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The reaction was carried out, under nitrogen, in a 2 L.x.4 neck flask equipped with a mechanical stirrer, water condenser (with gas inlet), and a thermocouple. The reactor was charged with 5-methylpyrazinecarboxylic acid (300.84 g), AMBERLYST.(R). 15 ion exchange resin (60.17 g), and ethanol (1004 g). The mixture was stirred at reflux for about 16 h after which the reaction was found to be complete by GC or GC/MS. The resin was removed by pressure filtration and rinsed with ethanol. The rinse was added to the alcohol solution of the ester. Evaporation of the solvent under reduced pressure gave 336.7 g (93percent) of 5-methylpyrazinecarboxylic acid, ethyl ester that was suitable for use in the following examples. It was also possible to pass the material through a thin film evaporator at 125° C./3 mm. The material from this distillation was almost colorless and crystallizes at about 20° C.
88%
for 5 h; Heating / reflux
A. Ethyl 5-methyl-2-pyrazinecarboxylate 5-methyl pyrazine-2-carboxylic acid (6.65 g, 48.14 mmol) was refluxed in 50 mL of EtOH containing a few drops of H2SO4 for 5h and then cooled and concentrated. The residue was redissolved in EtOAc and washed 1 x NaHCO3, 1 x brine and the organics dried (Na2SO4), filtered and concentrated to give the title compound (7.05 g, 42.42 mmol, 88percent yield) as a pale yellow oil :'H NMR (CDCI3, 400 MHz) 8 9.16 (s, 1H), 8.55 (s, 1H), 4.47 (dd, J= 14.1, 7.1 Hz), 2.64 (s, 3H), 1.42 (t, J = 7. 2 Hz, 3H).
84%
Stage #1: at 78℃; for 8 h; Heating / reflux Stage #2: at 20℃;
EXAMPLE 2 The reaction is carried out, under nitrogen, in a 1 L*4 neck flask equipped with a mechanical stirrer, water condenser (with gas inlet), and a thermocouple. The reactor is charged with 5-methylpyrazinecarboxylic acid (100 g), ethanol,(300 g) and sulfuric acid (2 g). The contents are refluxed for eight hours at 78° C. The reaction mixture is cooled to ambient temperature and sodium bicarbonate (4 g) is added. About 75percent of the solvent is removed under reduced pressure and the resulting suspension is allowed to stand overnight. The solids are filtered and washed with cold methanol (2*80 g). Drying under oven (25 inches of Hg) yielded 101.25 g (84percent) of 5-methyl-2-pyrazonecarboxylic acid, ethyl ester.
84%
Stage #1: for 8 h; Heating / reflux Stage #2: at 20℃;
The reaction is carried out, under nitrogen, in a 1 L.x.4 neck flask equipped with a mechanical stirrer, water condenser (with gas inlet), and a thermocouple. The reactor is charged with 5-methylpyrazinecarboxylic acid (100 g), ethanol (300 g) and sulfuric acid (2 g). The contents are refluxed for eight hours at 78° C. The reaction mixture is cooled to ambient temperature and sodium bicarbonate (4 g) is added. About 75percent of the solvent is removed under reduced pressure and the resulting suspension is allowed to stand overnight. The solids are filtered and washed with cold methanol (2.x.80 g). Drying under oven (25 inches of Hg) yielded 101.25 g (84percent) of 5-methyl-2-pyrazonecarboxylic acid, ethyl ester.
74%
for 4 h; Reflux
To the solution of 5-methyl-2-pyrazine carboxylic acid (1) (0.01 mol) in absolute ethyl alcohol (10 mL), conc. H2SO4 (2 mL) was added. The mixture was refluxed for 4 hwith constant stirring. After completion of the reaction (monitored by the TLC), the mixture was poured into ice-cold water. Crude product was collected by filtration, washed with 10 percent NaHCO3 solution, dried and recrystallized from ethyl alcohol to get pure 5-methyl-2-pyrazine carboxylic acid ethyl ester (2).
Reference：
[1] Patent: US2005/261312, 2005, A1, . Location in patent: Page/Page column 2
[2] Patent: WO2003/76440, 2003, A1, . Location in patent: Page/Page column 74-75
[3] Patent: US2005/239803, 2005, A1, . Location in patent: Page/Page column 2
[4] Patent: US2005/261312, 2005, A1, . Location in patent: Page/Page column 2
[5] Asian Journal of Chemistry, 2016, vol. 28, # 11, p. 2453 - 2456
With AMBERLYST 15 ion exchange resin; for 16.0h;Heating / reflux;
The reaction was carried out, under nitrogen, in a 2 L×4 neck flask equipped with a mechanical stirrer, water condenser (with gas inlet), and a thermocouple. The reactor was charged with 5-methylpyrazinecarboxylic acid (300.84 g), AMBERLYST 15 ion exchange resin (60.17 g), and ethanol (1004 g). The mixture was stirred at reflux for about 16 h after which the reaction was found to be complete by GC or GC/MS. The resin was removed by pressure filtration and rinsed with ethanol. The rinse was added to the alcohol solution of the ester. Evaporation of the solvent under reduced pressure gave 336.7 g (93%) of 5-methylpyrazinecarboxylic acid, ethyl ester that was suitable for use in the following examples. It was also possible to pass the material through a thin film evaporator at 125 C./3 mm. The material from this distillation was almost colorless and crystallizes at about 20 C.
88%
With sulfuric acid; for 5.0h;Heating / reflux;
A. Ethyl 5-methyl-2-pyrazinecarboxylate 5-methyl pyrazine-2-carboxylic acid (6.65 g, 48.14 mmol) was refluxed in 50 mL of EtOH containing a few drops of H2SO4 for 5h and then cooled and concentrated. The residue was redissolved in EtOAc and washed 1 x NaHCO3, 1 x brine and the organics dried (Na2SO4), filtered and concentrated to give the title compound (7.05 g, 42.42 mmol, 88% yield) as a pale yellow oil :'H NMR (CDCI3, 400 MHz) 8 9.16 (s, 1H), 8.55 (s, 1H), 4.47 (dd, J= 14.1, 7.1 Hz), 2.64 (s, 3H), 1.42 (t, J = 7. 2 Hz, 3H).
84%
EXAMPLE 2 The reaction is carried out, under nitrogen, in a 1 L*4 neck flask equipped with a mechanical stirrer, water condenser (with gas inlet), and a thermocouple. The reactor is charged with 5-methylpyrazinecarboxylic acid (100 g), ethanol,(300 g) and sulfuric acid (2 g). The contents are refluxed for eight hours at 78 C. The reaction mixture is cooled to ambient temperature and sodium bicarbonate (4 g) is added. About 75% of the solvent is removed under reduced pressure and the resulting suspension is allowed to stand overnight. The solids are filtered and washed with cold methanol (2*80 g). Drying under oven (25 inches of Hg) yielded 101.25 g (84%) of 5-methyl-2-pyrazonecarboxylic acid, ethyl ester.
84%
The reaction is carried out, under nitrogen, in a 1 L×4 neck flask equipped with a mechanical stirrer, water condenser (with gas inlet), and a thermocouple. The reactor is charged with 5-methylpyrazinecarboxylic acid (100 g), ethanol (300 g) and sulfuric acid (2 g). The contents are refluxed for eight hours at 78 C. The reaction mixture is cooled to ambient temperature and sodium bicarbonate (4 g) is added. About 75% of the solvent is removed under reduced pressure and the resulting suspension is allowed to stand overnight. The solids are filtered and washed with cold methanol (2×80 g). Drying under oven (25 inches of Hg) yielded 101.25 g (84%) of 5-methyl-2-pyrazonecarboxylic acid, ethyl ester.
74%
With sulfuric acid; for 4.0h;Reflux;
To the solution of 5-methyl-2-pyrazine carboxylic acid (1) (0.01 mol) in absolute ethyl alcohol (10 mL), conc. H2SO4 (2 mL) was added. The mixture was refluxed for 4 hwith constant stirring. After completion of the reaction (monitored by the TLC), the mixture was poured into ice-cold water. Crude product was collected by filtration, washed with 10 % NaHCO3 solution, dried and recrystallized from ethyl alcohol to get pure 5-methyl-2-pyrazine carboxylic acid ethyl ester (2).
With sulfuric acid; dihydrogen peroxide;sodium tungstate; In water; at 70℃; for 12.42h;pH 3.5;
The reaction was carried out, under nitrogen, in a 500 mL×4 neck flask equipped with a mechanical stirrer, water condenser (with gas inlet), and a thermocouple. The reactor was charged with sodium tungstate dihydrate (1.35 g) and water (30 g). The mixture was stirred to dissolve the solid (10 minutes). Aqueous sulfuric acid (50%) was added bringing the pH down to about 3.5. Aqueous 35% hydrogen peroxide (22.36 g) was added and the solution was stirred for 15 minutes. 5-Methylpyrazinecarboxylic acid ethyl ester (27.27 g) was then added. The reaction mixture was warmed to 70 C. and then stirred for a total of 12 hours after which the reaction was checked by GC or GC/MS and was found to be complete. The resulting solution was concentrated under reduced pressure to yield a light yellow solid. The reaction mixture was cooled in an ice-bath for 3 hours. The product was collected by filtration and washed with ice water (25 g). Drying the solid at 60 C. under house vacuum yielded 20.57 g (69%) of the ester N-oxide.
With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; for 4.0h;Heating / reflux; Irradiation;
Ethyl 5-methyl-2-pyrazinecarboxylate (10.0 g, 60.18 mmol), benzoyl peroxide (1. 46 g, 6. 02 mmol) and N-bromo succinimide (11. 78 g, 66. 19 mmol) in 80 mL CCl4 was heated to reflux while a 75W tungsten lamp was shining on the reaction mixture. After 4h the reaction mixture was cooled and the precipitate filtered off. The red filtrate was concentrated and the residue redissolved in EtOAc and washed with sat'd NaHC03, 5% Na2S203, brine and the organics dried (Na2SO4), filtered and concentrated. Chromatography on silica gel using 1: 1 Hexanes: EtOAc eluted the product. After concentration the title compound (6.64 g, 27.08 mmol, 45% yield) was isolated as a yellow oil :'H NMR (CDC13, 400 MHz) 8 9.22 (s, 1H), 8.80 (s, 1H), 4. 58 (s, 2H), 4.49 (dd, J= 14.3, 7.1 Hz, 2H), 1.43 (t, J= 7.2 Hz, 3H).
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; for 3.0h;Reflux;
Preparative Example 1 5.40 g of <strong>[41110-34-3]ethyl 5-methylpyrazine-2-carboxylate</strong> was dissolved in 54.0 mL of carbon tetrachloride, and 5.78 g of 1-bromosuccinimide and 267 mg of 2,2'-azobis(isobutyronitrile) were added thereto, followed by heating with reflux for 3 hours. The reaction liquid was left to be cooled to room temperature and then concentrated under reduced pressure, and the obtained residue was suspended in 100 mL of ethyl acetate and the insoluble materials were separated by filtration. The filtrate was washed with a saturated aqueous sodium hydrogen carbonate solution, water, and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1 to 1:1) to obtain 2.62 g of ethyl 5-(bromomethyl)pyrazine-2-carboxylate.
With hydrazine hydrate; In ethanol; for 3.0h;Reflux;
A mixture of 5-methyl-2-pyrazinecarboxylic acid ethyl ester (2) (0.01 mol) and hydrazine hydrate (0.02mol) in ethyl alcohol (20 mL) was refluxed for 3 h with consistent stirring. After realization of the reaction (examined by the TLC), the reaction mixture is cooled to room temperature and filtered. The crude product was recrystallized from ethanol to offer pure 5-methyl-2-pyrazine carboxylic acid hydrazide (3).
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