US 12,264,174 B2
Process for preparing imetelstat
Jale Muslehiddinoglu, Beerse (BE); Dinesh Gala, Beerse (BE); and Jennifer Elizabeth Albaneze-Walker, Beerse (BE)
Assigned to Geron Corporation, Foster City, CA (US)
Filed by Geron Corporation, Foster City, CA (US)
Filed on Feb. 7, 2024, as Appl. No. 18/435,848.
Application 18/435,848 is a continuation of application No. 18/487,919, filed on Oct. 16, 2023.
Application 18/487,919 is a continuation of application No. 17/979,311, filed on Nov. 2, 2022, abandoned.
Application 17/979,311 is a continuation of application No. 17/718,990, filed on Apr. 12, 2022, abandoned.
Application 17/718,990 is a continuation of application No. 16/623,984, granted, now 11,332,489, issued on May 17, 2022, previously published as PCT/EP2018/068485, filed on Jul. 9, 2018.
Claims priority of application No. 17180426 (EP), filed on Jul. 10, 2017.
Prior Publication US 2024/0262854 A1, Aug. 8, 2024
This patent is subject to a terminal disclaimer.
Int. Cl. C07H 1/00 (2006.01); C07H 21/04 (2006.01)
CPC C07H 1/00 (2013.01) [C07H 21/04 (2013.01)] 13 Claims
 
1. A method of synthesizing the N3′→P5′ thiophosphoramidate oligonucleotide imetelstat of formula imetelstat

OG Complex Work Unit Chemistry
the method comprising:
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;

OG Complex Work Unit Chemistry
b) deprotecting the protected 3′-amino group to form a free 3′-amino group;

OG Complex Work Unit Chemistry
c) reacting the free 3′-amino group with a protected 3′-aminonucleoside-5′-O-cyanoethyl-N,N-diisopropylaminophosphoramidite monomer of formula (B′n), wherein B′n with n=2 is protected A, to form an internucleoside N3′→P5′-phosphoramidite linkage;

OG Complex Work Unit Chemistry
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 nucleoside base B′ of monomer (B′n) is protected B except when B is thymine, and wherein Bn is successively 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) deprotecting and cleaving imetelstat from the solid-phase support;
characterized in that no additional capping step is performed in any of the reaction steps a) to e).