2-<3(S)-<amino>-2(R)-hydroxy-4-phenylbutyl>-N-tert-butyldecahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide | 136522-18-4

• 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)-<amino>-2(R)-hydroxy-4-phenylbutyl>-N-tert-butyldecahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide
• 英文别名: Z-Asn-Phe-psi (CH(OH)CH2N)DIQ-NH-tBu；benzyl N-[(2S)-1-[[(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]amino]-4-amino-1,4-dioxobutan-2-yl]carbamate
• CAS: 136522-18-4
• 化学式: C₃₆H₅₁N₅O₆
• 分子量: 649.831
• InChiKey: KWJAFFUEDWUZAR-WOVUZPOESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.9
• 重原子数：
  47
• 可旋转键数：
  15
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.56
• 拓扑面积：
  163
• 氢给体数：
  5
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  2-<3(S)-<amino>-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 32.0h， 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：

  N-叔丁基-十氢异喹啉-3(S)-甲酰胺 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， 25.0 ℃ 、344.73 kPa 条件下， 反应 93.0h， 生成 2-<3(S)-<amino>-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.

  具有公式## STR1##的化合物，其中R为苄氧羰基或2-喹啉基羰基，以及它们的药学上可接受的酸盐加合物，可以抑制病毒来源的蛋白酶，并可用作治疗哺乳动物、人类或非人类病毒感染的药物。
• Oxirane intermediates for novel alcohols
  申请人：Hoffmann-La Roche Inc.

  公开号：US05508430A1

  公开（公告）日：1996-04-16

  Novel alcohols of the formula ##STR1## wherein R.sup.a is azido or phthalimido, R.sup.4 is alkyl, cycloalkyl, cycloalkylalkyl, aryl or aralkyl, R.sup.7 and R.sup.8 together are a trimethylene or tetramethylene group which is optionally substituted by hydroxy, alkoxycarbonylamino or acylamino or in which one --CH.sub.2 -- group is replaced by --NH--, --N(alkoxycarbonyl)--, --N(acyl)-- or --S-- or which carries a fused cycloalkane, aromatic or heteroaromatic ring, and R.sup.9 is alkoxycarbonyl, monoalkylcarbamoyl, monoaralkylcarbamoyl, monoarylcarbamoyl or a group of the formula ##STR2## in which R.sup.10 and R.sup.11 each is alkyl, are described along with a process for their manufacture. These alcohols are useful as intermediates, for example in the manufacture of amino acid derivatives having antiviral activity.

  本发明涉及一种新型醇，其化学式为##STR1##其中R.sup.a为偶氮基或邻苯二甲酰亚胺基，R.sup.4为烷基、环烷基、环烷基烷基、芳基或芳基烷基，R.sup.7和R.sup.8共同为三亚甲基或四亚甲基基团，该基团可以被羟基、烷氧羰基氨基或酰胺基取代，或其中一个--CH.sub.2--基团被--NH--、--N(烷氧羰基)--、--N(酰基)--或--S--取代，或者带有融合的环烷基、芳香基或杂芳基环，R.sup.9为烷氧羰基、单烷基氨基甲酰基、单芳基氨基甲酰基、单芳基甲酰基或式中R.sup.10和R.sup.11各自为烷基的基团。同时，本发明还涉及一种制备这些醇的方法。这些醇可用作中间体，例如在制备具有抗病毒活性的氨基酸衍生物时。
• Alcohols
  申请人：Hoffmann-La Roche Inc.

  公开号：US05488115A1

  公开（公告）日：1996-01-30

  Novel alcohols of the formula ##STR1## wherein R.sup.a is azido or phthalimido, R.sup.4 is alkyl, cycloalkyl, cycloalkylalkyl, aryl or aralkyl, R.sup.7 and R.sup.8 together are a trimethylene or tetramethylene group which is optionally substituted by hydroxy, alkoxycarbonylamino or acylamino or in which one --CH.sub.2 -- group is replaced by --NH--, --N(alkoxycarbonyl)--, --N(acyl)-- or --S-- or which carries a fused cycloalkane, aromatic or heteroaromatic ring, and R.sup.9 is alkoxycarbonyl, monoalkylcarbamoyl, monoaralkylcarbamoyl, monoarylcarbamoyl or a group of the formula ##STR2## in which R.sup.10 and R.sup.11 each is alkyl, are described along with a process for their manufacture. These alcohols are useful as intermediates, for example in the manufacture of amino acid derivatives having antiviral activity.

  化合物的新型醇的公式为##STR1##其中R.sup.a是偶氮基或邻苯二甲酰亚胺基，R.sup.4是烷基，环烷基，环烷基烷基，芳基或芳基烷基，R.sup.7和R.sup.8组合起来是三亚甲基或四亚甲基基团，可以被羟基，烷氧羰基氨基或酰氨基取代，或其中一个--CH.sub.2--基团被--NH--，--N(烷氧羰基)--，--N(酰基)--或--S--取代或携带融合的环烷烃，芳香族或杂芳香族环，而R.sup.9是烷氧羰基，单烷基氨基甲酰基，单芳基氨基甲酰基，单芳基甲酰基或公式的基团##STR2##其中R.sup.10和R.sup.11各自是烷基，被描述，以及它们的制造过程。这些醇在中间体中很有用，例如在制造具有抗病毒活性的氨基酸衍生物时。
• Goehring, Wolfgang; Gokhale, Surendra; Hilpert, Hans, Chimia, 1996, vol. 50, # 11, p. 532 - 537
  作者：Goehring, Wolfgang、Gokhale, Surendra、Hilpert, Hans、Roessler, Felix、Schlageter, Markus、Vogt, Peter

  DOI：——

  日期：——
• The synthesis of labelled forms of saquinavir
  作者：H. R. Wiltshire、K. J. Prior、J. Dhesi、F. Trach、M. Schlageter、H. Schönenberger

  DOI：10.1002/(sici)1099-1344(199812)41:12<1103::aid-jlcr157>3.0.co;2-m

  日期：1998.12

  The development of the HIV-protease inhibitor, saquinavir (Ro 31-8959), required a range of analytical methods for the measurement of the parent drug and drug-related material in biological fluids. This paper describes the synthesis of 14-carbon and tritium labelled compounds used for in vivo and in vitro investigations of the absorption and disposition of saquinavir in animals and man. It also discusses the preparation of saquinavir labelled with deuterium and stable isotopes of carbon and nitrogen. These forms of the drug were needed for bioequivalence studies in which HPLC/MS/MS was employed for the measurement of plasma concentrations. Finally, the synthesis of a 125-iodine labelled tracer used in a radioimmunoassay for saquinavir is described.