Sodium Hydroxide → 1,1-Dimethylethyl 4-[({6-[2-fluoro-4-(methylsulfonyl)phenyl]-3-pyridinyl}oxy)methyl]-1-piperidinecarboxylate

HRID 423594Notes

Reaction equation

HRID 423594 reaction equation
Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([O:14][CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]3)=[CH:10][CH:9]=2)=[C:4]([F:29])[CH:3]=1.[Na+].[CH3:31][S:32]([O-:34])=[O:33].[OH-].[Na+]>CS(C)=O.O>[F:29][C:4]1[CH:3]=[C:2]([S:32]([CH3:31])(=[O:34])=[O:33])[CH:7]=[CH:6][C:5]=1[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)=[CH:10][CH:9]=1

Participants

6

Reactant 3

HCID 14798Sodium HydroxideHCID 2733271Sodium methanesulfinateHCID 666731501,1-Dimethylethyl 4-({[6-(4-bromo-2-fluorophenyl)-3-pyridinyl]oxy}methyl)-1-piperidinecarboxylate

Product 1

HCID 249943361,1-Dimethylethyl 4-[({6-[2-fluoro-4-(methylsulfonyl)phenyl]-3-pyridinyl}oxy)methyl]-1-piperidinecarboxylateYield 64.1%

Reagents, catalysts & solvents 2

HCID 679Dimethyl SulfoxideSolventHCID 962WaterSolvent

Conditions

Temperature
110 °C

Procedure

A mixture of 1,1-dimethylethyl 4-({[6-(4-bromo-2-fluorophenyl)-3-pyridinyl]oxy}methyl)-1-piperidinecarboxylate (0.781 g, 1.68 mmol), methanesulphinic acid sodium salt (0.86 g, 80%, 6.71 mmol), Cul (1.28 g, 6.71 mmol) and NaOH (81 mg, 2.02 mmol) in DMSO (20 mL) and water (0.5 mL) was degassed, purged with N2 and heated at 110° C. for 48 h. After cooled to ambient temperature, the mixture was poured into water (75 mL) and EtOAc (75 mL), and filtered through Celite®. The solid on Celite® was further washed with EtOAc. The filtrate and washing were combined and transferred to a separatory funnel. The organic layer was separated and washed with water and brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product as a yellow solid. The crude product was purified by chromatography on a silica gel column eluted with 25% EtOAc/CH2Cl2 followed by trituration with hot hexanes containing 1% of MeOH to give 0.5 g (64%) of 1,1-dimethylethyl 4-[({6-[2-fluoro-4-(methylsulfonyl)phenyl]-3-pyridinyl}oxy)methyl]-1-piperidinecarboxylate as a white solid. 1H NMR (400 MHz, CD3OD): δ 8.40 (d, 1H, J=3.0 Hz), 8.15-8.10 (m, 1H), 7.90-7.75 (m, 3H), 7.50 (dd, 1H, Ja=8.8 Hz, Jb=3.0 Hz), 4.20-4.10 (m, 2H), 4.00 (d, 2H, J=6.3 Hz), 3.18 (s, 3H), 2.90-2.75 (m, 2H), 2.15-2.00 (m, 1H), 1.90-1.80 (m, 2H), 1.46 (s, 9H), 1.40-1.25 (m, 2H); LRMS (ESI), m/z 465 (M+H).

Workup

  1. customwas degassed
  2. custompurged with N2
  3. temperatureAfter cooled to ambient temperature
  4. additionthe mixture was poured into water (75 mL) and EtOAc (75 mL)
  5. filtrationfiltered through Celite®
  6. washThe solid on Celite® was further washed with EtOAc
  7. washThe filtrate and washing
  8. customtransferred to a separatory funnel
  9. customThe organic layer was separated
  10. washwashed with water and brine
  11. dry with materialdried over Na2SO4
  12. filtrationfiltered
  13. concentrationthe filtrate was concentrated
  14. customto give the crude product as a yellow solid
  15. customThe crude product was purified by chromatography on a silica gel column
  16. washeluted with 25% EtOAc/CH2Cl2

Sources & evidence

ORD record
ord-4a30cb49b78f49029bc12c22844a3110
Source dataset
uspto-grants-2012_01
Patent number
US08101634B2

Reaction notes

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