反应详情

To a solution of 4-methyl-1-naphthoyl chloride (37 mg, 0.18 mmol) and 6,7,8,9-tetrahydropyrido[1,2-a]indole (30 mg, 0.18 mmol) in 1 mL CH2Cl2 at −70° C. was added dropwise ethyl aluminum dichloride (0.22 mL, 0.40 mmol, 1.8 M in toluene). The reaction mixture was allowed to slowly warm to room temperature and stirred for 3 d then cooled to −70° C. and 4-methyl-1-naphthoyl chloride (4 mg, 0.020 mmol) and ethyl aluminum dichloride (20 μL, 0.036 mmol) added and allowed to warm to room temperature and stirred 6 h. The reaction mixture was again cooled to −70° C. and 4-methyl-1-naphthoyl chloride (4 mg, 0.020 mmol) and ethyl aluminum dichloride (20 μL, 0.036 mmol) added and allowed to warm to room temperature overnight. It was again cooled to −70° C. and 4-methyl-1-naphthoyl chloride (8 mg, 0.040 mmol), ethyl aluminum dichloride (40 μL, 0.072 mmol), and 1 mL CH2Cl2 added and allowed to warm to room temperature overnight. The reaction mixture was then partitioned between ethyl acetate and cold H2O, and the aqueous layer extracted twice with ethyl acetate. The combined organic extract was washed successively with H2O, 10% K2CO3, and brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified via silica gel chromatography using a gradient from 0 to 25% ethyl acetate in hexanes to give CBX005 (22 mg, 0.065 mmol). 1H NMR (500 MHz, CDCl3, δ): 1.80-1.95 (m, 2H), 2.05-2.33 (m, 2H), 2.82 (s, 3H), 2.97 (t, J=6.3 Hz, 2H), 4.13 (t, J=6.2 Hz, 2H), 7.09 (t, J=7.6 Hz, 1H), 7.22 (t, J=7.6 Hz, 1H), 7.30-7.37 (m, 2H), 7.40 (d, J=7.1 Hz, 1H), 7.43-7.52 (m, 2H), 7.58 (t, J=7.6 Hz, 1H), 8.08-8.19 (m, 2H). 13C NMR (500 MHz, CDCl3, δ): 19.87, 20.03, 22.31, 25.20, 42.65, 108.94, 113.75, 121.25, 122.03, 122.44, 124.31, 124.99, 125.93, 126.05, 126.24, 126.41, 126.97, 130.34, 132.89, 136.27, 139.26, 147.09, 193.08. MS m/z 340.4 [M+H]+.

1. temperaturethen cooled to −70° C.
2. temperatureto warm to room temperature
3. stirringstirred 6 h
4. temperatureThe reaction mixture was again cooled to −70° C.
5. temperatureto warm to room temperature overnight
6. temperatureIt was again cooled to −70° C.
7. temperatureto warm to room temperature overnight
8. customThe reaction mixture was then partitioned between ethyl acetate and cold H2O
9. extractionthe aqueous layer extracted twice with ethyl acetate
10. extractionThe combined organic extract
11. washwas washed successively with H2O, 10% K2CO3, and brine
12. dry with materialdried over MgSO4
13. filtrationfiltered
14. concentrationconcentrated in vacuo
15. customThe crude product was purified via silica gel chromatography
16. customto give CBX005 (22 mg, 0.065 mmol)