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First, 21.6 g of 3-amino-4-methylpyridine was added to the reaction kettle,In the cold water bath slowly dropping 72mL concentrated hydrochloric acid,Stirring to clarify after warming to 40 C, 30 ~ 60min slowly dropping 30mL 30% hydrogen peroxide, temperature control reaction 2h.After completion of the reaction, the system rhoEta = 3 was adjusted with 45% sodium hydroxide solution, extracted with trichloromethane, dried and removed to obtain the crude product. Recrystallization from petroleum ether or n-hexane gave white or pale yellow needle-like crystals of 2-chloro-3-amino-4-methylpyridine with a purity of 99.0%, a yield of 83.2%
78%
Step 2[00286] 2-chloro-4-methyl-pyridin-3 -ylamine : A solution of 4-methylpyridin-3 -amine(200 g, 1.85 mol, 1.00 equiv) in concentrated hydrochloric acid (3 L) was placed in a 5 L 3- necked round-bottom flask. Hydrogen peroxide (30%) (210 g, 1.85 mol, 1.00 equiv) was added dropwise to the solution while maintaining the temperature at 20 C. The resulting solution was allowed to react overnight at ambient temperature. Saturated aqueous sodium carbonate was added to the solution, till a pH of 8 was reached. The solution was filtered, and the filter cake was washed with water (100 ml x3). The filter cake was dissolved in ethyl acetate (300OmL) and dried over sodium sulfate. The solution was filtered, and the filtrate was concentrated in vacuo <n="74"/>using a rotary evaporator. The product (204.6 g, purity: 90%, yield:78%) of 2-chloro-4-methyl- pyridin-3-ylamine was obtained as a light red solid. The material was used in next step without further purification.
With hydrogenchloride; sodium hydroxide; chlorine; In water;
F) Preparation of 3-amino-2-chloro-4-methylpyridine STR16 3-Amino-4-methylpyridine (21.6g, 0.2 mole) was suspended in 75 ml of water at room temperature. The mixture was dissolved by the addition of 25 ml conc. hydrochloric acid. The solution was cooled to 20 C. and 15.6 g (0.22 mole) of chlorine gas was introduced through an inlet tube reaching below the surface of the reaction mixture over 25 minutes. The mixture was stirred under a nitrogen purge for an additional 30 minutes, then cooled to 10 C. and basified by the addition of 70 mL of a 12.5 N. sodium hydroxide solution. Additional water (100 mL) was added to maintain efficient agitation of the mixture. The precipitate was collected, washed with water and dried to give 14.5g of the title product. The aqueous phase was extracted with 3 times 100 mL of methylene chloride. The organic phases were washed with water, dried over magnesium sulfate, and concentrated to give an additional 9.4g, mp 62-64
23.9 g (84%)
With hydrogenchloride; sodium hydroxide; chlorine; In water;
F) Preparation of 3-Amino-2-Chloro-4-Methylpyridine STR16 3-Amino-4-methylpyridine (21.6 g, 0.2 mole) was suspended in 75 ml of water at room temperature. The mixture was dissolved by the addition of 25 ml conc. hydrochloric acid. The solution was cooled to 20 C. and 15.6 g (0.22 mole) of chlorine gas was introduced through an inlet tube reaching below the surface of the reaction mixture over 25 minutes. The mixture was stirred under a nitrogen purge for an additional 30 minutes, then cooled to 10 C. and basified by the addition of 70 mL of a 12.5 N. sodium hydroxide solution. Additional water (100 mL) was added to maintain efficient agitation of the mixture. The precipitate was collected, washed with water and dried to give 14.5 g of the title product. The aqueous phase was extracted with 3 times 100 mL of methylene chloride. The organic phases were washed with water, dried over magnesium sulfate, and concentrated to give an additional 9.4 g, mp 62-64 C. Total yield, 23.9 g (84%).
With hydrogenchloride; dihydrogen peroxide; In water; at 0 - 20℃; for 1h;
62c) 2-chloro-4-methylpyridin-3-amine A mixture of 4-methylpyridin-3-amine (0.62 g), 12N hydrogen chloride (3.8 mL) and 30% hydrogen peroxide (0.75 mL) was stirred at 0 C. to room temperature for 1 h. The mixture was neutralized with K2CO3, and the mixture was extracted with AcOEt. The organic layer was dried over MgSO4, and concentrated in vacuo to give 2-chloro-4-methylpyridin-3-amine (0.75 g) as an orange solid.MS (API+): [M+H]+ 143.1.
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