Step 15.1: Synthesis of methyl 2-amino-5-bromoisonicotinate. Methyl 2-aminoisonicotinate (5.58 g, 36.7 mmol) was dissolved in DMF (56 mL) and cooled to -18°C (using an ice/MeOH bath). At -18 °C, N-bromosuccinimide (NBS, 7.21 g, 38.5 mmol) was added to the reaction mixture in batches and stirred for 1 h at the same temperature. After completion of the reaction, the mixture was diluted with ethyl acetate (AcOEt, 500 mL) and washed with water (2 x 250 mL). The organic layer was dried over anhydrous sodium sulfate (Na2SO4), filtered and concentrated under reduced pressure to give the crude product methyl 2-amino-5-bromoisonicotinate (3.0 g, 13.0 mmol, 35% yield) as a yellow solid, which was used directly in the next reaction without further purification. Mass spectrometry (MS): m/z 231 [M + H]+; high performance liquid chromatography (HPLC): retention time (Rt) = 0.70 min.
