(+/-)-cocaine | 21206-60-0

• 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: (+/-)-cocaine
• 英文别名: (+/-)-Cocain；(exo,exo)-(+/-)-3-(benzoyloxy)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylic acid, methyl ester；(+)Cocaine；methyl (1S,2S,3R,5R)-3-benzoyloxy-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate
• CAS: 21206-60-0
• 化学式: C₁₇H₂₁NO₄
• 分子量: 303.358
• InChiKey: ZPUCINDJVBIVPJ-BARDWOONSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  22
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.53
• 拓扑面积：
  55.8
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (+/-)-cocaine 在 L-酒石酸 作用下， 生成 古卡因
  参考文献：
  名称：

  CH105360

  摘要：

  公开号：
• 作为产物：
  描述：

  [(1S,2S,3R,5R)-2-carbamoyl-8-azabicyclo[3.2.1]octan-3-yl] benzoate 在 sodium cyanoborohydride 、 sodium nitrite 作用下， 以 二氯甲烷 、 乙酸酐 、 溶剂黄146 、 乙腈 为溶剂， 反应 25.0h， 生成 (+/-)-cocaine
  参考文献：
  名称：

  Enantiospecific Synthesis of Natural (−)-Cocaine and Unnatural (+)-Cocaine from d- and l-Glutamic Acid

  摘要：

  Natural (-)-cocaine and unnatural (+)-cocaine have been synthesized enantiospecifically from D- and L-glutamic acid, respectively. The axial-equatorial substitutents were introduced by a stereo- and regiospecific dipolar cycloaddition to the corresponding (LR,5S)- and (1S,5R)-N-BOC-nortropenes with (ethoxycarbonyl)formonitrile N-oxide. A sequence of subsequent stereochemically controlled transformations converted the fused isoxazoline to the requisite P-hydroxy ester. Synthesis of the key intermediate N-BOC-nortropenes involved construction of the 8-azabicyclo[3.2.1]octane framework by Dieckmann condensation of cis-5-substituted D-and L-proline esters. For comparison, (1R,SS)-N-BOC-nortropene also was derived by degradation from natural cocaine. The cis-5-substituted D-and L-proline esters were obtained by sulfide contraction and subsequent catalytic hydrogenation to induce stereospecifically the C-5 stereochemistry from D-and L-thiopyroglutamate, which in turn were prepared from D-and L-glutamic acids, respectively.

  DOI：

  10.1021/jo980153t

文献信息

• Concise Catalytic Asymmetric Total Synthesis of Biologically Active Tropane Alkaloids
  作者：Armando Córdova、Shuangzheng Lin、Abrehet Tseggai

  DOI：10.1002/adsc.201100917

  日期：2012.5.7

  the total asymmetric synthesis of valuable tropane alkaloids by catalytic stereoselective transformations is disclosed. The power of this approach is exemplified by the concise catalytic enantioselective total syntheses of (+)‐methylecgonine, (−)‐cocaine and (+)‐cocaine as well as the first catalytic asymmetric total syntheses of a cocaine C‐1 derivative and (+)‐ferruginine starting from 5‐oxo‐protected‐α

  公开了通过催化立体选择性转化完全不对称合成有价值的托烷生物碱的一般策略。（+）-甲基芽子碱，（-）-可卡因和（+）-可卡因的简洁催化对映选择性总合成以及可卡因C-1衍生物和（ +）-ferruginine分别仅使用两步和三步色谱纯化步骤从5-氧代保护的α，β-不饱和烯醛开始。
• Two-carbon bridge substituted cocaines: enantioselective synthesis, attribution of the absolute configuration and biological activity of novel 6- and 7-methoxylated cocaines
  作者：Daniele Simoni、Marinella Roberti、Vincenza Andrisano、Monica Manferdini、Riccardo Rondanin、Francesco Paolo Invidiata

  DOI：10.1016/s0014-827x(99)00027-0

  日期：1999.5

  structure-activity relationships of cocaine with the aim to elucidate those structural features that might confer antagonistic properties to such analogues, we describe herein our synthetic efforts to prepare two-carbon bridge functionalized (methoxylated and hydroxylated) analogues. Our approach makes use of a modification of the classical Willstatter synthesis of cocaine: Mannich type cyclization of acetonedicarboxylic

  为了更多地了解可卡因的一般结构-活性关系，以阐明可能赋予此类类似物拮抗特性的结构特征，我们在本文中描述了我们制备二碳桥官能化（甲氧基化和羟基化）的合成努力类似物。我们的方法利用了可卡因的经典Willstatter合成方法的改进方法：在柠檬酸盐缓冲溶液中用甲胺盐酸盐和2-甲氧基琥珀二醛对丙酮二羧酸单甲酯进行Mannich型环化，得到6和7-取代的2-carbomethoxy-3-tropinones图3a，b和4a，b的产率约为64％。用汞合金钠在硫酸溶液中还原（+/-）-肌钙蛋白衍生物，得到（+/-）-甲氧基芽子碱和（+/-）-甲氧基假芽子碱衍生物5、11和6、7， 12、13，这些醇的苯甲酰化作用可产生所需的可卡因和类伪可卡因化合物8、14和9、10、15、16。此外，我们证明使用猪肝酯酶（PLE）对这些可卡因类似物进行酶水解可提供实用的实现其化学拆分的方法。还从手性（+）-和（-）-6
• Asymmetric Total Synthesis of (<i>S</i>)-(+)-Cocaine and the First Synthesis of Cocaine C-1 Analogs from <i>N</i>-Sulfinyl β-Amino Ester Ketals
  作者：Franklin A. Davis、Naresh Theddu、Ram Edupuganti

  DOI：10.1021/ol1017118

  日期：2010.9.17

  Sulfinimine-derived α,β-unsaturated pyrrolidine nitrones, on heating with Al(O-t-Bu)3, undergo a highly stereoselective intramolecular [3 + 2] cycloaddition to give tricyclic isoxazolidines, which are transformed in three-steps to give C-1 substituted cocaine analogs.

  亚砜胺衍生的α，β-不饱和吡咯烷腈与Al（O- t- Bu）3加热时，经历高度立体选择性的分子内[3 + 2]环加成反应，得到三环异恶唑烷，将其分三步转化为C -1个取代的可卡因类似物。
• An Improved Cocaine Hydrolase: The A328Y Mutant of Human Butyrylcholinesterase is 4-fold More Efficient
  作者：Weihua Xie、Cibby Varkey Altamirano、Cynthia F. Bartels、Robert J. Speirs、John R. Cashman、Oksana Lockridge

  DOI：10.1124/mol.55.1.83

  日期：1999.1.1

  Butyrylcholinesterase (BChE) has a major role in cocaine detoxication. The rate at which human BChE hydrolyzes cocaine is slow, with a k cat of 3.9 min−1 and K m of 14 μM. Our goal was to improve cocaine hydrolase activity by mutating residues near the active site. The mutant A328Y had a k cat of 10.2 min−1 and K m of 9 μM for a 4-fold improvement in catalytic efficiency ( k cat/ K m). Since benzoylcholine ( k cat 15,000 min−1) and cocaine form the same acyl-enzyme intermediate but are hydrolyzed at 4000-fold different rates, it was concluded that a step leading to formation of the acyl-enzyme intermediate was rate-limiting. BChE purified from plasma of cat, horse, and chicken was tested for cocaine hydrolase activity. Compared with human BChE, horse BChE had a 2-fold higher k cat but a lower binding affinity, cat BChE was similar to human, and chicken BChE had only 10% of the catalytic efficiency. Naturally occurring genetic variants of human BChE were tested for cocaine hydrolase activity. The J and K variants (E497V and A539T) had k catand K m values similar to wild-type, but because these variants are reduced to 66 and 33% of normal levels in human blood, respectively, people with these variants may be at risk for cocaine toxicity. The atypical variant (D70G) had a 10-fold lower binding affinity for cocaine, suggesting that persons with the atypical variant of BChE may experience severe or fatal cocaine intoxication when administered a dose of cocaine that is not harmful to others.

  丁酰胆碱酯酶（BChE）在可卡因解毒过程中发挥着重要作用。人类 BChE 水解可卡因的速度很慢，其 k cat 为 3.9 min-1，K m 为 14 μM。我们的目标是通过突变活性位点附近的残基来提高可卡因水解酶的活性。突变体 A328Y 的 k cat 为 10.2 min-1，K m 为 9 μM，催化效率（k cat/ K m）提高了 4 倍。由于苯甲酰基胆碱（k cat 15,000 min-1）和可卡因形成相同的酰基酶中间体，但水解速度却相差 4000 倍，因此得出结论认为，形成酰基酶中间体的步骤是限速的。对从猫、马和鸡血浆中纯化的 BChE 进行了可卡因水解酶活性测试。与人类 BChE 相比，马 BChE 的 k cat 高 2 倍，但结合亲和力较低；猫 BChE 与人类相似；鸡 BChE 的催化效率只有人类的 10%。对人类 BChE 的天然基因变体进行了可卡因水解酶活性测试。J 和 K 变体（E497V 和 A539T）的 k cat 和 K m 值与野生型相似，但由于这些变体在人体血液中的含量分别降低到正常水平的 66% 和 33%，因此具有这些变体的人可能有可卡因中毒的风险。非典型变异体（D70G）与可卡因的结合亲和力低 10 倍，这表明，当输入对他人无害的可卡因剂量时，BChE 非典型变异体患者可能会出现严重或致命的可卡因中毒。
• [EN] METHODS FOR PRODUCING HYDROXYALKYL TROPANE ESTERS<br/>[FR] PROCÉDÉS DE PRODUCTION D'HYDROXYALKYL TROPANE ESTERS
  申请人：ENTROPIN INC

  公开号：WO2004018464A1

  公开（公告）日：2004-03-04

  This invention provides a method for preparing a hydroxyalkyl tropane ester, comprising: (a) contacting a tropane and 1,1'-carbonyldiimidazole to produce an activated tropane ester; (b) contacting the activated tropane ester with an excess of an alkanediol to form a reaction mixture; and (c) maintaining the reaction mixture at a temperature and for a sufficient time for the activated tropane ester to react with the alkanediol to form the corresponding hydroxyalkyl tropane ester. This method may be used to produce hydroxyalkyl derivatives of tropanes such as benzoylecgonine, ecgonine and ecgonidine.

  本发明提供了一种制备羟基烷基曲柳酯的方法，包括：（a）将曲柳和1,1'-羰基二咪唑接触以产生活化的曲柳酯；（b）将活化的曲柳酯与过量的脂肪二醇接触以形成反应混合物；并且（c）在足够的时间内将反应混合物保持在一定的温度下，使活化的曲柳酯与脂肪二醇反应形成相应的羟基烷基曲柳酯。该方法可用于生产苯甲酰异可卡因、异可卡因和异可吡啶等曲柳酯的羟基烷基衍生物。