4-Chloro-6-hydroxyquinoline

Synthesis

General procedure for the synthesis of 4-chloro-6-hydroxyquinoline from 4-chloro-6-methoxyquinoline: 1. Synthesis of 4-chloro-6-hydroxyquinoline: To a stirred solution of 4-chloro-6-methoxyquinoline (500 mg, 2.5 mmol) in dichloromethane (DCM, 10 mL) was added an aqueous solution of hydriodic acid (HI) (5 mL, 45%). The reaction mixture was heated to 100 °C and stirred for 5 hours. Upon completion of the reaction, the solution was cooled to room temperature and diluted by adding water (20 mL). The organic phase was separated, the aqueous phase was alkalized and extracted with dichloromethane (DCM, 30 mL x 3). The organic phases were combined, washed sequentially with water and brine, dried over anhydrous sodium sulfate (Na2SO4), filtered, and concentrated in vacuum to give 4-chloro-6-hydroxyquinoline (300 mg, 67% yield) as a white solid, which was used directly in the next step of the reaction. lc-MS (ESI) m/z = 180.3 ([M + H]+). 2. Synthesis of 2-((4-chloroquinolin-6-yl)oxy)acetonitrile: Bromoacetonitrile (240 mg, 2.0 mmol) and cesium carbonate (Cs2CO3, 350 mg, 2.5 mmol) were added to a solution of 4-chloro-6-hydroxyquinoline (300 mg, 1.7 mmol) obtained above in N,N-dimethylformamide (DMF, 10 mL). The reaction mixture was heated to 60 °C and stirred for 3 hours. After the reaction was completed, the solution was cooled to room temperature and diluted by adding water (50 mL). It was extracted with ethyl acetate (EtOAc, 50 mL x 3), and the organic phases were combined, washed sequentially with water and brine, dried over anhydrous sodium sulfate (Na2SO4), filtered, and concentrated in vacuo to give 2-((4-chloroquinolin-6-yl)oxy)acetonitrile (300 mg, 81% yield) as an off-white solid. lc-MS (ESI) m/z = 219.1 ([M + H]+) . 3. The target product 30 was obtained as an off-white solid by using 2-((4-chloroquinolin-6-yl)oxy)acetonitrile in step 1 according to General Method A. 1H NMR (400 MHz, CD3OD) δ 8.49 (d, J = 4.9 Hz, 1H), 7.95 (d, J = 9.2 Hz, 1H), 7.65 (d, J = 2.8 Hz, 1H). 7.51 (dd, J = 9.2,3.0 Hz, 1H), 7.44 (d, J = 4.4 Hz, 1H), 5.20 (s, 2H), 2.97-3.02 (m, 2H), 2.27-2.41 (m, 3H), 2.05-2.08 (m, 1H).LC-MS (ESI) m/z = 313.1 ([M - H]-).

References

[1] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 2, p. 277 - 282
[2] Journal of the American Chemical Society, 1947, vol. 69, p. 1659,1660
[3] Justus Liebigs Annalen der Chemie, 1950, vol. 568, p. 73,79
[4] Patent: US5506235, 1996, A
[5] Patent: KR2016/6207, 2016, A. Location in patent: Paragraph 0516; 0519-0522