Hydrochloric Acid → 2-Fluoro-4-methylbenzene-1-sulfonamide

2-Fluoro-4-methylaniline (3 g, 24 mmol) was dissolved in glacial acetic acid (45 ml) and concentrated hydrochloric acid (15 ml) and the solution was cooled to −10° C. with overhead stirring. Sodium nitrite (1.82 g, 26.4 mmol) in water (3 ml) was added dropwise over 0.5 h maintaining the temperature below −5° C. Stirring was continued for a further 0.5 h after the final addition. This mixture was added in small portions to a stirred, saturated solution of sulphur dioxide in acetic acid (30 ml) at 0° C. After addition the mixture was warmed to room temperature and stirred for 1 h before pouring into iced water. After stirring for 0.5 h the product was extracted into ether and the aqueous layer further extracted with dichloromethane. The organic layers were combined, washed with brine, dried (MgSO4) and concentrated (azeotroping with toluene to remove any remaining acetic acid). A mixture of 1,4-dioxan (30 ml) and aqueous ammonia (30 ml of 0.88M) was added to the residue which was stirred overnight. The 1,4-dioxan was removed in vacuo and the aqueous layer extracted with ethyl acetate (2×100 ml). The organic layers were combined, washed with brine (100 ml), dried (MgSO4) and concentrated. Flash column chromatography (elution with 99% dichloromethane/1% methanol) gave the product as a pale yellow solid (1.62 g).

1. temperaturemaintaining the temperature below −5° C
2. stirringStirring
3. additionafter the final addition
4. additionAfter addition the mixture
5. stirringstirred for 1 h
6. stirringAfter stirring for 0.5 h the product
7. extractionwas extracted into ether
8. extractionthe aqueous layer further extracted with dichloromethane
9. washwashed with brine
10. dry with materialdried (MgSO4)
11. concentrationconcentrated (
12. customazeotroping with toluene
13. customto remove any remaining acetic acid)
14. additionA mixture of 1,4-dioxan (30 ml) and aqueous ammonia (30 ml of 0.88M)
15. additionwas added to the residue which
16. stirringwas stirred overnight
17. customThe 1,4-dioxan was removed in vacuo
18. extractionthe aqueous layer extracted with ethyl acetate (2×100 ml)
19. washwashed with brine (100 ml)
20. dry with materialdried (MgSO4)
21. concentrationconcentrated
22. washFlash column chromatography (elution with 99% dichloromethane/1% methanol)

ORD record

ord-f16b511e433d405cb7ca65ff6b2877f2

Source dataset

uspto-grants-2002_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06384070B2