(5-acetylfuran-2-yl)phosphonic acid diethyl ester | 261365-06-4

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: (5-acetylfuran-2-yl)phosphonic acid diethyl ester
• 英文别名: diethyl 5-acetylfuran-2-ylphosphonate；5-diethylphosphono-2-acetylfuran；Diethyl (5-acetylfuran-2-yl)phosphonate；1-(5-diethoxyphosphorylfuran-2-yl)ethanone
• CAS: 261365-06-4
• 化学式: C₁₀H₁₅O₅P
• 分子量: 246.2
• InChiKey: CFAPYVAFHUVODT-UHFFFAOYSA-N

物化性质

• 沸点：
  349.6±27.0 °C(Predicted)
• 密度：
  1.19±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.2
• 重原子数：
  16
• 可旋转键数：
  6
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  65.7
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (5-acetylfuran-2-yl)phosphonic acid diethyl ester 在 copper(ll) bromide 作用下， 以 乙醇 、 氯仿 、 乙酸乙酯 为溶剂， 反应 26.0h， 生成 2-amino-4-[2-(5-diethylphosphono)furanyl]thiazole
  参考文献：
  名称：

  Discovery of a Series of Phosphonic Acid-Containing Thiazoles and Orally Bioavailable Diamide Prodrugs That Lower Glucose in Diabetic Animals Through Inhibition of Fructose-1,6-Bisphosphatase

  摘要：

  Oral delivery of previously disclosed purine and benzimidazole fructose-1,6 bisphosphatase (FBPase) inhibitors via prodrugs failed, which was likely due to their high molecular wright (> 600) Therefore, a smaller scaffold was desired, and a series of phosphonic acid-containing thiazoles, which exhibited high potency against human liver FBPase (IC(50) of 10-30 nM) and high selectivity relative to other 5'-adenosinemonophosphate (AMP)-binding enzymes, were discovered using a structure-guided drug design approach The initial lead compound (30j) produced profound glucose lowering in rodent models of type 2 diabetes mellitus (T2DM) after parenteral administration Various phosphonate prodrugs were explored without success, until a novel phosphonic diamide prodrug approach was Implemented, which delivered compound 30j with good oral bioavailability (OBAV) (22-47%) Extensive lead optimization of both the thiazole FBPase inhibitors and their prodrugs culminated in the discovery of compound 35n (MB06322) as the first oral FBPase inhibitor advancing to human clinical trials as a potential treatment for T2DM

  DOI：

  10.1021/jm101035x
• 作为产物：
  描述：

  5-diethylphosphono-2-acetylfuran cyclic ketal 在 盐酸 作用下， 以 甲醇 为溶剂， 反应 12.0h， 以112 g的产率得到(5-acetylfuran-2-yl)phosphonic acid diethyl ester
  参考文献：
  名称：

  发现用于治疗 2 型糖尿病的强效和特异性果糖-1,6-双磷酸酶抑制剂和一系列口服生物可利用的磷酸酰胺酶敏感性前药

  摘要：

  肝脏产生过多的葡萄糖，加上肌肉、脂肪和肝脏对葡萄糖的摄取和代谢减少，导致 2 型糖尿病患者的血糖水平长期升高。通过减少葡萄糖产生来治疗糖尿病的努力主要集中在糖异生途径和该途径中的限速酶，如果糖-1,6-双磷酸酶 (FBPase)。第一种有效的 FBPase 抑制剂是使用结构引导的药物设计策略 (Erion, MD; et al. J. Am. Chem. Soc. 2007, 129, 15480-15490) 鉴定的，但证明难以口服给药。在此处，我们报告了一系列口服生物可利用 FBPase 抑制剂的合成和表征，这些抑制剂是在结合发现具有增加效力的低分子量抑制剂系列和适合其口服给药的膦酸盐前药类别之后确定的。先导抑制剂 10A 是在 X 射线晶体学和分子建模的帮助下设计的，用于与 FBPase 的变构 AMP 结合位点结合。高效力 (IC50 = 16 nM) 和 FBPase 特异性是通过将

  DOI：

  10.1021/ja074871l

文献信息

• Novel Thiazole Inhibitors of Fructose 1,6-Bishosphatase
  申请人：Dang Qun

  公开号：US20070225259A1

  公开（公告）日：2007-09-27

  Compounds of Formula I, their prodrugs and salts, their preparation and their uses are described.

  公式I的化合物，它们的前药和盐，它们的制备以及它们的用途被描述了。
• Discovery of Phosphonic Diamide Prodrugs and Their Use for the Oral Delivery of a Series of Fructose 1,6-Bisphosphatase Inhibitors
  作者：Qun Dang、Srinivas Rao Kasibhatla、Tao Jiang、Kevin Fan、Yan Liu、Frank Taplin、William Schulz、Daniel K. Cashion、K. Raja Reddy、Paul D. van Poelje、James M. Fujitaki、Scott C. Potter、Mark D. Erion

  DOI：10.1021/jm8001235

  日期：2008.7.1

  Like most phosphonic acids, the recently discovered potent and selective thiazole phosphonic acid inhibitors of fructose 1,6-bisphosphatase (FBPase) exhibited low oral bioavailability (OBAV) and therefore required a prodrug to achieve oral efficacy. Syntheses of known phosphonate prodrugs did not afford the desired OBAV; hence, a new class of prodrugs was sought. Phosphonic diamides derived from amino

  像大多数膦酸一样，最近发现的果糖1,6-双磷酸酶（FBPase）的有效和选择性噻唑膦酸抑制剂表现出较低的口服生物利用度（OBAV），因此需要前药才能达到口服功效。已知的膦酸酯前药的合成不能提供所需的OBAV。因此，寻求一种新的前药。已发现衍生自氨基酸酯的膦酸二酰胺是可行的前药，它满足了我们预先设定的目标：在宽pH范围内具有出色的水稳定性，良性副产物（氨基酸和低分子量醇），最重要的是良好的OBAV，可产生坚固的口服葡萄糖降低效果。膦二酰胺的这些所需特性代表了对现有前药类别的显着改进。
• Combination of FBPase inhibitors and antidiabetic agents useful for the treatment of diabetes
  申请人：——

  公开号：US20030073728A1

  公开（公告）日：2003-04-17

  A combination therapy of at least one FBPase inhibitor and at least one other antidiabetic agent is disclosed.

  揭示了至少一种FBPase抑制剂和至少一种其他抗糖尿病药物的联合治疗。
• Novel bisamidate phosphonate prodrugs
  申请人：METABASIS THERAPEUTICS, INC.

  公开号：US20020173490A1

  公开（公告）日：2002-11-21

  Novel bisamidate phosphonate prodrugs of FBPase inhibitors of the Formula IA: 1 and their use in the treatment of diabetes and other conditions associated with elevated blood glucose.

  新颖的双酰胺磷酸酯前药，用于治疗糖尿病和其他与血糖升高相关的疾病的Formula IA:1中的FBPase抑制剂及其用途。
• Copper-Catalyzed C2 and C3 Phosphonation of Benzofuran and Benzothiophene with Trialkyl Phosphites
  作者：Yufeng Wang、Yajie Yang、Kun Jie、Ling Huang、Shengmei Guo、Hu Cai

  DOI：10.1002/cctc.201701361

  日期：2018.2.21

  A strategy for the selective phosphonation of benzofuran and benzothiophene with trialkyl phosphites was developed. In these reactions, the C−H phosphonation of benzofurans or benzothiophenes at the C2 or C3 position with trialkyl phosphites was successfully achieved without directing groups by using a copper catalyst. Additionally, the C5 phosphonation of furan was successful under the same conditions

  提出了用亚磷酸三烷基酯对苯并呋喃和苯并噻吩进行选择性磷酸化的策略。在这些反应中，通过使用铜催化剂成功地实现了亚磷酸三烷基酯在C2或C3位置处苯并呋喃或苯并噻吩的CHH膦酸酯化。另外，在相同条件下呋喃的C5磷酸化成功。