diisopropyl {[1-(hydroxymethyl)cyclopropyl]oxy}methylphosphonate | 441784-85-6

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 有机膦酸及其衍生物
• 英文名称: diisopropyl {[1-(hydroxymethyl)cyclopropyl]oxy}methylphosphonate
• 英文别名: diisopropyl {[1-(hydroxymethyl)-cyclopropyl]oxy}methylphosphonate；diisopropyl{1-[(hydroxymethyl)cyclopropyl]oxy}methyl phosphonate；DiiSopropyl ((1-(hydroxymethyl)cyclopropoxy)methyl)phosphonate；[1-[di(propan-2-yloxy)phosphorylmethoxy]cyclopropyl]methanol
• CAS: 441784-85-6
• 化学式: C₁₁H₂₃O₅P
• 分子量: 266.274
• InChiKey: HHZZOQSDZBZQFK-UHFFFAOYSA-N

物化性质

• 沸点：
  350.1±17.0 °C(Predicted)
• 密度：
  1.13±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0.7
• 重原子数：
  17
• 可旋转键数：
  8
• 环数：
  1.0
• sp3杂化的碳原子比例：
  1.0
• 拓扑面积：
  65
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  diisopropyl {[1-(hydroxymethyl)cyclopropyl]oxy}methylphosphonate 在 palladium on activated charcoal 三甲基溴硅烷 、 氢气 、 sodium hydride 、 三乙胺 作用下， 以 四氢呋喃 、 N-甲基吡咯烷酮 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 25.0~80.0 ℃ 、133.32 Pa 条件下， 反应 89.5h， 生成 LB-80380
  参考文献：
  名称：

  A Novel Class of Phosphonate Nucleosides. 9-[(1-Phosphonomethoxycyclopropyl)methyl]guanine as a Potent and Selective Anti-HBV Agent

  摘要：

  9-[1-(Phosphonomethoxycyclopropyl)methyl]guanine (PMCG, 1), representative of a novel class of phosphonate nucleosides, blocks HBV replication with excellent potency (EC50 = 0.5 muM) in a primary culture of HepG2 2.2.15 cells. It exhibits no significant cytotoxicity in several human cell lines up to 1.0 mM. It does not inhibit replication of human immunodeficiency virus (HIV-1) or herpes simplex virus (HSV-1) at 30 muM. Many purine base analogues of 1 also exhibit inhibitory activity against HBV, but at 30 muM, pyrimidine analogues do not. 1 is 4 times more potent than 9- [2-(phosphonomethoxy)ethyl] adenine (PMEA), which was used as a positive control (EC50 = 2.0 muM). The characteristic cyclopropyl moiety at the 2'-position of 1 was prepared by titanium-mediated Kulinkovich cyclopropanation. 1 was modified to give the orally available drug candidate, PMCDG Dipivoxil (2). Compound 2 exhibited excellent efficacy when administered at 5 mg per kg per day in a study with woodchucks infected with woodchuck hepatitis B virus (WHBV). Drug candidate 2 has successfully completed phase I clinical trials and is currently undergoing phase II clinical studies for evaluation of efficacy.

  DOI：

  10.1021/jm0305265
• 作为产物：
  描述：

  diisopropyl ((1-(trityloxymethyl)-cyclopropyl)oxy)methylphosphonate 在 三氟乙酸 作用下， 以 丙酮 为溶剂， 以100%的产率得到diisopropyl {[1-(hydroxymethyl)cyclopropyl]oxy}methylphosphonate
  参考文献：
  名称：

  [EN] PROCESS FOR PREPARING DI-ISOPROPYL ((1(HYDROXYMETHYL)-CYCLOPROPYL)OXY) METHYLPHOSPHONATE
  [FR] PROCEDE DE PREPARATION DE DI-ISOPROPYL ((1(HYDROXYMETHYL)-CYCLOPROPYL)OXY) METHYLPHOSPHONATE

  摘要：

  本发明涉及一种用于制备二异丙基{[1-(羟甲基)-环丙基]氧基}甲基膦酸酯（2）的新工艺，该化合物是合成抗病毒（特别是针对乙型肝炎病毒）核苷类似物的关键中间体。本发明还涉及新的中间体，以及从根据本发明制备的化合物（2）制备抗病毒核苷类似物的工艺。

  公开号：

  WO2006004330A1

文献信息

• [EN] NUCLEOSIDE PHOSPHONATE DERIVATIVES USEFUL IN THE TREATMENT OF HIV INFECTIONS<br/>[FR] DERIVES DE NUCLEOSIDE PHOSPHONATE UTILES DANS LE TRAITEMENT D'INFECTIONS VIH
  申请人：ANADYS PHARMACEUTICALS INC

  公开号：WO2005079812A1

  公开（公告）日：2005-09-01

  The present invention relates to a method of treating HIV infections by administering a nucleoside phosphonate derivative represented by formula (I).

  本发明涉及通过给予由式(I)表示的核苷酸膦酸衍生物来治疗HIV感染的方法。
• Process for preparing diisopropyl((1-(hydroxymethyl)-cyclopropyl)oxy)methylphosphonate
  申请人：LG Life Sciences Ltd.

  公开号：US07795463B2

  公开（公告）日：2010-09-14

  Disclosed is a process for preparing a compound of the following formula (2): including the steps of reacting a compound of the following formula (4): with trityl chloride to prepare trityloxy-acetic acid ethyl ester of the following formula (8): reacting the compound of formula (8) with ethyl magnesium halide to prepare 1-trityloxymethyl-cyclopropanol of the following formula (9): combining the 1-trityloxymethyl-cyclopropanol of formula (9) with diisopropylbromo-methylphosphonate in a solvent in the presence of a base to prepare (1-trityloxymethyl-cyclopropoxymethyl)-phosphonic acid diisopropyl ester of the following formula (10): as a solid form, and converting the trityl group of the compound of formula (10) into a hydroxyl group.

  公开了一种制备以下式(2)化合物的方法，包括以下步骤：将以下式(4)化合物与三苯甲基氯反应，制备以下式(8)的三苯甲氧基乙酸乙酯；将式(8)化合物与卤代乙基镁反应，制备以下式(9)的1-三苯甲氧基甲基环丙醇；将式(9)的1-三苯甲氧基甲基环丙醇与二异丙基溴甲基膦酸酯在溶剂中与碱的存在下结合，制备以下式(10)的(1-三苯甲氧基甲基环丙氧基甲基)-膦酸二异丙酯，以固体形式存在，并将式(10)化合物的三苯甲基基团转化为羟基基团。
• PROCESS FOR PREPARING DIISOPROPYL((1-(HYDROXYMETHYL)-CYCLOPROPYL)OXY)METHYLPHOSPHONATE
  申请人：YOON Suk-Kyoon

  公开号：US20100305364A1

  公开（公告）日：2010-12-02

  The present invention relates to a new process for preparing diisopropyl [1-(hydroxymethyl)-cyclopropyl]oxy}methylphosphonate (2), which is a key intermediate for synthesizing an antiviral (particularly, against hepatitis B virus) nucleoside analogue. The present invention also relates to new intermediates, and a process for preparing the antiviral nucleoside analogue from the compound (2) prepared according to the present invention.

  本发明涉及一种制备二异丙基[1-(羟甲基)-环丙基]氧基}甲基膦酸二异丙酯（2）的新工艺，该化合物是合成抗病毒（特别是对乙型肝炎病毒）核苷类似物的关键中间体。本发明还涉及新的中间体，以及从根据本发明制备的化合物（2）制备抗病毒核苷类似物的工艺。
• US7795463B2
  申请人：——

  公开号：US7795463B2

  公开（公告）日：2010-09-14
• A Novel Class of Phosphonate Nucleosides. 9-[(1-Phosphonomethoxycyclopropyl)methyl]guanine as a Potent and Selective Anti-HBV Agent
  作者：Jong-Ryoo Choi、Dong-Gyu Cho、Kee Y. Roh、Jae-Taeg Hwang、Sinbyoung Ahn、Hyun S. Jang、Woo-Young Cho、Kyong W. Kim、Young-Gyo Cho、Jeongmin Kim、Yong-Zu Kim

  DOI：10.1021/jm0305265

  日期：2004.5.1

  9-[1-(Phosphonomethoxycyclopropyl)methyl]guanine (PMCG, 1), representative of a novel class of phosphonate nucleosides, blocks HBV replication with excellent potency (EC50 = 0.5 muM) in a primary culture of HepG2 2.2.15 cells. It exhibits no significant cytotoxicity in several human cell lines up to 1.0 mM. It does not inhibit replication of human immunodeficiency virus (HIV-1) or herpes simplex virus (HSV-1) at 30 muM. Many purine base analogues of 1 also exhibit inhibitory activity against HBV, but at 30 muM, pyrimidine analogues do not. 1 is 4 times more potent than 9- [2-(phosphonomethoxy)ethyl] adenine (PMEA), which was used as a positive control (EC50 = 2.0 muM). The characteristic cyclopropyl moiety at the 2'-position of 1 was prepared by titanium-mediated Kulinkovich cyclopropanation. 1 was modified to give the orally available drug candidate, PMCDG Dipivoxil (2). Compound 2 exhibited excellent efficacy when administered at 5 mg per kg per day in a study with woodchucks infected with woodchuck hepatitis B virus (WHBV). Drug candidate 2 has successfully completed phase I clinical trials and is currently undergoing phase II clinical studies for evaluation of efficacy.