4-(2,5-difluorophenyl)-2-phenyl-2-[(1,1,2,2-tetramethylpropoxy)methyl]-2,5-dihydro-1H-pyrrole | 686320-28-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯啉
• 英文名称: 4-(2,5-difluorophenyl)-2-phenyl-2-[(1,1,2,2-tetramethylpropoxy)methyl]-2,5-dihydro-1H-pyrrole
• 英文别名: 2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-(2,5-difluoro-phenyl)-2-phenyl-2,5-dihydro-1H-pyrrole；2-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrole；tert-butyl-[[3-(2,5-difluorophenyl)-5-phenyl-1,2-dihydropyrrol-5-yl]methoxy]-dimethylsilane
• CAS: 686320-28-5
• 化学式: C₂₃H₂₉F₂NOSi
• 分子量: 401.572
• InChiKey: CPIZTJNMDOPINP-UHFFFAOYSA-N

物化性质

• 沸点：
  451.1±45.0 °C(Predicted)
• 密度：
  1.075±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  5.87
• 重原子数：
  28
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.39
• 拓扑面积：
  21.3
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  4-(2,5-difluorophenyl)-2-phenyl-2-[(1,1,2,2-tetramethylpropoxy)methyl]-2,5-dihydro-1H-pyrrole 在 palladium 10% on activated carbon 4-二甲氨基吡啶 、 1,4-环己二烯 、 三乙胺 作用下， 以 四氢呋喃 、 hexanes 、 乙醇 、 醋酸异丙酯 、 二乙胺 、 异丙醇 为溶剂， 反应 1.5h， 生成 (2S)-4-(2,5-difluorophenyl)-N-[(3R,4S)-3-fluoropiperidin-4-yl]-2-(hydroxymethyl)-N-methyl-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxamide
  参考文献：
  名称：

  WO2006/101780

  摘要：

  公开号：
• 作为产物：
  描述：

  2-氨基-2-苯基乙酸 在 盐酸 、 ruthenium trichloride 、 四(三苯基膦)钯 咪唑 、 盐酸 、 sodium hydroxide 、 sodium periodate 、 lithium aluminium tetrahydride 、 乙醇 、 水 、 sodium hexamethyldisilazane 、 sodium hydride 、 sodium carbonate 、 三乙胺 、 lithium chloride 、 lithium hexamethyldisilazane 作用下， 以 四氢呋喃 、 乙二醇二甲醚 、 乙醚 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 58.52h， 生成 4-(2,5-difluorophenyl)-2-phenyl-2-[(1,1,2,2-tetramethylpropoxy)methyl]-2,5-dihydro-1H-pyrrole
  参考文献：
  名称：

  WO2006/101780

  摘要：

  公开号：

文献信息

• Mitotic kinesin inhibitors
  申请人：Coleman J. Paul

  公开号：US20050038074A1

  公开（公告）日：2005-02-17

  The present invention relates to dihydropyrrole compounds that are useful for treating cellular proliferative diseases, for treating disorders associated with KSP kinesin activity, and for inhibiting KSP kinesin. The invention is also related to compositions which comprise these compounds, and methods of using them to treat cancer in mammals.

  本发明涉及对治疗细胞增殖性疾病、治疗与KSP动力蛋白活性相关的疾病以及抑制KSP动力蛋白的二氢吡咯化合物。该发明还涉及包含这些化合物的组合物，以及利用它们治疗哺乳动物癌症的方法。
• Process for the Preparation of 2,2-Disubstituted Pyrroles
  申请人：Javadi Gary

  公开号：US20070225499A1

  公开（公告）日：2007-09-27

  The present invention relates to the stereoselective preparation of 2,2-disubstituted-4-carbonatepyrroles from readily available chiral starting materials. Such pyrroles are useful as intermediates in the preparation of 2,2,4-trisubstituted 2,5-dihydropyrroles, that are inhibitors of mitotic kinesins and are useful for treating cellular proliferative diseases, for treating disorders associated with KSP kinesin activity, and for inhibiting KSP kinesin. The product of the process of the invention may be illustrated by the Formula (I).

  本发明涉及从易得手性起始材料中立体选择性地制备2,2-二取代-4-碳酸酯吡咯的方法。这样的吡咯在制备2,2,4-三取代-2,5-二氢吡咯的中间体时非常有用，该中间体是有丝分裂动力蛋白酶抑制剂，可用于治疗细胞增殖性疾病，治疗与KSP动力蛋白酶活性相关的疾病，并抑制KSP动力蛋白酶。本发明的产物可以用式(I)表示。
• Mitotic Kinesin Inhibitors
  申请人：Coleman Paul J.

  公开号：US20080207693A1

  公开（公告）日：2008-08-28

  The present invention relates to dihydropyrazole compounds that are useful for treating cellular proliferative diseases, for treating disorders associated with KSP kinesin activity, and for inhibiting KSP kinesin. The invention also related to compositions which comprise these compounds, and methods of using them to treat cancer in mammals.

  本发明涉及二氢吡唑化合物，对于治疗细胞增殖性疾病，治疗与KSP动力蛋白活性相关的疾病，以及抑制KSP动力蛋白具有用处。该发明还涉及包含这些化合物的组合物，以及使用它们治疗哺乳动物癌症的方法。
• Fluorinated 2,4-diaryl-2,5-dihydropyrrole inhibitors of the mitotic kinesin KSP
  申请人：Merck & Co., Inc.

  公开号：US07465746B2

  公开（公告）日：2008-12-16

  The present invention relates to dihydropyrrole compounds that are useful for treating cellular proliferative diseases, for treating disorders associated with KSP kinesin activity, and for inhibiting KSP kinesin. The invention is also related to compositions which comprise these compounds, and methods of using them to treat cancer in mammals.

  本发明涉及二氢吡咯化合物，其可用于治疗细胞增殖性疾病，治疗与KSP肌动蛋白活性有关的疾病，并抑制KSP肌动蛋白。本发明还涉及包含这些化合物的组合物，并使用它们来治疗哺乳动物癌症的方法。
• Kinesin Spindle Protein (KSP) Inhibitors. 9. Discovery of (2<i>S</i>)-4-(2,5-Difluorophenyl)-<i>N</i>-[(3<i>R</i>,4<i>S</i>)-3-fluoro-1-methylpiperidin-4-yl]-2-(hydroxymethyl)-<i>N</i>-methyl-2-phenyl-2,5-dihydro-1<i>H</i>-pyrrole-1-carboxamide (MK-0731) for the Treatment of Taxane-Refractory Cancer
  作者：Christopher D. Cox、Paul J. Coleman、Michael J. Breslin、David B. Whitman、Robert M. Garbaccio、Mark E. Fraley、Carolyn A. Buser、Eileen S. Walsh、Kelly Hamilton、Michael D. Schaber、Robert B. Lobell、Weikang Tao、Joseph P. Davide、Ronald E. Diehl、Marc T. Abrams、Vicki J. South、Hans E. Huber、Maricel Torrent、Thomayant Prueksaritanont、Chunze Li、Donald E. Slaughter、Elizabeth Mahan、Carmen Fernandez-Metzler、Youwei Yan、Lawrence C. Kuo、Nancy E. Kohl、George D. Hartman

  DOI：10.1021/jm800386y

  日期：2008.7.1

  Inhibition of kinesin spindle protein (KSP) is a novel mechanism for treatment of cancer with the potential to overcome limitations associated with currently employed cytotoxic agents. Herein, we describe a C2-hydroxymethyl dihydropyrrole KSP inhibitor ( 11) that circumvents hERG channel binding and poor in vivo potency, issues that limited earlier compounds from our program. However, introduction of the C2-hydroxymethyl group caused 11 to be a substrate for cellular efflux by P-glycoprotein (Pgp). Utilizing knowledge garnered from previous KSP inhibitors, we found that beta-fluorination modulated the p K a of the piperidine nitrogen and reduced Pgp efflux, but the resulting compound ( 14) generated a toxic metabolite in vivo. Incorporation of fluorine in a strategic, metabolically benign position by synthesis of an N-methyl-3-fluoro-4-(aminomethyl)piperidine urea led to compound 30 that has an optimal in vitro and metabolic profile. Compound 30 (MK-0731) was recently studied in a phase I clinical trial in patients with taxane-refractory solid tumors.