tert-butyl 4-(2-fluoroethyl)piperidine-1-carboxylate | 184042-54-4

• 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: tert-butyl 4-(2-fluoroethyl)piperidine-1-carboxylate
• 英文别名: 1-tert-butoxycarbonyl-4-(2-fluoroethyl)piperidine
• CAS: 184042-54-4
• 化学式: C₁₂H₂₂FNO₂
• 分子量: 231.311
• InChiKey: GZEKQGBJAAUAGK-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  16
• 可旋转键数：
  4
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.92
• 拓扑面积：
  29.5
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  tert-butyl 4-(2-fluoroethyl)piperidine-1-carboxylate 在 N-甲基吗啉 、 盐酸 、 溶剂黄146 、 N,N-二异丙基乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 10.0h， 生成 1-[(4S)-4-[(6-chloro-3,3-dimethyl-2,4-dihydro-1H-quinolin-8-yl)sulfonylamino]-5-[4-(2-fluoroethyl)piperidin-1-yl]-5-oxopentyl]-2-nitroguanidine
  参考文献：
  名称：

  Design and Synthesis of Thrombin Inhibitors:  Analogues of MD-805 with Reduced Stereogenicity and Improved Potency

  摘要：

  Mitsubishi's MD-805, a potent and selective inhibitor of thrombin which contains four stereogenic centers, has been the starting point for an optimization program. A systematic synthetic study resulted in thrombin inhibit;ors achiral at P2 and P3 but with a 10-fold increase in potency over the original lead. A number of 4-substituted piperidines were synthesized and examined as replacements for 2-carboxy-4-methylpiperidine at P2; 4-fluoroethylpiperidine (FEP) among others provided inhibitors (e.g. 45g) of increased potency. An enantioselective route was developed to 3(R)-methyl-1,2,3,4-tetrahydroquinolinesulfonyl chloride. Inhibitors containing this enantiomerically pure P3 (42d) had similar potency to the racemic material and provided support, with modeling studies, for the preparation of the gem 3,3-disubstituted compounds. A series of inhibitors containing the novel 3,3-dimethyl-1,2,3,4-tetrahydroquinolinesulfonyl (DMTHQS) P3 (Table 5) were synthesized and showed a similar activity profile as the monomethyl series. The combination of P3-DMTHQS, PB-FEP, and P1-arginine (45g) had a K-i of 6 nM (MD-805 K-i = 85 nM). In animal models of both venous and arterial thrombosis, one inhibitor (42e) was shown to produce a dose-dependent inhibition of thrombus formation that in some situations was superior to that of MD-805.

  DOI：

  10.1021/jm9811209
• 作为产物：
  描述：

  N-Boc-4-哌啶乙醇 在 二乙胺基三氟化硫 作用下， 以 二氯甲烷 为溶剂， 以40%的产率得到tert-butyl 4-(2-fluoroethyl)piperidine-1-carboxylate
  参考文献：
  名称：

  一系列凝血酶抑制剂中P2药效团的优化：赖氨酸60G的离子-偶极相互作用。

  摘要：

  描述了一系列凝血酶抑制剂中P2药效团的优化。参考抑制剂酶复合物的晶体结构，探索了许多哌啶P2功能与60G赖氨酸凝血酶的相互作用。引发了末端P2侧链基团和赖氨酸60G之间的主要离子-偶极相互作用，以解释该系列中的SAR。

  DOI：

  10.1016/s0960-894x(99)00172-9

文献信息

• [EN] 2-PHENYLIMIDAZO[1,2-A]PYRIMIDINES AS IMAGING AGENTS<br/>[FR] 2-PHÉNYLIMIDAZO[1,2-A]PYRIMIDINES EN TANT QU'AGENTS D'IMAGERIE
  申请人：HOFFMANN LA ROCHE

  公开号：WO2014187762A1

  公开（公告）日：2014-11-27

  The present invention relates to compounds of general formula (I) wherein R1 is phenyl, optionally substituted by one or two substituents, selected from 3H, halogen, lower alkyl, di-methyl-amino, NHC(O)-lower alkyl, C(O)O-lower alkyl, lower alkoxy, OC(3H)3, O11CH3, OCH2CH218F, lower alkoxy substituted by halogen, hydroxy, lower alkyl substituted by hydroxy, S-lower alkyl, or by a heterocyclyl group; or is benzo[d][l,3]dioxol-5-yl, 2,3-dihydrobenzo[b][l,4]dioxin-6-yl, indolin-2-one, or is heteroaryl, selected from the group consisting of thiophenyl, benzofuranyl, benzothiophenyl, pyrazinyl, or benzothiazolyl; R2 is hydrogen, lower alkyl or lower alkyl substituted by halogen; R3 is lower alkyl, C(3H)3, 11CH3, lower alkyl substituted by halogen, -(CH2)2-O-lower alkyl substituted by halogen or cycloalkyl; or R2 and R3 form together with the N-atom to which they are attach a ring containing -CH2CH2CHRCH2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2-NR-CH2CH2-, -CH2CH2-O-CH2CH2-, -CH2CH2CHRCH2-, -CH2CHRCH2- or (A); R is hydrogen, halogen, lower alkyl substituted by halogen or lower alkoxy; or to a pharmaceutically acceptable acid addition salt, to a racemic mixture or to its corresponding enantiomer and/or optical isomers thereof. The compounds are suitable as imaging tool, which will improve diagnosis by identifying potential patients with excess of tau aggregates in the brain, which may be likely to develop Alzheimer' s disease.

  本发明涉及通式(I)的化合物，其中R1为苯基，可选择性地被一个或两个取代基取代，这些取代基选自3H、卤素、低级烷基、二甲基氨基、NHC(O)-低级烷基、C(O)O-低级烷基、低级烷氧基、OC(3H)3、O11CH3、OCH2CH218F、被卤素取代的低级烷氧基、羟基、被羟基取代的低级烷基、S-低级烷基，或被杂环基团取代；或者R1为苯并[d][1,3]二氧环戊烯-5-基、2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基、茚满酮-2-基，或者为杂芳基，选自噻吩基、苯并呋喃基、苯并噻吩基、吡嗪基或苯并噻唑基；R2为氢、低级烷基或被卤素取代的低级烷基；R3为低级烷基、C(3H)3、11CH3、被卤素取代的低级烷基、-(CH2)2-O-被卤素取代的低级烷基或环烷基；或者R2和R3与其所连接的N原子一起形成含有-CH2CH2CHRCH2CH2-、-CH2CH2CH2CH2-、-CH2CH2CH2CH2-、-CH2CH2-NR-CH2CH2-、-CH2CH2-O-CH2CH2-、-CH2CH2CHRCH2-、-CH2CHRCH2-或(A)的环；R为氢、卤素、被卤素取代的低级烷基或低级烷氧基；或者为药学上可接受的酸加成盐，为外消旋混合物或其相应的对映异构体和/或光学异构体。这些化合物适合作为成像工具，通过识别大脑中tau聚集体过剩的潜在患者，从而改善诊断，这些患者可能发展为阿尔茨海默病。
• Identification of Three Novel Radiotracers for Imaging Aggregated Tau in Alzheimer’s Disease with Positron Emission Tomography
  作者：Luca C. Gobbi、Henner Knust、Matthias Körner、Michael Honer、Christian Czech、Sara Belli、Dieter Muri、Martin R. Edelmann、Thomas Hartung、Isabella Erbsmehl、Sandra Grall-Ulsemer、Andreas Koblet、Marianne Rueher、Sandra Steiner、Hayden T. Ravert、William B. Mathews、Daniel P. Holt、Hiroto Kuwabara、Heather Valentine、Robert F. Dannals、Dean F. Wong、Edilio Borroni

  DOI：10.1021/acs.jmedchem.7b00632

  日期：2017.9.14

  disease and are prominent targets for novel therapeutics as well as for biomarkers for diagnostic in vivo imaging. In recent years much attention has been devoted to the discovery and development of new PET tracers to image tau aggregates in the living human brain. Access to a selective PET tracer to image and quantify tau aggregates represents a unique tool to support the development of any novel therapeutic

  tau和β淀粉样蛋白（Aβ）斑块的聚集体构成了阿尔茨海默氏病的组织病理学标志，是新型疗法以及用于体内诊断的生物标志物的重要靶标。近年来，人们对新型PET示踪剂的发现和开发投入了大量精力，以描绘人脑中tau聚集体的图像。获得选择性PET示踪剂以成像和定量tau聚集体的方法代表了一种独特的工具，可支持针对tau病理形式的任何新型治疗剂的开发。本文所述研究的目的是鉴定这种新颖的放射性示踪剂。这项工作的结果是，我们发现了三种新颖的PET示踪剂（2-（4- [ 11 [ C]甲氧基苯基]咪唑并[1,2- a ]吡啶7-胺7]（[ 11 C] RO6924963），N- [ 11 C]甲基-2-（3-甲基苯基）咪唑并[1,2- a ]嘧啶-7-胺8（[ 11 C] RO6931643）和[ 18 F]对tau神经原纤维缠结具有高亲和力的2-（6-氟吡啶-3--3-基）吡咯并[2,3- b：4,5- c
• Nickel-catalyzed coupling reaction of alkyl halides with aryl Grignard reagents in the presence of 1,3-butadiene: mechanistic studies of four-component coupling and competing cross-coupling reactions
  作者：Takanori Iwasaki、Asuka Fukuoka、Wataru Yokoyama、Xin Min、Ichiro Hisaki、Tao Yang、Masahiro Ehara、Hitoshi Kuniyasu、Nobuaki Kambe

  DOI：10.1039/c7sc04675h

  日期：——

  the selectivity of the nickel-catalyzed four-component coupling reactions of alkyl fluorides, aryl Grignard reagents, and two molecules of 1,3-butadiene that affords a 1,6-octadiene carbon framework bearing alkyl and aryl groups at the 3- and 8-positions, respectively, and the competing cross-coupling reaction. Both the four-component coupling reaction and the cross-coupling reaction are triggered

  我们描述了烷基氟化物、芳基格氏试剂和两个提供 1,6-辛二烯碳骨架的 1,3-丁二烯分子的镍催化四组分偶联反应的机理、取代基效应和选择性起源分别在3-位和8-位带有烷基和芳基，以及竞争性交叉偶联反应。四组分偶联反应和交叉偶联反应都是由阴离子镍配合物的形成引发的，阴离子镍配合物是由两分子1,3-丁二烯在Ni(0)上氧化二聚并随后与Ni(0)上的络合产生的。芳基格氏试剂。氟化烷基与阴离子镍配合物的γ-碳形成C-C键，产生四组分偶联产物，而交叉偶联产物是通过Ni中心对烷基氟化物的亲核攻击产生的。这些步骤被发现是整个催化循环的速率决定和选择性决定步骤，其中烷基氟的C-F键被镁阳离子而不是锂或锌阳离子激活。芳基格氏试剂的邻位取代基抑制了交叉偶联反应，导致四组分产物的选择性形成。ate配合物的晶体结构表征和DFT计算清楚地证明了邻位取代基的这种空间效应。深入讨论了芳基格氏试剂的对位取代基对选择性和反应
• Co-Catalyzed Cross-Coupling Reaction of Alkyl Fluorides with Alkyl Grignard Reagents
  作者：Takanori Iwasaki、Koji Yamashita、Hitoshi Kuniyasu、Nobuaki Kambe

  DOI：10.1021/acs.orglett.7b01370

  日期：2017.7.21

  reaction of unactivated alkyl fluorides with alkyl Grignard reagents by a CoCl2/LiI/1,3-pentadiene catalytic system is described. The present reaction smoothly cleaved C–F bonds under mild conditions and achieved alkyl–alkyl cross-coupling even when sterically hindered tertiary alkyl Grignard reagents were employed. Since alkyl fluorides are inert toward many reagents and catalytic intermediates, the

  描述了未活化的烷基氟化物与烷基格氏试剂在CoCl 2 / LiI / 1,3-戊二烯催化体系下的交叉偶联反应。即使在空间位阻的叔烷基格氏试剂中，本反应在温和条件下也能顺利裂解C-F键，并实现烷基-烷基的交叉偶联。由于烷基氟化物对许多试剂和催化中间体是惰性的，因此本反应的使用使新的多步合成途径能够通过结合常规转化来构建碳骨架。
• Optimisation of the P2 pharmacophore in a series of thrombin inhibitors: Ion-dipole interactions with lysine 60G
  作者：John Ambler、Lyndon Brown、Xiao-Ling Cockcroft、Markus Grütter、Judy Hayler、Diana Janus、Darryl Jones、Peter Kane、Keith Menear、John Priestle、Garrick Smith、Mark Talbot、Clive V Walker、Bernard Wathey

  DOI：10.1016/s0960-894x(99)00172-9

  日期：1999.5

  The optimisation of the P2 pharmacophore in a series of thrombin inhibitors is described. The interaction of a number of piperidine P2 functionalities with lysine 60G of thrombin is explored with reference to the crystal structure of inhibitor enzyme complexes. A primary ion-dipole interaction between the terminal P2 side chain group and lysine 60G is evoked to explain the SAR in this series.

  描述了一系列凝血酶抑制剂中P2药效团的优化。参考抑制剂酶复合物的晶体结构，探索了许多哌啶P2功能与60G赖氨酸凝血酶的相互作用。引发了末端P2侧链基团和赖氨酸60G之间的主要离子-偶极相互作用，以解释该系列中的SAR。