US 12,030,907 B2
Modified nucleoside phosphoramidites
Sergei Gryaznov, San Mateo, CA (US); Jin Hong, Pacifica, CA (US); Vivek Kumar Rajwanshi, Cupertino, CA (US); and Leonid Beigelman, San Mateo, CA (US)
Assigned to Janssen BioPharma, Inc., South San Francisco, CA (US)
Filed by Janssen BioPharma, Inc., South San Francisco, CA (US)
Filed on Oct. 29, 2021, as Appl. No. 17/514,168.
Application 17/514,168 is a continuation of application No. 16/647,236, granted, now 11,180,524, previously published as PCT/IB2018/057077, filed on Sep. 14, 2018.
Claims priority of provisional application 62/558,763, filed on Sep. 14, 2017.
Prior Publication US 2022/0048941 A1, Feb. 17, 2022
Int. Cl. C07H 19/10 (2006.01); C07H 1/00 (2006.01); C07H 19/20 (2006.01)
CPC C07H 19/10 (2013.01) [C07H 1/00 (2013.01); C07H 19/20 (2013.01)] 18 Claims
 
1. A method of making a compound represented by Formula (I):

OG Complex Work Unit Chemistry
the method comprising the steps of
reducing the azide of compound 1 to form compound 2;
protecting the amine of compound 2 to form compound 3; and
phosphitylating the —OPG of compound 3 to form the compound represented by Formula (I);
wherein
compound 1 is:

OG Complex Work Unit Chemistry
compound 2 is:

OG Complex Work Unit Chemistry
compound 3 is:

OG Complex Work Unit Chemistry
X is NH;
Y is selected from the group consisting of —OCF3, —O(CR42)aCR43,
—O(CR42)bOCR43, and —O(CR42)b—CR4═CR42;
Z is H;
B is a nucleobase selected from the group consisting of adenine (A),
guanine (G), thymine (T), cytosine (C), uracil (U), 5-methylcytosine (5-me-C), 6-N-benzoyladenine (ABz), 4-N-benzoylcytosine (CBz), and 2-N-isobutyrylguanine (GiBu);
each R1 is independently C1-6 alkyl or C3-6 cycloalkyl;
R2 is —CH2CH2CN or C1-6 alkyl;
or R1 and R2 together form an optionally substituted heterocycloalkyl ring comprising one to six ring carbon atoms;
R3 is selected from the group consisting of H, trityl, monomethoxytriryl (MMTr), 4,4′-dimethoxytrityl (DMTr), and tritolyl;
each PG is an alcohol or amine protecting group independently selected from the group consisting of tert-butyldimethylsilyl (TBMDS), tert-butyldiphenylsilyl (TBDPS), tnisopropylsilyl (TIPS), benzoyl, trityl, monomethoxytrityl (MMTr),
4,4′-dimethoxytrityl (DMTr), and tritolyl;
each R4 is independently H or F;
a is 1 or 2; and
b is 1, 2, or 3.