A mixture of 2,6-dichloropyrazine (25 g, 168 mmol), 4-((3-methyloxetan-3- yl)methoxy)-2-nitrobenzenamine (40 g, 168 mmol), palladium (II) acetate (1.5 g, 6.72 mmol), (±)-2,2-bis(diphenylphosphino)- 1 ,1 '-binaphinyl [(±)-BINAP] (4.18 g, 6.72 mmol) and cesium carbonate (76.7 g, 235.2 mmol) in toluene (800 ml_) was stirred at 90 0C under N2 for 23 h. The mixture was filtered through a pad of Celite and washed with EtOAc. The filtrate was evaporated under reduced pressure and the crude product was purified by flash chromatography on silica (EtOAc: petroleum ether = 1 :5) which gave the title compound 9a as a red solid (22.4 g, 37% yield).
Patent reference: WO2010016005 (Pfizer)
A mixture of (6-bromo-4H-benzo[d][l,3]oxazin-2-yl)-(R)-indan-l-yl-amine (172 mg, 0.5 mmol), commercially available 2-amino-6-trifiuoromethyl-pyridine (162 mg, 1.0 mmol), tert-Bu-XPhos (34 mg, 0.08 mmol), Pd2dba3 (18 mg, 0.02 mmol), sodium tert-butylate (53 mg, 0.55 mmol), tert-butanol (0.5 ml) and dioxane (3 ml) was heated in a sealed tube at 120°C for 16 h. The reaction mixture was poured into water (15 ml) and extracted with ethyl acetate (2 x 30 ml). The combined organic layers were washed with water (20 ml) and brine (20 ml), dried (magnesium sulfate) and evaporated. Further purification of the crude product by flash chromatography on silica gel (ethyl acetate/ heptane) yielded the title compound (127 mg, 60%) as light brown foam.
Patent reference: WO2010026110 (Roche)
To a mixture of 2,5-dichloro-N-(5-methyl- l-(tetrahydro-2H-pyran- 2-yl)-lH-pyrazol-3-yl)pyrimidin-4-amine (150 mg, 0.45 mmol), tert-butyl-4-(6- amino-4-methylpyridin-3-yl)piperidine-l-carboxylate (120 mg, 0.41 mmol), Xantphos (24 mg, 0.04 mmol) and cesium carbonate ( 270 mg, 0.82 mmol) in THF (4 mL) was added palladium acetate (5 mg, 0.02 mmol). The mixture was purged with nitrogen and the tube was sealed. The mixture was heated in an oil bath at 100°C for 5 h. The mixture was filtered and concentrated. The residue was purified with silica chromatography (70% ethyl acetate in hexanes) to afford tert-butyl 4-(6-(5-chloro-4- (5-methyl-l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-3-ylamino)pyrimidin-2- ylamino)-4-methylpyridin-3-yl)piperidine-l-carboxylate as a yellow solid.
Patent reference: WO2009158431 (GSK)
To a stirred suspension of the compound of preparation 105 (25.27g, 82mmol) and 6-chloro-2-methylpyridazin-3(2H)-one (12g, 83.0mmol) in degassed toluene (500mL) at RT were added cesium carbonate (111 g, 339mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)- bis[diphenyl phosphine] (6.23g, 10.8mmol). The reaction mixture was purged twice with nitrogen. Palladium (II) diacetate (813mg, 3.62mmol) was added and the reaction was stirred under nitrogen at 115°C for 16h. The reaction mixture was filtered under reduced pressure and the residue was washed with 20ml toluene. The filtrate was concentrated in vacuo to give crude product residue. Purification by column chromatography on silica gel using heptane: ethyl acetate (gradient from 7:3 to pure EtOAc to EtOAc: MeOH, 95:5) gave 23.85g (83%) of the title compound as a yellow oil.
Patent reference: WO2010015972 (Pfizer)