Tert-Butylamine → N-tert-Butyl-2-methylpyridine-3-carboxamide

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Reaction Steps

A 12-L, three-neck, round-bottom flask equipped with a mechanical stirrer, a thermocouple, and a nitrogen inlet gas adapter is charged with 2-methyl nicotinic acid (302 g, 2.2 mol), EDCI (464 g, 2.4 mol), HOBt (327.3 g, 2.4 mol, 1.1 equiv) and 4.5 L of anhydrous acetonitrile. The mixture is stirred for 45 minutes at room temperature to dissolve most of the solids and is then cooled to 5° C. using an ice-water bath. A mixture of t-butylamine (242 mL, 2.5 mol) and Hunig's base (402 mL, 2.5 mol) in 500 mL of anhydrous acetonitrile and 500 mL of anhydrous dichloromethane is added slowly over 45 minutes, maintaining the temperature below 10° C. The mixture is stirred for 15 hours at room temperature under nitrogen. The solvent is removed under reduced pressure and the residue is dissolved in ethyl acetate (3.0 L) then washed with saturated ammonium chloride solution (2.0 L). The organic-phase is dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Purification of the resultant crude residue by silica gel flash column chromatography followed by trituration with 5% ethyl acetate/heptane gives the title compound.

Provenance & Evidence