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Preparation method for synthesizing vilanterol intermediate by catalysis with modified graphene

An intermediate and graphene technology, applied in chemical instruments and methods, physical/chemical process catalysts, chemical recovery, etc., can solve the problems of p-toluenesulfonic acid that is difficult to recycle, deep product color, poor color, etc., and achieve graphite The catalyzed synthetic route of ene is environmentally friendly, solves the problem of difficult recycling, and reduces the pressure on environmental protection

Pending Publication Date: 2019-11-08
UNIV OF JINAN
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] This synthesis method uses the protonic acid p-toluenesulfonic acid as a catalyst for catalysis, and there are mainly the following problems: (1) The reaction yield is 83%, which is low and there is still a lot of room for improvement; (2) Through experiments, it is found that The purity of the intermediate (II) obtained by this synthesis method is 98%, and liquid phase detection shows that about 1.3% p-toluenesulfonic acid remains, which needs to be removed through more than two recrystallizations, and p-toluenesulfonic acid is also difficult to recover and apply mechanically (3) A small amount of oligomers are formed during the reaction process, which leads to the color of the system becoming dark brown as the reaction progresses, resulting in a dark product with poor color, and the effect of decolorization by activated carbon is not good

Method used

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  • Preparation method for synthesizing vilanterol intermediate by catalysis with modified graphene
  • Preparation method for synthesizing vilanterol intermediate by catalysis with modified graphene
  • Preparation method for synthesizing vilanterol intermediate by catalysis with modified graphene

Examples

Experimental program
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Effect test

Embodiment 1

[0018] (1) Take a 3000mL glass beaker, measure 500 grams of 15% oleum, add it, and cool down to -3~2 in an ice-salt bath o C, under stirring, add 6.25 grams of graphite powder into the fuming sulfuric acid, after stirring and dispersing, continue to stir, slowly add 32 grams of potassium permanganate to the fuming sulfuric acid solution of graphite powder in batches, keep warm for -3~2 o C continued to stir for 2.5 hours, after the stirring ended, the reaction solution was warmed up to 45 oC , add 51.4 grams of deionized water to the reaction solution, and the reaction solution is warmed up to 100 oC , continue to stir and react for 4 hours;

[0019] (2) Naturally cool to 20 after stopping heating oC , under stirring, add 360 grams of hydrogen peroxide in batches to the reaction system, add 62 grams of 2mol / L hydrochloric acid after stirring for 1 hour, divide it into three times, each time use 1400mL deionized water, and wash the dialysis bag 5 times.

[0020] (3) Transfer t...

Embodiment 2

[0022] (1) Take a 5000mL glass beaker, measure 1000 grams of 30% fuming sulfuric acid, add it, and cool down to 0~2 in an ice-salt bath o C, add 20 grams of graphite powder into the fuming sulfuric acid solution under stirring, after stirring and dispersing, continue stirring, slowly add 40 grams of potassium permanganate in the fuming sulfuric acid solution of graphite powder in batches, keep warm for 0~2 o C continued to stir for 3 hours, after the stirring ended, the reaction solution was warmed up to 55 oC , add 200 grams of deionized water to the reaction solution, and raise the temperature of the reaction solution to 100 oC , continue to stir and react for 5 hours;

[0023] (2) Naturally cool to 20 after stopping heating oC , under stirring, add 1000 grams of hydrogen peroxide in batches to the reaction system, after stirring for 1 hour, add 62 grams of 2mol / L hydrochloric acid, and divide it several times, each time with 2000mL deionized water, and use a dialysis bag ...

Embodiment 3

[0031] Weigh 2.81g of vilanterol intermediate (I) tert-butyl (2 - (4 - hydroxy - 3-(hydroxymethyl) phenyl) - 2 - oxoethyl) carbamate and add 2.08g of 2,2-dimethoxypropane to In a 100 mL single-necked flask, add 60 mL of chlorobenzene, add magnets of appropriate size, stir and disperse, then add 4 mg of modified and synthesized edge highly carboxylated reduced graphene oxide, then heat the oil bath and keep it warm for 100 o C was reacted for 6 hours, and the reaction was detected. Add 30 mL of saturated sodium bicarbonate, stir and wash for 30 minutes, extract, collect the organic phase, filter the organic phase after drying with anhydrous sodium sulfate, collect the liquid phase, and concentrate by rotary evaporation. Add isopropyl ether into another 50mL single-necked flask, put in a suitable magnet, place it in a low-temperature reactor, and keep warm for 0~3 o C. Add the concentrated slurry dropwise to isopropyl ether under stirring. After the dropwise addition, keep warm ...

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Abstract

The invention discloses a method for synthesizing a vilanterol intermediate tert-butyl 2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-carbonylethylcarbamate by catalysis with modified reduced graphene oxide with a high carboxylation edge, and belongs to the technical field of organic catalysis. The method utilizes an acidic catalytic reaction of the relatively large amount of carboxyl groups at the edge of reduced graphene oxide to overcome the disadvantage that an adopted organic strong acid is difficult to recover in the prior art, solve the problem of heterogeneous phase and difficult recyclingapplication of a catalyst, and reduce environmental protection pressure. The catalytic synthesis method adopting graphene is environmentally friendly, and meets requirements of modern green industrial production.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and relates to an anti-asthma drug vilanterol intermediate 2-(2,2-dimethyl-4H-1,3-benzodioxine-6-yl)- Synthetic method of tert-butyl 2-carbonylethylcarbamate. Background technique [0002] Vilanterol is a long-acting beta drug developed by GlaxoSmithKline (GSK) 2 receptor agonists. 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-Benzodioxin-6-yl)-2-carbonylethylcarbamate tert-butyl ester is an impo...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D319/08B01J21/18
CPCC07D319/08B01J21/18Y02P20/584
Inventor 高令峰朱臣析郑庚修张启龙诸葛文云
Owner UNIV OF JINAN
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