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With hydrogenchloride; In 1,4-dioxane; at 20 - 70℃;
15 ml (60 mmol) of a 4M solution of hydrogen chloride in dioxane were added dropwise to 3.00 g (21.9 mmol) of 5-methylpyridine-2-carboxylic acid in 40 ml of methanol, and the mixture was stirred at room temperature overnight. 10 ml (40 mmol) of a 4M solution of hydrogen chloride in dioxane were then added dropwise, and the mixture was initially stirred at room temperature overnight and then at 70 C. overnight. Methanol and a further 20 ml (80 mmol) of a 4M solution of hydrogen chloride in dioxane were added and the mixture was stirred at reflux overnight. The mixture was then concentrated under reduced pressure, and water and dichloromethane were added to the residue. After phase separation, the aqueous phase was washed twice with dichloromethane and the combined organic phases were washed with sodium chloride solution and then dried over sodium sulphate. After filtration, the filtrate was concentrated under reduced pressure and the residue was dried under high vacuum. This gave 2.08 g (59% of theory) of the desired product. LC-MS (Method 1A): Rt=0.55 min; MS (ESIpos): m/z=152 [M+H]+
2.08g
With hydrogenchloride; In 1,4-dioxane; at 20 - 70℃;Reflux;
The 15ml (60mmol) in dioxane was added dropwise a 4M solution of hydrogen chloride in 40ml of methanol 3.00g (21.9mmol) of 5-methyl-pyridine-2-carboxylic acid, and the mixture was stirred overnight at room temperature .Then added dropwise 10ml (40mmol) in dioxane solution of 4M hydrogen chloride, and the mixture was stirred first overnight at room temperature and then stirred overnight at 70 .The methanol and additional 20ml (80mmol) of 4M solution of hydrogen chloride in dioxane was added and the mixture was stirred overnight at reflux.The mixture was then concentrated under reduced pressure, and water and dichloromethane were added to the residue.After the phases were separated, the aqueous phase was washed with dichloromethane and washed twice and the combined organic phases were washed with sodium chloride solution and then dried over sodium sulfate.After filtration, the filtrate was concentrated and the residue was dried under high vacuum under reduced pressure.The thus obtained 2.08g (59%, based on the theoretical value) of the desired product.
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; for 5h;Reflux;
A mixture of methyl 2-methylisonicotinate (leq) and a,a'-Azoisobutyronitrile (AIBN) (10%) was dissolved in carbontetrachloride (CC14). The solution was heated at 48C and N-bromosuccinimide (NBS) (1.1 eq) solution in CC14 was added drop wise and stirred for 5 hours. The reaction was cooled to room temperature and the solvent evaporated. The mixture was then extracted using dichloromethane and water followed by washing the organic layer with brine. The organic layer was dried over sodium sulfate, filtered, evaporated and the crude product was purified using SiO2 column chromatography and eluted with the solvent system EtOAc: hexanes = 2:3 to obtain pure product as white powder and the yield was 66%. 1H-NMR (400 MHz, DMSO-d6): d 8.78 (t, J= 1.48 Hz, 1H), 8.06 (d, J= 1.36 Hz, 2H), 4.82 (s, 2H), 3.89 (s, 3H). HRMS (ESI) m/z found 229.98 [M+H]+, Calculated 230.0586 [M]+.
57%
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; at 80℃; for 16h;
5-(Bromomethyl)pyridine-2-carboxylate In a 500-mL round bottom flask, NBS (14.13 g, 79.38 mmol, 1.20 equiv) and AIBN (217 mg, 1.32 mmol, 0.02 equiv) were added to a solution of methyl 5-methylpyridine-2-carboxylate (10 g, 66.15 mmol, 1.00 equiv) in CCl4 (200 mL) at room temperature. The resulting solution was stirred for 16 h at 80 C. After the reaction was done, the reaction mixture was concentrated under reduced pressure. The residue was purified in a silica gel column eluting with ethyl acetate in petroleum ether (5% to 25% gradient) to afford methyl 5-(bromomethyl)pyridine-2-carboxylate (9.6 g, 57%) as yellow solid. MS: m/z=229.9 [M+H]+
50%
With N-Bromosuccinimide;VAZO; In tetrachloromethane; for 18h;Heating / reflux;
To a solution of 5-methylpyridirie-2-carboxylic acid methyl ester (140 mg, 0.93 mmol) in CCl4 (8 mL) was added NBS (181 mg, 1.02 mmol) and VAZO (23 mg, 0.09 mmol). The reaction was stirred at reflux for 18 h. Standard work-up and purification by flash chromatography on silica gel (10% ether in CH2Cl2) afforded 5-bromomethylpyridine-2- carboxylic acid methyl ester (107 mg, 50%).
24%
With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; for 18h;Reflux;
INTERMEDIATE 37 - PREPARATION of Methyl 5-(bromomethyl)picolinate. To a mixture of methyl 5-methylpicolinate (1.25 g; 8.27 mmol) in carbon tetrachloride (45 mL) was added N-bromosuccinimide (1.78 g, 9.92 mmol) and benzoyl peroxide (0.205 g; 0.827 mmol). The mixture was refluxed for 18 hours and the resulting suspension was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluent 0 to 8% ethyl acetate in dichloromethane) to 0.450g (24%) of methyl 5- (bromomethyl)picolinate as a beige solid.ESI/APCI(+): 230 (M+H).
24%
With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; for 18h;Reflux;
To a mixture of methyl 5-methylpicolinate (1.25 g; 8.27 mmol) in carbon tetrachloride (45 mL) was added N-bromosuccinimide (1.78 g, 9.92 mmol) and benzoyl peroxide (0.205 g; 0.827 mmol). The mixture was refluxed for 18 hours and the resulting suspension was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluent 0 to 8% ethyl acetate in dichloromethane) to 0.450 g (24%) of methyl 5-(bromomethyl)picolinate as a beige solid. [0623] ESI/APCI(+): 230 (M+H).
11%
With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane;Reflux;
Example 8. Synthesis of 1-548-101. Into a 2000-mL 4-necked round-bottom flask, was placed a solution of methyl 5-methylpicolinate (85 g, 539.68 mmol, 1.00 equiv, 96%) in CC14 (1000 mL), N-bromosuccinimide (1 10 g, 617.98 mmol, 1.10 equiv), and benzoyl peroxide (3.5 g, 14.45 mmol, 0.03 equiv). The resulting solution was heated to reflux overnight. The solids were removed by filtration. The filtrate was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1 :30-l :5). This resulted in 15 g (1 1%) of methyl 5-(bromomethyl)picolinate as a light-yellow solid.LC-MS: (ES, m/z): 232 [M+H]+
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