(R)-5-amino-3-<2-<(diisopropylphosphono)methoxy>propyl>-3H-imidazo<4,5-d>pyrimidin-7-one | 160616-49-9

• 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: (R)-5-amino-3-<2-<(diisopropylphosphono)methoxy>propyl>-3H-imidazo<4,5-d>pyrimidin-7-one
• 英文别名: 2-amino-9-[(2S)-2-[di(propan-2-yloxy)phosphorylmethoxy]propyl]-1H-purin-6-one
• CAS: 160616-49-9
• 化学式: C₁₅H₂₆N₅O₅P
• 分子量: 387.376
• InChiKey: XOQQNSZRWKDOJI-NSHDSACASA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0
• 重原子数：
  26
• 可旋转键数：
  9
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.67
• 拓扑面积：
  130
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  (R)-5-amino-3-<2-<(diisopropylphosphono)methoxy>propyl>-3H-imidazo<4,5-d>pyrimidin-7-one 在 三甲基溴硅烷 作用下， 以 乙腈 为溶剂， 生成 (S)-9-(2-phosphonomethoxypropyl)guanine
  参考文献：
  名称：

  Synthesis of Enantiomeric N-(2-Phosphonomethoxypropyl) Derivatives of Purine and Pyrimidine Bases. I. The Stepwise Approach

  摘要：

  (R)和(S)-N-(2-磷酸甲氧基丙基)嘌呤和嘧啶碱（PMP衍生物）对逆转录病毒表现出非常高的活性。本文描述了对映异构体9-(2-磷酸甲氧基丙基)腺嘌呤（I和XXVII）、9-(2-磷酸甲氧基丙基)-2,6-二氨基嘌呤（II和XXXI）、9-(2-磷酸甲氧基丙基)鸟嘌呤（III和XXIX）和1-(R)-(2-磷酸甲氧基丙基)胞嘧啶（XIX）的合成，方法是用双(2-丙基) p-甲苯磺酰氧甲基膦酸酯（X）烷基化对应碱的N保护N-(2-羟基丙基)衍生物，然后逐步去保护中间体的N和O。关键中间体，N-(2-羟基丙基)衍生物IX和XXV，是通过将适当的杂环碱与(R)-或(S)-2-(2-四氢吡喃氧基)丙基 p-甲苯磺酸酯（VII或XXIII）烷基化，并酸水解得到的N-[2-(2-四氢吡喃氧基)丙基]衍生物VIII和XXII。手性合成物是通过对(R)-或(S)-2-(2-四氢吡喃氧基)丙醇（VI或XXI）进行对烯基化制备的，这些化合物可通过还原对映异构烷基2-O-四氢吡喃基乳酸酯V和XXI与双(2-甲氧基乙氧基)铝氢化钠反应得到。这种方法用于合成胞嘧啶、腺嘌呤和2,6-二氨基嘌呤衍生物，而从鸟嘌呤衍生物制备的化合物则是通过2-氨基-6-氯嘌呤中间体的水解制备的。胞嘧啶衍生物IXe也是通过对4-甲氧基-2-嘧啶酮的烷基化后接着中间体IXf的氨解合成的。

  DOI：

  10.1135/cccc19951196
• 作为产物：
  描述：

  三异丙基亚磷酸酯 在 palladium on activated charcoal 三乙烯二胺 、 盐酸 、 4-二甲氨基吡啶 、 氢气 、 sodium hydride 、 potassium carbonate 作用下， 以 吡啶 、 甲醇 、 水 、 N,N-二甲基甲酰胺 、 paraffin 为溶剂， 反应 13.0h， 生成 (R)-5-amino-3-<2-<(diisopropylphosphono)methoxy>propyl>-3H-imidazo<4,5-d>pyrimidin-7-one
  参考文献：
  名称：

  Synthesis of Enantiomeric N-(2-Phosphonomethoxypropyl) Derivatives of Purine and Pyrimidine Bases. II. The Synthon Approach

  摘要：

  描述了另一种合成嘧啶和嘌呤碱基的(R)和(S)-N-(2-磷酸甲氧丙基)衍生物（PMP衍生物）I和II的方法，包括用(R)和(S)-2-[双(2-丙基)磷酸甲氧基]丙基p-甲苯磺酸酯(X和XVIII)烷基化杂环碱基，然后通过中间体N-[2-双(2-丙基)磷酸甲氧基丙基]衍生物XI和XIX的转硅基化来制备。关键的中间体X和XVIII是从1-苄氧基丙醇VI和XIV通过两种途径获得的：（i）与双(2-丙基)p-甲苯磺酰氧甲基磷酸酯(XIII)缩合，氢解得到1-苄氧基-2-双(2-丙基)磷酸甲氧基丙烷VIII和XVI，再经Pd/C转化为2-双(2-丙基)磷酸甲氧基丙醇IX和XVII，然后对后者进行对甲苯磺酸基化或（ii）氯甲基化化合物VI和XIV，随后氯甲醚VII和XV与三(2-丙基)磷酸酯反应，进一步处理苄醚VIII和XVI类似对映体丙醇IX和XVII。这种方法被用于合成腺嘌呤(Ia，IIa)、2,6-二氨基嘌呤(Ib，IIb)和3-去氧腺嘌呤(Ic，IIc)的衍生物。它们的鸟嘌呤对应物Ie和IIe通过水解2-氨基-6-氯嘌呤中间体XId和XIXd制备。6-氯嘌呤通过与甲苯磺酸酯X反应转化为二酯XIi，再与硫脲反应并进行酯解得到6-硫嘌呤衍生物Ij。类似地，2-氨基-6-氯嘌呤衍生物XId与硫脲反应得到9-(R)-(2-磷酸甲氧丙基)-2-硫鸟嘌呤(If)，或与二甲胺反应形成(2-磷酸甲氧丙基)-2-氨基-6-二甲胺嘌呤(Ig)。化合物XId的氢解得到9-(R)-(2-磷酸甲氧丙基)-2-氨基嘌呤(Ik)。腺嘌呤衍生物Ia和IIa的水解脱氨基反应得到对映的(2-磷酸甲氧丙基)次黄嘌呤Ih和IIh。

  DOI：

  10.1135/cccc19951390

文献信息

• Synthesis and Antiviral Activity of 8-Aza Analogs of Chiral [2-(Phosphonomethoxy)propyl]guanines
  作者：Palmarisa Franchetti、Ghassan Abu Sheikha、Loredana Cappellacci、Mario Grifantini、Antonella De Montis、Giovanna Piras、Anna Giulia Loi、Paolo La Colla

  DOI：10.1021/jm00020a015

  日期：1995.9

  (R)- And (S)-8-aza-9-[2-(phosphonomethoxy)propyl] [(R)- and (S)-8-aza-PMPG] were synthesized and tested in vitro for anti-human immunodeficiency virus (HIV) activity. The synthesis of the above compounds and of (R)-9-[2-(phosphonomethoxy)propyl]guanine [(R)-PMPG] was carried out through the alkylation of 8-azaguanine or guanine with (R)- and (S)2-O-[(diisopropylphosphono)methyl]-1-O-(followed by deprotection of the phosphonic moiety. A different, even more convenient synthesis of (R)-8-aza-PMPG starting from 2-amino-6-chloro-5-nitro-4(3H)-pyrimidinone and (R)-[2-[(diisopropylphosphono)methoxy]propyl]amine is also reported. Both (R)-8-aza-PMPG and (R)-PMPG demonstrated anti-HIV activity in the MTT assay with EC(50) values of 12 and 4.5 mu M, respectively. The corresponding S enantiomers were found to be less potent. When evaluated in combination with AZT, ddI, or DABO 603, (R)-8-aza-PMPG gave additive, additive, and synergistic anti-HIV-1 effects, respectively.
• Synthesis of Enantiomeric N-(2-Phosphonomethoxypropyl) Derivatives of Purine and Pyrimidine Bases. II. The Synthon Approach
  作者：Antonín Holý、Hana Dvořáková、Milena Masojídková

  DOI：10.1135/cccc19951390

  日期：——

  Another approach to (R)- and (S)-N-(2-phosphonomethoxypropyl) derivatives of purine and pyrimidine bases (PMP derivatives) I and II is described, consisting in alkylation of the heterocyclic base with (R)- and (S)-2-[bis(2-propyl)phosphonylmethoxy]propyl p-toluenesulfonates (X and XVIII) followed by transsilylation of the intermediary N-[2-bis(2-propyl)phosphonylmethoxypropyl] derivatives XI and XIX. The key intermediates X and XVIII were obtained from 1-benzyloxypropanols VI and XIV by two routes: (i) condensation with bis(2-propyl) p-toluenesulfonyloxymethylphosphonate (XIII), hydrogenolysis of the obtained 1-benzyloxy-2-bis(2-propyl)phosphonylmethoxypropanes VIII and XVI over Pd/C to 2-bis(2-propyl)phosphonylmethoxypropanols IX and XVII and tosylation of the latter or (ii) chloromethylation of compounds VI and XIV and subsequent reaction of the chloromethyl ethers VII and XV with tris(2-propyl) phosphite and further processing of the benzyl ethers VIII and XVI analogous to the enantiomeric propanols IX and XVII. This approach was used for the synthesis of derivatives of adenine (Ia, IIa), 2,6-diaminopurine (Ib, IIb) and 3-deazaadenine (Ic, IIc). Their guanine counterparts Ie and IIe were prepared by hydrolysis of 2-amino-6-chloropurine intermediates XId and XIXd. 6-Chloropurine was converted into diester XIi by reaction with tosylate X, which on reaction with thiourea and subsequent ester cleavage afforded the 6-thiopurine derivative Ij. Analogously, 2-amino-6-chloropurine derivative XId reacted with thiourea to give 9-(R)-(2-phosphonomethoxypropyl)-2-thioguanine (If), or with dimethylamine under formation of (2-phosphonomethoxypropyl)-2-amino-6-dimethylaminopurine (Ig). Hydrogenolysis of compound XId gave 9-(R)-(2-phosphonomethoxypropyl)-2-aminopurine (Ik). Hydrolytic deamination of adenine derivatives Ia and IIa led to enantiomeric (2-phosphonomethoxypropyl)hypoxanthines Ih and IIh.

  描述了另一种合成嘧啶和嘌呤碱基的(R)和(S)-N-(2-磷酸甲氧丙基)衍生物（PMP衍生物）I和II的方法，包括用(R)和(S)-2-[双(2-丙基)磷酸甲氧基]丙基p-甲苯磺酸酯(X和XVIII)烷基化杂环碱基，然后通过中间体N-[2-双(2-丙基)磷酸甲氧基丙基]衍生物XI和XIX的转硅基化来制备。关键的中间体X和XVIII是从1-苄氧基丙醇VI和XIV通过两种途径获得的：（i）与双(2-丙基)p-甲苯磺酰氧甲基磷酸酯(XIII)缩合，氢解得到1-苄氧基-2-双(2-丙基)磷酸甲氧基丙烷VIII和XVI，再经Pd/C转化为2-双(2-丙基)磷酸甲氧基丙醇IX和XVII，然后对后者进行对甲苯磺酸基化或（ii）氯甲基化化合物VI和XIV，随后氯甲醚VII和XV与三(2-丙基)磷酸酯反应，进一步处理苄醚VIII和XVI类似对映体丙醇IX和XVII。这种方法被用于合成腺嘌呤(Ia，IIa)、2,6-二氨基嘌呤(Ib，IIb)和3-去氧腺嘌呤(Ic，IIc)的衍生物。它们的鸟嘌呤对应物Ie和IIe通过水解2-氨基-6-氯嘌呤中间体XId和XIXd制备。6-氯嘌呤通过与甲苯磺酸酯X反应转化为二酯XIi，再与硫脲反应并进行酯解得到6-硫嘌呤衍生物Ij。类似地，2-氨基-6-氯嘌呤衍生物XId与硫脲反应得到9-(R)-(2-磷酸甲氧丙基)-2-硫鸟嘌呤(If)，或与二甲胺反应形成(2-磷酸甲氧丙基)-2-氨基-6-二甲胺嘌呤(Ig)。化合物XId的氢解得到9-(R)-(2-磷酸甲氧丙基)-2-氨基嘌呤(Ik)。腺嘌呤衍生物Ia和IIa的水解脱氨基反应得到对映的(2-磷酸甲氧丙基)次黄嘌呤Ih和IIh。
• Synthesis of Enantiomeric N-(2-Phosphonomethoxypropyl) Derivatives of Purine and Pyrimidine Bases. I. The Stepwise Approach
  作者：Antonín Holý、Milena Masojídková

  DOI：10.1135/cccc19951196

  日期：——

  The (R)- and (S)-N-(2-phosphonomethoxypropyl) derivatives of purine and pyrimidine bases (PMP derivatives) exhibit very high activity against retroviruses. This paper describes the synthesis of enantiomeric 9-(2-phosphonomethoxypropyl)adenines (I and XXVII), 9-(2-phosphonomethoxypropyl)-2,6-diaminopurines (II and XXXI), 9-(2-phosphonomethoxypropyl)guanines (III and XXIX) and 1-(R)-(2-phosphonomethoxypropyl)cytosine (XIX) by alkylation of N-protected N-(2-hydroxypropyl) derivatives of the corresponding bases with bis(2-propyl) p-toluenesulfonyloxymethylphosphonate (X), followed by stepwise N- and O-deprotection of the intermediates. The key intermediates, N-(2-hydroxypropyl) derivatives IX and XXV, were obtained by alkylation of the appropriate heterocyclic base with (R)- or (S)-2-(2-tetrahydropyranyloxy)propyl p-toluenesulfonate (VII or XXIII) and acid hydrolysis of the resulting N-[2-(2-tetrahydropyranyloxy)propyl] derivatives VIII and XXII. The chiral synthons were prepared by tosylation of (R)- or (S)-2-(2-tetrahydropyranyloxy)propanol (VI or XXI) available by reduction of enantiomeric alkyl 2-O-tetrahydropyranyllactates V and XXI with sodium bis(2-methoxyethoxy)aluminum hydride. This approach was used for the synthesis of cytosine, adenine and 2,6-diaminopurine derivatives, while compounds derived from guanine were prepared by hydrolysis of 2-amino-6-chloropurine intermediates. Cytosine derivative IXe was also synthesized by alkylation of 4-methoxy-2-pyrimidone followed by ammonolysis of the intermediate IXf.

  (R)和(S)-N-(2-磷酸甲氧基丙基)嘌呤和嘧啶碱（PMP衍生物）对逆转录病毒表现出非常高的活性。本文描述了对映异构体9-(2-磷酸甲氧基丙基)腺嘌呤（I和XXVII）、9-(2-磷酸甲氧基丙基)-2,6-二氨基嘌呤（II和XXXI）、9-(2-磷酸甲氧基丙基)鸟嘌呤（III和XXIX）和1-(R)-(2-磷酸甲氧基丙基)胞嘧啶（XIX）的合成，方法是用双(2-丙基) p-甲苯磺酰氧甲基膦酸酯（X）烷基化对应碱的N保护N-(2-羟基丙基)衍生物，然后逐步去保护中间体的N和O。关键中间体，N-(2-羟基丙基)衍生物IX和XXV，是通过将适当的杂环碱与(R)-或(S)-2-(2-四氢吡喃氧基)丙基 p-甲苯磺酸酯（VII或XXIII）烷基化，并酸水解得到的N-[2-(2-四氢吡喃氧基)丙基]衍生物VIII和XXII。手性合成物是通过对(R)-或(S)-2-(2-四氢吡喃氧基)丙醇（VI或XXI）进行对烯基化制备的，这些化合物可通过还原对映异构烷基2-O-四氢吡喃基乳酸酯V和XXI与双(2-甲氧基乙氧基)铝氢化钠反应得到。这种方法用于合成胞嘧啶、腺嘌呤和2,6-二氨基嘌呤衍生物，而从鸟嘌呤衍生物制备的化合物则是通过2-氨基-6-氯嘌呤中间体的水解制备的。胞嘧啶衍生物IXe也是通过对4-甲氧基-2-嘧啶酮的烷基化后接着中间体IXf的氨解合成的。