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b. A solution of bromine (2.57 ml) in chloroform (40 mL) was slowly added over 30 minutes to a solution of 6-aminopyridine-2-carboxylic acid methyl ester (6.92 g) in chloroform (300 mL). The mixture was stirred overnight at room temperature and then loaded on silica and purified by chromatography (Si02, Heptane/EA) to afford 6-amino-5-bromopyridine-2-carboxylic acid methyl ester as a solid (2 g, 19percent) along with 6-amino-3-bromopyridine-2-carboxylic acid methyl ester (3 g, 29percent) and 6-amino-3,5-dibromopyridine-2-carboxylic acid methyl ester (2.6 g, 18percent). 1H NMR (400 MHz, CHLOROFORM-d): 3.97 (s, 3H), 5.22 (br. s., 2H), 7.38 (d, J=7.8 Hz, 1H) and 7.79 (d, J=7.8 Hz, 1H)
19%
With bromine In chloroform at 20℃;
b. A solution of bromine (2.57 ml) in chloroform (40 mL) was slowly added over 30 minutes to a solution of 6-aminopyridine-2-carboxylic acid methyl ester (6.92 g) in chloroform (300 mL). The mixture was stirred overnight at room temperature and then loaded on silica and purified by chromatography (SiO2, Heptane/EA) to afford 6-amino-5-bromopyridine-2-carboxylic acid methyl ester as a solid (2 g, 19percent) along with 6-amino-3-bromopyridine-2-carboxylic acid methyl ester (3 g, 29percent) and 6-amino-3,5-dibromopyridine-2-carboxylic acid methyl ester (2.6 g, 18percent). 1H NMR (400 MHz, CHLOROFORM-d): 3.97 (s, 3H), 5.22 (br. s., 2H), 7.38 (d, J=7.8 Hz, 1H) and 7.79 (d, J=7.8 Hz, 1H)
b. A solution of bromine (2.57 ml) in chloroform (40 mL) was slowly added over 30 minutes to a solution of 6-aminopyridine-2-carboxylic acid methyl ester (6.92 g) in chloroform (300 mL). The mixture was stirred overnight at room temperature and then loaded on silica and purified by chromatography (Si02, Heptane/EA) to afford 6-amino-5-bromopyridine-2-carboxylic acid methyl ester as a solid (2 g, 19percent) along with 6-amino-3-bromopyridine-2-carboxylic acid methyl ester (3 g, 29percent) and 6-amino-3,5-dibromopyridine-2-carboxylic acid methyl ester (2.6 g, 18percent). 1H NMR (400 MHz, CHLOROFORM-d): 3.97 (s, 3H), 5.22 (br. s., 2H), 7.38 (d, J=7.8 Hz, 1H) and 7.79 (d, J=7.8 Hz, 1H)
19%
With bromine In chloroform at 20℃;
b. A solution of bromine (2.57 ml) in chloroform (40 mL) was slowly added over 30 minutes to a solution of 6-aminopyridine-2-carboxylic acid methyl ester (6.92 g) in chloroform (300 mL). The mixture was stirred overnight at room temperature and then loaded on silica and purified by chromatography (SiO2, Heptane/EA) to afford 6-amino-5-bromopyridine-2-carboxylic acid methyl ester as a solid (2 g, 19percent) along with 6-amino-3-bromopyridine-2-carboxylic acid methyl ester (3 g, 29percent) and 6-amino-3,5-dibromopyridine-2-carboxylic acid methyl ester (2.6 g, 18percent). 1H NMR (400 MHz, CHLOROFORM-d): 3.97 (s, 3H), 5.22 (br. s., 2H), 7.38 (d, J=7.8 Hz, 1H) and 7.79 (d, J=7.8 Hz, 1H)
b. A solution of bromine (2.57 ml) in chloroform (40 mL) was slowly added over 30 minutes to a solution of 6-aminopyridine-2-carboxylic acid methyl ester (6.92 g) in chloroform (300 mL). The mixture was stirred overnight at room temperature and then loaded on silica and purified by chromatography (Si02, Heptane/EA) to afford 6-amino-5-bromopyridine-2-carboxylic acid methyl ester as a solid (2 g, 19percent) along with 6-amino-3-bromopyridine-2-carboxylic acid methyl ester (3 g, 29percent) and 6-amino-3,5-dibromopyridine-2-carboxylic acid methyl ester (2.6 g, 18percent). 1H NMR (400 MHz, CHLOROFORM-d): 3.97 (s, 3H), 5.22 (br. s., 2H), 7.38 (d, J=7.8 Hz, 1H) and 7.79 (d, J=7.8 Hz, 1H)
19%
With bromine In chloroform at 20℃;
b. A solution of bromine (2.57 ml) in chloroform (40 mL) was slowly added over 30 minutes to a solution of 6-aminopyridine-2-carboxylic acid methyl ester (6.92 g) in chloroform (300 mL). The mixture was stirred overnight at room temperature and then loaded on silica and purified by chromatography (SiO2, Heptane/EA) to afford 6-amino-5-bromopyridine-2-carboxylic acid methyl ester as a solid (2 g, 19percent) along with 6-amino-3-bromopyridine-2-carboxylic acid methyl ester (3 g, 29percent) and 6-amino-3,5-dibromopyridine-2-carboxylic acid methyl ester (2.6 g, 18percent). 1H NMR (400 MHz, CHLOROFORM-d): 3.97 (s, 3H), 5.22 (br. s., 2H), 7.38 (d, J=7.8 Hz, 1H) and 7.79 (d, J=7.8 Hz, 1H)
A solution of methyl 6-amino-3-bromopyridine-2-carboxylate (20.62 g) (T. R. Kelly and F. Lang, J Org. Chem. 61, 1996, 4623-4633) in chloroform (570 ml) was treated dropwise over 2 hours with bromine (4.62 ml) in chloroform (115 ml) and stirred 16 hours. The solution was washed with excess aqueous sodium bicarbonate, dried and evaporated. Crystallisation from EtOAc/hexane gave the bromopyridine (13.5 g). MS (APCI+) m/z 309,311, 313 (MH+, 70%), 295,297, 299 (100%).
Preparation 12; Preparation of 7-methyl-3-oxo-3,4-dihydro-2/-/-pyrido[3,2-ibiri ,41thiazine-6-carbaldehvde; a) Methyl 7-bromo-3-oxo-3,4-dihydro-2/-/-pyrido[3,2-lb][1 ,4]thiazine-6-carboxylate; A solution of ethyl 2-mercaptoacetate (18.4 ml) in DMF (650 ml) was ice-cooled and treated with sodium hydride (6.78 g of a 60% dispersion in oil). After 1 hour <strong>[443956-21-6]methyl 6-amino-3,5-dibromopyridine-2-carboxylate</strong> (50 g) (T.R. Kelly and F. Lang, J. Org. Chem. 61, 1996, 4623-4633) was added and the mixture stirred for 16 hours at room temperature. The solution was partitioned between EtOAc and water(2 litres each), shaken, separated and the EtOAc along with solid that crystallised out washed with water (2 x 1 litre). The EtOAc was evaporated to low volume, solid filtered, washed with water and EtOAc and dried. The filtrate was separated, EtOAc dried and evaporated. The residue was taken up in AcOH and heated to 1000C overnight, then evaporated. The white solid was triturated uder EtOAc, filtered off, washed with a little EtOAc and dried (Na2SO4). Combining the 2 batches of ester gave 33.35g (70%). MS (APCI") m/z 223([M-H]-, 100%).
64%
To a solution of ethyl-2-mercaptoacetate (2.97 mL, 3.26 g, 27.1 mmol) in DMF(100 mL) at 00C was added NaH (1.08 g, 27.1 mmol, 60% in mineral oil). Afer stirrring for 1h, methyl-6-amino-3,5-dibromopyridine-2-carboxylate (8.0 g, 25.8 mmol) was added. The mixture was warmed up to room temperature and stirred for 18 hr. It was then treated with addition of another batch of the mixture of NaH (0.124 g, 5.16 mmol) and ethyl-2-mercaptoacetate (0.57 mL, 5.16 mmol) which was prepared as indicated above. The resulting solution was diluted with ethyl acetate and water. The organic layer was separated and concentrated at high temperature to afford a residue. The residue was dissolved in acetic acid (100 mL) and heated at 1000C for 18 hr. The mixture was cooled down to room temperature affording a precipitate. The percipitate was triturated with ethyl acetate, filtered and dried to provide the title compound as an off-white solid (5.0 g, 64%): LC/MS (ES) m/e 304 (M+H)+.
b. A solution of bromine (2.57 ml) in chloroform (40 mL) was slowly added over 30 minutes to a solution of 6-aminopyridine-2-carboxylic acid methyl ester (6.92 g) in chloroform (300 mL). The mixture was stirred overnight at room temperature and then loaded on silica and purified by chromatography (Si02, Heptane/EA) to afford 6-amino-5-bromopyridine-2-carboxylic acid methyl ester as a solid (2 g, 19%) along with 6-amino-3-bromopyridine-2-carboxylic acid methyl ester (3 g, 29%) and 6-amino-3,5-dibromopyridine-2-carboxylic acid methyl ester (2.6 g, 18%). 1H NMR (400 MHz, CHLOROFORM-d): 3.97 (s, 3H), 5.22 (br. s., 2H), 7.38 (d, J=7.8 Hz, 1H) and 7.79 (d, J=7.8 Hz, 1H)
18%; 29%; 19%
With bromine; In chloroform; at 20℃;
b. A solution of bromine (2.57 ml) in chloroform (40 mL) was slowly added over 30 minutes to a solution of 6-aminopyridine-2-carboxylic acid methyl ester (6.92 g) in chloroform (300 mL). The mixture was stirred overnight at room temperature and then loaded on silica and purified by chromatography (SiO2, Heptane/EA) to afford 6-amino-5-bromopyridine-2-carboxylic acid methyl ester as a solid (2 g, 19%) along with 6-amino-3-bromopyridine-2-carboxylic acid methyl ester (3 g, 29%) and 6-amino-3,5-dibromopyridine-2-carboxylic acid methyl ester (2.6 g, 18%). 1H NMR (400 MHz, CHLOROFORM-d): 3.97 (s, 3H), 5.22 (br. s., 2H), 7.38 (d, J=7.8 Hz, 1H) and 7.79 (d, J=7.8 Hz, 1H)
A 200 mL round bottom flask was charged with methyl 6-amino-3,5- dibromopicolinate 1 (8.6g, 0.0277 mol), 2-chloroacetaldehyde (19.93 mL, 0.139 mol, 45% w/w in water) and isopropanol (100 mL). The mixture was stirred at 100 C for 9h. After this time, the reaction mixture was concentrated under reduced pressure, and the residue was partitioned between water and ethyl acetate. The organic layer was dried over sodium sulfate and the resulting residue was purified by column chromatography. The solvent was removed by Rota vapor to afford methyl 6,8-dibromoimidazo[l ,2-a]pyridine-5-carboxylate as an off- white solid.
In water; isopropyl alcohol; at 100℃; for 9h;
Example 10 Methyl 6,8-dibromoimidazo[1,2-a]pyridine-5-carboxylate A 200 mL round bottom flask was charged with <strong>[443956-21-6]methyl 6-amino-3,5-dibromopicolinate</strong> 1 (8.6 g, 0.0277 mol), 2-chloroacetaldehyde (19.93 mL, 0.139 mol, 45% w/w in water) and isopropanol (100 mL). The mixture was stirred at 100 C. for 9 h. After this time, the reaction mixture was concentrated under reduced pressure, and the residue was partitioned between water and ethyl acetate. The organic layer was dried over sodium sulfate and the resulting residue was purified by column chromatography. The solvent was removed by Rota vapor to afford methyl 6,8-dibromoimidazo[1,2-a]pyridine-5-carboxylate as an off-white solid.
methyl 6-amino-3-bromo-5-mercaptopicolinate hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
2.4 g
To a solution of ethyl 3-mercaptopropanoate (3.27 mL, 25.8 mmol) in DMF (100 mL) at 0 C was added 60% NaH (1.10 g, 27.4 mmol) and the resulting mixture was stirred for 1 h. Methyl 6-amino-3,5-dibromopicolinate (5.00 g, 16.1 mmol) was then added and the mixture was stirred at room temperature for 16 h. Water was then added and the mixture was extracted with ethyl acetate (200 mL X 2). The aqueous layer was then acidified with cone. HC1 (pH = 2) and precipitate formed was filtered, washed with water and dried under high vac to afford HC1 salt of title compound (2.4 g) as yellow solid. NMR (400 MHz, DMSO-de) delta 12.54 (br.s, 1H), 7.65 (s, 3H), 3.87 (s, 3H). LC/MS (M+H)+ = 262.65.
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