Improved Synthetic Process of Baloxavir Marboxil Intermediate 3-Benzyloxy-4-oxo-4H-pyran-2-carboxylic Acid

The article presents a process researchstudy of 3-benzyloxy-4-oxo-4H-pyran-2-carboxylicacid (1), a crucial intermediatein the synthesis of baloxavir marboxil. The original four-step sequenceexhibited various limitations, such as low yield (43%), the use ofproblematic solvents, a large excess of costly reagents, safety concerns,and impurity control difficulties. To address these challenges, processoptimization was carried out to achieve the desired goals for large-scaleindustrial production. Optimization of the enamine 4b synthesis was performed, resulting in the development of an azeotropicremoval method for the byproduct methanol. This improvement led tominimized ring-opening impurity 15 and a significantreduction in the consumption of the condensation reagent. Furthermore,a simplified one-pot two-step oxidation sequence was devised to streamlinethe process for the synthesis of compound 1. This optimizationinvolved controlling the formation of hydrolytic impurity 16 and its downstream aldol condensation form 17. Theoptimized process was successfully demonstrated on a 600 g scale witha product purity of 99.9%, and the overall yield was substantiallyimproved, rising from 43 to 66%.

Automated summary

The article presents a process research study on a crucial intermediate in the synthesis of baloxavir marboxil. The study focuses on addressing limitations of the original synthesis sequence and optimizing the process to achieve higher product purity and yield.