1-Hydroxybenzotriazole → 2'-(2-methyl-3-((1-methylcyclopropyl)amino)quinoxalin-5-yl)-1'H-spiro[cyclopropane-1,6'-pyrrolo[3,4-b]pyrrol]-4'(5'H)-one

Participants

Reaction Steps

Ethyl 2-(1-((tert-butoxycarbonyl)amino)cyclopropyl)-5-(2-methyl-3-((1-methylcyclopropyl)amino)quinoxalin-5-yl)-1H-pyrrole-3-carboxylate (329b) (925 mg, 1.829 mmol) was converted to 2-(1-aminocyclopropyl)-5-(2-methyl-3-((1-methylcyclopropyl)amino)quinoxalin-5-yl)-1H-pyrrole-3-carboxylic acid hydrochloride (329c: m/z (ESI, +ve) 378.1 (M+H)+) in a fashion similar to that described for Intermediate 324c. This material was used as crude. At RT, to a suspension of 2-(1-aminocyclopropyl)-5-(2-methyl-3-((1-methylcyclopropyl)amino)-quinoxalin-5-yl)-1H-pyrrole-3-carboxylic acid hydrochloride (329c) in 10 mL of DMF and 10 mL of DCM was sequentially added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (619 mg, 3.23 mmol), 1-hydroxybenzotriazole (436 mg, 3.23 mmol) and DIEA (1.77 mL, 10.20 mmol). The homogeneous reaction mixture was stirred at RT for 18 h. It was diluted with 80 mL of DCM, washed sequentially with 5 mL of water, 5 mL of 1 N NaOH and 5 mL of brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel chromatography (50-100% EtOAc in DCM followed by 1-5% MeOH in DCM) twice to give 2′-(2-methyl-3-((1-methylcyclopropyl)amino)quinoxalin-5-yl)-1′H-spiro[cyclopropane-1,6′-pyrrolo[3,4-b]pyrrol]-4′(5′H)-one (329) (192 mg, 30% yield) as a yellow crystalline solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.28 (1H, br.), 8.00 (1H, d, J=7.4 Hz), 7.73 (1H, s), 7.54-7.68 (2H, m), 7.36 (1H, t, J=7.8 Hz), 7.22 (1H, s), 2.52 (3H, s), 1.50 (3H, s), 1.48 (2H, m), 1.31 (2H, m), 0.94 (2H, m), 0.74 (2H, m). m/z (ESI, +ve) 360.2 (M+H)+.

Provenance & Evidence