Preparation background and overview of 2-fluoro-3-pyridylmethylamine
2-Fluoro-3-pyridylmethylamine can be used as a pharmaceutical synthesis intermediate. 2-Fluoro-3-pyridylmethylmethylamine can be prepared in three steps from 2-fluoronicotinic acid as a starting material.
Preparation of 2-fluoro-3-pyridylmethylamine
1) Add thionyl chloride (40 mL) to 2-fluoronicotinic acid (2.0 g, 14.3 mmol), reflux for 18 hours, cool to room temperature, and concentrate in vacuum. Benzene (100 mL) was added to the residue and ammonia gas was bubbled into the suspension for 3 hours. Stopper the bottle, stir for a further 18 hours, and then concentrate. Water was added to the residue and extracted with EtOAc. The EtOAc was washed with water, brine, then dried over Na2SO4, and concentrated in vacuo to give the title compound 2-fluoronicotinic acid amide (0.6 g, 30%). MS(ES)141.1(M+1)+. 1HNMR (MHz, CHCl3) δ8.32 (d, 1H, J=4.5), 8.17 (m, 1H), 7.92 (brs, 1H), 7.79 (brs, 1H), tetrahydrofuran 7.44 (m, 1H).
2) Add resin-bound triphenylphosphine (4.0g, 12.0mmol) to 2-fluoronicotinamide (0.6g, 4.3mmol) in dichloroethane (20.0mL) and carbon tetrachloride (20.0 mL) solution. Reflux for 18 hours, cool to room temperature, filter, and concentrate the filtrate in vacuo. Purification by flash column on silica gel, eluting with 10-60% EtOAc in hexane, afforded the title compound, 2-fluoronicotinonitrile (0.34 g, 64%). MS(ES)123.1(M+1)+. 1HNMR (MHz, CHCl3) δ8.46 (m, 1H), 8.09 (m, 1H), 7.37 (m, 1H).
3) At room temperature, add concentrated hydrochloric acid (0.46 mL) to the suspension of 2-fluoronicotinonitrile (0.34 g, 2.8 mmol) and 5% Pd/C (0.5 g) in methanol (10 mL). The suspension was stirred under a hydrogen atmosphere at 1 atm. 6 hours. The reaction mixture was filtered and the filtrate was concentrated. Diethyl ether was added to the residue, HCl gas was allowed to pass through the suspension, and the precipitate was filtered and dried to obtain the title compound 2-fluoro-3-pyridylmethylmethylamine (0.37g, 82%). MS(ES)127.1(M+1)+. 1HNMR (MHz, D calcium carbonate MSO) δ: 8.65 (brs, 3H), 8.24 (m, 1H), 8.16 (m, 1H), 7.41 (m, 1H), 4.06 (m ,2H).
