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

本研究课题的主要目的是开发关键中间体偕-双膦酰基乙烯（1）的合成方法，并通过1实现具有生物活性的杂芳取代双膦酸、氨基膦酸等化合物的高效合成。得到以下结果.通过钯催化的α-膦酰基萘磺酸酯与亚磷酸二烷基酯的交叉偶联反应，以较好的产率合成了偕-双膦酰基乙烯1.双膦酰基乙烯1与杂环取代的1，3-二噻烷碳负离子、咪唑或3-吡啶阴离子进行Michael加成反应，高产率地得到2-官能团取代的1，1-双膦酰基乙烯。当相同的反应用阳离子卤化剂如NCS和SELECTFLUOR淬灭时，产生相应的1-卤代 *1-双膦酸酯（X=Cl，F）。用Me_3Sil处理这些膦酸盐，可定量地得到所需的膦酸，有望作为骨质疏松症和骨疾病的治疗药物. 1与三溴甲基碳负离子反应，得到一种新型的小环化合物1，1-二溴-2，2-双膦酰基环丙烷. 1与磺酰胺在碘酰苯和氯化铜存在下反应，得到1-磺酰基-2，2-双（膦酰基）氮杂环丙烷，产率为75-54%。氮杂环丙烷类化合物经还原后以较高的产率得到β-氨基膦酸类似物N-[2，2-双膦酰基乙基]磺酰胺类化合物，从而实现了偕-双膦酰基乙烯类化合物的合成。我们已经表明，通过利用偕-双（膦酰基）乙烯，可以合成各种类型的偕-双膦酰基取代化合物，这些化合物不仅具有生物活性，而且还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.