Smith T H, Fujiwara A N, Henry D W
J Med Chem. 1979 Jan;22(1):40-4. doi: 10.1021/jm00187a010.
Synthetic approaches to anthracyclines bearing novel 9-acyl substituents were investigated. Reaction of the lithium enolate of N-(trifluoroacetyl)daunorubicin (9) with methyl iodide in tetrahydrofuran afforded only the 9-propionyl derivative 10 in high yield. Reaction of 10 under identical conditions cleanly afforded the 9-isobutyryl derivative 11. Extension of this procedure to other alkylating agents (ethyl iodide, benzyl bromide, and heptyl iodide) required hexamethylphosphoramide as cosolvent and afforded mixtures of mono- and dialkylated products as well as recovered 9. The amino group was deblocked with NaOH in aqueous tetrahydrofuran, except in the case of the dibenzyl derivative 13 which was inert under these conditions. The 9-formyl analogue 23 was prepared via NaIO4 cleavage of 13-dihydroadriamycin (21). Antitumor evaluation against P388 leukemia in mice showed 23 to have activity comparable to the parent compounds, while the C-alkylated analogues were less active.
研究了带有新型9-酰基取代基的蒽环类药物的合成方法。N-（三氟乙酰基）柔红霉素（9）的烯醇锂盐在四氢呋喃中与碘甲烷反应，仅以高产率得到9-丙酰基衍生物10。在相同条件下，10反应可顺利得到9-异丁酰基衍生物11。将此方法扩展到其他烷基化剂（碘乙烷、苄基溴和碘庚烷）时，需要六甲基磷酰胺作为共溶剂，得到单烷基化和二烷基化产物的混合物以及回收的9。氨基在含水四氢呋喃中用氢氧化钠脱保护，但二苄基衍生物13在这些条件下呈惰性。9-甲酰基类似物23是通过13-二氢阿霉素（21）的高碘酸钠裂解制备的。对小鼠P388白血病的抗肿瘤评估表明，23具有与母体化合物相当的活性，而C-烷基化类似物的活性较低。
