(6R,9R)-6-(2,3-difluorophenyl)-9-((triisopropylsilyl)oxy)-6,7,8,9-tetrahydro-5Hcyclohepta[b]pyridin-5-one | 1397526-07-6

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: (6R,9R)-6-(2,3-difluorophenyl)-9-((triisopropylsilyl)oxy)-6,7,8,9-tetrahydro-5Hcyclohepta[b]pyridin-5-one
• 英文别名: (6R,9R)-6-(2,3-difluorophenyl)-9-(triisopropylsilyloxy)-6,7,8,9-tetrahyrdocyclohepta[b]pyridine-5-one；5H-Cyclohepta[b]pyridin-5-one, 6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-9-[[tris(1-methylethyl)silyl]oxy]-, (6R,9R)-；(6R,9R)-6-(2,3-difluorophenyl)-9-tri(propan-2-yl)silyloxy-6,7,8,9-tetrahydrocyclohepta[b]pyridin-5-one
• CAS: 1397526-07-6
• 化学式: C₂₅H₃₃F₂NO₂Si
• 分子量: 445.625
• InChiKey: AIVVBBARCYSYDU-DENIHFKCSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7.35
• 重原子数：
  31
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.52
• 拓扑面积：
  39.2
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  2,3-吡啶二甲酸二甲酯 在 盐酸 、 Rh-(R-binapine)(COD)BF₄ 、 potassium tert-butylate 、 氢气 、 palladium diacetate 、 三乙胺 、 sodium t-butanolate 、 tri tert-butylphosphoniumtetrafluoroborate 作用下， 以 四氢呋喃 、 二氯甲烷 、 水 、 甲苯 为溶剂， 95.0 ℃ 、689.49 kPa 条件下， 反应 27.5h， 生成 (6R,9R)-6-(2,3-difluorophenyl)-9-((triisopropylsilyl)oxy)-6,7,8,9-tetrahydro-5Hcyclohepta[b]pyridin-5-one
  参考文献：
  名称：

  Efficient and Scalable Enantioselective Synthesis of a CGRP Antagonist

  摘要：

  An enantioselective synthesis of the CGRP antagonist BMS-846372, amenable to large scale preparation, is presented. This new synthesis showcases a chemo- and enantioselective reduction of a cyclohepta[b]pyridine-5,9-dione as well as a Pd-catalyzed alpha-arylation reaction to form the key carbon-carbon bond and set the absolute and relative stereochemistry.

  DOI：

  10.1021/ol302262q

文献信息

• CGRP Receptor Antagonists
  申请人：Luo Guanglin

  公开号：US20090258866A1

  公开（公告）日：2009-10-15

  The disclosure generally relates to the novel compounds of formula I, including their salts, which are CGRP receptor antagonists. The disclosure also relates to pharmaceutical compositions and methods for using the compounds in the treatment of CGRP related disorders including migraine and other headaches, neurogenic vasodilation, neurogenic inflammation, thermal injury, circulatory shock, flushing associated with menopause, airway inflammatory diseases such as asthma, and chronic obstructive pulmonary disease (COPD).

  本公开通常涉及公式I的新化合物，包括它们的盐，这些盐是CGRP受体拮抗剂。本公开还涉及用于治疗CGRP相关疾病，包括偏头痛和其他头痛、神经源性血管扩张、神经源性炎症、热损伤、循环性休克、与更年期相关的潮红、气道炎症性疾病如哮喘和慢性阻塞性肺病（COPD）的药物组合物和方法。
• Development of a scalable palladium-catalyzed α-arylation process for the synthesis of a CGRP antagonist
  作者：Lopa V. Desai、Michael B. Hay、David K. Leahy、Carolyn Wei、Dayne Fanfair、Thorsten Rosner、Yi Hsiao

  DOI：10.1016/j.tet.2013.04.057

  日期：2013.7

  The Pd-catalyzed alpha-arylation of cycloheptapyridyl ketone is a key complexity-building step in the synthesis of BMS-846372, a CGRP antagonist. A first-generation process utilized Pd(OAc)(2)/(PBu3)-Bu-t center dot HBF4 catalyst system with a strong base (NaOBu)-Bu-t. Although this process was demonstrated on multi-kilo scale, the harsh conditions led to non-selective metal catalyzed processes, which generated several operational, quality, and throughput issues. By acquiring detailed knowledge around several important process parameters, we were able to design an efficient and scalable second-generation alpha-arylation process using a Pd(OAc)(2)/RuPhos catalyst system with the weaker base, K3PO4 in tert-amyl alcohol. This new weak base process was high yielding, efficient, and superior in several respects compared to the strong base process. The strategy behind the reaction and isolation development and the process considerations important to scaling a catalytic reaction from laboratory to manufacturing scale will be discussed. (C) 2013 Elsevier Ltd. All rights reserved.
• Efficient and Scalable Enantioselective Synthesis of a CGRP Antagonist
  作者：David K. Leahy、Yu Fan、Lopa V. Desai、Collin Chan、Jason Zhu、Guanglin Luo、Ling Chen、Ronald L. Hanson、Masano Sugiyama、Thorsten Rosner、Nicolas Cuniere、Zhiwei Guo、Yi Hsiao、Qi Gao

  DOI：10.1021/ol302262q

  日期：2012.9.21

  An enantioselective synthesis of the CGRP antagonist BMS-846372, amenable to large scale preparation, is presented. This new synthesis showcases a chemo- and enantioselective reduction of a cyclohepta[b]pyridine-5,9-dione as well as a Pd-catalyzed alpha-arylation reaction to form the key carbon-carbon bond and set the absolute and relative stereochemistry.