Sodium hydride → Tert-butyl 4-{[(5-bromopyrimidin-2-yl)oxy]methyl}piperidine-1-carboxylate

HRID 423566Notes

Reaction equation

HRID 423566 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].[H-].[Na+].[Br:18][C:19]1[CH:20]=[N:21][C:22](I)=[N:23][CH:24]=1>CS(C)=O.O>[Br:18][C:19]1[CH:20]=[N:21][C:22]([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)=[N:23][CH:24]=1

Participants

6

Reactant 3

HCID 24758Sodium hydrideHCID 2764081Tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylateHCID 70066515-Bromo-2-iodopyrimidine

Product 1

HCID 59718897Tert-butyl 4-{[(5-bromopyrimidin-2-yl)oxy]methyl}piperidine-1-carboxylateYield 28%

Reagents, catalysts & solvents 2

HCID 679Dimethyl SulfoxideSolvent3×HCID 962WaterSolvent

Procedure

A solution of N-Boc-4-piperidinemethanol (1.0 g, 4.50 mmol) in DMSO (2 mL) was added dropwise to a suspension of NaH (60% in mineral oil, 0.27 g, 6.76 mmol) in DMSO (4 mL). The mixture was stirred at ambient temperature for 1 h, then 30 minutes at 50° C. Cooled to ambient temperature, a solution of 5-bromo-2-iodopyrimidine (1.38 g, 4.73 mmol) in DMSO (4 mL) was added dropwise, and the reaction mixture was stirred at ambient temperature overnight, then heated at 100° C. for 5 h. Cooled to ambient temperature, the mixture was poured in water, extracted with EtOAc. The organic extract was washed with water and brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product as a dark brown oil. The crude product was purified by chromatography on ISCO silica gel column eluted with a EtOAc:hexane gradient (hexane to 15% EtOAc) to give 0.455 g (28%) of 1,1-dimethylethyl 4-{[(5-bromo-2-pyrimidinyl)oxy]methyl}-1-piperidinecarboxylate as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.51 (s, 2H), 4.20-4.10 (m, 4H), 2.80-2.65 (m, 2H), 2.05-1.95 (m, 1H), 1.90-1.75 (m, 2H), 1.45 (s, 9H), 1.35-1.20 (m, 2H); LRMS (ESI), m/z 372/374 (M+H).

Workup

  1. custom30 minutes
  2. customat 50° C
  3. temperatureCooled to ambient temperature
  4. stirringthe reaction mixture was stirred at ambient temperature overnight
  5. temperatureheated at 100° C. for 5 h
  6. temperatureCooled to ambient temperature
  7. extractionextracted with EtOAc
  8. extractionThe organic extract
  9. washwas washed with water and brine
  10. dry with materialdried over Na2SO4
  11. filtrationfiltered
  12. concentrationthe filtrate was concentrated
  13. customto give the crude product as a dark brown oil
  14. customThe crude product was purified by chromatography on ISCO silica gel column
  15. washeluted with a EtOAc

Sources & evidence

ORD record
ord-53f9df1d8c924871b58a61c57f5f2ff6
Source dataset
uspto-grants-2012_01
Patent number
US08101634B2

Reaction notes

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