Synthesis of Filgotinib

Filgotinib is prepared using 2-amino-pyridine as raw material by condensation, cyclisation, coupling and other reactions. The specific synthesis steps are as follows:

The condensation of 2-amino-pyridine 139 with ethoxycarbonyl isothiocyanate, providing thiourea 140, which was carried forward as the crude material to the next step. Subjection of thiourea 140 to hydroxylamine hydrochloride in a mixture of ethanol and methanol triggered a cyclization reaction to secure the pyridyl aminotriazole subunit 141. The immediate subjection to acylation reaction conditions established the cyclopropyl amide. Heterocycle 142 was subsequently generated in 79% overall yield from 139 upon exposure to ammonia and methanol. Suzuki coupling with boronic acid 143 was followed by conversion of the benzyl alcohol to the corresponding bromide 145, which was further reacted with amine 146 to secure filgotinib, which was isolated as the HCl salt in excellent yield from 144.

Introduction of Filgotinib

Filgotinib is a potent, selective, and reversible Janus kinase-1 (JAK) inhibitor. Filgotinib was discovered and developed by Galapagos NV in collaboration with Gilead. Filgotinib is currently under clinical investigation for use in multiple indications, including Crohn's disease and ulcerative colitis (UC), and was approved by the European Medicines Agency (EMA) for the treatment of rheumatoid arthritis in 2020.