Studies toward the Large-Scale Synthesis of the HIV Proteinase Inhibitor Ro 31-8959
Studies toward the Large-Scale Synthesis of the HIV Proteinase Inhibitor Ro 31-8959
复制标题
HIV 蛋白酶抑制剂 Ro 31-8959 大规模合成的研究
DOI：
10.1021/jo00092a026
复制
发表时间：
1994
影响因子：
3.6
通讯作者：
Joseph A. Martin
中科院分区：
文献类型：
--
作者：
K. Parkes;D. Bushnell;P. Crackett;S. J. Dunsdon;A. Freeman;M. P. Gunn;R. A. Hopkins;R. Lambert;Joseph A. Martin
Ro 31-8959（1）是一种有效的选择性HIV蛋白酶抑制剂，目前正在进行III期临床试验。研究了六种大规模合成该化合物的方法。所有路线均采用与亲电L-苯丙氨酸同系物等价物13和十氢异喹啉衍生物5的初始断开。它们的不同之处在于采用环氧化物、环状硫酸酯或醛作为亲电实体，并从L-苯丙氨酸、D-酒石酸二甲酯或Sharpless环氧化反应中产生手性。优选的路线从N-邻苯二甲酰-L-苯丙氨酰氯开始，并使用三（（三甲基甲硅烷基）氧基）乙烯实现同系化成羟基酮30，其在五步两锅法中详细描述成N-邻苯二甲酰环氧化物33，并因此得到1。使用该路线制备了千克量的Ro 31-8959
Ro 31-8959 (1), a potent and selective inhibitor of HIV proteinase, is currently in phase III clinical trials. Six approaches for the large-scale synthesis of this compound have been studied. All routes employ an initial disconnection to an electrophilic L-phenylalanine homologue equivalent 13 and the decahydroisoquinoline derivative 5. They differ in adopting either an epoxide, a cyclic sulfate, or an aldehyde as the electrophilic entity and develop chirality from L-phenylalanine, dimethyl D-tartrate, or a Sharpless epoxidation. The preferred route starts from N-phthaloyl-L-phenylalaninyl chloride and uses tris((trimethylsilyl)oxy)ethene to effect homologation to hydroxy ketone 30, which is elaborated in a five-step two-pot procedure to N-phthaloyl epoxide 33 and hence 1. Kilogram quantities of Ro 31-8959 have been prepared using this route