Method for preparing drug Roflumilast for treating chronic obstructive pulmonary disease

Abstract

The invention relates to a method for preparing a drug Roflumilast for treating the chronic obstructive pulmonary disease. The Chinese chemical name of the drug Roflumilast is 3-(cyclopropylmethoxy)-N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)benzamide. According to the method, in a process route, a dihydroxyl-substituted benzoate derivative, which can be extensively obtained, is adopted as a starting raw material, so that the consumption of noble metal catalysts is avoided, the synthesis process route is shortened, and the production cost is reduced greatly; through introducing difluoromethoxy by replacing a gaseous reagent with a solid difluoromethyl etherification reagent, which is safe, efficient, cheap and readily available, side reactions are reduced, and the selectivity of the reaction is improved; and the target product is obtained efficiently through condensing carboxyl groups and amino groups.

Description

technical field [0001] The invention relates to a new synthesis method of Roflumilast, a drug for treating chronic obstructive pneumonia. It belongs to the field of chemical drug synthesis. Background technique [0002] Roflumilast (Daxas) is the first phosphodiesterase-4 (PDE4) inhibitor produced and marketed by Forest Pharmaceuticals, a subsidiary of Forest Lab, and was approved by the European Union and the United States on July 6, 2010 and 2011 respectively Approved on February 24 for the treatment of chronic obstructive pulmonary disease (COPD). This medicine is indicated for the treatment of cough and phlegm caused by bronchitis in patients with severe COPD. [0003] From the current literature, the synthetic route of Roflumil mainly has the following three methods: [0004] (1) The synthetic route reported in US6822114 and WO2004033430 patents is: using catechol as raw material, through O-alkylation, bromination, O-alkylation, carbonylation, acylation and other rea...

AI Technical Summary

Problems solved by technology

[0006] The limitations of this route are: low-temperature bromination is required, and the requirements for equipment are high; the gaseous difluoromethyl etherification reagent is used, which is highly toxic, and it is difficult to quantitatively control the amplification reaction, and there are many by-products; the use of noble metal Pd Catalytic carbonylation also uses highly toxic CO, which has high cost and poor industrial operability

[0012] The starting materials of this route are expensive and difficult to obtain widely; the synthetic route is long, the total yield is low, metal catalysts are used, and it is difficult to scale up the application

[0013] The limitations of the synthetic routes reported in the existing patent literature are: low-temperature bromination is required, and the requirements for equipment are high; gaseous difluoromethyl etherification reagents are used, which are highly toxic and difficult to quantitatively control during amplification reactions, and side effects are obtained. There are many products and the reaction selectivity is not high; the use of noble metal Pd to catalyze carbonylation also uses highly toxic CO, which is costly and poor in industrial operability

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