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(b) Preparation of 3-bromo-2-chloro-5-methylpyridine The product from (a) (145 g) was dissolved in concentrated hydrochloric acid (750 ml) and water (450 ml) and the solution cooled to -10 C. Sodium nitrite (54 g) in cold water (450 ml) was added dropwise with stirring over a period of 90 minutes while the mixture was kept at 5 C. The solution was stirred for a further 2 hours, and then basified with concentrated ammonia, keeping the temperature below 20 C. The solid which separated was washed with water, dried, dissolved in ether (1500 ml) and washed with cold sodium hydroxide solution (1 M; 1 liter). The ether solution was washed twice with water (1 liter portions), dried, and evaporated to give the required 3-bromo-2-chloro-5-methylpyridine.
(b) Preparation of 3-bromo-2-chloro-5-methylpyridine The product from (a) (145 g) was dissolved in concentrated hydrochloric acid (750 ml) and water (450 ml) and the solution cooled to -10 C. Sodium nitrite (54 g) in cold water (450 ml) was added dropwise with stirring over a period of 90 minutes while the mixture was kept at -5 C. The solution was stirred for a further 2 hours, and then basified with concentrated ammonia, keeping the temperature below 20 C. The solid which separated was washed with water, dried, dissolved in ether (1500 ml) and washed with cold sodium hydroxide solution (1 M; 1 liter). The ether solution was washed twice with water (1 liter portions), dried, and evaporated to give the required 3-bromo-2-chloro-5-methylpyridine.
(b) Preparation of 3-bromo-2-chloro-5-methylpyridine The product from (a) (145 g) was dissolved in concentrated hydrochloric acid (750 ml) and water (450 ml) and the solution cooled to -10 C. Sodium nitrite (54 g) in cold water (450 ml) was added dropwise with stirring over a period of 90 minutes while the mixture was kept at -5 C. The solution was stirred for a further 2 hours, and then basified with concentrated ammonia, keeping the temperature below 20 C. The solid which separated was washed with water, dried, dissolved in ether (1500 ml) and washed with cold sodium hydroxide solution (1 M; 1 liter). The ether solution was washed twice with water (1 liter portions), dried, and evaporated to give the required 3-bromo-2-chloro-5-methylpyridine.
2
[ 17282-00-7 ]
[ 17282-03-0 ]
Yield
Reaction Conditions
Operation in experiment
b)3-Bromo-2-chloro-5-methyl-pyridineTo a solution of 3-bromo-5-methyl-2-pyridinamuie (Example 64 (a)) (1.0 g) in a mixtureof concentrated hydrochloric acid (5 mL) and water (3 mL) at 0C was added a solution ofsodium nitrite (0.36 g) in water (3 mL). After the addition was complete, the reactionmixture was neutralised by the addition of 0.880 ammonia and the resulting precipitatecollected by filtration and purified by chromatography (SiOa, dichloromethane as eluant) togive the sub-title compound as a solid (0.47 g)MS: APCI(+ve) 206 (M+H+).
Sodium hydride dispersion in oil (70%, 0.68 g) was added in portions to a well stirred solution of phenol (1.33 g, 14 mmol) in DMA (100 mL). After stirring the mixture for 1 h at 50 C. <strong>[17282-03-0]3-bromo-2-chloro-5-methyl-pyridine</strong> (2.68 g, 13 mmol) was added and stirring continued for 28 h at 100 C. The cooled mixture was poured into water and extracted with diethyl ether. Organic phases were pooled, dried with Na2SO4 and the solvent was evaporated. The residue was purified by column chromatography on silica (n-heptane/ethyl acetate 8:1) to yield 1.4 g of the title compound as a colorless oil, 1H NMR (CDCl3): delta=2.27 (s, 3H), 7.12 (d, 2H), 7.19 (t, 1H), 7.39 (t, 2H), 7.76 (s, 1H), 7.88 (s, 1H).
3-Bromo-2-chloro-5-methyl-pyridine A mixture of 3-bromo-5-methyl-2(1H)-pyridinone (25 g, 0.13 mol) and phosphorus oxychloride (500 mL) was boiled with stirring for 20 h. Phosphorus oxychloride was removed by distillation and the residue was poured onto ice/water (800 mL). The mixture was adjusted to pH 8.5 with 2 N sodium hydroxide solution and extracted with diethyl ether. Organic phases were pooled, dried with Na2SO4 and the solvent was evaporated. The residue, 23.4 g of the title compound as a greyish solid was introduced into the next step without purification, MS (EI) 204.9, 206.9 (M)+.
With trichlorophosphate; for 20h;Heating / reflux;
A mixture of 3-bromo-5-methyl-2(1H)-pyridinone (25 g, 0.13 mol) and phosphorus oxychloride (500 mL) was boiled with stirring for 20 h. Phosphorus oxychloride was removed by distillation and the residue was poured onto ice/water (800 mL). The mixture was adjusted to pH 8.5 with 2 N sodium hydroxide solution and extracted with diethyl ether. Organic phases were pooled, dried with Na2SO4 and the solvent was evaporated. The residue, 23.4 g of the title compound as a greyish solid was introduced into the next step without purification, MS (EI) 204.9, 206.9 (M)+.
3-Bromo-2-butoxy-5-methyl-pyridine Sodium hydride dispersion in oil (55-65%, 1.16 g) was added in portions to a well stirred solution of 1-butanol (2.4 mL, 27 mmol) in DMF (50 mL). After stirring the mixture for 1 h at room temperature <strong>[17282-03-0]3-bromo-2-chloro-5-methyl-pyridine</strong> (5.0 g, 24 mmol) was added and stirring continued for 18 h at room temperature and for 4 h at 70 C. The cooled mixture was poured into saturated sodium bicarbonate solution and extracted with diethyl ether. Organic phases were pooled, dried with Na2SO4 and the solvent was evaporated. The residue was purified by column chromatography on silica (n-heptane/ethyl acetate 8:1) to yield 4.2 g of the title compound as a light red oil, MS (EI) 243.1, 245.1 (M)+.
Sodium hydride dispersion in oil (55-65%, 1.16 g) was added in portions to a well stirred solution of 1-butanol (2.4 mL, 27 mmol) in DMF (50 mL). After stirring the mixture for 1 h at room temperature <strong>[17282-03-0]3-bromo-2-chloro-5-methyl-pyridine</strong> (5.0 g, 24 mmol) was added and stirring continued for 18 h at room temperature and for 4 h at 70 C. The cooled mixture was poured into saturated sodium bicarbonate solution and extracted with diethyl ether. Organic phases were pooled, dried with Na2SO4 and the solvent was evaporated. The residue was purified by column chromatography on silica (n-heptane/ethyl acetate 8:1) to yield 4.2 g of the title compound as a light red oil, MS (EI) 243.1, 245.1 (M)+.
(a) Preparation of 3-bromo-2-chloro-5-pyridine carboxylic acid 3-Bromo-2-chloro-5-methylpyridine (30 g) in water (650 ml) containing potassium permanganate (60 g) was stirred and heated under reflux for 3 hours. Further potassium permanganate (20 g) was then added and the mixture heated and stirred for another 21/2 hours. The mixture was steam-distilled to remove unchanged starting material, and then filtered while hot. The residue was washed with hot water. The filtrate and washings were cooled and acidified with concentrated hydrochloric acid. The solid which separated was extracted with ether. The ether extract was dried and evaporated to give 3-bromo-2-chloropyridine-5-carboxylic acid.
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