PF-2413873 | 936345-35-6

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: PF-2413873
• 英文别名: 4-{[3-cyclopropyl-1-(mesylmethyl)-5-methyl-1H-pyrazol-4-yl]oxy}-2,6-dimethylbenzonitrile；4-[3-cyclopropyl-1-(methanesulfonylmethyl)-5-methyl-1H-pyrazol-4-yl]oxy-2,6-dimethylbenzonitrile；PF-02413873；4-[3-cyclopropyl-5-methyl-1-(methylsulfonylmethyl)pyrazol-4-yl]oxy-2,6-dimethylbenzonitrile
• CAS: 936345-35-6
• 化学式: C₁₈H₂₁N₃O₃S
• 分子量: 359.449
• InChiKey: QSFGZNVRVZHUGV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  25
• 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：
  93.4
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  PF-2413873 在 氘代甲醇 、 sodium hydride 作用下， 以 mineral oil 为溶剂， 以98%的产率得到4-[3-Cyclopropyl-1-[dideuterio(trideuteriomethylsulfonyl)methyl]-5-methylpyrazol-4-yl]oxy-2,6-dimethylbenzonitrile
  参考文献：
  名称：

  Unusual base-catalyzed exchange in the synthesis of deuterated PF-2413873

  摘要：

  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

  DOI：

  10.1002/jlcr.1657
• 作为产物：
  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

文献信息

• Compounds useful in therapy
  申请人：Bradley Anthony Paul

  公开号：US20070105909A1

  公开（公告）日：2007-05-10

  Compounds of formula (I), or a pharmaceutically acceptable derivative thereof, wherein R 1 and R 3 independently represent H, C 1-6 alkyl, C 3-8 cycloalkyl, or halogen; R 2 represents C 1-6 alkyl, CF 3 or aryl; a represents 1 or 2; R 4 , R 5 , R 7 and R 8 independently represent H, C 1-6 alkyl, C 1-6 alkyloxy, CN or halogen, or R 4 and R 5 , or R 7 and R 8 , together with the ring to which they are attached form an aryl or heterocyclic fused ring system; X represents C or N; Y represents CH 2 or O; R 6 represents H, CN or halo provided that, when X represents N, R 6 is absent. The compounds are useful for treating endometriosis, uterine fibroids (leiomyomata), menorrhagia, adenomyosis, primary and secondary dysmenorrhoea (including symptoms of dyspareunia, dyschexia and chronic pelvic pain), or chronic pelvic pain syndrome.

  式(I)的化合物，或其药学上可接受的衍生物，其中R1和R3独立地代表H、C1-6烷基、C3-8环烷基或卤素；R2代表C1-6烷基、CF3或芳基；a代表1或2；R4、R5、R7和R8独立地代表H、C1-6烷基、C1-6烷氧基、CN或卤素，或R4和R5，或R7和R8，与它们连接的环一起形成芳基或杂环融合环系统；X代表C或N；Y代表CH2或O；R6代表H、CN或卤素，但当X代表N时，R6不存在。这些化合物可用于治疗子宫内膜异位症、子宫肌瘤（平滑肌瘤）、月经过多、子宫腺肌病、原发性和继发性痛经（包括性交疼痛、性交困难和慢性盆腔疼痛症状）或慢性盆腔疼痛综合征。
• 1H-Pyrazoles Useful In Therapy
  申请人：Bradley Anthony Paul

  公开号：US20080085919A1

  公开（公告）日：2008-04-10

  Compounds of formula (I), or a pharmaceutically acceptable derivative thereof, wherein R 1 and R 3 independently represent H, C 1-6 alkyl, C 3-8 cycloalkyl, or halogen; R 2 represents C 1-6 alkyl, CF 3 or aryl; a represents 1 or 2; R 4 , R 5 , R 7 and R 8 independently represent H, C 1-6 alkyl, C 1-6 alkyloxy, CN or halogen, or R 4 and R 5 , or R 7 and R 8 , together with the ring to which they are attached form an aryl or heterocyclic fused ring system; X represents C or N; Y represents CH 2 or O; R 6 represents H, CN or halo provided that, when X represents N, R 6 is absent. The compounds are useful for treating endometriosis, uterine fibroids (leiomyomata), menorrhagia, adenomyosis, primary and secondary dysmenorrhoea (including symptoms of dyspareunia, dyschexia and chronic pelvic pain), or chronic pelvic pain syndrome.

  化合物的式子(I)，或其药学上可接受的衍生物，其中R1和R3独立地表示H，C1-6烷基，C3-8环烷基或卤素; R2表示C1-6烷基，CF3或芳基; a表示1或2; R4，R5，R7和R8独立地表示H，C1-6烷基，C1-6烷氧基，CN或卤素，或者R4和R5，或R7和R8，与它们连接的环共同形成芳基或杂环融合环系统; X表示C或N; Y表示CH2或O; R6表示H，CN或卤素，但当X表示N时，R6不存在。这些化合物可用于治疗子宫内膜异位症，子宫肌瘤（平滑肌瘤），月经过多，子宫内膜增生症，原发性和继发性痛经（包括性交疼痛，排便疼痛和慢性盆腔疼痛症状），或慢性盆腔疼痛综合征。
• 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.
• 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
  作者：Paul A. Bradley、Pieter D. de Koning、Patrick S. Johnson、Yann C. Lecouturier、David J. McManus、Aurelie Robin、Toby J. Underwood

  DOI：10.1021/op900110k

  日期：2009.9.18

  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.
• Org. Process Res. Dev. 2011, 15, 1081–1084
  作者：

  DOI：——

  日期：——