Hydrochloric Acid → HCID 71730240, compound

Participants

Reaction Conditions

Reaction Steps

A solution of ethyl 2-(1-((tert-butoxycarbonyl)amino)cyclopropyl)-5-(3-(cyclopropylamino)-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylate (325c; 190 mg, 0.39 mmol) in 2 mL of dioxane and 1.5 mL of water was added LiOH hydrate (81 mg, 1.93 mmol) and heated in a microwave at 110° C. for 80 min. It was lyophilized to give a yellow solid. m/z (ESI, +ve) 464.1 (M+H)+. To the yellow solid suspended in 3 mL of dioxane was added 3 mL of 4 N HCl in dioxane and stirred at RT for 1.5 h. The reaction mixture was concentrated to half of its volume. The insoluble solid was filtered, rinsed with 2×3 mL of hexanes/ether in 1/1 ratio. The filtrate was discarded. The orange solid was dried in a vacuum oven at RT for 18 h to 2-(1-aminocyclopropyl)-5-(3-(cyclopropylamino)-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylic acid hydrochloride (325d). m/z (ESI, +ve) 364.1 (M+H)+. This material was used as crude. At 0° C., a suspension of 2-(1-aminocyclopropyl)-5-(3-(cyclopropylamino)-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylic acid hydrochloride (325d) in 8 mL of DMF and 8 mL of DCM was sequentially treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (146 mg, 0.76 mmol), 1-hydroxybenzotriazole (103 mg, 0.76 mmol) and DIEA (0.40 mL, 2.28 mmol). The homogeneous reaction mixture was stirred at RT for 18 h. It was diluted with 100 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) to give 2′-(3-(cyclopropylamino)-2-methylquinoxalin-5-yl)-1′H-spiro[cyclopropane-1,6′-pyrrolo[3,4-b]pyrrol]-4′(5′H)-one (325) (86 mg, 60% yield) as a yellow crystalline solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.31 (1H, br.), 7.97 (1H, dd, J=7.5, 1.3 Hz), 7.69 (1H, s), 7.62 (1H, dd, J=8.0, 1.2 Hz), 7.51 (1H, d, J=2.2 Hz), 7.38 (1H, t, J=7.8 Hz), 7.19 (1H, d, J=1.4 Hz), 2.94 (1H, dd, J=6.5, 3.7 Hz), 2.53 (3H, s), 1.45 (2H, m), 1.35 (2H, m), 0.817 (2H, m), 0.68 (2H, m). m/z (ESI, +ve) 346.1 (M+H)+.

Provenance & Evidence