diisopropyl 2-(chloroethoxy)methylphosphonate | 151965-56-9

• 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 2-(chloroethoxy)methylphosphonate
• 英文别名: diisopropyl 2-chloroethoxymethanephosphonate；bis(2-propyl) 2-chloroethoxymethylphosphonate；Di-(2-propyl)-2-chloroethoxymethylphosphonate；2-[2-chloroethoxymethyl(propan-2-yloxy)phosphoryl]oxypropane
• CAS: 151965-56-9
• 化学式: C₉H₂₀ClO₄P
• 分子量: 258.682
• InChiKey: FLCGYFRJKHYTSU-UHFFFAOYSA-N

物化性质

• 沸点：
  313.8±22.0 °C(Predicted)
• 密度：
  1.112±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.6
• 重原子数：
  15
• 可旋转键数：
  8
• 环数：
  0.0
• sp3杂化的碳原子比例：
  1.0
• 拓扑面积：
  44.8
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  diisopropyl 2-(chloroethoxy)methylphosphonate 在 potassium tert-butylate 、 溴 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 0.33h， 生成 (1,2-Dibromo-ethoxymethyl)-phosphonic acid diisopropyl ester
  参考文献：
  名称：

  2′-C-ALKOXY AND 2′-C-ARYLOXY DERIVATIVES OFN-(2-PHOSPHONOMETHOXYETHYL)-PURINES AND -PYRIMIDINES: SYNTHESIS AND BIOLOGICAL ACTIVITY

  摘要：

  A series of novel, unusual type of acyclic phosphonate-based nucleotide analogues related to well-known antivirals (PMEA and HPMPA) was synthesized using easily available synthon. These compounds, which are distinguished for the presence of phosphonomethyl acetal linkage, form a group of derivatives that contribute to the understanding of structure-activity relationship within the area of acyclic nucleotide analogues.

  DOI：

  10.1081/ncn-100105244
• 作为产物：
  描述：

  三异丙基亚磷酸酯 、 2-氯乙基氯甲基醚 反应 3.0h， 以93%的产率得到diisopropyl 2-(chloroethoxy)methylphosphonate
  参考文献：
  名称：

  嘧啶和嘌呤N- [2-（2-膦酰基甲氧基）乙基]核苷酸类似物系列中的结构-抗病毒活性关系。1.在碱的碳原子上取代的衍生物。

  摘要：

  通过对烷基进行烷基化制备一系列嘌呤和嘧啶N- [2-（膦甲氧基）乙基]衍生物的二烷基酯，其在嘌呤碱的位置2、6或8或在嘧啶碱的位置2、4或5。在氢化钠，碳酸铯或1,8-二氮杂双环[5,4,0]十一碳-7-烯（DBU）存在下的二甲基甲酰胺中，与2-氯乙氧基甲基膦酸酯二酯形成合适的杂环碱。通过在适当修饰的中间体上对碱基进行转化，获得额外的衍生物，该中间体在碱基部分具有反应性功能。通过叠氮化钠处理将二酯转化为相应的单酯，同时通过依次用溴代三甲基硅烷处理和水解从二酯中获得游离酸。嘧啶系列中没有PME衍生物，它们的6-氮杂或3-氮杂类似物，除5-溴胞嘧啶衍生物外，对测试的DNA病毒或逆转录病毒均表现出任何活性。Cl，F或OH基团取代了PMEA中2位的腺嘌呤环，从而降低了其对所有测试的DNA病毒的活性。在0.07-2 microg / mL的浓度范围（EC50）中，PMEDAP对HSV-1，HSV-2

  DOI：

  10.1021/jm9811256

文献信息

• Synthesis of Cyclic and Acyclic Nucleoside Phosphonates and Sulfonamides Derived from 6‐(Thiophen‐2‐yl)‐7‐fluoro‐7‐deazapurine
  作者：Vincent Malnuit、Sabina Smoleń、Michal Tichý、Lenka Poštová Slavětínská、Michal Hocek

  DOI：10.1002/ejoc.201900509

  日期：2019.9

  Ribonuclosides derived from 6‐hetaryl‐7‐dezapurines are potent cytostatics, but their mechanism of action is unknown. Here we designed and synthesized a series of cyclic and acyclic nucleoside phosphonates, as well as carboxy, cyano, sulfo, and sulfonamide acyclic analogues derived from 6‐thiophen‐2‐yl‐7‐deazapurine and 7‐fluoro‐6‐thiophen‐2‐yl‐7‐deazapurine as ribonucleoside monophosphate mimics.

  衍生自6-杂芳基-7-十氮嘌呤的核糖核苷是有效的细胞抑制剂，但其作用机理尚不清楚。在这里，我们设计并合成了一系列环状和无环核苷膦酸酯，以及衍生自6-噻吩-2-yl-7-七氮杂嘌呤和7-氟-6-噻吩-2的羧基，氰基，磺基和磺酰胺无环类似物-7-基-7-脱氮嘌呤为核糖核苷单磷酸酯模拟物。这些类似物均未表现出明显的细胞毒性和抗病毒活性。
• Synthesis and Cytostatic Activity of N-[2-(Phosphonomethoxy)alkyl] Derivatives of N6-Substituted Adenines, 2,6-Diaminopurines and Related Compounds
  作者：Antonín Holý、Ivan Votruba、Eva Tloušťová、Milena Masojídková

  DOI：10.1135/cccc20011545

  日期：——

  N⁶-Substituted adenine and 2,6-diaminopurine derivatives of 9-[2-(phosphonomethoxy)- ethyl] (PME), 9-[(R)-2-(phosphonomethoxy)propyl] [(R)-PMP] and enantiomeric (S)-PMP series were synthesized by reactions of primary or secondary amines with 6-chloro-9-[2-(diisopropoxyphosphoryl)methoxy]alkyl}purines (26-28) or 2-amino-6-chloro-9-[2-(diisopropoxy- phosphoryl)methoxy]alkyl}purines (29-31) followed by treatment of the diester intermediates32with bromo(trimethyl)silane and hydrolysis. Diesters32were also obtained by reaction ofN⁶-substituted purines with synthons23-25bearing diisopropoxyphosphoryl group. Alkylation of 2-amino-6-chloropurine (9) with diethyl [2-(2-chloroethoxy)ethyl]phosphonate (148) gave the diester149which was analogously converted toN⁶-substituted 2,6-diamino- 9-[2-(2-phosphonoethoxy)ethyl]purines151-153. Alkylation ofN⁶-substituted 2,6-diaminopurines with (R)-[(trityloxy)methyl]oxirane (155) followed by reaction of thus-obtained intermediates156with dimethylformamide dimethylacetal and condensation with diisopropyl [(tosyloxy)methyl]phosphonate (158) followed by deprotection of the intermediates159gaveN⁶-substituted 2,6-diamino-9-[(S)-3-hydroxy-2-(phosphonomethoxy)propyl]purines160-163. The highest cytostatic activityin vitrowas exhibited by the followingN⁶-derivatives of 2,6-diamino-9-[2-(phosphonomethoxy)ethyl]purine (PMEDAP): 2,2,2-trifluoroethyl (53), allyl (54), [(2-dimethylamino)ethyl] (68), cyclopropyl (75) and dimethyl (91). In CCRF-CEM cells, the cyclopropyl derivative75is deaminated to the guanine derivative PMEG (3) which is then converted to its diphosphate.

  N6-取代腺嘌呤和2,6-二氨基嘌呤衍生物9-[2-(磷酸甲氧基)-乙基]（PME）、9-[(R)-2-(磷酸甲氧基)丙基] [(R)-PMP] 和对映体(S)-PMP 系列通过初级或次级胺与6-氯-9-[2-(二异丙氧磷酰基)甲氧基]烷基}嘌呤（26-28）或2-氨基-6-氯-9-[2-(二异丙氧磷酰基)甲氧基]烷基}嘌呤（29-31）的反应合成，随后用溴化(三甲基)硅烷和水解处理二酯中间体32。二酯32也可通过N6-取代嘌呤与带有二异丙氧磷酰基的合成物23-25发生反应获得。2-氨基-6-氯嘌呤（9）与二乙基[2-(2-氯乙氧基)乙基]磷酸酯（148）的烷基化反应得到二酯149，类似地转化为N6-取代2,6-二氨基-9-[2-(2-磷酸乙氧基)乙基]嘌呤151-153。N6-取代2,6-二氨基嘌呤与(R)-[(三苄氧基)甲基]环氧乙烷（155）发生烷基化反应，随后用二甲基甲酰胺二甲基缩醛和与异丙基[(对甲苯磺酰氧基)甲基]磷酸酯（158）发生缩合反应，然后去保护中间体159得到N6-取代2,6-二氨基-9-[(S)-3-羟基-2-(磷酸甲氧基)丙基]嘌呤160-163。体外细胞毒活性最高的是以下2,6-二氨基-9-[2-(磷酸甲氧基)乙基]嘌呤（PMEDAP）的N6-衍生物：2,2,2-三氟乙基（53）、烯丙基（54）、[(2-二甲基氨基)乙基]（68）、环丙基（75）和二甲基（91）。在CCRF-CEM细胞中，环丙基衍生物75被脱氨基化为鸟嘌呤衍生物PMEG（3），然后转化为其二磷酸盐。
• The synthesis of the 8-<i>C</i>-substituted 2,6-diamino-9-[2-(phosphonomethoxy)ethyl]purine (PMEDAP) derivatives by diverse cross-coupling reactions
  作者：Ondřej Sedláček、Petra Břehová、Radek Pohl、Antonín Holý、Zlatko Janeba

  DOI：10.1139/v11-001

  日期：2011.4

  Diisopropyl 8-bromo-2,6-diamino-9-[2-(phosphonomethoxy)ethyl]purine was used as a starting material for the synthesis of the 8-C-substituted 2,6-diamino-9-[2-(phosphonomethoxy)ethyl]purine (PMEDAP) analogues. A systematic screening of diverse cross-coupling reactions was carried out. Stille, Suzuki–Miyaura, Negishi, and Sonogashira cross-couplings, as well as Pd-catalysed reactions with trialkylaluminiums, were employed for the introduction of various alkyl, alkenyl, alkynyl, aryl, and hetaryl substituents to the C-8 position of the 2,6-diaminopurine moiety. In contrast to the potent parent compound PMEDAP, which exhibits potent antiretroviral and antitumor activity, none of the sixteen newly synthesized 8-C-substituted analogues of PMEDAP showed any specific antiviral activity.

  以 8-溴-2,6-二氨基-9-[2-(磷酰甲氧基)乙基]嘌呤二异丙基为起始原料，合成了 8-C 取代的 2,6-二氨基-9-[2-(磷酰甲氧基)乙基]嘌呤 (PMEDAP) 类似物。对各种交叉偶联反应进行了系统筛选。在 2,6-二氨基嘌呤分子的 C-8 位置引入各种烷基、烯基、炔基、芳基和己基取代基时，采用了 Stille、Suzuki-Miyaura、Negishi 和 Sonogashira 交叉耦合反应，以及与三烷基铝的钯催化反应。母体化合物 PMEDAP 具有很强的抗逆转录病毒和抗肿瘤活性，与之形成鲜明对比的是，新合成的 16 种 8-C 取代的 PMEDAP 类似物均未显示出任何特异性抗病毒活性。
• Novel compounds and methods for therapy
  申请人：INSTITUTE OF ORGANIC CHEMISTRY AND BIOCHEMISTRY ACADEMY OF SCIENCES

  公开号：US20030109499A1

  公开（公告）日：2003-06-12

  Novel compounds are provided having formula (I) 1 where R 1 , R 2 , R 3 , R 4 , Z, X and * are defined herein. Also provided are antiviral methods for use and processes for synthesis of the compounds of formula (I).

  提供具有以下化学式（I）的新化合物： 其中 R 1 ，R 2 ，R 3 ，R 4 ，Z，X和*在此处定义。还提供了用于抗病毒方法和合成化合物（I）的过程。
• Synthesis and biological evaluation of acyclic nucleotide analogues with a furo[2,3-<i>d</i>]pyrimidin-2(3<i>H</i>)-one base
  作者：Zlatko Janeba、Antonín Holý、Radek Pohl、Robert Snoeck、Graciela Andrei、Erik De Clercq、Jan Balzarini

  DOI：10.1139/v10-054

  日期：2010.7

  As a part of a broader structure–activity relationship (SAR) study of bicyclic nucleoside analogues (BCNAs) [anti-varicella-zoster virus (anti-VZV) and anti-human cytomegalovirus (anti-HCMV) agents], a novel series of 2-(phosphonomethoxy)ethyl (PME) substituted furo[2,3-d]pyrimidin-2(3H)-ones was synthesized. The target acyclic nucleotide analogues were prepared by Sonogashira coupling of protected 5-iodo-1-[2-(phosphonomethoxy)ethyl]uracil with various 1-alkynes, followed by in situ Cu(I)-promoted intramolecular cyclization and standard removal of the isopropyl ester groups. None of the prepared PME analogues were active at subtoxic concentrations against VZV thymidine kinase competent (TK⁺), VZV thymidine kinase deficient (TK^–), HCMV, or any other viruses tested.

  作为对双环核苷类似物（BCNAs）[抗水痘-带状疱疹病毒（anti-VZV）和抗人类巨细胞病毒（anti-HCMV）药物]进行更广泛的结构-活性关系（SAR）研究的一部分，合成了一系列新型 2-（膦甲氧基）乙基（PME）取代的呋喃并[2,3-d]嘧啶-2(3H)-酮。目标无环核苷酸类似物是通过受保护的 5-碘-1-[2-（磷酰甲氧基）乙基]尿嘧啶与各种 1-炔烃的 Sonogashira 偶联，然后在原位 Cu(I)促进下进行分子内环化，并以标准方式去除异丙酯基团而制备的。所制备的 PME 类似物在亚毒性浓度下对 VZV 胸苷激酶能力（TK+）、VZV 胸苷激酶缺陷（TK-）、HCMV 或任何其他受测病毒均无活性。