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Preparation method of Roflumilast

A technology of roflumilast and one-mouth bottle, which is applied in the field of drug synthesis, can solve the problems of incomplete oxidation reaction, cumbersome processing process, and high processing cost, and achieve the effects of reducing emissions, simple operation method, and simple production process

Active Publication Date: 2015-01-14
ZHENGZHOU MINGZE MEDICAL TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] However, there is an incomplete oxidation reaction in the above-mentioned method, and a large amount of thionyl chloride and sodium hydride need to be used in the acylation reaction, and the treatment process of these material components after the reaction is cumbersome and the treatment cost is high. cause serious harm

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  • Preparation method of Roflumilast

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Effect test

Embodiment 1

[0021] Embodiment 1 A kind of preparation method of roflumilast:

[0022] Add 380ml of pure water and 8g of sodium hydroxide to a 1000ml single-necked bottle, shake to dissolve them all, and add 24.2g of 3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzaldehyde, Add 1 g of catalyst (tetrabutylammonium bromide), and then add 19 g of potassium permanganate, and stir overnight at room temperature. TLC tracking, after confirming that the reaction is complete, filter, add 10% hydrochloric acid to the filtrate to adjust the pH value to 2~3, extract with 300ml ethyl acetate in 3 times, combine the organic phases, wash with water and saturated saline in sequence, and dry over anhydrous sodium sulfate , filter, evaporate the solvent under reduced pressure to nearly dryness, add 100ml of petroleum ether, stir to disperse, disperse evenly, filter, wash with petroleum ether, and dry in vacuo to obtain 21.9g of off-white crystalline solid, yield 85%, content (HPLC) ≥98.5%.

[0023] Add 21.9...

Embodiment 2

[0025] Embodiment 2 A preparation method of roflumilast:

[0026] Add 400ml of pure water and 8g of sodium hydroxide to a 1000ml single-necked bottle, shake to dissolve them all, add 24.2g of 3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzaldehyde after cooling down to room temperature, Then add 16g of potassium permanganate, and stir overnight at room temperature; TLC tracking, after confirming that the reaction is complete, filter, add 10% hydrochloric acid to the filtrate to adjust the pH value to 2-3, extract 240ml of ethyl acetate in 3 times, combine the organic phase, Then wash the obtained organic phase with pure water and saturated brine in turn, then dry with anhydrous sodium sulfate, filter, evaporate the solvent under reduced pressure to nearly dryness, add 80ml of petroleum ether, stir and disperse, filter evenly after dispersion, and wash with petroleum ether , dried in vacuo to obtain 20.1 g of off-white crystalline solid, yield 78%, content (HPLC) ≥ 98.5%.

[00...

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Abstract

The invention relates to a preparation method of Roflumilast. Potassium permanganate is used as an oxidizing agent to oxidize 3-(cyclopropyl methoxyl)-4-(difluoromethoxy) benzaldehyde into 3-(cyclopropyl methoxyl)-4-(difluoromethoxy) benzoic acid under alkaline condition; and then 3-(cyclopropyl methoxyl)-4-(difluoromethoxy) benzoic acid anhydride is generated in dimethyl formamide (DMF) and reacts with 3, 5-dichloro-4-aminopyridine in the presence of N, N' -carbonyldiimidazole to form a target product. The preparation method of Roflumilast provided by invention has simple technological process, convenient operation method, and high content and high yield of the prepared product, and can greatly reduce the emission of industrial ''three wastes''.

Description

technical field [0001] The invention relates to the technical field of drug synthesis, in particular to a preparation method of roflumilast. Background technique [0002] Roflumilast is a selective phosphodiesterase 4 (PDE4) inhibitor developed by Nycomed. It is mainly used clinically for the treatment of chronic obstructive pulmonary disease (COPD). The European Union has approved the listing in July 2010. Roflumilast is the first new class of COPD drugs approved by the European Union in more than a decade. Chronic obstructive pulmonary disease (COPD) is a progressive and life-threatening lung disease that is estimated to affect approximately 210 million people worldwide. COPD is expected to become the third leading cause of death worldwide by 2020. Roflumilast, as a new class of COPD treatment drug, has broad market prospects in the future. The chemical structure of Roflumilast is as follows: [0003] There are many synthetic methods of roflumilast in the prior art, ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D213/75
Inventor 李海涛张英斌徐贡杰徐培明
Owner ZHENGZHOU MINGZE MEDICAL TECH