Reaction Steps
A glass microwave reaction vessel was charged with 6-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (472a, 500 mg, 1.91 mmol) and 2-(tert-butylamino)-8-iodo-3-methylquinazolin-4(3H)-one (701) (681 mg, 1.91 mmol) in 1,4-dioxane (6.0 mL)/water (1.5 mL) followed by K3PO4 (1215 mg, 5.72 mmol), Xphos (91 mg, 0.191 mmol, Sigma-Aldrich) and Pd2dba3 (87 mg, 0.095 mmol, Strem). The reaction mixture was stirred and heated in a Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc.) at 105° C. for 45 min. The mixture was cooled to RT and EtOAc (50 mL) was added. The layers were separated and the aqueous layer was extracted with EtOAc (40 mL×2). The combined organic layers were dried (MgSO4), filtered and concentrated. The reaction was repeated on a 1000 mg scale and the residues were combined and purified with silica gel chromatography (eluted with 1-4% MeOH in DCM) to give 2-(tert-butylamino)-3-methyl-8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)quinazolin-4(3H)-one (472b, 740 mg, 36% yield) as a yellow solid. MS (ESI, pos. ion) m/z: 366 (M+1). This material was subjected to chiral SFC to give two eluents: the first eluent was Example 450 (530 mg); the second eluent was (S)-2-(tert-butylamino)-3-methyl-8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)quinazolin-4(3H)-one (472) (110 mg) as a tan solid. The SFC conditions were: [AS-H (Sum, 21 mm×25 cm, S/N=1071) with 45% organic modifier: 55% carbon dioxide, organic modifier: MeOH with 20 mM ammonia. Flow rate=50 mL/min]. The analytical data for (S)-2-(tert-butylamino)-3-methyl-8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)quinazolin-4(3H)-one (472) was: MS (ESI, pos. ion) m/z: 366.2 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 11.94 (1H, br. s.), 7.79-7.97 (2H, m), 7.61 (1H, s), 7.18 (1H, t, J=7.7 Hz), 6.72 (1H, d, J=1.4 Hz), 5.95 (1H, s), 4.53 (1H, q, J=6.6 Hz), 3.48 (3H, s), 1.51 (9H, s), 1.37 (3H, d, J=6.7 Hz).
