Hydrochloric Acid → HCID 9964829, compound

3,5-Difluoroaniline (250 g, 1.94 mol) was dissolved in THF (3800 ml) and cooled to −78° C. nBuLi (1.59 M, 2560 ml) was added drop wise over 5 hours keeping the temperature below −70° C. and the resulting white slurry was stirred for 1 hour. Chlorotrimethylsilane (502 ml, 4.07 mol) in THF (2000 ml) was added drop wise over 2.5 hours keeping the temperature below −70° C. and the resulting yellow slurry was allowed to warm to room temperature overnight. The brown solution was recooled to −78° C., nBuLi (1340 ml) was charged drop wise over 1.5 hours keeping the temperature below −70° C. and the reaction mixture was stirred for 5 hours. Tetrahydrothiopyran-4-one (241 g, 2.07 mol) in THF (1500 ml) was added drop wise over 2 hours keeping the temperature below −70° C. during the addition and then the reaction allowed to warm to room temperature overnight. The reaction was acidified to pH<1 using 5M HCl (approx 2000 ml) and it was extracted with diethyl ether (2500 ml). The organic layer was washed with 5M HCl (1000 ml) and the combined aqueous layers were basified using 880 ammonia to pH 11 (1500 ml), then extracted with diethyl ether (2500 ml×2), washed with saturated aqueous sodium chloride (1000 ml), dried over MgSO4 and evaporated. The residue was taken up in dichloromethane (800 ml) evaporated to a low volume, isohexane (1000 ml) was added and it was cooled under ice. The yellow solid was filtered and dried in a vacuum oven at 40° C. overnight to provide 287 g of the title compound.

1. additionwas added drop wise over 5 hours
2. customthe temperature below −70° C.
3. customthe temperature below −70° C.
4. customwas recooled to −78° C.
5. customthe temperature below −70° C.
6. stirringthe reaction mixture was stirred for 5 hours
7. customthe temperature below −70° C.
8. additionduring the addition
9. temperatureto warm to room temperature overnight
10. extractionwas extracted with diethyl ether (2500 ml)
11. washThe organic layer was washed with 5M HCl (1000 ml)
12. extractionextracted with diethyl ether (2500 ml×2)
13. washwashed with saturated aqueous sodium chloride (1000 ml)
14. dry with materialdried over MgSO4
15. customevaporated
16. customevaporated to a low volume, isohexane (1000 ml)
17. additionwas added
18. temperatureit was cooled under ice
19. filtrationThe yellow solid was filtered
20. customdried in a vacuum oven at 40° C. overnight

ORD record

ord-46d028f89e454a33beb69c9932c73d38

Source dataset

uspto-grants-2009_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07473699B2