rac-(2-(3-bromophenyl)-1-formylethyl)carbamic acid tert-butyl ester | 868274-66-2

• 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: rac-(2-(3-bromophenyl)-1-formylethyl)carbamic acid tert-butyl ester
• 英文别名: tert-butyl (1-(3-bromophenyl)-3-oxopropan-2-yl)carbamate；tert-butyl N-[1-(3-bromophenyl)-3-oxopropan-2-yl]carbamate
• CAS: 868274-66-2
• 化学式: C₁₄H₁₈BrNO₃
• 分子量: 328.206
• InChiKey: YQSNIBKWXMRCRN-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  19
• 可旋转键数：
  6
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  55.4
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  rac-(2-(3-bromophenyl)-1-formylethyl)carbamic acid tert-butyl ester 在 barium dihydroxide 、 三丁基硼 、 sodium hydride 、 三乙胺 、 lithium diisopropyl amide 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 二氯甲烷 为溶剂， 反应 14.0h， 生成 rac-(2S,3R,5S)-2-amino-1-(3-bromophenyl)-5-(4-fluorophenylsulfanyl)-7-methyloctan-3-ol
  参考文献：
  名称：

  Hydroxyethylene Sulfones as a New Scaffold To Address Aspartic Proteases:  Design, Synthesis, and Structural Characterization

  摘要：

  Hydroxyethylene sulfones were developed as novel scaffolds against aspartyl proteases. A diastereoselective synthesis has been established to introduce the required side chain decoration with desired stereochemistry. Depending on the substitution of the hydroxyethylene-sulfone core, micro- to submicromolar inhibition of HIV-1 protease is achieved for the S-configuration at P, and R-configuration at the hydroxy-group-bearing backbone atom. This stereochemical preference is consistent with the S,R configuration of amprenavir. The racemic mixture of the most potent derivative (K-i = 80 nM) was separated by chiral HPLC, revealing the S,R,S-enantiomer to be more active (K-i = 45 nM). Docking studies suggested this isomer as the more active one. The subsequently determined crystal structure with HIV-1 protease, cocrystallized from a racemic mixture, exclusively reveals the S,R,S-enantiomer accommodated to the binding pocket. The transition state mimicking hydroxy group of the inhibitor is centered between both catalytic aspartates, while either its carbonyl or sulfonyl group forms H-bonds to the structurally conserved water mediating interactions between ligand and Ile50NH/Ile50NH' of both flaps. Biological testing of the stereoisomeric hydroxyethylene sulfones against cathepsin D and beta-secretase did not reveal significant inhibition. Most likely, the latter proteases require inverted configuration at the hydroxy group.

  DOI：

  10.1021/jm050224y
• 作为产物：
  描述：

  3-溴苄溴 在 盐酸 、 草酰氯 、 sodium ethanolate 、 碳酸氢钠 、 二甲基亚砜 、 三乙胺 、 氯甲酸异丁酯 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 乙醇 、 二氯甲烷 为溶剂， 反应 24.0h， 生成 rac-(2-(3-bromophenyl)-1-formylethyl)carbamic acid tert-butyl ester
  参考文献：
  名称：

  Hydroxyethylene Sulfones as a New Scaffold To Address Aspartic Proteases:  Design, Synthesis, and Structural Characterization

  摘要：

  Hydroxyethylene sulfones were developed as novel scaffolds against aspartyl proteases. A diastereoselective synthesis has been established to introduce the required side chain decoration with desired stereochemistry. Depending on the substitution of the hydroxyethylene-sulfone core, micro- to submicromolar inhibition of HIV-1 protease is achieved for the S-configuration at P, and R-configuration at the hydroxy-group-bearing backbone atom. This stereochemical preference is consistent with the S,R configuration of amprenavir. The racemic mixture of the most potent derivative (K-i = 80 nM) was separated by chiral HPLC, revealing the S,R,S-enantiomer to be more active (K-i = 45 nM). Docking studies suggested this isomer as the more active one. The subsequently determined crystal structure with HIV-1 protease, cocrystallized from a racemic mixture, exclusively reveals the S,R,S-enantiomer accommodated to the binding pocket. The transition state mimicking hydroxy group of the inhibitor is centered between both catalytic aspartates, while either its carbonyl or sulfonyl group forms H-bonds to the structurally conserved water mediating interactions between ligand and Ile50NH/Ile50NH' of both flaps. Biological testing of the stereoisomeric hydroxyethylene sulfones against cathepsin D and beta-secretase did not reveal significant inhibition. Most likely, the latter proteases require inverted configuration at the hydroxy group.

  DOI：

  10.1021/jm050224y

文献信息

• [EN] INDOLE COMPOUNDS AND METHODS OF USE<br/>[FR] COMPOSÉS INDOLES ET PROCÉDÉS D'UTILISATION
  申请人：[en]GENZYME CORPORATION

  公开号：WO2023034992A1

  公开（公告）日：2023-03-09

  The invention relates to heterocyclic compounds, pharmaceutically acceptable salts thereof, and pharmaceutical preparations thereof. Also described herein are compositions and the use of such compounds in methods of treating diseases and conditions mediated by deficient CFTR activity, in particular cystic fibrosis.
• Hydroxyethylene Sulfones as a New Scaffold To Address Aspartic Proteases:  Design, Synthesis, and Structural Characterization
  作者：Edgar Specker、Jark Böttcher、Andreas Heine、Christoph A. Sotriffer、Hauke Lilie、Andreas Schoop、Gerhard Müller、Nils Griebenow、Gerhard Klebe

  DOI：10.1021/jm050224y

  日期：2005.10.1

  Hydroxyethylene sulfones were developed as novel scaffolds against aspartyl proteases. A diastereoselective synthesis has been established to introduce the required side chain decoration with desired stereochemistry. Depending on the substitution of the hydroxyethylene-sulfone core, micro- to submicromolar inhibition of HIV-1 protease is achieved for the S-configuration at P, and R-configuration at the hydroxy-group-bearing backbone atom. This stereochemical preference is consistent with the S,R configuration of amprenavir. The racemic mixture of the most potent derivative (K-i = 80 nM) was separated by chiral HPLC, revealing the S,R,S-enantiomer to be more active (K-i = 45 nM). Docking studies suggested this isomer as the more active one. The subsequently determined crystal structure with HIV-1 protease, cocrystallized from a racemic mixture, exclusively reveals the S,R,S-enantiomer accommodated to the binding pocket. The transition state mimicking hydroxy group of the inhibitor is centered between both catalytic aspartates, while either its carbonyl or sulfonyl group forms H-bonds to the structurally conserved water mediating interactions between ligand and Ile50NH/Ile50NH' of both flaps. Biological testing of the stereoisomeric hydroxyethylene sulfones against cathepsin D and beta-secretase did not reveal significant inhibition. Most likely, the latter proteases require inverted configuration at the hydroxy group.