(3R,3aR,6aS)-六氢呋喃并[2,3-b]呋喃-3-醇 | 252873-00-0

• 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: (3R,3aR,6aS)-六氢呋喃并[2,3-b]呋喃-3-醇
• 中文别名: BISTHF硝基衍生物3；BIS THF硝基衍生物3
• 英文名称: (3R,3aR,6aS)-hexahydrofuro[2,3-b]furan-3-ol
• 英文别名: (3aR,4R,6aS)-2,3,3a,4,5,6a-hexahydrofuro[2,3-b]furan-4-ol
• CAS: 252873-00-0
• 化学式: C₆H₁₀O₃
• 分子量: 130.144
• InChiKey: RCDXYCHYMULCDZ-SRQIZXRXSA-N

物化性质

• 沸点：
  251.5±20.0 °C(Predicted)
• 密度：
  1.275±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  -0.4
• 重原子数：
  9
• 可旋转键数：
  0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  1.0
• 拓扑面积：
  38.7
• 氢给体数：
  1
• 氢受体数：
  3

上下游信息

• 上游原料

  中文名称	英文名称	CAS号	化学式	分子量
  (3S,3aR,6aS)-六氢呋喃并[2,3-b]呋喃-3-醇	(3S,3aR,6aS)-hexahydrofuro[2,3-b]furan-3-ol	156928-10-8	C6H10O3	130.144
  六氢呋喃并[2,3-b]呋喃-3-醇	(3S,3aR,6aS)-Hexahydrofuro[2,3-b]furan-3-yl Acetate	162020-29-3	C8H12O4	172.181
  ——	(3R,3aR,6aS)-perhydrofuro[2,3-b]furan-3-yl acetate	605653-07-4	C8H12O4	172.181
  ——	(3R,4'R)-3-(2',2'-dimethyl-[1',3']dioxolane-4'-yl)tetrahydrofuran-2-ol	725264-67-5	C9H16O4	188.224
  莱克酮	(3aS,4S,6aR)-4-methoxy-tetrahydro-furo[3.4-b]furan-2(3H)-one	866594-60-7	C7H10O4	158.154

反应信息

• 作为反应物：
  描述：

  (3R,3aR,6aS)-六氢呋喃并[2,3-b]呋喃-3-醇 在 三乙胺 作用下， 以 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：

  六氢呋喃并[2,3-b]呋喃-3-醇 在 偶氮二甲酸二异丙酯 、 potassium carbonate 、 三苯基膦 作用下， 以 乙醇 为溶剂， 生成 (3R,3aR,6aS)-六氢呋喃并[2,3-b]呋喃-3-醇
  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
• 作为试剂：
  描述：

  、 (3R,3AS,6AR)-六氢呋喃并[2,3-B]呋喃-3-醇 、 (3S,3aS,6aR)-六氢呋喃并[2,3-b]呋喃-3-醇 、 Phosphoric Acid Dipotassium 、 sodium hypochlorite 在 (3S,3aR,6aS)-六氢呋喃并[2,3-b]呋喃-3-醇 、 (3R,3aR,6aS)-六氢呋喃并[2,3-b]呋喃-3-醇 、 溴化钾 2,2,6,6-tetramethylpiperidinyl-1-oxy 、 乙酸乙酯 、 Sodium sulfate-III 、 异丙醇 作用下， 以 乙酸乙酯 、 异丙醇 为溶剂， 反应 1.5h， 以to obtain a pale brown white crystal (3aR,6aR)-tetrahydrofuro[2,3-b]furan-3(2H)-one (7.4 g, purity 98%, yield 73%)的产率得到(3aR,6aR)-3a,4,5,6a-tetrahydrofuro[2,3-b]furan-3(2H)-one
  参考文献：
  名称：

  Process for producing hexahydrofurofuranol derivative

  摘要：

  本发明提供了一种制备化合物（IV）的方法，包括以下步骤：在可选择取代的环二级胺的存在下，将化合物（I）和化合物（II）反应，得到化合物（III）；然后顺序或同时消除化合物（III）中的R1和R2，再将消除R1和R2的化合物环化，得到由公式（IV）表示的化合物。本发明还提供了一种制备高纯度化合物（IV）的方法、其中间体以及制备中间体的方法。

  公开号：

  US07951977B2

文献信息

• 8-AMINOISOQUINOLINE COMPOUNDS AND USES THEREOF
  申请人：Genentech, Inc.

  公开号：US20200108075A1

  公开（公告）日：2020-04-09

  3-Carbonylamino-8-aminoisoquinoline compounds of formula (I): variations thereof, and their use as inhibitors of HPK1 (hematopoietic kinase 1) are described. The compounds are useful in treating HPK1-dependent disorders and enhancing an immune response. Also described are methods of inhibiting HPK1, methods of treating HPK1-dependent disorders, methods for enhancing an immune response, and methods for preparing the 3-carbonylamino-8-aminoisoquinoline compounds.

  公式（I）的3-羰基氨基异喹啉化合物及其变体，以及它们作为HPK1（造血激酶1）抑制剂的用途被描述。这些化合物在治疗HPK1依赖性疾病和增强免疫应答方面是有用的。还描述了抑制HPK1的方法，治疗HPK1依赖性疾病的方法，增强免疫应答的方法，以及制备3-羰基氨基异喹啉化合物的方法。
• Sulfonamide inhibitors of aspartyl protease
  申请人：——

  公开号：US20020049201A1

  公开（公告）日：2002-04-25

  The present invention relates to a novel class of sulfonamides which are aspartyl protease inhibitors. In one embodiment, this invention relates to a novel class of HIV aspartyl protease inhibitors characterized by specific structural and physicochemical features. This invention also relates to pharmaceutical compositions comprising these compounds. The compounds and pharmaceutical compositions of this invention are particularly well suited for inhibiting HIV-1 and HIV-2 protease activity and consequently, may be advantageously used as anti-viral agents against the HIV-1 and HIV-2 viruses. This invention also relates to methods for inhibiting the activity of HIV aspartyl protease using the compounds of this invention and methods for screening compounds for anti-HIV activity.

  本发明涉及一类新型磺胺类化合物，其为天冬氨酸蛋白酶抑制剂。在一个实施例中，本发明涉及一类新型HIV天冬氨酸蛋白酶抑制剂，其具有特定的结构和理化特征。本发明还涉及包含这些化合物的药物组合物。本发明的化合物和药物组合物特别适用于抑制HIV-1和HIV-2蛋白酶活性，因此，可以有利地用作抗HIV-1和HIV-2病毒的抗病毒剂。本发明还涉及使用本发明的化合物抑制HIV天冬氨酸蛋白酶活性的方法以及筛选具有抗HIV活性的化合物的方法。
• Production method of hexahydrofurofuranol derivative, intermediate therefor and production method thereof
  申请人：Sumika Fine Chemicals Co., Ltd.

  公开号：US20040162340A1

  公开（公告）日：2004-08-19

  The present invention provides a method for producing compound (XIV) useful as an intermediate for pharmaceutical agents efficiently and economically on an industrial scale without using ozone oxidation and highly toxic reagent, and an intermediate used for this method. Particularly, the present invention provides a method for producing a compound having an absolute configuration represented by the formula (XV) and an enantiomer thereof without using a technique such as optical resolution and the like, and an intermediate used for this method. (1) Compound (XIII) as a starting material is led to compound (I), and after introducing a protecting group, subjected to reduction and cyclization to give compound (XIV). Particularly, compound (XIII) as a material is led to compound (I) via compound (XX) to produce compound (XIV). Using an optically active compound (XIII) as a starting material, a compound having an absolute configuration represented by the formula (XV) and the like are produced highly stereoselectively. (2) Compound (XXI) as a starting material is stereoselectively reduced to give compound (XXII), and by introduction of a protecting group, reduction and cyclization, compound (XXVI) is obtained, and by inverting hydroxyl group, compound (XV) is produced. 1 wherein each symbol is as defined in the specification.

  本发明提供了一种在工业规模上高效且经济地生产化合物(XIV)的方法，该化合物可作为制药中间体，无需使用臭氧氧化和高毒性试剂，以及用于该方法的中间体。特别是，本发明提供了一种生产具有由公式(XV)表示的绝对构型及其对映体的化合物的方法，无需使用光学分辨等技术，以及用于该方法的中间体。(1) 以化合物(XIII)为起始材料，引导至化合物(I)，引入保护基团后，进行还原和环化以得到化合物(XIV)。特别是，化合物(XIII)作为原料通过化合物(XX)引导至化合物(I)，以生产化合物(XIV)。使用具有光学活性的化合物(XIII)作为起始材料，高度立体选择性地生产具有由公式(XV)表示的绝对构型等的化合物。(2) 以化合物(XXI)为起始材料，立体选择性地还原得到化合物(XXII)，通过引入保护基团、还原和环化，得到化合物(XXVI)，并通过反转羟基，生产化合物(XV)。其中每个符号的定义如说明书中所述。
• 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。
• [EN] PROCESS FOR THE PREPARATION OF (3R, 3AS, 6AR)-HEXAHYDROFURO [2, 3- B] FURAN-3-OL<br/>[FR] PROCÉDÉ POUR LA PRÉPARATION DE (3R,3AS,6AR)-HEXAHYDROFURO[2,3-B]FURAN-3-OL
  申请人：MATRIX LAB LTD

  公开号：WO2012070057A1

  公开（公告）日：2012-05-31

  The present invention relates to a novel process for the preparation of (3R, 3aS, 6aR)- hexahydrofuro [2, 3-b] furan-3-ol of formula I by reacting a compound of formula VII with the compound of formula R2-OH in the presence of haloginating agent to obtain a compound of formula VI and treating a compound of formula VI with dehaloginating agent to obtain a compound of formula V by reducing a compound of formula V, followed by cylization to obtain compound of formula IV and separating the enantiomer and diastereomers from compound of formula IV to yield a compound of formula I. Compound of formula I is useful as an intermediate in the preparation of protease inhibitors, in particular broad spectrum HIV protease inhibitors, the present invention also relates to process for the preparation of Darunavir from (3R, 3aS, 6aR)-hexahydrofuro [2, 3-b] furan-3-ol.

  本发明涉及一种新型制备(3R,3aS,6aR)-六氢呋喃[2,3-b]呋喃-3-醇(I)的方法，通过在卤化试剂存在下将化合物VII与化合物R2-OH反应以获得化合物VI，然后用去卤试剂处理化合物VI以获得化合物V。通过还原化合物V，随后环化以获得化合物IV，并从化合物IV中分离出对映异构体和顺反异构体，从而得到化合物I。化合物I在制备蛋白酶抑制剂，特别是广谱HIV蛋白酶抑制剂的中间体中有用。本发明还涉及从(3R,3aS,6aR)-六氢呋喃[2,3-b]呋喃-3-醇制备达芦那韦的方法。