Potassium Carbonate → 5-((4-chlorophenyl)(hydroxy)methyl)-1-methyl-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)-6-(3-(trifluoromethoxy)phenyl)pyrido[2,3-d]pyrimidine-2,4 (1H,3H)-dione

Participants

Reaction Conditions

Reaction Steps

To a mixture of 6-bromo-5-((4-chlorophenyl)(hydroxy)methyl)-1-methyl-3-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (See Compound 20, step 5, 120 mg, 0.22 mmol) and 3-(trifluoromethoxy)phenylboronic acid (60 mg, 0.33 mmol) in dioxane (3.2 ml) and water (0.8 mL) was added K2CO3 (92 mg, 0.67 mmol) and Pd(PPh3)4 (20 mg). The reaction was degassed with nitrogen (3×), heated at 100° C. for 18 h, cooled to RT, diluted with water (10 mL) then extracted with EA (2×10 mL). The combined organic layers were dried over Na2SO4 and concentrated to a residue which was purified by Prep TLC eluted with PE/EA (3:1) to give the intermediate 5-((4-chlorophenyl)(hydroxy)methyl)-1-methyl-3-(3-(tetrahydro-2H-pyran-2-yloxy) propyl)-6-(3-(trifluoromethoxy)phenyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (15 mg) as a white solid. The intermediate was dissolved in EtOH (3 mL) and acetyl chloride (0.3 mL) was added. The reaction was stirred at RT for 30 min then concentrated to a residue which was purified by Prep HPLC to give 5-((4-chlorophenyl)(hydroxy)methyl)-3-(3-hydroxypropyl)-1-methyl-6-(3-(trifluoromethoxy)phenyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (3 mg, 3% yield over 2 steps) as a white solid. 1H NMR (CDCl3) δ: 8.64 (s, 1H), 7.49 (t, J=8.0 Hz, 1H), 7.32 (d, J=8.4 Hz, 1H), 7.27 (d, J=7.2 Hz, 1H), 7.21-7.17 (m, 3H), 7.05 (d, J=8.0 Hz, 2H), 6.25 (s, 1H), 4.11-4.05 (m, 2H), 3.77 (s, 3H), 3.51 (t, J=6.4 Hz, 2H), 1.79-1.74 (m, 2H). LCMS: [M++Na] 558 and TR=3.048 min.

Provenance & Evidence