Methyl iodide → N-methyl-N-(2-nitro-3-trifluoromethyl-phenyl)-acetamide

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Reaction Steps

N-(2-Nitro-3-trifluoromethyl-phenyl)-acetamide (Helvetica 1947, p.107) (2.0 g) was dissolved in DMF (15 ml) prior to the addition of K2CO3 (2.07 g) and MeI (0.71 ml). After 2 h, the solution was concentrated and 1N HCl solution (aq) was added. The solution was extracted with EtOAc. The organic layer was washed with brine, dried, filtered, and concentrated. Filtration through a plug of silica of the resulting residue gave N-methyl-N-(2-nitro-3-trifluoromethyl-phenyl)-acetamide. This material (2 g) was dissolved in EtOH prior to the addition of a solution of NaOH (2 g) in H2O (2 ml). The mixture was heated to reflux for 2 h, cooled to rt, and neutralized with 1N HCl, and extracted twice with EtOAc. The organic extracts were combined, washed with brine, dried (MgSO4), filtered, and concentrated in vacuo. The resulting residue was dissolved in MeOH (50 ml) prior to the addition of 10% Pd/C (2.07 g). This solution was placed on a Parr apparatus under H2 (50 psi) for 2 h. The Pd/C was filtered off and the solution was concentrated. The resulting residue was dissolved in diethyl malonate. The reaction was heated at 160° C. oil bath for 45 min. After cooling to rt, flash chromatography of the crude reaction gave (1-methyl-4-trifluoromethyl-1H-benzoimidazol-2-yl)-acetic acid ethyl ester (1.05 g). A portion (200 mg) of this material was dissolved in THF (17 ml) prior to the addition of a solution of LiOH (31 mg) in H2O (6 ml). MeOH (6 ml) was added. After 2 h at rt, the reaction was concentrated and freeze-dried to provide (1-methyl-4-trifluoromethyl-1H-benzoimidazol-2-yl)-acetic acid lithium salt (189 mg). MS found: (M+H)+=259.2 (4b) A portion (13 mg) of the above derivative (4a) was dissolved in DMF (2 ml) prior to the addition of diisopropylethylamine (0.05 ml) and example (3i)(30 mg). After cooling to 0° C., BOP (23 mg) was added. The resulting mixture was warmed to rt and stirred overnight. The reaction was concentrated. Water was added and the solution was extracted with EtOAc. The EtOAc layer was washed with NaHCO3 solution (aq), dried (MgSO4), filtered, and concentrated. Reverse phase HPLC purification (gradient elution, water/acetonitrile/TFA) of the resulting residue provided the title compound (14 mg).

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