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目的合成具有较高抗HBV活性与较低肾细胞毒性的新型阿德福韦衍生物。方法低温下,硫代N-Boc-L-氨基酸与1,2-二溴乙烷在NaH条件下制备硫代N-Boc-L-氨基酸-3-溴-1-丙基酯;非甾体抗炎药(布洛芬、酮洛芬、氟比洛芬)与3-溴-1-丙醇在DCC/DMAP条件下转变为非甾体抗炎药-3-溴-1-丙基酯;以上两种原料与阿德福韦在缩合剂N,N’-二环己基-4-吗啉基-咪(DCMC)存在下通过“一锅法”制备目标化合物。结果合成了6个未见文献报道的阿德福韦单硫代L-氨基酸酯,单非甾体抗炎药羧酸酯前药5a～5f。结论目标化合物及重要中间体结构均经过1HNMR、ESI-MS以及HRMS确证。
Objective To synthesize new adefovir derivatives with higher anti-HBV activity and lower renal cell toxicity. Methods Thio N-Boc-L-amino acid 3-bromo-1-propyl thio N-Boc-L-amino acids were prepared with 1,2-dibromoethane under NaH at low temperature; Anti-inflammatory drugs (ibuprofen, ketoprofen, flurbiprofen) and 3-bromo-1-propanol were converted to the non-steroidal anti-inflammatory drug 3-bromo- 1 -propyl ester under DCC / DMAP conditions ; The above two starting materials and adefovir in the presence of a condensing agent N, N’-dicyclohexyl-4-morpholinyl-imidazole (DCMC) prepared by the “one-pot method” of the target compound. Results Six unreported adefovir monothio L-amino acid esters and single non-steroidal anti-inflammatory drug carboxylate prodrugs 5a-5f were synthesized. Conclusion The structures of target compounds and important intermediates were confirmed by 1HNMR, ESI-MS and HRMS.