Reaction #10508

Reaction equation

indole

KO-tBu

4-bromo-2-[4-(2-(R)-methyl-pyrrolidin-1-yl)-but-1-ynyl]-phenylamine

MeI

→

title compound

Yield 89.8%

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

Yield 89.8%

Solvents

H2O

NMP

NMP

Conditions

Workup

1. 1
   TemperatureTo a cooled
2. 2
   Otherthe temperature below 5° C
3. 3
   Otherwas consumed
4. 4
   workup.STIRRINGThe resulting mixture was stirred at room temperature for 2 hours
5. 5
   workup.ADDITIONfollowed by addition of IPAc (400 mL)
6. 6
   workup.STIRRINGThe resulting mixture was stirred for 5 minutes
7. 7
   Otherthe organic layer was separated
8. 8
   WashThe organic layer was washed with 20% brine (3×150 mL)
9. 9
   Dryingdried over Na2SO4
10. 10
    workup.ADDITIONtreated with activated carbon
11. 11
    FiltrationAfter filtration
12. 12
    Concentrationthe filtrate was concentrated under vacuum

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 roan 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.

Source