Water → 5-Methoxy-2-pyrazinecarboxylic acid

Temperature

65 °C

5-Chloropyrazine-2-carboxylic acid (5.0 g, 0.032 mol) was charged to a round-bottom flask equipped with a thermocouple, overhead stirrer and reflux condenser. Methanol (37.5 mL, 0.926 mol) was charged followed by conc. sulfuric acid (0.2 mL, 0.004 mol). The 3-neck flask was equipped with a heating mantle, and then the reaction mixture was heated to ca. 65.0° C. (T internal). The reaction mixture continued to stir at ca. 65.0° C. (T internal) for ca. 4 h. The reaction mixture cooled to ca. 25.8° C. (T internal). Methanol (12 mL, 0.31 mol) was charged and the slurry continued to stir at ca. 22.3° C. (T internal) for ca. 15 min then cooled to ca. 10.0° C. (T internal) under an atmosphere of nitrogen. 25% Sodium methoxide in methanol (1:3, Sodium methoxide:Methanol, 7.7 mL) was charged to flask while temperature remained below 30.0° C. (T internal). The reaction mixture was adjusted to 20.4° C. (T internal). After 30 min., sodium hydroxide (2.0 g, 0.04 mol) and water (37.5 mL, 2.08 mol) were combined to form a solution, and then the solution was charged to the reaction mixture. Water (50.0 mL, 2.78 mol) was charged and then the reaction mixture was heated to 40.0° C. (T internal) for ca. 60 mins. The heating mantle was removed, and then the reaction mixture cooled to ca. 25.4° C. (T internal). 38% aq. HCl Solution (38:62, hydrogen chloride:water, 4.0 mL) was added at a rate (ca. 5 min.) such that the temperature remained below 30.0° C. (T internal). The thick slurry was stirred for 1 h at ca. 21.4° C. (T internal), and then filtered over a sintered funnel. The solids were rinsed with water (10.0 mL, 0.555 mol) and dried under vacuum overnight to afford 5-methoxypyrazine-2-carboxylic acid (3.59 g). 1H NMR (500 MHz, DMSO) δ 13.24 (1H, br s), 8.79 (1H, d, J=1.2 Hz), 8.37 (1H, d, J=1.2 Hz), 3.98 (s, 3H); 13C NMR (125 MHz, DMSO) δ 165.36, 161.88, 143.88, 136.82, 135.55, 54.69.

1. customequipped with a thermocouple, overhead stirrer
2. temperaturereflux condenser
3. customThe 3-neck flask was equipped with a heating mantle
4. temperatureThe reaction mixture cooled to ca. 25.8° C. (T internal)
5. stirringto stir at ca. 22.3° C. (T internal) for ca. 15 min
6. temperaturethen cooled to ca. 10.0° C. (T internal) under an atmosphere of nitrogen
7. customremained below 30.0° C.
8. customwas adjusted to 20.4° C.
9. waitAfter 30 min.
10. customto form a solution
11. additionthe solution was charged to the reaction mixture
12. temperaturethe reaction mixture was heated to 40.0° C. (T internal) for ca. 60 mins
13. customThe heating mantle was removed
14. temperaturethe reaction mixture cooled to ca. 25.4° C. (T internal)
15. addition38% aq. HCl Solution (38:62, hydrogen chloride:water, 4.0 mL) was added at a rate (ca. 5 min.) such that the temperature
16. customremained below 30.0° C.
17. stirringThe thick slurry was stirred for 1 h at ca. 21.4° C. (T internal)
18. filtrationfiltered over a sintered funnel
19. customdried under vacuum overnight

ORD record

ord-4cbcfc1f10624797a95320f99c0a59f5

Source dataset

uspto-grants-2015_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08940734B2