Acetic Anhydride → Methyl 4-Hydroxy-2-(trifluoromethyl)-3-pyridinecarboxylate

Temperature

27.5 °C

A mixture of 105 g (0.5 mol) of methyl 2-acetyl-3-amino-4,4,4-trifluoro-2-butenoate (example 2 of U.S. Pat. No. 4,655,816), acetic anhydride (152 g), and trimethyl orthoformate (106 g) was held at reflux for 16 h then distilled to remove low boiling material (bp 65-90° C.). The remaining material was concentrated in vacuo and the residue was kugelrohr distilled at 2 torr (80-120° C.) to give 114 g of distillate. This distillate (44 g) was added dropwise to a mixture of 14.5 g of 60% sodium hydride oil dispersion in 100 ml of 1,2-dimethoxyethane (DME). The reaction mixture was maintained at 25-30° C. with an ice-water bath. The reaction mixture was stirred at room temperature for 18 h and poured into 300 ml of ice-water. The aqueous layer was extracted with ether and filtered. The aqueous layer was acidified with concentrated HCl. The oil precipitate was extracted into ether. The ether extract was extracted with 10% potassium carbonate. The potassium carbonate layer was acidified with concentrated HCl. The precipitate was filtered and air dried to give 20.4 g of the product, mp 78-82° C.

1. temperatureat reflux for 16 h
2. distillationthen distilled
3. customto remove low boiling material (bp 65-90° C.)
4. concentrationThe remaining material was concentrated in vacuo
5. distillationthe residue was kugelrohr distilled at 2 torr (80-120° C.)
6. customto give 114 g of distillate
7. extractionThe aqueous layer was extracted with ether
8. filtrationfiltered
9. extractionThe oil precipitate was extracted into ether
10. extractionThe ether extract
11. extractionwas extracted with 10% potassium carbonate
12. filtrationThe precipitate was filtered
13. customair dried

ORD record

ord-0c1009ff0f6e4f3ca65b9339384a1874

Source dataset

uspto-grants-2004_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06794396B2