(11aS)-7,8-dimethoxy-2,3,5,10,11,11a-hexahydro-1H-pyrrolo[2,1-c]-[1,4]benzodiazepine-5,11-dione

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯二氮卓类
• 英文名称: (11aS)-7,8-dimethoxy-2,3,5,10,11,11a-hexahydro-1H-pyrrolo[2,1-c]-[1,4]benzodiazepine-5,11-dione
• 英文别名: (11aS)-7,8-dimethoxy-2,3,5,10,11,11a-hexahydro-1H-pyrrolo[2,1-c][1,4]benzodiazepine-5,11-dione；(11aS)-7,8-dimethoxy-1,2,3,10,11,11a-hexahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5,11-dione；(11aS)-7,8-Dimethoxy-1,2,3,10,11,11a-hexahydro-5H-pyrrolo[2,1-c]-(1,4)-benzo-diazepine-5,11-dione；(6aS)-2,3-dimethoxy-6a,7,8,9-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-6,11-dione
• 化学式: C₁₄H₁₆N₂O₄
• 分子量: 276.292
• InChiKey: OTPXJHDUEWRZTQ-JTQLQIEISA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.8
• 重原子数：
  20
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  67.9
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  藜芦酸 在 hexacarbonyl molybdenum lithium hydroxide 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 、 [双(三氟乙酰氧基)碘]苯 作用下， 以 四氢呋喃 、 二氯甲烷 、 水 、 乙腈 为溶剂， 生成 (11aS)-7,8-dimethoxy-2,3,5,10,11,11a-hexahydro-1H-pyrrolo[2,1-c]-[1,4]benzodiazepine-5,11-dione
  参考文献：
  名称：

  一种高效，PIFA介导的苯并，萘和杂环吡咯并[ 2,1- c ] [1,4]二氮杂s的方法。有利获得抗肿瘤抗生素DC-81

  摘要：

  提出了从1-脯氨酸甲酯开始合成一系列光学纯的苯并，萘和杂环稠合的吡咯并[2,1- c ] [1,4]-二氮杂-5,11-二酮衍生物。合成计划包括在脯氨酸氮上进行芳构化步骤，然后将酯残基转化为N-甲氧基酰胺基团。随后的关键环化步骤包括PIFA介导的N的形成-酰基硝基re中间体及其后续的分子内被芳环的俘获。提出的通用方法解决了从不太容易获得的氨基（或相关功能）芳香族起始原料开始的需要，并且其有效性在抗肿瘤抗生素DC-81的合成中得到了证明。

  DOI：

  10.1021/jo047872u

文献信息

• One-Pot Microwave-Assisted Selective Azido Reduction/Tandem Cyclization in Condensed and Solid Phase with Nickel Boride
  作者：Ahmed Kamal、Leonardo Silva Santos、Nagula Shankaraiah、Nagula Markandeya、Marlene Espinoza-Moraga、Claudia Arancibia

  DOI：10.1055/s-0029-1216831

  日期：2009.7

  inexpensive method using microwave-assisted irradiation with Ni2B for the syntheses of aromatic amines, pyrrolobenzodiazepines as well as pyrroloquinazolinones was developed. This protocol was applied in the tandem resin-cleavage, azido reduction, and cyclization of compounds 3 and 5 that afforded substituted pyrrolo[2,1-c][1,4]benzodiazepines 4 and 6 in a one-pot manner. The microwave-assisted irradiation

  开发了一种高效且廉价的方法，该方法使用微波辅助的Ni 2 B辐射来合成芳族胺，吡咯并苯并二氮杂pine以及吡咯并喹唑啉酮。该方案适用于串联式树脂裂解，叠氮基还原和化合物3和5的环化反应，这些化合物以一锅方式提供取代的吡咯并[2,1- c ] [1,4]苯并二氮杂卓4和6。与常规的热反应相比，微波辅助的辐射反应以非常短的反应时间提高了产率。 吡咯并[2,1- c ] [1,4]苯并二氮杂卓-吡咯并喹唑啉酮-叠氮还原环化-硼化镍-微波辐射
• Chemoselective Aromatic Azido Reduction with Concomitant Aliphatic Azide Employing Al/Gd Triflates/NaI and ESI-MS Mechanistic Studies
  作者：Ahmed Kamal、Nagula Markandeya、Nagula Shankaraiah、C. Ratna Reddy、S. Prabhakar、C. Sanjeeva Reddy、Marcos N. Eberlin、Leonardo Silva Santos

  DOI：10.1002/chem.200900853

  日期：2009.7.20

  triflates catalyze the chemoselective reduction of aromatic azides to the corresponding amines in combination with sodium iodide. This mild chemoselective method has been applied to the synthesis of various aryl amines, C2‐azido‐substituted pyrrolo[2,1‐c][1,4]benzodiazepines, and fused[2,1‐b]quinazolinones by an intramolecular azido reduction tandem cyclization reaction. Interestingly, this methodology

  铝和ado三氟甲磺酸盐与碘化钠一起催化将芳族叠氮化物化学选择性还原为相应的胺。这种温和的化学选择性方法已应用于各种芳基胺的合成，C2叠氮基取代的吡咯并[2,1- c ^ ] [1,4]苯二氮，和稠合[2,1- b通过分子内还原叠氮]喹唑啉酮串联环化反应。有趣的是，这种方法选择性地还原了芳基叠氮化物，提高了产率，并且比以前的策略在较短的反应时间内进行。已对机理进行了研究，并通过ESI-MS在线监测反应来拦截和表征与这种选择性转化有关的中间体。
• [EN] UNSYMMETRICAL PYRROLOBENZODIAZEPINES-DIMERS FOR USE IN THE TREATMENT OF PROLIFERATIVE AND AUTOIMMUNE DISEASES<br/>[FR] DIMÈRES DE PYRROLOBENZODIAZÉPINES ASYMÉTRIQUES À UTILISER DANS LE TRAITEMENT DE MALADIES PROLIFÉRATIVES ET AUTO-IMMUNES
  申请人：SPIROGEN SARL

  公开号：WO2014096365A1

  公开（公告）日：2014-06-26

  A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein: R2 is of formula (IIa), formula (IIb) or formula (IIc): (a) where A is a C5-7 aryl group, and either (i) Q1 is a single bond, and Q2 is selected from a single bond and -Z-(CH2)n-, where Z is selected from a single bond, O, S and NH and n is from 1 to 3; or (ii) Q1 is -CH=CH-, and Q2 is a single bond; (b) where: RC1, RC2 and RC3 are independently selected from H and unsubstituted C1-2 alkyl; (c) where Q is selected from OH, SH and NRN, and RN is selected from H, methyl and ethyl X is selected from the group comprising: OH, SH, CO2H, COH, N=C=O, NHNH2, CONHNH2, (formula (x)), (formular (y), NHRN, wherein RN is selected from the group comprising H and C1-4 alkyl; and either: when there is a double bond present between C2' and C3', R12 is selected from the group consisting of: (ia) C5-10 aryl group, optionally substituted by one or more substituents selected from the group comprising: halo, nitro, cyano, ether, carboxy, ester, C1-7 alkyl, C3-7 heterocyclyl and bis-oxy-C1-3 alkylene; (ib) C1-5 saturated aliphatic alkyl; (ic) C3-6 saturated cycloalkyl; (id), wherein each of R21, R22 and R23 are independently selected from H, C1-3 saturated alkyl, C2-3 alkenyl, C2-3 alkynyl and cyclopropyl, where the total number of carbon atoms in the R12 group is no more than 5; (ie), wherein one of R25a and R25b is H and the other is selected from: phenyl, which phenyl is optionally substituted by a group selected from halo, methyl, methoxy; pyridyl; and thiophenyl; and (if), where R24 is selected from: H; C1-3 saturated alkyl; C2-3 alkenyl; C2-3 alkynyl; cyclopropyl; phenyl, which phenyl is optionally substituted by a group selected from halo, methyl, methoxy; pyridyl; and thiophenyl; when there is a single bond present between C2' and C3', R12 is (formula (z)), where R26a and R26b are independently selected from H, F, C1-4 saturated alkyl, C2-3 alkenyl, which alkyl and alkenyl groups are optionally substituted by a group selected from C1-4 alkyl amido and C1-4 alkyl ester; or, when one of R26a and R26b is H, the other is selected from nitrile and a C1-4 alkyl ester; R6 and R9 are independently selected from H, R, OH, OR, SH, SR, NH2, NHR, NRR', nitro, Me3Sn and halo; where R and R' are independently selected from optionally substituted C1-12 alkyl, C3-20 heterocyclyl and C5-20 aryl groups; R7 is selected from H, R, OH, OR, SH, SR, NH2, NHR, NHRR', nitro, Me3Sn and halo; R" is a C3-12 alkylene group, which chain may be interrupted by one or more heteroatoms, e.g. O, S, NRN2 (where RN2 is H or C1-4 alkyl), and/or aromatic rings, e.g. benzene or pyridine; Y and Y' are selected from O, S, or NH; R6', R7', R9' are selected from the same groups as R6, R7 and R9 respectively; either: (A) R20 is H or Me and R21a and R21b are both H or together form =O and either: (i) R10 is H, R11a is H and R11b is OH or ORA, where RA is C1-4 alkyl; or (ii) R10 and R11b form a nitrogen-carbon double bond between the nitrogen and carbon atoms to which they are bound and R11a is H; or (iii) R10 is H, R11a is H and R11b is SOzM, where z is 2 or 3 and M is a monovalent pharmaceutically acceptable cation; or (B) R10 is H or Me and R11a and R11b are both H or together form =O and either: (i) R20 is H, R21a is H and R21b is OH or ORA, where RA is C1-4 alkyl; or (ii) R20 and R21b form a nitrogen-carbon double bond between the nitrogen and carbon atoms to which they are bound and R11a is H; or (iii) R20 is H, R21a is H and R21b is SOzM, where z is 2 or 3 and M is a monovalent pharmaceutically acceptable cation.

  公式（I）的化合物或其药学上可接受的盐或溶剂，其中：R2为公式（IIa）、公式（IIb）或公式（IIc）：（a）其中A为C5-7芳基，且Q1为单键，Q2从单键和-Z-(CH2)n-中选择，其中Z从单键、O、S和NH中选择，n为1至3；或Q1为-CH=CH-，Q2为单键；（b）其中：RC1、RC2和RC3独立选择自H和未取代的C1-2烷基；（c）其中Q从OH、SH和NRN中选择，RN从H、甲基和乙基中选择，X从包括的组中选择：OH、SH、CO2H、COH、N=C=O、NHNH2、CONHNH2、（公式（x））、（公式（y））、NHRN，其中RN从H和C1-4烷基中选择；当C2'和C3'之间存在双键时，R12从以下组中选择：（ia）C5-10芳基，可选择地由以下一种或多种取代基取代：卤素、硝基、氰基、醚、羧基、酯、C1-7烷基、C3-7杂环烷基和双氧-C1-3烷基；（ib）C1-5饱和脂肪烷基；（ic）C3-6饱和环烷基；（id），其中R21、R22和R23各自独立选择自H、C1-3饱和烷基、C2-3烯基、C2-3炔基和环丙基，其中R12基中碳原子的总数不超过5；（ie），其中R25a和R25b中的一个为H，另一个从以下选择：苯基，该苯基可选择地由卤素、甲基、甲氧基中的一种取代基取代；吡啶基；和噻吩基；和（if），其中R24从以下选择：H；C1-3饱和烷基；C2-3烯基；C2-3炔基；环丙基；苯基，该苯基可选择地由卤素、甲基、甲氧基中的一种取代基取代；吡啶基；和噻吩基；当C2'和C3'之间存在单键时，R12为（公式（z）），其中R26a和R26b各自独立选择自H、F、C1-4饱和烷基、C2-3烯基，该烷基和烯基基团可选择地由C1-4烷基酰胺和C1-4烷基酯中的一种取代；或当R26a和R26b中的一个为H时，另一个从腈和C1-4烷基酯中选择；R6和R9独立选择自H、R、OH、OR、SH、SR、NH2、NHR、NRR'、硝基、Me3Sn和卤素；其中R和R'独立选择自可选择地取代的C1-12烷基、C3-20杂环烷基和C5-20芳基；R7从H、R、OH、OR、SH、SR、NH2、NHR、NHRR'、硝基、Me3Sn和卤素中选择；R"为C3-12烷基基团，该链可由一个或多个杂原子，例如O、S、NRN2（其中RN2为H或C1-4烷基），和/或芳香环，例如苯或吡啶，中断；Y和Y'从O、S或NH中选择；R6'、R7'、R9'从R6、R7和R9中选择的相同基团中选择；要么：（A）R20为H或Me，R21a和R21b都为H或一起形成=O，且要么：（i）R10为H，R11a为H，R11b为OH或ORA，其中RA为C1-4烷基；或（ii）R10和R11b在它们结合的氮和碳原子之间形成氮-碳双键，R11a为H；或（iii）R10为H，R11a为H，R11b为SOzM，其中z为2或3，M为一价的药学上可接受的阳离子；或（B）R10为H或Me，R11a和R11b都为H或一起形成=O，且要么：（i）R20为H，R21a为H，R21b为OH或ORA，其中RA为C1-4烷基；或（ii）R20和R21b在它们结合的氮和碳原子之间形成氮-碳双键，R11a为H；或（iii）R20为H，R21a为H，R21b为SOzM，其中z为2或3，M为一价的药学上可接受的阳离子。
• Synthesis of DNA-Interactive Pyrrolo[2,1-<i>c</i>][1,4]benzodiazepines by Employing Polymer-Supported Reagents: Preparation of DC-81
  作者：Ahmed Kamal、K. Reddy、V. Devaiah、N. Shankaraiah

  DOI：10.1055/s-2004-834821

  日期：——

  generation of combinatorial library of substituted pyrrolo[2,1-c][1,4]benzodiazepine derivatives that provides a clean and efficient preparation and does not require conventional purification techniques like chromatography. This methodology involves intra molecular aza-Wittig reaction and has been extended for the synthesis of the natural product DC-81 in good overall yields.

  聚合物支持的试剂已被用于生成取代吡咯并 [2,1-c][1,4] 苯二氮卓衍生物的组合文库，该文库提供了一种清洁高效的制备方法，并且不需要常规的纯化技术，如色谱法。这种方法涉及分子内 aza-Wittig 反应，并已扩展到以良好的总产率合成天然产物 DC-81。
• [EN] NOVEL BENZIMIDAZOLE LINKED PYRROLO[2,1-Q[1,4] BENZODIAZEPINE HYBRIDS AS POTENTIAL ANTITUMOUR AGENTS AND PROCESS FOR THE PREPARATION THEREOF<br/>[FR] NOUVEAUX HYBRIDES DE PYRROLO[2,1-Q[1,4] BENZODIAZÉPINE LIÉS AU UN CYCLE BENZIMIDAZOLE EN TANT QU'AGENTS ANTI-TUMORAUX ET LEURS PROCÉDÉS DE PRÉPARATION
  申请人：COUNCIL SCIENT IND RES

  公开号：WO2009113085A1

  公开（公告）日：2009-09-17

  The present invention provides a compounds of general formula (8), (11) and (14), useful as potential antitumour agents against human cancer cell lines. The present invention further provides a process for the preparation of pyrrolo [2,1-c][1,4]benzodiazepine hybrids of general formula (8), (11) and (14).

  本发明提供了一种通式（8）、（11）和（14）的化合物，可作为潜在的抗人类癌细胞系肿瘤药剂。本发明还提供了一种制备通式（8）、（11）和（14）的吡咯并[2,1-c][1,4]苯二氮杂环杂合物的方法。