Improved Process for Preparing Imetelstat

A method of synthesizing the N3′→P5′ thiophosphoramidate oligonucleotide imetelstat of formula

• the method comprises of
• a) providing a first 3′-amino protected nucleotide attached to a solid-phase support of formula (A) wherein PG is an acid-labile protecting group;
• b) deprotecting the protected 3′-amino group to form a free 3′-amino group;
• c) reacting the free 3′-amino group with a protected 3′-aminonucleoside-5′-O-cyanomethyl-N-N-disopropylaminophosphoramidite monomer of formula (B′n) wherein n=2 to form an internucleoside N3→P5′-phosphoramidite linkage;
• d) sulfurization of the internucleoside phosphoramidite group using an acyl disulfide to form a N3′→P5′ thiophosphoramidate;
• e) repeating 11 times in successive order the deprotection step b), the coupling step c) with a protected 3′-aminonucleoside-5′-O-cyanoethyl-N,N-diisopropylaminophosphoramidite monomer of formula (B′n) wherein the protected nucleoside base B′ in monomer (B′n) is successively the protected nucleobase B3 to B13 in the respective 11 coupling steps, and the sulfurization step d);
• f) removing the acid-labile protecting group PG;
• and
• g) cleaving and deprotecting imetelstat from the solid-phase support;
• characterized in that no additional capping step is performed in any of the reaction steps a) to e).