(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。
• Sustainable Manufacturing of trans-4-Trifluoromethyl-l-proline via Stereochemical Editing: A Combined In Silico and Experimental Approach
  作者：Russell F. Algera、Christophe Allais、Pablo J. Cabrera、María González-Esguevillas、Yanfei Guan、Chintelle James、Johnny W. Lee、Jeffrey M. Massicott、Emma L. McInturff、Robert J. Pearson、Hud Risley、Rebecca B. Watson

  DOI：10.1021/acs.oprd.4c00202

  日期：2024.10.18

  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。