Reaction Steps
Benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP) (AK Scientific, Inc., Union City, Calif.) (431 mg, 0.83 mmol) was added to a solution of 2-(1-aminoethyl)-5-(2-methyl-3-((2,2,2-trifluoroethyl)amino)quinoxalin-5-yl)-1H-pyrrole-3-carboxylic acid hydrochloride (293c) (274 mg, 0.64 mmol) and DIPEA (0.44 mL, 2.55 mmol) in CH2Cl2 (16 mL) and DMF (16 mL) at RT. After 30 min the reaction mixture was concentrated. The residue was diluted with EtOAc and washed sequentially with water, saturated NaHCO3 (aq.) and brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated. The crude material was absorbed onto a plug of silica gel and purified by silica gel chromatography (0-5% MeOH in CH2Cl2), to provide rac-6-methyl-2-(2-methyl-3-((2,2,2-trifluoroethyl)amino)quinoxalin-5-yl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (293d) (100 mg, 0.27 mmol, 42% yield) as a yellow solid. The mixture of enantiomers was subjected to chiral SFC (ChiralPak AS-H (21×250, 5 μm); additive in supercritical fluid CO2 was 25% MeOH with 20 mM NH3; 75 mL/min; column temperature 40° C.; outlet pressure 100 bar) to give separated enantiomers. Example 293 (first eluting peak): (S)-6-methyl-2-(2-methyl-3-((2,2,2-trifluoroethyl)amino)quinoxalin-5-yl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (3 mg, 7.99 μmol, 1% yield, >99% ee) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.83-11.95 (m, 1H), 7.86-7.93 (m, 1H), 7.74 (t, J=6.26 Hz, 1H), 7.68 (dd, J=8.12, 1.47 Hz, 1H), 7.64 (d, J=0.39 Hz, 1H), 7.44 (t, J=7.82 Hz, 1H), 6.85-6.92 (m, 1H), 4.52-4.66 (m, 1H), 4.16-4.33 (m, 1H), 4.09 (q, J=5.15 Hz, 1H), 2.60 (s, 3H), 1.39 (d, J=6.65 Hz, 3H). 19F NMR (376 MHz, DMSO-d6) δ ppm −69.51 (s, 3F). m/z (ESI, +ve) 376.1 (M+H); and Example 294 (second eluting peak): (R)-6-methyl-2-(2-methyl-3-((2,2,2-trifluoroethyl)amino)quinoxalin-5-yl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (44 mg, 0.12 mmol, 18% yield, >99% ee). m/z (ESI, +ve) 376.1 (M+H)+.
