4-Fluoro-3-methoxybenzaldehyde → [2-(4-fluoro-3-methoxyphenyl)-4-oxo-6-(3,6,6-trimethylperhydro-1,4-diazepin-1-yl)-4H-quinazolin-3-yl]acetic acid tert-butyl ester

HRID 1161856Notes

Reaction equation

HRID 1161856 reaction equation
[C:1]([O:5][C:6](=[O:28])[CH2:7][NH:8][C:9](=[O:27])[C:10]1[CH:15]=[C:14]([N:16]2[CH2:22][C:21]([CH3:24])([CH3:23])[CH2:20][NH:19][CH:18]([CH3:25])[CH2:17]2)[CH:13]=[CH:12][C:11]=1[NH2:26])([CH3:4])([CH3:3])[CH3:2].[F:29][C:30]1[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][C:31]=1[O:38][CH3:39]>C(O)(=O)C.[C-]#N.[C-]#N.[C-]#N.[C-]#N.[C-]#N.[C-]#N.[K+].[K+].[K+].[Fe+3].C(O)C>[C:1]([O:5][C:6](=[O:28])[CH2:7][N:8]1[C:9](=[O:27])[C:10]2[C:11](=[CH:12][CH:13]=[C:14]([N:16]3[CH2:22][C:21]([CH3:24])([CH3:23])[CH2:20][NH:19][CH:18]([CH3:25])[CH2:17]3)[CH:15]=2)[N:26]=[C:34]1[C:33]1[CH:36]=[CH:37][C:30]([F:29])=[C:31]([O:38][CH3:39])[CH:32]=1)([CH3:2])([CH3:3])[CH3:4]

Participants

6

Reactant 2

HCID 27373584-Fluoro-3-methoxybenzaldehydeHCID 67417517[2-Amino-5-(3,6,6-trimethylperhydro-1,4-diazepin-1-yl)benzoylamino]acetic acid tert-butyl ester

Product 1

HCID 59519067[2-(4-fluoro-3-methoxyphenyl)-4-oxo-6-(3,6,6-trimethylperhydro-1,4-diazepin-1-yl)-4H-quinazolin-3-yl]acetic acid tert-butyl esterYield 12%

Reagents, catalysts & solvents 3

HCID 176Acetic AcidCatalystHCID 26250Potassium ferricyanideCatalystHCID 702EthanolSolvent

Procedure

[2-Amino-5-(3,6,6-trimethylperhydro-1,4-diazepin-1-yl)benzoylamino]acetic acid tert-butyl ester (INTERMEDIATE V.44) (1.00 g, 2.56 mmol), 4-fluoro-3-methoxybenzaldehyde (414 mg, 2.69 mmol), ethanol (20 mL) and acetic acid (3 drops) were stirred overnight at reflux temperature. Solvent was evaporated under reduced pressure. The crude reaction mixture was purified by SCX with product eluted with 2N NH3/MeOH. Solvent was evaporated under reduced pressure and the product dissolved in toluene (10 mL) and water (10 mL). Potassium hexacyanoferrate (III) (8.43 g, 25.6 mmol) was added and the reaction mixture stirred vigorously overnight. The reaction was then quenched by the addition of methanol (300 mL), the mixture filtered through a celite pad and the cake washed with further methanol (200 mL). The filtrate was evaporated to dryness and purified by chromatography on silica gel with a gradient of DCM to DCM:MeOH (3:1, v/v) as eluent to afford [2-(4-fluoro-3-methoxyphenyl)-4-oxo-6-(3,6,6-trimethylperhydro-1,4-diazepin-1-yl)-4H-quinazolin-3-yl]acetic acid tert-butyl ester (INTERMEDIATE VII.12) (160 mg, 0.305 mmol, 12%).

Workup

  1. temperatureat reflux temperature
  2. customSolvent was evaporated under reduced pressure
  3. customThe crude reaction mixture
  4. customwas purified by SCX with product
  5. washeluted with 2N NH3/MeOH
  6. customSolvent was evaporated under reduced pressure
  7. dissolutionthe product dissolved in toluene (10 mL)
  8. customThe reaction was then quenched by the addition of methanol (300 mL)
  9. filtrationthe mixture filtered through a celite pad
  10. washthe cake washed with further methanol (200 mL)
  11. customThe filtrate was evaporated to dryness
  12. custompurified by chromatography on silica gel with a gradient of DCM to DCM:MeOH (3:1

Sources & evidence

ORD record
ord-92ba51e22f184c5184d06742ecf45f7a
Source dataset
uspto-grants-2010_10
Patent number
US07820649B2

Reaction notes

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