Potassium Carbonate → 6-bromo-2-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}quinoline

HRID 2390391Notes

Reaction equation

HRID 2390391 reaction equation
C([C@@H]([C@H](C(O)=O)O)O)(O)=O.[CH3:11][C@@H:12]1[CH2:16][CH2:15][CH2:14][NH:13]1.C(=O)([O-])[O-].[K+].[K+].CC1C=CC(S(O[CH2:34][CH2:35][C:36]2[CH:45]=[CH:44][C:43]3[C:38](=[CH:39][CH:40]=[C:41]([Br:46])[CH:42]=3)[N:37]=2)(=O)=O)=CC=1>C(#N)C>[Br:46][C:41]1[CH:42]=[C:43]2[C:38](=[CH:39][CH:40]=1)[N:37]=[C:36]([CH2:35][CH2:34][N:13]1[CH2:14][CH2:15][CH2:16][C@H:12]1[CH3:11])[CH:45]=[CH:44]2

Participants

5

Reactant 3

HCID 11430Potassium CarbonateHCID 11858493(R)-2-methylpyrrolidine L-tartrateHCID 865922242-(6-Bromo-2-quinolinyl)ethyl 4-methylbenzenesulfonate

Product 1

HCID 671046156-bromo-2-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}quinolineYield 92.2%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Conditions

Temperature
60 °C

Procedure

(2R)-2-Methylpyrrolidine L-tartrate (7.00 g, 0.0298 mole, milled), potassium carbonate (9.04 g, 0.0655 mole, milled), and acetonitrile (190 mL) were combined and heated at 60° C. with agitation for 48 hours. The mixture was allowed to cool to 30° C., and treated with the product from Example 42C (8.00 g, 0.0197 mole). The reaction mixture was heated at −60° C. for 36 hours and then distilled down to ˜1/4 volume, and isopropyl acetate (200 mL) was added. The mixture was washed with 5% NaHCO3 aq. solution (200 mL×2), and 25% brine (200 mL). The upper organic was dried over anhydrous sodium sulphate, filtered, and the filtrate was concentrated to dryness. The crude product was purified with a short-path silica gel column eluted with heptane:ethyl acetate:TEA (60:40:1) to give 5.8 g (92% yield) of product as an oil, which solidified on standing; mp 49-50° C. (uncorrected); MS (ESI): 319, 311 (M+H)+; 1H-NMR (CDCl3) δ 7.95 (1H, d, J=8.5 Hz), 7.91 (1H, d, J=2.2 Hz), 7.89 (1H, d, J=8.9 Hz), 7.72 (1H, dd, J=8.9, 2.2 Hz), 7.35 (1H, d, J=8.5 Hz), 3.23 (2H, m), 3.18 (2H, m), 2.55 (1H, m), 2.38 (1H, m), 2.25 (1H, q, J=8.9 Hz), 1.93 (1H, m), 1.80 (1H, m), 1.71 (1H, m), 1.42 (1H, m), 1.11 (3H, d, J=6.0 Hz); 13C-NMR (CDCl3) δ 161.3, 146.1, 134.7, 132.3, 130.3, 129.2, 127.6, 122.2, 119.2, 59.9, 54.0, 53.6, 38.6, 33.0, 22.0, 19.4.

Workup

  1. temperatureto cool to 30° C.
  2. temperatureThe reaction mixture was heated at −60° C. for 36 hours
  3. distillationdistilled down to ˜1/4 volume, and isopropyl acetate (200 mL)
  4. additionwas added
  5. washThe mixture was washed with 5% NaHCO3 aq. solution (200 mL×2), and 25% brine (200 mL)
  6. dry with materialThe upper organic was dried over anhydrous sodium sulphate
  7. filtrationfiltered
  8. concentrationthe filtrate was concentrated to dryness
  9. customThe crude product was purified with a short-path silica gel column
  10. washeluted with heptane:ethyl acetate:TEA (60:40:1)

Sources & evidence

ORD record
ord-09eaf217736d473ab10aa1c132955dfa
Source dataset
uspto-grants-2012_09
Patent number
US08273767B2

Reaction notes

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