(+/-)-cis-benzyl 3-fluoro-4-(methylamino)piperidine-1-carboxylate

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: (+/-)-cis-benzyl 3-fluoro-4-(methylamino)piperidine-1-carboxylate
• 英文别名: Benzyl cis-3-fluoro-4-(methylamino)piperidine-1-carboxylate；benzyl (3S,4R)-3-fluoro-4-(methylamino)piperidine-1-carboxylate
• 化学式: C₁₄H₁₉FN₂O₂
• 分子量: 266.315
• InChiKey: ABMWQTWKPOPMIO-QWHCGFSZSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.8
• 重原子数：
  19
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.5
• 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：

  (+/-)-cis-benzyl 3-fluoro-4-(methylamino)piperidine-1-carboxylate 、 二碳酸二叔丁酯 在 三乙胺 、 CHIRALPAK AD 作用下， 以 二氯甲烷 为溶剂， 反应 1.0h， 生成 benzyl (3S,4R)-4-[(tert-butoxycarbonyl)(methyl)amino]-3-fluoropiperidine-1-carboxylate
  参考文献：
  名称：

  [EN] A PROCESS FOR THE PREPARATION OF 2,2-DISUBSTITUTED PYRROLES
  [FR] PROCEDE DE PREPARATION DE PYRROLES DISUBSTITUES EN 2,2

  摘要：

  公开号：

  WO2005102996A3
• 作为产物：
  描述：

  3-氟-1-甲基哌啶-4-酮 、 甲胺 在 溶剂黄146 、 sodium cyanoborohydride 作用下， 以 四氢呋喃 、 甲醇 为溶剂， 反应 3.0h， 以35%的产率得到(+/-)-trans-benzyl 3-fluoro-4-(methylamino)piperidine-1-carboxylate
  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

文献信息

• [EN] 1,4 DISUBSTITUTED PYRROLIDINE - 3 - YL -AMINE DERIVATIVES AND THEIR USE FOR THE TREATMENT OF METABOLIC DISORDERS<br/>[FR] DÉRIVÉS DE PYROLIDIN-3-YL-AMINE 1,4 DISUBSTITUÉE ET LEUR UTILISATION POUR LE TRAITEMENT DE TROUBLES MÉTABOLIQUES
  申请人：PROSIDION LTD

  公开号：WO2013026587A1

  公开（公告）日：2013-02-28

  Therapeutic compounds are disclosed having the general formula (I) that are useful for the treatment of metabolic disorders, including type II diabetes. The compounds have activity as agonists of GPR1 19. Compounds having stereochemistry of formula (la) may also demonstrate DPP-IV inhibitory activity.

  揭示了具有一般式(I)的治疗化合物，可用于治疗代谢性疾病，包括2型糖尿病。这些化合物具有作为GPR1 19激动剂的活性。具有一般式(la)立体化学的化合物也可能表现出DPP-IV抑制活性。
• [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.
• [EN] A PROCESS FOR THE PREPARATION OF 2,2-DISUBSTITUTED PYRROLES<br/>[FR] PROCEDE DE PREPARATION DE PYRROLES DISUBSTITUES EN 2,2
  申请人：MERCK & CO INC

  公开号：WO2005102996A3

  公开（公告）日：2006-01-19
• 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.