tert-butyl 2-((4R,6S)-6-((E)-2-(4-(4-fluorophenyl)-6-isopropyl-2-(methylsulfonyl)pyrimidin-5-yl)vinyl)-2,2-dimethyl-1,3-dioxan-4-yl)-acetate

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 英文名称: tert-butyl 2-((4R,6S)-6-((E)-2-(4-(4-fluorophenyl)-6-isopropyl-2-(methylsulfonyl)pyrimidin-5-yl)vinyl)-2,2-dimethyl-1,3-dioxan-4-yl)-acetate
• 英文别名: Tert-butyl-7-[4-(4-fluorophenyl)-6-isopropyl-2-methylsulfonylpyrimidin-5-YL]-(3R,5S)-isopropylidene-(E)-6-heptenoate；tert-butyl 2-[(4R,6S)-6-[(E)-2-[4-(4-fluorophenyl)-2-methylsulfonyl-6-propan-2-ylpyrimidin-5-yl]ethenyl]-2,2-dimethyl-1,3-dioxan-4-yl]acetate
• 化学式: C₂₈H₃₇FN₂O₆S
• 分子量: 548.676
• InChiKey: BNJKDFDFKYYUGL-SVKRATOZSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.6
• 重原子数：
  38
• 可旋转键数：
  9
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.54
• 拓扑面积：
  113
• 氢给体数：
  0
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  tert-butyl 2-((4R,6S)-6-((E)-2-(4-(4-fluorophenyl)-6-isopropyl-2-(methylsulfonyl)pyrimidin-5-yl)vinyl)-2,2-dimethyl-1,3-dioxan-4-yl)-acetate 在 lithium hexamethyldisilazane 作用下， 生成 tert-butyl 2-((4R,6S)-6-((E)-2-(4-(4-fluorophenyl)-6-isopropyl-2-(methyl-(1-methyl-1H-1,2,4-triazol-5-yl)amino)pyrimidin-5-yl)vinyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate
  参考文献：
  名称：

  Development of a Scaleable Process for the Synthesis of a Next-Generation Statin

  摘要：

  This manuscript details life process research and development of a convergent and safe approach to 1 on a multikilo scale. Specific highlights of the process development efforts will be described, including the development of a dehydrogenation method for dihydropyrimidines and a thermochemically safe synthesis of a 1,2,4-aminotriazole fragment. A key feature of the synthesis is the use and optimization of a modified Julia-Kocienski olefination reaction. Specifically, we report an unprecedented dependence of the product olefin geometry on reaction temperature, where an E:Z ratio as high as 200:1 can be obtained. Initial insights into the mechanistic rationale for this observation are also provided. Finally, a purity upgrade sequence via an intermediate crystalline form is highlighted is a method of controlling the final API quality.

  DOI：

  10.1021/op100010n
• 作为产物：
  描述：

  乙基4-(4-氟苯基)-6-异丙基-2-(甲基磺酰基)嘧啶-5-羧酸酯 在 sodium hypochlorite 、 1-羟基-2,2,6,6-四甲基哌啶 、 二异丁基氢化铝 、 lithium hexamethyldisilazane 作用下， 以 四氢呋喃 、 二氯甲烷 、 水 、 乙酸乙酯 为溶剂， 生成 tert-butyl 2-((4R,6S)-6-((E)-2-(4-(4-fluorophenyl)-6-isopropyl-2-(methylsulfonyl)pyrimidin-5-yl)vinyl)-2,2-dimethyl-1,3-dioxan-4-yl)-acetate
  参考文献：
  名称：

  Development of a Scaleable Process for the Synthesis of a Next-Generation Statin

  摘要：

  This manuscript details life process research and development of a convergent and safe approach to 1 on a multikilo scale. Specific highlights of the process development efforts will be described, including the development of a dehydrogenation method for dihydropyrimidines and a thermochemically safe synthesis of a 1,2,4-aminotriazole fragment. A key feature of the synthesis is the use and optimization of a modified Julia-Kocienski olefination reaction. Specifically, we report an unprecedented dependence of the product olefin geometry on reaction temperature, where an E:Z ratio as high as 200:1 can be obtained. Initial insights into the mechanistic rationale for this observation are also provided. Finally, a purity upgrade sequence via an intermediate crystalline form is highlighted is a method of controlling the final API quality.

  DOI：

  10.1021/op100010n

文献信息

• [EN] PYRIMIDINE AND PYRIDINE DERIVATIVES USEFUL AS HMG-COA REDUCTASE INHIBITORS AND METHOD OF PREPARATION THEREOF<br/>[FR] DERIVES DE PYRIMIDINE ET DE PYRIDINE UTILES COMME INHIBITEURS DE LA HMG-COA REDUCTASE, ET METHODE DE PREPARATION DESDITS DERIVES
  申请人：BRISTOL MYERS SQUIBB CO

  公开号：WO2005030758A1

  公开（公告）日：2005-04-07

  Compounds are provided having the following structure which are HMG CoA reductase inhibitors and thus are active in inhibiting cholesterol biosynthesis, modulating blood serum lipids, for example, lowering LDL cholesterol and/or increasing HDL cholesterol, and treating hyperlipidemia, dyslipidemia, hormone replacement therapy, hypercholsterolemia, hypertriglyceridemia and atherosclerosis as well as Alzheimer's disease and osteoporosis identified in Formula (I) wherein X is N or CR5; and pharmaceutically acceptable salts thereof, Z is identified in Formula (II) or in Formula (III) ; wherein R1 to R7 are as defined herein. A method for treating the above diseases employing the above compounds is also provided.

  提供具有以下结构的化合物，这些化合物是HMG CoA还原酶抑制剂，因此在抑制胆固醇生物合成、调节血清脂质、例如降低LDL胆固醇和/或增加HDL胆固醇，并治疗高脂蛋白血症、脂质代谢异常、激素替代疗法、高胆固醇血症、高甘油三酯血症和动脉粥样硬化以及阿尔茨海默病和骨质疏松症，其中X为N或CR5；以及其药学上可接受的盐，Z在公式（II）或公式（III）中被识别；其中R1到R7如本文所定义。还提供了一种利用上述化合物治疗上述疾病的方法。
• (3<i>R,</i>5<i>S,E</i>)-7-(4-(4-Fluorophenyl)-6-isopropyl-2-(methyl(1-methyl-1<i>H</i>-1,2,4-triazol-5-yl)amino)pyrimidin-5-yl)-3,5-dihydroxyhept-6-enoic Acid (BMS-644950): A Rationally Designed Orally Efficacious 3-Hydroxy-3-methylglutaryl Coenzyme-A Reductase Inhibitor with Reduced Myotoxicity Potential
  作者：Saleem Ahmad、Cort S. Madsen、Philip D. Stein、Evan Janovitz、Christine Huang、Khehyong Ngu、Sharon Bisaha、Lawrence J. Kennedy、Bang-Chi Chen、Rulin Zhao、Doree Sitkoff、Hossain Monshizadegan、Xiaohong Yin、Carol S. Ryan、Rongan Zhang、Mary Giancarli、Eileen Bird、Ming Chang、Xing Chen、Robert Setters、Debra Search、Shaobin Zhuang、Van Nguyen-Tran、Carolyn A. Cuff、Thomas Harrity、Celia J. Darienzo、Tong Li、Richard A. Reeves、Michael A. Blanar、Joel C. Barrish、Robert Zahler、Jeffrey A. Robl

  DOI：10.1021/jm800001n

  日期：2008.5.1

  3-Hydroxy-3-methylglutaryl coenzyme-A reductase (HMGR) inhibitors, more commonly known as statins, represent the gold standard in treating hypercholesterolemia. Although statins are regarded as generally safe, they are known to cause myopathy and, in rare cases, rhabdomyolysis. Statin-dependent effects on plasma lipids are mediated through the inhibition of HMGR in the hepatocyte, whereas evidence suggests that myotoxicity is due to inhibition of HMGR within the myocyte. Thus, an inhibitor with increased selectivity for hepatocytes could potentially result in an improved therapeutic window. Implementation of a strategy that focused on in vitro potency, compound polarity, cell selectivity, and oral absorption, followed by extensive efficacy and safety modeling in guinea pig and rat, resulted in the identification of compound 1b (BMS-644950), Using this discovery pathway, we compared 1b to other marketed statins to demonstrate its outstanding efficacy and safety profile. With the potential to generate an excellent therapeutic window, 1b was advanced into clinical development.
• US7371759B2
  申请人：——

  公开号：US7371759B2

  公开（公告）日：2008-05-13
• Development of a Scaleable Process for the Synthesis of a Next-Generation Statin
  作者：Lindsay A. Hobson、Otute Akiti、Subodh S. Deshmukh、Shannon Harper、Kishta Katipally、Chiajen J. Lai、Robert C. Livingston、Ehrlic Lo、Michael M. Miller、Srividya Ramakrishnan、Lifen Shen、Jan Spink、Srinivas Tummala、Chenkou Wei、Kana Yamamoto、John Young、Rodney L. Parsons

  DOI：10.1021/op100010n

  日期：2010.3.19

  This manuscript details life process research and development of a convergent and safe approach to 1 on a multikilo scale. Specific highlights of the process development efforts will be described, including the development of a dehydrogenation method for dihydropyrimidines and a thermochemically safe synthesis of a 1,2,4-aminotriazole fragment. A key feature of the synthesis is the use and optimization of a modified Julia-Kocienski olefination reaction. Specifically, we report an unprecedented dependence of the product olefin geometry on reaction temperature, where an E:Z ratio as high as 200:1 can be obtained. Initial insights into the mechanistic rationale for this observation are also provided. Finally, a purity upgrade sequence via an intermediate crystalline form is highlighted is a method of controlling the final API quality.