6-(trifluoromethoxy)picolinic acid synthesis

Yield:1221172-11-7 60%

Reaction Conditions:

Stage #1: 2-bromo-6-(trifluoromethoxy)pyridinewith n-butyllithium in hexane;toluene at -78;
Stage #2: carbon dioxide in hexane;toluene;
Stage #3: with hydrogenchloride in water; pH=3;

Steps:

2

6-Trifluoromethoxypicolinic acid (56); At -78 ⁰C, butyllithium (1.56 M in hexane, 0.8 mL, 1.2 mmol, 1 eq) was added dropwise to a solution 2-bromo-6-trifluoromethoxypyridine (55, 0.3 g, 1.2 mmol) in dried toluene (4 mL). After 40 min at -78 ⁰C, the mixture was poured onto an excess of freshly crushed dry ice before being treated with an aqueous solution of sodium hydroxide (5%, 4 mL). The resulting aqueous layer was collected, washed with diethylether (4 mL) and acidified to pH 3 by dropwise addition of hydrochloric acid (6 N, 1 mL) before being extracted with ethyl acetate (3 x 4 mL). The combined organic layers were dried over sodium sulfate and evaporated to afford pure 6- trifluoromethoxypicolinic acid (56, 150 mg, 0.7 mmol, 60%) as a white powder; m.p. 126-128 ⁰C.¹H NMR (CDCl₃, 300 MHz): δ = 8.10 (d, J = 7.4 Hz, 1 H), 8.00 (t, J= 7.8, 1 H), 7.25 (d, J = 8.1, 1 H). - ¹⁹F NMR ((CD₃)₂CO, 282 MHz): δ = -57.6 - ¹³C NMR (CDCl₃, 75 MHz): δ = 162.9, 155.4, 144.6, 142.6, 122.1, 120.4 (q, J= 260 Hz), 117.5.

References:

WO2010/40461,2010,A1 Location in patent:Page/Page column 51