Potassium Carbonate → (R)-4-(3-Fluoropyrrolidin-1-yl)-1-(5-methoxy-2-methyl-4-nitrophenyl)piperidine

HRID 1256009Notes

Reaction equation

HRID 1256009 reaction equation
[CH3:1][O:2][C:3]1[C:4]([N+:20]([O-:22])=[O:21])=[CH:5][C:6]([CH3:19])=[C:7]([N:9]2[CH2:18][CH2:17][C:12]3(OCCO3)[CH2:11][CH2:10]2)[CH:8]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].COC1C([N+]([O-])=O)=CC(C)=C(N2CCC(=O)CC2)C=1.Cl.[F:61][C@@H:62]1[CH2:66][CH2:65][NH:64][CH2:63]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O.C(#N)C>[F:61][C@@H:62]1[CH2:66][CH2:65][N:64]([CH:12]2[CH2:11][CH2:10][N:9]([C:7]3[CH:8]=[C:3]([O:2][CH3:1])[C:4]([N+:20]([O-:22])=[O:21])=[CH:5][C:6]=3[CH3:19])[CH2:18][CH2:17]2)[CH2:63]1

Participants

9

Reactant 6

HCID 11430Potassium CarbonateHCID 521998p-Toluenesulfonic acid monohydrateHCID 2759162(3R)-3-fluoropyrrolidine hydrochlorideHCID 5049666Sodium triacetoxyborohydrideHCID 580714988-(5-Methoxy-2-methyl-4-nitrophenyl)-1,4-dioxa-8-azaspiro[4.5]decane2×HCID 667101521-(5-Methoxy-2-methyl-4-nitrophenyl)piperidin-4-one

Product 1

HCID 58071475(R)-4-(3-Fluoropyrrolidin-1-yl)-1-(5-methoxy-2-methyl-4-nitrophenyl)piperidine

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6342AcetonitrileSolvent

Procedure

8-(5-Methoxy-2-methyl-4-nitrophenyl)-1,4-dioxa-8-azaspiro[4.5]decane (INTERMEDIATE 16, 0.350 g, 1.14 mmol) and 4-toluenesulfonic acid hydrate (0.217 g, 1.14 mmol) in water (25 mL) were stirred under reflux for 6 h. The reaction mixture was allowed to cooled to RT and adjusted to pH 7 with potassium carbonate The mixture was concentrated in vacuo. The crude residue was taken up in EtOAc, washed with water and brine, dried over magnesium sulfate, filtered and concentrated in vacuo. To the resultant crude 1-(5-methoxy-2-methyl-4-nitrophenyl)piperidin-4-one (0.30 g, 1.14 mmol) in acetonitrile (15 mL) was added (R)-3-fluoropyrrolidine hydrochloride (0.102 g, 1.14 mmol) and sodium triacetoxyborohydride (0.481 g, 2.27 mmol) and the reaction mixture was stirred at RT for 16 h. The mixture was concentrated in vacuo and the crude residue was taken up in EtOAc and washed with 10% aqueous sodium carbonate and brine. The organic layer was separated, dried over sodium sulfate and concentrated in vacuo to give the title product which was used in the next step without further purification (0.19 g, 50%). m/z 338.

Workup

  1. temperatureunder reflux for 6 h
  2. concentrationwas concentrated in vacuo
  3. washwashed with water and brine
  4. dry with materialdried over magnesium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo
  7. concentrationThe mixture was concentrated in vacuo
  8. washwashed with 10% aqueous sodium carbonate and brine
  9. customThe organic layer was separated
  10. dry with materialdried over sodium sulfate
  11. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-a945589cabf34ec1a57a41561a162d00
Source dataset
uspto-grants-2013_06
Patent number
US08461170B2

Reaction notes

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