高选择性MMP-12抑制剂RXP470.1的合成

Synthesis of the MMP-12 selective inhibitor RXP470.1

目的:合成高选择性MMP-12抑制剂RXP470.1。方法:4-溴苯基次膦酸(1)和2-炔丙基丙烯酸乙酯(4)通过麦克尔加成反应生成4-溴苯基-(2-乙氧羰基-4-戊炔基)次膦酸(5);5和3'-氯-联苯-4-氧化腈(9)发生1,3-偶极环加成反应生成4-溴苯基-{(2-乙氧羰基-3-[3-(3'-氯联苯-4-基)-异恶唑-5-基]丙基}次膦酸(10);10通过保护膦羟基、脱酯基得到12;最后通过固相肽合成反应得到RXP470.1(14)。结果:成功合成RXP470.1。结论:该合成方法可行,适合工业化。

Objective： To synthesize the MMP-12 selective inhibitor RXP470. 1. Methods：(4-Bromophenyl）[2-(ethoxycarbonyl） pent-4-ynyl] phosphinic acid(5） was synthesized by Michael addition reaction via 4-bromophenylphosphinic acid(1） and ethyl 2-methylene-4-pentynoate(4）; compound 5 reacted with 3’-chlorobiphenyl-4-nitrile oxide(9） through 1,3-dipolar cycloaddition to give(4-bromophenyl）(2-{ [3-(3’-chloro-[1,1’-biphenyl-4-yl） isoxazol-5-yl]methyl}-3-ethoxy-3-oxopropyl） phosphinic acid(10）; the hydroxyl group of compound 10 was protected with Ad and removed the ester group subsequently to yield 3-{ [(adamantan-1-yl） oxy](4-bromophenyl）phosphoryl}-2-{ [3-(3’-chloro-[1,1’-biphenyl]-4-yl） isoxazol-5-yl] methyl } propanoic acid(12）; RXP470. 1(14） was finally synthesized through solid phase peptide synthesis strategy. Results： RXP470. 1(14） was successfully synthesized. Conclusion： The synthetic method is feasible and suitable for industrialization.