Turhanen Petri A, Niemi Riku, Peräkylä Mikael, Järvinen Tomi, Vepsäläinen Jouko J
University of Kuopio, Department of Chemistry, Finland.
Org Biomol Chem. 2003 Sep 21;1(18):3223-6. doi: 10.1039/b305979k.
Methods for the preparation of mixed tetra-amide esters 1 and 2, the partial amide ester 3, and tri- and P,P-diamides 4 and 5 from monophosphorus spieces 12, 8 and 9, respectively, were developed. Compounds 8 and 9 were obtained from phosphorus trichloride via MeOPCl2, which was treated with 2 eq. and 4 eq. of piperidine, followed by water or acetyl chloride, respectively. Tetrasubstituted amide bisphosphonates 1 and 2 were selectively dealkylated with lithium or silyl halide to achieve target compounds 3-5. Piperidine was found to be a good desilylation reagent. Quantum mechanical calculations illustrate why derivative 2 was produced in low yield. The usefulness of compounds 1, 3 and 4 as prodrugs of etidronate was determined in aqueous buffer and human serum.
分别从单磷物种12、8和9制备混合四酰胺酯1和2、部分酰胺酯3以及三酰胺和P，P -二酰胺4和5的方法被开发出来。化合物8和9由三氯化磷经MeOPCl2制得，MeOPCl2分别与2当量和4当量的哌啶反应，随后分别与水或乙酰氯反应。四取代酰胺双膦酸盐1和2用锂或卤化硅选择性脱烷基以得到目标化合物3 - 5。发现哌啶是一种良好的脱硅试剂。量子力学计算说明了衍生物2产率低的原因。在水性缓冲液和人血清中测定了化合物1、3和4作为依替膦酸前药的效用。
