Réaction #661793

Équation de réaction

4-methyl-1-naphthoyl chloride

ethyl aluminum dichloride

4-methyl-1-naphthoyl chloride

6,7,8,9-tetrahydropyrido[1,2-a]indole

ethyl aluminum dichloride

4-methyl-1-naphthoyl chloride

ethyl aluminum dichloride

4-methyl-1-naphthoyl chloride

ethyl aluminum dichloride

→

(4-methylnaphthalen-1-yl)(6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl)methanone

Solvants

CH2Cl2

CH2Cl2

Conditions de réaction

Traitement

1. 1
   Températurethen cooled to −70° C.
2. 2
   Températureto warm to room temperature
3. 3
   workup.STIRRINGstirred 6 h
4. 4
   TempératureThe reaction mixture was again cooled to −70° C.
5. 5
   Températureto warm to room temperature overnight
6. 6
   TempératureIt was again cooled to −70° C.
7. 7
   Températureto warm to room temperature overnight
8. 8
   AutreThe reaction mixture was then partitioned between ethyl acetate and cold H2O
9. 9
   Extractionthe aqueous layer extracted twice with ethyl acetate
10. 10
    ExtractionThe combined organic extract
11. 11
    Lavagewas washed successively with H2O, 10% K2CO3, and brine
12. 12
    Séchagedried over MgSO4
13. 13
    Filtrationfiltered
14. 14
    Concentrationconcentrated in vacuo
15. 15
    AutreThe crude product was purified via silica gel chromatography
16. 16
    Autreto give CBX005 (22 mg, 0.065 mmol)

Mode opératoire

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]+.

Source