3,5-dichloro-N-(2-(((1s,3R,5S)-3,5-dimethylcyclohexyl)oxy)-6-((R)-4-isopropyl-4,5-dihydrooxazol-2-yl)phenyl)benzenesulfonamide | 1192815-29-4

• 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: 3,5-dichloro-N-(2-(((1s,3R,5S)-3,5-dimethylcyclohexyl)oxy)-6-((R)-4-isopropyl-4,5-dihydrooxazol-2-yl)phenyl)benzenesulfonamide
• CAS: 1192815-29-4
• 化学式: C₂₆H₃₂Cl₂N₂O₄S
• 分子量: 539.523
• InChiKey: XWVFMVXHFSHCGA-OITUCODZSA-N

物化性质

• 熔点：
  97 °C
• 沸点：
  653.4±65.0 °C(Predicted)
• 密度：
  1.36±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  6.8
• 重原子数：
  35.0
• 可旋转键数：
  7.0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  76.99
• 氢给体数：
  1.0
• 氢受体数：
  5.0

反应信息

• 作为产物：
  描述：

  3,5-二氯苯磺酰氯 、 在 吡啶 、 4-二甲氨基吡啶 、 甲醇 、 potassium carbonate 作用下， 生成 3,5-dichloro-N-(2-(((1s,3R,5S)-3,5-dimethylcyclohexyl)oxy)-6-((R)-4-isopropyl-4,5-dihydrooxazol-2-yl)phenyl)benzenesulfonamide
  参考文献：
  名称：

  Toolbox Approach to the Search for Effective Ligands for Catalytic Asymmetric Cr-Mediated Coupling Reactions

  摘要：

  Chromium catalysts derived from chiral sulfonamides represented by A effect the couplings of aldehydes with vinyl, allyl, or alkyl halides. With three distinct sites for structural modification, A affords access to a structurally diverse pool of chiral sulfonamides. The Cr catalysts derived from these sulfonamides exhibit a broad range of catalyst-substrate matching profiles. A strategy is presented to search for a satisfactory chiral sulfonamide for a given substrate. In order to demonstrate the generality and effectiveness of this approach, five diverse C-C bond-forming cases have been selected from the halichondrin synthesis. For each of the cases, two ligands have been deliberately searched for, to induce the formation of (R)and (S)-alcohols, respectively, at the arbitrarily chosen efficiency level of ">= 80% yield with >= 20:1 stereoselectivity in the presence of <= 20 mol % of a Cr catalyst". For 9 out of the 10 cases studied, a satisfactory catalyst has been found within this pool of sulfonamides. Even for the remaining case, a Cr catalyst inducing stereoselectivity up to 8:1 has been identified.

  DOI：

  10.1021/ja905843e
• 作为试剂：
  描述：

  4-oxobutyl benzoate 、 (R)-tert-butyl((4-chloro-6-iodohept-6-en-1-yl)oxy)diphenylsilane 在 chromium dichloride 、 锰 、 二氯二茂锆 、 di-μ-chloro-bis[chloro(4,7-dimethyl-1,10-phenanthroline)]nickel(II) 、 3,5-dichloro-N-(2-(((1s,3R,5S)-3,5-dimethylcyclohexyl)oxy)-6-((R)-4-isopropyl-4,5-dihydrooxazol-2-yl)phenyl)benzenesulfonamide 、 1,8-双二甲氨基萘 、 lithium chloride 作用下， 以 乙腈 为溶剂， 生成 [(4S,7R)-10-[tert-butyl(diphenyl)silyl]oxy-7-chloro-4-hydroxy-5-methylidenedecyl] benzoate
  参考文献：
  名称：

  Toolbox Approach to the Search for Effective Ligands for Catalytic Asymmetric Cr-Mediated Coupling Reactions

  摘要：

  Chromium catalysts derived from chiral sulfonamides represented by A effect the couplings of aldehydes with vinyl, allyl, or alkyl halides. With three distinct sites for structural modification, A affords access to a structurally diverse pool of chiral sulfonamides. The Cr catalysts derived from these sulfonamides exhibit a broad range of catalyst-substrate matching profiles. A strategy is presented to search for a satisfactory chiral sulfonamide for a given substrate. In order to demonstrate the generality and effectiveness of this approach, five diverse C-C bond-forming cases have been selected from the halichondrin synthesis. For each of the cases, two ligands have been deliberately searched for, to induce the formation of (R)and (S)-alcohols, respectively, at the arbitrarily chosen efficiency level of ">= 80% yield with >= 20:1 stereoselectivity in the presence of <= 20 mol % of a Cr catalyst". For 9 out of the 10 cases studied, a satisfactory catalyst has been found within this pool of sulfonamides. Even for the remaining case, a Cr catalyst inducing stereoselectivity up to 8:1 has been identified.

  DOI：

  10.1021/ja905843e

文献信息

• [EN] SYNTHESIS OF HALICHONDRIN ANALOGS AND USES THEREOF<br/>[FR] SYNTHÈSE D'ANALOGUES D'HALOCHONDRINES ET LEURS UTILISATIONS
  申请人：HARVARD COLLEGE

  公开号：WO2016003975A1

  公开（公告）日：2016-01-07

  The present invention provides halichondrin analogs, such as compounds of Formula (I). The compounds may bind to microtubule sites, thereby inhibiting microtubule dynamics. Also provided are methods of synthesis, pharmaceutical compositions, kits, methods of treatment, and uses that involve the compounds for treatment of a proliferative disease (e.g., cancer). Compounds of the present invention are particularly useful for the treatment of metastatic breast cancer, non-small cell lung cancer, prostate cancer, and sarcoma. The included methods of synthesis are useful for the preparation of compounds of Formula (I)-(III) along with naturally occurring halicondrins (e.g., halichondrin B & C, norhalichondrin A, B, & C, and homohalichondrin A, B, & C). Also included are methods for interconverting between the halichondrins, norhalichondrins, and homohalichondrins and their unnatural epimers at the C38 ketal stereocenter through the use of an acid-mediated equilibration.

  本发明提供了半龙胆碱类似物，如化合物的结构式(I)所示。这些化合物可能结合到微管位点，从而抑制微管动力学。还提供了合成方法、药物组合物、试剂盒、治疗方法和利用这些化合物治疗增生性疾病（例如癌症）的用途。本发明的化合物特别适用于转移性乳腺癌、非小细胞肺癌、前列腺癌和肉瘤的治疗。所包括的合成方法适用于制备结构式(I)-(III)化合物以及天然存在的半龙胆碱（例如半龙胆碱B和C、诺半龙胆碱A、B和C以及同半龙胆碱A、B和C）。还包括通过使用酸介导的平衡方法在C38酮缩醛立体中心之间相互转化半龙胆碱、诺半龙胆碱和同半龙胆碱及其不自然对映体的方法。
• Unified Synthesis of Right Halves of Halichondrins A–C
  作者：Kenzo Yahata、Ning Ye、Kentaro Iso、Santhosh Reddy Naini、Shuji Yamashita、Yanran Ai、Yoshito Kishi

  DOI：10.1021/acs.joc.7b01283

  日期：2017.9.1

  respectively. Catalytic, asymmetric Ni/Cr-mediated coupling was used for three C–C bond formations. For all cases, the stereochemistry was controlled with the Cr catalyst prepared from the chiral sulfonamide identified via the toolbox approach. For (3 + 4)-, (6 + 7)-, and (9 + 10)-couplings, the stereoselectivity of 28:1, >40:1, and ∼20:1 was achieved by the Cr catalysts prepared from (S)-H, (S)-I, and (R)-L

  通过分别将共同的C20-C37结构单元9与C1-C19结构单元10a - c耦合，合成了右半部分的软骨素A-C 。催化的，不对称的Ni / Cr介导的偶联被用于三个C–C键的形成。对于所有情况，均采用通过工具箱方法鉴定的由手性磺酰胺制备的Cr催化剂控制立体化学。对于（3 + 4）-，（6 + 7）-和（9 + 10）偶联，通过（S）-H，（S）-I和（R）-大号，分别。与第一和第二偶联不同，第三偶联使用结构复杂的亲核试剂。已经证明，即使亲电试剂/亲核试剂的摩尔比＝ 1.0 / 1.1，偶联效率也优异。另外，第三偶联是通过带有游离羟基的底物实现的。在Ni / Cr介导的偶联中获得的产物以优异的总收率被转化为halichondrins A-C的右半部分。分别从商业d-半乳糖分28、24和24个步骤合成了右半数的halichondrins A-C（1a – c），总产率分别为13.4％，21.1％和16
• Synthesis of halichondrin analogs and uses thereof
  申请人：President and Fellows of Harvard College

  公开号：US10556910B2

  公开（公告）日：2020-02-11

  The present invention provides halichondrin analogs, such as compounds of Formula (I). The compounds may bind to microtubule sites, thereby inhibiting microtubule dynamics. Also provided are methods of synthesis, pharmaceutical compositions, kits, methods of treatment, and uses that involve the compounds for treatment of a proliferative disease (e.g., cancer). Compounds of the present invention are particularly useful for the treatment of metastatic breast cancer, non-small cell lung cancer, prostate cancer, and sarcoma. The included methods of synthesis are useful for the preparation of compounds of Formula (I)-(III) along with naturally occurring halicondrins (e.g., halichondrin B & C, norhalichondrin A, B, & C, and homohalichondrin A, B, & C). Also included are methods for interconverting between the halichondrins, norhalichondrins, and homohalichondrins and their unnatural epimers at the C38 ketal stereocenter through the use of an acid-mediated equilibration.

  本发明提供了卤虫菊酯类似物，如式（I）化合物。这些化合物可与微管位点结合，从而抑制微管动力学。本发明还提供了化合物的合成方法、药物组合物、试剂盒、治疗方法以及用于治疗增殖性疾病（如癌症）的用途。本发明的化合物尤其适用于治疗转移性乳腺癌、非小细胞肺癌、前列腺癌和肉瘤。本发明所包含的合成方法可用于制备式（I）-（III）化合物以及天然卤化膦（例如，卤化膦 B 和 C，去卤化膦 A、B 和 C，同卤化膦 A、B 和 C）。此外，还包括通过使用酸介导的平衡，在 C38 酮立体中心实现卤化琼脂、去卤化琼脂和高卤化琼脂及其非天然表聚物之间相互转化的方法。
• SYNTHESIS OF HALICHONDRINS
  申请人：President and Fellows of Harvard College

  公开号：EP3649135B1

  公开（公告）日：2022-12-28
• SYNTHESIS OF HALICHONDRIN ANALOGS AND USES THEREOF
  申请人：President and Fellows of Harvard College

  公开号：US20170137437A1

  公开（公告）日：2017-05-18

  The present invention provides halichondrin analogs, such as compounds of Formula (I). The compounds may bind to microtubule sites, thereby inhibiting microtubule dynamics. Also provided are methods of synthesis, pharmaceutical compositions, kits, methods of treatment, and uses that involve the compounds for treatment of a proliferative disease (e.g., cancer). Compounds of the present invention are particularly useful for the treatment of metastatic breast cancer, non-small cell lung cancer, prostate cancer, and sarcoma. The included methods of synthesis are useful for the preparation of compounds of Formula (I)-(III) along with naturally occurring halicondrins (e.g., halichondrin B & C, norhalichondrin A, B, & C, and homohalichondrin A, B, & C). Also included are methods for interconverting between the halichondrins, norhalichondrins, and homohalichondrins and their unnatural epimers at the C38 ketal stereocenter through the use of an acid-mediated equilibration.