Methyl iodide → 2-Fluoro-4-(methylsulfanyl)aniline

Temperature

50 °C

A solution of the product of Example 26, Step A, 4-amino-3-fluorophenyl thiocyanate (500 mg, 2.97 mmol), in ethanol (7.5 mL) was added to a solution of sodium sulfide monohydrate (714 mg, 2.97 mmol) in water (1.5 mL) and the mixture heated at 50° C. for 2 hours. Methyl iodide (464 mg, 3.27 mmol) in ethanol (0.5 mL) was added and heating continued for a further 4 hours. The reaction mixture was then diluted with water (15 mL) and extracted with Et2O (4×5 mL). The combined Et2O extracts were washed with water (3×10 mL), saturated NaCl (10 mL), and dried (Na2SO4), followed by removal of the solvent under reduced pressure to afford a pale yellow oil. This material was purified by dry flash column chromatography on silica (5% Et2O/hexanes as eluant) to give 2-fluoro-4-methylthioaniline as a pale yellow oil (407 mg, 87%); 1H NMR (400 MHz, CDCl3) δ 7.01 (dd, J=11.3, 2.1 Hz, 1 H), 6.94 (ddd, J=8.2, 2.1, 0.9 Hz, 1 H), 6.71 (dd, J=9.3, 8.2 Hz, 1 H), 3.67 (br s, 2 H), 2.42 (s, 3 H). Step C: Preparation of 3,4-difluoro-2-[[2-fluoro-4-(methylthio)phenyl]amino]-benzoic acid

1. temperatureheating
2. extractionextracted with Et2O (4×5 mL)
3. washThe combined Et2O extracts were washed with water (3×10 mL), saturated NaCl (10 mL)
4. dry with materialdried (Na2SO4)
5. customfollowed by removal of the solvent under reduced pressure
6. customto afford a pale yellow oil
7. customThis material was purified
8. customby dry flash column chromatography on silica (5% Et2O/hexanes as eluant)

ORD record

ord-c87a57336eb54791baa7fdb8a5a560fa

Source dataset

uspto-grants-2005_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06891066B2