Study On Synthesis Of Intermediate Of Roflumilast

Roflumilast as a drug acts a selective, long-acting inhibitor of the enzyme PDE4. It has antiinflammatory effects and is under development as an orally administered drug for the treatment of inflammatory conditions of the lungs such as asthma, and chronic obstructive pulmonary disease (COPD).The synthesis of3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid is studied in this paper, which is one of the key intermediate of Roflumilast.3,4-dihydroxybenzoic acid was firstly converted to the corresponding methyl ester, followed by alkylation reaction with benzyl bromide giving the intermediate methyl4-benzyloxy-3-hydroxybenzoate which was transformed into methyl4-benzyloxy-3-cyclopropylmethyloxybenzate by alkylation reaction with cyclopropylmethyl bromide again. Thereafter, the protective group was removed in the presence of the catalytic amount of PdVC and hydrogen. The target product was synthesized in one-pot with the last step.The synthesis investigation of every intermediate was carried out:methyl3,4-dihydroxyzoate was afforded in quantitative yield using3,4-dihydroxybenzoic acid and thionyl chloride; Methyl4-benzyloxy-3-hydroxybenzoate was obtained in42.8%yield;4-benzyloxy-3-cyclopropylmethyloxybenzate was produced above95%yield.; The target product3-cyclopropylmethoxy-4-difluoromethoxy-benzoic acid was syntheticed in using4-benzyloxy-3-cyclopropylmethyloxybenzate in total yield59.4%via one-pot reaction. The overall yield was24.0%.