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

Abstract

<div> <div> <p>Pyrrolo[2,1-f][1,2,4]triazine (<b>1</b>) is an important regulatory starting material in the production of Remdesivir (Veklury®). Compound<b> 1</b> was produced through a newly developed synthetic methodology utilizing the simple building blocks pyrrole, chloramine and formamidine acetate by examining the mechanistic pathway for the process optimization exercise. Triazine <b>1</b> was obtained in 55% overall yield in a two-reactor operated process. This work describes the safety of the process, impurity profiles and control, and efforts towards the scale-up of triazine for the preparation of kilogram quantity.</p> </div> </div> <br>

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. 8,9 The known procedures involve the use of sodium hydride and multiple charge of chloramine (up to 2−3 times). Also, Paymode et al 8 made an attempt to transfer the synthesis of 1-amino-2-cyanopyrrole 4 to the continuous flow mode.…”

“…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.…”

An Industrial Approach to Production of Tofacitinib Citrate (TFC) as an Anti-COVID-19 Agent: A Joint Experimental and Theoretical Study

“…For example, reports for the successful use of umifenovir, favipiravir, and remdesivir (Figure 1) attracted the attention of scientists. Somehow, many experts started to fnd new or more facile ways for synthesizing these drugs [14]. Easier, cheaper, or greener ways for synthesizing selected organic compounds have always been important for the involved researchers [15][16][17].…”