Sulfuric Acid → Methyl 5-fluoro-2-hydroxybenzoate

Temperature

66 °C

5-Fluorosalicylic acid (272.6 g, 1.74 mol) was dissolved in methanol (1.3 L) to form a clear solution. Concentrated sulfuric acid (50 ml) was slowly added to the methanol solution with vigorous stirring. The solution was heated to reflux for 4 hours. Trimethyl orthoformate (200 ml) was added slowly to the reaction solution. 300 ml of solvents (methyl formate and methanol) was distilled off. The remaining reaction solution was heated at 66° C. (refluxing temperature) for 16 hours. HPLC analysis indicated that the reaction was complete. Reaction solution was cooled to ambient temperature. Solvent was removed under reduced pressure. The residue was partitioned between water (140 ml) and methylene chloride (220 ml). Organic layer was separated. Aqueous layer was extracted with methylene chloride (3×220 ml). The combined organic layer was washed with water (270 ml), brine (270 ml) and dried with MgSO4. The organic solution was concentrated to dryness to afford crude product (293.8 g). This crude material was used in the next step without further purification. 1H NMR (300 MHz, CDCl3) δ 3.96 (s, 3H), 6.94 (dd, 1H, J=4.5 Hz and J=9.0 Hz), 7.19 (m, 1H), 7.50 (dd, 1H, J=3.3 Hz and J=8.7 Hz), 10.508 (s, 1H).

1. customto form a clear solution
2. temperatureThe solution was heated
3. temperatureto reflux for 4 hours
4. distillation300 ml of solvents (methyl formate and methanol) was distilled off
5. customThe remaining reaction solution
6. temperature(refluxing temperature) for 16 hours
7. customReaction solution
8. temperaturewas cooled to ambient temperature
9. customSolvent was removed under reduced pressure
10. customThe residue was partitioned between water (140 ml) and methylene chloride (220 ml)
11. customOrganic layer was separated
12. extractionAqueous layer was extracted with methylene chloride (3×220 ml)
13. washThe combined organic layer was washed with water (270 ml), brine (270 ml)
14. dry with materialdried with MgSO4
15. concentrationThe organic solution was concentrated to dryness

ORD record

ord-e88b8cb6a823455f9e27801a4b8b5b64

Source dataset

uspto-grants-2008_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07323562B2