(2R,4S)-2-hydroxymethyl-4-trifluoromethyl-N-[(1,1-dimethyl)ethoxycarbonyl]pyrrolidine | 497103-75-0

• 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: (2R,4S)-2-hydroxymethyl-4-trifluoromethyl-N-[(1,1-dimethyl)ethoxycarbonyl]pyrrolidine
• 英文别名: (2R,4S)-tert-butyl 2-(hydroxymethyl)-4-(trifluoromethyl)pyrrolidine-1-carboxylate；Tert-butyl (2R,4S)-2-(hydroxymethyl)-4-(trifluoromethyl)pyrrolidine-1-carboxylate
• CAS: 497103-75-0
• 化学式: C₁₁H₁₈F₃NO₃
• 分子量: 269.264
• InChiKey: CRSWFECHMDRHHV-JGVFFNPUSA-N

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：

  (2R,4S)-2-hydroxymethyl-4-trifluoromethyl-N-[(1,1-dimethyl)ethoxycarbonyl]pyrrolidine 在 盐酸 、 copper(l) iodide 、 sodium hydroxide 作用下， 以 1,4-二氧六环 、 异丙醇 为溶剂， 反应 1.0h， 生成 ((2R,4S)-1-(4-((2'-fluoro-5'-methoxy-3-methylbiphenyl-4-yl)methyl)phenyl)-4-(trifluoromethyl)pyrrolidin-2-yl)methanol
  参考文献：
  名称：

  Discovery of Pyrrolidine-Containing GPR40 Agonists: Stereochemistry Effects a Change in Binding Mode

  摘要：

  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.

  DOI：

  10.1021/acs.jmedchem.6b01559
• 作为产物：
  描述：

  N-Boc-4-羰基-L-脯氨酸甲酯 在 4-二甲氨基吡啶 、 锂硼氢 、 Crabtree's catalyst 、 四丁基氟化铵 、 氢气 、 sodium hydride 、 三乙胺 、 对甲苯磺酰氯 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， -78.0~20.0 ℃ 、101.33 kPa 条件下， 反应 2.0h， 生成 (2R,4S)-2-hydroxymethyl-4-trifluoromethyl-N-[(1,1-dimethyl)ethoxycarbonyl]pyrrolidine
  参考文献：
  名称：

  Discovery of Pyrrolidine-Containing GPR40 Agonists: Stereochemistry Effects a Change in Binding Mode

  摘要：

  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.

  DOI：

  10.1021/acs.jmedchem.6b01559

文献信息

• Synthesis of Boc-protected cis- and trans-4-trifluoromethyl-d-prolines
  作者：Xiao-long Qiu、Feng-ling Qing

  DOI：10.1039/b206719f

  日期：2002.9.11

  Both Boc-protected trans- and cis-4-trifluoromethyl prolines were synthesized starting from L-serine simultaneously. In our synthetic route, the key intermediate 4 was obtained through the reaction of Garner's aldehyde 1 with ylide 2 followed by trifluoromethylation with FSO2CF2COOMe–CuI. After hydrogenation followed by reduction of 4, the alcohol 5 was obtained in low diastereoselectivity, however, the two diastereoisomers could be separated easily by flash chromatography in the following steps. The bromide 8b obtained from the alcohol 5 in a straightforward fashion could not afford the desired cyclization product because of the strong electron-withdrawing properties of the trifluoromethyl group and the low ability of bromide as a leaving group. Instead, mesylation of alcohols 12a and 12b followed by treatment with potassium bis(trimethylsilyl)amide (KHMDS) afforded the desired cyclization products 13a and 13b respectively, which were transformed into Boc-protected cis- and trans-4-trifluoromethyl-D-prolines in a straightforward fashion.

  同时从L-丝氨酸出发，合成了Boc保护的反式和顺式4-三氟甲基脯氨酸。在我们的合成路线中，关键中间体4是通过加纳醛1与亚胺2反应，然后用FSO2CF2COOMe-CuI进行三氟甲基化反应获得的。在4氢化和还原后，获得了低立体选择性醇5，然而，通过以下步骤的快速色谱法可以很容易地将两种非对映异构体分离。由于三氟甲基基团的强吸电子性和溴化物作为离开基团的低能力，从醇5中直接获得的溴化物8b不能提供所需的环化产物。相反，醇12a和12b的甲磺化，然后用双(三甲基硅基)氨基钾(KHMDS)处理，分别得到了所需的环化产物13a和13b，它们被直接转化为Boc保护的顺式和反式4-三氟甲基-D-脯氨酸。
• 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。
• 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.