Reaction Steps
To a solution of (3S)-3-[4-chloro-2-(morpholin-4-yl)-5,6-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-N-(2-hydroxy-2-methylpropyl)-3-methylpyrrolidine-1-carbothioamide (62 mg, 0.14 mmol) in ethanol (1.36 mL) was added diisopropylethylamine (52.2 μL, 0.30 mmol) and methyl iodide (28.1 μL, 0.45 mmol) followed by DCM (1.36 mL) at room temperature and the mixture was stirred for 24 h. Additional diisopropylethylamine (52.2 μL, 0.30 mmol) was added and stirring was continued for 1.5 h, whereupon additional methyl iodide (20.0 μL, 0.32 mmol) was added. After stirring for 25 h, the reaction mixture was partitioned between dichloromethane and 50% brine solution. The organic layer was separated, dried with Na2SO4, filtered and concentrated to give 4-chloro-7-[(3S)-1-(5,5-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)-3-methylpyrrolidin-3-yl]-2-(morpholin-4-yl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine (86 mg) which was used in the next step directly without purification. This material (86 mg, 0.14 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (45.4 mg, 0.21 mmol) were suspended in acetonitrile (2.74 mL) and argon was bubbled into the mixture. A 1 M solution of aqueous cesium fluoride (0.21 mL) and 1,1′-bis(di-tert-butylphosphino)ferrocene palladium dichloride (8.9 mg, 0.014 mmol) were added at room temperature. The argon line was removed and the reaction vessel was sealed. The reaction mixture was heated at 80° C. for 4 h, and allowed to cool to room temperature. The reaction mixture was then heated at 100° C. for 30 min in a microwave reactor and then heated to 120° C. for 15 min in a microwave reactor. After cooling to room temperature, argon was bubbled into the reaction mixture and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (20.0 mg, 0.092 mmol) and 1,1′-bis(di-tert-butylphosphino)ferrocene palladium dichloride (5 mg, 0.0079 mmol) were added. The argon line was removed and the reaction vessel was sealed. The reaction mixture was heated at 120° C. for 30 min in a microwave reactor. Additional 1,1′-bis(di-tert-butylphosphino)ferrocene palladium dichloride (5 mg, 0.0079 mmol) was added and the reaction mixture was heated at 120° C. for 30 min in a microwave reactor. The reaction mixture was partitioned between DCM (containing ˜5% ethanol) and 50% brine solution. The organic layer was separated, dried with Na2SO4, filtered and concentrated. The residue was purified by preparative HPLC (Phenomenex Gemini-NX C18 150×21.2 mm, 5 μm, 100A column) eluting with 18-50% acetonitrile containing 10 mM ammonium acetate with a flow rate of 40 mL/min to give the title compound (14 mg, 21%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.73 (s, 2 H), 6.60 (s, 2 H), 3.80 (d, J=10.7 Hz, 1 H), 3.67 (s, 8 H), 3.52-3.65 (m, 3 H), 3.30-3.44 (m, 4 H), 3.06-3.11 (m, 2 H), 2.41-2.48 (m, 1 H), 2.08 (ddd, J=12.4, 7.2, 5.1 Hz, 1 H), 1.34 (br s, 3 H), 1.34 (s, 3 H), 1.33 (s, 3 H). m/z (APCI+) for C24H33N9O4 480.2 (M+H)+.
