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New synthesis method of long-acting beta2 receptor agonist vilanterol

A synthetic route and solvent technology, applied in the new field of synthesis of vilanterol, can solve the problems of restricting vilanterol industrial scale-up, cumbersome preparation, long steps, etc. The effect of short steps

Inactive Publication Date: 2015-07-01
成都伊诺达博医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

And the preparation of raw material compound 5 is very loaded down with trivial details, take p-hydroxyacetophenone or 2-hydroxyl-4-bromo-benzaldehyde as raw material preparation, need to go through 7-8 step reaction and just can make, not only step is long, and yield is low, Reagents that are not suitable for industrial scale-up, such as bromine, butyllithium, and sodium hydride, need to be used

Method used

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  • New synthesis method of long-acting beta2 receptor agonist vilanterol
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  • New synthesis method of long-acting beta2 receptor agonist vilanterol

Examples

Experimental program
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Effect test

Embodiment 1

[0024] (2R)-Hydroxy-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-N-3-[6-[2-[(2,6- Preparation of dichlorophenyl)methoxy]ethoxy]hexyl]-ethylamine

[0025] Add 300ml of DMF to a 500ml three-necked flask, and add 38.4g of 2-({2-[(6-bromo-hexyloxy)]-ethoxy}methyl)-1,3-dichlorobenzene successively under stirring 22.3 g(2R)-hydroxy-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-ethylamine, slowly add 11.1g triethylamine dropwise, and finally add 4.5 g sodium iodide. Stir at room temperature for about 6 h, and monitor the completion of the reaction by TLC. Add the reaction solution to 900ml of water, stir for 30min, add isopropyl ether to extract 3 times, wash with saturated brine 3 times, dry over anhydrous sodium sulfate, dry and concentrate under reduced pressure, and the residue is purified by column chromatography to obtain (2R)-hydroxyl -2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-N-3-[6-[2-[(2,6-dichlorophenyl) Methoxyl]ethoxyl]hexyl]-ethylamine 45.3g, yield 86.2%.

Embodiment 2

[0027] 4-{(1R)-2-[(6-{2-[(2,6-dichlorophenyl)methoxy]ethoxy}hexyl)amine]-1-hydroxyethyl}-2- ( Preparation of hydroxymethyl)phenol (vilanterol)

[0028] (2R)-Hydroxy-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-N-3-[6-[2-[(2,6 Add 45.3 g of -dichlorophenyl)methoxy]ethoxy]hexyl]-ethylamine to 200ml of acetic acid, then add 100ml of water, stir at room temperature for 7-8h, and monitor the completion of the reaction by TLC. Concentrate under reduced pressure, add 400ml of dichloromethane to the residue, adjust the pH to 7-8 with saturated sodium bicarbonate, separate the layers, wash the organic phase once with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. Purified by chromatography to obtain 38.2 g of vilanterol with a yield of about 91.5%.

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Abstract

The present invention discloses a new synthesis method of a long-acting beta2 receptor agonist vilanterol, and provides a completely-new synthesis method of a long-acting beta2 receptor agonist vilanterol. According to the method, the idea that the Schiff base is firstly produced and then reduction is performed is adopted to effectively avoid disadvantages of harsh reaction conditions (such as anhydrous reaction), expensive reagents and the like of the existing process, and the method has characteristics of easily available raw materials, short route, high yield, and market competitiveness.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical synthesis technology, and in particular relates to a new synthetic method for synthesizing Vilanterol. Background technique [0002] Chronic obstructive pulmonary disease (COPD) is characterized by incomplete airflow limitation and progressive aggravation, and has become the fifth leading cause of death in patients. Actively controlling symptoms and improving lung function are the mainstays of treatment for this disease. important goal. At present, the drugs used to relieve the symptoms of COPD patients are mainly long-acting β2 receptor agonists such as formoterol and salmeterol, which need to be taken twice a day. [0003] Vilanterol is a long-acting β2-adrenoceptor agonist (LABA), and in vitro tests have shown that its functional selectivity is similar to that of salmeterol. The pharmacological effects of β2-adrenoceptor agonists, including Vilanterol, are at least in part due to their...

Claims

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Application Information

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IPC IPC(8): C07C217/08C07C213/00C07C213/08
Inventor 付清泉岳利剑林强邹涛周平赵茂先秦艳
Owner 成都伊诺达博医药科技有限公司
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