7-(3-CHLORO-PROPOXY)-4-(2,4-DICHLORO-5-METHOXY-PHENYLAMINO)-6-METHOXY-QUINOLINE-3-CARBONITRILE

A mixture of compound 25 (31.2 g, 0.10 mol), 2, 4-dichloro-5-methoxyaniline (30, 21.1 g, 0.11 mol), and pyridine hydrochloride (12.8 g, 0.11 mol) in 2-methoxyethanol (150 g) was heated to 120 °C for 3 h. The suspension was cooled to r.t. and poured into water (600 g) while stirring. The resulting solid was filtered, washed with water (2 × 40 g), and dried at 50 °C to give product 31 (35.9 g, 77percent) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ = 2.28 (m, J = 6.0 Hz, 2 H), 3.82 (t, J = 6.0 Hz, 2 H), 3.87 (s, 3 H), 3.97 (s, 3 H), 4.30 (t, J = 6.0 Hz, 2 H), 7.35(s, 1 H), 7.37 (s, 1 H), 7.75 (s, 1 H), 7.85 (s, 1 H), 8.43 (s, 1 H), 9.63 (s, 1H).13C NMR (100 MHz, DMSO-d6): δ = 31.9, 42.1, 56.7, 57.3, 65.8, 86.9, 102.4, 110.0, 113.1, 114.0, 117.4, 120.9, 123.6, 130.3, 136.7, 146.2, 149.8, 149.9, 151.3, 152.9, 154.5.MS (ESI): m/z = 468.0 [M + H]+.A solution of 2, 4-dichloro-5-methoxyaniline (1.9 g, 10 mmol), pyridine hydrochloride (1.2 g, 10 mmol) and4-chloro-7-(3-chloro-propoxy) -6-methoxy-quinoline-3-carbonitrile (3.1 g, 10 mmol)Placed in sealed tube, Anhydrous 2-ethoxyethanol (30 mL) was added, The mixture was heated at 140 ° C for 2 hours.After completion of the reaction, After the reaction solution was cooled to room temperature, Diluted with water (500 mL)Dichloromethane extraction (250 mL X2), The organic phases were combined, Respectively, with water, Washed with a saturated saline solution, Dried over anhydrous sodium sulfate, filter, Concentrated under reduced pressure, Purified by column chromatography7-(3-chloro-propoxy) _4_ (2, 4-dichloro-5-methoxy-phenylamino)-6-methoxy-quinoline-3-carbonitrile(Gray solid, 3.0 g), Yield 67percent.1) The substrate 7-hydroxy-6-methoxy-4-(2, 4-dichloro-5-methoxyanilino)-3-cyanoquinoline (100 mmol, 1.0 eq), solvent 500 ml ( Isopropyl acetate/water = 95:5), cuprous iodide (8 mmol, 0.08 eq), cesium carbonate (150 mmol, 1.5 eq) were stirred and dissolved at room temperature;2) The temperature was raised to 60-65 ° C, then 1-bromo-3-chloropropane (150 mmol, 1.5 eq) was slowly added dropwise, and the reaction was incubated after the completion of the dropwise addition;3) After 5h, HPLC, 7-hydroxy-6-methoxy-4-(2, 4-dichloro-5-methoxyanilino)-3-cyanoquinoline was completely reacted (conversion rate was 99.8percent) , the selectivity is 93.6 &), stop the reaction;4) After cooling to room temperature, the citric acid is adjusted to pH=6.0-6.5, then 350 ml of water is added for extraction and liquid separation.The organic phase is collected to obtain an acid-washed organic phase; the acid-washed organic phase is washed with 350 ml of saturated brine to obtain a salt-washed organic phase, and the salt-washed organic phase is added with an aqueous solution of 10percent V triethylamine to adjust the pH of the system to 7.2-7.5, and the temperature is raised. To 50 ° C, then n-heptane was added dropwise, crystallized, filtered and dried to give 38.8 g of high purity 7-(3-chloropropoxy)-6-methoxy-4-(2, 4-dichloro-5-methoxyanilino)-3-cyanoquinoline, the yield was 83.2percent, and the HPLC purity was 99.8percent.A mixture of compound 25 (31.2 g, 0.10 mol), 2, 4-dichloro-5-methoxyaniline (30, 21.1 g, 0.11 mol), and pyridine hydrochloride (12.8 g, 0.11 mol) in 2-methoxyethanol (150 g) was heated to 120 C for 3 h. The suspension was cooled to r.t. and poured into water (600 g) while stirring. The resulting solid was filtered, washed with water (2 × 40 g), and dried at 50 C to give product 31 (35.9 g, 77%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): delta = 2.28 (m, J = 6.0 Hz, 2 H), 3.82 (t, J = 6.0 Hz, 2 H), 3.87 (s, 3 H), 3.97 (s, 3 H), 4.30 (t, J = 6.0 Hz, 2 H), 7.35(s, 1 H), 7.37 (s, 1 H), 7.75 (s, 1 H), 7.85 (s, 1 H), 8.43 (s, 1 H), 9.63 (s, 1H).13C NMR (100 MHz, DMSO-d6): delta = 31.9, 42.1, 56.7, 57.3, 65.8, 86.9, 102.4, 110.0, 113.1, 114.0, 117.4, 120.9, 123.6, 130.3, 136.7, 146.2, 149.8, 149.9, 151.3, 152.9, 154.5.MS (ESI): m/z = 468.0 [M + H]+.A solution of 2, 4-dichloro-5-methoxyaniline (1.9 g, 10 mmol), pyridine hydrochloride (1.2 g, 10 mmol) and4-chloro-7-(3-chloro-propoxy) -6-methoxy-quinoline-3-carbonitrile (3.1 g, 10 mmol)Placed in sealed tube, Anhydrous 2-ethoxyethanol (30 mL) was added, The mixture was heated at 140 C for 2 hours.After completion of the reaction, After the reaction solution was cooled to room temperature, Diluted with water (500 mL)Dichloromethane extraction (250 mL X2), The organic phases were combined, Respectively, with water, Washed with a saturated saline solution, Dried over anhydrous sodium sulfate, filter, Concentrated under reduced pressure, Purified by column chromatography7-(3-chloro-propoxy) _4_ (2, 4-dichloro-5-methoxy-phenylamino)-6-methoxy-quinoline-3-carbonitrile(Gray solid, 3.0 g), Yield 67%.A mixture of 7- [3-chloropropoxy]-4- [ (2, 4-dichloro-5-methoxyphenyl) amino] -6- methoxy-3-quinolinecarbonitrile (3.50g, 7.50 mmol), sodium iodide (1.12 g, 7.50 mmol) and 4.8 mL of N-ethylpiperazine in 5 mL of ethylene glycol dimethyl ether was heated at 95C for 20 h. The reaction mixture was concentrated in vacuo and partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was washed with saturated aqueous sodium bicarbonate, followed by brine, dried over sodium sulfate, filtered and concentrated in vacuo. Diethyl ether was added to the residue and the white solid was collected by filtration to provide 1.80 g (44%) of 4- [ (2, 4-dichloro-5-methoxyphenyl) amino]- 7- [3- (4-ethyl-I- piperazinyl) propoxy]-6-methoxy-3-quinolinecarbonitrile : mp 102-104C ; MS (ES) m/z 544.3, 546.4 (M+1).

Molecular Weight:466.7
XLogP3:6.1
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:6
Rotatable Bond Count:8
Exact Mass:465.041375
Monoisotopic Mass:465.041375
Topological Polar Surface Area:76.4
Heavy Atom Count:30
Complexity:592
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes