trans-tert-butyl (3-fluoropiperidin-4-yl)(methyl)carbamate

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 英文名称: trans-tert-butyl (3-fluoropiperidin-4-yl)(methyl)carbamate
• 英文别名: trans-(3-Fluoro-piperidin-4-yl)methyl-carbamic acid tert-butyl ester；tert-butyl N-[(3R,4R)-3-fluoropiperidin-4-yl]-N-methylcarbamate
• 化学式: C₁₁H₂₁FN₂O₂
• 分子量: 232.298
• InChiKey: VGCKWWMMIKCCKU-RKDXNWHRSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.3
• 重原子数：
  16
• 可旋转键数：
  3
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.91
• 拓扑面积：
  41.6
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  聚合甲醛 、 trans-tert-butyl (3-fluoropiperidin-4-yl)(methyl)carbamate 在 溶剂黄146 、 sodium cyanoborohydride 作用下， 以 甲醇 、 水 为溶剂， 反应 2.0h， 生成
  参考文献：
  名称：

  Kinesin Spindle Protein (KSP) Inhibitors. 9. Discovery of (2S)-4-(2,5-Difluorophenyl)-N-[(3R,4S)-3-fluoro-1-methylpiperidin-4-yl]-2-(hydroxymethyl)-N-methyl-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxamide (MK-0731) for the Treatment of Taxane-Refractory Cancer

  摘要：

  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.

  DOI：

  10.1021/jm800386y
• 作为产物：
  描述：

  benzyl (3S,4S)-4-[(tert-butoxycarbonyl)(methyl)amino]-3-fluoropiperidine-1-carboxylate 在 palladium 10% on activated carbon 、 氢气 作用下， 以 甲醇 为溶剂， 以100 %的产率得到trans-tert-butyl (3-fluoropiperidin-4-yl)(methyl)carbamate
  参考文献：
  名称：

  [EN] HETEROCYCLIC AMIDE AND UREA COMPOUNDS AS JAK2 INHIBITORS
  [FR] COMPOSÉS D'URÉE ET D'AMIDE HÉTÉROCYCLIQUES EN TANT QU'INHIBITEURS DE JAK2

  摘要：

  The present disclosure provides heterocyclic amide and urea compounds and compositions thereof useful for inhibiting JAK2.

  公开号：

  WO2024035627A1

文献信息

• [EN] HETEROCYCLIC AMIDE AND UREA COMPOUNDS AS JAK2 INHIBITORS<br/>[FR] COMPOSÉS D'URÉE ET D'AMIDE HÉTÉROCYCLIQUES EN TANT QU'INHIBITEURS DE JAK2
  申请人：[en]AJAX THERAPEUTICS, INC.

  公开号：WO2024035627A1

  公开（公告）日：2024-02-15

  The present disclosure provides heterocyclic amide and urea compounds and compositions thereof useful for inhibiting JAK2.
• 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.