General procedure for the synthesis of 5-fluoropyridine-2-methylamine from 2-cyano-5-fluoropyridine:
1. hydrogenation reaction: 2-cyano-5-fluoropyridine (63.2 g, 0.52 mol), nickel ruanne (22.5 g) and ammonia-saturated ethanol (1.5 L) were mixed and reacted at 70°C for 16 hours under 500 psi hydrogen pressure.
2. Purification: After completion of the reaction, the dark purple liquid was separated by fast silica gel column chromatography (eluent: dichloromethane/methanol/ammonium hydroxide = 95:4.5:0.5). Concentration gave the free base of 5-fluoropyridine-2-methylamine in yellow liquid in a yield of 25.0 g (44%).
Characterization data: 1H NMR (DMSO-d6) δ 8.43 (d, J=2.9Hz, 1H), 7.66 (m, 1H), 7.50 (m, 1H), 3.77 (s, 2H), 2.10 (br, 2H); MS (ESI) m/z 127 (M+H).
3. Salt-forming reaction: the free base (20.0 g, 159.0 mmol) was dissolved in 1,4-dioxane (150 mL) and a dioxane solution (150 mL, 3.8 eq.) of 4N HCl was added to immediately precipitate a white solid. It was diluted with ether (300 mL) and filtered to give 5-fluoropyridine-2-methylamine dihydrochloride.
4. Drying: The product was dried at 20 mmHg, 60°C to give pure dihydrochloride in a yield of 30.0 g (95%).
Characterization data: 1H NMR (DMSO-d6) δ 8.61 (d, J=2.9Hz, 1H), 8.50 (brs, 3H), 7.82 (m, 1H), 7.62 (m, 1H), 7.50 (br, 1H), 4.18 (m, 2H); MS (ESI) m/z 127 (M+H, free base).
