1-tert-butyl 4-ethyl 3-oxopiperidine-1,4-dicarboxylate | 206111-40-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 英文名称: 1-tert-butyl 4-ethyl 3-oxopiperidine-1,4-dicarboxylate
• 英文别名: 1-tert-Butyl 4-ethyl 3-hydroxy-5,6-dihydropyridine-1,4(2H)-dicarboxylate；1-O-tert-butyl 4-O-ethyl 5-hydroxy-3,6-dihydro-2H-pyridine-1,4-dicarboxylate
• CAS: 206111-40-2
• 化学式: C₁₃H₂₁NO₅
• 分子量: 271.313
• InChiKey: FPSLWSBYFHBAKB-UHFFFAOYSA-N

物化性质

• 沸点：
  375.5±42.0 °C(Predicted)
• 密度：
  1.205±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.7
• 重原子数：
  19
• 可旋转键数：
  5
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.69
• 拓扑面积：
  76.1
• 氢给体数：
  1
• 氢受体数：
  5

安全信息

• 危险性防范说明：
  P261,P305+P351+P338
• 危险性描述：
  H302,H315,H319,H335

反应信息

• 作为反应物：
  描述：

  1-tert-butyl 4-ethyl 3-oxopiperidine-1,4-dicarboxylate 在 ammonium acetate 作用下， 以 乙醇 为溶剂， 反应 4.0h， 以100%的产率得到1-(tert-butyl) 4-ethyl 5-amino-3,6-dihydropyridine-1,4(2H)-dicarboxylate
  参考文献：
  名称：

  Discovery of a Brain-Penetrant S1P₃-Sparing Direct Agonist of the S1P₁ and S1P₅ Receptors Efficacious at Low Oral Dose

  摘要：

  2-Amino-2-(4-octylphenethyl)propane-1,3-diol 1 (fingolimod, FTY720) has been recently marketed in the United States for the treatment of patients with remitting relapsing multiple sclerosis (RRMS). Its efficacy has been primarily linked to the agonism on T cells of S1P(1), one of the five sphingosine 1-phosphate (S1P) G-protein-coupled receptors, while its cardiovascular side effects have been associated with activity at S1P(3). Emerging data suggest that the ability of this molecule to cross the blood-brain barrier and to interact with both S1P(1) and S1P(5) in the central nervous system (CNS) may contribute to its efficacy in treating patients with RAMS. We have recently disclosed the structure of an advanced, first generation S1P(3)-sparing S1P(1) agonist, a zwitterion with limited CNS exposure. In this Article, we highlight our strategy toward the identification of CNS-penetrant S1P(3)-sparing S1P(1) and S1P5 agonists resulting in the discovery of 5-(3-{2-[2-hydroxy-1- (hydroxymethyl)ethyl]-5-methyl-1,2,3,4-tetrahydro-6-isoquinolinyl}-1,2,4-oxadiazol-5-yl)-2-[(1-methylethyl)oxy]benzonitrile 15. Its exceptional in vivo potency and good pharmacokinetic properties translate into a very low predicted therapeutic dose in human (< 1 mg p.o. once daily).

  DOI：

  10.1021/jm200609t
• 作为产物：
  描述：

  1-苄基-3-氧杂-4-哌啶甲酸乙酯 在 palladium on activated charcoal 盐酸 、 氢气 、 sodium carbonate 作用下， 以 四氢呋喃 、 乙醇 、 水 为溶剂， 25.0 ℃ 、607.95 kPa 条件下， 反应 50.0h， 生成 1-tert-butyl 4-ethyl 3-oxopiperidine-1,4-dicarboxylate
  参考文献：
  名称：

  A Study of Baker's Yeast Reduction of Piperidone-carboxylates.

  摘要：

  The stereoselective baker's yeast reduction of various N-protected piperidone-carboxylic acids have been studied, and the enantioselectivity was found to be widely dependent on whether fermenting or non-fermenting conditions were employed. Thus reaction of N-tert-butoxycarbonyl-4-oxopiperidine-3-carboxylic acid ethyl ester (6) with fermenting baker's yeast gave almost racemic N-tert-butoxycarbonyl-4-hydroxypiperidine-3-carboxylic acid ethyl ester (7), however, with complete diastereoselectivity. Reduction of 6 with non-fermenting yeast gave 7 with a 24-41% enantiomeric excess. Similarly, reduction of N-tert-butoxycarbonyl-3-oxopiperidine-4-carboxylic acid ethyl ester (17) with fermenting baker's yeast gave racemic N-tert-butoxycarbonyl-3-hydroxypiperidine-4-carboxylic acid ethyl ester [(+/-)-18] diastereoselectively. A convenient method for determining the enantiomeric excess of the hydroxypiperidine carboxylic acids derivatives was found in the reaction with Sanger's reagent followed by HPLC on a chiral column.

  DOI：

  10.3891/acta.chem.scand.52-0461

文献信息

• KRAS G12C INHIBITORS
  申请人：Mirati Therapeutics, Inc.

  公开号：US20190144444A1

  公开（公告）日：2019-05-16

  The present invention relates to compounds that inhibit KRas G12C. In particular, the present invention relates to compounds that irreversibly inhibit the activity of KRas G12C, pharmaceutical compositions comprising the compounds and methods of use therefor.

  本发明涉及抑制KRas G12C的化合物。特别地，本发明涉及不可逆抑制KRas G12C活性的化合物、包含这些化合物的药物组合物及其使用方法。
• KRas G12C inhibitors
  申请人：Mirati Therapeutics, Inc.

  公开号：US10689377B2

  公开（公告）日：2020-06-23

  The present invention relates to compounds that inhibit KRas G12C. In particular, the present invention relates to compounds that irreversibly inhibit the activity of KRas G12C, pharmaceutical compositions comprising the compounds and methods of use therefor.

  本发明涉及抑制 KRas G12C 的化合物。特别是，本发明涉及不可逆地抑制 KRas G12C 活性的化合物、包含该化合物的药物组合物及其使用方法。
• Discovery of a Brain-Penetrant S1P₃-Sparing Direct Agonist of the S1P₁ and S1P₅ Receptors Efficacious at Low Oral Dose
  作者：Emmanuel H. Demont、Sandra Arpino、Rino A. Bit、Colin A. Campbell、Nigel Deeks、Sapna Desai、Simon J. Dowell、Pam Gaskin、James R. J. Gray、Lee A. Harrison、Andrea Haynes、Tom D. Heightman、Duncan S. Holmes、Philip G. Humphreys、Umesh Kumar、Mary A. Morse、Greg J. Osborne、Terry Panchal、Karen L. Philpott、Simon Taylor、Robert Watson、Robert Willis、Jason Witherington

  DOI：10.1021/jm200609t

  日期：2011.10.13

  2-Amino-2-(4-octylphenethyl)propane-1,3-diol 1 (fingolimod, FTY720) has been recently marketed in the United States for the treatment of patients with remitting relapsing multiple sclerosis (RRMS). Its efficacy has been primarily linked to the agonism on T cells of S1P(1), one of the five sphingosine 1-phosphate (S1P) G-protein-coupled receptors, while its cardiovascular side effects have been associated with activity at S1P(3). Emerging data suggest that the ability of this molecule to cross the blood-brain barrier and to interact with both S1P(1) and S1P(5) in the central nervous system (CNS) may contribute to its efficacy in treating patients with RAMS. We have recently disclosed the structure of an advanced, first generation S1P(3)-sparing S1P(1) agonist, a zwitterion with limited CNS exposure. In this Article, we highlight our strategy toward the identification of CNS-penetrant S1P(3)-sparing S1P(1) and S1P5 agonists resulting in the discovery of 5-(3-2-[2-hydroxy-1- (hydroxymethyl)ethyl]-5-methyl-1,2,3,4-tetrahydro-6-isoquinolinyl}-1,2,4-oxadiazol-5-yl)-2-[(1-methylethyl)oxy]benzonitrile 15. Its exceptional in vivo potency and good pharmacokinetic properties translate into a very low predicted therapeutic dose in human (< 1 mg p.o. once daily).
• A Study of Baker's Yeast Reduction of Piperidone-carboxylates.
  作者：Marianne Willert、Mikael Bols、Anders Hjelholt Pedersen、Palle Schneider、Louisa Barré、Ole Hammerich、Inger Søtofte、Bengt Långström

  DOI：10.3891/acta.chem.scand.52-0461

  日期：——

  The stereoselective baker's yeast reduction of various N-protected piperidone-carboxylic acids have been studied, and the enantioselectivity was found to be widely dependent on whether fermenting or non-fermenting conditions were employed. Thus reaction of N-tert-butoxycarbonyl-4-oxopiperidine-3-carboxylic acid ethyl ester (6) with fermenting baker's yeast gave almost racemic N-tert-butoxycarbonyl-4-hydroxypiperidine-3-carboxylic acid ethyl ester (7), however, with complete diastereoselectivity. Reduction of 6 with non-fermenting yeast gave 7 with a 24-41% enantiomeric excess. Similarly, reduction of N-tert-butoxycarbonyl-3-oxopiperidine-4-carboxylic acid ethyl ester (17) with fermenting baker's yeast gave racemic N-tert-butoxycarbonyl-3-hydroxypiperidine-4-carboxylic acid ethyl ester [(+/-)-18] diastereoselectively. A convenient method for determining the enantiomeric excess of the hydroxypiperidine carboxylic acids derivatives was found in the reaction with Sanger's reagent followed by HPLC on a chiral column.