Sodium Carbonate → Methyl 5-(2,2,2-trifluoroethoxy)pyridine-2-carboxylate

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Reaction Conditions

Reaction Steps

Under an atmosphere of nitrogen a solution of 5-hydroxy-pyridine-2-carboxylic acid methyl ester (200 mg, 1.31 mmol) in N,N-dimethylformamide (2 ml) was treated at room temperature with sodium hydride (55% dispersion in oil, 64 mg). After the gas formation had ceased, the suspension was cooled to 0° C. and trifluoro-methanesulphonic acid 2,2,2-trifluoro-ethyl ester (364 mg, 1.57 mmol) was added. After stirring at room temperature for 2 hours about 50% of the starting material was left. Another 364 mg of trifluoro-methanesulphonic acid 2,2,2-trifluoro-ethyl ester were added and after 30 minutes the reaction was complete. For the workup, the reaction mixture was treated with a saturated solution of sodium carbonate, then extracted with ethyl acetate (3×). The combined organic layers were washed with brine, dried over sodium sulphate, and evaporated at reduced pressure. The crude product was purified by chromatography on silica gel using a 3:1-mixture of heptane and ethyl acetate as the eluent. The 5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid methyl ester was obtained as a white solid (216 mg, 70% of theory). MS (ISP): m/z=236.3 [M+H]+. b) 5-(2,2,2-Trifluoro-ethoxy)-pyridine-2-carboxylic acid Under an atmosphere of nitrogen a solution of 5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid methyl ester (216 mg, 0.92 mmol) in methanol (1 ml) was treated with a solution of lithium hydroxide monohydrate (78 mg, 1.84 mmol) in methanol (0.1 ml). After stirring for 2 hours the reaction mixture was evaporated at reduced pressure. The residue was treated with hydrochloric acid (1N), the solid material was filtered then washed with water, finally dried at high vacuum. The 5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid was obtained as a white solid (125 mg, 61% of theory).

Provenance & Evidence