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With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In chloroform at 60℃; for 6 h;
Commercially available 2-cyano-5-methylpyridine (1.90 g, 16.1 mmol) was dissolved in chloroform (100 mL), and the mixture was stirred at 60°C for 6 hours after adding N-bromosuccinimide (4.29 g, 24.1 mmol) and α,α-azobisisobutyronitrile (0.792 g, 4.82 mmol). After ice-cooling the reaction mixture, the precipitate was separated by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 5-bromomethyl-2-cyanopyridine (1.69 g, 53percent). 1H NMR (CDCl3) δ(ppm) 4.80 (s, 2H), 8.03 (dd, J = 0.92, 8.07 Hz, 1H), 8.12 (dd, J = 2.20, 8.07 Hz, 1H), 8.81 (bd, J = 1.83 Hz, 1H).
44%
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In tetrachloromethane for 4 h; Heating / reflux
Preparation 16; 2-Aminomethyl-5-o-propylthiomethyl-pyridine; 5-Bromomethyl-pyridine-2-carbonitrile; Add AIBN (0.25 g, 1.5 mmol) to a slurry of 5- methyl-pyridine-2-carbonitrile (2.5 g, 21.1 mmol) and NBS (3.7 g, 21.1 mmol) in carbon tetrachloride (150 mL) at reflux under a nitrogen atmosphere. Add AIBN (3x0.25 g, 3x1.5 mmol) to the reaction in 0.25 g portions every hour for 3 h. Stir the resulting mixture for one additional hour at reflux. Cool the mixture to room temperature and wash with saturated aqueous NaHCO3 (30 mL). Collect the organic phase, concentrate in EPO <DP n="72"/>vacuo and purify the residue by chromatography on silica gel (330 g) eluting with DCM to obtain the desired intermediate (1.8 g, 44percent). MS (ES+) m/z: 199 (M+2)+.
B) 6-Cyano-3-picolylbromide A mixture of 6-cyano-3-picoline (1.32 g, 11.19 mmol), benzoylperoxide (0.54 g, 2.24 mmol), and N-bromosuccinimide (2.8 g, 15.7 mmol) in carbontetrachloride (30 mL) was heated at reflux for 2 h. The resulting suspension was filtered and the filtrate diluted with dichloromethane (400 mL), washed with a saturated sodium bicarbonate solution, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by column chromatography (EtOAc: n-hexane, 1:9) to give the title compound as a yellow oil (1.12 g, 51percent). 1H NMR (CDCl3) δ8.64 (s, 1H), 7.76 (d, 1H), 7.63 (d, 1H), 4.55 (s, 2H). FAB MS: 197 [M+1]+
With sulfuric acid; sodium hydrogencarbonate; In ethanol;
Synthesis Example 1 Ethyl 5-methylpyridine-2-carboxylate STR24 200 ml of ethanol and 100 ml (1.88 mol) of concentrated sulfuric acid were added to 55.5 g of 5-methylpyridine-2-carbonitrile to form a homogeneous solution, followed by heating under reflux for 2 days. The reaction liquid was gradually poured into a saturated aqueous solution of sodium hydrogencarbonate under cooling with ice to neutralize the sulfuric acid, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous solution of common salt and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated in a reduced pressure to give 78.1 g of a brown oil of the title compound as the crude product.
To a solution of 21 5-methylpyridine-2-carbonitrile (5 g, 42.3 mmol, 1.00 equiv) in 37 ethanol (40 mL) was added 38 sulfuric acid (10 mL, 4.00 equiv). The resulting solution was stirred for 2 days at 80 C. The reaction mixture was cooled to 25 C. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with water (100 mL). The pH value of the solution was adjusted to 8-9 with potassium carbonate. The resulting solution was extracted with ethyl acetate (3×100 mL). The organic layers were washed with water (3×50 mL) and brine (3×50 mL). The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum to afford 3 g (43%) of 36 methyl 5-methylpyridine-2-carboxylate as light yellow oil. LC-MS: m/z=166[M+H]+.
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