Water → 1-(1-(2-Ethyl-5-methoxy-4-nitrophenyl)piperidin-4-yl)-4-(methylsulfonyl)piperazine

HRID 419598Notes

Reaction equation

HRID 419598 reaction equation
[CH2:1]([C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6]([O:12][CH3:13])=[CH:5][C:4]=1F)[CH3:2].Cl.Cl.[CH3:17][S:18]([N:21]1[CH2:26][CH2:25][N:24]([CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH2:23][CH2:22]1)(=[O:20])=[O:19].C([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[CH2:1]([C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6]([O:12][CH3:13])=[CH:5][C:4]=1[N:30]1[CH2:29][CH2:28][CH:27]([N:24]2[CH2:25][CH2:26][N:21]([S:18]([CH3:17])(=[O:20])=[O:19])[CH2:22][CH2:23]2)[CH2:32][CH2:31]1)[CH3:2]

Participants

6

Reactant 4

HCID 962WaterHCID 11430Potassium CarbonateHCID 594528471-Ethyl-2-fluoro-4-methoxy-5-nitrobenzeneHCID 666497911-(Methylsulfonyl)-4-(4-piperidinyl)piperazine dihydrochloride

Product 1

HCID 594529781-(1-(2-Ethyl-5-methoxy-4-nitrophenyl)piperidin-4-yl)-4-(methylsulfonyl)piperazineYield 56.2%

Reagents, catalysts & solvents 1

HCID 679Dimethyl SulfoxideSolvent

Conditions

Temperature
90 °C

Procedure

A mixture of 1-ethyl-2-fluoro-4-(methyloxy)-5-nitrobenzene (Example 187, step C) (0.93 g, 4.67 mmol), 1-(methylsulfonyl)-4-(4-piperidinyl)piperazine (Example 204, step C) (1.16 g, 4.67 mmol) and K2CO3 (0.774 g, 5.60 mmol) in DMSO (20 mL) was heated at 90° C. for 48 h. The reaction had not progressed sufficiently so the reaction was then heated at 120° C. for an additional 4 h. The reaction was cooled to rt, poured into H2O and extracted with DCM. Some saturated brine solution was added and the resultant was exhaustively extracted with DCM. The combined organics were washed with H2O then dried over MgSO4. The resultant solution was concentrated onto silica and purified by flash chromatography to afford 1-{1-[2-ethyl-5-(methyloxy)-4-nitrophenyl]-4-piperidinyl}-4-(methylsulfonyl)piperazine (1.12 g, 56%). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.73-7.80 (m, 1H), 6.75 (s, 1H), 3.91 (s, 3H), 3.23-3.30 (m, 1H), 3.05-3.19 (m, 3H), 2.87 (s, 2H), 2.70-2.84 (m, 2H), 2.53-2.67 (m, 5H), 1.77-1.94 (m, 2H), 1.48-1.67 (m, 2H), 1.19 (t, J=7.42 Hz, 3H).

Workup

  1. temperaturewas then heated at 120° C. for an additional 4 h
  2. temperatureThe reaction was cooled to rt
  3. extractionextracted with DCM
  4. additionSome saturated brine solution was added
  5. extractionthe resultant was exhaustively extracted with DCM
  6. washThe combined organics were washed with H2O
  7. dry with materialthen dried over MgSO4
  8. concentrationThe resultant solution was concentrated onto silica
  9. custompurified by flash chromatography

Sources & evidence

ORD record
ord-bd242b5d9fd548ddbf0125fad5e77dc9
Source dataset
uspto-grants-2012_01
Patent number
US08093239B2

Reaction notes

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