Ethyl Acetate → 2-Nitro-3-(trifluoromethyl)aniline

Temperature

105 °C

N-(2-Nitro-3-trifluoromethyl-phenyl)-acetamide (Helvetica 1947, p.107) (3.6 g) was dissolved in EtOH and heated to 105° C. prior to the addition of 1N NaOH (60 ml) and 50% NaOH (10 ml). After 2.5 h, the reaction was cooled to rt and EtOAc was added. The organic layer was washed with water and brine. Then it was dried and concentrated to give a crude 2-nitro-3-trifluoromethyl-phenylamine (2.79 g): 1H NMR (CDCl3, δ ppm, 300 mHz) 5.0 (s, 2H), 7.02 (d, 1H), 7.10 (d, 1H), 7.38 (t, 1H). (1b) A portion (1.42 g) of the above derivative (1a) was dissolved in MeOH (20 mL) prior to the addition of 10% Pd/C (260 mg). The reaction was placed on a Parr apparatus under hydrogen at 60 psi for 3 h. The Pd/C was filtered off and solvent was concentrated to give 3-trifluoromethyl-benzene-1,2-diamine (1.16 g): 1H NMR (CDCl3, δ ppm, 300 mHz) 3.40 (s, 2H), 3.94 (s, 2H), 6.70 (t, 1H), 6.85 (d, 1H), 7.02 (d, 1H). (1c) A portion (1.15 g) of the above derivative (1b) was dissolved in diethyl malonate. The reaction was heated at 160° C. (oil bath temperature) for 1.5 h. After cooling to rt, flash chromatography of the crude reaction gave (4-trifluoromethyl-1H-benzoimidazol-2-yl)-acetic acid ethyl ester (1.14 g). MS found: (M+H)+=273.0 (1d) A portion (200 mg) of the above derivative (1c) was dissolved in THF (2 mL) prior to the addition of a solution of LiOH.H2O (37 mg) in water (0.1 ml). A couple drops of MeOH were added until the solution became clear. After 2 h at rt, the reaction was concentrated and freeze-dried to provide (4-trifluoromethyl-1H-benzoimidazol-2-yl)-acetic acid lithium salt (175 mg).

1. temperaturethe reaction was cooled to rt
2. washThe organic layer was washed with water and brine
3. customThen it was dried
4. concentrationconcentrated

ORD record

ord-71632a2f070442c29d7bf49fcea78248

Source dataset

uspto-grants-2007_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07291615B2