Ammonium Chloride → 4-(3,4-difluorobenzyl)-3-oxo-N-{(1R)-2-[(2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)oxy]-1-phenylethyl}-3,4-dihydropyrazine-2-carboxamide

Participants

Reaction Steps

4-(3,4-Difluorobenzyl)-3-oxo-3,4-dihydropyrazine-2-carboxylic acid (48 mg, 0.18 mmol) was placed in a 25-mL RBF under a nitrogen atmosphere followed by HATU (82 mg, 0.22 mmol), then NMP (1.0 mL) and finally N,N-diisopropylethylamine (0.11 mL, 0.63 mmol). The reaction was stirred for five minutes at room temperature, and was added to a solution of 5-[(2R)-2-amino-2-phenylethoxy]-1,3-dihydro-2H-benzimidazol-2-one (55 mg, 0.18 mmol) in NMP (1.0 mL). The reaction was allowed to stir at room temperature for forty minutes, then was added to a separatory funnel containing ethyl acetate (75 mL) and dilute aqueous NH4Cl (50 mL); the phases were separated and the organic layer was washed with saturated aqueous NaHCO3 (50 mL), followed by brine (50 mL) and dried over anhydrous Na2SO4, then concentrated in vacuo. The crude product was purified by silica gel chromatography (10-gram column) using 0-10% CH3OH in CH2Cl2, with the product eluting at 8% CH3OH in CH2Cl2, to afford 4-(3,4-difluorobenzyl)-3-oxo-N-{(1R)-2-[(2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)oxy]-1-phenylethyl}-3,4-dihydropyrazine-2-carboxamide as a light yellow solid. 1H NMR (500 MHz, C2D6SO) δ 10.51 (s, 1H), 10.38 (s, 1H), 9.82 (d, 1H), 8.05 (d, 1H), 7.57 (d, 1H), 7.50 (m, 1H), 7.43 (m, 3H), 7.35 (t, 2H), 7.27 (t, 1H), 7.24 (m, 1H), 6.75 (d, 1H), 6.51 (d, 2H), 5.34 (m, 1H), 5.16 (s, 2H), 4.09 (m, 2H). LRMS (ESI) calc'd for (C27H23F2N5O4) [M+H]+, 518.2; found 518.2.

Provenance & Evidence