Hydrochloric Acid → 3-(2,5-difluoro-4-(methylsulfonyl)phenoxy)-1,4'-bipiperidin-2-one HCl salt

HRID 407897Notes

Reaction equation

HRID 407897 reaction equation
Br[C:2]1[C:28]([F:29])=[CH:27][C:5]([O:6][CH:7]2[CH2:12][CH2:11][CH2:10][N:9]([CH:13]3[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]3)[C:8]2=[O:26])=[C:4]([F:30])[CH:3]=1.[CH3:31][S:32]([O-:34])=[O:33].[Na+].[C@@H]1(N)CCCC[C@H]1N.[ClH:44]>CS(C)=O.O.CCOC(C)=O.C(Cl)Cl.CCOCC>[ClH:44].[F:30][C:4]1[CH:3]=[C:2]([S:32]([CH3:31])(=[O:34])=[O:33])[C:28]([F:29])=[CH:27][C:5]=1[O:6][CH:7]1[CH2:12][CH2:11][CH2:10][N:9]([CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[C:8]1=[O:26]

Participants

10

Reactant 4

HCID 313Hydrochloric AcidHCID 438061,2-Diaminocyclohexane, trans-HCID 2733271Sodium methanesulfinateHCID 66803528Tert-butyl 3-(4-bromo-2,5-difluorophenoxy)-2-oxo-1,4'-bipiperidine-1'-carboxylate

Product 1

HCID 866880843-(2,5-difluoro-4-(methylsulfonyl)phenoxy)-1,4'-bipiperidin-2-one HCl saltYield 89%

Reagents, catalysts & solvents 5

HCID 679Dimethyl SulfoxideSolventHCID 962WaterSolventHCID 3283Diethyl EtherSolventHCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
110 °C

Procedure

To a solution of tert-butyl 3-(4-bromo-2,5-difluorophenoxy)-2-oxo-1,4′-bipiperidine-1′-carboxylate (710 mg, 1.45 mmol) in DMSO (4 mL) was added Cu(I) triflate benzene complex (73 mg, 0.145 mmol), sodium methanesulfinate (222 mg, 2.18 mmol) and trans-cyclohexane-1,2-diamine (66.3 mg, 0.580 mmol). The reaction was heated at 110° C. overnight. The reaction was cooled to ambient temperature and diluted with water (5 mL) and EtOAc (5 mL). The organic layer was separated and the aqueous washed with EtOAc (2×10 mL). The combined organic layers were dried with MgSO4 and concentrated. The crude residue was purified over silica gel (2:1 hexanes/EtOAc) to give a clear oil. This material was then dissolved in CH2Cl2 (10 mL) and excess 2 N HCl in ether (5 mL) added. The reaction was allowed to stir overnight and then concentrated under vacuum to give 3-(2,5-difluoro-4-(methylsulfonyl)phenoxy)-1,4′-bipiperidin-2-one HCl salt (238 mg, 89%) was an off white solid.

Workup

  1. temperatureThe reaction was cooled to ambient temperature
  2. customThe organic layer was separated
  3. washthe aqueous washed with EtOAc (2×10 mL)
  4. dry with materialThe combined organic layers were dried with MgSO4
  5. concentrationconcentrated
  6. customThe crude residue was purified over silica gel (2:1 hexanes/EtOAc)
  7. customto give a clear oil
  8. concentrationconcentrated under vacuum

Sources & evidence

ORD record
ord-3e8f7d66bf5d40a093e21aa1238f632a
Source dataset
uspto-grants-2014_06
Patent number
US08754226B2

Reaction notes

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