The article presents a process research
study of 3-benzyloxy-4-oxo-4H-pyran-2-carboxylic
acid (1), a crucial intermediate
in the synthesis of baloxavir marboxil. The original four-step sequence
exhibited various limitations, such as low yield (43%), the use of
problematic solvents, a large excess of costly reagents, safety concerns,
and impurity control difficulties. To address these challenges, process
optimization was carried out to achieve the desired goals for large-scale
industrial production. Optimization of the enamine 4b synthesis was performed, resulting in the development of an azeotropic
removal method for the byproduct methanol. This improvement led to
minimized ring-opening impurity 15 and a significant
reduction in the consumption of the condensation reagent. Furthermore,
a simplified one-pot two-step oxidation sequence was devised to streamline
the process for the synthesis of compound 1. This optimization
involved controlling the formation of hydrolytic impurity 16 and its downstream aldol condensation form 17. The
optimized process was successfully demonstrated on a 600 g scale with
a product purity of 99.9%, and the overall yield was substantially
improved, rising from 43 to 66%.