反应详情

温度

120 °C

To a solution of 4-[7-(2-methanesulfonyloxy-ethoxy)-quinazolin-4-yl]-piperidine-1-carboxylic acid tert-butyl ester (40.6 mg, 0.09 mmol) in DMSO (0.4 mL) was added (S)-(+)-2-pyrrolidinemethanol (90.9 mg, 0.9 mmol). The mixture was stirred at 120° C. overnight and subsequently partitioned between EtOAc and water. The combined organic extracts were washed with brine, dried over Na2SO4 and evaporated. The residue was treated with 50% TFA/CH2Cl2 (8 mL) for 2 h, the solvents (TFA/CH2Cl2) were removed under reduced pressure and half of the residue was re-dissolved in CH2Cl2. DIPEA (55 μL) was added to the above solution, followed by (4-pyrrolidin-1-yl-phenyl)-carbamic acid 4-nitro-phenyl ester hydrochloride (19.6 mg, 0.054 mmol), which was prepared as described in Example 74a. The reaction mixture was stirred for 1 h, diluted with water. The organic phase was collected and the solvents were evaporated. The crude residue was purified by flash column chromatography on silica gel (15% MeOH/EtOAc as eluent) to afford a white solid (10 mg, 40.8% overall yield). 1H NMR (CD3OD) δ 9.03 (s, 1H), 8.35 (d, J=9.44 Hz, 1H), 7.40 (dd, J=9.25 and 2.54 Hz, 1H), 7.34 (d, J=2.48 Hz, 1H), 7.13 (d, J=8.87 Hz, 2H), 6.54 (d, J=8.96 Hz, 2H), 4.29-4.36 (4H), 3.92 (m, 1H), 3.60 (dd, J=10.98 and 4.81 Hz, 1H), 3.52 (dd, J=11.00 and 5.90 Hz, 1H), 3.40 (m, 1H), 3.27 (m, 1H), 3.24 (t, J=6.61 Hz, 4H), 3.15 (td, J=12.57 and 2.55 Hz, 2H), 2.88 (dt, J=13.67 and 5.50 Hz, 1H), 2.71 (m, 1H), 2.47 (m, 1H), 1.90-2.09 (9H), 1.79 (m, 2H), 1.66 (m, 1H). Calcd for C31H41N6O3 (MH+) 545.3, found 545.3.

1. customsubsequently partitioned between EtOAc and water
2. washThe combined organic extracts were washed with brine
3. dry with materialdried over Na2SO4
4. customevaporated
5. additionThe residue was treated with 50% TFA/CH2Cl2 (8 mL) for 2 h
6. customthe solvents (TFA/CH2Cl2) were removed under reduced pressure and half of the residue
7. dissolutionwas re-dissolved in CH2Cl2
8. additionDIPEA (55 μL) was added to the above solution
9. customwas prepared
10. stirringThe reaction mixture was stirred for 1 h
11. customThe organic phase was collected
12. customthe solvents were evaporated
13. customThe crude residue was purified by flash column chromatography on silica gel (15% MeOH/EtOAc as eluent)
14. customto afford
15. customa white solid (10 mg, 40.8% overall yield)