent to fully dissolve the raw material (II), continue to feed argon for bubbling and degassing, and continue bubbling for 1.5 hours; the degassing is completed. Under an argon atmosphere, add 2.5g of catalyst (R,R)-DIOPRuCl2(R)-Me-BIMAH from the feeding port, and finally add 150g of potassium tert-butoxide. After the addition, quickly close the feeding port.

[0043] Secondly, replace the argon with hydrogen, slowly introduce hydrogen to 35 atmospheres, then close the inflation valve, close the hydrogen channel, and finally stir, keep the reaction at 35°C, and the pressure will drop after starting to stir, observe the change of pressure, When the pressure rema...

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Abstract

The invention discloses a preparation method for a montelukast sodium intermediate. The preparation method comprises the steps that a raw material methyl2-(3-(3-bromophenyl)-3-oxo-propyl)-methyl benzoate (II) is dissolved with solvent C under protection of inert gas, alkali B is added into the raw material, stirring is performed for 1 h-10 h, a catalyst A is added, stirring is continuously performed for 2 h-10 h, the inert gas is replaced by hydrogen, the pressure is increased to 2 atm-60 atm, stirring is performed under the pressure until the pressure keeps invariable, and then the montelukast sodium intermediate IV is obtained.

Description

technical field [0001] The invention belongs to the field of synthesis of pharmaceutical and chemical intermediates, and in particular relates to a preparation method of Montelustena intermediates. Background technique [0002] Montelukast sodium (montelukastsodium, structural formula I), chemical name [R-(E)]-1-[[[1-[3-[2-(7-chloro-2-quinolyl)ethyl] Phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]thio]methyl]cyclopropyl sodium acetate is a selective leukotriene D4 developed by MERK in the United States receptor antagonists. Montelukast sodium blocks the action of allergic mediators, improves respiratory inflammation, and unblocks the airway. It is an anti-asthma, anti-inflammatory and anti-allergic drug with high efficiency, low toxicity and good safety, and has broad application prospects. The structural formula I of montelukast sodium is as follows: [0003] [0004] In the synthesis route of montelukast sodium, there is a method of reducing the carbonyl group t...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C67/31C07C69/76
CPCC07C67/31C07C69/76
Inventor 徐亮黄志鸿李彦雄毛波
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