Dimethylformamide → N-{[2-[(4-Bromo-2-fluorophenyl)methyl]-5-hydroxy-6-(1-methylethyl)-3-oxo-2,3-dihydro-4-pyridazinyl]carbonyl}glycine

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Reaction Steps

Ethyl 2-[(4-bromo-2-fluorophenyl)methyl]-5-hydroxy-6-(1-methylethyl)-3-oxo-2,3-dihydro-4-pyridazinecarboxylate. To a solution of ethyl 5-hydroxy-6-(1-methylethyl)-3-oxo-2,3-dihydro-4-pyridazinecarboxylate (9.5 g, 42.0 mmol) in N,N-Dimethylformamide (DMF) (250 ml) at 0° C. was added sodium hydride (60% in oil, 2.52 g, 63.0 mmol) in portions. The reaction mixture was stirred at room temperature for 45 minutes and then cooled back to 0° C. and 4-bromo-2-fluorobenzyl bromide (12.38 g, 46.2 mmol) was added portionwise. The mixture was stirred at ambient temperature for 2.5 hours then quenched with 1N HCl (10 ml) and diluted with water (30 ml). The aqueous solution was extracted with ethyl acetate (2×100 ml), the organic layers combined and washed with water (100 ml) and brine (100 ml), dried over Magnesium sulfate, filtered and solvents removed with rotary evaporation. The crude oil was purified by flash column chromatography (10-100% ethyl acetate in hexanes) to provide the crude product (8 g, ˜75% pure, 35% yield) as a pale yellow solid. The material was purified by reverse phase HPLC (C18, 75-90% acetonitrile/0.3 M aqueous ammonium formate) to give the title compound as a white powder. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.13 (d, J=6.82 Hz, 6H) 1.26 (t, J=7.20 Hz, 3H) 3.09-3.17 (m, 1H) 4.26 (q, J=7.07 Hz, 2H) 5.16 (s, 2H) 7.21 (t, J=8.08 Hz, 1H) 7.40 (dd, J=8.34, 1.77 Hz, 1H) 7.57 (dd, J=9.73, 1.89 Hz, 1H) 12.31 (s, 1H). MS (ES+) m/e 413 [M+H]+.

Provenance & Evidence