4-Vinylbenzoic acid → 4-(2-(1,2-Dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)vinyl)benzoic acid

HRID 2289267Notes

Reaction equation

HRID 2289267 reaction equation
Br[C:2]1[CH:3]=[CH:4][C:5]2[CH:14]=[CH:13][C:12]3[N:11]=[C:10]([CH3:15])[NH:9][C:8](=[O:16])[C:7]=3[C:6]=2[CH:17]=1.[CH:18]([C:20]1[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=1)=[CH2:19].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:15][C:10]1[NH:9][C:8](=[O:16])[C:7]2[C:6]3[CH:17]=[C:2]([CH:19]=[CH:18][C:20]4[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=4)[CH:3]=[CH:4][C:5]=3[CH:14]=[CH:13][C:12]=2[N:11]=1

Participants

6

Reactant 3

HCID 140984-Vinylbenzoic acidHCID 80271Tri-o-tolylphosphine2×HCID 1358381559-bromo-3-methylbenzo[f]quinazolin-1(2H)-one

Product 1

HCID 1359905654-(2-(1,2-Dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)vinyl)benzoic acid

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalyst2×HCID 79724-MethylmorpholineSolvent

Procedure

A solution of 9-bromo-3-methylbenzo[f]quinazolin-1(2H)-one (0.87 g, 3.0 mmol), 4-vinylbenzoic acid (0.87 g, 5.9 mmol), palladium acetate (0.45 g, 2.0 mmol), and tri (2-tolyl) phosphine (1.2 g, 3.9 mmol) in N-methylmorpholine (90 ml) was stirred under nitrogen at reflux for 1 hour. Additional palladium acetate (0.45 g, 2.0 mmol) and tri(2-tolyl)phosphine (1.2 g, 3.9 mmol) were added and the reaction mixture was refluxed for a further 4 hours. The resulting suspension was allowed to cool, the solid filtered and washed with diethyl ether. The solid was resuspended in a small volume of boiling ethanol, filtered hot, washed with diethyl ether and dried under vacuum at 80° C. to give 4-(2-(1,2-dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)vinyl) benzoic acid 1H NMR (DMSO-d6, 300 MHz) δ: 2.44 (s, 3H, CH3), 7.50 (d, J =16.5 Hz, 1H, vinyl CH), 7.61 (d, J=8 Hz, H, Ar), 7.65 (d, J=16 Hz, 1H, vinyl CH), 7.83 (d, J=8 Hz, 2H, Ar), 7.96 (d, J=8 Hz, 2H Ar), 8.05 (s, 2H, Ar), 8.23 (d, J=9 Hz, 1H, Ar), 9.96 (s, 1H, Ar), 12-13.2 (v br s, 1H, CO2H), 12.6 (br s, 1H, N2H) containing 6.7% by NMR of 9-bromo-3-methylbenzo[f]quinazolin-1-(2H)-one (0.80 g). To a suspension of the acid in a solution of L-glutamic acid diethyl ester hydrochloride (0.72 g, 3.0 mmol) and triethylamine (0.42 ml, 3.0 mmol) in dimethylformamide (50 ml) was added 1-(3-dimethylaminopropyl)3-ethylcarbodiimide hydrochloride (0.48 g, 2.5 mmol). After stirring the mixture for 4 hours, more dimethylformamide (50 ml) was added and the suspension stirred overnight. The reaction mixture was heated to 1-(3-dimethylaminopropyl)3-ethylcarbodiimide hydrochloride (0.32 g, 1.7 mmol) was added and the suspension was stirred for 6 hours to give a homogeneous solution. The solution was stirred for 60 hours at room temperature, then concentrated in vacuo onto silica gel (10 g). Purification by chromatography on silica gel (450 g) eluting with methanol:methylene chloride (1:39 to 1:24), evaporation, filtration of the resulting solid from a small volume of methanol and drying under high vacuum gave diethyl(E)-N-(4-(2-(1,2-dihydro-3-methyl-1-oxobenzo [f]quinazolin-9-yl)vinyl)benzoyl)-L-glutamate (0.22 g). 1H NMR (DMSO-d6, 300 MHz) δ: 1.17 (t, J=7 Hz, 3H, ester CH3), 1.20 (t, J=7 Hz, 3H, ester CH3), 1.95-2.20 (m, 2H, glu CH2), 2.44 (s, 3H, C3 --CH3), 2.47 (t, J=7 Hz, 2H, gluCH2), 4.06 (q, J=7 Hz, 2H, ester CH2), 4.12 (q, J=7 Hz, 2H, ester CH2), 4.41-4.51 (m, 1H, gluCH), 7.50 (d, J=16.5 Hz, 1H, vinyl CH), 7.61 (d, J=9 Hz, 1H, Ar), 7.64 (d, J=16.5 Hz, 1H, vinyl CH), 7.83 (d, J=8.5 Hz, 2H, Ar), 7.93 (d, J=8.5 Hz, 2H, Ar), 8.05 (s, 2H, Ar), 8.24 (d, J=9 Hz, 1H, Ar), 8.76 (d, J=7.5 Hz, 1H, glu NH), 9.96 (s, 1H, Ar), 12.58 (br, s, 1H, N2H). Mass spectrum (Cl--CH4): 542 (M+1, 100%). Anal. Calculated for C31H31N3O6 0.55H2O: C, 67.51; H, 5.87; N, 7.62. Found: C, 67.40; H, 5.72; N, 7.67.

Workup

  1. temperatureat reflux for 1 hour
  2. temperaturethe reaction mixture was refluxed for a further 4 hours
  3. temperatureto cool
  4. filtrationthe solid filtered
  5. washwashed with diethyl ether
  6. filtrationfiltered hot
  7. washwashed with diethyl ether
  8. customdried under vacuum at 80° C.

Sources & evidence

ORD record
ord-7946dd9f34194c748b1fff7bef518a0e
Source dataset
uspto-grants-2000_07
Patent number
US06090941

Reaction notes

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