1-(4-fluorophenyl)-5-formyl-4-isopropyl-1H-pyrazole-3-carboxylic acid 4-methylbenzylamide | 1260620-74-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 1-(4-fluorophenyl)-5-formyl-4-isopropyl-1H-pyrazole-3-carboxylic acid 4-methylbenzylamide
• CAS: 1260620-74-3
• 化学式: C₂₂H₂₂FN₃O₂
• 分子量: 379.434
• InChiKey: NKRUTPHAXLMHDI-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.19
• 重原子数：
  28.0
• 可旋转键数：
  6.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.23
• 拓扑面积：
  63.99
• 氢给体数：
  1.0
• 氢受体数：
  4.0

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 在 diethylmethoxyborane 、 氢氟酸 作用下， 以 四氢呋喃 、 甲醇 、 水 、 甲苯 、 乙腈 为溶剂， 反应 56.5h， 生成 7-[2-(4-fluorophenyl)-4-isopropyl-5-(4-methylbenzylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-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：

  Ethyl 1-(4-fluorophenyl)-5-formyl-4-propan-2-ylpyrazole-3-carboxylate 反应 20.0h， 生成 1-(4-fluorophenyl)-5-formyl-4-isopropyl-1H-pyrazole-3-carboxylic acid 4-methylbenzylamide
  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

文献信息

• Substituted Pyrazoles as Hepatoselective HMG-CoA Reductase Inhibitors: Discovery of (3<i>R</i>,5<i>R</i>)-7-[2-(4-Fluoro-phenyl)-4-isopropyl-5-(4-methyl-benzylcarbamoyl)-2<i>H</i>-pyrazol-3-yl]-3,5-dihydroxyheptanoic Acid (PF-3052334) as a Candidate for the Treatment of Hypercholesterolemia
  作者：Jeffrey A. Pfefferkorn、Chulho Choi、Scott D. Larsen、Bruce Auerbach、Richard Hutchings、William Park、Valerie Askew、Lisa Dillon、Jeffrey C. Hanselman、Zhiwu Lin、Gina H. Lu、Andrew Robertson、Catherine Sekerke、Melissa S. Harris、Alexander Pavlovsky、Graeme Bainbridge、Nicole Caspers、Mark Kowala、Bradley D. Tait

  DOI：10.1021/jm070849r

  日期：2008.1.1

  In light of accumulating evidence that aggressive LDL-lowering therapy may offer increased protection against coronary heart disease, we undertook the design and synthesis of a novel series of HMG-CoA reductase inhibitors based upon a substituted pyrazole template. Optimizing this series using both structure-based design and molecular property considerations afforded a class of highly efficacious and hepatoselective inhibitors resulting in the identification of (3 R,5 R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-methyl-benzylcarbamoyl)-2 H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic (PF-3052334) as a candidate for the treatment of hypercholesterolemia.