Synthesis
Example 1. Preparation of methyl quinoline-6-acetate: Concentrated sulfuric acid (206 mL, 3.868 mol) was slowly added dropwise to a solution of 6-quinolineacetic acid (Compound 1001, 658.2 g, 3.516 mol, Okeanos Tech Co., Catalog No. OK-J-05024) dissolved in 6.5 L of methanol as shown in step i of Scheme 1. A slight exotherm was observed during the dropwise addition. After dropwise addition, the reaction mixture was stirred under reflux conditions for 4 hours. After completion of the reaction, it was cooled to room temperature and the volatile solvent was removed by distillation under reduced pressure. The residue was diluted with 4 L of ethyl acetate and cooled in an ice bath. Subsequently, the pH was adjusted to 4 with 2 N NaOH solution (2.1 L, 1.2 eq.) and then with saturated sodium bicarbonate solution to 8. The organic and aqueous layers were separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic phases were washed sequentially with saturated sodium bicarbonate solution, water and brine, and then dried with anhydrous MgSO4. After filtration, the solvent was evaporated under reduced pressure to give methyl quinoline-6-acetate (compound 1002, 696.8 g, 98% yield) as a clear brown oil: ESMS (M + 1), 202.14; 1H NMR (300.0 MHz, DMSO-d6) δ 8.90 (1H, dd, J = 1.7, 4.2 Hz), 8.14-8.10 (1H , m), 8.08 (1H, d, J = 8.7 Hz), 7.72 (1H, d, J = 1.4 Hz), 7.65 (1H, dd, J = 2.0, 8.7 Hz), 7.40 (1H, dd, J = 4.2, 8.3 Hz), 3.83 (2H, s), 3.73 (3H, s).
References
[1] Patent: WO2010/59668, 2010, A1. Location in patent: Page/Page column 20-21
[2] Patent: WO2016/8011, 2016, A1. Location in patent: Page/Page column 67
[3] Patent: WO2013/19682, 2013, A1. Location in patent: Page/Page column 117
[4] Patent: WO2008/144767, 2008, A1. Location in patent: Page/Page column 110; 115
[5] Journal of Medicinal Chemistry, 2013, vol. 56, # 17, p. 6651 - 6665
