Study On The Synthesis Of Intermediate Of Pranlukast

Pranlukast is a kind of Leukotriene receptor antagonists (LTRAs), which can be used in treatment of various kinds of asthma and allergic diseases with a good effect and small side effect.According to the preparation methods we summarized, two new routes were designed to synthesize the key intermediate of Pranlukast, 8-amino-2-(1H-tetrazol-5-yl)-4H-1-benzopyran-4-one from 3-amino-2-hydroxyacetophenone hydrochloride and o-nitrophenol respectively.Firstly,8-amino-2-(1H-tetrazol-5-yl)-4H-1-benzopyran-4-one was synthesized with an overall yield of 28% via neutralization, condensation with diethyl oxalate, cyclization, acetylization, aminolysis, dehydration with phosphorus oxychloride as the dehydrant, cycloaddition with NaN3 and deprotection from 3-amino-2-hydroxyacetophenone hydrochloride. The target product was identified by 1HNMR and MS. In addition, a one-pot reaction was used in the two steps of condensation and cyclization, which reduced the amount of solvent and reaction time and improve the yield. The new synthetic route has some advantages such as low cost, high availability of substrates and reagents, mild and safe reaction conditions, simple operation and suitable for industrial production.Secondly,8-nitro-2-ethoxy formyl-4-oxo-4H-1-benzopyran was synthesized by the second route via nucleophilic addition and Friedel-Crafts reaction from o-nitrophenol. Then 8-amino-2-(1H-tetrazol-5-yl)-4H-1-benzopyran-4-one could be synthesized via aminolysis, dehydration with phosphorus oxychloride as the dehydrant, cycloaddition with NaN3 and hydrogenation from 8-nitro-2-ethoxy formyl-4-oxo-4H-1-benzopyran, which was consistent with the previously reported methods. So any specific research on the last four steps hadn't been done. The target product was identified by HNMR and MS. The second synthetic route hasn't been reported by predecessors, which is a supplement for the synthesis of the intermediate.