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

HRID 1377095

反応式

HRID 1377095 の反応式
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

参加物

5

反応物 3

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

生成物 1

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

試薬・触媒・溶媒 1

HCID 6228Dimethylformamide溶媒

実験手順

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, ester CH3), 1.16 (t, J=7 Hz, 3H, ester CH3), 1.28 (s, 9H, t-butyl), 1.87-2.13 (m, 2H, glu CH2), 2.39 (t, J=7 Hz, 2H, glu CH2), 4.03 (q, J=7 Hz, 2H, ester CH2), 4.07 (q, J=7 Hz, 2H, ester CH2), 4.30-4.40 (m, 1H, glu CH), 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, glu NH), 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; N, 6.25; N, 11.10.

後処理

  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

出典と根拠

ORDレコード
ord-eec1e9d9707d40568d199eb378521940
出典データセット
uspto-grants-1997_09
特許番号
US05663337

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