Process for Preparing Imetelstat
The present invention relates to a process for preparing the telomerase inhibitor imetelstat using a 3 steps per cycle solid-phase support bound process comprising the steps of deprotection of the 3′-amino group of the support-bound oligonucleotide, coupling with a 5′-phosphoramidite, and sulfurization with an acyl disulfide, characterized by the absence of an additional capping step in each cycle that is used to prevent unreacted 3′-amino oligonucleotide groups from reacting during subsequent cycles. Imetelstat has formula below.
1 . 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-cyanoethyl-N,N-diisopropylaminophosphoramidite 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-diisopropylamino-phosphoramidite monomer of formula (B′ n ) wherein the protected nucleoside base B′ in monomer (B′ n ) is successively the protected nucleobase B 3 to B 13 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).
2 - 13 . (canceled)