3-Bromo-5-methoxypyridine

White to yellow low melting solid

A suspension of 60percent sodium hydride (11.4 g, 285 mmol) in DMF (450 mL) was charged with methanol (11.5 mL, 285 mmol) at room temperature and heated to 60°C. The resulting solution was charged with 3, 5-dibromopyridine (45 g, 190 mmol) and heated to 90°Cfor 1 h. The reaction mixture was cooled to room temperature, diluted with water (50 mL) and extracted with diethyl ether (3 X 50 mL). The combined organic layers were washed with brine, dried over anhydrous Na2504, filtered and concentrated in vacuo resulting in crude compound which was purified by chromatography on silica gel, eluting with 5-10percent ethyl acetate in hexane to give 26.1 g, 73percent yield of the title compound as an off white solid. ‘H NMR (400 MHz, CDC13): ö = 8.27 (d, J= 17.20 Hz, 2 H), 7.36 (s, 1 H), 3.86 (br. s, 3 H); MS (E5): m/z = 187.85 [M-Hf; LCMS: tR = 1.81 mm.Example 43A A suspension of NaH (0.47 g, 19.6 mmol) in DMF (20 mL) was cautiously treated with methanol (0.59 g, 18.4 mmol). After 30 minutes, the mixture was treated with a solution of 3, 5-dibromopyridine (4.0 g, 16.9 mmol) in DMF (5.0 mL). After stirring overnight, the reaction mixture was quenched with saturated aqueous NH4Cl and extracted with diethyl ether (200 mL). The organic phase was dried (MgSO4) and concentrated under reduced pressure. The residue was purified by chromatography on SiO2 (CH2Cl2) to provide the title compound (2.24 g, 70percent yield) as a yellow solid.Sodium (2.33 g, 101.3 mmol) was added to methanol (50 ml) and was allowed to react, the mixture was evaporated. 3.5-Dibromopyridine (20.0 g, 84.4 mmol) and dimethyl sulfoxide (100 ml) were added. Using reported procedures, 3, 5-dibromopyridine 1 (5 g, 21 mmol) was dissolved in 100 mL anhydrous methanol (Figure 2). The solution was cooled to OA solution of 3, 5-dibromopyridine (32, 20 g, 84.4 mmol) in DMF (200 mL) was stirred at RT under nitrogen atmosphere and 21.3 mL of sodium methoxide (25percent by wt. in methanol, 92.8 mmol) was added slowly. The reaction mixture was stirred overnight at 70° C. under NA solution of 3, 5-dibromopyridine (134a, 20 g, 84.4 mmol) in DMF (200 mL) was stirred at RT under nitrogen atmosphere and then 21.3 mL of sodium methoxide (25percent by wt. in methanol (92.8 mmol) was added slowly. The reaction mixture was stirred overnight at 70° C. under N2. The reaction was cooled to RT and quenched with water (200 mL) and extracted with Et2O (2.x.200 mL). The combined organic extracts was washed with brine, dried (MgSO4) and concentrated in vacuo. The crude 3-bromo-5-methoxypyridine (134b 14.8 g, 93percent theory) afforded a colorless oil after purification by flash chromatography on silica gel (EtOAc:hexane 1:10).3, 5-Dibromopyridine (29.41 g, 0.12 mol) was dissolved in dimethylformamide (300 ml), 28percent sodium methoxide (40.00 ml, 0.19 mol) was added, and the mixture was stirred with heating at 40° C. for 1 hr, and the mixture was stirred at room temperature for 17 hr. Water (500 ml) was added to the reaction mixture, and the mixture was extracted three times with diethyl ether. The organic layer was washed with saturated brine, and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography (hexane:ethyl acetate=10:1 to 4:1) to give the object product as a white solid (20.28 g, yield 87percent). To a solution of 3, 5-dibromopyridine (10.0 g, 42.2 mmol) in DMF (10 mL) in a flask with a distillation head was added NaOMe solution 25percent wt/wt (10 mL) and the mixture was heated to 100° C. for 3 hours. At the end of 3 hours 8 mL of MeOH was collected. The DMF solution was cooled to room temperature and diluted with HSodium methoxide (255 mmol) was added to a solution of 3, 5-dibromopyridine (124 mmol) inN, N-dimethylformamide (200 mL) and the reaction mixture was heated at 40 °C for 24 h. The resulting mixture was diluted with water (200 mL) and was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried (magnesium sulfate) and concentrated. The residue was purified by Flash chromatography (40/1 petroleum ether/ethyl acetate) to provide 3-bromo-5-methoxypyridine in 59percent yield as a white solidIntermediate 12: Synthesis of 5-methoxypyridine-3-sulfonyl chloride.1. Synthesis ofSodium methoxide (255 mmol) was added to a solution of 3, 5-dibromopyridine (124 mmol) in N, 7V-dimethylformamide (200 mL) and the reaction mixture was heated at 40 Intermediate 12: Synthesis of 5-methoxypyridine-3-sulfonyl chloride.B 1. Synthesis ofSodium methoxide (255 mmol) was added to a solution of 3, 5-dibromopyridine (124 mmol) in N, N-dimethylformamide (200 mL) and the reaction mixture was heated at 40 Add sodium (0. 583 g, 25 mmol) to methanol (10 mL) at 0 °C. Stir the mixture at 0 °C until obtain a solution and concentrate. Add N, N-dimethylformamide (25 mL) and add 3, 5-dibromopyridine (3. 0 g, 12. 66 mmol). Stir at 70 °C for 4 h. Cool to room temperature and add water. Extract twice with diethyl ether. Combine the organic phases, wash once with water, dry over sodium sulfate and concentrate. Purify the residue by silica gel chromatography, eluting with a gradient of 100 : 0 to 50 : 50 hexanes : ethyl acetate, to give the title compound as a solid (1. 37 g, 57percent). LC-MS (ES) : =187. 9, 190. 0 [M+H) +.Reference Example 104 5-(methyloxy)pyridine-3-carbonitrile (1793) (1794) A suspension of 3, 5-dibromopyridine (3.0 g, 12.6 mmol) and sodium methoxide (3.4 g, 62.9 mmol) in DMF (20 mL) was stirred at room temperature for 15 hrs and the solvent was evaporated under reduced pressure. The concentrated residue was extracted with ethyl acetate and water. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (2percent-20percent ethyl acetate/hexane) to give 3-bromo-5-(methyloxy)pyridine as a white powder (1.25 g, 53percent). A suspension of the obtained 3-bromo-5-(methyloxy)pyridine (500 mg, 2.659 mmol), zinc cyanide (187 mg, 1.59 mmol) and tetrakistriphenylphosphine palladium (154 mg, 0.133 mmol) in DMF was reacted in a microwave reaction apparatus at 80° C. for 10 min. and then at 120° C. for 10 min. The mixture was allowed to cool to room temperature and the solvent was evaporated under reduced pressure. The concentrated residue was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (2percent-30percent ethyl acetate/hexane) to give the title compound as a colorless oil (300 mg, 84percent). (1795) Sodium methoxide (124 g, 2.30 mol), 3, 5-dibromopyridine (300 g, 1.26 mol) and a mixture of DMF and methanol (1200 ml_, 4:1) were added to a 2-L 3-neck flask fitted with a reflux condenser and under a nitrogen atmosphere. The resulting suspension was heated (8O

Molecular Weight:188.02
XLogP3:1.5
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:1
Exact Mass:186.96328
Monoisotopic Mass:186.96328
Topological Polar Surface Area:22.1
Heavy Atom Count:9
Complexity:89.1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes