(S)-2-amino-6-chloro-9-<2-<(diisopropylphosphono)methoxy>-3-fluoropropyl>purine | 151223-41-5

• 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: (S)-2-amino-6-chloro-9-<2-<(diisopropylphosphono)methoxy>-3-fluoropropyl>purine
• 英文别名: (S)-2-amino-6-chloro-9-{2-[(diisopropoxyphosphoryl)-methoxy]-3-fluoropropyl}purine；(S)-2-amino-6-chloro-9-(2-diisopropylphosphonylmethoxy-3-fluoropropyl)purine；(S)-2-amino-6-chloro-9-{2-[(diisopropylphosphono)methoxy]-3-fluoropropyl}purine；6-chloro-9-[(2S)-2-[di(propan-2-yloxy)phosphorylmethoxy]-3-fluoropropyl]purin-2-amine
• CAS: 151223-41-5
• 化学式: C₁₅H₂₄ClFN₅O₄P
• 分子量: 423.812
• InChiKey: AAJUBYFCGHVUGE-LLVKDONJSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.8
• 重原子数：
  27
• 可旋转键数：
  10
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.67
• 拓扑面积：
  114
• 氢给体数：
  1
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  (S)-2-amino-6-chloro-9-<2-<(diisopropylphosphono)methoxy>-3-fluoropropyl>purine 在 palladium on activated charcoal 氢气 作用下， 以 甲醇 为溶剂， 反应 4.0h， 以67%的产率得到(S)-2-amino-9-(diisopropylphosphonylmethoxy-3-fluoropropyl)purine
  参考文献：
  名称：

  Synthesis of N-(3-Fluoro-2-phosphonomethoxypropyl) (FPMP) Derivatives of Heterocyclic Bases

  摘要：

  已合成一组新化合物：嘌呤和嘧啶碱基的N-(3-氟-2-磷甲氧基丙基)（FPMP）衍生物，对广谱逆转录病毒表现出显著的选择性活性。从相应的N-(3-氟-2-羟基丙基)衍生物经过异构环上氨基选择性苯甲酰化、与异丙基对甲苯磺酰氧甲基磷酸二异丙酯（II）反应，以及随后去除保护基制备了腺嘌呤（V）、鸟嘌呤（IX）、胞嘧啶（XIII）、2,6-二氨基嘌呤（XXI）、3-去氧腺嘌呤（XVII）、黄嘌呤（X）和次黄嘌呤（VI）的消旋N-(3-氟-2-磷甲氧基丙基)衍生物。手性FPMP衍生物通过异构碱基与相应的手性合成物（XXX、XXXVII）反应后去保护基制备。所需的手性合成物是通过两种方法从对映异构体3-氟-1,2-丙二醇获得的。在第一种方法中，首要羟基进行三苯甲酰化，得到的衍生物与化合物II反应，去除三苯甲基基团，然后进行甲磺酰化以得到合成物XXXVII。第二种途径包括选择性对磺酰化首要羟基，将次要羟基转化为乙酰氧甲基醚通过甲氧基甲基醚；将乙酰氧化合物与溴三甲基硅烷和三异丙基磷酸酯处理后得到所需的合成物XXX。

  DOI：

  10.1135/cccc19931645
• 作为产物：
  描述：

  diisopropyl (S)-({[1-fluoro-3-(trityloxy)propan-2-yl]oxy}methyl)phosphonate 在 4-二甲氨基吡啶 、 水 、 sodium hydride 、 溶剂黄146 、 三乙胺 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 、 mineral oil 为溶剂， 反应 4.58h， 生成 (S)-2-amino-6-chloro-9-<2-<(diisopropylphosphono)methoxy>-3-fluoropropyl>purine
  参考文献：
  名称：

  Synthesis and antiviral activity of N9-[3-fluoro-2-(phosphonomethoxy)propyl] analogues derived from N6-substituted adenines and 2,6-diaminopurines

  摘要：

  An efficient method for the synthesis of N-9-[3-fluoro-2-(phosphonomethoxy) propyl] (FPMP) derivatives of purine bases has been developed. Both (R)- and (S)-enantiomers of the N-6-substituted FPMP derivatives of adenine and 2,6-diaminopurine were prepared and their anti-human immunodeficiency virus (HIV) and anti-Moloney murine sarcoma virus (MSV) activity was evaluated. Whereas none of the 6-substituted FPMPA derivatives showed any antiviral activity, several FPMPDAP derivatives had a moderate antiretroviral activity. Moreover, the data obtained from the study of the substrate activity of the active derivatives towards N-6-methyl-AMP aminohydrolase support the notion that the studied N-6-substituted FPMPDAP derivatives act as prodrugs of the antiretroviral FPMPG analogues. (C) 2011 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2011.02.050

文献信息

• Synthesis and antiviral activity of 2'-substituted 9-[2-(phosphonomethoxy)ethyl]guanine analogs
  作者：Kuo Long Yu、Joanne J. Bronson、Hyekyung Yang、Amy Patick、Masud Alam、Vera Brankovan、Roelf Datema、Michael J. M. Hitchcock、John C. Martin

  DOI：10.1021/jm00071a003

  日期：1993.9

  A series of 2'-substituted derivatives of 9-[2-(phosphonomethoxy)ethyl]guanine (PMEG, 1) have been synthesized and evaluated in vitro for anti-human immunodeficiency virus (HIV) activity in the XTT assay and for anti-herpes activity in the plaque reduction assay. It has been observed that the anti-HIV activity of these derivatives depends on the size and the nature of the substituent as well as the

  已经合成了一系列9- [2-（膦酰基甲氧基）乙基]鸟嘌呤（PMEG，1）的2'-取代衍生物，并在XTT分析中体外评估了其抗人免疫缺陷病毒（HIV）的活性以及对斑减少试验中的疱疹活性。已经观察到这些衍生物的抗HIV活性取决于取代基的大小和性质以及在PMEG 2'-位的手性。此外，与疱疹病毒相比，这些化合物通常具有更大的抗HIV活性。这些研究中出现的最有趣的类似物是（R）-2'-（叠氮基甲基）-PMEG [[R] -5]和（R）-2'-乙烯基-PMEG [[R-11]]。前者在CEM细胞中显示出抗HIV活性，IC50为5 microM，细胞毒性（CC50）大于1.4 mM。后者的抗HIV活性IC50为13 microM，CC50大于1.6 mM。此外，我们已经证明用胞嘧啶取代这些2'-取代的PMEG类似物的鸟嘌呤碱基会大大降低抗HIV和抗疱疹的活性。
• Microwave-assisted hydrolysis of phosphonate diesters: an efficient protocol for the preparation of phosphonic acids
  作者：Petr Jansa、Ondřej Baszczyňski、Eliška Procházková、Martin Dračínský、Zlatko Janeba

  DOI：10.1039/c2gc35547g

  日期：——

  A new highly efficient method for the hydrolysis of acyclic nucleoside phosphonate diesters (or generally of any organophosphonates) to the corresponding phosphonic acids has been developed. This novel methodology employs inexpensive hydrochloric acid in equimolar amounts to the number of ester groups present in the molecule and thus, avoids using trimethylsilyl halogenides, the standard reagents for

  一种新型高效的无环核苷膦酸酯水解方法 二酯 （或通常是任何有机膦酸酯） 膦酸已经被开发出来。这种新颖的方法使用廉价盐酸以等摩尔的量表示分子中存在的酯基的数目，因此避免使用三甲基甲硅烷基卤化物，这是用于这些类型转化的标准试剂。此外，对反应混合物进行简单，轻松的后处理即可提供非常干净的产品，且收率很高（通常为77％至93％）。所述水解的另一个优点是膦酸酯 二酯事实是可以通过反应容器中的压力变化立即监控反应过程。这种“绿色”方法也已成功用于制备否则难以合成的（膦酰基甲氧基）乙基（PME）的导数 鸟嘌呤 （PMEG）和 黄嘌呤 （PMEHx），此外，该方法还可以使用重要的新型无环核苷膦酸酯，这些膦酸酯衍生自 2-氯次黄嘌呤 和从 黄嘌呤（例如PMEX）。
• The effect of novel [3-fluoro-(2-phosphonoethoxy)propyl]purines on the inhibition of Plasmodium falciparum, Plasmodium vivax and human hypoxanthine–guanine–(xanthine) phosphoribosyltransferases
  作者：Ondřej Baszczyňski、Dana Hocková、Zlatko Janeba、Antonín Holý、Petr Jansa、Martin Dračínský、Dianne T. Keough、Luke W. Guddat

  DOI：10.1016/j.ejmech.2013.06.032

  日期：2013.9

  Protozoan parasites from the Plasmodiidae family are the causative agents of malaria. Inhibition of hypoxanthine guanine-(xanthine) phosphoribosyltransferase (HG(X)PRT) has been suggested as a target for development of new anti-malarial therapeutics. Acyclic nucleoside phosphonates (ANPs) are potent and selective inhibitors of plasmodial HG(X)PRTs. A new series of ANPs, based on the chemical structure and inhibitory activity of three ANPs, 2-(phosphonoethoxy)ethyl with either guanine or hypoxanthine as the base (PEEG and PEEHx) and 3-hydroxy-2-(phosphonomethoxy)propyl with guanine as the base (HPMPG), were prepared. These compounds are stereoisomers of 3-fluoro-(2-phosphonoethoxy)propyl (FPEPs) and 3-fluoro-(2-phosphonomethoxy)propyl (FPMPs) analogues. Both the (R)- and (S)-isomers of these fluorinated derivatives have higher K-i values (by 10- to 1000-fold) for human HGPRT and Plasmodium falciparum HGXPRT than the non-fluorinated ANPs. Possible explanations for these changes in affinity are proposed based on docking studies using the known crystal structures of human HGPRT in complex with PEEG. (C) 2013 Elsevier Masson SAS. All rights reserved.
• Synthesis and antiviral activity of N9-[3-fluoro-2-(phosphonomethoxy)propyl] analogues derived from N6-substituted adenines and 2,6-diaminopurines
  作者：Ondřej Baszczyňski、Petr Jansa、Martin Dračínský、Blanka Klepetářová、Antonín Holý、Ivan Votruba、Erik de Clercq、Jan Balzarini、Zlatko Janeba

  DOI：10.1016/j.bmc.2011.02.050

  日期：2011.4

  An efficient method for the synthesis of N-9-[3-fluoro-2-(phosphonomethoxy) propyl] (FPMP) derivatives of purine bases has been developed. Both (R)- and (S)-enantiomers of the N-6-substituted FPMP derivatives of adenine and 2,6-diaminopurine were prepared and their anti-human immunodeficiency virus (HIV) and anti-Moloney murine sarcoma virus (MSV) activity was evaluated. Whereas none of the 6-substituted FPMPA derivatives showed any antiviral activity, several FPMPDAP derivatives had a moderate antiretroviral activity. Moreover, the data obtained from the study of the substrate activity of the active derivatives towards N-6-methyl-AMP aminohydrolase support the notion that the studied N-6-substituted FPMPDAP derivatives act as prodrugs of the antiretroviral FPMPG analogues. (C) 2011 Elsevier Ltd. All rights reserved.
• Synthesis of N-(3-Fluoro-2-phosphonomethoxypropyl) (FPMP) Derivatives of Heterocyclic Bases
  作者：Jindřich Jindřich、Antonín Holý、Hana Dvořáková

  DOI：10.1135/cccc19931645

  日期：——

  A new group of compounds has been prepared: N-(3-fluoro-2-phosphonomethoxypropyl) (FPMP) derivatives of purine and pyrimidine bases which exhibit a significant selective activity against a broad spectrum of retroviruses. Racemic N-(3-fluoro-2-phosphonomethoxypropyl) derivatives of adenin (V), guanine (IX), cytosine (XIII), 2,6-diaminopurine (XXI), 3-deazaadenin e(XVII), xanthine (X) and hypoxanthin (VI) were prepared from the corresponding N-(3-fluoro-2-hydroxypropyl) derivatives after protection of amino group at the heterocyclic ring by selective benzoylation, reaction with diisopropyl p-toluenesulfonyloxymethylphosphonate (II), and subsequent removal of the protecting groups. Chiral FPMP derivatives were prepared by reaction of heterocyclic base with the corresponding chiral synthon (XXX, XXXVII) followed by deprotection. The required chiral synthons were obtained from enantiomeric 3-fluoro-1,2-propanediols by two methods. In the first, the primary hydroxyl group was tritylated, the obtained derivative was reacted with compound II, the trityl group was removed and the product was mesylated to give synthon XXXVII. The second pathway consisted in selective tosylation of the primary hydroxyl group and conversion of the secondary hydroxyl into the acetoxymethyl ether via the methoxymethyl ether; treatment of the acetoxy compound with bromotrimethylsilane and triisopropyl phosphite afforded the desired synthon XXX.

  已合成一组新化合物：嘌呤和嘧啶碱基的N-(3-氟-2-磷甲氧基丙基)（FPMP）衍生物，对广谱逆转录病毒表现出显著的选择性活性。从相应的N-(3-氟-2-羟基丙基)衍生物经过异构环上氨基选择性苯甲酰化、与异丙基对甲苯磺酰氧甲基磷酸二异丙酯（II）反应，以及随后去除保护基制备了腺嘌呤（V）、鸟嘌呤（IX）、胞嘧啶（XIII）、2,6-二氨基嘌呤（XXI）、3-去氧腺嘌呤（XVII）、黄嘌呤（X）和次黄嘌呤（VI）的消旋N-(3-氟-2-磷甲氧基丙基)衍生物。手性FPMP衍生物通过异构碱基与相应的手性合成物（XXX、XXXVII）反应后去保护基制备。所需的手性合成物是通过两种方法从对映异构体3-氟-1,2-丙二醇获得的。在第一种方法中，首要羟基进行三苯甲酰化，得到的衍生物与化合物II反应，去除三苯甲基基团，然后进行甲磺酰化以得到合成物XXXVII。第二种途径包括选择性对磺酰化首要羟基，将次要羟基转化为乙酰氧甲基醚通过甲氧基甲基醚；将乙酰氧化合物与溴三甲基硅烷和三异丙基磷酸酯处理后得到所需的合成物XXX。