N-((2R,3S)-3-amino-2-hydroxy-4-phenylbutyl)-N-isobutyl-4-nitrobenzenesulfonamide | 251105-80-3

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: N-((2R,3S)-3-amino-2-hydroxy-4-phenylbutyl)-N-isobutyl-4-nitrobenzenesulfonamide
• 英文别名: Benzenesulfonamide,N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N-(2-methylpropyl)-4-nitro-；N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N-(2-methylpropyl)-4-nitrobenzenesulfonamide
• CAS: 251105-80-3
• 化学式: C₂₀H₂₇N₃O₅S
• 分子量: 421.517
• InChiKey: BPRSPRGTVGSTKD-VQTJNVASSA-N

物化性质

• 溶解度：
  溶于DMSO、甲醇

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  29
• 可旋转键数：
  9
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  138
• 氢给体数：
  2
• 氢受体数：
  7

制备方法与用途

用途

本品适用于有机合成。

反应信息

• 作为反应物：
  描述：

  N-((2R,3S)-3-amino-2-hydroxy-4-phenylbutyl)-N-isobutyl-4-nitrobenzenesulfonamide 在 盐酸 、 铁粉 作用下， 以86.7 %的产率得到4-氨基-N-[(2R, 3S)-3-氨基-2-羟基-4-苯丁基]-N-异丁基苯磺酰胺
  参考文献：
  名称：

  含有 2-苯基乙酰胺衍生物作为 P2 配体的新型 HIV-1 蛋白酶抑制剂的合理设计、合成和生物学评价，对 DRV 耐药 HIV-1 变种具有有效活性

  摘要：

   [显示省略]

  DOI：

  10.1016/j.bmcl.2024.129651
• 作为产物：
  描述：

  [(1S,2R)-1-苄基-1-苄氧羰基氨基-2-羟基-4-N-异丁基氨基丙烷 在 三甲基溴硅烷 、 三氟乙酸 茴香硫醚 、 1,2-乙二硫醇 、 间甲酚 、 三乙胺 作用下， 以 氯仿 为溶剂， 反应 48.0h， 生成 N-((2R,3S)-3-amino-2-hydroxy-4-phenylbutyl)-N-isobutyl-4-nitrobenzenesulfonamide
  参考文献：
  名称：

  Reduction of Peptide Character of HIV Protease Inhibitors That Exhibit Nanomolar Potency against Multidrug Resistant HIV-1 Strains

  摘要：

  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).

  DOI：

  10.1021/jm020537i

文献信息

• PROCESS FOR SYNTHESIS OF SYN AZIDO EPOXIDE AND ITS USE AS INTERMEDIATE FOR THE SYNTHESIS OF AMPRENAVIR & SAQUINAVIR
  申请人：Council of Scientific & Industrial Research

  公开号：US20150011782A1

  公开（公告）日：2015-01-08

  Disclosed herein is a novel route of synthesis of syn azide epoxide of formula 5, which is used as a common intermediate for asymmetric synthesis of HIV protease inhibitors such as Amprenavir, Fosamprenavir, Saquinavir and formal synthesis of Darunavir and Palinavir obtained by Cobalt-catalyzed hydrolytic kinetic resolution of racemic anti-(2SR,3SR)-3-azido-4-phenyl-1,2-epoxybutane (azido-epoxide).

  本文披露了一种合成公式5的syn叠氮环氧化物的新路线，该化合物被用作HIV蛋白酶抑制剂的不对称合成的常见中间体，如Amprenavir、Fosamprenavir、Saquinavir以及通过钴催化的拆分手性反式-(2SR,3SR)-3-叠氮-4-苯基-1,2-环氧丁烷(叠氮环氧化物)合成Darunavir和Palinavir。
• [EN] NOVEL CARBOXAMIDE DERIVATIVES AS HIV INHIBITORS<br/>[FR] NOUVEAUX DÉRIVÉS CARBOXAMIDES COMME INHIBITEURS DU VIH
  申请人：HETERO RESEARCH FOUNDATION

  公开号：WO2011061590A1

  公开（公告）日：2011-05-26

  The present invention relates to carboxamide derivatives of Formula (I), where B1, B2, X, L, n, R, R1, R2, Z1, Z2, Rx and Ry are as defined in the claims, as compounds and compositions for inhibiting Human Immunodeficiency Virus (HIV) and process for making the compounds.

  本发明涉及公式（I）的羧酰胺衍生物，其中B1、B2、X、L、n、R、R1、R2、Z1、Z2、Rx和Ry如权利要求中所定义的那样，作为抑制人类免疫缺陷病毒（HIV）的化合物和组合物，以及制备这些化合物的方法。
• Design and synthesis of potent HIV-1 protease inhibitors incorporating hydroxyprolinamides as novel P2 ligands
  作者：Bing-Lei Gao、Cheng-Mei Zhang、Yi-Zhen Yin、Long-Qian Tang、Zhao-Peng Liu

  DOI：10.1016/j.bmcl.2011.04.070

  日期：2011.6

  of new HIV-1 protease inhibitors with the hydroxyethylamine core and different hydroxyprolinamide P2 ligands were designed and synthesized. Variation of substitutions at the P2 significantly affected the enzyme inhibitory potency of the inhibitors. Compounds 2a and 2d showed excellent enzyme inhibitory activity with IC50 values in the nanomolar range. An active site binding model for inhibitors 2a and

  设计并合成了一系列具有羟乙胺核心和不同羟脯氨酰胺P2配体的新型HIV-1蛋白酶抑制剂。P2处的取代变化显着影响了抑制剂的酶抑制能力。化合物2a和2d表现出优异的酶抑制活性，IC 50值在纳摩尔范围内。根据配体与HIV-1蛋白酶的计算对接结果，提出了抑制剂2a和2d的活性位点结合模型。该模型提供了有关羟基脯氨酰胺衍生的新型P2-配体的配体结合位点相互作用的分子见解。
• PROCESS FOR PREPARATION OF SUBSTANTIALLY PURE FOSAMPRENAVIR CALCIUM AND ITS INTERMEDIATES
  申请人：Arora Surinder Kumar

  公开号：US20130174651A1

  公开（公告）日：2013-07-11

  The present invention relates to fosamprenavir calcium (Ia) substantially free of isomer impurity, (3R) tetrahydro -3 -furanyl(1S,2R)-3-[[(4-aminophenyl)sulfonyl](isobutyl)amino]-1-benzyl-2-(phosphonooxy)propyl carbamate (Ib), and its process for preparation thereof. The present invention also provides fosamprenavir calcium intermediate, (S)-3-tetrahydrofuranyl-N-succinimidyl carbonate (IIa) substantially free of (R)-3-tetrahydrofuranylsuccinimidyl carbonate (IIb) and its process for preparation thereof.

  本发明涉及基本上不含异构杂质的福扎韦钙（Ia），(3R)四氢呋喃基(1S,2R)-3-[[（4-氨基苯基）磺酰](异丁基)氨基]-1-苄基-2-(磷酸酯基)丙烯基氨基甲酸酯（Ib），以及其制备方法。本发明还提供福扎韦钙中间体，(S)-3-四氢呋喃基-N-琥珀酰亚胺基碳酸酯（IIa），基本上不含(R)-3-四氢呋喃基琥珀酰亚胺基碳酸酯（IIb），以及其制备方法。
• Preclinical Pharmacology and Pharmacokinetics of GW433908, a Water-Soluble Prodrug of the Human Immunodeficiency Virus Protease Inhibitor Amprenavir
  作者：Eric S. Furfine、Christopher T. Baker、Michael R. Hale、David J. Reynolds、Jo A. Salisbury、Andy D. Searle、Scott D. Studenberg、Dan Todd、Roger D. Tung、Andrew Spaltenstein

  DOI：10.1128/aac.48.3.791-798.2004

  日期：2004.3

  GW433908 is the water-soluble, phosphate ester prodrug of the human immunodeficiency virus type 1 protease inhibitor amprenavir (APV). A high-yield synthesis of GW433908 is achieved by phosphorylation of the penultimate precursor of APV with phosphorous oxychloride (POCl ₃ ) in pyridine. A single-dose pharmacokinetic study of GW433908 sodium salt in dogs showed that APV exposure was similar to that achieved with an equivalent molar dose of the APV clinical formulation (Agenerase) and that systemic exposure to the prodrug was minimal (0.3% of the APV exposure). However, the sodium salt of GW433908 was a hygroscopic, amorphous solid and thus not suitable for pharmaceutical development. The calcium salt was a developable crystalline solid, but oral dosing afforded only 24% of the APV exposure in dogs compared with Agenerase. Acidification of the dog stomach by coadministration of HCl increased the bioavailability of the calcium salt to levels near those of the sodium salt. Single-dose administration of GW433908 calcium salt in dogs and rats produced portal vein GW433908 concentrations that were maximally 1.72 and 0.79% of those of APV concentrations, respectively. Furthermore, GW433908 had poor transepithelial flux and APV showed significant flux across human-derived Caco-2 cell monolayers (a model of intestinal permeability). Taken together, these results suggest that GW433908 is primarily metabolized to APV at or in the epithelial cells of the intestine and that the prodrug is not substantially absorbed. Based in part on these findings, GW433908 was advanced to clinical development.

  摘要 GW433908 是人类免疫缺陷病毒 1 型蛋白酶抑制剂安非那韦（APV）的水溶性磷酸酯原药。GW433908 的高产合成是通过用氧氯化磷（POCl 3 ) 在吡啶中进行磷酸化，从而高产合成了 APV。对狗进行的 GW433908 钠盐单剂量药代动力学研究表明，APV 的暴露量与同等摩尔剂量的 APV 临床制剂（Agenerase）的暴露量相似，而且该原药的全身暴露量极小（为 APV 暴露量的 0.3%）。不过，GW433908 的钠盐是一种吸湿性无定形固体，因此不适合用于药物开发。钙盐是一种可开发的结晶固体，但与 Agenerase 相比，口服药物在狗体内只能产生 24% 的 APV 暴露量。通过同时给药盐酸来酸化狗胃，可将钙盐的生物利用度提高到接近钠盐的水平。狗和大鼠单剂量服用 GW433908 钙盐后，门静脉 GW433908 浓度最高分别为 APV 浓度的 1.72% 和 0.79%。此外，GW433908 的跨上皮通透性较差，而 APV 在人源 Caco-2 细胞单层（肠道通透性模型）上显示出显著的通透性。综上所述，这些结果表明，GW433908 主要在肠道上皮细胞内或在肠道上皮细胞内代谢为 APV，原药不会被大量吸收。部分基于这些研究结果，GW433908 被推进到临床开发阶段。