Diisopropylethylamine → 2'-(3-((2,2-difluoroethyl)amino)-2-methylquinoxalin-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-(34(2,2-difluoroethyl)amino)-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylate (331b) (378 mg, 0.73 mmol) was converted to 2-(1-aminocyclopropyl)-5-(3-((2,2-difluoroethyl)amino)-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylic acid hydrochloride (331c: m/z (ESI, +ve) 388.1 (M+H)+) in a fashion similar to that described for Intermediate 324c. This material was used as crude. A suspension of 2-(1-aminocyclopropyl)-5-(3-((2,2-difluoroethyl)amino)-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylic acid hydrochloride (331c) in DMF (5 mL) and DCM (5 mL) at 0° C. was treated with DIEA (0.76 mL, 4.38 mmol) followed by (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (456 mg, 0.87 mmol). The ice bath was removed and the resulting mixture was stirred at RT for 18 h. It was treated with 20 G of ice, the yellow solid was filtered, washed sequentially with 5 mL of water, 5 mL of 0.5 N NaOH, 5 mL of water and 2×5 mL of DCM. The yellow solid was dried in a vacuum oven at 45° C. for 5 h to give 2′-(3-((2,2-difluoroethyl)amino)-2-methylquinoxalin-5-yl)-1′H-spiro[cyclopropane-1,6′-pyrrolo[3,4-b]pyrrol]-4′(5′H)-one (331) (179 mg, 0.48 mmol, 66% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.59 (1H, br.), 7.83 (1H, d, J=8.0 Hz), 7.65 (2H, m), 7.58 (1H, br.), 7.40 (1H, t, J=7.5 Hz), 6.85 (1H, s), 6.43 (0.25; H, m), 6.29 (0.5; H, m), 6.14 (0.25; H, m), 3.92 (2H, m), 2.57 (3H, s), 1.42 (2H, m), 1.38 (2H, m). 19F NMR (376 MHz, DMSO-d6) δ ppm −120.48. m/z (ESI, +ve) 370.1 (M+H)+.

Provenance & Evidence