反应详情

To a solution of rac-ethyl 2-((4S,6S,7R)-4-(4-chloro-2-methylphenyl)-1,3,7-trimethyl-4,6,7,8-tetrahydro-1H-pyrazolo[3,4-e][1,4]thiazepin-6-yl)acetate (0.39 g, 0.97 mmol) in THF (9 mL) at about 0° C. was added DIBAL-H (2.6 mL, 2.6 mmol). After about 30 min the reaction mixture was warmed to ambient temperature and stirred for about 4 h. To the reaction mixture was added EtOAc (10 mL) and 10% aqueous Rochelle's salt (15 mL) and stirred for about 16 h. The layers were separated and the aqueous layer was back extracted with EtOAc (2×10 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was dissolved in THF (9 mL) and cooled to about 0° C. and LAH (1 M solution in Et2O, 1.3 mL, 1.3 mmol) was added dropwise. The ice bath was removed and the reaction was stirred for about 30 min. The reaction was cooled to 0° C. and aqueous NH4Cl (10 mL) was added to the reaction mixture. Ethyl acetate (20 mL) was added and the mixture was stirred at rt for about 1 h. The layers were separated and the aqueous layer was back extracted with EtOAc (10 mL). The combined organic layers were washed with brine (10 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography (SiO2, DCM/MeOH 100:0 to 95:5) to afford rac-2-((4S,6S,7R)-4-(4-chloro-2-methylphenyl)-1,3,7-trimethyl-4,6,7,8-tetrahydro-1H-pyrazolo[3,4-e][1,4]thiazepin-6-yl)ethanol (0.09 g, 0.24 mmol, 18%). LC-MS (Table 1, Method g) Rt=1.98, m/z 366 (M+H)+. 1H-NMR (DMSO-d6, Bruker 400 MHz) δ 7.24 (s, 1H), 7.13-7.08 (m, 2H), 5.55-5.50 (m, 1H), 4.86 (s, 1H), 4.334-4.26 (m, 1H), 3.54 (s, 3H), 3.50-3.42 (m, 1H), 3.42-3.34 (m, 1H), 3.22-3.08 (m, 2H), 2.45 (s, 3H), 1.81 (s, 3H), 1.54-1.42 (m, 1H), 1.38-1.28 (m, 1H), 1.01 (d, J=6.4 Hz, 3H).

1. stirringstirred for about 16 h
2. customThe layers were separated
3. extractionthe aqueous layer was back extracted with EtOAc (2×10 mL)
4. dry with materialThe combined organic layers were dried over MgSO4
5. filtrationfiltered
6. concentrationconcentrated under reduced pressure
7. dissolutionThe residue was dissolved in THF (9 mL)
8. temperaturecooled to about 0° C.
9. customThe ice bath was removed
10. stirringthe reaction was stirred for about 30 min
11. temperatureThe reaction was cooled to 0° C.
12. additionaqueous NH4Cl (10 mL) was added to the reaction mixture
13. additionEthyl acetate (20 mL) was added
14. stirringthe mixture was stirred at rt for about 1 h
15. customThe layers were separated
16. extractionthe aqueous layer was back extracted with EtOAc (10 mL)
17. washThe combined organic layers were washed with brine (10 mL)
18. dry with materialdried over MgSO4
19. filtrationfiltered
20. concentrationconcentrated under reduced pressure
21. customThe crude material was purified by column chromatography (SiO2, DCM/MeOH 100:0 to 95:5)