六氢呋喃并[2,3-b]呋喃-3-醇 | 162020-29-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 呋喃类
• 中文名称: 六氢呋喃并[2,3-b]呋喃-3-醇
• 中文别名: 六氢呋喃并[2,3-B]呋喃-3-醇
• 英文名称: (3S,3aR,6aS)-Hexahydrofuro[2,3-b]furan-3-yl Acetate
• 英文别名: [(3aR,4S,6aS)-2,3,3a,4,5,6a-hexahydrofuro[2,3-b]furan-4-yl] acetate
• CAS: 162020-29-3
• 化学式: C₈H₁₂O₄
• 分子量: 172.181
• InChiKey: RCXLRBOCGWECNI-PRJMDXOYSA-N

物化性质

• 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)：
  0.2
• 重原子数：
  12
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.88
• 拓扑面积：
  44.8
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  六氢呋喃并[2,3-b]呋喃-3-醇 在 potassium carbonate 、 三乙胺 作用下， 以 乙醇 、 二氯甲烷 为溶剂， 生成 darunavir
  参考文献：
  名称：

  Discovery and Selection of TMC114, a Next Generation HIV-1 Protease Inhibitor

  摘要：

  The screening of known HIV-1 protease inhibitors against a panel of multi-drug-resistant viruses revealed the potent activity of TMC126 on drug-resistant mutants. In comparison to amprenavir, the improved affinity of TMC126 is largely the result of one extra hydrogen bond to the backbone of the protein in the P2 pocket. Modification of the substitution pattern on the phenylsulfonamide P2 ' substituent of TMC126 created an interesting SAR, with the close analogue TMC114 being found to have a similar antiviral activity against the mutant and the wild-type viruses. X-ray and thermodynamic studies on both wild-type and mutant enzymes showed an extremely high enthalpy driven affinity of TMC114 for HIV-1 protease. In vitro selection of mutants resistant to TMC 114 starting from wild-type virus proved to be extremely difficult; this was not the case for other close analogues. Therefore, the extra H-bond to the backbone in the P2 pocket cannot be the only explanation for the interesting antiviral profile of TMC114. Absorption studies in animals indicated that TMC114 has pharmacokinetic properties comparable to currently approved HIV-1 protease inhibitors.

  DOI：

  10.1021/jm049560p
• 作为产物：
  描述：

  Rel-(3aS,6aS)-tetrahydrofuro[2,3-b]furan-3(2H)-one 在 sodium tetrahydroborate 、 乙酸酐 作用下， 以 乙二醇二甲醚 、 乙醇 为溶剂， 反应 4.0h， 生成 六氢呋喃并[2,3-b]呋喃-3-醇
  参考文献：
  名称：

  高亲和力P 2-配体对HIV-1蛋白酶抑制剂的合成及光学拆分

  摘要：

  外消旋的双-四氢呋喃配体6是有效的合成，利用催化钴肟10介导的自由基环化作为关键步骤。用固定化的天麻脂酶光学拆分外消旋醇，得到光学纯的配体。

  DOI：

  10.1016/0040-4039(94)02296-n

文献信息

• Crystalline Darunavir
  申请人：Mylan Laboratories LTD

  公开号：US20140350270A1

  公开（公告）日：2014-11-27

  The present invention relates to a non-solvated crystalline Darunavir, process for its preparation and pharmaceutical composition comprising it. The present invention also relates to a process for the preparation of amorphous Darunavir from a non-solvated crystalline Darunavir.

  本发明涉及一种非溶剂化结晶的达芦那韦，其制备方法以及包含它的药物组合物。本发明还涉及从非溶剂化结晶的达芦那韦制备无定形达芦那韦的过程。
• A Concise One-Pot Organo- and Biocatalyzed Preparation of Enantiopure Hexahydrofuro[2,3-<i>b</i>]furan-3-ol: An Approach to the Synthesis of HIV Protease Inhibitors
  作者：Takuya Kanemitsu、Mizuho Inoue、Nono Yoshimura、Kazutoshi Yoneyama、Rie Watarai、Michiko Miyazaki、Yuki Odanaka、Kazuhiro Nagata、Takashi Itoh

  DOI：10.1002/ejoc.201600062

  日期：2016.4

  A simple and efficient one-pot synthesis of enantiopure hexahydrofuro[2,3-b]furan-3-ol, a crucial component of HIV-1 protease inhibitors, was developed. The one-pot process involves an organocatalytic condensation followed by an enzymatic optical resolution. The condensation of 1,2-dihydrofuran and glycolaldehyde was achieved using Schreiner's thiourea catalyst (1 mol-%). A subsequent lipase-catalyzed

  开发了一种简单高效的对映体纯六氢呋喃 [2,3-b] 呋喃-3-醇（HIV-1 蛋白酶抑制剂的重要成分）的一锅法合成方法。一锅法包括有机催化缩合，然后是酶促光学拆分。1,2-二氢呋喃和乙醇醛的缩合是使用 Schreiner 硫脲催化剂（1 mol%）实现的。随后的脂肪酶催化动力学拆分得到具有 >99% ee 的目标醇。为了证明这种方法的实用性，合成了一种用于治疗多重耐药 HIV 的 HIV-1 蛋白酶抑制剂 Darunavir。
• Probing Multidrug-Resistance and Protein-Ligand Interactions with Oxatricyclic Designed Ligands in HIV-1 Protease Inhibitors
  作者：Arun K. Ghosh、Chun-Xiao Xu、Kalapala Venkateswara Rao、Abigail Baldridge、Johnson Agniswamy、Yuan-Fang Wang、Irene T. Weber、Manabu Aoki、Salcedo Gomez Pedro Miguel、Masayuki Amano、Hiroaki Mitsuya

  DOI：10.1002/cmdc.201000318

  日期：2010.11.8

  design, synthesis, biological evaluation, and X‐ray crystallographic analysis of a new class of HIV‐1 protease inhibitors. Compound 4 proved to be an extremely potent inhibitor toward various multidrug‐resistant HIV‐1 variants, representing a near 10‐fold improvement over darunavir (DRV). Compound 4 also blocked protease dimerization with at least 10‐fold greater potency than DRV.

  更健康的HAART：我们报告了一类新型HIV-1蛋白酶抑制剂的设计、合成、生物学评价和X射线晶体学分析。化合物4被证明是针对多种多重耐药 HIV-1 变体的极其有效的抑制剂，比地芦那韦 (DRV) 改善了近 10 倍。化合物4还可以阻断蛋白酶二聚化，其效力比 DRV 至少高 10 倍。
• Asymmetric One-Pot Synthesis of (3<i>R</i>,3a<i>S</i>,6a<i>R</i>)-Hexahydrofuro[2,3-<i>b</i>]furan-3-ol: A Key Component of Current HIV Protease Inhibitors
  作者：Adrian Sevenich、Gong-Qing Liu、Anthony J. Arduengo、B. Frank Gupton、Till Opatz

  DOI：10.1021/acs.joc.6b02588

  日期：2017.1.20

  A concise and efficient synthesis of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol, a key building block for several clinical and experimental HIV protease inhibitors including the highly important drug darunavir, was achieved via a one-pot procedure using furan and Cbz-protected glycol aldehyde as starting materials. A [2+2]-photocycloaddition between both reactants which can be prepared from wood-based

  简明而高效的合成（3 R，3a S，6a R）-六氢呋喃[2,3- b ]呋喃-3-醇，它是几种临床和实验HIV蛋白酶抑制剂（包括非常重要的药物darunavir）的关键组成部分，通过一锅法使用呋喃和Cbz保护的乙二醇醛作为起始原料来实现。两种反应物之间的[2 + 2]-光环加成反应可以根据木糖化学原理从木质基原料制备，然后进行氢化和脂肪酶催化的动力学拆分，从而以高收率和高达99％ee的浓度提供了目标化合物。
• Synthesis and optical resolution of high affinity P2-ligands for HIV-1 protease inhibitors
  作者：Arun K. Ghosh、Yan Chen

  DOI：10.1016/0040-4039(94)02296-n

  日期：1995.1

  Racemic bis-tetrahydrofuran ligand 6 was efficiently synthesized utilizing catalytic cobaloxime 10 mediated radical cyclization as the key step. Optical resolution of the racemic alcohol with immobilized-Amano lipase, afforded optically pure ligands.

  外消旋的双-四氢呋喃配体6是有效的合成，利用催化钴肟10介导的自由基环化作为关键步骤。用固定化的天麻脂酶光学拆分外消旋醇，得到光学纯的配体。