Hexachloroethane → 4-Chloro-2-(trifluoromethyl)nicotinic acid

Temperature

-78 °C

To a stirred solution of 2,2,6,6-tetramethylpiperidine (21.0 mL, 124 mmol) in dry THF (200 mL) in a −78° C. bath is added n-Butyl lithium (66.2 mL of a 2.5M solution in hexanes, 166 mmol). The solution is stirred at −78° C. for 30 minutes, followed by the addition of a solution of 2-(trifluoromethyl)nicotinic acid (7.90 g, 41.4 mmol) in THF (35 mL) via canula. The solution is stirred at −78° C. for 20 minutes, followed by warming to −50° C. for 1 hour (to provide the corresponding lithiated pyridine). In a separate flask, hexachloroethane (29.4 g, 124 mmol) is dissolved in THF (200 mL) and cooled to −15° C. and stirred rapidly. The solution containing the lithiated pyridine is added to the hexachloroethane solution via canula. After complete addition, the mixture is allowed to ward to room temperature. Water (ca 200 mL) is added, followed by removal of the tetrathydrofuran in vacuo. The remaining aqueous residue is extracted with ether-pentane (1:1, 100 mL). The organic layer was discarded. The aqueous layer is acidified with hydrochloric acid (ca. 50 mL of a 1.0 M solution). The aqueous layer is extracted with ethyl acetate. The organic layer is dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford 8.75 g (94%) of the title compound as a tan solid: 1H NMR (400 MHz, CD3OD), 8.63 (d, 1H), 7.79 (d, 1H). LC/MS (M+1)=226.1; [see: Schlosser et al., Eur. J. Org. Chem. 2003, 1559].

1. stirringThe solution is stirred at −78° C. for 20 minutes
2. temperatureby warming to −50° C. for 1 hour (
3. temperaturecooled to −15° C.
4. stirringstirred rapidly
5. additionAfter complete addition
6. customto ward to room temperature
7. customfollowed by removal of the tetrathydrofuran in vacuo
8. extractionThe remaining aqueous residue is extracted with ether-pentane (1:1, 100 mL)
9. extractionThe aqueous layer is extracted with ethyl acetate
10. dry with materialThe organic layer is dried over anhydrous magnesium sulfate
11. filtrationfiltered
12. concentrationconcentrated in vacuo

ORD record

ord-ca619d64d8e841d89a77b4a6d5a374f8

Source dataset

uspto-grants-2010_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07829572B2