Development of Highly Efficient Synthetic Method of Biologically Active Phosphonic Acid Derivatives via Key Intermediate Bis(phosphono)ethylene

在本研究项目中，我们的目标是开发关键中间体宝石-双（膦）乙烯的合成(1)，并实现杂芳取代双膦酸、氨基膦酸等生物活性化合物的高效合成方法(1)。得到了以下结果：通过pd催化α-膦酸盐与二烷基磷酸酯的交叉偶联反应，获得了产率较高的双膦基乙烯1。通过杂芳取代的1,3-二硫烷碳离子与咪唑或3-吡啶阴离子的Michael加成得到2官能团取代的1,1 -二膦乙烯，收率较高。当同样的反应用阳离子卤化剂如NCS和SELECTFLUOR猝灭时，生成相应的1-halo*1-双膦酸盐（X=Cl， F）。用Me_3Sil处理膦酸盐可以定量地得到所需的膦酸，有望作为治疗骨质疏松症和骨病的药物。3 . 1与三溴甲基碳离子反应得到一种新型小环化合物：1,1 -二溴- 2,2 -二（膦）环丙烷。在碘基苯和氯化铜存在下，用磺胺处理1，得到1-磺酰- 2,2 -二（膦）亚氮吡啶，产率为75-54%。将氮基吡啶还原成β-氨基膦酸类似物N-[2,2双（膦）乙基]磺胺，收率高。总之，我们实现了方便的宝石铋（膦）乙烯的合成。我们已经证明，利用双膦乙烯可以合成各种类型的宝石双膦取代化合物，这些化合物不仅具有生物活性，而且具有其他有趣的性质。

In this research project, we aimed at development of synthesis of key intermediate gem-bis(phosphono)ethylenes (1), and at achievement of highly efficient synthetic method of biologically active compounds such as heteroaromatic-substituted bisphosphonic acids, aminophosphonic acids, etc. via1. The following results were obtained.1. The gem-bis(phosphono)ethylenes 1 were achieved to synthesize in good yields by Pd-catalyzed cross-coupling reaction of α-phosphonononaflates with dialkylphosphites.2. The bis(phosphono)ethylenes 1 underwent Michael addition of heteroaromatics-substituted 1,3-dithiane carbanions, and imidazole or 3-pyridyl anion to give 2-functional group substituted-1, 1-bis(phosphono)ethylenes in high yields. When the same reaction was quenched with cationic halogenating agents such as NCS and SELECTFLUOR, the corresponding 1-halo*1-bisphosphonates (X=Cl, F) were produced. Treatment of the phosphonates with Me_3Sil led to the desired phosphonic acids quantitatively, which can be expected to act as curatives for osteoporosis and bone disease therapy.3. The reaction of 1 with a tribromomethyl carbanion gave a new type of small-ring compound, 1, 1-dibromo-2, 2-bis(phosphono)cyclopropane.4. Treatment of 1 with sulfonamide in the presence of iodosylbenzene and copper chloride led to 1-sulfonyl-2, 2-bis(phosphono)aziridines in 75-54% yields. Reduction of the aziridines converted into β-amino phosphonic acid analogue, N-[2, 2bis(phosphono)ethyl]sulfonamides in good yields.In conclusion, we achieved convenient synthesis of gem-bisbis(phosphono)ethylenes. We have shown that synthesis of various type of gem-bisphosphono-substituted compounds expecting to exhibit not only biologically active but also other interesting properties can be made by utilizing gem-bis(phosphono)ethylenes.