(2S,4R)-tert-butyl 2-(hydroxymethyl)-4-(trifluoromethyl)pyrrolidine-1-carboxylate | 470482-43-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯烷类
• 英文名称: (2S,4R)-tert-butyl 2-(hydroxymethyl)-4-(trifluoromethyl)pyrrolidine-1-carboxylate
• 英文别名: tert-butyl (2S,4R)-2-(hydroxymethyl)-4-(trifluoromethyl)pyrrolidine-1-carboxylate；(2S,4R)-N-(tert-butyloxy)carbonyl-4-trifluoromethyl-2-hydroxymethylpyrrolidine；Boc-(4R)-trifluoromethyl-L-prolinol；(2S,4R)-1-Boc-4-trifluoromethylpyrrolidine-2-methanol
• CAS: 470482-43-0
• 化学式: C₁₁H₁₈F₃NO₃
• 分子量: 269.264
• InChiKey: CRSWFECHMDRHHV-SFYZADRCSA-N

物化性质

• 沸点：
  293.0±35.0 °C(Predicted)
• 密度：
  1.231±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2
• 重原子数：
  18
• 可旋转键数：
  3
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.91
• 拓扑面积：
  49.8
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  (2S,4R)-tert-butyl 2-(hydroxymethyl)-4-(trifluoromethyl)pyrrolidine-1-carboxylate 在 sodium chlorite 、 disodium hydrogenphosphate 、 2,2,6,6-四甲基哌啶氧化物 作用下， 以 水 、 乙腈 为溶剂， 生成 (2S,4R)-1-(叔丁氧基羰基)-4-(三氟甲基)吡咯烷-2-羧酸
  参考文献：
  名称：

  [EN] PROTEASE INHIBITORS FOR TREATING OR PREVENTING CORONAVIRUS INFECTION
  [FR] INHIBITEURS DE PROTÉASE POUR TRAITER OU PRÉVENIR UNE INFECTION À CORONAVIRUS

  摘要：

  The present invention provides a compound of Formula I wherein A, M, R1, R2, R3a, R3b, and subscripts m and n are as described herein and pharmaceutical compositions comprising one or more said compounds, and methods for using said compounds for the treatment, inhibition, or amelioration of one or more disease states that could benefit from inhibition of a coronavirus, including SARS-CoV, MERS-CoV and SARS-CoV-2. The compounds of this invention could further be used in combination with other therapeutically effective agents, including but not limited to, other drugs useful for the treatment of coronavirus infection. The invention furthermore relates to processes for preparing compounds of Formula I, and pharmaceutical compositions which comprise compounds of Formula I and pharmaceutically acceptable salts thereof.

  公开号：

  WO2023133174A1
• 作为产物：
  描述：

  N-Boc-反式-4-羟基-L-脯氨酸甲酯 在 4-二甲氨基吡啶 、 氟化铵 、 sodium tetrahydroborate 、 2,2,6,6-四甲基哌啶氧化物 、 Crabtree's catalyst 、 三氯异氰尿酸 、 四丁基氟化铵 、 氢气 、 sodium hydride 、 三乙胺 、 lithium chloride 作用下， 以 四氢呋喃 、 甲醇 、 乙醇 、 二氯甲烷 为溶剂， 反应 103.5h， 生成 (2S,4R)-tert-butyl 2-(hydroxymethyl)-4-(trifluoromethyl)pyrrolidine-1-carboxylate
  参考文献：
  名称：

  [EN] PROTEASE INHIBITORS FOR TREATING OR PREVENTING CORONAVIRUS INFECTION
  [FR] INHIBITEURS DE PROTÉASE POUR TRAITER OU PRÉVENIR UNE INFECTION À CORONAVIRUS

  摘要：

  The present invention provides a compound of Formula I wherein A, M, R1, R2, R3a, R3b, and subscripts m and n are as described herein and pharmaceutical compositions comprising one or more said compounds, and methods for using said compounds for the treatment, inhibition, or amelioration of one or more disease states that could benefit from inhibition of a coronavirus, including SARS-CoV, MERS-CoV and SARS-CoV-2. The compounds of this invention could further be used in combination with other therapeutically effective agents, including but not limited to, other drugs useful for the treatment of coronavirus infection. The invention furthermore relates to processes for preparing compounds of Formula I, and pharmaceutical compositions which comprise compounds of Formula I and pharmaceutically acceptable salts thereof.

  公开号：

  WO2023133174A1

文献信息

• [EN] KRAS G12D INHIBITORS<br/>[FR] INHIBITEURS DE KRAS G12D
  申请人：MIRATI THERAPEUTICS INC

  公开号：WO2021041671A1

  公开（公告）日：2021-03-04

  The present invention relates to compounds that inhibit KRas G12D. In particular, the present invention relates to compounds that inhibit the activity of KRas G12D, pharmaceutical compositions comprising the compounds and methods of use therefor.

  本发明涉及抑制KRas G12D的化合物。具体地，本发明涉及抑制KRas G12D活性的化合物，包括这些化合物的药物组合物以及使用方法。
• 10.1021/acs.oprd.4c00202
  作者：Algera, Russell F.、Allais, Christophe、Cabrera, Pablo J.、González-Esguevillas, María、Guan, Yanfei、James, Chintelle、Lee, Johnny W.、Massicott, Jeffrey M.、McInturff, Emma L.、Pearson, Robert J.、Risley, Hud、Watson, Rebecca B.

  DOI：10.1021/acs.oprd.4c00202

  日期：——

  Ibuzatrelvir (1) is a second-generation, orally bioavailable, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease inhibitor clinical candidate. Herein, we report the implementation of an in silico and high-throughput experimentation strategy leading to the identification of a rapid, efficient, and sustainable route to trans-4-trifluoromethyl-l-proline (2), a key building block

  Ibuzazrelvir （1） 是第二代口服生物可利用的严重急性呼吸系统综合症冠状病毒 2 （SARS-CoV-2） 主要蛋白酶抑制剂临床候选药物。在此，我们报告了计算机和高通量实验策略的实施，从而确定了一种快速、高效和可持续的途径来获得反式 4-三氟甲基-l-脯氨酸 （2），这是 ibuzatrelvir 的关键组成部分。这种新颖的合成路线具有一个关键的立体化学编辑步骤，可实现高效且可扩展的方案，该方案在温和条件下以高立体选择性运行，以五步合成序列从现成的起始材料中有效获取超过 235 kg 的反式-4-三氟甲基-l-脯氨酸 2。
• Influence of 4- or 5-substituents on the pyrrolidine ring of 5-[1-(2-methoxymethylpyrrolidinyl)sulfonyl]isatin derivatives on their inhibitory activities towards caspases-3 and -7
  作者：Panupun Limpachayaporn、Burkhard Riemann、Klaus Kopka、Otmar Schober、Michael Schäfers、Günter Haufe

  DOI：10.1016/j.ejmech.2013.04.011

  日期：2013.6

  A series of new 4- or 5-substituted pyrrolidine derivatives of 5-[1-(2-methoxymethylpyrrolidinyl)sulfonyl]isatin bearing additional n-butyl or 4-fluorobutyl groups at the isatin nitrogen were prepared and their inhibitory activities have been tested against caspases-3 and -7, which are known to participate in the execution of the programmed cell death, called apoptosis. Several analogues fluorinated at the 4-position of the pyrrolidine ring were also synthesized since such inhibitors might be developed as F-18-radiotracers for molecular imaging of activated caspases in vivo by PET. Enantiomerically pure diastereomeric 4-fluoropyrrolidinyl derivatives inhibited the enzymes in the nanomolar scale, i.e.100-1000 times more efficient than the corresponding 4-methoxy analogues. The 4,4-difluorinated compound showed the best result with IC50 = 362 nM and 178 nM for the aforementioned caspases. In contrast, the 4-methoxy and 4-trifluoromethyl analogues exhibited less inhibition potencies for the enzymes in the mu M scale, whereas all 4-OPEG(4) (PEG(4) = tetraethyleneglycol) and 5-methoxymethyl derivatives were inactive. (C) 2013 Elsevier Masson SAS. All rights reserved.
• Discovery of Pyrrolidine-Containing GPR40 Agonists: Stereochemistry Effects a Change in Binding Mode
  作者：Elizabeth A. Jurica、Ximao Wu、Kristin N. Williams、Andres S. Hernandez、David S. Nirschl、Richard A. Rampulla、Arvind Mathur、Min Zhou、Gary Cao、Chunshan Xie、Biji Jacob、Hong Cai、Tao Wang、Brian J. Murphy、Heng Liu、Carrie Xu、Lori K. Kunselman、Michael B. Hicks、Qin Sun、Dora M. Schnur、Doree F. Sitkoff、Elizabeth A. Dierks、Atsu Apedo、Douglas B. Moore、Kimberly A. Foster、Mary Ellen Cvijic、Reshma Panemangalore、Neil A. Flynn、Brad D. Maxwell、Yang Hong、Yuan Tian、Jason J. Wilkes、Bradley A. Zinker、Jean M. Whaley、Joel C. Barrish、Jeffrey A. Robl、William R. Ewing、Bruce A. Ellsworth

  DOI：10.1021/acs.jmedchem.6b01559

  日期：2017.2.23

  A novel series of pyrrolidine-containing GPR40 agonists is described as a potential treatment for type 2 diabetes. The initial pyrrolidine hit was modified by moving the position of the carboxylic acid, a key pharmacophore for GPR40. Addition of a 4-cis-CF3 to the pyrrolidine improves the human GPR40 binding K-i and agonist efficacy. After further optimization, the discovery of a minor enantiomeric impurity with agonist activity led to the finding that enantiomers (R,R)-68 and (S,S)-68 have differential effects on the radioligand used for the binding assay, with (R,R)-68 potentiating the radioligand and (S,S)-68 displacing the radioligand. Compound (R,R)-68 activates both G(q)-coupled intracellular Ca2+ flux and G(s)-coupled cAMP accumulation. This signaling bias results in a dual mechanism of action for compound (R,R)-68, demonstrating glucose-dependent insulin and GLP-1 secretion in vitro. In vivo, compound (R,R)-68 significantly lowers plasma glucose levels in mice during an oral glucose challenge, encouraging further development of the series.
• [EN] PROTEASE INHIBITORS FOR TREATING OR PREVENTING CORONAVIRUS INFECTION<br/>[FR] INHIBITEURS DE PROTÉASE POUR TRAITER OU PRÉVENIR UNE INFECTION À CORONAVIRUS
  申请人：[en]MERCK SHARP & DOHME LLC

  公开号：WO2023133174A1

  公开（公告）日：2023-07-13

  The present invention provides a compound of Formula I wherein A, M, R1, R2, R3a, R3b, and subscripts m and n are as described herein and pharmaceutical compositions comprising one or more said compounds, and methods for using said compounds for the treatment, inhibition, or amelioration of one or more disease states that could benefit from inhibition of a coronavirus, including SARS-CoV, MERS-CoV and SARS-CoV-2. The compounds of this invention could further be used in combination with other therapeutically effective agents, including but not limited to, other drugs useful for the treatment of coronavirus infection. The invention furthermore relates to processes for preparing compounds of Formula I, and pharmaceutical compositions which comprise compounds of Formula I and pharmaceutically acceptable salts thereof.