一种新型磷酰胺吗啉代寡鸟苷酸单体的合成及工艺优化

Synthesis and process optimization for a novel phosphorodiamidate morpholinoguanylic monomer

发展了一种以鸟苷为原料的新型磷酰胺吗啉代寡鸟苷酸单体的合成路线。在对碱基上氨基和核糖5'位羟基进行保护的基础上,将核糖环转变为吗啉环,得到保护的吗啉代鸟苷。在吗啉环上进行三苯甲基化反应,并利用Mitsunobu反应对嘌呤6-O位进行修饰;对脱保护后的羟基进行N,N-二甲基氨基磷酰化反应,合成得到目标产物。对Mitsunobu反应和磷酰化反应的条件进行了优化。在优化的条件下,新合成路线的总产率为14.1%。通过LC-MS、^(1)H NMR和^(31)P NMR等技术手段对中间产物和目标产物进行了结构表征。

A synthesis route of a novel phosphoramide morpholinoline-oligoguanylate monomer using guanosine as raw material was developed.Based on the protection of the amino group on the base and 5'-OH in ribose,the ribose ring is converted into a morpholine ring to obtain the protected morpholine guanosine.A triphenylmethylation reaction was carried out on the morpholine ring and purine 6-O position was modified using the Mitsunobu reaction.N,N-dimethylaminophosphorylation reaction is performed on the deprotected hydroxyl group to synthesize the target product.In this study,the conditions of the Mitsunobu reaction and phosphorylation reaction were optimized.Under optimized conditions,the total yield of the new synthetic route was 14.1%.The structure of intermediate products and target products were characterized by LC-MS,^(1)H NMR and ^(31) P NMR.