Sodium Carbonate → 4-[5-(3-Methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]-1,4-diazepan-2-one

Participants

Reaction Conditions

Reaction Steps

N-[3-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-4-(trifluoromethyl)-pyrimidin-2-amine (Intermediate IV, 35.4 g, 93 mmol) and 4-(5-bromo-1,3-thiazol-2-yl)-1,4-diazepan-2-one (21.5, 78 mmol) were combined in a 2 L RB flask follwed by DMF (473 mL) and aqueous Na2CO3 solution (1 M, 311 mL). The solution was sparged with N2 for 15 minutes and then [Pd(Ph3P)4](3.6 g, 3.11 mmol) was added. The mixture was heated at 85° C. for 12-15 hours. The reaction was cooled to 0° C. and saturated NH4Cl (500 mL) was added followed by EtOAc (2 L) and DCM (2 L). The aqueous layer was extracted with DCM (1 L) and the combined organic layer was washed with 10% aqueous LiCl solution (1 L) and then dried over Na2SO4. The organic layer was concentrated and slurried in MTBE (500 mL) and filtered. The solid was then dissolved in THF (870 mL), degassed and then treated with 300 wt % Silicycle Si-triamine resin at 40° C. for 1 hour. The suspension was then filtered, the residue washed with 40° C. THF (400 mL) and concentrated. A final slurrying in MTBE (200 mL) for 1.5 hours, filtration and drying gave 13.1 g of 4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]-1,4-diazepan-2-one (37%). MS APCI: [M+H]+ m/z 449.2. 1H NMR (600 MHz, DMSO-d6): δ 10.14 (s, 1H), 8.79 (d, J=6.0 Hz, 1H); 7.77 (s, 1H), 7.57 (t, J=4.7 Hz, 1H); 7.44 (s, 1H); 7.34 (s, 1H); 7.23 (d, J=4.9 Hz, 1H); 6.9 (s, 1H), 4.19 (s, 2H); 3.76 (m, 2H); 3.19 (m, 2H); 2.26 (s, 3H), 1.76 (m, 2H). rhSyk=+++

Provenance & Evidence