4-Bromobenzaldehyde → 2-[(E)-2-(4-Bromophenyl)ethenyl]-5-chloropyridine-3-carboxylic acid

Participants

Reaction Conditions

Reaction Steps

A stirred solution of methyl 5-chloro-2-methylnicotinate (7.26 kg, 96.4 wt %, 37.7 mol) and 4-bromobenzaldehyde (6.98 kg, 37.7 mol, 1.0 equiv) in THF (112 L) was put under a nitrogen atmosphere, and then cooled to −5° C. A solution of potassium tert-butoxide (8.46 kg, 75.4 mol, 2.0 equiv) in THF (53 L) was then added via a 1 μm filter, whilst maintaining the internal temperature at <0° C. The resulting reaction mixture was warmed to 25° C., and then aged at this temperature until the reaction was complete (typically 1 h). The reaction was then quenched by addition of water (54 L), ensuring the batch temperature remained <30° C. The biphasic mixture was stirred for ˜10 min, and the lower aqueous layer was then removed. The remaining THF layer was diluted with ethyl acetate (54 L), and then washed with 2 M hydrochloric acid (27 L) followed by half-saturated brine (20 L). The resulting organic layer was solvent-switched to ethyl acetate (to a final volume of 27 L), and then to methanol (to give a final volume of ˜106 L). The temperature of the resulting slurry was adjusted to ˜20° C., and it was then filtered, washing the filter-cake with methanol (11 L). The resulting solid was dried under vacuum at 50° C. to afford the title compound.

Provenance & Evidence