* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Stage #1: With 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione In tetrahydrofuran at 20℃; for 48 h; In the dark Stage #2: With sodium thiosulfate In tetrahydrofuran; water for 1 h;
Step B. 3-Bromo-6-methoxy-2-methyl-pyridine. A mixture of 2-methoxy-6-methyl-pyridine (15.2 g, 123 mmol) and 1,3-dibromo-5,5-dimethyl hydantoin (35.3 g, 123 mmol) in THF (1 L) was stirred at rt for 48 h in the dark. The mixture was treated with 10percent aq. Na2S2O3 (100 mL) and stirred for 1 h. The mixture was extracted with Et2O. The organic layer was washed with H2O (2*), dried (MgSO4), and concentrated. The residue was purified (SiO2; 0-5percent EtOAc/hexanes) to give the title compound (18.7 g, 76percent). MS (ESI): mass calcd. for C7H8BrNO, 200.98; m/z found, 202.2 [M+H]+. 1H NMR (CDCl3): 7.60 (d, J=8.6, 1H), 8.45 (d, J=8.7, 1H), 3.90 (s, 3H), 2.54 (s, 3H).
Reference：
[1] Tetrahedron, 2000, vol. 56, # 20, p. 3181 - 3187
[2] Journal of the American Chemical Society, 2009, vol. 131, # 31, p. 11187 - 11194
[3] Synthetic Communications, 1997, vol. 27, # 1, p. 61 - 68
[4] Tetrahedron Letters, 1997, vol. 38, # 25, p. 4415 - 4416
[5] Journal of the Chemical Society - Perkin Transactions 1, 1998, # 19, p. 3151 - 3155
[6] Patent: US2006/287292, 2006, A1, . Location in patent: Page/Page column 28
[7] Patent: EP1847535, 2007, A1, . Location in patent: Page/Page column 123-124
[8] Patent: US2011/294857, 2011, A1,
[9] Science China Chemistry, 2012, vol. 55, # 6, p. 1097 - 1100
2
[ 54923-31-8 ]
[ 74-88-4 ]
[ 126717-59-7 ]
Yield
Reaction Conditions
Operation in experiment
63%
Stage #1: With silver carbonate In chloroform at 20℃; Stage #2: With triethylamine In chloroform for 1.5 h;
Example 3 3-(2,5-Dimethyl-6-oxo-1 6-dihydropyridin-3-(at)l)benzonitrile Step 1: 3-Bromo-6-methoxy-2-methylpyridine: A mixture of 5-bromo-6-methyl-1H-pyridin- 2-one (5.5 g, 29 mmol), silver carbonate (10.89 g, 39 mmol), iodomethane (13.6 mL, 217 mmol) and chloroform (115 mL) is stirred overnight in the dark at room temperature. Triethylamine (10 mL) is added and stirring continued for 1.5 hr. The reaction mixture is filtered through a pad of Hi-Flo and the filtrate is washed with water (100 mL), dried, filtered and concentrated. The residue is purified by filtration through a pad of silica gel washing with cyclohexane-20percent ethyl acetate. The solvent is concentrated to afford 3-bromo-6-methoxy-2- methylpyridine (3.7 g, 63percent yield) as an oil. LC/MS RT 3.76 min; MS m/e = 202/204 (M); NMR (CDCl3) 7.6 (1H, d), 6.43 (lH, d), 3.89 (3H, s), 2.57 (3H, s).
A solution of 2,5-dibromo-6-picoline (30.6 kg, 122 mol, 1.00 eq) intoluene (154.2 kg) was dried by vacuum distillation at 40 °C 775 mmHg to remove 105.7 kg of distillate to produce a solution containing 40 ppm water. This was mixed with 25 weight percent sodium methoxide in methanol (124.1 kg, 574 mol, 4.71 eq) and the mixture was heated at 65-75 °C for 6 hours until reaction completion, (HPLC analysis indicated 1.6 area percent starting material remained). The mixture was cooled to 5 °C and water (98 L) was charged to the mixture followed by t-butylmethylether (97 kg). The layers were separated and the organic phase washed twice with 5percent brine (139 kg) and once with 20percent brine (165 kg). The organic phase was clarified by filtration and 51 kg was removed by vacuum distillation at 40 °C to produce a 2-methoxy-5-bromo-6-picoline solution (58.4 kg) of 40.6 wt percent purity (96percent yield). Part of this was purified by distillation for the purposes of recording the 13C NMR spectrum: 13C NMR (400 MHz, CDC13) 8 162.4, 154.4, 142.0, 111.8, 109.5, 53.6, 24.6.
Stage #1: With 3-chloro-benzenecarboperoxoic acid In chloroform at 0 - 20℃; for 24 h; Stage #2: at 120℃; for 3 h; Stage #3: With potassium carbonate In methanol; water at 20℃; for 1 h;
To a solution of 3-bromo-6-methoxy-2-methylpyridine (CAS No. 126717-59-7) (5.5 g, 27.2 mmol, 1 equivalent) in chloroform (100 mL) was added 65percent mCPBA (10.8 g, 40.8 mmol, 1.5 equivalents) at 0° C. The reaction mixture was warmed up to room temperature and stirred for 24 hours. To the reaction mixture were added an aqueous sodium thiosulfate pentahydrate solution and a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with chloroform. The resulting organic layer was dried over magnesium sulfate, filtered, and then concentrated under reduced pressure. The residue was purified with silica gel column chromatography (silica gel, 0percent-20percent methanol/ethyl acetate). The resulting compound was stirred in acetic anhydride (20 mL) at 120° C. for 3 hours. To the reaction mixture was added methanol, and the mixture was concentrated under reduced pressure. To the residue was added water, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with a saturated aqueous sodium chloride solution. The organic layers were dried over magnesium sulfate, filtered, and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (silica gel, 20percent-75percent ethyl acetate/n-heptane). To the resulting compound in methanol (22 mL) was added potassium carbonate (1 M aqueous solution, 10.4 mL) at room temperature. After stirring at the same temperature for 1 hour, the reaction mixture was concentrated under reduced pressure. To the residue was added water, and the mixture was extracted with chloroform. The combined organic layers were washed with a saturated aqueous sodium chloride solution. The organic layers were dried over magnesium sulfate, filtered, and then concentrated under reduced pressure to afford the title compound (1.75 g). 1H-NMR (400 MHz, CDCl3) δ (ppm): 3.97 (s, 3H), 4.03 (t, J=4.7 Hz, 1H), 4.68 (dd, J=4.7, 0.8 Hz, 2H), 6.57-6.64 (m, 1H), 7.69 (d, J=8.6 Hz, 1H).
3-bromo-2-(dibromomethyl)-6-methoxypyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); acetic acid; In tetrahydrofuran; for 12h;Reflux;
The compound <strong>[126717-59-7]3-bromo-6-methoxy-2-methylpyridine</strong> (15 g, 0.076 mol), N-bromosuccinimide (40 g, 0.22 mol),Tetrahydrofuran (100 mL), acetic acid (7.5 mL),Azobisisobutyronitrile (0.45 g, 2.7 mmol) was added to a 500 ml single-mouth flask equipped with a reflux apparatus, and the reaction system was heated to reflux for 12 hours.Cool to room temperature and add ethyl acetate (150 mL).Adjust the pH to about 8 with a saturated aqueous solution of sodium bicarbonate (40 mL).The organic phase was washed with saturated brine (30 mL) and dried over anhydrous sodium sulfate.Dry to give a clear oily mixture of compound 3-bromo-2-(dibromomethyl)-6-methoxypyridine and 3-bromo-2-(bromomethyl)-6-methoxypyridine (26 g ),Used directly in the next step.
(3) The synthesis of 6-methoxy-2-methylpyridine-3-boronic acid 21.2g of <strong>[126717-59-7]3-bromo-6-methoxy-2-methylpyridine</strong> was dissolved in 100ml of anhydrous tetrahydrofuran, 79ml of n-butyllithium (1.6M hexane solution) was added dropwise for 30 minutes at -70 C under nitrogen atmosphere. After dropping, stirring was carried out for 30 minutes at -70 C, a solution of 37ml of triisopropyl borate in 50ml of anhydrous tetrahydrofuran was added dropwise for 40 minutes at -70 C. After completion of dropping, dry ice-acetone bath was removed, which was stirred for 16 hours at room temperature. Afterwards, 12ml of acetic acid was added at room temperature followed by stirring for another hour. Water and ethyl acetate were added to reaction liquid, and the organic layer was separated. The resulting organic layer was washed with brine and then dried over anhydrous magnesium sulfate. After removing the drying agent by filtration, the organic layer was concentrated under a reduced pressure, and recrystallized from diethyl ether to give 6.31g of the title compound.
A solution of 2,5-dibromo-6-picoline (30.6 kg, 122 mol, 1.00 eq) intoluene (154.2 kg) was dried by vacuum distillation at 40 °C 775 mmHg to remove 105.7 kg of distillate to produce a solution containing 40 ppm water. This was mixed with 25 weight percent sodium methoxide in methanol (124.1 kg, 574 mol, 4.71 eq) and the mixture was heated at 65-75 °C for 6 hours until reaction completion, (HPLC analysis indicated 1.6 area percent starting material remained). The mixture was cooled to 5 °C and water (98 L) was charged to the mixture followed by t-butylmethylether (97 kg). The layers were separated and the organic phase washed twice with 5percent brine (139 kg) and once with 20percent brine (165 kg). The organic phase was clarified by filtration and 51 kg was removed by vacuum distillation at 40 °C to produce a 2-methoxy-5-bromo-6-picoline solution (58.4 kg) of 40.6 wt percent purity (96percent yield). Part of this was purified by distillation for the purposes of recording the 13C NMR spectrum: 13C NMR (400 MHz, CDC13) 8 162.4, 154.4, 142.0, 111.8, 109.5, 53.6, 24.6.
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