反应详情

The (1-benzhydrylazetidin-3-yl)-carbamic acid tert-butyl ester (500 mg, 1.48 mmol), Pd/C (10% w/w, 157 mg, 0.07 mmol), and ammonium formate (932 mg, 14.8 mmol) were weighed into a 25 RBF equipped with a condenser, degassed 3 times, and suspended/dissolved in 6 mL of methanol. The mixture was heated to 60 C for 4 hours to completion and was allowed to cool to room temperature. The mixture was filtered through a plug of celite washed with ethanol, and the filtrate was concentrated in vacuo. The residue was re-dissolved in 30 mL of DCM, dried over Na2SO4, filtered, and concentrated in vacuo to afford the crude intermediate. The intermediate and 4-chloroquinazoline (268 mg, 1.63 mmol) were dissolved in 6 mL of NMP, then treated with diisopropylethyl amine (515 μL, 2.96 mmol). The solution was heated to 80° C. overnight to completion affording an orange mixture. After cooling to room temperature, the solution was diluted with ethyl acetate and poured into diluted NaHCO3 solution. The aqueous was extracted with ethyl acetate, and the organics were combined. The organic was washed with water, brine, separated, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by chromatography (silica gel eluted with 9:1 MeOH:EtAc) to afford the pure (1-quinazolin-4-yl-azetidin-3-yl)-carbamic acid tert-butyl ester as a tan solid (390 mg, 88%). 1H NMR (DMSO-d6, 400 MHz) δ 8.47 (s, 1H), 7.94 (d, J=8.4 Hz, 1H), 7.78 (t, J=7.6 Hz, 1H), 7.72 (d, J=8.4 Hz, 1H), 7.67 (m, 1H), 7.48 (t, J=7.6 Hz, 1H), 4.73 (m, 2H), 4.50 (m, 1H), 4.30 (m, 2H), 1.41 (s, 9H). LCMS (APCI+) m/z 301 [M+H]+; Rt=2.26 min.

1. customequipped with a condenser
2. customdegassed 3 times
3. dissolutionsuspended/dissolved in 6 mL of methanol
4. temperatureThe mixture was heated to 60 C for 4 hours to completion
5. filtrationThe mixture was filtered through a plug of celite
6. washwashed with ethanol
7. concentrationthe filtrate was concentrated in vacuo
8. dissolutionThe residue was re-dissolved in 30 mL of DCM
9. dry with materialdried over Na2SO4
10. filtrationfiltered
11. concentrationconcentrated in vacuo
12. customto afford the crude intermediate
13. temperatureThe solution was heated to 80° C. overnight to completion
14. customaffording an orange mixture
15. temperatureAfter cooling to room temperature
16. extractionThe aqueous was extracted with ethyl acetate
17. washThe organic was washed with water, brine
18. customseparated
19. dry with materialdried over MgSO4
20. filtrationfiltered
21. concentrationconcentrated in vacuo
22. customThe residue was purified by chromatography (silica gel eluted with 9:1 MeOH:EtAc)