(S)-desisopropylcarazolol

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: (S)-desisopropylcarazolol
• 英文别名: (R)-1-Amino-3-(9H-carbazol-4-yloxy)-2-propanol；(2R)-1-amino-3-(9H-carbazol-4-yloxy)propan-2-ol
• 化学式: C₁₅H₁₆N₂O₂
• 分子量: 256.304
• InChiKey: UUUATVREIARQHR-SNVBAGLBSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  19
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.2
• 拓扑面积：
  71.3
• 氢给体数：
  3
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  氟代丙酮 、 (S)-desisopropylcarazolol 在 sodium cyanoborohydride 、 溶剂黄146 作用下， 以 甲醇 为溶剂， 反应 2.0h， 以62%的产率得到(R)-Fluorocarazolol
  参考文献：
  名称：

  Synthesis, Binding Properties, and 18F Labeling of Fluorocarazolol, a High-Affinity .beta.-Adrenergic Receptor Antagonist

  摘要：

  New beta-adrenergic receptor antagonists, 2-(R)-(+)- and 2-(S)-(-)-1-(9H-earbazol-4-yl-oxy)-3-[[1-(fluoromethyl)ethyl]amino]-2-propanol ((S)- and (R)-fluorocarazolols), were labeled with fluorine-18 at the no-carrier-added level by reductive alkylation of desisopropylcarazolol (4-(2-hydroxy-3-amino-1-propoxy)carbazole) with [F-18]fluoroacetone. The latter was prepared by nucleophilic substitution of fluoride on acetol tosylate and may serve as a useful synthetic precursor for other radiotracers. The radiochemical yield of [F-18]fluorocarazolol (500-1200 Ci/mmol) from [F-18]fluoride was 40 +/- 10% at the end of the 45 min synthesis. Chiral HPLC showed >99% enantiomeric purity of 2-(S)- and 2-(R)- [F-18] fluorocarazolols. The log P of fluorocarazolol was 2.2 at pH 7.4. The in vitro K-D values of(S)- and (R)-fluorocarazolol for the beta-adrenergic receptor were measured in a rat heart preparation to be K-D= 68 and 1128 pM, respectively. Biodistribution experiments in mice demonstrated specific beta-adrenergic receptor binding of (S)-[F-18]fluorocarazolol. (R)-[F-18]fluorocarazolol showed no observable specific binding to beta-receptors in vivo. The uptake of (R)-[F-18]fluorocarazolol may therefore be used as an estimation of nonspecific binding. Positron emission tomography images of pigs showed receptor-specific uptake of(S)-[F-18]fluorocarazolol in the heart and lung. Washout of dissociated ligand from the tissue was observed only after 70 min postinjection. The maximum ratio of specific to nonspecific uptake in pig heart and lung was ca. 10 at 150 min postinjection. Observed levels of fluorocarazolol metabolites in mouse and pig blood were relatively low and remained fairly constant during the period from 10 to 180 min postinjection. These results indicate that (S)-(-)-[F-18]fluorocarazolol is of interest for use as a radiopharmaceutical for estimation of beta-adrenergic receptors with positron tomography.

  DOI：

  10.1021/jm00046a005
• 作为产物：
  描述：

  在 肼 作用下， 以 5,5-dimethyl-1,3-cyclohexadiene 、 异丙醇 为溶剂， 生成 (S)-desisopropylcarazolol
  参考文献：
  名称：

  开发对映体富集的 β-肾上腺素分解剂的新型化学酶途径。关于普萘洛尔、阿普洛尔、吲哚洛尔、卡拉唑洛、莫普洛尔和美托洛尔的案例研究。

  摘要：

  合成肾上腺素能 β 受体阻滞剂的两种对映异构体的有效化学酶途径是通过鉴定中心手性结构单元来完成的，该结构单元首先使用脂肪酶催化动力学拆分 (KR, Amano PS-IM) 作为 5 克的不对称步骤制备-刻度（209 mM 浓度）。随后获得的对映体纯 (R)-氯醇 (>99% ee) 用于合成一系列模型 (R)-(+)-β-受体阻滞剂（即普萘洛尔、阿普洛尔、吲哚洛尔、卡唑洛尔、莫普洛尔和美托洛尔），其产生的对映体过量在 96-99.9% 范围内。以普萘洛尔为模型的药学相关 (S)-对应物是通过使用乙酸铯和催化量的 18-Crown 对各自的对映体纯 (R)-甲磺酸盐进行乙酰解以优异的对映体纯度 (99% ee) 合成的-6, 然后将形成的(S)-乙酸酯进行酸水解。或者，使用含有来自乳酸杆菌的过表达重组乙醇脱氢酶的冻干大肠杆菌细胞进行前手性酮的不对称还原，即 2-(3-chloro-2-ox

  DOI：

  10.1039/d2ra04302e

文献信息

• Synthesis, Binding Properties, and 18F Labeling of Fluorocarazolol, a High-Affinity .beta.-Adrenergic Receptor Antagonist
  作者：Lei Zheng、Marc S. Berridge、Paul Ernsberger

  DOI：10.1021/jm00046a005

  日期：1994.9

  New beta-adrenergic receptor antagonists, 2-(R)-(+)- and 2-(S)-(-)-1-(9H-earbazol-4-yl-oxy)-3-[[1-(fluoromethyl)ethyl]amino]-2-propanol ((S)- and (R)-fluorocarazolols), were labeled with fluorine-18 at the no-carrier-added level by reductive alkylation of desisopropylcarazolol (4-(2-hydroxy-3-amino-1-propoxy)carbazole) with [F-18]fluoroacetone. The latter was prepared by nucleophilic substitution of fluoride on acetol tosylate and may serve as a useful synthetic precursor for other radiotracers. The radiochemical yield of [F-18]fluorocarazolol (500-1200 Ci/mmol) from [F-18]fluoride was 40 +/- 10% at the end of the 45 min synthesis. Chiral HPLC showed >99% enantiomeric purity of 2-(S)- and 2-(R)- [F-18] fluorocarazolols. The log P of fluorocarazolol was 2.2 at pH 7.4. The in vitro K-D values of(S)- and (R)-fluorocarazolol for the beta-adrenergic receptor were measured in a rat heart preparation to be K-D= 68 and 1128 pM, respectively. Biodistribution experiments in mice demonstrated specific beta-adrenergic receptor binding of (S)-[F-18]fluorocarazolol. (R)-[F-18]fluorocarazolol showed no observable specific binding to beta-receptors in vivo. The uptake of (R)-[F-18]fluorocarazolol may therefore be used as an estimation of nonspecific binding. Positron emission tomography images of pigs showed receptor-specific uptake of(S)-[F-18]fluorocarazolol in the heart and lung. Washout of dissociated ligand from the tissue was observed only after 70 min postinjection. The maximum ratio of specific to nonspecific uptake in pig heart and lung was ca. 10 at 150 min postinjection. Observed levels of fluorocarazolol metabolites in mouse and pig blood were relatively low and remained fairly constant during the period from 10 to 180 min postinjection. These results indicate that (S)-(-)-[F-18]fluorocarazolol is of interest for use as a radiopharmaceutical for estimation of beta-adrenergic receptors with positron tomography.
• Development of a novel chemoenzymatic route to enantiomerically enriched β-adrenolytic agents. A case study toward propranolol, alprenolol, pindolol, carazolol, moprolol, and metoprolol
  作者：Paweł Borowiecki、Beata Zdun、Natalia Popow、Magdalena Wiklińska、Tamara Reiter、Wolfgang Kroutil

  DOI：10.1039/d2ra04302e

  日期：——

  a series of model (R)-(+)-β-blockers (i.e., propranolol, alprenolol, pindolol, carazolol, moprolol, and metoprolol), which were produced with enantiomeric excess in the range of 96-99.9%. The pharmaceutically relevant (S)-counterpart, taking propranolol as a model, was synthesized in excellent enantiomeric purity (99% ee) via acetolysis of the respective enantiomerically pure (R)-mesylate by using

  合成肾上腺素能 β 受体阻滞剂的两种对映异构体的有效化学酶途径是通过鉴定中心手性结构单元来完成的，该结构单元首先使用脂肪酶催化动力学拆分 (KR, Amano PS-IM) 作为 5 克的不对称步骤制备-刻度（209 mM 浓度）。随后获得的对映体纯 (R)-氯醇 (>99% ee) 用于合成一系列模型 (R)-(+)-β-受体阻滞剂（即普萘洛尔、阿普洛尔、吲哚洛尔、卡唑洛尔、莫普洛尔和美托洛尔），其产生的对映体过量在 96-99.9% 范围内。以普萘洛尔为模型的药学相关 (S)-对应物是通过使用乙酸铯和催化量的 18-Crown 对各自的对映体纯 (R)-甲磺酸盐进行乙酰解以优异的对映体纯度 (99% ee) 合成的-6, 然后将形成的(S)-乙酸酯进行酸水解。或者，使用含有来自乳酸杆菌的过表达重组乙醇脱氢酶的冻干大肠杆菌细胞进行前手性酮的不对称还原，即 2-(3-chloro-2-ox