(R)-3-(4-fluorobenzyl)piperidine | 794464-41-8

• 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: (R)-3-(4-fluorobenzyl)piperidine
• 英文别名: (3R)-3-[(4-fluorophenyl)methyl]piperidine
• CAS: 794464-41-8
• 化学式: C₁₂H₁₆FN
• 分子量: 193.264
• InChiKey: WATWKPHWUDHKGA-LLVKDONJSA-N

物化性质

• 沸点：
  276.6±13.0 °C(Predicted)
• 密度：
  1.044±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  14
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  12
• 氢给体数：
  1
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  (1R,2R)-2-(benzyloxycarbonylamino)cyclohexanecarboxaldehyde 、 (R)-3-(4-fluorobenzyl)piperidine 在 三乙酰氧基硼氢化钠 作用下， 以 二氯甲烷 为溶剂， 生成 {(1R,2S)-2-[(R)-3-(4-Fluoro-benzyl)-piperidin-1-ylmethyl]-cyclohexyl}-carbamic acid benzyl ester
  参考文献：
  名称：

  Discovery of CC Chemokine Receptor-3 (CCR3) Antagonists with Picomolar Potency

  摘要：

  Starting with our previously described(20) class of CC chemokine receptor-3 (CCR3) antagonist, we improved the potency by replacing the phenyl linker of 1 with a cyclohexyl linker and by replacing the 4-benzylpiperidine with a 3-benzylpiperidine. The resulting compound, 32, is a potent and selective antagonist of CCR3. SAR studies showed that the 3-acetylphenyl urea of 32 could be replaced with heterocyclic ureas or heterocyclic-substituted phenyl ureas and still maintain the potency (inhibition of eotaxin-induced chemotaxis) of this class of compounds in the low-picomolar range (IC50 = 10-60 pM), representing some of the most potent CCR3 antagonists reported to date. The potency of 32 for mouse CCR3 (chemotaxis IC50 = 41 nM) and its oral bioavailability in mice (20% F) were adequate to assess the efficacy in animal models of allergic airway inflammation. Oral administration of 32 reduced eosinophil recruitment into the lungs in a dose-dependent manner in these animal models. On the basis of its overall potency, selectivity, efficacy, and safety profile, the benzenesulfonate salt of 32, designated DPC168, entered phase 1 clinical trials.

  DOI：

  10.1021/jm049530m
• 作为产物：
  描述：

  哌啶酮 在 lithium aluminium tetrahydride 、 [(S,S)-(BDPP)Ir(COD)]BF₄ 、 potassium tert-butylate 、 氢气 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 甲苯 为溶剂， 20.0~55.0 ℃ 、448.17 kPa 条件下， 反应 28.5h， 生成 (R)-3-(4-fluorobenzyl)piperidine
  参考文献：
  名称：

  Enantioselective Hydrogenation of 3-Alkylidenelactams:  High-Throughput Screening Provides a Surprising Solution

  摘要：

  High-throughput screening of 256 potential catalysts (8 metal precursors x 32 phosphine ligands) has identified [(BDPP)Ir(COD)]BF4 as a catalyst for the enantioselective hydrogenation of 3-alkylidenelactams. This result is surprising given the highly flexible backbone of the BDPP ligand and the ineffectiveness of this catalyst in other applications. The asymmetric hydrogenation appears fairly general for five- and six-membered lactams and in one case has been scaled up to a 20 kg level.

  DOI：

  10.1021/ja028043y

文献信息

• Rhodium-catalyzed asymmetric hydrogenation of exocyclic α,β-unsaturated carbonyl compounds
  作者：Jiaxin Yang、Xiuxiu Li、Cai You、Shuailong Li、Yu-Qing Guan、Hui Lv、Xumu Zhang

  DOI：10.1039/c9ob02536g

  日期：——

  A highly enantioselective hydrogenation of exocyclic α,β-unsaturated carbonyl compounds catalyzed by Rh/bisphosphine-thiourea (ZhaoPhos) has been developed, giving the corresponding α-chiral cyclic lactones, lactams and ketones with high yields and excellent enantioselectivities (up to 99% yield and 99% ee). Remarkably, the hydrogen bond between the substrate and the catalyst plays a critical role

  已开发出由Rh /双膦-硫脲（ZhaoPhos）催化的对环外α，β-不饱和羰基化合物的高度对映选择性氢化，可提供相应的α-手性环状内酯，内酰胺和酮，产率高且对映选择性极好（高达99％收率和99％ee）。显着地，底物和催化剂之间的氢键在该转变中起关键作用。该协议的合成用途已通过有效合成手性3-（4-氟苄基）哌啶（一种生物活性分子的关键手性片段）得到了证明。
• [EN] PYRAN DERIVATIVES AS CCR3 MODULATORS<br/>[FR] DÉRIVÉS DE PYRANE EN TANT QUE MODULATEURS DU CCR3
  申请人：NYCOMED GMBH

  公开号：WO2010069979A1

  公开（公告）日：2010-06-24

  The compounds of formula (1) wherein A, B, R1, R2 and R3 have the meanings as given in the description, the stereoisomers, as well as the salts of the stereoisomers thereof are effective CCR3 modulators.

  式（1）中A、B、R1、R2和R3具有描述中给定的含义的化合物，其立体异构体以及其立体异构体的盐是有效的CCR3调节剂。
• Stereoselective Process for a CCR3 Antagonist
  作者：Tai-Yuen Yue、Douglas D. McLeod、Kevin B. Albertson、Steven R. Beck、Joerg Deerberg、Joseph M. Fortunak、William A. Nugent、Lilian A. Radesca、Liya Tang、Cathie Dong Xiang

  DOI：10.1021/op050202l

  日期：2006.3.1

  A convergent, multikilogram, stereoselective synthesis of 1 is described. A key fragment, (S)-3-(4-fluorobenzyl)piperidine (2) was synthesized from valerolactam in three steps using our recently discovered Ir-BDPP-catalyzed asymmetric hydrogenation. Another key fragment, (IR,2R)-2-(benzyloxycarbonylamino)cyclohexanecarboxaldehyde (3) was synthesized from meso-hexahydrophthalic anhydride in seven steps. The stereochemistry was set in the first step of this sequence via a quinidine-mediated desymmetrization of the meso-anhydride. Coupling of the fragments 2 and 3 followed by deprotection provided the penultimate 23. The active pharmaceutical ingredient (API) free base I was obtained by treatment of 23 with the aminothiazole fragment 4 under mild conditions.
• Discovery of CC Chemokine Receptor-3 (CCR3) Antagonists with Picomolar Potency
  作者：George V. De Lucca、Ui Tae Kim、Brian J. Vargo、John V. Duncia、Joseph B. Santella、Daniel S. Gardner、Changsheng Zheng、Ann Liauw、Zhang Wang、George Emmett、Dean A. Wacker、Patricia K. Welch、Maryanne Covington、Nicole C. Stowell、Eric A. Wadman、Anuk M. Das、Paul Davies、Swamy Yeleswaram、Danielle M. Graden、Kimberly A. Solomon、Robert C. Newton、George L. Trainor、Carl P. Decicco、Soo. S. Ko

  DOI：10.1021/jm049530m

  日期：2005.3.1

  Starting with our previously described(20) class of CC chemokine receptor-3 (CCR3) antagonist, we improved the potency by replacing the phenyl linker of 1 with a cyclohexyl linker and by replacing the 4-benzylpiperidine with a 3-benzylpiperidine. The resulting compound, 32, is a potent and selective antagonist of CCR3. SAR studies showed that the 3-acetylphenyl urea of 32 could be replaced with heterocyclic ureas or heterocyclic-substituted phenyl ureas and still maintain the potency (inhibition of eotaxin-induced chemotaxis) of this class of compounds in the low-picomolar range (IC50 = 10-60 pM), representing some of the most potent CCR3 antagonists reported to date. The potency of 32 for mouse CCR3 (chemotaxis IC50 = 41 nM) and its oral bioavailability in mice (20% F) were adequate to assess the efficacy in animal models of allergic airway inflammation. Oral administration of 32 reduced eosinophil recruitment into the lungs in a dose-dependent manner in these animal models. On the basis of its overall potency, selectivity, efficacy, and safety profile, the benzenesulfonate salt of 32, designated DPC168, entered phase 1 clinical trials.
• Enantioselective Hydrogenation of 3-Alkylidenelactams:  High-Throughput Screening Provides a Surprising Solution
  作者：Tai-Yuen Yue、William A. Nugent

  DOI：10.1021/ja028043y

  日期：2002.11.1

  High-throughput screening of 256 potential catalysts (8 metal precursors x 32 phosphine ligands) has identified [(BDPP)Ir(COD)]BF4 as a catalyst for the enantioselective hydrogenation of 3-alkylidenelactams. This result is surprising given the highly flexible backbone of the BDPP ligand and the ineffectiveness of this catalyst in other applications. The asymmetric hydrogenation appears fairly general for five- and six-membered lactams and in one case has been scaled up to a 20 kg level.