Diisopropylethylamine → 2'-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-1'H-spiro[cyclopropane-1,6'-pyrrolo[3,4-b]pyrrol]-4'(5'H)-one

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Reaction Steps

A solution of ethyl 2-(1-((tert-butoxycarbonyl)amino)cyclopropyl)-5-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylate (324b) (1.1 g, 2.16 mmol) in 8 mL of dioxane and 8 mL of water was added LiOH monohydrate (0.45 g, 10.83 mmol) and heated in an oil bath at 110° C. for 18 h. It was concentrated under reduced pressure to half of its volume. The remaining mixture was lyophilized for 24 h to give a yellow solid. m/z (ESI, +ve) 480.2 (M+H)+. To the yellow solid suspended in 5 mL of dioxane at 0° C. was treated with 10 mL of 4 N HCl in dioxane. The resulting orange mixture was stirred at RT for 3 h. The mixture was concentrated to half of its volume. The insoluble solid was filtered, rinsed with 2×5 mL of ether. The filtrate was discarded. The orange solid was dried in a vacuum oven at 40° C. for 1 h to give 2-(1-aminocyclopropyl)-5-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylic acid hydrochloride (324c), which was used as crude material and based on theoretical yield. m/z (ESI, +ve) 380.2 (M+H)+. A suspension of the above obtained 2-(1-aminocyclopropyl)-5-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylic acid hydrochloride (324c) in 12 mL of DMF and 12 mL of DCM was treated with DIEA (2.25 mL, 12.93 mmol) followed by (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (1.40 g, 2.70 mmol). The resulting homogeneous solution was stirred at RT for 2 h. It was diluted with 200 mL of DCM, washed sequentially with 25 mL of water, 25 mL of 1 N NaOH and 25 mL of brine. The organic solution was concentrated and the residue was purified on a silica gel column (50% EtOAc in hexanes followed by 1-3% MeOH in EtOAc) to give 2′-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-1′H-spiro[cyclopropane-1,6′-pyrrolo[3,4-b]pyrrol]-4′(5′H)-one (324) (540 mg, 1.494 mmol, 69% yield) as a yellow crystalline solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.64 (1H, br.), 7.78 (1H, d, J=6.5 Hz), 7.67 (1H, s), 7.60 (1H, m), 7.35 (1H, t, J=7.8 Hz), 6.90 (1H, m), 6.00 (1H, s), 2.56 (3H, s), 1.52 (9H, s), 1.42 (2H, m), 1.33 (2H, m). m/z (ESI, +ve) 362.1 (M+H)+.

Provenance & Evidence