Sulfuric Acid → HCID 58198617, compound

Temperature

0 °C

To a solution of 3 g (22 mmol) of 4-amino-3-fluoro-benzonitrile in acetic acid (60 mL) at 0° C. were added 20 mL of sulfuric acid and the mixture was cooled to 0° C. A solution of 2.03 g (29.4 mmol) of sodium nitrite in water (15 mL) was added dropwise over 10 min whilst maintaining the temperature below 10° C. The resulting solution was stirred at 0° C. for 20 min, then 0.5 g (832 mmol) of urea were added and the mixture was stirred for 5 min at 0° C. To this solution was added a solution of 4.4 g (23 mmol) of copper iodide in water (10 mL) and the mixture was stirred for 5 min before a solution of 13 g (81.3 mmol) of potassium ethyl xanthate in water (90 mL) at 0° C. was added. The resulting mixture was heated to 80° C. for 1 h. After cooling to room temperature, the mixture was extracted with DCM (3×40 mL). The organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting oil was dissolved in 100 mL ethanol, degassed under nitrogen atmosphere for 20 min, and 3.6 g (63 mmol) of potassium hydroxide were added. The reaction was heated to 80° C. for 1 h, before 10 mL (67.4 mmol) of ethyl α-bromoisobutyrate were added. The mixture was stirred at room temperature for 18 h and then concentrated under reduced pressure. Purification by column chromatography (silica, eluent heptanes, ethyl acetate 0-20%), followed by distillation under reduced pressure afforded 1.1 g of 2-(4-cyano-2-fluoro-phenylsulfanyl)-2-methyl-propionic acid ethyl ester. 1H NMR (400 MHz, CHLOROFORM-d): δ ppm 1.25 (3 H, t, J=7.09 Hz), 1.54 (6 H, s), 4.15 (2 H, q, J=7.09 Hz), 7.37-7.45 (2 H, m), 7.56-7.62 (1 H, m)

1. temperaturewhilst maintaining the temperature below 10° C
2. stirringthe mixture was stirred for 5 min at 0° C
3. additionwas added
4. temperatureThe resulting mixture was heated to 80° C. for 1 h
5. temperatureAfter cooling to room temperature
6. extractionthe mixture was extracted with DCM (3×40 mL)
7. dry with materialThe organic extracts were dried over Na2SO4
8. filtrationfiltered
9. concentrationconcentrated under reduced pressure
10. dissolutionThe resulting oil was dissolved in 100 mL ethanol
11. customdegassed under nitrogen atmosphere for 20 min
12. additionwere added
13. stirringThe mixture was stirred at room temperature for 18 h
14. concentrationconcentrated under reduced pressure
15. customPurification by column chromatography (silica, eluent heptanes, ethyl acetate 0-20%)
16. distillationfollowed by distillation under reduced pressure

ORD record

ord-28a87ac3b14d42f292ac989ac91f48e5

Source dataset

uspto-grants-2011_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07935715B2