Process Optimization For The Synthesis Of Pranlukast

Pranlucast, a novel leukotriene receptor antagonist (LTRAs), is effective for the treatment of asthma. Reported methods for its synthesis mainly fall into two categories concerning whether the amide structure was generated in the last step or not.In the present approach, Pranlucast was synthesized from starting material p-bromophenol via9steps reaction, which include acetylation, Fries rearrangement, nitrification, condensation and subsequent cyclization, ammonolysis, dehydration, cycloaddition, hydrogenation reduction and acylation with4-(4-phenylbutoxy)benzoic. The final product was obtained with98.14%purity (ESI:480.2).Compared with the reported methods, the improved process has the following advantages or improvements:The process is more capable for industrial production partly because of the cheap and easily obtained raw material, partly because of the mild conditions for operation. The total yield reached36.2%after the complete of the process optimization. The yield of the first three synthesis steps was raised from52.7%to74.2%, and21.5%to48.8%for the last six synthesis steps respectively.The intermediates do not need to be separated with the same solvent tetrachloroethylene from the first step to the third step, which including the reaction of Acetylation, Fries rearrangement and nitrification. This improvement is environmental friendly because it reduces the amounts of the solvent consumption and avoids the loss of product caused from separation process.The yield was raised to92.5%when condensation and cyclization were carried out in one-pot method.Water was used as the only solvent instead of DMF in the reaction of cycloaddition with the advantage of more efficient for operation and environment friendly, in the meantime the yield was raised to91.9%with the purity of98.14%.There was less side reactions and thus higher yield for the step of hydrogenation reduction due to the replacement of solvent from methanol to water.