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a 3-Bromo-6-hydroxy-4-methyl pyridine Sodium nitrite (5.44 g, 78.8 mmol) in water (14 ml) was added dropwise to 2-amino-5-bromo-4-methylpyridine (12.83 g, 68.6 mmol) in sulphuric acid (20%) (69 ml) at 0-5 C. After 1 h at 0 C. the solution was heated to reflux for 1 h. The solution was basified to pH 10 with sodium hydroxide solution (40%) and cooled to 5 C. and the precipitated product separated by filtration. Recrystallisation from ethanol gave the title compound (5.97 g, 31%) as white needles (m.p.200-201 C.); δH (D6 -DMSO) 2.17 (3H, s, CH3), 6.40 (1H, s, 3-H), 7.76 (1H, s, 6-H), 11.58 (1H, s, NH): m/z (E.I.) 189 (M+, 100%), 187 (M+, 97%); (Found: M+, 186.9634. C6 H6 NOBr requires M, 186.9633).
6-[2-{(2S,3R,4R,5S)-3,4-Dihydroxy-5-[(2S,3S)-3-((1S,2S)-2-hydroxy-1-methyl-propyl)-oxiranylmethyl]-tetrahydro-pyran-2-yl}-1-methyl-eth-(E)-ylidene]-3-methoxy-5,6-dihydro-[2]pyrindin-7-one[ No CAS ]
Production Example 35 In an atmosphere of nitrogen, sodium hydride was added under ice-cooling to a mixture of <strong>[164513-38-6]5-bromo-4-methylpyridin-2-ol</strong> and DMF, followed by stirring at room temperature for 1 hour. Then, 3-hydroxy-3-methylbutyl 4-methylbenzenesulfonate was added thereto, followed by stirring at 40C for 14 hours to obtain 4-[(5-bromo-4-methylpyridin-2-yl)oxy]2-methylbutan-2-ol and 5-bromo-1-(3-hydroxy-3-methylbutyl)-4-methylpyridin-2(1H)-one.
<Step 2> Synthesis of 4-(5-bromo-4-methylpyridin-2-yloxy)-2-methylbutan-2-ol To a suspension of sodium hydride (to which about 40% of a mineral oil was added, 0.23 g) in N,N-dimethylformamide (10 mL), <strong>[164513-38-6]5-bromo-2-hydroxy-4-methylpyridine</strong> (1.00 g) was added under ice-cooling and the resultant reaction mixture was stirred for 30 minutes. To the reaction mixture, 3-hydroxy-3-methylbutyl 4-methylbenzene sulfonate (1.51 g) was added and the resultant reaction mixture was stirred at 60 C. for 4 hours. To the reaction mixture, a aqueous solution of saturated ammonium chloride was added and the resultant reaction mixture was extracted with ethyl acetate. The organic phase was washed with saturated saline and was dried over anhydrous sodium sulfate. From the organic phase, the solvent was distilled off under reduced pressure and the resultant residue was purified by silica gel column chromatography (eluate; n-hexane:ethyl acetate=50:50 to 33:67) to obtain the subject compound (0.92 g) as a light yellow oil.
<Step 2> Synthesis of 4-(5-bromo-4-methylpyridin-2-yloxy)-2-methylbutan-2-ol To a suspension of sodium hydride (to which about 40% of a mineral oil was added, 0.23 g) in N,N-dimethylformamide (10 mL), <strong>[164513-38-6]5-bromo-2-hydroxy-4-methylpyridine</strong> (1.00 g) was added under ice-cooling and the resultant reaction mixture was stirred for 30 minutes. To the reaction mixture, 3-hydroxy-3-methylbutyl 4-methylbenzene sulfonate (1.51 g) was added and the resultant reaction mixture was stirred at 60 C. for 4 hours. To the reaction mixture, a saturated ammonium chloride aqueous solution was added and the resultant reaction mixture was extracted with ethyl acetate. The organic phase was washed with a saturated saline and was dried over anhydrous sodium sulfate. From the organic phase, the solvent was distilled off under reduced pressure and the resultant residue was purified by silica gel column chromatography (eluate; n-hexane:ethyl acetate=50:50 to 33:67) to obtain the subject compound (0.92 g) as a pale yellow oil.
With sodium hydroxide; In tetrahydrofuran; water; at 70℃;
5N aqueous solution of sodium hydroxide (5.70 mL) was added to the tetrahydrofuran solution (28 mL) of <strong>[164513-38-6]5-bromo-2-hydroxy-4-methylpyridine</strong> (1.07 g). The reaction mixture was stirred at 70C under chlorodifluoromethane gas atmosphere. The reaction mixture was cooled to room temperature after the disappearance of raw material, diluted with tert-butyl methyl ether, and extracted. The organic layer was washed by water and a saturated aqueous solution of sodium chloride, and dried with magnesium sulfate. The organic layer was concentrated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (high flash-SI, size L (made in Yamazen corporation)) to obtain a title compound (751 mg) having the following physical data. TLC:Rf 0.58 (ethyl acetate/n-hexane=5/95); 1H-NMR(CDCl3): δ 2.40 (d, J=0.7 Hz, 3 H), 6.80 (s, 1 H), 7.39 (t, J=72.9 Hz, 1 H), 8.22 (s, 1 H).
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