Piperazine → HCID 135524901, compound

HRID 2109891Notes

Reaction equation

HRID 2109891 reaction equation
Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8](=O)[NH:7][C:6]=2[CH:17]=1.[C:18]1(B(O)O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+].[NH:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>C1(C)C=CC=CC=1.CCO.O.CCOC(C)=O.O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Ti](Cl)(Cl)Cl>[C:18]1([C:2]2[CH:3]=[CH:4][C:5]3[NH:11][C:10]4[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=4[C:8]([N:33]4[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]4)=[N:7][C:6]=3[CH:17]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1

Participants

10

Reactant 4

HCID 4837PiperazineHCID 11430Potassium CarbonateHCID 66827Phenylboronic AcidHCID 12434785HCID 12434785, compound

Product 1

HCID 135524901HCID 135524901, compoundYield 37.6%

Reagents, catalysts & solvents 5

HCID 24193Titanium TetrachlorideCatalystHCID 178418397HCID 178418397, compoundCatalystHCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent2×HCID 86587398Ethanol toluene waterSolvent

Conditions

Temperature
80 °C

Procedure

Tetrakis(triphenylphosphine)palladium(0) (catalytic amount) was added to a mixture of 8-bromo-5,10-dihydro-dibenzo[b,e][1,4]diazepine-11-one (166JO31) (30 mg, 0.12 mmol), benzene boronic acid (18 mg, 0.15 mmol) and K2CO3 (34 mg, 0.24 mmol) in deoxygenised toluene/EtOH/H2O (1.5 mL) and the resulting mixture was stirred at 80° C. over night. The mixture was diluted with EtOAc, washed with saturated aqueous NaHCO3-solution, dried (Na2SO4) and concentrated to give crude 8-phenyl lactam. The intermediate 8-phenyl lactam in dioxane (1 mL) was added to a mixture of TiCl4 (0.24 mL, 0.24 mmol, 1 M in toluene) and piperazine (0.103 g, 1.2 mmol) in dioxane at 50° C. The resulting mixture was stirred at 100° C. over night, and then allowed to obtain room temperature. Aqueous HCl-(3 mL, 2 M) was added to the mixture and then the aqueous phase was extracted with EtOAc (2×4 mL). Aqueous NaOH (6 mL, 2 M) was added to the aqueous phase and the resulting suspension was extracted with EtOAc (3×3 mL). The combined organic phases were applied onto a SCX-2 ion exchange column. The column was washed with MeOH, and then the product was eluted with NH3 (7 N in MeOH), concentrated, and purified by HPLC to give 16 mg of the title compound (189JO53). MS (ESI) 355 (MH+). Purity for MH+ (UV/MS) 100/100.

Workup

  1. washwashed with saturated aqueous NaHCO3-solution
  2. dry with materialdried (Na2SO4)
  3. concentrationconcentrated
  4. customto give crude 8-phenyl lactam
  5. stirringThe resulting mixture was stirred at 100° C. over night
  6. customto obtain room temperature
  7. extractionthe aqueous phase was extracted with EtOAc (2×4 mL)
  8. additionAqueous NaOH (6 mL, 2 M) was added to the aqueous phase
  9. extractionthe resulting suspension was extracted with EtOAc (3×3 mL)
  10. washThe column was washed with MeOH
  11. washthe product was eluted with NH3 (7 N in MeOH)
  12. concentrationconcentrated
  13. custompurified by HPLC

Sources & evidence

ORD record
ord-4a3b7b3d2da8402a958ffdbe6b463b04
Source dataset
uspto-grants-2009_04
Patent number
US07517871B2

Reaction notes

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