Method for synthesizing Vilanterol midbody by virtue of solid acid catalysis

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...

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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-toluenesulfonic acid residues, which need to be removed through more than two recrystallizations, and p-toluenesulfonic acid is also difficult to realize recovery and application (3) a small amount of oligomers are generated in the reaction process, causing the system color to become dark brown as the reaction progresses, resulting in dark product color and poor color, and the decolorization effect by activated carbon is not good

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