2-Bromopyridine → tert-Butyl 4-(methyl(pyridin-2-yl)amino)piperidine-1-carboxylate

HRID 222332Notes

Reaction equation

HRID 222332 reaction equation
[CH3:1][NH:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.Br[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1.C(N(CC)C(C)C)(C)C.C(=O)([O-])[O-].[K+].[K+]>>[CH3:1][N:2]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)[CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1

Participants

5

Reactant 4

HCID 79732-Bromopyridine2×HCID 11430Potassium CarbonateHCID 81531DiisopropylethylamineHCID 15380702tert-Butyl 4-(methylamino)piperidine-1-carboxylate

Product 1

HCID 57753882tert-Butyl 4-(methyl(pyridin-2-yl)amino)piperidine-1-carboxylateYield 24%

Conditions

Temperature
130 °C

Procedure

A mixture of tert-butyl 4-(methylamino)piperidine-1-carboxylate (WO 03/089412, p 22), (2 g, 9.33 mmol), 2-bromopyridine (1.35 mL, 13.99 mmol) and N,N-diisopropylethylamine (2.5 mL, 13.99 mmol) was heated at 130° C. for 3 hours. Potassium carbonate (2 g, 14 mmol) was added and the reaction mixture was heated at 130° C. for a further 8 hours. 2-Bromopyridine (1 mL, 10.36 mmol) was then added to the mixture and heating continued at 130° C. for 36 hours. The reaction mixture was then cooled and partitioned between ethyl acetate (30 mL) and water (15 mL). The organic layer was separated and extracted with saturated citric acid solution (2×15 mL), and the combined aqueous solution was basified with sodium hydrogen carbonate and extracted with dichloromethane (2×30 mL). The combined organic solution was dried over magnesium sulfate, concentrated in vacuo and the residue was purified by column chromatography on silica gel, eluting with ethyl acetate:pentane, 0:100 to 50:50, to afford the title compound in 24% yield, 646 mg. 1H NMR (CDCl3, 400 MHz) δ: 1.45 (s, 9H), 1.55-1.70 (m, 4H), 2.78-2.90 (m, 5H), 4.10-4.30 (m, 2H), 4.65-4.80 (m, 1H), 6.45-6.55 (m, 2H), 7.40-7.45 (m, 1H), 8.10-8.15 (m, 1H); LRMS APCI m/z 292 [M+H]+

Workup

  1. temperaturethe reaction mixture was heated at 130° C. for a further 8 hours
  2. temperatureheating
  3. temperatureThe reaction mixture was then cooled
  4. custompartitioned between ethyl acetate (30 mL) and water (15 mL)
  5. customThe organic layer was separated
  6. extractionextracted with saturated citric acid solution (2×15 mL)
  7. extractionextracted with dichloromethane (2×30 mL)
  8. dry with materialThe combined organic solution was dried over magnesium sulfate
  9. concentrationconcentrated in vacuo
  10. customthe residue was purified by column chromatography on silica gel
  11. washeluting with ethyl acetate

Sources & evidence

ORD record
ord-b7422b7e8bd343f3a93011f6da8a6b9c
Source dataset
uspto-grants-2012_06
Patent number
US08207198B2

Reaction notes

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