Dimethylformamide → ethyl (4S)-4-((tert-butoxycarbonyl)amino)-2-(2-(2-methyl-3-((1-methylcyclopropyl)amino)-5-quinoxalinyl)-2-oxoethyl)-3-oxopentanoate

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Reaction Steps

To a 1000 mL round bottomed flask was added 2-bromo-1-(2-methyl-3-((1-methylcyclopropyl)amino)-5-quinoxalinyl)ethanone (611) (14.6 g, 43.7 mmol), DMF (35 mL), THF (35 mL), ethyl (4R)-4-((tert-butoxycarbonyl)amino)-3-oxopentanoate (602) (13.7 g, 52.7 mmol) and K2CO3 (15.1 g, 109 mmol). The mixture was stirred at RT. After 4 h, the mixture was diluted with sat NaHCO3 and extracted with EtOAc (3×100 mL). The combined extracts were washed with water (2×100 mL) and brine (100 mL) and then dried (Na2SO4) and concentrated to afford ethyl (4S)-4-((tert-butoxycarbonyl)amino)-2-(2-(2-methyl-3-((1-methylcyclopropyl)amino)-5-quinoxalinyl)-2-oxoethyl)-3-oxopentanoate as a brown amorphous solid which was used without further purification. m/z (ESI, +ve) 513.2 (M+H)+. The brown amorphous solid was treated with EtOH (80 mL), AcOH (8.0 mL), and finally NH4OAc (10.1 g, 131 mmol). The mixture was stirred at RT for 12 h. The solution was partially concentrated and then was diluted with sat NaHCO3 and EtOAc. The phases were separated and the organic phase was washed with water, dried (Na2SO4) and concentrated onto silica. Purification by silica gel chromatography (half of the material was purified on a Redisep Gold 330 g column, 0-50% EtOAc/hexanes and the other half on an Interchim 300 g column, 25 micron, 10 to 35% isocratic at 35% EtOAc/Hex) afforded ethyl 2-(1-((tert-butoxycarbonyl)amino)ethyl)-5-(2-methyl-3-((1-methylcyclopropyl)amino)-5-quinoxalinyl)-1H-pyrrole-3-carboxylate (6.96 g, 14.1 mmol, 32% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.72 (br s., 1H), 7.87-7.96 (m, 2H), 7.59 (dd, J=8.0, 1.2 Hz, 1H), 7.47 (s, 1H), 7.33-7.40 (m, 1H), 7.06 (d, J=7.0 Hz, 1H), 5.32-5.45 (m, 1H), 4.17-4.28 (m, 2H), 2.47 (s, 3H), 1.57 (s, 3H), 1.32-1.44 (m, 12H), 1.28 (t, J=7.0 Hz, 3H), 0.91-1.05 (m, 2H), 0.80-0.91 (m, 2H). m/z (ESI, +ve) 494.1 (M+H)+.

Provenance & Evidence