Cesium carbonate → 1-Methyl-4-[2-methyl-4-nitro-5-(propan-2-yloxy)phenyl]piperazine

HRID 518824Notes

Reaction equation

HRID 518824 reaction equation
C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:49][N:50]1[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1.Cl[C:57]1[CH:62]=[C:61]([O:63][CH:64]([CH3:66])[CH3:65])[C:60]([N+:67]([O-:69])=[O:68])=[CH:59][C:58]=1[CH3:70]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:49][N:50]1[CH2:55][CH2:54][N:53]([C:57]2[CH:62]=[C:61]([O:63][CH:64]([CH3:65])[CH3:66])[C:60]([N+:67]([O-:69])=[O:68])=[CH:59][C:58]=2[CH3:70])[CH2:52][CH2:51]1

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 531671-MethylpiperazineHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 457903241-Chloro-5-isopropoxy-2-methyl-4-nitrobenzene2×

Product 1

HCID 866979901-Methyl-4-[2-methyl-4-nitro-5-(propan-2-yloxy)phenyl]piperazineYield 57.5%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 312751,4-DioxaneSolvent

Procedure

24.9 g of caesium carbonate, 745 mg of palladium acetate, 2.88 g of (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) and 4.89 g of 1-methylpiperazine are added to a solution of 7.62 g of 1-chloro-2-methyl-4-nitro-5-(propan-2-yloxy)benzene (prepared according to WO2008/073687, p. 31) in 380 ml of dioxane under argon. The mixture is refluxed for 5.5 h, and then cooled to ambient temperature. The mixture is combined with the crude product of one and the same reaction carried out on 1.89 g of 1-chloro-2-methyl-4-nitro-5-(propan-2-yloxy)benzene under the same conditions. The mixture is concentrated under vacuum and the residue is taken up with 100 ml of water, 200 ml of ethyl acetate and a little methanol. The mixture is filtered on Clarcel and the aqueous phase is extracted twice with 100 ml of ethyl acetate. The combined organic phases are washed with 100 ml of a saturated sodium chloride solution, dried over magnesium sulfate and concentrated under vacuum. The crude product is purified on 340 g of silica, elution being carried out with 0-100% of acetone in dichloromethane, so as to obtain 5.60 g of 1-methyl-4-[2-methyl-4-nitro-5-(propan-2-yloxy)phenyl]piperazine in the form of a black solid.

Workup

  1. temperatureThe mixture is refluxed for 5.5 h
  2. customthe same reaction
  3. concentrationThe mixture is concentrated under vacuum
  4. filtrationThe mixture is filtered on Clarcel
  5. extractionthe aqueous phase is extracted twice with 100 ml of ethyl acetate
  6. washThe combined organic phases are washed with 100 ml of a saturated sodium chloride solution
  7. dry with materialdried over magnesium sulfate
  8. concentrationconcentrated under vacuum
  9. customThe crude product is purified on 340 g of silica, elution

Sources & evidence

ORD record
ord-41859a61d4f8408fa520ebbc055592cc
Source dataset
uspto-grants-2015_08
Patent number
US09115140B2

Reaction notes

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