3β-hydroxy-1R-(exo,exo)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylic acid isopropyl ester | 153926-03-5

• 分子结构分类: 有机化合物 - 生物碱及其衍生物 - 托烷生物碱
• 英文名称: 3β-hydroxy-1R-(exo,exo)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylic acid isopropyl ester
• 英文别名: 2β-isopropyl ecgonine；propan-2-yl (1R,2R,3S,5S)-3-hydroxy-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate
• CAS: 153926-03-5
• 化学式: C₁₂H₂₁NO₃
• 分子量: 227.304
• InChiKey: WVIVACYSISJCTP-ZRUFSTJUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.6
• 重原子数：
  16
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.92
• 拓扑面积：
  49.8
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  3β-hydroxy-1R-(exo,exo)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylic acid isopropyl ester 在 palladium on activated charcoal 氢气 、 三乙胺 作用下， 以 环己烷 、 苯 为溶剂， 反应 30.0h， 生成 3β-[(2'-aminobenzoyl)oxy]-1R-(exo,exo)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylic acid isopropyl ester
  参考文献：
  名称：

  Synthesis and dopamine transporter binding of 2β-isopropyl ester analogs of cocaine

  摘要：

  A series of 2beta-isopropyl ester analogs of cocaine (7-11) was synthesised and evaluated in an in vitro dopamine transporter (DAT) binding assays. Ecgonine HCl (5) was obtained from (-)-cocaine (1) by hydrolysis using I N HCl. Acid catalysed esterification of 5 using 2-propanol and HCl gas afforded 2beta-isopropyl ecgonine (6). Compounds 7-9 were obtained via esterification of the 3beta-hydroxyl group of 6 using the appropriate acid chloride. Compound 10 was obtained via selective hydrolysis and re-esterification of 7 using 2-propanol and HCl gas. Compound I I was obtained by reduction of 9 using H-2/Pd-C. Compounds 7, 10 and I I showed high binding affinity to the DAT (as indicated from the inhibition of the binding of [H-3]WIN 35,428 (3)) with IC50 values (mean +/- S.E.M.) 208.5 +/- 9.5, 47.43 +/- 1.79 and 11.25 +/- 3.37 nM, respectively). Compound 7 is comparatively as active as cocaine, 10 is ca. fivefold more active than cocaine and 11 is ca. 20-fold more active than cocaine and even twice more active than the radioligand 3. Compound It, like its methyl ester analog (2' aminococaine), exhibited the highest affinity to the DAT. These results, along with previous results, emphasise the importance of a hydrogen-bond donor group at the T-position of cocaine and its isopropyl ester analogs to enhance binding affinity to the DAT. (C) 2002 Published by Editions scientifiques et medicalcs Elsevier SAS.

  DOI：

  10.1016/s0223-5234(01)01314-9
• 作为产物：
  描述：

  古卡因 在 盐酸 作用下， 生成 3β-hydroxy-1R-(exo,exo)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylic acid isopropyl ester
  参考文献：
  名称：

  Synthesis and dopamine transporter binding of 2β-isopropyl ester analogs of cocaine

  摘要：

  A series of 2beta-isopropyl ester analogs of cocaine (7-11) was synthesised and evaluated in an in vitro dopamine transporter (DAT) binding assays. Ecgonine HCl (5) was obtained from (-)-cocaine (1) by hydrolysis using I N HCl. Acid catalysed esterification of 5 using 2-propanol and HCl gas afforded 2beta-isopropyl ecgonine (6). Compounds 7-9 were obtained via esterification of the 3beta-hydroxyl group of 6 using the appropriate acid chloride. Compound 10 was obtained via selective hydrolysis and re-esterification of 7 using 2-propanol and HCl gas. Compound I I was obtained by reduction of 9 using H-2/Pd-C. Compounds 7, 10 and I I showed high binding affinity to the DAT (as indicated from the inhibition of the binding of [H-3]WIN 35,428 (3)) with IC50 values (mean +/- S.E.M.) 208.5 +/- 9.5, 47.43 +/- 1.79 and 11.25 +/- 3.37 nM, respectively). Compound 7 is comparatively as active as cocaine, 10 is ca. fivefold more active than cocaine and 11 is ca. 20-fold more active than cocaine and even twice more active than the radioligand 3. Compound It, like its methyl ester analog (2' aminococaine), exhibited the highest affinity to the DAT. These results, along with previous results, emphasise the importance of a hydrogen-bond donor group at the T-position of cocaine and its isopropyl ester analogs to enhance binding affinity to the DAT. (C) 2002 Published by Editions scientifiques et medicalcs Elsevier SAS.

  DOI：

  10.1016/s0223-5234(01)01314-9

文献信息

• 2β-Substituted Analogues of 4‘-Iodococaine:  Synthesis and Dopamine Transporter Binding Potencies
  作者：Kwasi S. Avor、Satendra Singh、Thomas W. Seale、Buddy Pouw、Garo P. Basmadjian

  DOI：10.1021/jm980061w

  日期：1998.6.1

  4'-iodococaine (3) was synthesized and evaluated in an in vitro dopamine transporter (DAT) binding assay. Selective hydrolysis at the 2beta-position of 3 gave the carboxylic acid 15 that served as the intermediate for the synthesis of compounds 4, 5, and 6-11. The 2beta-alkyl derivatives were obtained from ecgonine methyl ester (17) through a series of reactions leading to the aldehyde 20. Wittig reaction

  合成了一系列2β-取代的4'-碘多卡因（3）类似物，并在体外多巴胺转运蛋白（DAT）结合测定中进行了评估。在3的2β位选择性水解得到羧酸15，其用作合成化合物4、5和6-11的中间体。2-8烷基衍生物是从芽子碱甲酯（17）通过一系列导致醛20的反应获得的。20与甲基三苯基磷烷的Wittig反应，然后进行氢化和苯甲酰化，得到产物12和13。4'-的结合亲和力碘多卡因（3）比可卡因少10倍。3的羟甲烷，乙酸酯，酰胺，苄基酯，氧化唑和乙烷衍生物显示出降低的结合，而乙烯基，苯基和乙酯显示出适度的结合亲和力。与4'-碘多卡因相比，只有异丙基衍生物8的结合亲和力提高了2倍（3）。8'在2'位的羟基化反应得到14，不仅使DAT的结合力提高了2倍，而且还增强了DAT相对于去甲肾上腺素和5-羟色胺转运蛋白的选择性。在宽剂量范围内，化合物14未能在C57BL / 6J小鼠中刺激运动活性，并阻止了可卡因诱导的运动刺激作用。