Hydrochloric Acid → Methyl (3-amino-4-fluoro-5-(4-methylpiperazin-1-yl)phenyl)(4-methoxybenzyl)carbamate

HRID 921746Notes

Reaction equation

HRID 921746 reaction equation
Br[C:2]1[CH:3]=[C:4]([N:10]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:11](=[O:14])[O:12][CH3:13])[CH:5]=[C:6](Br)[C:7]=1[F:8].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(=O)([O-])[O-].[Cs+].[Cs+].[CH3:76][N:77]1[CH2:82][CH2:81][NH:80][CH2:79][CH2:78]1.C(=[NH:96])(C1C=CC=CC=1)C1C=CC=CC=1.Cl>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[NH2:96][C:2]1[CH:3]=[C:4]([N:10]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:11](=[O:14])[O:12][CH3:13])[CH:5]=[C:6]([N:80]2[CH2:81][CH2:82][N:77]([CH3:76])[CH2:78][CH2:79]2)[C:7]=1[F:8]

Participants

9

Reactant 6

HCID 313Hydrochloric AcidHCID 10796Cesium carbonateHCID 531671-MethylpiperazineHCID 136809Benzophenone imineHCID 634876Binap, (A+-)-HCID 86708628Methyl (3,5-dibromo-4-fluorophenyl)(4-methoxybenzyl)carbamate

Product 1

HCID 86708629Methyl (3-amino-4-fluoro-5-(4-methylpiperazin-1-yl)phenyl)(4-methoxybenzyl)carbamateYield 69.1%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 312751,4-DioxaneSolvent2×

Conditions

Temperature
90 °C

Procedure

A round bottom flask was loaded with methyl (3,5-dibromo-4-fluorophenyl)(4-methoxybenzyl)carbamate (350 mg, 0.744 mmol), (S)-BINAP (69.5 mg, 0.112 mmol), Cesium carbonate (969 mg, 2.97 mmol) and Pd2dba3 (34.1 mg, 0.037 mmol). The flask was evacuated and filled with nitrogen 3 times. Dioxane (10 mL) and 1-methylpiperazine (0.091 mL, 0.818 mmol) were added and the vial evacuated and filled with nitrogen 3 times. The reaction mixture was heated to 90° C. for 20 hours. Benzophenone imine (0.187 mL, 1.116 mmol) was added, the temperature increased to 110° C. and stirring under nitrogen continued for 24 hours. The reaction mixture was cooled to room temperature (immersed into a room temperature water bath). Dioxane (10 ml) and aq. HCl (1.0 molar, 10 ml, 10 mmol) were added and the reaction mixture stirred at room temperature for 2 hours. The reaction mixture was partitioned between EtOAc and aq. NaHCO3 solution. The organic layer was washed with NaHCO3 solution and brine, then dried over MgSO4, filtered and concentrated in vacuum. The crude was purified by column chromatography on silica (80 g cartridge, gradient from 100% EtOAc to 20% MeOH in EtOAc) gave methyl (3-amino-4-fluoro-5-(4-methylpiperazin-1-yl)phenyl)(4-methoxybenzyl)carbamate (207 mg)

Workup

  1. customThe flask was evacuated
  2. additionfilled with nitrogen 3 times
  3. customthe vial evacuated
  4. additionfilled with nitrogen 3 times
  5. temperaturethe temperature increased to 110° C.
  6. temperatureThe reaction mixture was cooled to room temperature (
  7. customimmersed into a room temperature
  8. stirringthe reaction mixture stirred at room temperature for 2 hours
  9. customThe reaction mixture was partitioned between EtOAc and aq. NaHCO3 solution
  10. washThe organic layer was washed with NaHCO3 solution and brine
  11. dry with materialdried over MgSO4
  12. filtrationfiltered
  13. concentrationconcentrated in vacuum
  14. customThe crude was purified by column chromatography on silica (80 g cartridge, gradient from 100% EtOAc to 20% MeOH in EtOAc)

Sources & evidence

ORD record
ord-5dd90a9e229a411090f79d9763edb77d
Source dataset
uspto-grants-2016_03
Patent number
US09273057B2

Reaction notes

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