Exploration and optimization of processes for key intermediates of phosphorodiamidate morpholino oligonucleotides.

Objective: To explore and optimize the processes for synthesis of key intermediates of phosphorodiamidate morpholino oligonucleotides-7'-hydroxy-N-trityl morpholino nucleoside monomer in order to contribute to the research of phosphorodiamidate morpholino oligonucleotides antisense nucleotides. Methods: With N-benzoylcytidine,guanosine and 5-methyluridine as starting materials,the ribose was modified to morpholino and the key chemical groups were protected to obtain 7'-hydroxy-N-trityl morpholino nucleoside monomer. Results: Compounds N4-benzoyl-7'-hydroxy-N-trityl morpholinocytidine,N2-benzoyl-7'-hydroxy-N-trityl morpholinoguanosine and 7'-hydroxy-N-trityl morpholinothymidine were synthesized.The synthetic processes were optimized as well.The structures of all the intermediates and title compounds were characterized. Conclusion: The synthetic processes of 7'-hydroxy-N-trityl morpholino nucleoside monomers have been optimized,which can be employed to prepare title compounds on a large scale.