2-chloro-5-(trifluoroMethoxy)isonicotinic acid synthesis

Yield:1221171-77-2 75%

Reaction Conditions:

Stage #1: 2-chloro-5-(trifluoromethoxy)pyridinewith n-butyllithium;diisopropylamine in tetrahydrofuran;hexane at -78;
Stage #2: carbon dioxide in tetrahydrofuran;hexane at 25;
Stage #3: with hydrogenchloride in water; pH=4;

Steps:

1

1. Functionalized 3-OCF₃-pyridine:; 2-Chloro-5-trifluoromethoxy isonicotinic acid (17); At 0 ⁰C, diisopropylamine (0.25 g, 0.35 mL, 2.5 mmol, 1 eq) was added dropwise to a solution of butyllithium (1.56 M in hexane, 1.6 mL, 2.5 mmol, 1 eq) in THF (4 mL). At -78 ⁰C, a solution of 2-chloro-5-trifluoromethoxypyridine (6, 0.5 g, 2.5 mmol, 1 eq) in THF (2 mL) was added dropwise and the reaction mixture was stirred for 2 h at this temperature. Then, the mixture was poured onto an excess of freshly crushed dry ice and allowed to reach 25 ⁰C before being treated with an aqueous solution of sodium hydroxide (5%, 5 mL). The resulting aqueous layer was collected, washed with diethylether (2 mL) and acidified to pH 4 by dropwise addition of hydrochloric acid (6 N, 1 mL) before being extracted with ethyl acetate (3 >< 3 mL). The combined organic layers were dried over sodium sulfate and the solvents evaporated to afford pure 2- chloro-5-trifluoromethoxy isonicotinic acid (17, 0.46 g, 1.9 mmol, 75%) as a white powder; m.p. 150-152 ⁰C.¹H NMR (CDCl₃, 300 MHz): δ = 8.45 (s, 1 H), 7.84 (s, 1 H), 3.88 (br s, IH). - ¹⁹F NMR (CDCl₃, 282 MHz): δ = -57.8. - ¹³C NMR (CDCl₃, 75 MHz): δ = 150.3, 144.9, 142.5, 137.1, 133.8, 126.1, 120.3 (q, J = 260 Hz). - MS(APCI+): m/z = 241 [M⁺], 197 [M⁺-CO₂].

References:

WO2010/40461,2010,A1 Location in patent:Page/Page column 31-32