Continuous Flow C-Glycosylation via Metal–Halogen Exchange: Process Understanding and Improvements toward Efficient Manufacturing of Remdesivir

Abstract

As remdesivir is the first approved treatment for COVID-19 (SARS-CoV-2), its production is likely to be of vital importance in the near future. Continuous flow processing has been demonstrated as a key technology in the manufacturing of highvolume active pharmaceutical ingredients and is considered for use in this synthetic sequence. In particular, the challenging Cglycosylation of a pyrrolotriazinamine via metal−halogen exchange was identified as a transformation with significant potential benefit, as exemplified by calorimetric analysis of each reaction step. Multiple simplifications of this process were attempted in batch but in general were found to be unfruitful. The five-feed process was then transferred to a flow setup, where specific conditions were found to circumvent solid formation and permit stable processing. Detailed optimization of stoichiometries provided an improvement upon batch conditions with a total residence time of <1 min.

COVID‐19 into Chemical Science Perspective: Chemical Preventive Measures and Drug Development

“…However, this lengthy C‐glycosylation of a pyrrolotriazinamine is associated with consumption of long time and energy due to the requirement of multiple prolonged addition of reagents for the exothermic reactions to happen in batch. In a very recent study, Keppe and coworkers improved this lengthy C‐glycosylation by carrying out the organometallic reactions at a higher temperature in continuous flow processing instead of batch [109] . Thorough optimization of stoichiometry offered an improvement upon batch conditions with a total residence time of less than 1 min and the specific conditions were standardized to avoid solid formation and allow stable processing.…”

“…In a very recent study, Keppe and coworkers improved this lengthy C-glycosylation by carrying out the organometallic reactions at a higher temperature in continuous flow processing instead of batch. [109] Thorough optimization of stoichiometry offered an improvement upon batch conditions with a total residence time of less than 1 min and the specific conditions were standardized to avoid solid formation and allow stable processing. Despite of these advantages, continuous flow procedure did not bring about a considerable advancement in yield compared to the second generation synthesis (47 % vs 40 %), still it showed a great improvement in terms of processability.…”

Synthesis and crystal structures of 7,8-bromo (dibromo)-3-tert-butylpyrazolo[5,1-c][1,2,4]triazines

“…Fused triazines exhibit diverse conformational behavior depending on the nature of an annulated ring [ 10 , 11 ]. Azolo[1,2,4] triazines [ 12 ] constitute an important class of such compounds which have found broad use as effective antiviral agents, e.g., 1,2,4-triazolo[5,1- с ][1,2,4]triazine (triazavirin) [ 13 ] and pyrrolo[2,1- f ][1,2,4]triazine (remdesivir) [ 14 , 15 ]. Nevertheless, the structural features of such systems are still relatively poorly studied.…”

“…g . , 1 , 2 , 4triazolo [5,1-с] [1,2,4]triazine (triazavirin) [13] and pyrrolo[2,1-f] [1,2,4]triazine (remdesivir) [14,15]. Nevertheless, the structural features of such systems are still relatively poorly studied.…”

CRYSTAL STRUCTURE OF 3-tert-BUTYL- PYRAZOLO[5,1-с][1,2,4]TRIAZINE-3,4-DIYL DICARBOXYLATES

“…Conformational features of polycyclic triazines largely depend on the nature of the annelated cycle. Azolo[1,2,4]triazines [ 11 ] is an important class of biologically active compounds applied as effective antiviral drugs, such as triazavirin (1,2,4-triazolo[5,1- с ][1,2,4]triazine) and remdesivir(pyrrolo[2,1- f ][1,2,4]triazine) [ 12 , 13 ]. Nonetheless, the structural features of hydrogenated azolotriazines still remain poorly studied.…”