反应详情

温度

90 °C

A mixture of ethyl 6-bromo-1-benzothiophene-2-carboxylate (250 mg, 0.88 mmol), tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate (200 mg, 0.83 mmol), and K3PO4 (1.00 g, 4.72 mmol) in 2 mL of DMAc was deoxygenated by the freeze-pump-thaw method. The mixture was treated with Pd[P(tert-Bu)3]2 (130 mg, 0.250 mmol) and stirred at 90° C. overnight. The reaction mixture was partitioned between EtOAc and sat'd NaHCO3, the organic layer dried (Na2SO4), filtered and concentrated. The residue was dissolved in 1 mL of MeOH, 1 mL of THF and 1 mL of H2O, treated with LiOH monohydrate (100 mg, 2.40 mmol) and stirred for 12 h. The mixture was poured into EtOAc and washed with 2 N HCl, water, dried (Na2SO4), filtered and concentrated. The oily residue was dissolved in 2 mL of DMF, treated with intermediate C (200 mg, 0.980 mmol), BOP (300 mg, 0.679 mmol), i-Pr2NEt (0.250 mL, 1.41 mmol) and stirred for 1 day at ambient temperature followed by 5 days at 60° C. The mixture was partitioned between EtOAc and sat'd NaHCO3, the organic layer was dried (Na2SO4) and concentrated. Chromatography on SiO2 (0 to 100% EtOAc/CH2Cl2) gave pure intermediate. The oil was stirred in 2 mL of 1:1 TFA/CH2Cl2 for 1 h and concentrated. The oil was dissolved in EtOAc, washed with sat'd NaHCO3, dried (Na2SO4) and concentrated, providing the title compound: MS (ESI+): cal'd [M+H]+ 483.2, obs'd 483.3.

1. customwas deoxygenated by the freeze-pump-thaw method
2. customThe reaction mixture was partitioned between EtOAc
3. dry with materialthe organic layer dried (Na2SO4)
4. filtrationfiltered
5. concentrationconcentrated
6. dissolutionThe residue was dissolved in 1 mL of MeOH
7. stirringstirred for 12 h
8. washwashed with 2 N HCl, water
9. dry with materialdried (Na2SO4)
10. filtrationfiltered
11. concentrationconcentrated
12. dissolutionThe oily residue was dissolved in 2 mL of DMF
13. stirringstirred for 1 day at ambient temperature
14. waitfollowed by 5 days at 60° C
15. customThe mixture was partitioned between EtOAc
16. dry with materialthe organic layer was dried (Na2SO4)
17. concentrationconcentrated
18. customChromatography on SiO2 (0 to 100% EtOAc/CH2Cl2) gave pure intermediate
19. concentrationconcentrated
20. dissolutionThe oil was dissolved in EtOAc
21. washwashed with sat'd NaHCO3
22. dry with materialdried (Na2SO4)
23. concentrationconcentrated