反应详情

A solution of (1R,2S)-N-methylephedrine (81.3 g, 0.454 mol) in 1.2 L of anhydrous diethyl ether was added to lithium aluminum hydride (1.0M in diethyl ether, 416 mL, 0.416 mol) over 45 minutes. The mixture was heated under reflux for 1 hour and then allowed to cool to room temperature. A solution of 2-ethylaminopyridine (110.7 g, 0.907 mol) in 100 mL of anhydrous diethyl ether was added over 45 minutes. The mixture was heated under reflux for 1 hour and then cooled to -65° C. A solution of 5,7-difluoro-1,2,3,4-tetrahydro naphthalen-2-one (23.0 g, 0.107 mol) in 100 mL of diethyl ether was added dropwise such that the reaction temperature did not exceed -60° C. The mixture was stirred at -65° C. to -68° C. for 3 hours and then 100 mL of methanol was added such that the reaction temperature did not exceed -60° C. The mixture was stirred at -65° C. to -68° C. for 10 minutes, then allowed to warm to -20° C., and 3.0 L of 3N hydrochloric acid was added such that the reaction temperature did not exceed 35° C. The diethyl ether layer was separated, washed with 200 mL of saturated sodium chloride, and dried over magnesium sulfate. The mixture was filtered and the filtrate concentrated under reduced pressure. Crystallization from 20 mL of diethyl ether and 200 mL of hexane and drying in vacuo gave (R)-5,7-difluoro-1,2,3,4-tetrahydro-2-hydroxynaphthalene (10.87 g, 0.05 mol), m.p. 85° C. [α]D25 =+36.03° (c=1.59, CHCl3).

1. temperatureThe mixture was heated
2. temperatureunder reflux for 1 hour
3. temperatureThe mixture was heated
4. temperatureunder reflux for 1 hour
5. temperaturecooled to -65° C
6. customdid not exceed -60° C
7. customdid not exceed -60° C
8. stirringThe mixture was stirred at -65° C. to -68° C. for 10 minutes
9. temperatureto warm to -20° C.
10. customdid not exceed 35° C
11. customThe diethyl ether layer was separated
12. washwashed with 200 mL of saturated sodium chloride
13. dry with materialdried over magnesium sulfate
14. filtrationThe mixture was filtered
15. concentrationthe filtrate concentrated under reduced pressure
16. customCrystallization from 20 mL of diethyl ether and 200 mL of hexane
17. customdrying in vacuo