Practical Manufacturing Process for Baloxavir Marboxil: Efficient Route to a Tricyclic Triazinanone Scaffold

Abstract

Baloxavir marboxil, a cap-dependent endonuclease inhibitor, is an antiviral drug for influenza. This paper presents the development of two alternative routes for the industry-oriented preparation of a key tricyclic triazinanone intermediate, 7-(benzyloxy)-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione, in order to overcome the drawbacks of the initial scaled-up synthetic route used in the kilo lab. The first candidate route is based on a late-stage reductive approach to the target starting with raw materials used in the previous route, namely, morpholin-3-one and a pyridone carboxylic acid derivative. The highlight of this approach is the tandem condensation of the morpholine and pyridone units to construct the tricyclic core of the substrate for the final reduction step. The other candidate route engages less expensive raw materials, combination of a protected 2-aminoethanol and 2-bromo-1,1-dimethoxyethane instead of morpholin-3-one, and six chemical steps in total. The efficient transformation was accomplished by a single-step conversion consisting of four elementary steps, including tandem cyclizations accompanied by deprotections. The latter process proved to be robust for production of more than tens of kilograms for practical large-scale manufacturing, providing >27 kg of the targeted triazinanone intermediate per batch in 56% overall yield with satisfactory purity.