Hydrochloric Acid → 6-Amino-4-(3-chloro-4-fluoroanilino)-3-cyano-7-ethyloxyquinoline

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A stirred mixture of N-(4-chloro-3-cyano-7-ethoxy-6N-acetylquinoline (274.5 g, 0.947 mol), 3-chloro-4-fluoroaniline (180 g, 1.24 mol), methanesulfonic acid, (5.5 g, 0.057 mol), and 2-propanol (6.7 L) was warmed to reflux (84° C.) for 6.5 hours. After stirring overnight at room temperature, the mixture was warmed to 80° C. Water (3.2 L) containing concentrated hydrochloric acid (655 mL of 38% aqueous HCl) was added. The reaction was kept at reflux for 5 hours. The reaction mixture was cooled to 0° C.-10° C. for 1 hour. The yellow solid product is collected by vacuum filtration and washed with 20% 2-propanol/water (700 mL) and water (2×700 mL). Drying the product in vacuo at 60° C. gave 344.8 g (91%, 99% by HPLC) of 6-Amino-4-(3-chloro-4-fluoro-phenylamino)-7-ethoxy-quinoline-3-carbonitrile as a hydrochloride salt. 1H NMR (DMSO-d6+D2O) δ1.42 (t, 3H), 4.25 (q, 2H), 7.05 (m, 1H), 7.1 (s, 1H), 7.35-7.50 (m, 3H), 7.65 (dd, 1H), 8.65 (s, 1H).

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