Step 1: Synthesis of 4-bromo-2-nitrobenzoic acid
The reference method was modified as follows (Boojamra, C.G.; Burow, K.M.; Thompson, L.A.; Ellman, J.A. J. Org. Chem., 1997, 62, 1240-1256):
1. An aqueous solution (65 mL) of NaNO2 (1.9 g, 27.4 mmol) was slowly added to a stirring solution of 4-amino-2-nitrobenzoic acid (1) (5 g, 27.4 mmol) dissolved in 48% aqueous HBr (40 mL) at 0 °C. After about 15 minutes, the turbid reaction mixture transformed into a clarified orange-yellow solution.
2. After continued stirring for 25 minutes, the solution was added dropwise to a solution of CuBr (5.2 g, 36.3 mmol) dissolved in 48% aqueous HBr (90 mL) at 0°C. Yellow foam generation and gas release from the purple-brown mixture were observed during the reaction.
3. After stirring at 0 °C for 1 h, the reaction mixture was concentrated under reduced pressure.
4. The aqueous layer was extracted with EtOAc (4 x 300 mL), the organic phases were combined, dried over Na2SO4 and concentrated to dryness to give a dark solid crude product.
5. The crude product was filtered through a column of Florisilica clay (~20 g) and washed with EtOAc.
6. The combined organic fractions were evaporated to about 50 mL, 200 mL of water was added, washed sequentially with 1 M HCl (2 x 50 mL), brine (50 mL), then dried with Na2SO4, filtered and concentrated to dryness to give 6.1 g of light yellow solid product (2) in 91% yield and >90% HPLC purity.
