Ethyl Acetate → 2-Fluoro-3-methoxyaniline

A solution of 2-fluoro-3-methoxybenzoic acid (5.00 g, 29.39 mmol) and diisopropylethylamine (4.56 g, 35.27 mmol) in a mixture of anhydrous toluene (25 mL) and anhydrous tert-butanol (25 mL) was stirred over activated 4 A molecular sieves (4 g) for 1 h. Diphenyl phosphoryl azide (9.71 g, 35.27 mmol) was added and the mixture was heated at reflux for 15 h. The reaction mixture was cooled and filtered. To the filtrate was added ethyl acetate (200 mL) and the solution was washed with water (2×100 mL) and brine (100 mL). The organic phase was separated and dried over MgSO4. Filtration followed by concentration under reduced pressure gave crude tert-butyl 2-fluoro-3-methoxyphenylcarbamate. The crude product was dissolved in a solution of 6M HCl in ethyl acetate (20 mL, 0.12 mol) and the mixture stirred at rt for 2 h. The resulting precipitate was filtered and dried. The solid was taken up in a saturated aqueous solution of sodium hydrogen carbonate (50 mL) and the mixture extracted with dichloromethane (2×100 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to afford 2-fluoro-3-methoxyaniline (3.00 g, 72%) as brown oil, which was taken on without further purification. 1H NMR (400 MHz, DMSO-d6) δ 6.80-7.02 (m, 3H), 3.82 (s, 3H); LC-MS (ESI) m/z 142 (M+H)+.

1. temperaturethe mixture was heated
2. temperatureat reflux for 15 h
3. temperatureThe reaction mixture was cooled
4. filtrationfiltered
5. additionTo the filtrate was added ethyl acetate (200 mL)
6. washthe solution was washed with water (2×100 mL) and brine (100 mL)
7. customThe organic phase was separated
8. dry with materialdried over MgSO4
9. filtrationFiltration
10. concentrationfollowed by concentration under reduced pressure
11. customgave crude tert-butyl 2-fluoro-3-methoxyphenylcarbamate
12. stirringthe mixture stirred at rt for 2 h
13. filtrationThe resulting precipitate was filtered
14. customdried
15. extractionthe mixture extracted with dichloromethane (2×100 mL)
16. dry with materialThe combined organic layers were dried over Na2SO4
17. filtrationfiltered
18. concentrationconcentrated under reduced pressure

ORD record

ord-c3b6caf1ed9f42eeb46b7d8b9967edc5

Source dataset

uspto-grants-2016_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09320739B2