Methanol → 5-Cyano-2-[3-methyl-2,5-dioxo-1-(3-trifluoromethyl-phenyl)-1,2,3,4,5,6,7,8-octahydro-quinazolin-4-yl]-benzoic acid methyl ester

HRID 59656Notes

Reaction equation

HRID 59656 reaction equation
Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH:10]1[C:19]2[C:18](=[O:20])[CH2:17][CH2:16][CH2:15][C:14]=2[N:13]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=2)[C:12](=[O:31])[N:11]1[CH3:32])[C:5]#[N:6].[C:33]([O-:36])(=[O:35])C.[Na+].[C]=O.[CH3:40]O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:40][O:36][C:33](=[O:35])[C:2]1[CH:3]=[C:4]([C:5]#[N:6])[CH:7]=[CH:8][C:9]=1[CH:10]1[C:19]2[C:18](=[O:20])[CH2:17][CH2:16][CH2:15][C:14]=2[N:13]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:30])[F:29])[CH:22]=2)[C:12](=[O:31])[N:11]1[CH3:32]

Participants

6

Reactant 4

HCID 887MethanolHCID 517045Sodium AcetateHCID 1186921643-Bromo-4-[3-methyl-2,5-dioxo-1-(3-trifluoromethyl-phenyl)-1,2,3,4,5,6,7,8-octahydro-quinazolin-4-yl]-benzonitrile2×HCID 178418416HCID 178418416, compound

Product 1

HCID 1186921505-Cyano-2-[3-methyl-2,5-dioxo-1-(3-trifluoromethyl-phenyl)-1,2,3,4,5,6,7,8-octahydro-quinazolin-4-yl]-benzoic acid methyl ester

Reagents, catalysts & solvents 1

HCID 167845palladium(II) acetateCatalyst

Procedure

3-Bromo-4-[3-methyl-2,5-dioxo-1-(3-trifluoromethyl-phenyl)-1,2,3,4,5,6,7,8-octahydro-quinazolin-4-yl]-benzonitrile (INTERMEDIATE 23, 10.5 g, 20.8 mmol), 1.1-bis(diphenylphosphino)-ferrocen (1.15 g, 2.08 mmol), palladium acetate (233 mg, 1.04 mmol) and sodium acetate (5.12 g, 62.5 mmol) are suspended in methanol (180 mL) and treated with carbon monoxide at 5 bar and 100° C. for 40 h. The product begins to crystallize from the reaction mixture. Diisopropylether and dichloromethane are added and further crystals are collected. Further purification is performed by recrystallization from methanol and by flash chromatography on silica (dichloromethane/methanol 99:1). Yield: 1.7 g. ESI mass spectrum: [M+H]+=484; Retention time HPLC: 0.68 min (X012_S02).

Workup

  1. customto crystallize from the reaction mixture
  2. additionDiisopropylether and dichloromethane are added
  3. customfurther crystals are collected
  4. customFurther purification
  5. customis performed by recrystallization from methanol and by flash chromatography on silica (dichloromethane/methanol 99:1)
  6. custom0.68 min (X012_S02)

Sources & evidence

ORD record
ord-b41fa4a89fa34a38a256c12eca32e8a1
Source dataset
uspto-grants-2016_09
Patent number
US09440930B2

Reaction notes

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