4-Bromo-2-[4-(2-(R)-methyl-pyrrolidin-1-yl)-but-1-ynyl]-phenylamine → 5-Bromo-1-methyl-2-[2-(2-(R)-methyl-pyrrolidin-1-yl)-ethyl]-1H-indole

HRID 1157722Notes

Reaction equation

HRID 1157722 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>CN1C(=O)CCC1>[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

4

Reactant 2

HCID 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 1

HCID 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. Mel (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. additionMel (1.95 mL, 31.3 mmol) was then added
  5. stirringThe resulting mixture was stirred at room temperature for 2 hours
  6. additionH2O (300 mL) was added slowly to the reaction mixture
  7. additionfollowed by addition of IPAc (400 mL)
  8. stirringThe resulting mixture was stirred for 5 minutes
  9. customthe organic layer was separated
  10. washThe organic layer was washed with 20% brine (3×150 mL)
  11. dry with materialdried over Na2SO4
  12. additiontreated with activated carbon
  13. filtrationAfter filtration
  14. concentrationthe filtrate was concentrated under vacuum

Sources & evidence

ORD record
ord-337616c2990a411bb9c8a376d1e76adb
Source dataset
uspto-grants-2010_10
Patent number
US07807697B2

Reaction notes

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