反应详情

温度

0 °C

Under a dry nitrogen atmosphere, a 2.5 molar solution of butyllithium in hexane, 8.4 mL (21 mmol) was added by syringe to 20 mL pentane. The solution was cooled to 0° C. and 2.75 mL (2.13 g, 21 mmol) diisopropylamine was added by syringe over six minutes. The solution was warmed to 25° C. and stirred for three hours, then volatiles were removed in vacuo. Tetrahydrofuran, 20 mL, was added via syringe to the residue, and the resulting yellow solution cooled to 0° C. A solution of 2.42 g (10.5 mmol) N-[3-(1H-benzimidazol-2-yl)propyl]-N-methylacetamide in 10 mL tetrahydrofuran was added by syringe over nine minutes. The yellow solution was stirred at 0° C. for fifteen minutes, then cooled to -78° C. (S)-6-Fluoro-1-isopropyl-3,4-dihydro-1H-naphthalen-2-one, 2.166 g, 87.2% pure, 97.6:2.4 S:R, in 2 mL toluene was added by syringe over twelve minutes, and a further 2 mL toluene was used to complete the transfer. After stirring at -78° C. for two hours, the viscous yellow mixture was added to 50 mL water at less than 10° C. The suspension that formed was extracted with 50 mL diethyl ether, then with a further 25 mL diethyl ether; and the combined ether extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford 3.74 g of impure (1S,2S)-N-[3-(1H-benzimidazol-2-yl)propyl]-2-(6-fluoro-2-hydroxy-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl)-N-methylacetamide as a yellow foam. The foam was recrystallized from 6-8 mL toluene, and washed on the filter with 5 mL of toluene at -30° C. to afford 2.69 g of (1S,2S)-N-[3-(1H-benzimidazol-2-yl)propyl]-2-(6-fluoro-2-hydroxy-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl)-N-methylacetamide as a colorless solid, m.p. 132°-138° C. This material may be recrystallized a second time from toluene to remove residual (S)-6-fluoro-1-isopropyl-3,4-dihydro-1H-naphthalen-2-one if necessary and desired.

1. temperatureThe solution was warmed to 25° C.
2. customvolatiles were removed in vacuo
3. additionTetrahydrofuran, 20 mL, was added via syringe to the residue
4. temperaturethe resulting yellow solution cooled to 0° C
5. stirringThe yellow solution was stirred at 0° C. for fifteen minutes
6. stirringAfter stirring at -78° C. for two hours
7. customThe suspension that formed
8. extractionwas extracted with 50 mL diethyl ether
9. dry with materialand the combined ether extracts were dried over anhydrous magnesium sulfate
10. filtrationfiltered
11. concentrationconcentrated in vacuo