2-<3(S)-(Benzyloxyformamido)-2(R)-hydroxy-4-phenylbutyl>-N-tert-butyldecahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide | 137431-05-1

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: 2-<3(S)-(Benzyloxyformamido)-2(R)-hydroxy-4-phenylbutyl>-N-tert-butyldecahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide
• 英文别名: 2-[2(R)-hydroxy-4-phenyl-3(S)-[[N-(phenylmethoxy)carbonyl]amino]butyl]-N-tert-butyldecahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide；[(1S,2R)-1-Benzyl-3-((3S,4aS,8aS)-3-tert-butylcarbamoyl-octahydro-isoquinolin-2-yl)-2-hydroxy-propyl]-carbamic acid benzyl ester；benzyl N-[(2S,3R)-4-[(3S,4aS,8aS)-3-(tert-butylcarbamoyl)-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-3-hydroxy-1-phenylbutan-2-yl]carbamate
• CAS: 137431-05-1
• 化学式: C₃₂H₄₅N₃O₄
• 分子量: 535.727
• InChiKey: ZJCRACQKNWUFFC-UCWKTGAJSA-N

物化性质

• 沸点：
  735.5±60.0 °C(Predicted)
• 密度：
  1.128±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  5.6
• 重原子数：
  39
• 可旋转键数：
  11
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.56
• 拓扑面积：
  90.9
• 氢给体数：
  3
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  2-<3(S)-(Benzyloxyformamido)-2(R)-hydroxy-4-phenylbutyl>-N-tert-butyldecahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide 在 palladium on activated charcoal N-乙基吗啉 、 氢气 、 1-羟基苯并三唑一水物 、 N,N'-二环己基碳二亚胺 作用下， 以 四氢呋喃 、 乙醇 为溶剂， 反应 120.0h， 生成 沙喹那韦
  参考文献：
  名称：

  Studies toward the Large-Scale Synthesis of the HIV Proteinase Inhibitor Ro 31-8959

  摘要：

  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.

  DOI：

  10.1021/jo00092a026
• 作为产物：
  描述：

  4(S)-Benzyl-3-(benzyloxycarbonyl)-2,2-dimethyl-5(R)-oxazolidineacetic acid 在 盐酸 、 4-二甲氨基吡啶 、 氢氧化钾 、 草酰氯 、 三氯溴甲烷 、 2-mercaptopyridine-1-oxide sodium salt 、 溶剂黄146 、 N,N-二甲基甲酰胺 作用下， 以 甲醇 、 异丙醇 、 甲苯 为溶剂， 反应 14.0h， 生成 2-<3(S)-(Benzyloxyformamido)-2(R)-hydroxy-4-phenylbutyl>-N-tert-butyldecahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide
  参考文献：
  名称：

  Studies toward the Large-Scale Synthesis of the HIV Proteinase Inhibitor Ro 31-8959

  摘要：

  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.

  DOI：

  10.1021/jo00092a026

文献信息

• Amino acid derivatives
  申请人：Hoffmann-La Roche Inc.

  公开号：US05196438A1

  公开（公告）日：1993-03-23

  Compounds having the formula ##STR1## wherein R is benzyloxycarbonyl or 2-quinolylcarbonyl, and their pharmaceutically acceptable acid addition salts inhibit proteases of viral origin and can be used as medicaments for the treatment of prophylaxis of viral infections in mammals, humans or non-humans.

  具有以下分子式##STR1##的化合物，其中R为苄氧羰基或2-喹啉基羰基，及其药用酸盐可以抑制病毒来源的蛋白酶，并可用作哺乳动物、人类或非人类的预防或治疗病毒感染的药物。
• Retroviral protease inhibitors
  申请人：Tally J. John

  公开号：US20080103311A1

  公开（公告）日：2008-05-01

  N-heterocyclic moiety containing hydroxyethylamino compounds are effective as retroviral protease inhibitors, and in particular as inhibitors of HIV protease.

  含有羟乙基氨基的N-杂环基团化合物可作为反转录病毒蛋白酶抑制剂，特别是作为HIV蛋白酶的抑制剂。
• Cyclic sulfone containing retroviral protease inhibitors
  申请人：Bertenshaw E. Deborah

  公开号：US20070015818A1

  公开（公告）日：2007-01-18

  The present invention relates to cyclic sulfone moiety-containing hydroxyethylamine protease inhibitor compounds and pharmaceutical or method of use therefor, particularly as an inhibitor of HIV protease.

  本发明涉及含有环磺酮基团的羟乙基胺蛋白酶抑制剂化合物及其制药或使用方法，特别是作为HIV蛋白酶抑制剂。
• Inhibitors of HIV protease useful for the treatment of aids
  申请人：ELI LILLY AND COMPANY

  公开号：EP0604185A1

  公开（公告）日：1994-06-29

  The present invention provides novel HIV protease inhibitors of formula I, pharmaceutical formulations containing those compounds and methods of treating and/or preventing HIV infection and/or AIDS. wherein: R is a group having the formula: R² is an amino acid side chain or -(CH₂)y-X-R2a; y is 0, 1 or 2; and X, R⁰, R³ and Y¹ are as defined in the application.

  本发明提供了式 I 的新型 HIV 蛋白酶抑制剂、含有这些化合物的药物制剂以及治疗和/或预防 HIV 感染和/或艾滋病的方法。 其中 R 是具有式的基团： R² 是氨基酸侧链或-(CH₂)y-X-R2a； y 是 0、1 或 2； X、R⁰、R³ 和 Y¹ 如本申请中所定义。
• Reduction of Peptide Character of HIV Protease Inhibitors That Exhibit Nanomolar Potency against Multidrug Resistant HIV-1 Strains
  作者：Hirokazu Tamamura、Yasuhiro Koh、Satoshi Ueda、Yoshikazu Sasaki、Tomonori Yamasaki、Manabu Aoki、Kenji Maeda、Yoriko Watai、Hisashi Arikuni、Akira Otaka、Hiroaki Mitsuya、Nobutaka Fujii

  DOI：10.1021/jm020537i

  日期：2003.4.1

  Novel HIV protease inhibitors containing a hydroxyethylamine dipeptide isostere as a transition state-mimic king structure were synthesized by combining substructures of known HIV protease inhibitors. Among them, TYA5 and TYB5 were proven to be not only potent enzyme inhibitors (K-i = 0.12 nM and 0.10 nM, respectively) but also strong anti-HIV agents (IC50 = 9.5 nM and 66 nM, respectively), even against viral strains with multidrug resistance. Furthermore, insertion of an (E)-alkene dipeptide isostere at the P-1-P-2 position of TYB5 led to development of a purely nonpeptidic protease inhibitor, TYB1 (K-i = 0.38 nM, IC50 = 160 nM).