(R)-利卡西平乙酸酯 | 186694-45-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯氮卓类
• 中文名称: (R)-利卡西平乙酸酯
• 中文别名: 醋酸奥曲肽杂质
• 英文名称: (R)-(+)-10-acetoxy-10,11-dihydro-5H-dibenz[b,f]azepine-5-carboxamide
• 英文别名: (+)-Licarbazepine acetate；(R)-Licarbazepine Acetate；[(5R)-11-carbamoyl-5,6-dihydrobenzo[b][1]benzazepin-5-yl] acetate
• CAS: 186694-45-1
• 化学式: C₁₇H₁₆N₂O₃
• 分子量: 296.326
• InChiKey: QIALRBLEEWJACW-MRXNPFEDSA-N

物化性质

• 溶解度：
  DMSO（微量）、吡啶（微量）

计算性质

• 辛醇/水分配系数(LogP)：
  2
• 重原子数：
  22
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.18
• 拓扑面积：
  72.6
• 氢给体数：
  1
• 氢受体数：
  3

制备方法与用途

(R)- Licarbazepine acetate is a promising antiepileptic drug, structurally related to carbamazepine and oxcarbazepine.

反应信息

• 作为反应物：
  描述：

  醋酸艾司利卡西平 、 (R)-利卡西平乙酸酯 、 艾司利卡西平 、 (10R)-10,11-二氢-10-羟基-5H-二苯并[b,f]氮杂卓-5-甲酰胺 以are obtained by enantioselective reduction of 10,11-dihydro-10-oxo-5H-dibenz[b,f]azepine-5-carboxamide or derivatives的产率得到奥卡西平
  参考文献：
  名称：

  Process for the preparation of (S)-(+)- or (R)-(-)-10-hydroxy dihydrodibenz[B,F]azepines by enantioselective reduction of 10,11-dihydro-10-OXO-5H-dibenz[B,F]azepines and polymorphs thereof

  摘要：

  本发明提供了一种新型方法，利用硼酸酯或其衍生物从10,11-二氢-10-氧代-5H-二苯并[b,f]氮杂环制备取代的光学纯(S)-(+)-或(R)-(-)-10-羟基-二氢二苯并[b,f]氮杂环或其衍生物。本发明还提供了利用这样制备的(S)-(+)-或(R)-(-)-10-羟基-二氢二苯并[b,f]氮杂环制备它们的酯，如(S)-(-)-10-乙酰氧基-10,11-二氢-5H-二苯并[b,f]氮杂环-5-羧酰胺或(R)-(+)-10-乙酰氧基-10,11-二氢-5H-二苯并[b,f]氮杂环-5-羧酰胺。本发明还提供了新的固态晶体形式J1、J2、J3、J4和eslicarbazepine的非晶态形式及其制备方法。此外，本发明还提供了eslicarbazepine乙酸盐的新型固态晶体形式和非晶态形式及其制备方法。eslicarbazepine的新型固态形式对于制备eslicarbazepine乙酸盐等eslicarbazepine衍生物有用。

  公开号：

  US09346760B2
• 作为产物：
  描述：

  奥卡西平 在 吡啶 、 4-二甲氨基吡啶 、 sodium tetrahydroborate 作用下， 以 乙醇 、 二氯甲烷 、 水 为溶剂， 反应 2.0h， 生成 (R)-利卡西平乙酸酯
  参考文献：
  名称：

  Anticonvulsant and Sodium Channel-Blocking Properties of Novel 10,11-Dihydro-5H-dibenz[b,f]azepine-5-carboxamide Derivatives

  摘要：

  A. series of esters of the major metabolite of oxcarbazepine (2), 10,11-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5-carboxamide, were synthesized and evaluated for their anticonvulsant and brain sodium channel-blocking properties. The compounds were assayed intraperitoneally and per os in rats against seizures induced by maximal electroshock (MES). Neurologic deficit was evaluated by the rotarod test. The enantiomeric acetates (R)-11 and (S)-12 were the most active of the series against MES-induced seizures with oral ED50 values at t(max) of 10.9 +/- 2.3 and 4.7 +/- 9 mg/kg, respectively. After intraperitoneal administration, carbamazepine (1) behaved more potently than 2 and all other new dibenz[b,f]azepine-5-carboxamide derivatives in the MES test; compounds 2 and 12 were equally potent. In the rotarod test, low doses of 1. produced considerable motor impairment, which did not occur with 2, enantiomeric alcohols (S)-6;, (R)-7, and racemic alcohol, or racemic acetate 10 or (R)-11. The potencies of the racemic and enantiomerically pure alcohols 8, (S)-6, and (R)-7 derived from 2 in the MES and rotarod test were found to be similar between them, and consequently they exhibit similar protective index values. All three forms of the alcohol and their corresponding acetates (pairs 8 & 10, 6 & 12, and 7 & 11) were found to differ in the MES or rotarod tests; the ED50 value for (S)-6 against MES-induced seizures was nearly 3-fold that for (S)-12. The protective index also differed markedly between all stereoisomers of the alcohol and their corresponding acetates, most pronouncedly for compound (S)-12 which attained the highest value (12.5) among all compounds tested. Blockade of voltage-sensitive sodium channels was studied by investigating [H-3]-batrachotoxinin A 20-alpha-benzoate ([H-3]BTX) binding. Acetates (R)-11 and (S)-12 were more potent than the standards 1 and-2 at inhibiting the binding of [H-3]BTX to sodium channels and the influx: of Na-22(+) into rat brain synaptosomes. It is concluded that acetates (R)-11 and (5)-12 are not simple metabolic precursors of alcohols (R)-7 and (S)-6 in rodents but that they possess anticonvulsant and sodium channel-blocking properties in their own right.

  DOI：

  10.1021/jm980627g

文献信息

• PROCESS FOR THE PREPARATION OF (S)-(+)- OR (R)-(-)-10-HYDROXY DIHYDRODIBENZ[B,F]AZEPINES BY ENANTIOSELECTIVE REDUCTION OF 10,11-DIHYDRO-10-OXO-5H-DIBENZ[B,F]AZEPINES AND POLYMORPHS THEREOF
  申请人：Biswas Sujay

  公开号：US20130345198A1

  公开（公告）日：2013-12-26

  The present invention provides a novel process for the preparation of substituted optically pure (S)-(+)- or (R)-(−)-10-hydroxy-dihydrodibenz[b,f]azepines or derivatives thereof, starting from 10,11-dihydro-10-oxo-5H-dibenz[b,f]azepines using boronate esters or their derivatives. The present invention also provides use of thus prepared (S)-(+)- or (R)-(−)-10-hydroxy-dihydrodibenz[b,f]azepines for the preparation of their ester such as (S)-(−)-10-acetoxy-10,11-dihydro-5H-dibenz[b,f]azepine-5-carboxamide or (R)-(+)-10-acetoxy-10,11-dihydro-5H-dibenz[b,f]azepine-5-carboxamide. The present invention also provides novel solid state crystalline forms J 1 , J 2 , J 3 , J 4 and amorphous form of eslicarbazepine and the process for the preparation thereof. Also, the present invention provides novel solid state crystalline form and amorphous form of eslicarbazepine acetate and the process for the preparation thereof. The novel solid state forms of eslicarbazepine are useful for the preparation of derivatives of eslicarbazepine such as eslicarbazepine acetate.

  本发明提供了一种新颖的方法，用于从10,11-二氢-10-氧代-5H-二苯并[b,f]氮杂环己烯起始，利用硼酸酯或其衍生物制备取代的光学纯(S)-(+)-或(R)-(-)-10-羟基-二氢二苯并[b,f]氮杂环己烯或其衍生物。本发明还提供了利用这样制备的(S)-(+)-或(R)-(-)-10-羟基-二氢二苯并[b,f]氮杂环己烯制备它们的酯，如(S)-(-)-10-乙酰氧基-10,11-二氢-5H-二苯并[b,f]氮杂环己烯-5-羧酰胺或(R)-(+)-10-乙酰氧基-10,11-二氢-5H-二苯并[b,f]氮杂环己烯-5-羧酰胺。本发明还提供了新颖的固态结晶形式J1、J2、J3、J4和eslicarbazepine的非晶态形式及其制备方法。此外，本发明提供了eslicarbazepine乙酸盐的新颖固态结晶形式和非晶态形式以及其制备方法。eslicarbazepine的新颖固态形式对于制备eslicarbazepine乙酸盐等eslicarbazepine的衍生物非常有用。
• One-step lipase-catalysed preparation of eslicarbazepine
  作者：M. F. El-Behairy、E. Sundby

  DOI：10.1039/c6ra23915c

  日期：——

  RS-licarbazepine via lipase catalysed kinetic resolution. A novel stereoselective simultaneous HPLC separations of RS-licarbazepine (1) and its racemic esters RS-2–5 have been developed on Lux® cellulose-2 column using cyclohexane/ethanol 1/1 v/v as mobile phase. The developed enantioselective HPLC separations have been utilized for monitoring of lipase catalyzed kinetic resolution of RS-licarbazepine (1). Lipase

  抗癫痫药依斯卡西平（S -licarbazepine）是由外消旋形式RS-利卡卡西平通过脂肪酶催化的动力学拆分一步制备的。的一种新的立体选择性同时HPLC分离RS -licarbazepine（1）和其外消旋酯RS - 2-5已经对Lux®纤维素-2柱，使用环己烷/乙醇1/1 V / V作为流动相显影。已开发的对映选择性HPLC分离已用于监测脂肪酶催化的RS-利卡西平的动力学拆分（1）。已经进行了脂肪酶催化的酯交换和水解反应。研究了四种不同的酯（乙酸酯（2），丙酸酯（3），丁酸酯（4）和苯甲酸酯（5））的酯交换和水解反应，使用了十种来自多种来源的脂肪酶。用的反式酯化所示的对映体选择性最好RS与以M苯甲酸乙烯酯-licarbazepine吨BE从溶剂和脂肪酶皱褶假丝酵母，其中所述药理学活性对映异构体，小号- （+） -利卡西平，已完成[ ë = 31，EE = 97％，产率84％，α 20 d=
• [EN] METHOD FOR CHIRAL INVERSION OF (S)-(+)- AND (R)-(-)-10,11-DIHYDRO-10-HYDROXY-5H-DIBENZ/B,F/AZEPINE-5-CARBOXAMIDE AND OPTICALLY ENRICHED MIXTURES THEREOF<br/>[FR] PROCEDE D'INVERSION CHIRALE DE (S)-(+)- ET (R)-(-)-10,11-DIHYDRO-10-HYDROXY-5H-DIBENZ/B,F/AZEPINE-5-CARBOXAMIDE ET MELANGES OPTIQUEMENT ENRICHIS DE CEUX-CI
  申请人：PORTELA & CA SA

  公开号：WO2006005951A1

  公开（公告）日：2006-01-19

  A method for chiral inversion of optically pure or optically enriched mixtures of (S)-(+)-10,11-dihydro-10-hydroxy-5H-dibenz/b,f/azepine-5-carboxamide (I) and (R)-(-)-10,11­dihydro-10-hydroxy-5H-dibenz/b,f/azepine-5-carboxamide (II) with a carboxylic acid nucleophile in the presence of a trisubstituted phosphine and a disubstituted azodicarboxylate in a substantially inert solvent is disclosed.

  一种用于手性反转的方法，包括在基本惰性溶剂中，以存在三取代膦和二取代偶氮二羧酸酯的情况下，利用羧酸亲核试剂对光学纯或光学富集的(S)-(+)-10,11-二氢-10-羟基-5H-二苯并/b,f/氮杂七环-5-羧酰胺(I)和(R)-(-)-10,11-二氢-10-羟基-5H-二苯并/b,f/氮杂七环-5-羧酰胺(II)进行手性反转。
• [EN] PROCESS FOR PREPARATION OF ENANTIOMERS OF LICARBAZEPINE<br/>[FR] PROCÉDÉ DE PRÉPARATION D'ÉNANTIOMÈRES DE LICARBAZÉPINE
  申请人：INTAS PHARMACEUTICALS LTD

  公开号：WO2011117885A1

  公开（公告）日：2011-09-29

  The present invention provides a process for the preparation of eslicarbazepine and rlicarbazepine and their acetates by resolution of racemic licarbazepine using acetyl mandelic acid.

  本发明提供了一种通过使用乙酰苯甲酸对混合性利卡巴嗪进行分离，制备艾司卡巴嗪和艾利卡巴嗪及其乙酸盐的方法。
• 不对称催化氢化反应的前体反应物的重结晶纯化工艺
  申请人：天津安浩生物科技有限公司

  公开号：CN108840825A

  公开（公告）日：2018-11-20

  本发明提供了一种Eslicarbazepine及其衍生物制备的前体反应物(precursor)的重结晶纯化装置，其特征在于：采用重结晶纯化工艺和装置，去除前体反应物中的未反应的原料、副产物及杂质，消除了手性催化剂的毒化，大大提高手性催化剂的转化率，有效改进了不对称氢化的收率，实现了更佳的生产效率，有效地提高了Eslicarbazepine及其衍生物批量生产的性价比。