Butyric acid 2-(2-amino-6-fluoro-purin-9-ylmethoxy)-3-hydroxy-propyl 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: Butyric acid 2-(2-amino-6-fluoro-purin-9-ylmethoxy)-3-hydroxy-propyl ester
• 英文别名: [2-[(2-amino-6-fluoropurin-9-yl)methoxy]-3-hydroxypropyl] butanoate
• 化学式: C₁₃H₁₈FN₅O₄
• 分子量: 327.315
• InChiKey: PWZLULHOYWZDFP-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.1
• 重原子数：
  23
• 可旋转键数：
  9
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.54
• 拓扑面积：
  125
• 氢给体数：
  2
• 氢受体数：
  9

反应信息

• 作为产物：
  描述：

  9-<<2-hydroxy-1-(hydroxymethyl)ethoxy>methyl>-6-chloro-2-aminopurine 在 4-二甲氨基吡啶 、 potassium fluoride 、 三甲胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 4.0h， 生成 Butyric acid 2-(2-amino-6-fluoro-purin-9-ylmethoxy)-3-hydroxy-propyl ester
  参考文献：
  名称：

  Synthesis and Evaluation of 2-Amino-9-(1,3-dihydroxy-2-propoxymethyl)- 6-fluoropurine Mono- and Diesters as Potential Prodrugs of Ganciclovir

  摘要：

  A series of 2-amino-9-(1,3-dihydroxy-2-propoxymethyl)-6-floropurine mono- and diesters, 6a- h, were synthesized as potential prodrugs of ganciclovir and evaluated for their oral ganciclovir bioavailability in rats. Treatment of 2-amino-6-chloro-9-(1,3-dihydroxy-2-propoxymethyl)purine (4) with Me3N in DMF/THF (1/4) followed by the reaction of the resulting trimethylammonium chloride salt 5 with KF in DMF gave 2-amino-9-( 1,3-dihydroxy-2-propoxymethyl)-6-fluoropurine (2) in 83% yield. Esterification of 2 with an appropriate acid anhydride (Ac2O, (EtCO)(2)O, (n-PrCO)(2)O, or (i-PrCO)(2)O) (6 equiv for 6a-d or 1 equiv for 6e-h) in DMF in the presence of a catalytic amount of DMAP produced the diesters 6a-d in 92-98% yields and the monoesters 6e-h in 37-44% yields. Of the prodrugs tested in rats, the monoisobutyrate 6h achieved the highest ganciclovir bioavailability (45%) that is 15-fold higher than that from ganciclovir (3%), followed in order by the diisobutyrate Sd (42%), the diacetate 6a (41%), the monobutyrate 6g (41%), the monopropionate 6f (39%), the dipropionate 6b (35%), the dibutyrate 6c (35%), and the monoacetate 6e (29%). The prodrugs 6e-h were found to be quite stable at pH 6.0 (t(1/2) = >29 days), 7.4 (t(1/2) =>7 days), and 8.0 (t(1/2) = >2 days) but had relatively short half-lives at pH 1.2 (t(1/2) = 60-83 min).

  DOI：

  10.1021/jm980321+

文献信息

• Synthesis and Evaluation of 2-Amino-9-(1,3-dihydroxy-2-propoxymethyl)- 6-fluoropurine Mono- and Diesters as Potential Prodrugs of Ganciclovir
  作者：Dae-Kee Kim、Kieyoung Chang、Guang-Jin Im、Hun-Taek Kim、Namkyu Lee、Key H. Kim

  DOI：10.1021/jm980321+

  日期：1999.1.1

  A series of 2-amino-9-(1,3-dihydroxy-2-propoxymethyl)-6-floropurine mono- and diesters, 6a- h, were synthesized as potential prodrugs of ganciclovir and evaluated for their oral ganciclovir bioavailability in rats. Treatment of 2-amino-6-chloro-9-(1,3-dihydroxy-2-propoxymethyl)purine (4) with Me3N in DMF/THF (1/4) followed by the reaction of the resulting trimethylammonium chloride salt 5 with KF in DMF gave 2-amino-9-( 1,3-dihydroxy-2-propoxymethyl)-6-fluoropurine (2) in 83% yield. Esterification of 2 with an appropriate acid anhydride (Ac2O, (EtCO)(2)O, (n-PrCO)(2)O, or (i-PrCO)(2)O) (6 equiv for 6a-d or 1 equiv for 6e-h) in DMF in the presence of a catalytic amount of DMAP produced the diesters 6a-d in 92-98% yields and the monoesters 6e-h in 37-44% yields. Of the prodrugs tested in rats, the monoisobutyrate 6h achieved the highest ganciclovir bioavailability (45%) that is 15-fold higher than that from ganciclovir (3%), followed in order by the diisobutyrate Sd (42%), the diacetate 6a (41%), the monobutyrate 6g (41%), the monopropionate 6f (39%), the dipropionate 6b (35%), the dibutyrate 6c (35%), and the monoacetate 6e (29%). The prodrugs 6e-h were found to be quite stable at pH 6.0 (t(1/2) = >29 days), 7.4 (t(1/2) =>7 days), and 8.0 (t(1/2) = >2 days) but had relatively short half-lives at pH 1.2 (t(1/2) = 60-83 min).