N-(双膦羧次甲基)-6-(5-氟-2,4-二氧代-3,4-二氢-2H-嘧啶-1-基)-6-氧代-己酰胺的合成及其初步的骨靶向性研究

Synthesis and bone targeting activity of N-(bisphosphonomethyl)-6-(5-fluo-ro-2,4dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-6-oxo-hexanamide

目的合成N-(双膦羧次甲基)-6-(5-氟-2,4-二氧代-3,4-二氢-2H-嘧啶-1-基)-6-氧代-己酰胺,并进行初步体外骨靶向性实验。方法以5-氟尿嘧啶为原料,经硅烷化、缩合、氢解3步合成6-(5-氟-2,4-二氧代-3,4-二氢-2H-嘧啶-1-基)-6-氧代-己酸(2),用二氯亚砜氯化后再与含氨基的偕二膦酸酯偶联,最后再用溴代三甲基硅烷特异性解离掉膦酸酯得到目标化合物L,并采用羟磷灰石晶体吸附实验考察目标物的骨靶向性。结果合成了目标物L,并利用1H-NMR、IR和MS进行了结构确证。结论体外骨靶向性实验结果显示目标物L有较好的骨靶向性。

OBJECTIVE To synthesize N- （bisphosphonomethyl） -6-（5-fluoro-2, 4-dioxo-3, 4-dihydro-2H-pyri- midin-l-yl）-6-oxo-hexanamide, and to test its bone targeting activities. METHODS The title compound L was prepared from 6- （5-fluoro-2, 4-diox-3, 4-dihydr-2H-pyrimidin-l-yl） -6-oxohexanoic acid （2）, which was condensed with amino functionalized bisphosphonates M, followed by the cleavage of the phosphonate ester using bromotrimethylsilane （TMSBr）. Compound 2 was obtained from 5-fluorouracil via three steps： silylation, acylation and hydrogenolysis. Its bone targeting ability was evaluated by hydroxyapatite adhesion tests. RESULTS The title compound L was synthesized and confirmed by ^1H-NMR, IR and MS spectral data. CONCLUSIONS The title compound L showed good bone targeting ability in hydroxyapatite adhesion tests.