Yield: 76%

Reaction Conditions:

Stage #1:2-methoxy-ethanol with sodium hydride in tetrahydrofuran at 20; for 0.166667 h;
Stage #2:2-Fluoro-5-nitrobenzotrifluoride in tetrahydrofuran at 60; for 5 h;
Stage #3: with hydrogen;sodium hydrogencarbonate;palladium 10% on activated carbonmore than 3 stages;

Steps:

1 Preparation of 4-(2-methoxy)ethoxy-3-(trifluoromethyl)aniline
Preparation of 4-(2-methoxy)ethoxy-3-(trifluoromethyl)aniline 2-Methoxyethanol (219 mg, 2.88 mmol) was dissolved in THF (6 mL), and sodium hydride (60%, 39 mg, 0.96 mmol) was added thereto. The mixture was stirred at room temperature for 10 minutes, and 2-fluoro-5-nitrobenzotrifluoride (200 mg, 0.96 mmol) was added thereto. The resulting mixture was heated at 60°C for 5 hours. The reaction solution was poured in a saturated sodium bicarbonate solution and extracted with ethyl acetate and washed with saturated brine. To the organic layer, 10% palladium carbon (20 mg) and methanol (2 mL) were added. The resulting mixture was stirred under hydrogen atmosphere at atmospheric pressure at room temperature for 16 hours. The catalyst was removed by filtration, and the filtrate was concentrated. The residue was purified by silica-gel column chromatography (n-hexane: ethyl acetate = 5:1) to give the desired material (170 mg, yield: 76%) as a yellow oil. ¹H-NMR (270MHz, CDCl₃) δ (ppm): 3.26 (3H, s), 3.60 (2H, t, J=6.5Hz), 4.10 (2H, t, J=6.5Hz), 5.08 (2H, s), 6.70-6.80 (2H, m), 6.89 (1H, d, J=12.0Hz) ESI (LC-MS positive mode) m/z 236 (M+H).

References:

CHUGAI SEIYAKU KABUSHIKI KAISHA;The University of Tokyo EP1921078, 2008, A1 Location in patent:Page/Page column 39