(S)-4-(4-fluorophenyl)-6-oxo-1,4,5,6-tetrahydropyridine-3-carboxylic acid methyl ester | 1220248-47-4

• 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: (S)-4-(4-fluorophenyl)-6-oxo-1,4,5,6-tetrahydropyridine-3-carboxylic acid methyl ester
• 英文别名: methyl (4S)-4-(4-fluorophenyl)-2-oxo-3,4-dihydro-1H-pyridine-5-carboxylate
• CAS: 1220248-47-4
• 化学式: C₁₃H₁₂FNO₃
• 分子量: 249.242
• InChiKey: WLUPRPUBSXOSLV-JTQLQIEISA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.1
• 重原子数：
  18
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.23
• 拓扑面积：
  55.4
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  (S)-4-(4-fluorophenyl)-6-oxo-1,4,5,6-tetrahydropyridine-3-carboxylic acid methyl ester 在 lithium hydroxide 、 氯化亚砜 、 N,N-二甲基甲酰胺 作用下， 以 甲醇 、 水 、 二氯甲烷 为溶剂， 生成 (4S)-4-(4-fluorophenyl)-2-oxo-3,4-dihydro-1H-pyridine-5-carbonyl chloride
  参考文献：
  名称：

  Novel Series of Dihydropyridinone P2X7 Receptor Antagonists

  摘要：

  Identification of singleton P2X7 inhibitor 1 from HTS gave a pharmacophore that eventually turned into potential clinical candidates 17 and 19. During development, a number of issues were successfully addressed, such as metabolic stability, plasma stability, GSH adduct formation, and aniline mutagenicity. Thus, careful modification of the molecule, such as conversion of the 1,4-dihydropyridinone to the 1,2-dihydropyridinone system, proper substitution at C-5", and in some cases addition of fluorine atoms to the aniline ring allowed for the identification of a novel class of potent P2X7 inhibitors suitable for evaluating the role of P2X7 in inflammatory, immune, neurologic, or musculoskeletal disorders.

  DOI：

  10.1021/acs.jmedchem.5b00365
• 作为产物：
  描述：

  4-fluorochalcone 在 盐酸 、 potassium dihydrogenphosphate 、 正丁基锂 、 氯化亚砜 、 5%-palladium/activated carbon 、 1-[3,5-bis(trifluoromethyl)phenyl]-3-[(1S,2R)-3-[tert-butyl(dimethyl)silyl]oxy-1-(dimethylamino)-1-(4-nitrophenyl)propan-2-yl]thiourea 、 氢气 、 sodium carbonate 、 三乙胺 、 二异丙胺 、 间氯过氧苯甲酸 作用下， 以 四氢呋喃 、 正己烷 、 甲苯 为溶剂， 反应 301.67h， 生成 (S)-4-(4-fluorophenyl)-6-oxo-1,4,5,6-tetrahydropyridine-3-carboxylic acid methyl ester
  参考文献：
  名称：

  Chloramphenicol base chemistry. Part 11: 1 chloramphenicol base-derived thiourea-catalyzed enantioselective Michael addition of malononitrile to α , β -unsaturated ketones

  摘要：

  The first chloramphenicol base-derived thiourea-catalyzed enantioselective Michael addition of malononitrile to alpha,beta-unsaturated ketones is reported. The Michael adducts were obtained in good to excellent yields (up to 98% yield) and enantioselectivities (up to 94% ee). This reaction has a broad substrate scope to various alpha,beta-unsaturated ketones. With this in mind, this methodology was successfully applied to the synthesis of a chiral piperidone, an advanced building block for dihydropyridinone P2X(7) receptor antagonists. (C) 2017 Published by Elsevier Ltd.

  DOI：

  10.1016/j.tetasy.2017.05.015

文献信息

• A family of novel bifunctional organocatalysts: Highly enantioselective alcoholysis of meso cyclic anhydrides and its application for synthesis of the key intermediate of P2X7 receptor antagonists
  作者：Hong-Jun Yang、Fang-Jun Xiong、Jie Li、Fen-Er Chen

  DOI：10.1016/j.cclet.2013.04.009

  日期：2013.7

  Abstract A family of novel squaramides/sulfamides based on 1,2-alkamine was developed as chiral bifunctional catalysts to promote the asymmetric alcoholysis of meso cyclic anhydrides. The hemiesters were obtained in high yield with up to 93% ee. The usefulness of this methodology was demonstrated in the asymmetric synthesis of the key intermediate of P2X7 receptor antagonists.

  摘要研制了一系列以1,2-链胺为基础的新型方酸/亚磺酰胺作为手性双官能催化剂，以促进内消旋环酸酐的不对称醇解。半酯以高达93％ee的高收率获得。P2X7受体拮抗剂关键中间体的不对称合成证明了该方法的有效性。
• Pilot-Plant Preparation of 3,4-Dihydropyridin-2-one Derivatives, the Core Structures of P2X₇Receptor Antagonists
  作者：Xiaojun Huang、Scott Broadbent、Charles Dvorak、Shu-Hai Zhao

  DOI：10.1021/op1000447

  日期：2010.5.21

  The pilot-plant syntheses of 3 and 4, the core structures of a series of P2X7 antagonists are described. The sole stereogenic center in the dihydropyridinone ring was generated by catalytic desymmetrization. Selective formylation, followed by a tandem imination/lactamization sequence, produced the 3,4-dihydropyridin-2-one ring. The compounds 3 and 4 were produced at multikilogram scale in good overall

  描述了3和4的中试植物合成，这是一系列P2X 7拮抗剂的核心结构。二氢吡啶酮环中唯一的立体异构中心是通过催化去对称作用生成的。选择性的甲酰化，然后串联串联的内酰胺化/内酰胺化序列，产生了3,4-二氢吡啶-2--2-环。以多千克规模生产化合物3和4，具有良好的总收率（在六个步骤中为约22％）和优异的立体化学纯度（对于3，为97％ee，对于4，为100％ee ）。
• The first asymmetric synthesis of a 4-aryl-substituted 5-carboxy-3,4-dihydropyridin-2-one derivative
  作者：Xiaojun Huang、Jiang Zhu、Scott Broadbent

  DOI：10.1016/j.tetlet.2010.01.049

  日期：2010.3

  A simple and practical route for the asymmetric synthesis of (S)-4-(4-fluorophenyl)-1,4,5,6-tetrahydro-6-oxo-3-pyridinecarboxylic acid (1) is presented. The procedure comprises catalytic desymmetrization of a meso-anhydride using a chiral thiourea organocatalyst, followed by selective formylation and cyclization.

  提出了一种不对称合成（S）-4-（4-氟苯基）-1,4,5,6-四氢-6-氧代-3-吡啶羧酸（1）的简单实用途径。该方法包括使用手性硫脲有机催化剂对内消旋酸酐进行催化脱对称，然后进行选择性甲酰化和环化。
• Chloramphenicol base chemistry. Part 11: 1 chloramphenicol base-derived thiourea-catalyzed enantioselective Michael addition of malononitrile to α , β -unsaturated ketones
  作者：Linjie Yan、Haifeng Wang、Fangjun Xiong、Yuan Tao、Yan Wu、Fener Chen

  DOI：10.1016/j.tetasy.2017.05.015

  日期：2017.7

  The first chloramphenicol base-derived thiourea-catalyzed enantioselective Michael addition of malononitrile to alpha,beta-unsaturated ketones is reported. The Michael adducts were obtained in good to excellent yields (up to 98% yield) and enantioselectivities (up to 94% ee). This reaction has a broad substrate scope to various alpha,beta-unsaturated ketones. With this in mind, this methodology was successfully applied to the synthesis of a chiral piperidone, an advanced building block for dihydropyridinone P2X(7) receptor antagonists. (C) 2017 Published by Elsevier Ltd.
• Novel Series of Dihydropyridinone P2X7 Receptor Antagonists
  作者：Francisco Lopez-Tapia、Keith A. M. Walker、Christine Brotherton-Pleiss、Joanie Caroon、Dov Nitzan、Lee Lowrie、Shelley Gleason、Shu-Hai Zhao、Jacob Berger、Debra Cockayne、Deborah Phippard、Rebecca Suttmann、William L. Fitch、David Bourdet、Pankaj Rege、Xiaojun Huang、Scott Broadbent、Charles Dvorak、Jiang Zhu、Paul Wagner、Fernando Padilla、Brad Loe、Alam Jahangir、André Alker

  DOI：10.1021/acs.jmedchem.5b00365

  日期：2015.11.12

  Identification of singleton P2X7 inhibitor 1 from HTS gave a pharmacophore that eventually turned into potential clinical candidates 17 and 19. During development, a number of issues were successfully addressed, such as metabolic stability, plasma stability, GSH adduct formation, and aniline mutagenicity. Thus, careful modification of the molecule, such as conversion of the 1,4-dihydropyridinone to the 1,2-dihydropyridinone system, proper substitution at C-5", and in some cases addition of fluorine atoms to the aniline ring allowed for the identification of a novel class of potent P2X7 inhibitors suitable for evaluating the role of P2X7 in inflammatory, immune, neurologic, or musculoskeletal disorders.