Process Improvement on Synthesis of Prostaglandin D2 Receptor Antagonists Key Intermediate
Prostaglandin D2 receptor antagonists are potential agents for the treatment of asthma and re-lated allergic diseases,and the synthesis of key intermediate has only been rarely reported.Tert-butyl 2-(1H-indol-1-yl)acetate and cyclic N-sulfonyl aldimine were used as substrates through Friedel-Crafts alkylation reaction by using spiro oxazoline ligand and Lewis acid to give prostaglandin D2 receptor an-tagonists key intermediate.In the ligand screening process,we found ligand was the critical factor to get the high yield.The zinc complex of a new spiro quinox ligand was proved to be a suitable catalyst,the reaction gave high yield and without the by-product.The Friedel-Crafts alkylation reaction was studied by exploring reaction solvent,substrate equivalent and temperature to found the optimized reac-tion conditions.The dichloromethane as the solvent at 0 ℃,and tert-butyl 2-(1H-indol-1-yl)acetate:cyclic N-sulfonyl aldimine=1∶1(n∶n),the highest yield of the target product was 97％.The highlights of this method include mild reaction conditions,and the use of cheap and environmen-tally friendly metal catalyst,avoiding the corrosive and explosive materials in traditional methods.
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