반응 단계
A mixture of 4-(5-chloro-4-(3-methylpiperidin-4-yloxy)-2-oxopyridin-1(2H)-yl)-2-fluorobenzonitrile hydrochloride (159 mg, 0.399 mmol), 2-chloro-5-cyclopropylpyrimidine (67.9 mg, 0.439 mmol) and potassium carbonate (221 mg, 1.597 mmol) in DMSO (1.5 mL) was heated at 90-110° C. for 40 hrs and then additional potassium carbonate (110 mg, 0.788 mmol) was added. The resulting mixture was continuously heated at 100° C. overnight and then partitioned between EtOAc and water. The aqueous layer was extracted further with EtOAc (3×). The combined organic extracts were washed with water and brine, dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (0-100% EtOAc/hexane) to yield cis-4-(5-chloro-4-(1-(5-cyclopropylpyrimidin-2-yl)-3-methylpiperidin-4-yloxy)-2-oxopyridin-1(2H)-yl)-2-fluorobenzonitrile (10.2 mg, 5%, top spot on TLC plate) as a light yellow solid and to yield trans-4-(5-chloro-4-(1-(5-cyclopropylpyrimidin-2-yl)-3-methylpiperidin-4-yloxy)-2-oxopyridin-1(2H)-yl)-2-fluorobenzonitrile (34.4 mg, 15%, bottom spot on TLC plate) as a light yellow solid. Cis-isomers: 1H NMR (500 MHz, CDCl3) δ ppm 8.13 (s, 2H), 7.76 (t, J=7.42 Hz, 1H), 7.36-7.41 (m, 2H), 7.33 (d, J=8.25 Hz, 1H), 6.04 (s, 1H), 4.48-4.62 (m, 2H), 4.16 (td, J=8.80, 3.85 Hz, 1H), 3.19-3.29 (m, 1H), 2.98 (dd, J=13.75, 9.90 Hz, 1H), 2.18-2.30 (m, 1H), 2.01-2.12 (m, 1H), 1.63-1.77 (m, 2H), 1.08 (d, J=6.60 Hz, 3H), 0.89-0.95 (m, 2H), 0.57-0.62 (m, 2H). MS (ESI) 480 (M+H). Trans-isomers: 1H NMR (500 MHz, CDCl3) δ ppm 8.13 (s, 2H), 7.76 (t, J=7.42 Hz, 1H), 7.36-7.43 (m, 2H), 7.33 (d, J=8.25 Hz, 1H), 6.03 (s, 1H), 4.58 (app br s, 1H), 4.29-4.42 (m, 2H), 3.28-3.40 (m, 2H), 2.01-2.17 (m, 2H), 1.77-1.89 (m, 1H), 1.68-1.77 (m, 1H), 0.99-1.12 (m, 3H), 0.85-0.97 (m, 2H), 0.51-0.63 (m, 2H). MS (ESI) 480 (M+H).
