Propionic acid 4-(2-amino-purin-9-yl)-2-isopropoxycarbonyloxymethyl-butyl ester

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 咪唑并嘧啶类
• 英文名称: Propionic acid 4-(2-amino-purin-9-yl)-2-isopropoxycarbonyloxymethyl-butyl ester
• 英文别名: [4-(2-Aminopurin-9-yl)-2-(propan-2-yloxycarbonyloxymethyl)butyl] propanoate；[4-(2-aminopurin-9-yl)-2-(propan-2-yloxycarbonyloxymethyl)butyl] propanoate
• 化学式: C₁₇H₂₅N₅O₅
• 分子量: 379.416
• InChiKey: MQCFPUXOGYJGMM-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.7
• 重原子数：
  27
• 可旋转键数：
  12
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.59
• 拓扑面积：
  131
• 氢给体数：
  1
• 氢受体数：
  9

反应信息

• 作为产物：
  描述：

  2-[2-(2-氨基-9h-嘌呤-9-基)乙基]-1,3-丙二醇 在 4-二甲氨基吡啶 、 对甲苯磺酸 作用下， 以 吡啶 、 N,N-二甲基甲酰胺 为溶剂， 反应 22.0h， 生成 Propionic acid 4-(2-amino-purin-9-yl)-2-isopropoxycarbonyloxymethyl-butyl ester
  参考文献：
  名称：

  Synthesis and evaluation of 2-Amino-9-(3-acyloxymethyl-4-alkoxycarbonyloxybut-1-yl)purines and 2-Amino-9-(3-alkoxycarbonyloxymethyl-4-alkoxycarbonyloxybut-1-yl)purines as potential prodrugs of penciclovir

  摘要：

  A series of 2-amino-9-(3-acyloxymethyl-4-alkoxycarbonyloxybut-1-yl)purines (1-8) and 2-amino-9-(3-alkoxycarbonyl-oxymethyl-4-alkoxycarbonyloxybut-1-yl)purines (9-12) were synthesized as potential prodrugs of penciclovir. Treatment of 6-deoxypenciclovir with trimethyl orthoacetate or triethyl orthopropionate (1.2 equiv) in DMF in the presence of p-TsOH . H2O (0.1 equiv) followed by quenching with excess H2O gave the corresponding mono-O-acetyl or mono-O-propionyl compound, 17 or 18, in excellent yields of 95 and 92%, respectively. Reactions of 17 or 18 with an appropriate alkyl (Me, Et, n-Pr, and i-Pr) 4-nitrophenyl carbonate (1.2 equiv) in pyridine in the presence of a catalytic amount of DMAP (0.1 equiv) at 80 degrees C afforded the monoacyl, monocarbonate derivatives of 6-deoxypenciclovir, 1-8, in 86-94% yields. Similar reactions of 6-deoxypenciclovir with 2.1 equiv of alkyl 4-nitrophenyl carbonate produced the dicarbonate derivatives 9-12 in 81-83% yields. Of the prodrugs tested in rats, 2-amino-9-(3-acetoxymethyl-4-isopropoxycarbonyloxybut-1-yl)purine (4) achieved the highest mean urinary recovery of penciclovir (36%), followed in order by compounds 2 (35%), 6 (35%), 7 (34%), 10 (34%), 8 (32%), 3 (32%), and famciclovir (31%). The mean urinary recovery of penciclovir and concentrations of penciclovir in the blood from 4 in mice were also slightly higher than those from famciclovir. The in vivo antiviral efficacy of 4 in HSV-1-infected normal BALB/c mice was higher than those of famciclovir and valaciclovir in terms of mortality (100, 80, and 40%) and mean survival time (>21, 13 +/- 5.0 (SEM), and 13 +/- 1.6 days). Compound 4 demonstrated an effective anti-hepadnaviral response with intrahepatic viral load being reduced by 90%, the viral supercoiled DNA levels reduced by 70% and Pre-S expression inhibited by 30% against duck hepatitis B virus (DHBV) in vivo, and did not cause any significant hepatotoxicity after 4 weeks of treatment. (C) 1999 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0968-0896(99)00086-3

文献信息

• Synthesis and evaluation of 2-Amino-9-(3-acyloxymethyl-4-alkoxycarbonyloxybut-1-yl)purines and 2-Amino-9-(3-alkoxycarbonyloxymethyl-4-alkoxycarbonyloxybut-1-yl)purines as potential prodrugs of penciclovir
  作者：Dae-Kee Kim、Namkyu Lee、Do Hyun Ryu、Young-Woo Kim、Jae-Sun Kim、Kieyoung Chang、Guang-Jin Im、Won-Son Choi、Yong-Baik Cho、Key H. Kim、Danni Colledge、Stephen Locarnini

  DOI：10.1016/s0968-0896(99)00086-3

  日期：1999.8

  A series of 2-amino-9-(3-acyloxymethyl-4-alkoxycarbonyloxybut-1-yl)purines (1-8) and 2-amino-9-(3-alkoxycarbonyl-oxymethyl-4-alkoxycarbonyloxybut-1-yl)purines (9-12) were synthesized as potential prodrugs of penciclovir. Treatment of 6-deoxypenciclovir with trimethyl orthoacetate or triethyl orthopropionate (1.2 equiv) in DMF in the presence of p-TsOH . H2O (0.1 equiv) followed by quenching with excess H2O gave the corresponding mono-O-acetyl or mono-O-propionyl compound, 17 or 18, in excellent yields of 95 and 92%, respectively. Reactions of 17 or 18 with an appropriate alkyl (Me, Et, n-Pr, and i-Pr) 4-nitrophenyl carbonate (1.2 equiv) in pyridine in the presence of a catalytic amount of DMAP (0.1 equiv) at 80 degrees C afforded the monoacyl, monocarbonate derivatives of 6-deoxypenciclovir, 1-8, in 86-94% yields. Similar reactions of 6-deoxypenciclovir with 2.1 equiv of alkyl 4-nitrophenyl carbonate produced the dicarbonate derivatives 9-12 in 81-83% yields. Of the prodrugs tested in rats, 2-amino-9-(3-acetoxymethyl-4-isopropoxycarbonyloxybut-1-yl)purine (4) achieved the highest mean urinary recovery of penciclovir (36%), followed in order by compounds 2 (35%), 6 (35%), 7 (34%), 10 (34%), 8 (32%), 3 (32%), and famciclovir (31%). The mean urinary recovery of penciclovir and concentrations of penciclovir in the blood from 4 in mice were also slightly higher than those from famciclovir. The in vivo antiviral efficacy of 4 in HSV-1-infected normal BALB/c mice was higher than those of famciclovir and valaciclovir in terms of mortality (100, 80, and 40%) and mean survival time (>21, 13 +/- 5.0 (SEM), and 13 +/- 1.6 days). Compound 4 demonstrated an effective anti-hepadnaviral response with intrahepatic viral load being reduced by 90%, the viral supercoiled DNA levels reduced by 70% and Pre-S expression inhibited by 30% against duck hepatitis B virus (DHBV) in vivo, and did not cause any significant hepatotoxicity after 4 weeks of treatment. (C) 1999 Elsevier Science Ltd. All rights reserved.