Indole → 5-Bromo-1-methyl-2-[2-(2-(R)-methyl-pyrrolidin-1-yl)-ethyl]-1H-indole

HRID 900203Notes

Reaction equation

HRID 900203 reaction equation
O([C:3](C)(C)C)[K].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[C:10]([C:15]#[C:16][CH2:17][CH2:18][N:19]2[CH2:23][CH2:22][CH2:21][C@H:20]2[CH3:24])[CH:9]=1.CI.N1C2C(=CC=CC=2)C=C1>CN1C(=O)CCC1.O>[Br:7][C:8]1[CH:9]=[C:10]2[C:11](=[CH:12][CH:13]=1)[N:14]([CH3:3])[C:16]([CH2:17][CH2:18][N:19]1[CH2:23][CH2:22][CH2:21][C@H:20]1[CH3:24])=[CH:15]2

Participants

7

Reactant 4

HCID 798IndoleHCID 6328Methyl iodideHCID 210414944-Bromo-2-[4-(2-(R)-methyl-pyrrolidin-1-yl)-but-1-ynyl]-phenylamineHCID 178418922HCID 178418922, compound

Product 1

HCID 210414955-Bromo-1-methyl-2-[2-(2-(R)-methyl-pyrrolidin-1-yl)-ethyl]-1H-indoleYield 89.8%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 13387N-methyl-2-pyrrolidoneSolvent2×

Procedure

To a cooled (0° C.) suspension of KO-tBu (95%, 6.2 g, 52 mmol) in NMP (120 mL) was added a solution of 4-bromo-2-[4-(2-(R)-methyl-pyrrolidin-1-yl)-but-1-ynyl]-phenylamine (8.0 g, 26 mmol) in NMP (50 mL) dropwise keeping the temperature below 5° C. The resulting mixture was then stirred at room temperature for 3 hours under nitrogen. HPLC indicated that all the starting material was consumed. MeI (1.95 mL, 31.3 mmol) was then added. The resulting mixture was stirred at room temperature for 2 hours. HPLC indicated that all the indole intermediate was methylated. H2O (300 mL) was added slowly to the reaction mixture followed by addition of IPAc (400 mL). The resulting mixture was stirred for 5 minutes and the organic layer was separated. The organic layer was washed with 20% brine (3×150 mL), dried over Na2SO4 and treated with activated carbon. After filtration, the filtrate was concentrated under vacuum to give the title compound as a thick oil (7.5 g), which was used in the next coupling reaction without further purification. 1H NMR (400 MHz, CDCl3) δ 7.78 (d, J=1.8 Hz, 1H), 7.36 (dd, J=1.8, 8.7 Hz, 1H), 7.26 (d, J=8.6 Hz, 1H), 6.37 (s, 1H), 3.81 (s, 1H), 3.40-3.45 (m, 1H), 3.26-3.34 (m, 1H), 3.04-3.16 (m, 2H), 2.51-2.61 (m, 2H), 2.39 (q, J=8.78 Hz, 1H), 2.09-2.14 (m, 1H), 1.87-1.99 (m, 2H), 1.61-1.68 (m, 1H), 1.30 (d, J=6.2 Hz, 3H). 13C NMR (400 MHz, CDCl3) δ 140.30, 135.60, 129.18, 123.08, 121.92, 112.29, 109.95, 98035, 60.16, 54.22, 53.19, 32091, 29.86, 26.85, 22.00, 19.34. [M+H]+ at m/z 322.

Workup

  1. temperatureTo a cooled
  2. customthe temperature below 5° C
  3. customwas consumed
  4. stirringThe resulting mixture was stirred at room temperature for 2 hours
  5. additionfollowed by addition of IPAc (400 mL)
  6. stirringThe resulting mixture was stirred for 5 minutes
  7. customthe organic layer was separated
  8. washThe organic layer was washed with 20% brine (3×150 mL)
  9. dry with materialdried over Na2SO4
  10. additiontreated with activated carbon
  11. filtrationAfter filtration
  12. concentrationthe filtrate was concentrated under vacuum

Sources & evidence

ORD record
ord-532574b73143456f94647fae51959bcc
Source dataset
uspto-grants-2008_04
Patent number
US07358263B2

Reaction notes

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