Diisopropylethylamine → N4-((2-(2-chlorophenyl)-8-methylquinolin-3-yl)methyl)-5-(trifluoromethyl)-pyrimidine-2,4-diamine

Participants

Reaction Conditions

Reaction Steps

A mixture of (2-(2-chlorophenyl)-8-methylquinolin-3-yl)methanamine (81.1 mg, 0.261 mmol), 2,4-dichloro-5-(trifluoromethyl)pyrimidine (51.6 mg, 0.261 mmol), and DIEA (0.09 mL, 0.52 mmol, 2 eq) in 1-pentanol (1.3 mL) was stirred at 80° C. for 30 min. The mixture was transferred to a pressure vessel and ammonia gas was bubbled through the mixture at rt for 15 min. The mixture was stirred at 100° C. 14 h. The mixture was concentrated under reduced pressure. The crude product was purified by column chromatography on a 40 g of Redi-Sep™ column using 0 to 100% gradient of EtOAc in hexane over 14 min as eluent to provide N4-((2-(2-chlorophenyl)-8-methylquinolin-3-yl)methyl)-5-(trifluoromethyl)-pyrimidine-2,4-diamine [PI3Kδ IC50=127 nM] as light yellow solid (Example 3) and N2-((2-(2-chlorophenyl)-8-methylquinolin-3-yl)methyl)-5-(trifluoromethyl)-pyrimidine-2,4-diamine [PI3Kδ IC50=2825 nM] (Example 4) as light yellow solid. For Example 3: 1H NMR (DMSO-d6) δ ppm 8.12 (1H, s), 8.01 (1H, d, J=0.8 Hz), 7.82 (1H, d, J=8.2 Hz), 7.43-7.65 (6H, m), 7.17 (1H, t, J=5.7 Hz), 6.57 (2H, br. s.), 4.51 (2H, t, J=5.9 Hz), 2.65 (3H, s); Mass Spectrum (ESI) m/e=444.1 (M+1). For Example 4: 1H NMR (DMSO-d6) δ ppm 8.17-8.28 (1H, m), 8.00 (1H, s), 7.85 (1H, d, J=7.8 Hz), 7.23-7.72 (7H, m), 6.68 (2H, s), 4.39 (2H, s), 2.65 (3H, s); Mass Spectrum (ESI) m/e=444.1 (M+1).

Provenance & Evidence