反应详情

A mixture of tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate (200 mg, 0.833 mmol), NEt3 (0.200 mL, 1.44 mmol) and Ac2O (0.100 mL, 1.06 mmol) in 1 mL of DMF was stirred for 5 h. The reaction mixture was partitioned between EtOAc and saturated NaHCO3, the organic layer was dried (Na2SO4), filtered and concentrated. The mixture was treated with 1:1 TFA/CH2Cl2, stirred for 1 h and concentrated. The oily residue was azeotroped with methanol and placed under high vacuum overnight. The resulting thick residue was then dissolved in 2 mL of DMSO containing tert-butyl [2-{[(6-chloropyridin-3-yl)carbonyl]amino}-4-(2-thienyl)phenyl]carbamate (100 mg, 0.233 mmol), treated with NEt3 (0.50 mL) and stirred at 90° C. for 12 h. The reaction mixture was partitioned between EtOAc and saturated NaHCO3, the organic layer was dried (Na2SO4), filtered and concentrated. Finally, the residue was dissolved in 1:1 TFA/CH2Cl2, stirred for 1 h and concentrated. Reverse-phase chromatography (10-100% MeCN/water with 0.05% TFA) followed by TFA removal by EtOAc/saturated extraction and drying (Na2SO4) gave the title compound: 1H NMR (600 MHz, CD3OD): δ 8.69 and 8.71 (2s, 1H), 8.05 and 8.07 (2d, J=9.1 Hz, 1H), 7.47 (s, 1H), 7.35 (d, J=8.2 Hz, 1H), 7.23 (d, J=5.0 Hz, 1H), 7.20 (d, J=3.5 Hz, 1H), 7.01 (dd, J=5.0, 3.5 Hz, 1H), 6.91 (d, J=8.2 Hz, 1H), 6.82 (dd, J=9.1, 6.2 Hz, 1H), 3.75 (m, 2H), 3.65 (m, 1H), 3.52 (m, 3H), 3.03 and 3.19 (2d, J=12.3 Hz, 1H), 2.00 and 2.04 (2s, 3H), 1.6-1.9 (m, 6H); MS (ESI+): cal'd [M+H]+ 476.2, obs'd 476.2.

1. customThe reaction mixture was partitioned between EtOAc and saturated NaHCO3
2. dry with materialthe organic layer was dried (Na2SO4)
3. filtrationfiltered
4. concentrationconcentrated
5. additionThe mixture was treated with 1:1 TFA/CH2Cl2
6. stirringstirred for 1 h
7. concentrationconcentrated
8. customThe oily residue was azeotroped with methanol
9. customplaced under high vacuum overnight
10. dissolutionThe resulting thick residue was then dissolved in 2 mL of DMSO
11. stirringstirred at 90° C. for 12 h
12. customThe reaction mixture was partitioned between EtOAc and saturated NaHCO3
13. dry with materialthe organic layer was dried (Na2SO4)
14. filtrationfiltered
15. concentrationconcentrated
16. dissolutionFinally, the residue was dissolved in 1:1 TFA/CH2Cl2
17. stirringstirred for 1 h
18. concentrationconcentrated
19. customReverse-phase chromatography (10-100% MeCN/water with 0.05% TFA) followed by TFA removal by EtOAc/saturated extraction
20. dry with materialdrying (Na2SO4)