3-BroMo-4-forMylbenzoic acid

1403326-77-1

91760-66-6

Intermediate 33 (1860 g, 4.23 mol, 1.0 eq.) was suspended in water (5 L) and the suspension was heated to 40 °C. Subsequently, solid Na2CO3 (1460 g, 13.77 mol, 3.25 eq.) was added in small portions, taking 20 min. Foam was generated upon initial addition, so EtOAc (0.2 L) was added to defoam and inhibit further foaming. After addition, the brown suspension was heated to 90 °C over 40 min and stirred at 90 °C for 90 min, then cooled to 40 °C over 90 min. EtOAc (1.5 L) was added, followed by slow addition of concentrated aqueous hydrochloric acid (0.7 L) through a dropping funnel, which vigorously released CO2 gas and evaporated most of the EtOAc. A further addition of EtOAc (1 L) was made to wash the foam products from the condenser and reactor walls, followed by the addition of EtOAc (0.3 L), and the crude slurry was stirred overnight at room temperature. The slurry was heated to 40 °C and additional concentrated aqueous hydrochloric acid was added through a dropping funnel under vigorous stirring over 45 min, resulting in the escape of CO2 gas, the evaporation of most of the EtOAc and the formation of a solid. Stirring was stopped and the solid floated to the top of the aqueous phase (pH 1). Separate most of the aqueous layer (~5 L) and add 2-MeTHF (5 L). The clarified aqueous layer was discarded and the organic layer was diluted to 10 L with additional 2-MeTHF and heated to 50 °C to give a dark orange solution. After the organic layer was washed with 1 M HCl (0.5 L), the solvent was evaporated and azeotroped with toluene to give a brown solid 3-bromo-4-formylbenzoic acid (960.3 g). LCMS (Method 4): rt 2.73 min, m/z 227,229 [MH]+. 1H NMR (300 MHz, DMSO): δ 10.26 (1H, d, J = 0.8 Hz), 8.20 (1H, d, J = 1.5 Hz), 8.08-8.04 (1H, m), 7.95 (1H, d, J = 8.0 Hz).