反应详情

For the preparation of the starting material 25.1, see Example 25. Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, a solution of trans-4-(morpholin-4-yl)cyclohexan-1-ol (528 mg, 2.85 mmol, 1.50 equiv) in freshly distilled THF (30 mL) was added sodium hydride (304 mg, 7.60 mmol, 4.01 equiv, 60% dispersion in mineral oil) portionwise at 0° C. under nitrogen. The resulting mixture was stirred for 30 min in a water/ice bath. Then a solution of (3R)-3-[2-[(tert-butyldimethylsilyl)oxy]ethyl]-12-chloro-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraene (700 mg, 1.90 mmol, 1.00 equiv) in 5 mL of THF was added via syringe and the resulting solution was allowed to react, with stirring, for an additional 4 hr at 55° C. in an oil bath. After completion, the reaction was quenched by the addition of 20 mL of saturated aqueous NH4Cl and extracted with 3×80 mL of ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column with ethyl acetate/petroleum ether (1:5 to 1:0) to afford the desired (3R)-3-[2-[(tert-butyldimethylsilyl)oxy]ethyl]-12-[[4-(morpholin-4-yl)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraene (850 mg, 87%) as a colorless oil. MS (ES): m/z 518 [M+H]+.

1. customInto a 100-mL round-bottom flask purged
2. temperaturemaintained with an inert atmosphere of nitrogen
3. customto react
4. stirringwith stirring, for an additional 4 hr at 55° C. in an oil bath
5. customAfter completion, the reaction was quenched by the addition of 20 mL of saturated aqueous NH4Cl
6. extractionextracted with 3×80 mL of ethyl acetate
7. washThe combined organic layers were washed with brine
8. dry with materialdried over sodium sulfate
9. concentrationconcentrated under vacuum
10. customThe residue was purified on a silica gel column with ethyl acetate/petroleum ether (1:5 to 1:0)