Ethyl aluminium dichloride → (5-chloro-2-methyl-1-(2-morpholino ethyl)-1H-indol-3-yl)(4-methylnaphthalen-1-yl)methanone

HRID 574603Notes

Reaction equation

HRID 574603 reaction equation
[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12](Cl)=[O:13])=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)[C:20]([CH3:33])=[CH:19]2.[Cl-].[Cl-].C([Al+2])C>C(Cl)Cl>[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([CH2:25][CH2:26][N:27]1[CH2:28][CH2:29][O:30][CH2:31][CH2:32]1)[C:20]([CH3:33])=[C:19]2[C:12]([C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([CH3:1])=[CH:3][CH:4]=1)=[O:13]

Participants

5

Reactant 3

HCID 16686341Ethyl aluminium dichlorideHCID 248874124-Methylnaphthalene-1-carbonyl chlorideHCID 667647404-(2-(5-chloro-2-methyl-1H-indol-1-yl)ethyl)morpholine

Product 1

HCID 66764962(5-chloro-2-methyl-1-(2-morpholino ethyl)-1H-indol-3-yl)(4-methylnaphthalen-1-yl)methanone

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a solution of 4-methyl-1-naphthoyl chloride (106 mg, 0.52 mmol) and 4-(2-(5-chloro-2-methyl-1H-indol-1-yl)ethyl)morpholine (154 mg, 0.55 mmol) in 8 mL CH2Cl2 at −70° C. was added dropwise ethyl aluminum dichloride (0.63 mL, 1.14 mmol, 1.8 M in toluene). The reaction mixture was allowed to slowly 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 10% MeOH in CH2Cl2 to give CBX002 (141 mg, 0.32 mmol). 1H NMR (500 MHz, CDCl3, δ): 2.32 (s, 3H), 2.47 (t, J=4.3 Hz, 4H), 2.66 (t, J=6.9 Hz, 2H), 2.79 (s, 3H), 3.68 (t, J=4.4 Hz, 4H), 4.19 (t, J=6.9 Hz, 2H), 7.14-7.21 (m, 1H), 7.23 (d, J=8.6 Hz, 1H), 7.36 (d, J=7.2 Hz, 1H), 7.43-7.52 (m, 2H), 7.58 (t, J=7.6 Hz, 1H), 7.61 (d, J=1.8 Hz, 1H), 8.10 (d, J=8.4 Hz, 1H), 8.18 (d, J=8.4 Hz, 1H). 13C NMR (500 MHz, CDCl3, δ): 12.69, 19.92, 41.47, 54.08, 57.34, 66.87, 110.25, 115.09, 121.16, 122.69, 124.45, 125.75, 125.99, 126.06, 126.23, 126.66, 127.98, 128.34, 130.46, 132.95, 134.43, 137.27, 138.21, 146.37, 193.24. MS m/z 447.5 [M+H]+.

Workup

  1. customThe reaction mixture was then partitioned between ethyl acetate and cold H2O
  2. extractionthe aqueous layer extracted twice with ethyl acetate
  3. extractionThe combined organic extract
  4. washwas washed successively with H2O, 10% K2CO3, and brine
  5. dry with materialdried over MgSO4
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. customThe crude product was purified via silica gel chromatography
  9. customto give CBX002 (141 mg, 0.32 mmol)

Sources & evidence

ORD record
ord-adc01723b7f34d84ba5cdf4864ef0d68
Source dataset
uspto-grants-2015_05
Patent number
US09034895B2

Reaction notes

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