Dimethylformamide → HCID 89783847, compound

Participants

Reaction Steps

Ethyl 2-(1-((tert-butoxycarbonyl)amino)cyclopropyl)-5-(6-fluoro-2-methyl-3-((1-methylcyclopropyl)amino)quinoxalin-5-yl)-1H-pyrrole-3-carboxylate (378a) (455 mg, 0.87 mmol, 42% yield) as yellow foam was prepared according to the procedures described for Intermediate 283d, using 2-bromo-1-(6-fluoro-2-methyl-3-((1-methylcyclopropyl)amino)quinoxalin-5-yl)ethanone (610) (735 mg, 2.087 mmol), ethyl 3-(1-((tert-butoxycarbonyl)amino)cyclopropyl)-3-oxopropanoate (604) (849 mg, 3.13 mmol) as the stratingmaterials, followed by the subsequent treatment of the resulting ethyl 2-(1-((tert-butoxycarbonyl)amino)cyclopropanecarbonyl)-4-(6-fluoro-2-methyl-3-((1-methylcyclopropyl)amino)quinoxalin-5-yl)-4-oxobutanoate (610 mg, 54% yield as a viscous yellow oil; m/z (ESI, +ve ion) 543.2 (M+H)+) with NH4OAc (965 mg, 12.52 mmol) in EtOH (2.5 mL) and HOAc (2.5 mL). 19F NMR (376 MHz, CDCl3) δ ppm −108.30 (1F, s). m/z (ESI, +ve ion) 524.3 (M+H)+. To a suspension of ethyl 2-(1-((tert-butoxycarbonyl)amino)cyclopropyl)-5-(6-fluoro-2-methyl-3-((1-methylcyclopropyl)amino)quinoxalin-5-yl)-1H-pyrrole-3-carboxylate (378a) (450 mg, 0.86 mmol) in dioxane (6 mL) and water (3.00 mL) was treated with LiOH monohydrate (144 mg, 3.44 mmol) and heated to 110° C. for 1.5 h. LC-MS indicated ca. 40% conversion to the carboxylic acid. The reaction mixture was treated with another 50 mg of LiOHH2O and heated again at 110° C. for another 2.5 h. The reaction mixture was transferred to a 250 mL RBF and the volatiles were removed under reduced pressure. The residue was treated with 4 M HCl in dioxane (12 mL) and stirred at RT for 1 h. The reaction mixture was concentrated to dryness on the rotovap affording 378b (m/z (ESI, +ve ion) 396.2 (M+H)+) as a bright orange solid, which was used in the subsequent step without further purification. To a solution of 1-(3-carboxy-5-(6-fluoro-2-methyl-3-((1-methylcyclopropyl)amino)quinoxalin-5-yl)-1H-pyrrol-2-yl)cyclopropanaminium chloride (371 mg, 0.859 mmol) was treated with DCM (15 mL) and DMF (15.00 mL) followed by DIEA (0.60 mL, 3.44 mmol) and (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (581 mg, 1.117 mmol). The reaction mixture was then stirred at RT for 10 min. It was diluted with 200 mL of DCM, washed with 20 mL of sat. NaHCO3 followed by 20 mL of brine. The organic solution was concentrated and the residue was purified a silica gel column (0-15% MeOH in DCM) affording the desired product, m/z (ESI, +ve ion) 378.2 (M+H)+, in about 95% pure. The material was washed with Et2O (6×15 mL) to remove the residual tri(pyrrolidin-1-yl)phosphine oxide (about 5%) (m/z (ESI, +ve ion) 258.2 (M+H)+) to provide 2′-(6-fluoro-2-methyl-3-((1-methylcyclopropyl)amino)quinoxalin-5-yl)-1′H-spiro[cyclopropane-1,6′-pyrrolo[3,4-b]pyrrol]-4′(5′H)-one (378) (193 mg, 0.51 mmol, 60% yield) as a light yellow crystalline solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.52 (1H, s), 7.77 (1H, s), 7.81 (1H, s), 7.65 (1H, dd, J=8.9, 6.0 Hz), 7.34 (1H, dd, J=11.9, 9.0 Hz), 7.00 (1H, d, J=2.3 Hz), 2.48 (3H, s), 1.45-1.52 (5H, m), 1.31-1.37 (2H, m), 0.90-0.97 (2H, m), 0.69-0.75 (2H, m). 19F NMR (376 MHz, DMSO-d6) δ ppm −108.46 (1F, s). m/z (ESI, +ve ion) 378.2 (M+H)+.

Provenance & Evidence