Method for synthesizing Vilanterol midbody by virtue of solid acid catalysis

A technology of solid acid catalysis and intermediates, applied in chemical recycling, organic chemistry, etc., can solve the problems of low yield, poor color, deep product color, etc., achieve simple post-processing, reduce environmental protection pressure, and increase productivity.

Active Publication Date: 2019-04-05
ANHUI DEXINJIA BIOPHARM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] This synthetic method adopts protonic acid p-toluenesulfonic acid to catalyze as catalyst, mainly has the following problems: (1) the reaction yield is 83%, the yield is on the low side, and there is still a lot of room for improvement; (2) it is found through experiments that The purity of the intermediate (II) obtained by this synthesis method is 98%, and liquid phase detection shows that there are about 1.3% p-tolu

Method used

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  • Method for synthesizing Vilanterol midbody by virtue of solid acid catalysis
  • Method for synthesizing Vilanterol midbody by virtue of solid acid catalysis
  • Method for synthesizing Vilanterol midbody by virtue of solid acid catalysis

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Experimental program
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Effect test

Embodiment 1

[0020] Add 28.1g intermediate (I), 2,2-dimethoxypropane (20.8g), SO 4 2- / ZrO 2 (1.4g), add chloroform (140mL), heat up to 60°C, react for 2 hours, and the reaction is completed in TLC. Cool down to room temperature, filter, and concentrate the filtrate in vacuo to obtain a crude product, which is recrystallized from isopropyl ether to obtain 29.2 g of a white solid with a yield of 91% and a purity of 99%.

Embodiment 2

[0022] Add 28.1g intermediate (I), 2,2-dimethoxypropane (20.8g), SO 4 2- / TiO 2 (1.4g), add 1,2-dichloroethane (140mL), heat up to 55°C, react for 3 hours, and the reaction is completed in TLC. Cool down to room temperature, filter, and concentrate the filtrate in vacuo to obtain a crude product, which is recrystallized from isopropyl ether to obtain 29.5 g of a white solid with a yield of 92% and a purity of 99%.

Embodiment 3

[0024] Add 28.1g intermediate (I), 2,2-dimethoxypropane (20.8g), PO 4 3- / TiO 2 (1.4g), add acetone (140mL), heat up to 50°C, react for 3 hours, and the reaction is completed in TLC. Cool down to room temperature, filter, and concentrate the filtrate in vacuo to obtain a crude product, which is recrystallized from isopropyl ether to obtain 29.2 g of a white solid with a yield of 91% and a purity of 99%.

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Abstract

The invention discloses a method for synthesizing Vilanterol midbody 2-(2,2-dimethyl-4H-1,3-benzodiazepine-6-group)-2-carbonyl ethyl carbamate tert-butyl ester (II) by virtue of solid acid catalysis,which belongs to the technical field of organic catalysis. According to the method, the solid acid is used to catalyze the synthesis of Vilanterol midbody (II),so that the defect in the prior art by adopting organic strong acid can be solved, the recycling of the catalyst is realized, and the pressure of environmental protection can be alleviated. The solid acid catalyzed synthesis route of the invention is environment-friendly and meets the requirements of modern pollution-free industrialized production.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and relates to a solid acid catalyzed synthesis of an anti-asthma drug vilanterol intermediate 2-(2,2-dimethyl-4H-1,3-benzodioxine-6 -yl)-2-carbonylethylcarbamate tert-butyl ester method. Background technique [0002] Vilanterol is a long-acting beta drug developed by GlaxoSmithKline (GSK) 2 receptor agonist. Its compound preparation with fluticasone furoate and its compound preparation with umeclidinium bromide were approved by FDA in May and December 2013, respectively, for the treatment of obstructive pulmonary disease and asthma. Vilanterol has a molecular weight of 486.4 and a molecular formula of C 24 h 33 Cl 2 NO 5 , CAS: 503068-34-6, Chinese name: Chemical name: (R)-4-[2-[[6-[(2,6-dichlorobenzyl)oxy]-ethoxy]ethyl ]amino]-1-hydroxyethyl]-2-hydroxyethyl]-2-hydroxymethylphenol, wherein the intermediate of vilanterol (II) 2-(2,2-dimethyl-4H-1, 3-benzodioxine-6-yl)-2-carbonylethylcarbamat...

Claims

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Application Information

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IPC IPC(8): C07D319/08
CPCC07D319/08Y02P20/584
Inventor 王红磊许坤张启龙汪崇文林建华
Owner ANHUI DEXINJIA BIOPHARM
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