A solution phase synthesis method for preparing an oligonucleotide,
wherein at least some of the reagents are solid supported. The method
suitable for large-scale synthesis comprises coupling a protected
compound with a nucleotide derivative having a protection group in the
presence of a solid supported activator to give an elongated
oligonucleotide with a P(III)-internucleotide bond; optionally processing
the elongated oligonucleotide by capping by reaction with a solid
supported capping agent and/or by oxidizing or sulfurizing by reaction of
the oligonucleotide with a solid supported oxidizing or sulfurization
reagent; and removing the protection group. The coupling may include
reacting a 3'-protected compound of formula:
##STR00001##
with a nucleotide derivative having a 5'-protection group, or reacting a
5'-protected compound of formula
##STR00002##
with a nucleotide derivative having a 3'-protection group.