Facile and Scalable Methodology for the Pyrrolo[2,1-f][1,2,4]triazine of Remdesivir

Abstract

Pyrrolo[2,1- f ][1,2,4]triazine ( 1 ) is an important regulatory starting material in the production of the antiviral drug remdesivir. Compound 1 was produced through a newly developed synthetic methodology utilizing simple building blocks such as pyrrole, chloramine, and formamidine acetate by examining the mechanistic pathway for the process optimization exercise. Triazine 1 was obtained in 55% overall yield in a two-vessel-operated process. This work describes the safety of the process, impurity profiles and control, and efforts toward the scale-up of triazine for the preparation of kilogram quantity.

Synthesis and antiproliferative activity characterization of new imidazothiazolotriazine oxindolylidene derivatives containing various substituents in the oxindole ring

“…Polyheteroatomic heterocyclic compounds are widely represented in medicinal chemistry and materials science. 1 Some 1,2,4-triazine derivatives containing fused rings of other heterocycles are used as antibiotics (toxoflavin, fervenulin, and reumycin), 2 effective antiviral drugs (triazavirin 3 and remdesivir 4 ), and have been identified as bacterial pigments (nostocine, pseudoiodinin, and fluviols) that also show antitumor activity against certain cell lines. 5 …”

Development of Continuous Flow Processes to Access Pyrrolo[2,1-f][1,2,4]triazin-4-amine: An RSM for the Synthesis of Antiviral Drugs

“…Literature analysis showed several procedures for performing the amination step in a batch process, both separately and with triazine formation in one-pot. , The known procedures involve the use of sodium hydride and multiple charge of chloramine (up to 2–3 times). Also, Paymode et al made an attempt to transfer the synthesis of 1-amino-2-cyanopyrrole 4 to the continuous flow mode.…”

“…The N -amination of compound 3 was realized using sodium hydride as the base in DMF solvent. The overall yield of compound 1 was increased from 33% to 55% after extensive process safety studies using a RC1 system . Furthermore, dilute reaction conditions were applied to mitigate the safety concerns of the reaction utilizing NaH in DMF.…”

“…8 We further reported the process development efforts to synthesize the triazine 1 on a kilogram scale in a two-vessel-operated batch process. 9 The cyanopyrrole 3 was synthesized, in batch, starting from the pyrrole 2 which reacts with Vilsmeier's reagent to generate the intermediate aldehyde 2a after aqueous quench. The addition of hydroxylamine at elevated temperatures results in the formation of compound 3.…”

“…The overall yield of compound 1 was increased from 33% to 55% after extensive process safety studies using a RC1 system. 9 Furthermore, dilute reaction conditions were applied to mitigate the safety concerns of the reaction utilizing NaH in DMF. Sodium hydride is not a preferred reagent for process scale-up in either batch or continuous flow mode, and its potential safety risk in polar nonprotic solvents was well documented.…”