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Example 1; A. 3-Methyl-isonicotinonitrile.; To 3-methyl-pyridine 1 -oxide (15.90 g, 150 mmol) is added at 0 0C during 30 min. dimethylsulfate (15.60 mL). The resulting reaction mixture is stirred overnight at 40 0C. A solution of KCN (10.75 g, 165 mmol) in a mixture of EtOH/water 1 : 1 (120 mL) is added and the reaction mixture is stirred overnight at 40 0C. The reaction mixture is concentrated in vacuo and the residue is partitioned between EtOAc and water. The aqueous phase is extracted with EtOAc and the combined organic layers are dried over Na2SO4, filtered and concentrated at reduced pressure. Purification by flash column chromatography (silica gel, cyclohexane / EtOAc 85 : 15) affords the title compound as orange crystals (6.00 g, 50.80 mmol, 34%). 1H NMR (400 MHz, DMSO-(Z6) delta ppm 8.76 (s, 1 H), 8.64 (d, J = 4.9 Hz, 1 H), 7.80 (d, J = 4.9 Hz, 1 H).
34%
3-Methyl-isonicotinonitrile; To 3-methyl-pyridine 1 -oxide (15.9 g, 150 mmol) is added at 0 0C during 30 min. dimethylsulfate (15.6 ml_). The resulting reaction mixture is stirred overnight at 40 0C. A solution of KCN (10.75 g, 165 mmol) in a mixture of EtOH / water 1 : 1 (120 mL) is added and the reaction mixture is stirred overnight at 40 0C. The reaction mixture is concentrated in vacuo and the residue is partitioned between EtOAc and water. The aqueous phase is extracted with EtOAc and the combined organic layers are dried over Na2SO4, filtered and concentrated at reduced pressure. Purification by FCC (silica gel, cyclohexane / EtOAc 85 : 15) affords the title compound as orange crystals (6.0 g, 50.8 mmol, 34%). 1H NMR (400 MHz, DMSO-d6, 298 K): delta = 8.76 (s, 1 H), 8.64 (d, J = 4.9 Hz, 1 H), 7.80 (d, J = 4.9 Hz, 1 H).
A. A mixture of 3-methyl-pyridine 1-oxide (20 g, 0.183 mol) and iodoethane (32 mL, 0.403 mmol) is stirred 16 h. 200 mL water is added, the aqueous layer is separated and washed with Et2O. The collected aqueous layer is warmed to 50 C. and a solution of KCN (24 g, 0.366 mol) in 60 mL of water is added slowly in one hour. After an additional one hour stirring, the mixture is extracted with Et2O. The combined solvent is dried and concentrated to dryness. The residue is purified by silica gel column chromatography with hexanes:EtOAc=4:1 as eluent to provide 3-methyl-isonicotinonitrile.
Step A: To a solution of 3-methylpyridine-N-oxide (240 g, 2.2 mol) in dichloromethane (4 L) is added ethyl iodide (530 mL, 6.6 mol). The mixture is stirred at reflux overnight. Then the suspension is cooled. The resulting precipitate is collected by filtration and washed with diethyl ether (500 mL) to give a white solid. The solid is dissolved in water (2.4 L) and warmed to 500C. A solution of sodium cyanide (200 g, 4 mol) in water (600 mL) is slowly added over 1 h, keeping the internal temperature below 600C. The reaction mixture is stirred at 55C for another 1 h. The reaction mixture is extracted with diethyl ether (3 x 1.5 L). The combined extracts are dried over MgSO4 and concentrated to yield 4-cyano-3-methylpyridine 1 as a brown oil: 1H NMR (400 MHz, CDCl3) delta = 8.66 (s, IH), 8.58 (dd, J = 6.8, 1.0 Hz, IH), 7.46 (d, J= 6.8 Hz, IH), 2.54 (s, 3H).
Preparation 62 3-Methylisonicotinonitrile To a solution of 3-methylpyridine 1-oxide (10,59g, 0.1 mol) in ACN (22ml) was added iodoethane (17.5m1, 0.22mol) dropwise and the mixture stirred at r.t. for 2h. The solid formed was filtered off, redissolved in water (48ml) and warm up to 55C. At this temperature KCN (12.3g, 0.1 9mol) in water (32ml) was added dropwise over 3.5h. Then the reaction mixture was stirred at this temperature for 2h and at r.t. overnight. The desired product was extracted with ether, washed with brine and concentrated. The solid obtained was recrystallized in diisopropyl ether. Yield=49% LRMS: m/z 119 (M+1)+ Retention time: 3.77 min (Method B)
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