替拉瑞韦的合成工艺改进

摘要

Telaprevir(1) was prepared by(2S)-2-cyclohexyl-N-(2-pyrazinylcarbonyl) glycyl-3-methyl-L-Valine(2) through one-pot condensation with(1S,3aR,6aS)-octahydro cyclopenta[c]pyrrole-1-carboxylic acid ethyl ester hydrochloride(3),hydrolysis with NaOH,another one-pot condensation with(3S)-3-amino-N-cyclopropyl-2-hydroxy-Hexanamide hydrochloride(4),Dess-Martin oxi-dation with overall yield of64%and the HPLC purity of 99. 9%.%(2S)-2-环己基-N-(2-吡嗪基羰基)甘氨酰-3-甲基-L-缬氨酸(2)与(1S,3aR,6aS)-八氢环戊烯并[ c]吡咯-1-羧酸乙酯盐酸盐(3)缩合得到(1S,3aR,6aS)-2-((2S)-2-(((2S)-2-环己基-2-(吡嗪羰基)氨基)乙酰基)氨基)-3,3-二甲基-1-氧代丁基)-八氢环戊二烯并[c]吡咯-1-羧酸乙酯(5),5水解得到(1S,3aR,6aS)-2-((2S)-2-(((2S)-2-环己基-2-(吡嗪羰基)氨基)乙酰基)氨基)-3,3-二甲基-1-氧代丁基)-八氢环戊二烯并[c]吡咯-1-羧酸(6),此中间体再与(3S)-3-氨基-N-环丙基-2-羟基己酰胺盐酸盐(4)经过酰胺化、戴斯-马丁氧化得到替拉瑞韦(1),反应总收率为64%,HPLC色谱纯度99．9%。