Triethylamine → Diethyl n-(4-(((1,2-dihydro-1-oxo-3-pivalamido-benzo[f]quinazolin-9-yl)methyl)amino)benzoyl)-l-glutamate

HRID 1884048Notes

Reaction equation

HRID 1884048 reaction equation
Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:15]=[CH:14][C:13]3[N:12]=[C:11]([NH:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])[NH:10][C:9](=[O:23])[C:8]=3[C:7]=2[CH:24]=1.[CH2:25]([O:27][C:28](=[O:47])[C@H:29]([CH2:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])[NH:30][C:31](=[O:39])[C:32]1[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=1)[CH3:26].C(N(CC)CC)C>CN(C=O)C>[O:23]=[C:9]1[C:8]2[C:7]3[CH:24]=[C:3]([CH2:2][NH:38][C:35]4[CH:36]=[CH:37][C:32]([C:31]([NH:30][C@H:29]([C:28]([O:27][CH2:25][CH3:26])=[O:47])[CH2:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])=[O:39])=[CH:33][CH:34]=4)[CH:4]=[CH:5][C:6]=3[CH:15]=[CH:14][C:13]=2[N:12]=[C:11]([NH:16][C:17](=[O:22])[C:18]([CH3:20])([CH3:19])[CH3:21])[NH:10]1

Participants

5

Reactant 3

HCID 8471TriethylamineHCID 73002Diethyl N-(4-aminobenzoyl)-L-glutamateHCID 135525312N-(9-Bromomethyl-1,2-dihydro-1-oxobenzo[f]quinazolin-3-yl)pivalamide

Product 1

HCID 135448916Diethyl n-(4-(((1,2-dihydro-1-oxo-3-pivalamido-benzo[f]quinazolin-9-yl)methyl)amino)benzoyl)-l-glutamate

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

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. temperatureto cool
  2. concentrationthe solution was concentrated under high vacuum
  3. customThe residue was purified by chromatography on silica gel (130 g)
  4. washeluting with ethyl acetate:methylene chloride (1:19→2:3)
  5. customfollowed by recrystallization of the solid from ethanol/diethyl ether
  6. filtrationThis was filtered
  7. customdried under high vacuum

Sources & evidence

ORD record
ord-40a23d180c3d4531b2bcc37517883170
Source dataset
uspto-grants-2004_07
Patent number
US06762188B1

Reaction notes

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