tetra(pivaloyloxymethyl) (dichloromethylene)bisphosphonate | 134606-32-9

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: tetra(pivaloyloxymethyl) (dichloromethylene)bisphosphonate
• 英文别名: dichloromethylene-1,1-bisphosphonic acid tetra(pivaloyloxymethyl) ester；[[Bis(2,2-dimethylpropanoyloxymethoxy)phosphoryl-dichloromethyl]-(2,2-dimethylpropanoyloxymethoxy)phosphoryl]oxymethyl 2,2-dimethylpropanoate
• CAS: 134606-32-9
• 化学式: C₂₅H₄₄Cl₂O₁₄P₂
• 分子量: 701.469
• InChiKey: DQVKNOIZHLUCMZ-UHFFFAOYSA-N

物化性质

• 沸点：
  638.1±55.0 °C(Predicted)
• 密度：
  1.271±0.06 g/cm3(Temp: 20 °C; Press: 760 Torr)(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  5.6
• 重原子数：
  43
• 可旋转键数：
  22
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.84
• 拓扑面积：
  176
• 氢给体数：
  0
• 氢受体数：
  14

反应信息

• 作为反应物：
  描述：

  三乙胺 、 tetra(pivaloyloxymethyl) (dichloromethylene)bisphosphonate 以 乙腈 为溶剂， 反应 2.0h， 以100%的产率得到tri(pivaloyloxymethyl) (dichloromethylene)bisphosphonate N,N,N-triethyl-N-(pivaloyloxymethyl) ammonium salt
  参考文献：
  名称：

  Bisphosphonate Prodrugs:  Synthesis and in Vitro Evaluation of Novel Acyloxyalkyl Esters of Clodronic Acid

  摘要：

  Novel tetra-, tri-, and P,P'-dipivaloyloxymethyl esters of clodronic acid were synthesized, and their properties as possible prodrugs of clodronate were evaluated in vitro. All pivaloyloxymethyl esters were significantly more lipophilic (log P-app ranged from -2.1 to 7.4) than clodronate (log P-app less than or equal to -5.4), which suggests that it may be possible to change the intestinal absorption mechanism of clodronate from a paracellular to a transcellular pathway by a prodrug approach. Pivaloyloxymethyl esters degraded rapidly in 10% rabbit liver homogenate, and half-lives of tri- and P,P'-diesters were 1.1 and 14 min, respectively. The intermediate degradation products were further degraded, and clodronic acid was released in quantitative amounts. In human serum, the stability of pivaloyloxymethyl esters was comparable to their stability in phosphate buffer (pH 7.4), which suggests that their degradation in human serum is mostly due to the chemical hydrolysis. Benzoyloxypropyl esters of clodronic acid were also synthesized, but they did not release clodronic acid due to the enzymatic and chemical stability of the formed S-hydroxypropyl phosphonate esters and are, therefore, not prodrugs.

  DOI：

  10.1021/jm991109o
• 作为产物：
  描述：

  四甲基亚甲基二磷酸酯 在 sodium hypochlorite 、 碳酸氢钠 、 sodium iodide 作用下， 以 乙腈 为溶剂， 反应 12.5h， 生成 tetra(pivaloyloxymethyl) (dichloromethylene)bisphosphonate
  参考文献：
  名称：

  双膦酸酯前药：亚甲基双膦酸酯的四酰氧基甲基酯的新合成策略

  摘要：

  提出了一种简洁，简便的方法，从H 2 C [P（O）（OMe）2 ] 2开始以高选择性和合理的收率制备Cl 2 C [P（O）（OCH 2 O 2 CCMe 3）2 ] 2。。

  DOI：

  10.1016/s0040-4039(99)01799-2

文献信息

• Acyloxymethyl esters of bisphosphonic acids as bone resorption inhibitors
  申请人：Merck & Co., Inc.

  公开号：US05227506A1

  公开（公告）日：1993-07-13

  The invention relates to acyloxymethyl esters of bisphosphonic acids, halo-bisphosphonic acids and hydroxy-bisphosphonic acids which exhibit oral bioavailability and are useful in the treatment of disturbances involving calcium or phosphate metabolism, in particular, the treatment and prevention of diseases involving bone resorption, especially osteoporosis, Paget's disease, malignant hypercalcemia, and metastatic bone disease.

  该发明涉及酰氧甲基双膦酸酯、卤代双膦酸和羟基双膦酸，具有口服生物利用度，并且在治疗涉及钙或磷代谢紊乱的疾病中有用，特别是在治疗和预防涉及骨吸收的疾病方面，尤其是骨质疏松症、帕盖特病、恶性高钙血症和转移性骨病方面。
• METHODS AND COMPOSITIONS FOR TREATMENT OF MUSCULAR DYSTROPHY
  申请人：Whalen Anne

  公开号：US20110224128A1

  公开（公告）日：2011-09-15

  The invention features methods, compositions, and kits useful for the treatment of muscular dystrophy, e.g., Duchenne muscular dystrophy, in a patient.
• US5227506A
  申请人：——

  公开号：US5227506A

  公开（公告）日：1993-07-13
• Bisphosphonate prodrugs: a new synthetic strategy to tetraacyloxymethyl esters of methylenebisphosphonates
  作者：Jouko J. Vepsäläinen

  DOI：10.1016/s0040-4039(99)01799-2

  日期：1999.11

  A concise and simple method to prepare Cl2C[P(O)(OCH2O2CCMe3)2]2 starting from H2C[P(O)(OMe)2]2 with high selectivity and reasonable yield is developed.

  提出了一种简洁，简便的方法，从H 2 C [P（O）（OMe）2 ] 2开始以高选择性和合理的收率制备Cl 2 C [P（O）（OCH 2 O 2 CCMe 3）2 ] 2。。
• Bisphosphonate Prodrugs:  Synthesis and in Vitro Evaluation of Novel Acyloxyalkyl Esters of Clodronic Acid
  作者：Riku Niemi、Jouko Vepsäläinen、Hannu Taipale、Tomi Järvinen

  DOI：10.1021/jm991109o

  日期：1999.12.2

  Novel tetra-, tri-, and P,P'-dipivaloyloxymethyl esters of clodronic acid were synthesized, and their properties as possible prodrugs of clodronate were evaluated in vitro. All pivaloyloxymethyl esters were significantly more lipophilic (log P-app ranged from -2.1 to 7.4) than clodronate (log P-app less than or equal to -5.4), which suggests that it may be possible to change the intestinal absorption mechanism of clodronate from a paracellular to a transcellular pathway by a prodrug approach. Pivaloyloxymethyl esters degraded rapidly in 10% rabbit liver homogenate, and half-lives of tri- and P,P'-diesters were 1.1 and 14 min, respectively. The intermediate degradation products were further degraded, and clodronic acid was released in quantitative amounts. In human serum, the stability of pivaloyloxymethyl esters was comparable to their stability in phosphate buffer (pH 7.4), which suggests that their degradation in human serum is mostly due to the chemical hydrolysis. Benzoyloxypropyl esters of clodronic acid were also synthesized, but they did not release clodronic acid due to the enzymatic and chemical stability of the formed S-hydroxypropyl phosphonate esters and are, therefore, not prodrugs.