The Study On Synthesis Of Pranlukast

Pranlukast, developed by Ono Sokki Co. of Japan and launched to the market as a new medication for the treatment of asthma in th 1990s', is one of the three LTRAs that receive wide international attention.The synthetic process of Pranlukast reported in the references can be summarized in two types according to the different primary intermediates. In the first type, the primary intermediate is 8-amino-4-oxo-2-(tetrazol-5-yl)-4H-l-benzopyran; in the second type, the primary intermediate is N-(3-acetyl-2-hydroxyphenyl)-4-(4-but oxybenzyl)benzamide.Following the route of the first type as model, a new route for the synthetic of Pranlukast was designed and introduced in this paper. 5-bromo-2-hydroxy-3-nitro acetophenone is selected as the initial material, vie condensation with diethyl oxalate, cyclization, ammonolysis, dehydration with phosphorus oxychloride as the dehydrant, cycloaddition with NaN₃ in the existence of NH₄Cl as the catalyst, combined the reduction and debromination together with Pd/C by hydrogenation to get 8-amino-4-oxo-2-(5-lH-tetrazolyl)-4H-l-benzopyran, acylation with 4-(4-phenyl butoxy)benzoyl chloride to get Pranlukast.The process for preparation of Pranlukast is optimized and improved. The details of the improvement are as follows: a new process of preparation of Pranlukast is designed, which reduced the steps of the reaction, the yield attached to 21.25%, the amide, cyanide, nitro- tetrazole are new compounds never reported by CA; combined the reduction and debromination together to get 8-amino-4-oxo-2-(5-1H-tetrazolyl)-4H-1-benzopyran; choos an appropriate ring-closing agent in the preparation of 2-carboxamide-6-bromo-8-nitro-4-oxo-4H-chromene; Choose triethylamine- dichloromethane system in the acylation to get Pranlukast, which reduced the production cost.