Disclosed is an improved method of synthesis for Treprostinil comprising condensation reaction of compound (4) with a hydroxyl-protected alkynol (5) to give the condensation product, compound (6). Subjecting compound (6) to oxidation, reduction, hydroxyl protection and carbonylation, cyclization reactions gives the tricyclic derivative (10). Further reactions comprising reduction, hydrogenation and deprotection of the phenolic and side-chain hydroxyl groups, wherein the sequence and choice of reagents is governed by protecting groups, give the triol intermediate, compound (14). Cyanoalkylation at phenolic hydroxyl functionality and further hydrolysis yields the prostacyclin compound, Treprostinil (1) and its pharmaceutically acceptable salts with desired purity.
揭示了一种改进的Treprostinil合成方法,包括将化合物(4)与羟基保护的炔醇(5)进行缩合反应,得到缩合产物,化合物(6)。将化合物(6)进行氧化、还原、羟基保护和羰基化、环化反应,得到
三环衍
生物(10)。进一步的反应包括还原、氢化和去保护
酚基和侧链羟基,其中试剂的顺序和选择受到保护基的控制,得到三醇中间体,化合物(14)。在
酚羟基官能团上进行
氰基烷基化,进一步
水解产生
前列环素化合物Treprostinil(1)及其具有所需纯度的药用盐。