tert-Butyl piperazine-1-carboxylate → 4-[1-(3-Fluoro-benzyl)-3-methyl-2-oxo-1,2,3,4-tetrahydro-quinazolin-5-yl]-piperazine-1-carboxylic acid tert-butyl ester

HRID 901867Notes

Reaction equation

HRID 901867 reaction equation
Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][N:5]([CH3:21])[C:6](=[O:20])[N:7]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1.[C:22]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:25]([O:24][C:22]([N:29]1[CH2:34][CH2:33][N:32]([C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH2:4][N:5]([CH3:21])[C:6](=[O:20])[N:7]3[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)[CH2:31][CH2:30]1)=[O:23])([CH3:28])([CH3:26])[CH3:27]

Participants

7

Reactant 4

HCID 143452tert-Butyl piperazine-1-carboxylateHCID 634876Binap, (A+-)-2×HCID 184445195-bromo-1-(3-fluoro-benzyl)-3-methyl-3,4-dihydro-1H-quinazolin-2-oneHCID 23676156Sodium t-butoxide

Product 1

HCID 691151024-[1-(3-Fluoro-benzyl)-3-methyl-2-oxo-1,2,3,4-tetrahydro-quinazolin-5-yl]-piperazine-1-carboxylic acid tert-butyl esterYield 35.2%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 1140TolueneSolvent

Procedure

A solution of 5-bromo-1-(3-fluoro-benzyl)-3-methyl-3,4-dihydro-1H-quinazolin-2-one (156 mg, 0.45 mmol) and 1-Boc-piperazine (100 mg, 0.54 mmol) in 1 ml toluene was added to a mixture of Pd2(dba)3 (8 mg, 0.009 mmol), BINAP (2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (14 mg, 0.022 mmol), and NaOt-Bu (65 mg, 0.67 mmol). With stirring, the solution was heated at 95° C.-100° C. for 1 hour and was allowed to cool to room temperature. The reaction mixture was filtered through celite and washed with ethyl acetate. The filtrate was washed with water and brine. After drying over MgSO4, the organic fraction was concentrated in vacuo and resulting brown residue was purified by prep TLC to give 72 mg 4-[1-(3-fluoro-benzyl)-3-methyl-2-oxo-1,2,3,4-tetrahydro-quinazolin-5-yl]-piperazine-1-carboxylic acid tert-butyl ester as yellow solid (75 mg, 35%).

Workup

  1. temperaturethe solution was heated at 95° C.-100° C. for 1 hour
  2. filtrationThe reaction mixture was filtered through celite
  3. washwashed with ethyl acetate
  4. washThe filtrate was washed with water and brine
  5. dry with materialAfter drying over MgSO4
  6. concentrationthe organic fraction was concentrated in vacuo
  7. customresulting brown residue
  8. customwas purified by prep TLC

Sources & evidence

ORD record
ord-33d245776f8a4bf8aa469671fa78f767
Source dataset
uspto-grants-2008_04
Patent number
US07365063B2

Reaction notes

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