5-BROMO-2-METHOXY-3-NITRO-PYRIDINE

To a cooled solvent of MeOH (50.0 mL) was added Na (2.90 g, 126.4 mmol) portion-wise, then the mixture was warmed to rt and stirred until Na was all dissolved, then the solution was added to a suspension of 5-bromo-2-chloro-3-nitropyridine (10.0 g, 42.12 mmol, Shanghai long sheng hua gong, china) in MeOH (100 mL) at 0° C. The reaction mixture was stirred at 0° C. for 1 hour, then warmed up to rt and stirred further for 16 hours, then concentrated to 80 mL and quenched with water (100 mL). The precipitate was filtered, washed with water (50 mL*2) and dried under infrared light to give the title compound as a pale yellow solid (9.62 g, 98percent). MS (ESI, pos. ion) m/z: 233.0 [M+H]Sodium methoxide (17.2 g, 318.4 mmol)was added to a stirred solution of 5-bromo-2-chloro-3-nitropyridine (15.0 g, 64.2 mmol) inmethanol (125 mL). After addition, the reaction mixture was heated at reflux for 2 h. Themixture was concentrated under reduced pressure, and the residue was diluted with water (200mL). The resulting precipitate was collected by filtration, washed with water, and dried underreduced pressure to give the title compound (12.0 g, 82percent yield) as a brown solid.To a solution of sodium methanolate (0.52 g, 9.64 mmol) in MeOH (10 mL) wasadded 5-bromo-2-chloro-3-nitropyridine (0.57 g, 2.41 mmol) at 0°C. The reaction was stirred at0°C for 1 h, then warmed up to rt and stired further for 18 h. The reaction was quenched withH20 (20 mL), adjusted to pH 7 with 3M HCl and then filtered. The seperated organic phase wasconcentrated in vacuo to give the title compound as a light yellow solid (0.4 g, 71.4percent). Thetitle compound was characterized by LC-MS and 1H NMR as shown below:LC-MS (ESI, pos. ion) m/z: 233 [M+Ht;1H NMR (400 MHz, CDCh) 8 (ppm): 3.93 (s, 3H), 8.08 (s, 1H), 8.89 (s, 1H).Example 4N-(2-Methyl-3-(5-(5-(4-methylpiperazin-l-yl)pyridine-2-ylamino)-6-oxo-l, 6- dihydropyridin-3-yl)phenyl)-4, 5, 6, 7-tetrahydrobenzo[Z>]thiophene-2- carboxamide (19); 5-Bromo-2-methoxy-3-nitropyridine (15)[00197] In a 1 L, round-bottomed, single-necked flask equipped with a magnetic stirring bar was placed 5-bromo-3-nitropyridin-2-ol (50.0 g, 0.23 mol) in CHClMethod B: to a suspension of 14 (5.0 g, 22.8 mmol) in anhydrous CH5 -Bromo-2-chloro-3 -nitropyridineTo a stirred solution of 5 -bromo-2-chloro-3 -nitropyridine (20.4 g, 86 mMol) in methanol (75 rnL) at 0 To a solution of sodium methanolate (0.52 g, 9.64 mmol) in MeOH (10 mL) was added 5-bromo-2-chloro-3-nitropyridine (0.57 g, 2.41 mmol) at 0° C. The mixture was stirred at 0° C. for 1 hour, then warmed to rt and stirred for 18 hours. The mixture was quenched with water (20 mL), adjusted to pH=7 with aq. HCl (3 M), and then filtered. The organic phase was separated and concentrated in vacuo to give the title compound as a light yellow solid (0.4 g, 71.4percent).a) 5 -bromo-2-(methyloxy)-3 -nitropyridine. To a stirred solution of 5-bromo-2-chloro-3-nitropyridine (86 mmol) in methanol (75 mL) at 0 To a stirred solution of 5-bromo-2-chloro-3-nitropyridine (86 mmol) in methanol (75 mL) at 0 A solution of 20.0 g (84.2 mmol) 5-bromo-2-chloro-3-nitro-pyridine in 50 mL MeOH is cooled to 0°C and 15.8 mL (84.2 mmol) of a NaOMe solution in MeOH (30percent) is added drop wise. The mixture is stirred at RT over night and then stirred under reflux for 24 h. The precipitate is filtered off, suspended in water and the suspension is stirred for lh. The product is filtered off and dried und vacuum at 60°C. Yield: 18.7 g (95percent).A solution of 20.0 g (84.2 mmol) 5-bromo-2-chloro-3-nitro-pyridine in 50 mL MeOH is cooled to 0°C and 15.8 mL (84.2 mmol) of a NaOMe solution in MeOH (30percent) is added drop wise. The mixture is stirred at RT over night and then stirred under reflux for 24 h. The precipitate is filtered off, suspended in water and the suspension is stirred for lh. The product is filtered off and dried und vacuum at 60°C. Yield: 18.7 g (95percent).A solution of 20.0 g (84.2 mmol) 5-bromo-2-chloro-3-nitropyridine in 50 mL MeOH is cooled to 0°C and 15.8 mL (84.2 mmol) of a NaOMe solution in MeOH (30percent) is added drop wise. The mixture is stirred at RT over night and then stirred under reflux for 24 h. The precipitate is filtered off, suspended in water and the suspension is stirred for 1h. The product is filtered off and dried und vacuum at 60°C. Yield: 18.7 g (95percent).A solution of 20.0 g (84.2 mmol) 5-bromo-2-chloro-3-nitro-pyridine in 50 mL MeOH is cooled to 0° C. and 15.8 mL (84.2 mmol) of a NaOMe solution in MeOH (30percent) is added drop wise. Intermediate 1; λ/-[5-Bromo-2-(methyloxy)-3-pyridinyl]-2, 4-difluorobenzenesulfonamide; a) 5-bromo-2-(methyloxy)-3-nitropyridine; To a cooled (0 a) 4.1.1 Sodium methoxide (17.2 g, 318.4 mmol) was added to a stirred solution of 5-bromo-2-chloro- 3-nitropyridine (15.0 g, 64.2 mmol) in methanol (125 mL). After addition, the reactionmixture was heated at reflux for 2 h. The mixture was concentrated under reduced pressure, and the residue was diluted with water (200 mL). The resulting precipitate was collected by filtration, washed with water, and dried under reduced pressure to give the title compound (12.0 g, 8 1.5percent yield) as a brown solid. 44 NMR (400MHz, CDCI3): 6 8.43 (d, Jr 2.4 Hz, 1 H), 8.38 (d, J 2.0 Hz, 1 H), 4.09 (s, 311).Sodium methoxide (17.2 g, 318.4 mmol) was added to a stirred solution of 5-bromo-2-chloro-3- nitropyridine (15.0 g, 64.2 mmol) in methanol (125 mL). After addition, the reaction mixture was heated at reflux for 2 h, at which time TLC indicated the reaction had gone to completion. The mixture was concentrated under reduced pressure, and the residue was diluted with water (200 mL). The resulting precipitate was collected by filtration, washed with water, and dried under reduced pressure to give the title compound (12, 0 g, 81.5percent yield) as a brown solid. Sodium methoxide (17.2 g, 318.4 mmol) was added to a stirred solution of 5-bromo-2-chloro-3- nitropyridine (15.0 g, 64.2 mmol) in methanol (125 mL). After addition, the reaction mixture was heated at reflux for 2 h. The mixture was concentrated under reduced pressure, and the residue was diluted with water (200 mL). The resulting precipitate was collected by filtration, washed with water, and dried under reduced pressure to give the title compound (12.0 g, 81.5percent yield) as a brown solid. 1H NMR (400MHz, CDC1Sodium methoxide (17.2 g, 318.4 mmol) was added to a stirred solution of 5-bromo-2-chloro-3-nitropyridine (15.0 g, 64.2 mmol) in MeOH (125 mL). The reaction was heated at refluxtemperature for 2 h and then concentrated under reduced pressure. The residue was diluted with water (200 mL). The resulting precipitate was collected by filtration, washed with water, and dried under reduced pressure to give the title compound (12.0 g, 8 1.5percent yield) as a brown solid.‘H NMR (400MHz, CDC13): 6 8.43 (d, J= 2.4 Hz, 1 H), 8.38 (d, J= 2.0 Hz, 1 H), 4.09 (s, 3 H).At 0 , sodium methoxide (0.52g, 9.64mmol) in MeOH (10mL) was added 5-bromo-2-chloro-3-nitropyridine (0.57g, 2.41mmol).The reaction was maintained with stirring at 0 1 hour and then cooled to room temperature, stirring was continued for 18 hours.The reaction solution was added water (20 mL) after being quenched with 3M hydrochloric acid and adjusted to pH 7, and filtered.The separated organic phase was concentrated under reduced pressure to give the title compound as a pale yellow solid (0.4g, 71.4percent)Method A: to a cooled suspension of 15 (15.0 g, 63.2 mmol) in anhydrous MeOH (60 mL) was added 20percent NaOMe in MeOH (15 mL, 66.4 mmol) dropwise at 0 °C. After the reaction mixture was allowed to warm to rt and stirred overnight, the pale yellow precipitate was filtered off to give the crude product. The crude product was diluted with water and stirred for 1 h. The solid was collected by filtration, washed with water and dried to afford 16 (9.22 g, 62percent) as a pale yellow solid. The original filtrate was concentrated in vacuo and diluted with water. Saturated aqueous NH5-Bromo-2-(methyloxy)-3-nitropyridine

Molecular Weight:233.02
XLogP3:1.7
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:1
Exact Mass:231.94835
Monoisotopic Mass:231.94835
Topological Polar Surface Area:67.9
Heavy Atom Count:12
Complexity:173
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes