We describe the development and scale-up of a nickel-catalyzed reductive cross-electrophile coupling reaction between a substituted 2-chloropyridine and ethyl 3-chloropropanoate using manganese dust as the terminal reductant. Several additives were screened for the activation of the manganese reductant in situ, and chlorotriethylsilane (TESCl) was found to provide the optimal conversion. A focused beam reflectance measurement (FBRM) probe was utilized to monitor particle attrition as well as manganese activation during the reaction. Modeling was employed to garner an understanding of mixing requirements that would ensure effective suspension of the manganese during scale-up. The process was successfully demonstrated on a 7 kg scale and afforded 2 in 64% yield.
Two approaches to a 1-aryl-4-trifluoromethyltriazole are described. Initially, a late-stage trifluoromethylation of the corresponding 1-aryl-4-iodotriazole using methyl fluorosulfonyldifluoroacetate (MDFA) was employed. However, the reaction was fraught with several safety and operational challenges, primarily due to the evolution of ∼33 equiv of gas per equiv of substrate. While some of these challenges were either addressed or mitigated through operations in plug flow, the process remained low yielding and suboptimal. Subsequently, a more convergent, longer-term route involving a Cu-mediated decarboxylative Click reaction was developed.
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.
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