US 11,730,822 B2
Process for the preparation of glucuronide drug-linkers and intermediates thereof
Yunyu Mao, Everett, WA (US); Philip Moquist, Seattle, WA (US); Anusuya Choudhury, Churchville, PA (US); and Wendel Doubleday, Snohomish, WA (US)
Assigned to Seagen Inc., Bothell, WA (US)
Appl. No. 16/497,133
Filed by SEAGEN INC., Bothell, WA (US)
PCT Filed Mar. 23, 2018, PCT No. PCT/US2018/024191
§ 371(c)(1), (2) Date Sep. 24, 2019,
PCT Pub. No. WO2018/175994, PCT Pub. Date Sep. 27, 2018.
Claims priority of provisional application 62/476,605, filed on Mar. 24, 2017.
Prior Publication US 2020/0222553 A1, Jul. 16, 2020
This patent is subject to a terminal disclaimer.
Int. Cl. A61K 47/68 (2017.01); C07H 15/26 (2006.01); C07D 487/04 (2006.01)
CPC A61K 47/6889 (2017.08) [A61K 47/6809 (2017.08); C07D 487/04 (2013.01); C07H 15/26 (2013.01)] 48 Claims
 
1. A method for preparing a Drug Linker compound intermediate of Formula VID:

OG Complex Work Unit Chemistry
or a salt thereof, wherein
Q is a suitably protected hydroxyl, thiol or amine functional group;
A is an optional Connector Unit;
B is absent;
S* is a Self-Immolating Unit of Formula XV or Formula XVI:

OG Complex Work Unit Chemistry
wherein the wavy line indicates the point of attachment to A, and # indicates the point of attachment to the glycosidic oxygen atom of the glucuronic acid moiety;
D is a Drug Unit incorporating a DNA minor groove binder, DNA damaging agent or DNA replication inhibitor having a functional group comprising heteroatom T*, wherein T* is oxygen or sulfur, or an optionally substituted nitrogen;
R is hydrogen or optionally substituted C1-C6 alkyl, and one of R1 and R2 is hydrogen and the other is hydrogen, or optionally substituted C1-C6 alkyl or
both R and R1 together with the nitrogen and carbon atoms to which they are attached form a pyrrolodinyl or piperidinyl moiety and R2 is hydrogen;
R7 is C1-C8 alkyl or optionally substituted phenyl so that —OR7 provides for an ester functional group that is a suitable carboxylic acid protecting group; and
subscript t is 1,
the method comprising the step of:
(c) contacting a compound of Formula VIC with a Grignard reagent or an alkoxy magnesium halide with either in a suitable alcohol-containing solvent, wherein the Formula VIC compound has the structure of:

OG Complex Work Unit Chemistry
or a salt thereof, wherein
each of R6 is independently C1-C8 alkyl or optionally substituted phenyl such that R6C(═O)— provides for an ester functional group that is a suitable hydroxyl protecting group; and the remaining variable groups are as previously defined for Formula VID,
wherein said contacting with the Grignard reagent or alkoxy magnesium halide selectively removes the hydroxyl protecting groups whereby the Formula VID compound or its salt is obtained.