ETHYL 4-HYDROXY-6-METHOXYQUINOLINE-3-CARBOXYLATE

b) Ethyl 4-hydroxy-6-(methyloxy)-3-quinolinecarboxylate; Diethyl ({[4-(methyloxy)phenyl]amino}methylidene)propanedioate (100 g, 0.34 mol) was taken up in Dowtherm (500 mL) and heated at 250 0C for 1.5 h; 75percent conversion. The reaction solution was cooled, treated with hexanes (750 mL) and cooled to 0 0C in ice bath. The brown solid was filtered off and washed with hexanes (2X) and dried under vacuum to give 60 g (71percent).General procedure: Polyphosphoric acid (PPA) (2 equiv by weight) was added to corresponding intermediate 1 (40 mmol) to this phosphorousoxychloride (POCl3) (10 mmol) was added. The reaction mixture was heated to 75 °C for 8 h, monitored by TLC, after completion of the reaction. The reaction mixture was quenched slowly with 10percent sodium hydroxide solution by keeping it in an ice bath and the PH was adjusted to a pH ~ 7, the solid separated was filtered, dried and washed with diethyl ether (3*20 mL) to afford desired compound in good yield.A solution of diethyl 2-[(4-methoxyanilino)methylene]propanedioate (5, 71.4 g, 0.24 mol) in 150 ml of diphenyl ether was slowly heated in a metal bath to 243 °C. During 3 h at this temperature 15 ml liquid were distilled off. The reaction mixture was cooled to room temperature and taken up in 250 ml hexane. This mixture was stirred for 3 h, then filtered. The solid was washed with hexane and dried to deliver ethyl 4-hydroxy-6-methoxyquinoline-3-carboxylate (6, 25.0 g, 0.10 mol, 41 percent) which was pure enough to be directly used in the next step. 1H-NMR (CDClCompound 2 (61 g) was taken up in dowtherm( 400ml) and heated at 250°C for 3h. The reaction mixture was cooled to (RT) and treated with pentane (300 mL) and filtered under suction. The resulting solids were washed thoroughly with excess of pentane and dried under vacuum to give 3 (23 g).A solution of 4-methoxyaniline (4Og, 0.32 mole) and diethyl ethoxymethylenemalonate (65 mL, 0.32 mole) in Dowtherm A (500 mL) was heated at reflux in a flask fitted with side-arm and condenser, and heating was continued until all the ethanol had distilled off (ca. 0.5 hr). The solution was cooled and pentane was added to give a sticky precipitate. The solvents were decanted off and the residue was treated with more pentane and allowed to stand overnight. The solid was filtered off and washed well with pentane to give the title compound (62.4 g; 78percent, contains traces of Dowtherm A).Preparation 10; Preparation of 4-ethenyl-3-fluoro-6-(methyloxy)quinoline; a) 4-Hydroxy-6-methoxy-quinoline-3-carboxylic acid ethyl ester; A solution of 4-methoxyaniline (4Og, 0.32 mole) and diethyl ethoxymethylenemalonate (65 mL, 0.32 mole) in Dowtherm A (500 mL) was heated at reflux in a flask fitted with side-arm and condenser, and heating was continued until all the ethanol had distilled off (ca. 0.5 hr). The solution was cooled and pentane was added to give a sticky precipitate. The solvents were decanted off and the residue was treated with more pentane and allowed to stand overnight. The solid was filtered off and washed well with pentane to give the title compound (62.4 g; 78percent, contains traces of Dowtherm A).Preparation 8; Preparation of 4-ethenvl-3-fluoro-6-(methvloxv)quinoline; a) 4-Hydroxy-6-methoxy-quinoline-3-carboxylic acid ethyl ester; A solution of 4-methoxyaniline (40g, 0.32 mole) and diethylethoxymethylenemalonate (65 ml, 0.32 mole) in Dowtherm A (500 ml_) was heated atreflux in a flask fitted with side-arm and condenser, and heating was continued until all theethanol had distilled off (ca. 0.5 hr). The solution was cooled and pentane was added togive a sticky precipitate. The solvents were decanted off and the residue was treated withmore pentane and allowed to stand overnight. The solid was filtered off and washed wellwith pentane to give the title compound (62.4 g; 78percent, contains traces of Dowtherm A).A mixture of 4-methoxyaniline (12.3 g, 100 mmol) and diethyl 2-(ethoxymethylene)malonate (21.6 g, 100 mmol) was stirred at 120 °C under nitrogen for 4 hrs. The solution was cooled to room temperature and Ph20 (100 mL) was added. The reaction mixture was refluxed at 260 °C under nitrogen for 8 hrs. The solution was cooled to room temperature and diluted with hexanes. The resultant precipitate was collected by filtration, washed with 25percent ethyl acetate in hexanes, and dried under vacuum to give ethyl 4-hydroxy-6-methoxyquinoline-3-carboxylate as a pale- yellow solid (4.21 g, 17percent). 1H NMR (400 MHz, DMSO-i¾ δ 1.26 (t, J = 7.0 Hz, 3H), 3.83 (s, 3H), 4.19 (q, J = 7.0 Hz, 2H), 7.32 (dd, J = 3.2, 9.6 Hz, 1H), 7.55 (d, J = 3.2 Hz, 1H), 7.56 (d, J = 9.6 Hz, 1H), 8.47 (s, 1H), 12.27 (s, 1H). MS 248 (MH+).Example 1c

Molecular Weight:247.25
XLogP3:2
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:5
Rotatable Bond Count:4
Exact Mass:247.08445790
Monoisotopic Mass:247.08445790
Topological Polar Surface Area:64.6
Heavy Atom Count:18
Complexity:377
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes