Hydrochloric Acid → Methyl 3-bromo-2-pyridinecarboxylate

Temperature

2.5 °C

A 50 L three-neck round bottom flask is equipped with a mechanical stirrer, thermocouple, nitrogen inlet and reflux condenser. The flask is charged with HCl (20 L) and 3-bromopyridine-2-carbonitrile (6790 g, 37.1 mol) (prepared, for example, essentially as described in the Alternate Procedure for Intermediate 3). The reaction mixture is heated to reflux and the starting material dissolves and a pink suspension forms. The reaction mixture is stirred for 20 h at reflux. The reaction progress is monitored by TLC (heptane:EtOAc, 1:1). No starting material is present at Rf=0.5 or intermediate amide at Rf=0.15. Once the reaction is deemed complete, the reaction mixture is cooled to 0-5° C. and then stirred at this temperature for 3 h. After this time the solids are collected by filtration (do not wash and press on a filter). The solids (3-bromopyridine-2-carboxylic acid) are dried in a vacuum oven at 50° C. with use of appropriate trapping as HCl is present in the wet product. A 50 L three-neck round bottom flask is equipped with a mechanical stirrer, thermocouple and reflux condenser. The flask is charged with MeOH (25.5 L), and 3-bromoopyridine-2-carboxylic acid (5.098 kg) followed by HCl (15 mL). The reaction mixture is heated to reflux at about 64-65° C. and stirred at this temperature for 9 h. The reaction mixture is allowed to cool to 40-50° C. and then concentrated to a paste. A 50 L separatory funnel is charged with water (12 L) and solid NaHCO3 (2338 g) and the mixture is stirred for 10-15 min. The residue from the concentrated paste is added in portions to the stirred sodium bicarbonate solution at a rate to control foaming. After all of the residue is added, EtOAc (10 L) is charged to the to the funnel and stirred for 10-15 min. The aqueous layer is separated and the organic layer washed with saturated aqueous sodium bicarbonate solution (1 L), then dried over magnesium sulfate, filtered, and concentrated. The combined aqueous layers are extracted with EtOAc (2×2 L) and the combined organic layers are washed with saturated aqueous sodium bicarbonate solution (1 L), then dried over magnesium sulfate, filtered, and concentrated along with the first extract. A pale yellow oil is obtained which solidifies on cooling. The resulting material is dried in a vacuum oven overnight at room temperature.

1. customA 50 L three-neck round bottom flask is equipped with a mechanical stirrer
2. temperaturethermocouple, nitrogen inlet and reflux condenser
3. temperatureThe reaction mixture is heated
4. temperatureto reflux
5. dissolutionthe starting material dissolves
6. temperatureat reflux
7. stirringstirred at this temperature for 3 h
8. filtrationAfter this time the solids are collected by filtration (
9. washdo not wash
10. filtrationa filter)
11. dry with materialThe solids (3-bromopyridine-2-carboxylic acid) are dried in a vacuum oven at 50° C. with use of appropriate trapping as HCl
12. customA 50 L three-neck round bottom flask is equipped with a mechanical stirrer
13. temperaturethermocouple and reflux condenser
14. additionThe flask is charged with MeOH (25.5 L), and 3-bromoopyridine-2-carboxylic acid (5.098 kg)
15. temperatureThe reaction mixture is heated
16. temperatureto reflux at about 64-65° C.
17. stirringstirred at this temperature for 9 h
18. temperatureto cool to 40-50° C.
19. concentrationconcentrated to a paste
20. additionA 50 L separatory funnel is charged with water (12 L) and solid NaHCO3 (2338 g)
21. stirringthe mixture is stirred for 10-15 min
22. additionThe residue from the concentrated paste is added in portions to the stirred sodium bicarbonate solution at a rate
23. additionAfter all of the residue is added
24. additionEtOAc (10 L) is charged to the to the funnel
25. stirringstirred for 10-15 min
26. customThe aqueous layer is separated
27. washthe organic layer washed with saturated aqueous sodium bicarbonate solution (1 L)
28. dry with materialdried over magnesium sulfate
29. filtrationfiltered
30. concentrationconcentrated
31. extractionThe combined aqueous layers are extracted with EtOAc (2×2 L)
32. washthe combined organic layers are washed with saturated aqueous sodium bicarbonate solution (1 L)
33. dry with materialdried over magnesium sulfate
34. filtrationfiltered
35. concentrationconcentrated along with the first extract
36. customA pale yellow oil is obtained which
37. temperatureon cooling
38. customThe resulting material is dried in a vacuum oven overnight at room temperature

ORD record

ord-44d7dd4017c04a3fa498ba2cc2347347

Source dataset

uspto-grants-2012_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08101760B2