<3aR-(3aα,4α,7α,7aα)>-hydroxyhexahydro-4,7-epoxyisobenzofuran | 404575-34-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 呋喃类
• 英文名称: <3aR-(3aα,4α,7α,7aα)>-hydroxyhexahydro-4,7-epoxyisobenzofuran
• 英文别名: (+)-exo-hexahydro-4,7-epoxyisobenzofuran-1-ol；(3aR-(3aα,4α,7α,7aα))-hydroxyhexahydro-4,7-epoxyisobenzofuran；(3aR,4R,7S,7aR)-Octahydro-4,7-epoxyisobenzofuran-1-ol；(1S,2R,6R,7R)-4,10-dioxatricyclo[5.2.1.02,6]decan-3-ol
• CAS: 404575-34-4
• 化学式: C₈H₁₂O₃
• 分子量: 156.181
• InChiKey: JYTQKTKMMXLVJR-KEWYIRBNSA-N

物化性质

• 沸点：
  301.2±32.0 °C(Predicted)
• 密度：
  1.317±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0.1
• 重原子数：
  11
• 可旋转键数：
  0
• 环数：
  3.0
• 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

反应信息

• 作为反应物：
  描述：

  <3aR-(3aα,4α,7α,7aα)>-hydroxyhexahydro-4,7-epoxyisobenzofuran 在 palladium hydroxide on carbon 吡啶 、 乙基溴化镁 、 四丁基氟化铵 、 氢气 、 溶剂黄146 作用下， 以 四氢呋喃 为溶剂， 25.0 ℃ 、101.33 kPa 条件下， 生成 Acetic acid (1R,2R,3R,4S)-3-[2-(3-hydroxy-2,2-dimethyl-propyl)-benzyl]-7-oxa-bicyclo[2.2.1]hept-2-ylmethyl ester
  参考文献：
  名称：

  Interphenylene 7-oxabicyclo[2.2.1]heptane oxazoles. Highly potent, selective, and long-acting thromboxane A2 receptor antagonists

  摘要：

  A series of interphenylene 7-oxabicyclo[2.2.1]heptane oxazoles (2) were prepared and evaluated for their thromboxane (TxA2) antagonistic activity in vitro and duration of action in vivo. Examination of the carboxyl side chain indicated that the interphenylene ring substitution pattern and, to a lesser extent, chain length were important factors in determining TxA2 antagonistic potency. For the carboxyl side chain, ortho substitution, a single methylene spacer between the interphenylene and oxabicycloheptane rings, and a propionic acid side-chain length were determined to be optimal. With respect to the oxazole side chain a wide range of amide substituents with diverse structures and lipophilicities were compatible with potent antagonistic activity. Finally. an acidic functional group on the alpha-chain and a hydrogen bond acceptor on the 4-position of the oxazole ring were critical for potent activity. From the analogs prepared 42 {BMS-180,291: [(+)-1S-(1alpha,2alpha,3alpha,4alpha)]-2-[[3-[4-[(n-pentylamino)carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoic acid} was found to be a potent, selective, and orally-active TxA2 antagonist with a long duration of action and has been selected as a candidate for clinical development. In human platelet-rich plasma, 42 inhibited arachidonic acid (800 muM) and U-46,619 (10 muM) induced aggregation with I50 values of 7 and 21 nM, respectively. Radioligand binding studies of 42 with [H-3]-SQ 29,548 showed a K(d) value of 4.0 +/- 1.0 nM in human platelet membranes. Both in vitro and in vivo studies indicated 42 was devoid of direct agonistic activity. In vivo 42 (0.2 mg/kg, po) showed extended protection (T50 = 14.4 h) from U-46,619 (2 mg/kg, iv) induced death in mice, and a single oral dose of 42 (3 mg/kg) abolished U46,619-induced platelet aggregation ex vivo in African green monkeys for >24 h.

  DOI：

  10.1021/jm00062a013
• 作为产物：
  描述：

  3α-hydroxymethyl-7α-oxabicyclo[2.2.1]heptane-2α-carboxylic acid lactone 在 4-二甲氨基吡啶 、 sodium hydroxide 、 二异丁基氢化铝 、 N,N'-二环己基碳二亚胺 作用下， 以 四氢呋喃 、 二氯甲烷 、 甲苯 为溶剂， 反应 90.5h， 生成 <3aR-(3aα,4α,7α,7aα)>-hydroxyhexahydro-4,7-epoxyisobenzofuran
  参考文献：
  名称：

  血栓烷A2 / PGH2的7-氧杂双环[2.2.1]庚烷类似物的合成及体外药理作用。

  摘要：

  为了寻找有用的TXA2 / PGH2介导的病理生理抑制剂，制备了一系列以天然产物的结构为模型的化学稳定的TXA2 / PGH2类似物。以手性形式制备结构1所示的16种异构体，并评估其在血小板和平滑肌中的体外活性。根据相对的侧链和甲醇的立体化学，观察到TXA2 / PGH2激动剂和拮抗剂，以及令人惊讶的是PGD2 / PGI2激动剂活性。具有1所示的α杂环的对映体通常比其镜像异构体更有效。

  DOI：

  10.1021/jm00149a007

文献信息

• Interphenylene 7-oxabicyclo[2.2.1]heptane thromboxane A2(TxA2)antagonists. Semicarbazone .omega.-chains
  作者：Raj N. Misra、Baerbel R. Brown、Wen Ching Han、Don N. Harris、Anders Hedberg、Maria L. Webb、Steven E. Hall

  DOI：10.1021/jm00113a030

  日期：1991.9

  A series of chiral interphenylene 7-oxabicyclo[2.2.1]heptane semicarbazones 19-26 were prepared and evaluated for their in vitro thromboxane (TxA2) antagonistic activity and in vivo duration of action. The potency of 19-26 was found to highly dependent on the substitution pattern of the interphenylene ring and decreased in the order ortho greater than meta much greater than para. SQ 35,091 (25), [1S-(1

  制备了一系列手性联苯间7-氧杂双环[2.2.1]庚烷半咔唑酮19-26，并对其体外血栓烷（TxA2）拮抗活性和体内作用时间进行了评估。发现19-26的效力高度依赖于亚间苯环的取代模式，并且以大于间位大于邻位的顺序降低。SQ 35,091（25），[1S-（1 alpha，2 alpha，3 alpha，4 alpha）]-2-[[3-[[[[（（苯基氨基）羰基]肼基]甲基] -7-氧杂双环[2.2.1 [庚基-2-基]甲基]苯丙酸被鉴定为有效且长效的TxA2拮抗剂。在富含人血小板的血浆中，SQ 35,091抑制了花生四烯酸（800 microM）和U-46,619（10 microM）诱导的聚集，I50值分别为3和12 nM。相反，大于1000 microM时未观察到对ADP（20 microM）诱导的聚集的抑制。用[3H] -SQ 29,548进行的受体结合研究表明，SQ 35,091是
• PROSTAGLANDIN E RECEPTOR ANTAGONISTS
  申请人：Woodward David F.

  公开号：US20100256385A1

  公开（公告）日：2010-10-07

  The present invention provides prostaglandin receptor antagonist compounds represented by the general formula I, wherein A, R, R 1 and R 2 are as defined in the specification.

  本发明提供了由一般式I表示的前列腺素受体拮抗剂化合物，其中A、R、R1和R2如规范中所定义。
• Thromboxane A2 receptor antagonists. I. Synthesis and pharmacological activity of 7-oxabicyclo-(2.2.1)heptane derivatives with the benzenesulfonylamino group.
  作者：Sanji HAGISHITA、Kaoru SENO

  DOI：10.1248/cpb.37.327

  日期：——

  Four stereoisomers of 7-oxabicyclo[2.2.1]heptane derivatives with the benzenesulfonylamino group, 11, 14, 23 and 33, were synthesized and their sodium salts were examined in vitro for inhibitory activity against aggregation of rabbit platelet-rich plasma and of rat washed platelets. The trans-isomer 23 exhibited high potency but showed a partial agonistic effect. Compound 11 did not show a partial

  合成了具有苯磺酰基氨基基团的7-氧杂双环[2.2.1]庚烷衍生物的四种立体异构体，分别在体外检查了其钠盐对兔富含血小板血浆和大鼠聚集的抑制活性洗净的血小板。反式异构体23显示出高效力，但显示出部分激动作用。尽管化合物11是活性较低的抑制剂，但它没有显示出部分激动作用。合成了以下反式化合物，并测量了其IC50值：具有一个亚甲基链的同系反式异构体（47和53），烯烃衍生物（58）和光学活性衍生物[-]-11和（+）-23） 。
• Synthesis of four chiral pharmaceutical intermediates by biocatalysis
  作者：Ramesh N. Patel、Amit Banerjee、Laszlo J. Szarka

  DOI：10.1007/bf02546196

  日期：1995.11

  Chiral intermediates were prepared by biocatalytic processes for the chemical synthesis of four pharmaceutical drug candidates. These include: (i) the microbial reduction of 3,5‐dioxo‐6‐(benzyloxy) hexanoic ethyl ester to (3S,5R)‐dihydroxy‐6‐(benzyloxy) hexanoic acid ethyl ester, an intermediate for a new anticholesterol drug; (ii) synthesis of (2R,3S)‐(‐)‐N‐benzoyl‐3‐phenyl isoserine ethyl ester, a taxol side‐chain synthon; (iii) the microbial oxygenation of 2,2‐dimethyl‐2H‐1‐benzopyran‐6‐carbonitrile to the corresponding (3S,4S) epoxide and (3S,4R)‐trans diol, intermediates for synthesis of potassium channel opener; (iv) the biotransformation of (exo,exo)‐7‐oxabicyclo [2.2.1] heptane‐2,3‐dimethanol to the corresponding chiral lactol and lactone, intermediates for thromboxane A₂ antagonist.

  摘要 通过生物催化过程制备了手性中间体，用于四种候选药物的化学合成。这些中间体包括(i) 微生物将 3,5-二氧代-6-（苄氧基）己酸乙酯还原为(3S,5R)-二羟基-6-（苄氧基）己酸乙酯，这是一种新型抗胆固醇药物的中间体；(ii) 合成(2R,3S)-(-)-N-苯甲酰基-3-苯基异丝氨酸乙酯，这是一种紫杉醇侧链合成物；(iii) 微生物氧合 2,2-二甲基-2H-1-苯并吡喃-6-甲腈，生成相应的(3S,4S) 环氧化物和(3S,4R)-反式二醇，这是合成钾通道开放剂的中间体；(iv) 生物转化(exo,exo)-7-氧杂双环[2.2.1]庚烷-2,3-二甲醇的生物转化，生成相应的手性内醇和内酯，这是血栓素 A2 拮抗剂的中间体。
• Synthesis of Optically Active 7-Oxabicyclo[2.2.1]heptanes and Assignment of Absolute Configuration
  作者：Jagabandhu Das、Martin F. Haslanger、J. Z. Gougoutas、Mary F. Malley

  DOI：10.1055/s-1987-28183

  日期：——

  The synthesis of optically active 7-oxabicyclo[2.2.1]heptane derivatives is described. The synthetic route requires the conversion of prochiral 7-oxabicyclo[2.2.1]heptane-2,3-dicarboxylic anhydride (2) to an easily separable mixture of diastereoisomeric acid-esters 3 and 5. Each of the pure diastereoisomers is obtained by use of the commercially available optical antipodes of menthol. Diastereoisomerically pure acid-esters 3 and 5 are separately transformed to enantiomerically pure lactones (+)- 1 and (-)-1 (ee > 98%). Lactone (+)-1 is converted to a d-menthyl acetal 8a and its absolute configuration is determined by X-ray analysis.

  描述了光学活性7-氧杂双环[2.2.1]庚烷衍生物的合成。该合成路线需要将前手性 7-氧杂双环[2.2.1]庚烷-2,3-二甲酸酐 (2) 转化为易于分离的非对映异构酸酯 3 和 5 的混合物。每种纯非对映异构体均通过使用获得市售的薄荷醇光学对映体。非对映异构纯的酸酯3和5分别转化为对映异构纯的内酯(+)-1和(-)-1(ee > 98%)。内酯 (+)-1 转化为 d-薄荷醇缩醛 8a，并通过 X 射线分析确定其绝对构型。