Azobisisobutyronitrile → N-(9-Bromomethyl-1,2-dihydro-1-oxobenzo[f]quinazolin-3-yl)pivalamide

HRID 1884047Notes

Reaction equation

HRID 1884047 reaction equation
[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:14]=[CH:13][C:12]3[N:11]=[C:10]([NH:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])[NH:9][C:8](=[O:22])[C:7]=3[C:6]=2[CH:23]=1.[Br:24]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C1C=CC=CC=1>[Br:24][CH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:14]=[CH:13][C:12]3[N:11]=[C:10]([NH:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:18])[CH3:19])[NH:9][C:8](=[O:22])[C:7]=3[C:6]=2[CH:23]=1

Participants

5

Reactant 3

HCID 6547AzobisisobutyronitrileHCID 67184N-bromobutanimideHCID 135622212n-(1,2-Dihydro-9-methyl-1-oxobenzo[f]quinazolin-3-yl)pivalamide

Product 1

HCID 135525312N-(9-Bromomethyl-1,2-dihydro-1-oxobenzo[f]quinazolin-3-yl)pivalamide

Reagents, catalysts & solvents 1

HCID 241BenzeneSolvent

Procedure

To a hot solution of N-(1,2-dihydro-9-methyl-1-oxobenzo[f]quinazolin-3-yl)pivalamide (0.94 g, 3.0 mmol) in benzene (250 ml) under nitrogen were added N-bromosuccinimide (0.57 g, 3.2 mmol) (Kodak) and 2,2′-azobisisobutyronitrile (AIBN) (35 mg, 0.21 mmol) (Kodak). The solution was stirred at reflux for 1.5 hours and then concentrated in vacuo to give crude N-(9-bromomethyl-1,2-dihydro-1-oxobenzo[f]quinazolin-3-yl)pivalamide. The pivalamide and N-(4-aminobenzoyl)-L-glutamic acid diethyl ester (2.5 g, 7.8 mmol) (Aldrich) in DMF (10 ml) were stirred under nitrogen at 105-110° C. for 5 minutes and then allowed to cool. Triethylamine (0.5 ml, 3.6 mmol) was added and the solution was concentrated under high vacuum. The residue was purified by chromatography on silica gel (130 g) eluting with ethyl acetate:methylene chloride (1:19→2:3), followed by recrystallization of the solid from ethanol/diethyl ether. This was filtered and dried under high vacuum to give diethyl N-(4-(((1,2-dihydro-1-oxo-3-pivalamido-benzo[f]quinazolin-9-yl)methyl)amino)benzoyl)-L-glutamate (0.32 g) as a white solid. The filtrate was concentrated and the residue purified by chromatography and crystallization to give an additional 0.243 g. 1H NMR (DMSO-d6, 300 MHz) δ: 1.15 (t, J=7 Hz, 3H, esterCH3), 1.16 (t, J=7 Hz, 3H, esterCH3), 1.28 (s, 9H, t-butyl), 1.87-2.13 (m, 2H, gluCH2), 2.39 (t, J=7 Hz, 2H, gluCH2), 4.03 (q, J=7 Hz, 2H, esterCH2), 4.07 (q, J=7 Hz, 2H, esterCH2), 4.30-4.40 (m, 1H, gluCH), 4.57 (d, J=6 Hz, 2H, C9—CH2), 6.63 (d, J=9 Hz, 2H, Ar), 7.04 (t, J=6 Hz, 1H, ArNH), 7.53 (d, J=9 Hz, 1H, Ar), 7.61 (dd, J=8, 2 Hz, 1H, Ar), 7.62 (d, J=9 Hz, 2H, Ar), 7.99 (d, J=8 Hz, 1H, Ar), 8.21 (d, J=8 Hz, 1H, gluNH), 8.22 (d, J=9 Hz, 1H, Ar), 9.75 (s, 1H, Ar), 11.25 (s, 1H, N2H), 12.30 (br s, 1H, NH). Mass spectrum (CI-CH4) 630 (M+1, 6.5%), 243 (100%). Anal. Calculated for C34H39N5O7: C, 64.85; H, 6.24; N, 11.12. Found: C, 64.74; H, 6.25; N, 11.10.

Workup

  1. temperatureat reflux for 1.5 hours
  2. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-f92c7fb038a443c5ba4eff4f3962f64b
Source dataset
uspto-grants-2004_07
Patent number
US06762188B1

Reaction notes

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