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

Abstract

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%.

Practical Manufacturing Process for Baloxavir Marboxil: Effective Selection and Replacement of Protective Group toward Enhancement of Crystallization-Induced Diastereomer Transformation

“…The aim was to minimize the change from the original one in order to prepare 3b as soon as possible in response to public demand for the drug substance . The synthetic methodology had been well-established with regard to 3a starting from 3-benzyloxy-4-oxo-4 H -pyran-2-carboxylic acid, which was a readily available intermediate employed for the production of dolutegravir sodium. , …”

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

“…However, there were challenging issues in the medicinal chemistry synthetic method anticipating scale-up in terms of preparation of racemic triazinanone 5 . Scheme A shows the original synthetic route employed for the initial scale-up in the kilo lab. ,, Starting from readily available 4-oxo-3-(phenylmethoxy)-4 H -pyran-2-carboxylic acid ( 10 ), , the p -nitrobenzyl ester 11 underwent skeletal transformation by dehydration condensation with tert -butyl carbazate to give 4-pyridone 12 . Subsequent removal of the tert -butoxycarbonyl (Boc) group on 12 gave the primary amine of intermediate 13 .…”