4-chloro-7-Methoxyquinoline-6-carboxaMide

4.1) In a 500 mL three-necked flask in which ammonia (200 mL, 5.2 mol) is placed, the compound IV (10 g, 39.8 mmol) obtained in the step 3.3) is added to obtain a mixture H;4.2) The mixture H obtained in step 4.1) was placed at 60 ° C, after 4 h reaction, cooled to room temperature to obtain a mixture I;4.3) Adding dichloromethane to the mixture I and extracting three times to obtain a pale yellow compound V (yield 85.17percent)Methyl 4-chloro-7-methoxy-quinoline-6-carboxylate (120 mg) was dissolved in methanol (6 ml), 28percent aqueous ammonia (6 ml) was added thereto, and the mixture was stirred at 40°C overnight. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography with a methanol-chloroform system to give 4-chloro-7-methoxy-quinoline-6-carboxylic acid amide (91 mg, yield 80percent). 4-Chloro-7-methoxy-quinoline-6-carboxylic acid amide (91 mg), 5, 6-dimethyl-[2, 2']bipyridinyl-3-ol (115 mg), and 4-dimethylaminopyridine (141 mg) were dissolved in dimethylsulfoxide (3 ml), cesium carbonate (375 mg) was added to the solution, and the mixture was stirred overnight at 130°C. The mixture was cooled to room temperature, and water was added to the reaction mixture. The organic layer was extracted with chloroform, and the chloroform layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography with a methanol-chloroform system to give the title compound (33 mg, yield 22percent). 218 g of 6-cyano-7-methoxy-4-chloroquinoline, dissolved in acetic acid solution, glacial acetic acid and The volume ratio of water was 1:1500, and the mixture was heated to 90 C for 23 hours. After the reaction was completed, 222 g of the white solid of was operated.The synthesis method can refer to Example 1, and the equivalent ratio and the reaction conditions in step (1) and step (2) are unchanged.Step (3) Compound (I-2e) (8.36 g, 0.024 mol) and (3) Compound (I-1e) (7.54 g, 0.024 mol) and Weigh 1 ml of purified water into the reaction flask, and weigh potassium hydroxide (0.71g) into the reaction flask, stir until dissolved, add 9ml DMSO, stir, will4-((2-Chloro-4-hydroxyphenyl)amino)-7-methoxyquinoline-6-carboxamide(2.18 g) and 4-chloro-7-methoxyquinolin-6-amide (1.0 g) were sequentially added to a reaction flask, and the mixture was heated to 110 ° C and stirred for 2 hours.The reaction was monitored by TLC (developing solvent: dichloromethane: isopropyl alcohol = 20:1, 4-(4-((6-carbamoyl-7-methoxyquinolin-4-yl)amino)-3-chlorophenoxy)-7-methoxyquinolin-6-carboxamide Rf value 0.2), 3 ml of acetone and 27 ml of purified water were added to the reaction solution.Cool down to room temperature, Stirring for 2 hours, Filtration, the filter cake was dissolved in 20 ml of ethyl acetate / methanol (1:1 by volume).After stirring at room temperature, methyl tert-butyl ether (60 ml) was added for crystallization.filterTarget productLuvutinib mesylate impurity 4-(4-((6-carbamoyl-7-methoxyquinolin-4-yl)amino)-3-chlorophenoxy)-7-methoxy Quinoline-6-carboxamide (1.96 g), The yield was 85.2percent, and the HPLC purity was 99percent.4-Chloro-7-methoxyquinolin-6-amide (10g) and4-amino-3-chlorophenol hydrochloride (11.5 g), Potassium iodide (25 g) was added to the reaction flask, and ethanol (150 ml) was added thereto, and the mixture was stirred and heated to reflux.Stir the reaction for 20 hours, The reaction was monitored by TLC (developing solvent: dichloromethane: methanol = 10:1, 4-((2-chloro-4-hydroxyphenyl)amino)-7-methoxyquinoline-6-carboxamide, Rf value 0.3), The reaction solution was cooled to room temperature, and water (450 ml) was added to stir and crystallize for 2 hours.filterThe target product was 13.5 g (mass yield 135percent), The HPLC purity was 98.7percent.Compound 4 (1.8 g, 7.63 mmol), NMP (40 mE), Compound la (1.797 g, 11.45 mmol) and DIPEA(5.9 g, 45.78 mmol) were sequentially added to a 150 mE three-necked flask. The mixture was heated to 160 C. for 2 hours. Afier cooling to room temperature, the reaction mixture was added to water to precipitate a solid. The mixture was filtered, and the filter cake was washed with water and dried to give Intermediate 5 (2.2 g, 80% yield) as a gray solid. ECMS showed a molecular ion peak mIz[MH]: 358.1.

Molecular Weight:236.65
XLogP3:1.7
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:2
Exact Mass:236.0352552
Monoisotopic Mass:236.0352552
Topological Polar Surface Area:65.2
Heavy Atom Count:16
Complexity:275
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes