Hydrochloric Acid → HCID 9964829, compound

3,5-Difluoroaniline (12.9 g, 0.1 M) in dry tetrahydrofuran (400 ml) was stirred and cooled under nitrogen to −78°. n-Butyllithium (1.6M in hexanes, 131 ml, 0.21 M) was run in slowly over 15 minutes, maintaining the temperature below −65°. Stirring was continued at the same temperature for 30 minutes, then trimethylsilyl chloride (22.8 g, 0.21 M) in tetrahydrofuran (100 ml) was added dropwise over 15 minutes. The temperature was then allowed to rise to ambient, and the mixture stirred overnight. After recooling to −78°, further n-butyllithium (1.6M in hexanes, 68.8 ml, 0.11 M) was added dropwise below −70°, and stirring continued for 5 hours to form anion. A solution of tetrahydrothiopyran-4-one (12.5 g, 0.107 M) in tetrahydrofuran (80 ml) was added dropwise, keeping the temperature below −70°, and the temperature allowed to warm to ambient overnight. The mixture was cooled in an ice-bath and acidified to pH<1 by slow addition of hydrochloric acid (1M, ˜500 ml). After stirring 15 minutes, diethyl ether (1 L) was added, and the phases separated. The organic layer was washed with hydrochloric acid (1M, 200 ml), and the combined aqueous layers made basic with concentrated ammonia solution, then extracted with diethyl ether (600 ml). The extract was washed with water (100 ml), brine (100 ml), dried (magnesium sulfate) and evaporated. After dissolving the residue in dichloromethane, the desired product was precipitated by the addition of isohexane (17.4 g). MS (Negative ES): 244 (M—H—) for C11H13F2NOS

1. temperaturecooled under nitrogen to −78°
2. customslowly over 15 minutes
3. temperaturemaintaining the temperature below −65°
4. stirringstirred overnight
5. customAfter recooling to −78°
6. stirringstirring
7. waitcontinued for 5 hours
8. customto form anion
9. customthe temperature below −70°
10. temperatureto warm to ambient overnight
11. temperatureThe mixture was cooled in an ice-bath
12. stirringAfter stirring 15 minutes
13. customthe phases separated
14. washThe organic layer was washed with hydrochloric acid (1M, 200 ml)
15. extractionextracted with diethyl ether (600 ml)
16. washThe extract was washed with water (100 ml), brine (100 ml)
17. dry with materialdried (magnesium sulfate)
18. customevaporated
19. dissolutionAfter dissolving the residue in dichloromethane
20. customthe desired product was precipitated by the addition of isohexane (17.4 g)

ORD record

ord-9574e83bf0e7415b9faf1acbeb6f4bf7

Source dataset

uspto-grants-2006_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07141583B2