2-Pyridinamine, N-(1-methylethyl)-5-(trifluoromethyl)- synthesis

Yield:847240-94-2 92%

Reaction Conditions:

at 100; for 8 h;Sealed tube;

Steps:

152.1

A solution of 2-bromo-5-(trifluoromethyl)pyridine (6.0 g, 26.55 mmol) and isopropyl amine (9.08 mL, 106.18 mmol) in sealed tube was maintained at 100 °C for 8 h. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2 x 150 mL). The combined organic layer was washed with water (50 mL), brine (50 ml), dried over anhydrous Na2SO4 and concentrated. The crude product was purified by column chromatography over silica gel (100 - 200 mesh) using a solvent gradient of 20 % ethyl acetate in pet-ether to afford 5.0 g (92 %) of N-isopropyl-5-(trifluoromethyl)pyridin-2- amine 152-1 as an off white solid. NMR (400 MHz, DMSO-d6): c5 8.27 (5, 1 H), 7.58 (dd, J= 2.8, 9.2 Hz, 1H), 7.16 (d, J= 6.8 Hz, 1H), 6.53 (d, J= 8.8 Hz, 1H), 4.02-4.10 (m, 1H), 1.14 (d, J= 6.4 Hz, 6H). ESI-LC/MS: m/z205.0(M÷H); R= 4.57 mm [Agilent LCwith Ion trap Detector; Xterra MS- 018, 2.5 pm, 4.6 X 50 mm column; gradient of 80:20 H20 (0.01 M Ammonium Bicarbonate): CH3CN to 10:90 H20 (0.01 M Ammonium Bicarbonate):CH3CN in 4.0 minu and hold for 3.0 mm with flow rate of 1 .0 mLlmin].

References:

WO2014/78802,2014,A1 Location in patent:Page/Page column 239; 240