8-amino-2-methyl-3,4-dihydroisoquinolin-1-one

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of 8-amino-2-methyl-3,4-dihydroisoquinolin-1-one (23.06 mg, 0.13 mmol), N-(1,3-dimethylpyrazol-4-yl)-4-iodo-5-(trifluoromethyl)pyridin-2-amine (50 mg, 0.13 mmol, Ex. 2.02), palladium(II) acetate (1.469 mg, 6.54 μmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (7.57 mg, 0.01 mmol) and cesium carbonate (85 mg, 0.26 mmol) in dioxane (1 ml) was stirred at 80° C. overnight under nitrogen. The same reactants were dissolved in DMA (1 mL) and sealed into a microwave tube. Argon was bubbled through the reaction mixture then the reaction was heated to 150° C. over a period of 30 minutes in a microwave reactor. The crudes were combined, poured onto a silica gel column and purified by flash chromatography eluting with 0 to 5% MeOH in EtOAc/DCM (1:1). The solvent was evaporated to dryness. Trituration with a few drops of MeCN gave a solid which was taken up into Et2O, collected by filtration and dried to afford the title compound (19 mg, 33.7%) as a white solid. 1H NMR spectrum (500 MHz, CDCl3): 2.16 (s, 3H), 2.90-2.99 (m, 2H), 3.14 (s, 3H), 3.51-3.58 (m, 2H), 3.79 (s, 3H), 5.94 (s, 1H), 6.42 (s, 1H), 6.90 (d, 1H), 7.20 (dd, 1H), 7.29 (d, 1H), 7.37 (s, 1H), 8.26 (s, 1H), 11.13 (s, 1H); Mass spectrum: ESI+ MH+ 431. sealed into a microwave tube Argon was bubbled through the reaction mixture the reaction was heated to 150° C. over a period of 30 minutes in a microwave reactor poured onto a silica gel column purified by flash chromatography eluting with 0 to 5% MeOH in EtOAc/DCM (1:1) The solvent was evaporated to dryness Trituration with a few drops of MeCN gave a solid which collected by filtration dried

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 8-amino-2-methyl-3,4-dihydroisoquinolin-1-one (1.369 g, 7.77 mmol), cesium carbonate (5.06 g, 15.54 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.270 g, 0.47 mmol), palladium(II) acetate (0.070 g, 0.31 mmol) were added in order to a mixture of 2-chloro-5-fluoro-4-iodopyridine (2.000 g, 7.77 mmol) in dioxane (150 mL) at 20° C. under an atmosphere of nitrogen. The resulting suspension was heated at 80° C. for 4 hours and then left to stand at room temperature overnight. The mixture was filtered through Celite and the residue washed with CH2Cl2 (20 mL). The filtrate was evaporated and the residue dissolved in CH2Cl2 (100 mL) and then washed sequentially with water (2×150 mL) and a saturated solution of NaCl (100 mL). The organic layer was dried over Na2SO4 and then evaporated to leave a solid. The solid was triturated with Et2O and then dried under vacuum to afford 8-[(2-chloro-5-fluoropyridin-4-yl)amino]-2-methyl-3,4-dihydroisoquinolin-1-one (2.117 g, 89% yield); 1H NMR spectrum (300 MHz, DMSO): δ 2.97 (2H, t), 3.06 (3H, s), 3.57 (2H, t), 6.97 (1H, dd), 7.42 (1H, d), 7.47-7.49 (2H, m), 8.26 (1H, d), 11.66 (1H, s); Mass spectrum: m/z (ESI+) (M+H)+ =306.39 and 308.36. left The mixture was filtered through Celite the residue washed with CH2Cl2 (20 mL) The filtrate was evaporated the residue dissolved in CH2Cl2 (100 mL) washed sequentially with water (2×150 mL) The organic layer was dried over Na2SO4 evaporated to leave a solid The solid was triturated with Et2O dried under vacuum

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Palladium(II) acetate (0.093 g, 0.41 mmol) was added to 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.360 g, 0.62 mmol), cesium carbonate (6.76 g, 20.74 mmol), 2,5-dichloro-4-iodopyridine (2.84 g, 10.37 mmol) and 8-amino-2-methyl-3,4-dihydroisoquinolin-1-one (1.827 g, 10.37 mmol) in dioxane (100 mL) under an atmosphere of nitrogen. The resulting suspension was heated at 80° C. for 18 hours then allowed to cool to room temperature. The mixture was filtered and then evaporated. The residue was dissolved in EtOAc (100 mL), and washed sequentially with a saturated solution of NaHCO3 (50 mL), water (50 mL), and finally with a saturated solution of NaCl (50 mL). The organic layer was separated, dried over MgSO4, and then evaporated. The residue was triturated with Et2O to leave a solid. The solid was purified by chromatography on silica, eluting with a gradient of 0-5% MeOH in CH2Cl2. Fractions containing product were combined and evaporated to afford 8-[(2,5-dichloropyridin-4-yl)amino]-2-methyl-3,4-dihydroisoquinolin-1-one (2.398 g, 72% yield); 1H NMR spectrum: (300 MHz, DMSO) δ 2.97 (2H, t), 3.05 (3H, s), 3.57 (2H, t), 7.00 (1H, m), 7.34 (1H, s), 7.44-7.51 (2H, m), 8.31 (1H, s), 11.63 (1H, s); Mass spectrum: m/z (ESI+) (M+H)+=322.29 and 324.28 and 326.29. to cool to room temperature The mixture was filtered evaporated The residue was dissolved in EtOAc (100 mL) washed sequentially with a saturated solution of NaHCO3 (50 mL), water (50 mL) The organic layer was separated dried over MgSO4 evaporated The residue was triturated with Et2O to leave a solid The solid was purified by chromatography on silica eluting with a gradient of 0-5% MeOH in CH2Cl2 Fractions containing product evaporated