Cesium carbonate → 3-[(R*)-1-[(S)-1-(2,3-Dihydro-benzo[1,4]dioxin-2-yl)methyl]-piperidin-3-yl]-phenylamine

HRID 2366037Notes

Reaction equation

HRID 2366037 reaction equation
[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][C@H:14]([C:18]2[CH:19]=[C:20](OS(C(F)(F)F)(=O)=O)[CH:21]=[CH:22][CH:23]=2)[CH2:13]1.C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(=[NH:97])(C1C=CC=CC=1)C1C=CC=CC=1.C([O-])(=O)C.[Na+].Cl.NO>O1CCCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][C@H:14]([C:18]2[CH:19]=[C:20]([NH2:97])[CH:21]=[CH:22][CH:23]=2)[CH2:13]1

Participants

9

Reactant 6

HCID 10796Cesium carbonateHCID 136809Benzophenone imineHCID 443297Hydroxyamine hydrochlorideHCID 517045Sodium AcetateHCID 634876Binap, (A+-)-HCID 86644712Trifluoromethanesulfonic acid 3-{(R*)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-piperidin-3-yl}phenyl ester

Product 1

HCID 251762893-[(R*)-1-[(S)-1-(2,3-Dihydro-benzo[1,4]dioxin-2-yl)methyl]-piperidin-3-yl]-phenylamineYield 20.5%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
80 °C

Procedure

A mixture of trifluoro-methanesulfonic acid 3-{(R*)-1-[(S)-1-(2,3-dihydro-benzo[1,4]dioxin-2-yl)methyl]-piperidin-3-yl}-phenyl ester (1.039 g, 2.27 mmol), cesium carbonate (1.036 g, 3.18 mmol), palladium acetate (0.015, 0.068 mmol), (R)-(+)-2,2-bis(diphenylphosphino)-1,1-binaphthyl (0.064 g, 0.102 mmol) and benzophenone imine (0.457 ml, 2.73 mmol) in dry tetrahydrofuran (6 ml) was heated in a microwave reactor at 80° C. for 10 hours. The mixture was filtered and evaporated to dryness. The crude product was purified by flash chromatography using a gradient of heptane and EtOAc as eluent. The residue on evaporation was dissolved in dry methanol, sodium acetate (0.54 g, 6.55 mmol) and hydroxylamine hydrochloride (0.36 g, 5.24 mmol) was added and the mixture was stirred at room temperature for 1.5 h. The mixture was evaporated to dryness, dissolved in EtOAc and washed with 1M Na2CO3. The organic layer was dried (Na2SO4), filtered and evaporated to dryness. The crude product was purified by flash chromatography using gradient of heptane and EtOAc as eluent to give 151 mg of the title compound.

Workup

  1. filtrationThe mixture was filtered
  2. customevaporated to dryness
  3. customThe crude product was purified by flash chromatography
  4. customThe residue on evaporation
  5. dissolutionwas dissolved in dry methanol
  6. customThe mixture was evaporated to dryness
  7. dissolutiondissolved in EtOAc
  8. washwashed with 1M Na2CO3
  9. dry with materialThe organic layer was dried (Na2SO4)
  10. filtrationfiltered
  11. customevaporated to dryness
  12. customThe crude product was purified by flash chromatography

Sources & evidence

ORD record
ord-ba68f6328f474f0d9580b7a084d9681d
Source dataset
uspto-grants-2014_04
Patent number
US08697723B2

Reaction notes

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