Dimethyl Disulfide → 4-Fluoro-2-methylsulfanyl-benzoic acid

Temperature

-78 °C

A solution of 2-bromo-4-fluorobenzoic acid (15 g, 68.5 mmol, Aldrich) in THF (150 mL) under Argon at 0 degrees C. was treated with chloro(methyl)magnesium (5.64 g, 75.34 mmol, 2.94 M in THF) over 5 minutes. The temperature during addition was maintained below 10 degrees C. The resulting solution was cooled to −78 degrees C. and n-butyllithium (9.65 g, 150.7 mmol, 2.5M in hexanes) was added over 10 minutes. The reaction was kept below −65 degrees C. during the addition. The reaction was stirred at −78 degrees C. for 50 minutes. A solution of (methyldithio)methane (38.71 g, 410.9 mmol) in THF (20 mL), precooled to −78 degrees C., was added by cannula. The reaction was stirred for 10 minutes, warmed to zero degrees C. and stirred at zero degrees C. for 2 hours until a solid began to precipitate. The reaction was allowed to warm to 25 degrees C. The material was filtered and the solid partitioned between ethyl acetate (400 mL) and water (400 mL). The water layer was acidified with HCl to pH of less than 1 and then extracted with ethyl acetate (4×500 mL). The organic was dried over Na2SO4, filtered, and reduced to a small volume in vacuo to produce crystals. The crystals were filtered and dried in vacuo to afford the title compound.

1. customat 0 degrees C
2. additionThe temperature during addition
3. temperaturewas maintained below 10 degrees C
4. customwas kept below −65 degrees C
5. additionduring the addition
6. customprecooled to −78 degrees C
7. addition, was added by cannula
8. stirringThe reaction was stirred for 10 minutes
9. temperaturewarmed to zero degrees C
10. stirringand stirred at zero degrees C
11. waitfor 2 hours until a solid began
12. customto precipitate
13. temperatureto warm to 25 degrees C
14. filtrationThe material was filtered
15. customthe solid partitioned between ethyl acetate (400 mL) and water (400 mL)
16. extractionextracted with ethyl acetate (4×500 mL)
17. dry with materialThe organic was dried over Na2SO4
18. filtrationfiltered
19. customto produce crystals
20. filtrationThe crystals were filtered
21. customdried in vacuo

ORD record

ord-3562edb90af74e54ac2a53b6e13f581e

Source dataset

uspto-grants-2005_07

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06921759B2