| 1.64%; 19.70% |
In methanol; at 60℃; for 12h; |
To a solution of 2,6-dichloronicotinonitrile (0.50 g, 2.89 mmol) in MeOH (10 mL) was added sodium methoxide (0.62 g, 2.89 mmol) at ambient temperature and the resulting mixture was stirred at 60 C for 12 h. The reaction mixture was cooled to ambient temperature, concentrated to dryness under reduced pressure. The residue was diluted with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layes were washed with brine (30 mL), dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by preparative HPLC [Xbridge Phenyl (250 x 21.2 ID) 5 micron; Solvent A: 0.1%TFA in water, Solvent B: Acetonitrile, Gradient: 0-100 % B over 20 min, Flow: 20 mL/min, UV 220 nm]. First eluted compound (retention time 15.34 min), designated as Intermediate 41A, was obtained (0.10 g, 19.70%) as white solid, 1H NMR (400 MHz, CDCl3) delta ppm 4.08 (s, 3 H), 7.02 (d, J = 7.83 Hz, 1 H), 7.82 (d, J = 7.83 Hz, 1 H). LCMS ( Method-D): retention time 1.94 min, [M+1H] 169.2. Second eluted compound (retention time 16.74 min), designated as Intermediate 41B, was obtained (0.04 g, 1.64%) as an off-white solid.1H NMR (400 MHz, DMSO-d6) delta ppm 3.95 (s, 3 H), 7.07 (s, 1 H), 8.29 (d, J = 8.53 Hz, 1 H). LCMS (Method-D): retention time 1.89 min, [M+1H] 169.2. Structure of Intermediate 41A and 41B was determined by single- crystal X-ray diffraction method. |
|
With methanol; at 0 - 20℃; for 16h; |
6-Chloro-2-methoxy-nicotinonitrile and 2-Chloro-6-methoxy-nicotinonitrile (27 and 28) (0800) To a solution of 2,6-dichloro-nicotinonitrile (26, 5.0 g, 28.90 mmol) in methanol (25 mL) was added sodium methoxide (25% solution in methanol, 6.24 mL, 28.90 mmol) slowly at 0 C. and stirred for 16 h at room temperature. Methanol was distilled off and the residue was diluted with EtOAc (150 mL), washed with water (2×50 mL) and brine (50 mL), dried over Na2SO4, filtered, and concentrated to give crude mixture, which was recrystallized from ether to give inseparable mixture of compounds 27 and 28 in a ratio of 1:2 (4.8 g, quantitative) as white solid. 1H NMR 400 MHz (DMSO-d6) delta: 8.30 (d, J=8.2 Hz, 1H), 8.27 (d, J=8.6 Hz, 1H), 7.31 (d, J=7.7 Hz, 1H), 7.00 (d, J=8.6 Hz, 1H), 3.98 (s, 3H), 3.92 (s, 3H). |
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In methanol; at 20℃; for 1h;Cooling with ice; |
In the ice bath,Sodium metal (700 mg) was added to 30 mL of anhydrous methanol.Stir for one hour at room temperature until the sodium completely disappears.Stir at room temperatureThe above-mentioned new sodium methoxide solution,The solution was slowly added dropwise to a solution of 2,6-dichloro-3-cyanopyridine (5.0 g) in methanol (50 mL) via a constant pressure funnel.Reaction for 1 hour.Concentrate under reduced pressure,Add ethyl acetate to dissolve the residue,Insoluble sodium chloride precipitate is filtered off.The filtrate was concentrated to give a mixture of 6-chloro-2-methoxynicotinonitrile and 2-chloro-6-methoxynicotinonitrile (4.87 g).The results of nuclear magnetic profiling showed that the ratio of 6-chloro-2-methoxynicotinonitrile and 2-chloro-6-methoxynicotinonitrile was 2:1.Yellow solid. |
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