Sodium hydride → 6-((2,2,2-Trifluoroethoxy)methyl)nicotinic acid

To a solution of methyl 6-(hydroxymethyl)nicotinate (500 mg, 2.99 mmol) in tetrahydrofuran (30 mL) was added sodium hydride 60% dispersion in mineral oil (126 mg, 3.14 mmol) and the reaction mixture was stirred at ambient temperature for 5 min. 2,2,2-trifluoroethyl trifluoromethanesulphonate (729 mg, 3.14 mmol) was added and the reaction mixture was stirred at ambient temperature for 4 h. Additional sodium hydride (42 mg, 1.05 mmol) was added followed by 2,2,2-Trifluoroethyl trifluoromethanesulphonate (243 mg, 1.45 mmol) after 5 min. Water (20 mL) was added carefully followed by lithium hydroxide monohydrate (0.376 g, 8.97 mmol) and the formed reaction mixture was stirred at ambient temperature for 5.5 h. The solvent was partially removed in vacuo and 1M hydrochloric acid added until an acidic pH was reached. The mixture was extracted with ethyl acetate (3×25 mL) and the combined organic layer was dried over magnesium sulfate and concentrated in vacuo. Purification by column chromatography using a gradient of methanol in dichloromethane yielded 171 mg (24%) of the title compound; 1H NMR (400 MHz, DMSO-d6) δ ppm 9.02 (dd, 1 H), 8.32 (dd, 1 H), 7.56 (dd, 1 H), 4.84 (s, 2 H), 4.26 (q, 2 H); MS (ESI) m/z 236[M+H+].

1. stirringthe reaction mixture was stirred at ambient temperature for 4 h
2. customthe formed reaction mixture
3. stirringwas stirred at ambient temperature for 5.5 h
4. customThe solvent was partially removed in vacuo and 1M hydrochloric acid
5. additionadded until an acidic pH
6. extractionThe mixture was extracted with ethyl acetate (3×25 mL)
7. dry with materialthe combined organic layer was dried over magnesium sulfate
8. concentrationconcentrated in vacuo
9. customPurification by column chromatography

ORD record

ord-77d248ed276c4469bacbf5f7f876ff82

Source dataset

uspto-grants-2012_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08143408B2