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A kind of method of solid acid catalysis synthetic vilanterol intermediate

A solid acid catalysis and intermediate technology, applied in organic chemistry, chemical recycling, etc., can solve problems such as poor color, dark product color, and low yield, and achieve the effects of reducing environmental protection pressure, increasing yield, and simple post-processing

Active Publication Date: 2020-11-27
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-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

Method used

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  • A kind of method of solid acid catalysis synthetic vilanterol intermediate
  • A kind of method of solid acid catalysis synthetic vilanterol intermediate
  • A kind of method of solid acid catalysis synthetic vilanterol intermediate

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Experimental program
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Effect test

Embodiment 1

[0020] 28.1g of intermediate (I), 2,2-dimethoxypropane (20.8g), SO 4 2- / ZrO 2 (1.4g), add chloroform (140mL), heat up to 60 ℃, react for 2 hours, and the reaction is completed by TLC. It was cooled to room temperature, filtered, and the filtrate was concentrated in vacuo to obtain a crude product. The crude product was 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] 28.1g of intermediate (I), 2,2-dimethoxypropane (20.8g), SO 4 2- / TiO 2 (1.4 g), 1,2-dichloroethane (140 mL) was added, the temperature was raised to 55° C., and the reaction was carried out for 3 hours, and the reaction was completed under TLC control. It was cooled to room temperature, filtered, and the filtrate was concentrated in vacuo to obtain a crude product. The crude product was recrystallized with isopropyl ether to obtain 29.5 g of a white solid with a yield of 92% and a purity of 99%.

Embodiment 3

[0024] 28.1g of intermediate (I), 2,2-dimethoxypropane (20.8g), PO were added to the 500mL three-necked flask 4 3- / TiO 2 (1.4g), acetone (140mL) was added, the temperature was raised to 50°C, and the reaction was carried out for 3 hours, and the reaction was completed under TLC control. It was cooled to room temperature, filtered, and the filtrate was concentrated in vacuo to obtain a crude product. The crude product was 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-benzodioxin-6 -yl)-2-carbonylethylcarbamate tert-butyl ester method. Background technique [0002] Vilanterol is a long-acting beta developed by GlaxoSmithKline (GSK) 2 receptor agonists. Its combination with fluticasone furoate and umeclidinium bromide were approved by the FDA in May and December 2013, respectively, for the treatment of obstructive pulmonary disease and asthma. The molecular weight of vilanterol is 486.4 and the molecular formula is C 24 H 33 Cl 2 NO 5 , CAS: 503068-34-6, Chinese name is: Chemical name: (R)-4-[2-[[6-[(2,6-dichlorobenzyl)oxy]-ethoxy]ethyl ] amino]-1-hydroxyethyl]-2-hydroxyethyl]-2-hydroxymethylphenol, wherein vilanterol intermediate (II) 2-(2,2-dimethyl-4H-1, 3-Benzodioxen-6-yl)-2-carbonylethylcarbamate tert-butyl ester is an important interm...

Claims

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Application Information

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Patent Type & Authority Patents(China)
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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