9 research outputs found
Telescoped Process to Manufacture 6,6,6-Trifluorofucose via Diastereoselective Transfer Hydrogenation: Scalable Access to an Inhibitor of Fucosylation Utilized in Monoclonal Antibody Production
IgG1
monoclonal antibodies with reduced glycan fucosylation have
been shown to improve antibody-dependent cellular cytotoxicity (ADCC)
by allowing more effective binding of the Fc region of these proteins
to T cells receptors. Increased in vivo efficacy in animal models
and oncology clinical trials has been associated with the enhanced
ADCC provided by these engineered mAbs. 6,6,6-Trifluorofucose (<b>1</b>) is a new inhibitor of fucosylation that has been demonstrated
to allow the preparation of IgG1 monoclonal antibodies with lower
fucosylation levels and thus improve the ADCC of these proteins. A
new process has been developed to support the preparation of <b>1</b> on large-scale for wide mAb manufacture applications. The
target fucosylation inhibitor (<b>1</b>) was synthesized from
readily available d-arabinose in 11% overall yield and >99.5/0.5
dr (diastereomeric ratio). The heavily telescoped process includes
seven steps, two crystallizations as purification handles, and no
chromatography. The key transformation of the sequence involves the
diastereoselective preparation of the desired trifluoromethyl-bearing
alcohol in >9/1 dr from a trimethylsilylketal intermediate via
a ruthenium-catalyzed
tandem ketal hydrolysisâtransfer hydrogenation process