1-(S)-1-(2,3-dihydrobenzofuran-5-yl)-2,3,4,9-tetrahydro-1H-βcarboline N-acetyl-D-leucine salt

• 分子结构分类: 有机化合物 - 生物碱及其衍生物 - 哈马拉生物碱
• 英文名称: 1-(S)-1-(2,3-dihydrobenzofuran-5-yl)-2,3,4,9-tetrahydro-1H-βcarboline N-acetyl-D-leucine salt
• 英文别名: (1S)-1-(2,3-dihydrobenzofuran-5-yl)-2,3 ,4,9-tetrahydro-1H-β-carbol-2-ium (R)-(-)-2-acetylamino-4-methylpentanoate；(2R)-2-acetamido-4-methylpentanoate;(1S)-1-(2,3-dihydro-1-benzofuran-5-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-2-ium
• 化学式: C₈H₁₅NO₃*C₁₉H₁₈N₂O
• 分子量: 463.577
• InChiKey: XMBXRIKUABVYAF-DWAJDJCRSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.96
• 重原子数：
  34
• 可旋转键数：
  5
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.41
• 拓扑面积：
  103
• 氢给体数：
  4
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  2,3-二氢苯并呋喃-5-甲醛 以 甲醇 、 乙酸乙酯 、 甲苯 为溶剂， 反应 20.67h， 生成 1-(R)-1-(2,3-dihydrobenzofuran-5-yl)-2,3,4,9-tetrahydro-1H-β-carboline N-acetyl-D-leucine salt 、 1-(S)-1-(2,3-dihydrobenzofuran-5-yl)-2,3,4,9-tetrahydro-1H-βcarboline N-acetyl-D-leucine salt
  参考文献：
  名称：

  An Efficient Process for Synthesis of 3-(R)-3-(2,3-Dihydrobenzofuran-5-yl)- 1,2,3,4-tetrahydropyrrolo[3,4-b]quinolin-9-one

  摘要：

  3-(R)-3-(2,3-Dihydrobenzofuran-5-yl)-1,2,3,4-tetrahydropyrrolo[3,4-b]quinolin-9-one (1) is a key intermediate in the synthesis of pyrroloquinolone analogues, a series of highly potent and selective phosphodiesterase 5 (PDE5) inhibitors. Racemic 1-(2,3-dihydrobenzofuran-5-yl)-2,3,4,9-tetrahydro-1H-beta-carboline (6, Scheme 2) was prepared by Pictet-Spenger condensation in 84% isolated yield with > 97% chemical purity. The desired intermediate, 1-(R)-1-(2,3-dihydrobenzofuran-5-yl)2,3,4,9-tetrahydro-1H-beta-carboline N-acetyl-D-leucine salt (8), was obtained in 35% isolated yield with high chiral purity (> 97% ee) from the chemical resolution of 6 with N-acetyl-D-leucine (7). A racemization step was developed for recycling enriched 1-(S)-beta-carboline 9 freebase (8/9, 25 +/- 3%/75 +/- 3%) to a near racemic mixture (8/9, 47 +/- 1%153 +/- 1%). Furthermore, the resolving reagent 7 was recovered in > 76% yield, which, together with the recycled racemic mixture (8/9, 47 1%153 1%), afforded 35% more salt 8 after two recycles (>= 97.0% ee). The salt 8 was converted to 1-(R)-1-(2,3-dihydrobenzofuran-5-yl)-2-benzyl-2,3,4,9-tetrahydro-1H-beta-carbo- line (10) in excellent yield (94%). A modified Winterfeldt oxidation of compound 10 using Aliquat 175 as a phase transfer catalyst produced 3-(R)-2-benzyl-3-(2,3-dihydrobenzofuran-5yl)-1,2,3,4-tetrahydropyrrolo[3,4-b]quinolin-9-one (12) in moderate 42% yield. Hydrogenolysis of compound 12 gave the desired compound 1 in quantitative yield with retention of chiral purity (>= 97.0% ee). This efficient, reproducible, economical, and nonchromatography scale-up process could be used to make multikilogram quantities of compound 1.

  DOI：

  10.1021/op050079y

文献信息

• WO2006/93719
  申请人：——

  公开号：——

  公开（公告）日：——
• An Efficient Process for Synthesis of 3-(<i>R</i>)-3-(2,3-Dihydrobenzofuran-5-yl)- 1,2,3,4-tetrahydropyrrolo[3,4-<i>b</i>]quinolin-9-one
  作者：Xun Li、Shawn Branum、Ronald K. Russell、Weiqin Jiang、Zhihua Sui

  DOI：10.1021/op050079y

  日期：2005.9.1

  3-(R)-3-(2,3-Dihydrobenzofuran-5-yl)-1,2,3,4-tetrahydropyrrolo[3,4-b]quinolin-9-one (1) is a key intermediate in the synthesis of pyrroloquinolone analogues, a series of highly potent and selective phosphodiesterase 5 (PDE5) inhibitors. Racemic 1-(2,3-dihydrobenzofuran-5-yl)-2,3,4,9-tetrahydro-1H-beta-carboline (6, Scheme 2) was prepared by Pictet-Spenger condensation in 84% isolated yield with > 97% chemical purity. The desired intermediate, 1-(R)-1-(2,3-dihydrobenzofuran-5-yl)2,3,4,9-tetrahydro-1H-beta-carboline N-acetyl-D-leucine salt (8), was obtained in 35% isolated yield with high chiral purity (> 97% ee) from the chemical resolution of 6 with N-acetyl-D-leucine (7). A racemization step was developed for recycling enriched 1-(S)-beta-carboline 9 freebase (8/9, 25 +/- 3%/75 +/- 3%) to a near racemic mixture (8/9, 47 +/- 1%153 +/- 1%). Furthermore, the resolving reagent 7 was recovered in > 76% yield, which, together with the recycled racemic mixture (8/9, 47 1%153 1%), afforded 35% more salt 8 after two recycles (>= 97.0% ee). The salt 8 was converted to 1-(R)-1-(2,3-dihydrobenzofuran-5-yl)-2-benzyl-2,3,4,9-tetrahydro-1H-beta-carbo- line (10) in excellent yield (94%). A modified Winterfeldt oxidation of compound 10 using Aliquat 175 as a phase transfer catalyst produced 3-(R)-2-benzyl-3-(2,3-dihydrobenzofuran-5yl)-1,2,3,4-tetrahydropyrrolo[3,4-b]quinolin-9-one (12) in moderate 42% yield. Hydrogenolysis of compound 12 gave the desired compound 1 in quantitative yield with retention of chiral purity (>= 97.0% ee). This efficient, reproducible, economical, and nonchromatography scale-up process could be used to make multikilogram quantities of compound 1.