4-({3-cyclopropyl-5-methyl-1-[(methylsulfanyl)methyl]-1H-pyrazol-4-yl}oxy)-2,6-dimethylbenzonitrile | 1174495-31-8

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 4-({3-cyclopropyl-5-methyl-1-[(methylsulfanyl)methyl]-1H-pyrazol-4-yl}oxy)-2,6-dimethylbenzonitrile
• 英文别名: 4-[3-Cyclopropyl-5-methyl-1-(methylsulfanylmethyl)pyrazol-4-yl]oxy-2,6-dimethylbenzonitrile
• CAS: 1174495-31-8
• 化学式: C₁₈H₂₁N₃OS
• 分子量: 327.45
• InChiKey: PBSLFRDXHNJYDK-UHFFFAOYSA-N

物化性质

• 沸点：
  454.3±45.0 °C(Predicted)
• 密度：
  1.22±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.9
• 重原子数：
  23
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.44
• 拓扑面积：
  76.1
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  4-({3-cyclopropyl-5-methyl-1-[(methylsulfanyl)methyl]-1H-pyrazol-4-yl}oxy)-2,6-dimethylbenzonitrile 在 Oxone 作用下， 以 甲醇 、 水 为溶剂， 反应 6.0h， 以90%的产率得到PF-2413873
  参考文献：
  名称：

  Synthetic Studies on a Nonsteroidal Progesterone Metabolite: Regioselective N-Alkylation of an Activated Pyrazole

  摘要：

  本文描述了一种孕酮受体代谢物的大规模合成。该序列的关键步骤是选择性吡唑N-烷基化反应。

  DOI：

  10.1055/s-0029-1219535
• 作为产物：
  描述：

  4-({3-cyclopropyl-5-methyl-1-[(methylsulfanyl)methyl]-1H-pyrazol-4-yl}oxy)-2,6-dimethylbenzonitrile hydrogen sulfate 在 水 作用下， 以 乙酸乙酯 为溶剂， 生成 4-({3-cyclopropyl-5-methyl-1-[(methylsulfanyl)methyl]-1H-pyrazol-4-yl}oxy)-2,6-dimethylbenzonitrile
  参考文献：
  名称：

  Development of a Practical Synthesis of the Progesterone Receptor Antagonist 4-{[3-Cyclopropyl-1-(mesylmethyl)-5-methyl-1H-pyrazol-4-yl]oxy}-2,6-dimethylbenzonitrile

  摘要：

  The development and implementation of a scaleable process for the manufacture of the nonsteroidal progesterone receptor antagonist 8 is described. Key aspects of the synthesis include (i) a telescoped chlorination-etherification sequence to prepare diketone 4 and (ii) separation of pyrazole regioisomers 6 and 7 through formation of their hydrogen sulfate salts and selective crystallization, followed by oxidation to 8.

  DOI：

  10.1021/op900110k

文献信息

• Unusual base-catalyzed exchange in the synthesis of deuterated PF-2413873
  作者：Stuart J. Rozze、M. Jonathan Fray

  DOI：10.1002/jlcr.1657

  日期：2009.8

  The preparation of deuterated PF-2413873 (4-[3-cyclopropyl-1-(methanesulfonylmethyl)-5-methyl-1H-pyrazol-4-yl]oxy-2,6-dimethylbenzonitrile, 1) is described for use as a bioanalytical standard in clinical trials. Two strategies were investigated. The sulfone-containing substituent was labelled by base-catalyzed exchange, but unacceptable deuterium loss was noted under assay conditions. Alternatively, labelling 4-cyano-3,5-dimethylphenol was achieved by heating with deuterium oxide over platinum oxide. After building up the pyrazole ring we discovered that, during the subsequent alkylation to attach the methylthiomethyl group, the base, potassium t-butoxide, caused unwanted scrambling of deuteriums on the aromatic portion and the methylthiomethyl group. Thus, it was necessary to remove all base-labile hydrogens to prevent their exchange. This was accomplished by alkylating the pyrazole with per-deuterated chloromethyl methylsulfide, oxidation to the sulfone, and selective removal of its deuteriums by treatment with sodium hydroxide. The unusual sensitivity and selectivity of these base-promoted exchange reactions are discussed. Thus, 4-[3-cyclopropyl-1-(methanesulfonylmethyl)-5-methyl-1H-pyrazol-4-yl]oxy-[2H6]2,6-dimethyl-[3,5-2H]benzonitrile (17) was obtained, labelled with eight deuterium atoms and an acceptable D0/D8 ratio. Copyright © 2009 John Wiley & Sons, Ltd.

  氘化 PF-2413873 (4-[3-环丙基-1-(甲磺酰基甲基)-5-甲基-1H-吡唑-4-基]氧基-2,6-二甲基苯甲腈，1) 的制备被描述为用作生物分析临床试验标准。研究了两种策略。含砜取代基通过碱催化交换进行标记，但在测定条件下注意到不可接受的氘损失。或者，通过在氧化铂上用氧化氘加热来标记 4-氰基-3,5-二甲基苯酚。在构建吡唑环后，我们发现，在随后的烷基化以连接甲硫基甲基的过程中，碱叔丁醇钾导致芳香部分和甲硫基甲基上的氘发生不必要的扰乱。因此，有必要除去所有碱不稳定的氢以防止它们的交换。这是通过用全氘代氯甲基甲硫醚将吡唑烷基化、氧化成砜、并通过用氢氧化钠处理选择性去除其氘来实现的。讨论了这些碱促进的交换反应的异常敏感性和选择性。因此，4-[3-环丙基-1-(甲磺酰基甲基)-5-甲基-1H-吡唑-4-基]氧基-[2H6]2,6-二甲基-[3,5-2H]苯甲腈(17)是获得，用八个氘原子和可接受的 D0/D8 比率标记。版权所有 © 2009 约翰·威利父子有限公司
• Work-Up Optimization en Route to an Improved Process To Prepare a Progesterone Receptor Antagonist
  作者：Pieter D. de Koning、David J. McManus、George R. Bandurek

  DOI：10.1021/op200145j

  日期：2011.9.16

  When the process to prepare nonsteroidal progesterone receptor antagonist 5 was scaled up, significant problems were encountered, and as a result lower than expected yields were obtained. In particular, the alkylation of pyrazole 2 with chloromethyl methyl sulfide failed to reach completion, and partial degradation of the product occurred during the work-up, resulting in a modest yield of alkylated pyrazole 3a. Further investigation has revealed the root cause of this problem, and an improved, robust process to 5 has been developed.
• Org. Process Res. Dev. 2011, 15, 1081–1084
  作者：

  DOI：——

  日期：——