Triethylamine → 1,1-Dimethylethyl 4-{[(6-bromo-3-pyridinyl)oxy]methyl}-1-piperidinecarboxylate

HRID 423592Notes

Reaction equation

HRID 423592 reaction equation
[C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CCN(CC)CC.CS(Cl)(=O)=O.[Br:28][C:29]1[N:34]=[CH:33][C:32](O)=[CH:31][CH:30]=1.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.CN(C=O)C>[Br:28][C:29]1[N:34]=[CH:33][C:32]([O:15][CH2:14][CH:11]2[CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9][CH2:10]2)=[CH:31][CH:30]=1

Participants

8

Reactant 5

HCID 8471TriethylamineHCID 11430Potassium CarbonateHCID 31297Methanesulfonyl chlorideHCID 27628652-Bromo-5-hydroxypyridineHCID 2764081Tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate

Product 1

HCID 579302011,1-Dimethylethyl 4-{[(6-bromo-3-pyridinyl)oxy]methyl}-1-piperidinecarboxylateYield 68.2%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent2×

Conditions

Temperature
0 °C

Procedure

A mixture of N-Boc-4-piperidinemethanol (5.0 g, 23.22 mmol), Et3N (4.85 mL, 34.83 mmol) in CH2Cl2 (100 mL) at 0° C. was treated dropwise with methanesulfonyl chloride (2.16 mL, 27.86 mmol). The reaction mixture was stirred at 0° C. for 0.5 h, diluted with CH2Cl2 and washed with water and brine. The CH2Cl2 layer was dried over Na2SO4, filtered, and the filtrate was concentrated. The residue was mixed with 6-bromo-3-pyridinol (6.06 g, 34.83 mmol) and K2CO3 (6.41 g, 46.44 mmol) in DMF. The resulting mixture was heated at 65° C. overnight, cooled to ambient temperature and partitioned between water and EtOAc. The organic layer was separated and washed with 2N NaOH, water, brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product, which was purified by chromatography on a silica gel column to give 5.88 g (68%) of 1,1-dimethylethyl 4-{[(6-bromo-3-pyridinyl)oxy]methyl}-1-piperidinecarboxylate. 1H NMR (400 MHz, CDCl3): δ 8.00 (1H, d, J=3.1 Hz), 7.32 (d, 1H, J=8.6 Hz), 7.05 (dd, 1H, Ja=8.7 Hz, Jb=3.2 Hz), 4.13 (bs, 2H), 3.79 (d, 2H, J=6.5 Hz), 2.80-2.65 (m, 2H), 2.00-1.85 (m, 1H), 1.80-1.70 (m, 2H), 1.43 (s, 9H), 1.30-1.15 (m, 2H).

Workup

  1. washwashed with water and brine
  2. dry with materialThe CH2Cl2 layer was dried over Na2SO4
  3. filtrationfiltered
  4. concentrationthe filtrate was concentrated
  5. temperatureThe resulting mixture was heated at 65° C. overnight
  6. temperaturecooled to ambient temperature
  7. custompartitioned between water and EtOAc
  8. customThe organic layer was separated
  9. washwashed with 2N NaOH, water, brine
  10. dry with materialdried over Na2SO4
  11. filtrationfiltered
  12. concentrationthe filtrate was concentrated
  13. customto give the crude product, which
  14. customwas purified by chromatography on a silica gel column

Sources & evidence

ORD record
ord-0149448629a84ab28dcfbe59b4fc6d41
Source dataset
uspto-grants-2012_01
Patent number
US08101634B2

Reaction notes

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