5-BROMO-2-METHOXY-3-CYANOPYRIDINE

To a suspension of 5-bromo-2-methoxy-3-nitropyridine (9.62 g, 41.3 mmol) in ethanol (100 mL) and water (10 mL) was added Iron powder (9.25 g, 165.2 mmol, Tianjin guangfukeji) and NH5- Bromo-2-methoxypyridin-3-amine (16); [00198] In a 500 mL, round-bottomed, single-necked flask equipped with a magnetic stirring bar was placed 5-bromo-2-methoxy-3-nitropyridine (15) (20.0 g, 0.086 mol), Fe (20.0 g, 0.36 mol), and NHTo a suspension of 5-bromo-2-methoxy-3-nitropyridine (0.4 g, 1.72 mmol) in EtOH(5 mL) and H20 (5 mL) was added iron powder (0.38 g, 6.87 mmol) and NH4Cl (0.39 g, 7.21mmol). The reaction refluxed for 1 h, then cooled down to rt and concentrated in vacuo. Theresidue was diluted with EtOAc (1 0 mL) and the resulted mixture was filtered through a pad ofcelite. The filtrate was extracted with EtOAc (10 mL x 3) and the combined organic phases werewashed with brine (10 mL), dried over anhydrous Na2S04 and concentrated in vacuo to give thetitle compound as a yellow solid (0.3 g, 86percent). The title compound was characterized byLC-MS and 1H NMR as shown below:LC-MS (ESI, pos. ion) m/z: 203 [M+Ht;1H NMR (400 MHz, CDCh) 8 (ppm): 3.92 (s, 3H), 4.86 (s, 2H), 7.03 (d, J = 2.0 Hz, 1H), 7.41 (d, J = 2.0 Hz, 1H).To a suspension of 5-bromo-2-methoxy-3-nitropyridine (0.4 g, 1.72 mmol) in EtOH (5 mL) and HThe 5-bromo-2-methoxy-3-nitro pyridine (0.4g, 1 . 72mmol) suspended in EtOH (5 ml) and H b) 5 -bromo-2-(methyloxy)-3 -pyridinamine. To a solution of 5 -bromo-2-(methyloxy)-3 -nitropyridine (82 mmol) in ethyl acetate (300 mL) was added tin(II)chloride dihydrate (328 mmol). The reaction mixture was stirred for 3 h at reflux. (Caution: during the initial exotherm, that subsided after ~10 min, the heating bath was temporarily removed.) After cooling to room temperature, the mixture was concentrated under vacuum to a pale yellow slurry. The slurry was poured into 6 N aq. sodium hyroxide (300 mL), ice water (300 mL), and dichloromethane (300 niL) and stirred for 2 h until mostly dissolved. The small amount of insoluble material was filtered off and the organic phase was separated, dried over sodium sulfate, filtered, and evaporated to dryness. The resultant brown oil was triturated with hexanes to obtain a solid, which was filtered and dried in vacuo to afford the title product (81percent) as a pale green solid. MS(ES)+ m/e 202.8 [M+H]+.3 - Amino-5 -bromo-2-methoxypyridineTo 5 -Bromo-2-methoxy-3 -nitropyridine (19.0 g, 82 mmol) in EtOAc (300 mL) was added Tin(II)chloride dihydrate (74 g, 328 mmol). The reaction was stirred and refluxed for 3 h. (During the initial exotherm, that subsided after ~10 minutes, the heating bath was temporarily removed.) After cooling to RT the reaction was concentrated under vacuum to a pale yellow slurry. The slurry was poured into aq. 6 N NaOH (300 mL), ice (300 mL) and CH2CI2 (300 mL) and stirred for 2 h till mostly dissolved. The small amount of insoluble material was filtered off, the organic phase separated, dried (Na2SO4), filtered and evaporated to dryness. Trituration with hexanes solidified the brown oil which remained. Filtration and drying under vacuum gave the title product (13.40 g, 81percent) as a pale green solid: MS(ES)+ m/e 202.8 [M+H]Step D 5-bromo-2-methoxypyridin-3-amine[00298] Tin (II) chloride dihydrate (87 g, 386.2 mmol) was added into a solution of 5- bromo-2-methoxy-3-nitropyridine (18 g, 72.2 mmol) in acetyl acetae (450 mL) at r.t. and the resulting mixture was refluxed for 3 hours with TLC monitoring. After the full conversion of starting material, the reaction mixture was cooled to r.t. and slowly poured into 6 N NaOH (500 mL) and stirred for a period of 10 minutes. The precipitate was filtered out with suction, and the filtrate was extracted with EtOAc (500 mL x 3). The combined organic layer was dried over NaTo a solution of 16 (12.0 g, 51.7 mmol) in EtOAc (200 mL) was added SnCl4.1.2 A solution of 985 mg (4.23 mmol) C-4 in 10 mL EtOAc is treated with 3.82 g (16.9 mmol) tin-II-chloride dihydrate. The mixture is stirred under reflux for 3 h. After cooling to RT, the solvent is removed under reduced pressure and the crude product is taken up in 9.5 mL aqueous 2 N NaOH. After stirring at RT for 1 h, DCM is added and the mixture is filtered over Celite. The aqueous phase is extracted with DCM, the combined organic layers are dried over MgSOb) 5-bromo-2-(methyloxy)-3-pyridinamine; To a solution of 5-bromo-2-(methyloxy)-3-nitropyridine (45 g, 193 mmol) in ethyl acetate (1 L) was added tin(II) chloride dihydrate (174 g, 772 mmol). The reaction mixture was heated at reflux for 4 h. LC/MS indicated some starting material remained, so added 20 molpercent tin (II) chloride dihydrate and continued to heat at reflux. After 2 h, the reaction was allowed to cool to ambient temperature and concentrated in vacuo. The residue was treated with 2 N sodium hydroxide and the mixture stirred for 1 h. The mixture was then with methylene chloride (1 L), filtered through Celite, and washed with methylene chloride (500 mL). The layers were separated and the organics dried over magnesium sulfate and concentrated to give 5-bromo-2-(methyloxy)-3-pyridinamine (23 g, 113 mmol, 58.7 percent yield). The product was used crude in subsequent reactions. MS(ES)+ m/e 201.9, 203.9 [M+H]b) 5-Bromo-2-(methyloxy)-3-pyridinamine

Molecular Weight:203.04
XLogP3:1.2
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:1
Exact Mass:201.97418
Monoisotopic Mass:201.97418
Topological Polar Surface Area:48.1
Heavy Atom Count:10
Complexity:112
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes