Hydrochloric Acid → Methyl 3-bromo-2-pyridinecarboxylate

Participants

Reaction Conditions

Reaction Steps

A 50 L three-neck round bottom flask is equipped with a mechanical stirrer, thermocouple, nitrogen inlet and reflux condenser. The flask is charged with HCl (20 L) and 3-bromopyridine-2-carbonitrile (6790 g, 37.1 mol) (prepared, for example, essentially as described in the Alternate Procedure for Intermediate 3). The reaction mixture is heated to reflux and the starting material dissolves and a pink suspension forms. The reaction mixture is stirred for 20 h at reflux. The reaction progress is monitored by TLC (heptane:EtOAc, 1:1). No starting material is present at Rf=0.5 or intermediate amide at Rf=0.15. Once the reaction is deemed complete, the reaction mixture is cooled to 0-5° C. and then stirred at this temperature for 3 h. After this time the solids are collected by filtration (do not wash and press on a filter). The solids (3-bromopyridine-2-carboxylic acid) are dried in a vacuum oven at 50° C. with use of appropriate trapping as HCl is present in the wet product. A 50 L three-neck round bottom flask is equipped with a mechanical stirrer, thermocouple and reflux condenser. The flask is charged with MeOH (25.5 L), and 3-bromoopyridine-2-carboxylic acid (5.098 kg) followed by HCl (15 mL). The reaction mixture is heated to reflux at about 64-65° C. and stirred at this temperature for 9 h. The reaction mixture is allowed to cool to 40-50° C. and then concentrated to a paste. A 50 L separatory funnel is charged with water (12 L) and solid NaHCO3 (2338 g) and the mixture is stirred for 10-15 min. The residue from the concentrated paste is added in portions to the stirred sodium bicarbonate solution at a rate to control foaming. After all of the residue is added, EtOAc (10 L) is charged to the to the funnel and stirred for 10-15 min. The aqueous layer is separated and the organic layer washed with saturated aqueous sodium bicarbonate solution (1 L), then dried over magnesium sulfate, filtered, and concentrated. The combined aqueous layers are extracted with EtOAc (2×2 L) and the combined organic layers are washed with saturated aqueous sodium bicarbonate solution (1 L), then dried over magnesium sulfate, filtered, and concentrated along with the first extract. A pale yellow oil is obtained which solidifies on cooling. The resulting material is dried in a vacuum oven overnight at room temperature.

Provenance & Evidence