反应详情

Heat a mixture of 4-[2-(2-hydroxycyclopentylamino)ethyl]phenol (210.5 mg, 0.95 mmol), K2CO3 (395 mg, 2.85 mmol) and 6-chloronicotinamide (223.4 mg, 1.43 mmol) in 1:3 toluene/DMF (6 mL) at 165° C. for 2 hours, while removing H2O azeotropically with toluene. Remove DMF azeotropically with xylenes and take up the residue in H2O (50 mL) and 10% MeOH in CH2Cl2 (50 mL). Shake and separate the layers. Extract the aqueous layer with 10% MeOH in CH2Cl2 (2×50 mL) and 10% MeOH in EtOAc (50 mL). Combine the organic layers, dry over MgSO4 and concentrate. Concentrate the aqueous layer, which still contains the product by TLC, to dryness and extract the product out with MeOH. Dry the solution with Na2SO4, filter and combine with the organic concentrate above. Concentrate, re-dissolve in MeOH and filter through a Na2SO4 pad. Concentrate and purify by flash chromatography, eluting with 10:15:75 2.0 M NH3 in MeOH/CH2CL2/EtOAc to afford the title compound (137.4 mg) along with the (cis)-isomer of the starting phenol (59.0 mg) recovered: MS ES+ 342.0 (M+H)+, HRMS calcd for C19H24N3O3 342.1818 (M+H)+, found 342.1812, time 0.34 min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), acetonitrile in water containing 0.01% concentrated HCl at 1.0 mL/min, 5-95% over 19 min], tR=16.76 min, 100% purity; Anal. Calcd for C19H23N3O30.1CH2Cl2 0.1EtOAc: C, 65.29; H, 6.74; N, 11.71. Found: C, 65.35; H, 6.61; N, 11.98.

1. temperatureHeat
2. customwhile removing H2O azeotropically with toluene
3. customShake and separate the layers
4. extractionExtract the aqueous layer with 10% MeOH in CH2Cl2 (2×50 mL) and 10% MeOH in EtOAc (50 mL)
5. dry with materialCombine the organic layers, dry over MgSO4
6. concentrationconcentrate
7. concentrationConcentrate the aqueous layer, which
8. extractionto dryness and extract the product out with MeOH
9. dry with materialDry the solution with Na2SO4
10. filtrationfilter
11. concentrationorganic concentrate above
12. concentrationConcentrate
13. dissolutionre-dissolve in MeOH
14. filtrationfilter through a Na2SO4 pad
15. concentrationConcentrate
16. custompurify by flash chromatography
17. washeluting with 10:15:75 2.0 M NH3 in MeOH/CH2CL2/EtOAc