2,4-Dichloro-5-methoxybenzenamine

A suspension of 29 (100.7 g, 0.43 mol) in EtOH (500 g), H2O (500 g), and concd HCl (300 g, 3 mol) was stirred and heated to 70 °C for 12 h to give a brown solution. EtOH (~200 g) was removed under vacuum, and the resulting mixture was stirred and cooled to r.t. for 2 h. The resulting solid was filtered, washed with water (2 × 200 g), and dried at 35 °C under vacuum to give product 30 (69.4 g, 84percent) as a light tan solid; mp 49.5–51.1 °C (Lit.14 50.5–51.5 °C). 1H NMR (400 MHz, DMSO-d6): δ = 3.76 (s, 3 H), 5.13 (br s, 2 H), 6.58 (s, 1 H), 7.23 (s, 1 H).MS (EI): m/z (percent) = 191 (100).General procedure: A mixture of carboxylic acid (1 equiv., 0.5 mmol), CuBr2 or CuCl2 (2 equiv., 1 mmol), Ag2CO3 (1 equiv., 0.5 mmol) and PdCl2 (0.1 equiv.) was heated inTHF (3 mL) under reflux at 110 oC for 24 h. After the reaction finished, the mixture was evaporated under vacuum and purified by columnchromatography to afford the desired product.EXAMPLE 7 4-[(2, 4-Dichloro-5-methoxyphenyl)amino]-2-iodothieno[2, 3-b]pyridine-5-carbonitrile A mixture of Example 7 4-[(2, 4-DICHLORO-5-METHOXYPHENYL) amino] -2-iodothieno [2, 3-b] pyridine-5-carbonitrile A mixture of 2, 4-dichloro-5-methoxyaniline (1.1 g, 5.7 MMOL) and 60% sodium hydride (285 mg, 9.9 MMOL) in 30 mL of tetrahydrofuran is heated at reflux for 1 hour. The solution is cooled and 4-CHLORO-2-IODOTHIENO [2, 3-b] pyridine-5-carbonitrile (1.0 g, 3.12 MMOL) is added. The reaction mixture is heated at reflux for 5 hours then allowed to stir at room temperature overnight. The resultant dark solution is partitioned between ethyl acetate and water. The organic layer is washed with water, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with 0.5 : 9.5 methanol : DICHLOROMETHANE to provide 0.28 g of 4-[(2, 4-DICHLORO-5-METHOXYPHENYL) amino] -2- iodothieno [2, 3-b] pyridine-5-carbonitrile as an off white solid, mp 231-233C. An additional 0.09 g is obtained by chromatography of a mixture of unreacted starting material and product using a gradient of 9: 1 to 1: 1 hexane: ethyl acetate.'H NMR (DMSO-D6) 8 3.87 (s, 3H), 7.36 (s, 1 H), 7.76 (s, 1 H), 8.11 (s, 1 H), 8.39 (s, 1 H), 9.76 (s, 1 H) ; MS 473.8 (M-H) -. Analysis for C15H8CI21N3OS-0. 05 H20 : Calcd : C, 37.84 ; H, 1.69 ; N, 8.83. Found: C, 37.77 ; H, 1.71 ; N, 8.81.EXAMPLE 4 7-[(2, 4-Dichloro-5-methoxyphenyl)amino]-2-iodothieno[3, 2-b]pyridine-6-carbonitrile A mixture of Example 4 7-[(2, 4-DICHLORO-5-METHOXYPHENYL) amino] -2-iodothieno [3, 2-b] pyridine-6-carbonitrile A mixture of 2, 4-dichloro-5-methoxyaniline (380 mg, 2.0 MMOL) and 60% sodium hydride (80 mg, 2.0 MMOL) in 20 mL of tetrahydrofuran is heated at reflux for 1 hour. The solution is cooled and 7-chloro-2-iodothieno [3, 2-B] PYRIDINE-6-CARBONITRILE (320 mg, 1. 0 mmol) is added and the reaction mixture is heated at reflux overnight. The reaction mixture is cooled to room temperature and partitioned between ethyl acetate and water. The organic layer is washed with water, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with 2% methanol in chloroform to provide 240 mg of 7- [ (2, 4- dichloro-5-methoxyphenyl) amino] -2-iodothieno [3, 2-b] pyridine-6-carbonitrile as yellow crystals, mp 233-234C ; 1 H NMR (DMSO-D6) 83. 85 (s, 3H), 7.38 (s, 1 H), 7.77 (s, 1 H), 7.79 (s, 1 H), 8.56 (s, 1 H), 9.74 (s, 1 H) ; MS 475.9 (M+H) +. Analysis for CL5H8CI2N3OS : Calcd : C, 37.84 ; H, 1.69 ; N, 8.83. Found: C, 37.44 ; H, 1.75 ; N, 8.80.7-[(2, 4-DICHLORO-5-METHOXYANILINO)] thieno [3, 2-b] pyridine-6-carbonitrile A mixture of 2, 4-dichloro-5-methoxyaniline (336 mg, 1.75 MMOL) and 60% sodium hydride (70 mg, 1.75 MMOL) in 10 mL of tetrahydrofuran is heated at reflux for 30 minutes. The solution is cooled and 7-chlorothieno [3, 2-B] PYRIDINE-6-CARBONITRILE (200 mg, 1.02 MMOL) is added. The reaction mixture is heated at reflux for 3.5 hours then allowed to stir at room temperature overnight. The resultant black solution is partitioned between ethyl acetate and water. The organic layer is washed with water, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with 1: 1 ethyl acetate: hexane. The fractions containing product are combined and concentrated. Diethyl ether is added and the insoluble material collected by filtration to provide 131 mg of 7-[(2, 4-DICHLORO- 5-methoxyphenyl) amino] thieno [3, 2-B] PYRIDINE-6-CARBONITRILE as a tan solid, mp 216- 220C ; 1 H NMR (DMSO-D6) 83. 85 (s, 3H), 7.40 (3, 1 H), 7.46 (d, J = 5 Hz, 1 H), 7.76 (s, 1 H), 8.11 (d, J = 5 Hz, 1 H), 8.61 (s, 1 H), 9.71 (s, 1 H); MS 350.2 (M+H) +. Analysis for DGHGCNSOS-0. 25 H2O : Calcd : C, 50.79 ; H, 2.70 ; N, 11.85. Found: C, 50. 79; H, 2.48 ; N, 11.56.EXAMPLE 165 4-(2, 4-Dichloro-5-methoxyanilino)-7, 8-dimethoxybenzo[b][1, 8]naphthyridine-3-carbonitrile A mixture of 4-chloro-7.8-dimethoxybenzo[b][1, 8]naphthyridine-3-carbonitrile (150 mg, 0.50 mmol), 1) 4-L-6-methoxy 7-fluoro-quinoline-3-carbonitrile (236 g, 1 mol) was added to a 10 L double-layer glass reactor.2, 4-Dichloro-5-methoxyaniline (236 g, 1.23 eq) and silica-supported acidic ionic liquid IL/TFASiO2 (35.4 g, 15wt%), Stirring in 5L nitromethylpyrrolidone, heating at 60-70 C;2) After 5h, HPLC detection, the concentration of 4-chloro-6-methoxy 7-fluoro-quinoline-3-carbonitrile in the reaction solution no longer decreased, and the reaction was stopped.Cooling to room temperature, filtering to remove the silica-supported acidic ionic liquid to obtain a filtrate;3) The filtrate is divided into two parts according to the weight, respectively W-1 and W-2;The following methods are used for post-processing of W-1 and W-2: Alkali water droplets are added to the organic phase:The W-1 filtrate was warmed to 45-50 C, and then an aqueous ammonia solution having a pH of 8.5-9.0 was added dropwise.When the solid is precipitated in the system, stop adding and holding the crystal for 20-30 minutes.Then, the concentration of 4-(2, 4-dichloro-5-methoxybenzidine)-7-fluoro-6-methoxyquinoline-3-carbonitrile which is continuously added dropwise to the liquid phase is no longer changed ( A total of 15L pH=8.5-9.0 ammonia water was added dropwise, and the temperature was naturally lowered to room temperature;Then, the temperature is raised to 50-55 C at a heating rate of 2-5 C / min, and then naturally cooled to room temperature.Filtration and drying under reduced pressure at 50 C gave 4-(2, 4-dichloro-5-methoxyphenylamino)-7-fluoro-6-methoxyquinolin-3-carbonitrile. The organic phase is added dropwise to the alkaline water:Add W-2 filter to 15L 45-50 C, pH=8.5-9.0 ammonia water, stir and stir for 20-30min after the addition.Then cool to room temperature and filter, Drying under reduced pressure at 50 C to constant weight gave 4-(2, 4-dichloro-5-methoxyphenylamino)-7-fluoro-6-methoxyquinoline-3-carbonitrile.A mixture of 4-chloro-7-fluoro-6-methoxy-3-quinolinecarbonitrile (4.12 g, 18 mmol) 2, 4-dichloro-5-methoxyaniline (4.56 g, 24 mmol) (Theodoridis, G.; Pestic. Sci. 1990, 30, 259) and pyridine hydrochloride (2.31 g, 19.9 mmol) in 45 mL of 2- ethoxyethanol was heated at 120C for 3 hours then cooled to room temperature. The reaction mixture was added to aqueous sodium bicarbonate and stirred for 20 minutes. The solids were collected by filtration to provide 4.89 g of 4-[(2, 4-dichloro-5- methoxyphenyl) amino]-7-fluoro-6-methoxy-3-quinolinecarbonitrile, mp >260C. HRMS theory 392. 03. 634 ; found 392.03556 (M+H) + Analysis forCl8Hl2Cl2FN302-2. 0 H20 Calcd : C, 50.48 ; H, 3.77 ; N, 9.81. Found: C, 50. 41 ; H, 2.82 ; N, 9.78.A mixture of 4-chloro-7-fluoro-6-methoxy-3-quinolinecarbonitrile (4.12 g , 18 mmol)

Molecular Weight:192.04
XLogP3:2.5
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:1
Exact Mass:190.9904692
Monoisotopic Mass:190.9904692
Topological Polar Surface Area:35.2
Heavy Atom Count:11
Complexity:134
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes