Carbamic acid, ((1S,2R)-3-((3S,4aS,8aS)-3-(((1,1-dimethylethyl)amino)carbonyl)octahydro-2(1H)-isoquinolinyl)-2-hydroxy-1-(phenylmethyl)propyl)-, 1,1-dimethylethyl ester | 142580-65-2

• 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: Carbamic acid, ((1S,2R)-3-((3S,4aS,8aS)-3-(((1,1-dimethylethyl)amino)carbonyl)octahydro-2(1H)-isoquinolinyl)-2-hydroxy-1-(phenylmethyl)propyl)-, 1,1-dimethylethyl ester
• 英文别名: tert-butyl 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: 142580-65-2
• 化学式: C₂₉H₄₇N₃O₄
• 分子量: 501.71
• InChiKey: LYMBPRXTWAXSBF-VMAPGKTHSA-N

物化性质

• 熔点：
  >71oC (dec.)
• 沸点：
  680.5±55.0 °C(Predicted)
• 密度：
  1.082±0.06 g/cm3(Predicted)
• 溶解度：
  可溶于氯仿（少许）、甲醇（少许）

计算性质

• 辛醇/水分配系数(LogP)：
  5.1
• 重原子数：
  36
• 可旋转键数：
  10
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.72
• 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：

  Carbamic acid, ((1S,2R)-3-((3S,4aS,8aS)-3-(((1,1-dimethylethyl)amino)carbonyl)octahydro-2(1H)-isoquinolinyl)-2-hydroxy-1-(phenylmethyl)propyl)-, 1,1-dimethylethyl ester 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 、 三氟乙酸 作用下， 以 四氢呋喃 、 乙醇 为溶剂， 反应 97.0h， 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：

  (2S,3S)-3-N-tert-butoxycarbonylamino-4-phenylbutane-1,2-diol 在 1-(chlorocarbonyl)-1-methylene acetate 、 sodium methylate 作用下， 以 异丙醇 为溶剂， 反应 9.0h， 生成 Carbamic acid, ((1S,2R)-3-((3S,4aS,8aS)-3-(((1,1-dimethylethyl)amino)carbonyl)octahydro-2(1H)-isoquinolinyl)-2-hydroxy-1-(phenylmethyl)propyl)-, 1,1-dimethylethyl ester
  参考文献：
  名称：

  羟乙胺等排体的不对称羟醛路线：沙奎那韦核心单元的立体选择性合成。

  摘要：

  DOI：

  10.1021/jo9706943

文献信息

• A series of potent HIV-1 protease inhibitors containing a hydroxyethyl secondary amine transition state isostere: synthesis, enzyme inhibition, and antiviral activity
  作者：Thomas J. Tucker、William C. Lumma、Linda S. Payne、Jenny M. Wai、S. Jane De Solms、Elizabeth A. Giuliani、Paul L. Darke、Jill C. Heimbach、Joan A. Zugay

  DOI：10.1021/jm00092a002

  日期：1992.7

  A series of HIV-1 protease inhibitors containing a novel hydroxyethyl secondary amine transition state isostere has been synthesized. The compounds exhibit a strong preference for the (R) stereochemistry at the transition state hydroxyl group. Molecular modeling studies with the prototype compound 11 have provided important insights into the structural requirements for good inhibitor-active site binding

  已经合成了一系列含有新型羟乙基仲胺过渡态等排体的HIV-1蛋白酶抑制剂。化合物在过渡态羟基上强烈偏爱（R）立体化学。原型化合物11的分子模型研究为良好的抑制剂-活性位点结合相互作用的结构要求提供了重要见识。N端11延伸到P2-P3区导致发现19，这是该系列中最有效的酶抑制剂（IC50 = 5.4 nM）。已显示19在培养的MT-4人T淋巴细胞中具有有效的抗病毒活性。
• Crystal Structures of Two (3S,4aS, 8aS)-N-(1,1-dimethyl)decahydro-2-[(2R,3S)-2-hydroxy-arylsulfonyl]amino]-4-phenylbutyl]-3-isoquinolinecarboxamide. Hemihydrates: Compounds with Moderate Activity as Aspartyl Protease Inhibitors
  作者：Wilson Cunico、Maria de Lourdes G. Ferreira、James L. Wardell、Solange M. S. V. Wardell

  DOI：10.1007/s10870-016-0673-8

  日期：2016.12

  The crystal structures of two hemihydrates of (3S,4aS, 8aS)-N-(1,1-dimethyl)decahydro-2-[(2R,3S)-2-hydroxy-3-[[arylsulfonyl]amino]-4-phenylbutyl]-3-isoquinolinecarboxamides [aryl = 4-nitrophenyl: [(1:X = 4-O 2 N) 2 ·H 2 O]; and aryl = 4-bromophenyl: [(1:X = 4-Br) 2 ·H 2 O] are reported. The chiral anhydrous compounds, prepared from (2S,3S)-Boc-phenylalanine epoxide, have been reported to exhibit moderate antimalarial activity in vitro against Plasmodium falciparum. The molecular conformations and major intermolecular interactions of the two hydrates are similar, despite there being two independent, albeit similar, molecules in [(1:X = Br) 2 ·H 2 O] compared to only one in [(1:X = 4-O 2 N) 2 ·H 2 O]. A common feature of both structures is that each water molecule is linked to four molecules of 1 via classical hydrogen bonds to form [[(1:X)4(H2O)] units, (X = 4-O2N or 4-Br). As a consequence of the water molecules in [(1:X = 4-O 2 N) 2 ·H 2 O] being in special positions and the slight differences between molecules, A and B, in [(1:X = 4-Br) 2 ·H 2 O], the former has as a symmetrical struture. Emanating from each water molecule in both structures are four chains of alternating molecules of water and 1: these are linked into three dimensional arrays. Compound [(1:X = 4-O 2 N) 2 H 2 O] crystallizes in the monoclinic space group C2 with a = 21.1431(9), b = 10.4886(6), c = 15.4597(9) Å, b = 111.145(3)°and Z = 4. Compound [(1:X = 4-O 2 N) 2 H 2 O] crystallizes in the monoclinic space group P21 with a = 11.0860(9), b = 28.559(2), c = 11.5220(10) Å, b = 117.585(3)° and Z = 4. A feature of both structures is that each water molecule is linked to four molecules of the sulfonamide via classical hydrogen bonds.

  (3S,4aS,8aS)-N-(1,1-二甲基)十氢-2-[(2R,3S)-2-羟基-3-[[芳基磺酰基]氨基]-4-苯基丁基]-3-异喹啉甲酰胺[芳基 = 4-硝基苯基：报告了[(1:X = 4-O 2 N) 2 -H 2 O]；以及芳基 = 4-溴苯基：[(1:X = 4-Br) 2 -H 2 O]。据报道，由(2S,3S)-Boc-苯丙氨酸环氧化物制备的手性无水化合物在体外对恶性疟原虫表现出中等抗疟活性。尽管[(1:X = Br) 2 -H 2 O]中有两个独立但相似的分子，而[(1:X = 4-O 2 N) 2 -H 2 O]中只有一个独立的分子，但这两种水合物的分子构象和主要的分子间相互作用是相似的。这两种结构的一个共同特点是，每个水分子都通过经典氢键与四个 1 分子相连，形成[[(1:X)4(H2O)]单元（X = 4-O2N 或 4-Br）。由于[(1:X = 4-O 2 N) 2 -H 2 O]中水分子的位置特殊，以及[(1:X = 4-Br) 2 -H 2 O]中分子 A 和分子 B 之间的细微差别，前者具有对称的结构。在这两种结构中，从每个水分子发出的是由水分子和 1 分子交替组成的四条链：这些链连接成三维阵列。化合物[(1:X = 4-O 2 N) 2 H 2 O]在单斜空间群 C2 中结晶，a = 21.1431(9)，b = 10.4886(6)，c = 15.化合物[(1:X = 4-O 2 N) 2 H 2 O]在单斜空间群 P21 中结晶，a = 11.0860(9)，b = 111.145(3)°，Z = 4。这两种结构的一个特点是每个水分子都通过经典氢键与四个磺酰胺分子相连。
• 2‘,6‘-Dimethylphenoxyacetyl:  A New Achiral High Affinity P₃-P₂ Ligand for Peptidomimetic-Based HIV Protease Inhibitors
  作者：Pierre L. Beaulieu、Paul C. Anderson、Dale R. Cameron、Gilbert Croteau、Vida Gorys、Chantal Grand-Maître、Daniel Lamarre、Francine Liard、William Paris、Louis Plamondon、François Soucy、Diane Thibeault、Dominik Wernic、Christiane Yoakim、Susan Pav、Liang Tong

  DOI：10.1021/jm990336n

  日期：2000.3.1

  Starting from palinavir (1), our lead HIV protease inhibitor, we have discovered a new series of truncated analogues in which the P-3-P-2 quinaldic-valine portion of 1 was replaced by 2',6'-dimethylphenoxyacetyl. With EC50's in the 1-2 nM range, some of these compounds are among the most potent inhibitors of HIV replication in vitro, reported to date. One of the most promising members in this series (compound 27, BILA 2185 BS) exhibited a favorable overall pharmacokinetic profile, with 61% apparent oral bioavailability in rat. X-ray crystal structures and molecular modeling were used to rationalize the high potency resulting from incorporation of this structurally simple, achiral ligand into the P-3-P-2 position of hydroxyethylamine-based HIV protease inhibitors.
• Development of a New Type of Protease Inhibitors, Efficacious against FIV and HIV Variants
  作者：Taekyu Lee、Van-Duc Le、Dongyeol Lim、Ying-Chuan Lin、Garrett M. Morris、Andrew L. Wong、Arthur J. Olson、John H. Elder、Chi-Huey Wong

  DOI：10.1021/ja982893p

  日期：1999.2.1

  Based on the structural analysis of FIV protease and drug-resistant HIV proteases and molecular modeling, a new type of inhibitors with a small P3 residue has been developed. These inhibitors are effective against HIV and its drug-resistant mutants, as well as SIV and FIV. Modification of existing HIV protease inhibitors by reducing the size of the P3 residue has the same effect. This finding provides a new strategy for the development of HIV protease inhibitors effective against the wild-type and drug-resistant mutants. It further supports the use of FIV protease as a useful model for drug-resistant HIV proteases, which often have a more constricted binding region for the P3 group or the combined P3 and P1 groups.
• Asymmetric Aldol Route to Hydroxyethylamine Isostere:  Stereoselective Synthesis of the Core Unit of Saquinavir
  作者：Arun K. Ghosh、Khaja Azhar Hussain、Steve Fidanze

  DOI：10.1021/jo9706943

  日期：1997.8.1