摘要
目的制备用于全合成新型卡泊芬类环六脂肽抗真菌剂的关键脂三肽中间体4′-烷氧基-1,1′-联苯-4-羧酸脂三肽。方法以L-脯氨酸叔丁酯为原料,依次经与N-(9-芴甲氧羰基)-L-苏氨酸叔丁醚(a)或N-(9-芴甲氧羰基)-L-丝氨酸叔丁醚(b)缩合、脱N-保护基后与Nα-(9-芴甲氧羰基)-Nδ-苄氧羰基-L-鸟氨酸缩合、再脱Nα-保护基后与4′-烷氧基-1,1′-联苯-4-羧酸-N-羟基苯并三氮唑"活泼酯"(Ie^If)缩合5步反应制备目标脂三肽1。结果以67.4%~80.0%的总收率合成了8个脂三肽1ae^1ah和1be^1bh,其结构经电喷雾质谱(ESI-MS)和元素分析确证。结论该合成路线具有反应条件温和、操作简便、总收率高的优点。
Objective To prepare 4′-alkoxy-1, l′-bisphenyl-4-carboxylic acid lipotripeptides , which is the key intermediates for total synthesis of novel caspofungin -like eyclohexalipopeptide antifungal agents. Methods Starting from Pro-O-t-Bu , the target compound 1 were prepared via 5 steps including condensation with N-Fmoc-L-Thr（O-t-Bu）-OH （a） or N-Fmoc-L-Ser （O-t-Bn）-OH （b） , then removed of N-Fmoc group and coupling with N^α-Fmoc - N^δ-Cbz-L-Orn-OH followed by removal of N^α-Fmoc group and reaction with 4′-alkoxy-1,1-4-earboxylic acid N-hydroxybenzotriazole ester （Ie -If）. Results 8 target compounds 1 ae-1af and l be - lbf had been synthesized in an overall yield ranged from 67.4% to 80.0% . The structures were confirmed by ESI-MS spectra and elemental analysis. Conclusion The process developed had several adventages of facile reaction conditions, convenient workup and high yield.
出处
《药学实践杂志》
CAS
2011年第1期17-20,共4页
Journal of Pharmaceutical Practice
基金
国家自然科学基金(30772674
30930107)
上海市重点学科建设基金(B906)资助项目
关键词
药物化学
合成
脂三肽
卡泊芬净
环六脂肽
抗真菌剂
medicinal chemistry
synthesis
lipotripeptide
caspofungin
cyclohexalipopeptide
antifungal agent
