反应详情

温度

80 °C

The (1-quinazolin-4-yl-azetidin-3-yl)-carbamic acid tert-butyl ester (390 mg, 1.30 mmol) was dissolved in 7 mL, of 4M HCl and allowed to stir at 80° C. to completion after three hours. The aqueous solution was washed with ether (discarded), and the aqueous layer was concentrated in vacuo to afford the de-protected intermediate as a white solid. The flask containing this solid was charged with HOBt (193 mg, 1.43 mmol), EDCI (274 mg, 1.43 mmol), and the 2(S)-tert-butoxycarbonylamino-3-(4-chlorophenyl)-propionic acid (389 mg. 1.30 mmol). The mixture was suspended/dissolved in 12.0 mL of DMF and treated with TEA (905 μL, 6.49 mmol). The mixture was allowed to stir for four hours to completion. The contents were partitioned between ethyl acetate and 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 to afford the crude Boc-intermediate as a white solid. The material was dissolved in 7 mL of DCM and treated with 4.0 mL of TFA. After two hours, the reaction solution was concentrated in vacuo to afford a pale yellow oil. The contents were partitioned between ethyl acetate and diluted NaHCO3 solution. The aqueous was extracted with ethyl acetate, and the organics were combined. The organic was washed with brine, separated, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by chromatography (silica gel eluted with 9:1 MeOH:DCM) to afford the pure 2(R)-amino-3-(4-chlorophenyl)-N-(1-quinazolin-4-yl-azetidin-3-yl)-propionamide as a colorless oil (177 mg, 30%). 1H NMR (CDCl3, 400 MHz) δ 8.60 (s, 1H), 8.02 (brs, 1H), 7.82 (d, J=8.4 Hz, 1H), 7.75 (d, J=8.8 Hz, 1H), 7.72 (t, J=8.4 Hz, 1H), 7.40 (t, J=7.6 Hz, 1H), 7.29 (d, J=8.4 Hz, 1H), 7.15 (d, J=8.4 Hz, 1H), 4.85 (m, 3H), 4.29 (dd, J=15.6, 5.6 Hz, 2H), 3.64 (dd, J=8.8, 4.0 Hz, 1H), 3.22 (dd, J=13.6, 4.0 Hz, 1H), 2.78 (dd, J=14.0, 8.8 Hz, 1H). LCMS (APCI+) m/z 382 [M+H]+; Rt=0.76 min.

1. washThe aqueous solution was washed with ether (discarded)
2. concentrationthe aqueous layer was concentrated in vacuo
3. customto afford the de-protected intermediate as a white solid
4. additionThe flask containing this solid
5. stirringto stir for four hours to completion
6. customThe contents were partitioned between ethyl acetate and diluted NaHCO3 solution
7. extractionThe aqueous was extracted with ethyl acetate
8. washThe organic was washed with water, brine
9. customseparated
10. dry with materialdried over MgSO4
11. filtrationfiltered
12. concentrationconcentrated in vacuo
13. customto afford the crude Boc-intermediate as a white solid
14. waitAfter two hours
15. concentrationthe reaction solution was concentrated in vacuo
16. customto afford a pale yellow oil
17. customThe contents were partitioned between ethyl acetate and diluted NaHCO3 solution
18. extractionThe aqueous was extracted with ethyl acetate
19. washThe organic was washed with brine
20. customseparated
21. dry with materialdried over Na2SO4
22. filtrationfiltered
23. concentrationconcentrated in vacuo
24. customThe residue was purified by chromatography (silica gel eluted with 9:1 MeOH:DCM)