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With lithium aluminium tetrahydride In tetrahydrofuran at -70℃; for 2.25 h;
To a solution of 5-bromo-3-chloro-N-methoxy-N-methylpicolinamide (9.0 g, 32.3 mmol, 1 eq) in THF (100 mL), the LAH solution (IM in THF) (16.12 mL, 16.1 mmol, 0.5 eq) was added at -70°C for 15 mm. Reaction was continued at the same temperature for another 2 h. After completion of reaction (monitored by TLC), RM was quenched with sat. Na2SO4 solution and extracted with EtOAc (3x250 mL). The organiclayer was washed with water (500 mL), brine (500 mL), dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure to get the crude product which was purified by flash CC to afford 5- bromo-3-chloropicolinaldehyde (5.0 g, 71percent) as brown gum.
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 20h;
Example 99[0344] [Formula 123] [0345] 1) In N,N-dimethylformamide (24 mL) was dissolved 5-bromo-3-chloropyridine-2- carboxylic acid (2.36 g), 1-hydroxybenzotriazole (2.2 g) and 3-ethyl-3-(3-dimethyl- aminopropyl)carbodiimide hydrochloride (2.87 g), Nu,Omicron-dimethylhydroxylamine hydrochloride (1.27 g) and triethylamine (1.95 mL) was added to the solution, and the resulting mixture was stirred at room temperature for 20 hours. Water was added to the obtained residue, extracted with ethyl acetate, and the organic layer was washed with water and then with a saturated brine. After drying the mixture over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure to obtain 5- bromo-3-chloro-N-methoxy-N-methylpyridine-2-carboxamide (2.67 g).MS (m/z): 279/281/283 [M+H]+
9.11 g
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; for 16h;Cooling with ice;
9.02 g of <strong>[1189513-51-6]5-bromo-3-chloropyridine-2-carboxylic acid</strong>, 9.10 g of 1-ethyl-3- (3- dimethylaminopropyl) carbodiimide hydrochloride, 4.11 g of N, O-dimethylhydroxylamine hydrochloride, To a mixture of 0.93 g of 4- (dimethylamino) pyridine and 100 mL of chloroform, 10.6 mL of triethylamine was added dropwise under ice cooling. After raising the temperature to room temperature and stirring for 16 hours, a saturated aqueous sodium hydrogen carbonate solution was added and the mixture was extracted with chloroform. The obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to column chromatography to obtain Intermediate 11 represented by the following formula9.11 g was obtained.
With lithium aluminium tetrahydride; In tetrahydrofuran; at -70℃; for 2.25h;
To a solution of 5-bromo-3-chloro-N-methoxy-N-methylpicolinamide (9.0 g, 32.3 mmol, 1 eq) in THF (100 mL), the LAH solution (IM in THF) (16.12 mL, 16.1 mmol, 0.5 eq) was added at -70C for 15 mm. Reaction was continued at the same temperature for another 2 h. After completion of reaction (monitored by TLC), RM was quenched with sat. Na2SO4 solution and extracted with EtOAc (3x250 mL). The organiclayer was washed with water (500 mL), brine (500 mL), dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure to get the crude product which was purified by flash CC to afford 5- bromo-3-chloropicolinaldehyde (5.0 g, 71%) as brown gum.
2) In tetrahydrofuran (27 mL) was dissolved 5-bromo-3-chloro-N-methoxy-N-methyl- pyridine-2-carboxamide (2.66 g), the mixture was cooled under nitrogen atmosphere at -70C or lower, and a tetrahydrofuran (5 mL) suspension of lithium aluminum hydride (180 mg) was added dropwise to the mixture. The mixture was stirred at -70C or lower for 2 hours, then, water (10 mL) and a saturated brine (10 mL) were added dropwise to the mixture. A temperature of the mixture was raised to room temperature, the mixture was extracted with ethyl acetate, and the organic layer was washed with water and a saturated brine. The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate=100:0 to 90: 10) to obtain a mixture of an aldehyde compound and an aldehyde equivalent (2.1 g). To water (36 mL) were added 3,3-dibromo-l,l,l-trifluoropropan-2-one (6.61 g) and sodium acetate (4.02 g) and the mixture was stirred at 95C for 30 minutes. An aqueous solution obtained by ice-cooling the mixture was added to a mixture comprising the previously obtained mixture of the aldehyde/ aldehyde equivalent (1.8 g), 28% aqueous ammonia (18 mL) and methanol (36 mL) at room temperature, and the resulting mixture was stirred at room temperature for 17 hours. The reaction mixture was concentrated, the residue was extracted with ethyl acetate, and the organic layer was washed with a saturated brine, and then, dried over anhydrous magnesium sulfate. After concentrating the mixture under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate=80:20), and the obtained solid was collected by filtration, washed with isopropyl ether and dried to obtain 5-bromo-3-chloro-2-[5- (trifluoromethyl)-lH-imidazol-2-yl]pyridine (935 mg).MS (m/z): 326/328/330 [M+H]+
To a solution of <strong>[1189513-51-6]5-bromo-3-chloropicolinic acid</strong> (15.0 g, 63.424 mmol, 1 eq) in DMF (150 mL), EDCI(17.72 g, 114.16 mmol, 1.8 eq), HOBT (13.71 g, 101.47 mmol, 1.6 eq) and DIPEA (23.0 mL, 164.9 mmol,2.6 eq) was added at RT. After stirring the RM at RT for 10 mm MeNH(OMe) (7.95 g, 82.45 mmol, 1.3 eq)was added and the mixture was stirred at RT for 16 h. After completion of reaction (monitored by TLC), RM was diluted with water (250 mL) and extracted with EtOAc (3x250 mL). The organic layer was washed with brine (500 mL), dried over Na2SO4, filtered and evaporated under reduced pressure to get the crude product which was purified by flash CC to afford 5-bromo-3-chloro-N-methoxy-N- methylpicolinamide (9.0 g, 51percent) as white solid.