ethyl (3R)-(tert-butyldimethylsilyloxy)-5-oxo-6-(triphenylphosphoranylidene)-hexanoate | 917752-46-6

• 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: ethyl (3R)-(tert-butyldimethylsilyloxy)-5-oxo-6-(triphenylphosphoranylidene)-hexanoate
• 英文别名: ethyl (3R)-3-[tert-butyl(dimethyl)silyl]oxy-5-oxo-6-(triphenyl-lambda5-phosphanylidene)hexanoate；ethyl (3R)-3-[tert-butyl(dimethyl)silyl]oxy-5-oxo-6-(triphenyl-λ5-phosphanylidene)hexanoate
• CAS: 917752-46-6
• 化学式: C₃₂H₄₁O₄PSi
• 分子量: 548.734
• InChiKey: KPVOVUDNCGMDLU-HHHXNRCGSA-N

物化性质

• 沸点：
  614.4±65.0 °C(Predicted)
• 密度：
  1.09±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  6.09
• 重原子数：
  38
• 可旋转键数：
  13
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.34
• 拓扑面积：
  52.6
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  1-(4-fluorophenyl)-5-formyl-4-isopropyl-1H-pyrazole-3-carboxylic acid 4-methylbenzylamide 、 ethyl (3R)-(tert-butyldimethylsilyloxy)-5-oxo-6-(triphenylphosphoranylidene)-hexanoate 以 甲苯 为溶剂， 反应 36.0h， 以95%的产率得到3-(tert-butyl-dimethyl-silanyloxy)-7-[2-(4-fluorophenyl)-4-isopropyl-5-(4-methyl-benzylcarbamoyl)-2H-pyrazol-3-yl]-5-oxo-hept-6-enoic acid ethyl ester
  参考文献：
  名称：

  Development of an Early Enabling Synthesis for PF-03052334-02: A Novel Hepatoselective HMG-CoA Reductase Inhibitor

  摘要：

  Early process development work toward a promising pyrazole-based HMG-CoA reductase inhibitor is described. PF-03052334-02 (1) was prepared in 14 synthetic steps with a 21% overall yield, highlighted by a modified three-step hydroxypyrazole formation in which the yield was improved from 37% to 73%, a Suzuki/ozonolysis pathway that streamlined the downstream chemistry, and a reversed Wittig olefination strategy that improved the key coupling step from 50% to 95% yield. Multiple process hazards and most chromatography steps were removed, and a highly effective active pharmaceutical ingredient (API) salt formation, purification, and isolation protocol was also developed.

  DOI：

  10.1021/op100268e
• 作为产物：
  描述：

  3-羟基戊二酸二乙酯 在 咪唑 、 正丁基锂 、 α-chymotrypsin 、 三乙胺 作用下， 以 四氢呋喃 、 正己烷 、 甲基叔丁基醚 为溶剂， 反应 54.0h， 生成 ethyl (3R)-(tert-butyldimethylsilyloxy)-5-oxo-6-(triphenylphosphoranylidene)-hexanoate
  参考文献：
  名称：

  在没有中间隔离的情况下，在多步药物合成中进行集成生物催化：瑞舒伐他汀关键构建模块的从头研究方法

  摘要：

  在这项贡献中，我们报告了化学酶法制备活性药物成分瑞舒伐他汀的关键组成部分，瑞舒伐他汀是2012年全球市场价值62.5亿美元的“前五名重磅炸弹药物”之一，通过七步合成法进行了分离中间体，并结合了两种高效的生物转化方法。通过使用高浓度的底物（每升几百克），该化学酶促过程达到了极好的时空产率，强调了生物催化在与药物合成相关的工业过程中的潜力，以及酶化学与经典有机合成的相容性。

  DOI：

  10.1021/acs.oprd.5b00057

文献信息

• ROSUVASTATIN CALCIUM INTERMEDIATE AND METHOD FOR PREPARING THE SAME
  申请人：LIN Wenqing

  公开号：US20120310000A1

  公开（公告）日：2012-12-06

  A method for preparing a rosuvastatin calcium intermediate, including a) contacting a halogenated ethene with magnesium metal to obtain a halogenated ethene Grignard reagent, and carrying out a Grignard reaction between the halogenated ethene Grignard reagent and R-epichlorohydrin; b) adding sodium cyanide for carrying out a nucleophilic substitution reaction; c) adding alcohol for carrying out an alcoholysis reaction; d) adding a basic solvent for carrying out protection of a first hydroxyl group; e) selectively oxidizing a second hydroxyl group; and f) adding triphenylphosphine in alkaline condition for carrying out a Wittig reaction.

  一种制备罗苏伐他汀钙中间体的方法，包括a) 将卤代乙烯与镁金属接触以获得卤代乙烯格氏试剂，并在卤代乙烯格氏试剂和R-环氧氯丙烷之间进行格氏反应；b) 添加氰化钠进行亲核取代反应；c) 添加醇进行醇解反应；d) 添加碱性溶剂以保护第一个羟基团；e) 选择性氧化第二个羟基团；f) 在碱性条件下添加三苯基膦进行威特希格反应。
• ROSUVASTATIN CALCIUM INTERMEDIATE AND PREPARATION METHOD THEREOF
  申请人：Porton Fine Chemicals Ltd

  公开号：EP2557084B1

  公开（公告）日：2014-06-18
• Development of an Early Enabling Synthesis for PF-03052334-02: A Novel Hepatoselective HMG-CoA Reductase Inhibitor
  作者：Daniel M. Bowles、David C. Boyles、Chulho Choi、Jeffrey A. Pfefferkorn、Stephanie Schuyler、Edward J. Hessler

  DOI：10.1021/op100268e

  日期：2011.1.21

  Early process development work toward a promising pyrazole-based HMG-CoA reductase inhibitor is described. PF-03052334-02 (1) was prepared in 14 synthetic steps with a 21% overall yield, highlighted by a modified three-step hydroxypyrazole formation in which the yield was improved from 37% to 73%, a Suzuki/ozonolysis pathway that streamlined the downstream chemistry, and a reversed Wittig olefination strategy that improved the key coupling step from 50% to 95% yield. Multiple process hazards and most chromatography steps were removed, and a highly effective active pharmaceutical ingredient (API) salt formation, purification, and isolation protocol was also developed.
• Integrated Biocatalysis in Multistep Drug Synthesis without Intermediate Isolation: A de Novo Approach toward a Rosuvastatin Key Building Block
  作者：Richard Metzner、Werner Hummel、Frank Wetterich、Burghard König、Harald Gröger

  DOI：10.1021/acs.oprd.5b00057

  日期：2015.6.19

  preparation of a key building block for the active pharmaceutical ingredient rosuvastatin, one of the “top 5 blockbuster drugs” with a worldwide market value of 6.25 billion USD in 2012, via a seven-step synthesis without isolation of intermediates and with incorporation of two highly efficient biotransformations. This chemoenzymatic process reaches excellent space-time yields by using high substrate concentrations

  在这项贡献中，我们报告了化学酶法制备活性药物成分瑞舒伐他汀的关键组成部分，瑞舒伐他汀是2012年全球市场价值62.5亿美元的“前五名重磅炸弹药物”之一，通过七步合成法进行了分离中间体，并结合了两种高效的生物转化方法。通过使用高浓度的底物（每升几百克），该化学酶促过程达到了极好的时空产率，强调了生物催化在与药物合成相关的工业过程中的潜力，以及酶化学与经典有机合成的相容性。