Acetic Acid → diethyl (S)-2-(5-(((1,2-dihydro-3-methyl-1-oxo-benzo-[f]quinazolin-9-yl)methyl)amino)-1-oxo-2-isoindolinyl)glutarate

HRID 381586Notes

Reaction equation

HRID 381586 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]([CH3:16])[NH:10][C:9](=[O:17])[C:8]=3[C:7]=2[CH:18]=1.[NH2:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[C:25](=[O:29])[N:24]([C@@H:30]([CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])[C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:23]2.C([O-])(O)=O.[Na+].C(O)(=O)C>CN(C=O)C.C(O)C>[CH3:16][C:11]1[NH:10][C:9](=[O:17])[C:8]2[C:7]3[CH:18]=[C:3]([CH2:2][NH:19][C:20]4[CH:21]=[C:22]5[C:26](=[CH:27][CH:28]=4)[C:25](=[O:29])[N:24]([C@@H:30]([CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])[C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:23]5)[CH:4]=[CH:5][C:6]=3[CH:15]=[CH:14][C:13]=2[N:12]=1

Participants

7

Reactant 4

HCID 176Acetic AcidHCID 516892Sodium BicarbonateHCID 10382223HCID 10382223, compoundHCID 1354009769-bromomethyl-3-methylbenzo[f]quinazolin-1(2H)-one

Product 1

HCID 135539140diethyl (S)-2-(5-(((1,2-dihydro-3-methyl-1-oxo-benzo-[f]quinazolin-9-yl)methyl)amino)-1-oxo-2-isoindolinyl)glutarateYield 49%

Reagents, catalysts & solvents 2

HCID 702EthanolSolventHCID 6228DimethylformamideSolvent

Procedure

A solution of crude 9-bromomethyl-3-methylbenzo[f]quinazolin-1(2H)-one (4.32 g), (S)-diethyl 2-(5-amino-1-oxo-2-isoindolinyl)glutarate (4.0 g, 12 mmol), and NaHCO3 (2.0 g, 24 mmol) in DMF (30 ml) was stirred under nitrogen at 105° C. for 1.5 hours. After cooling, acetic acid (1 ml, 17 mmol) was added, the reaction mixture transferred to a larger round bottom flask with ethanol, and then concentrated in vacuo onto silica gel (30 g). The absorbed material was purified by chromatography on silica gel eluting with methanol:methylene chloride (1:24) and then precipitation of the solid from methylene chloride (˜20 ml) with ethyl acetate (˜45 ml) and methanol (˜5 ml). The white solid was filtered under nitrogen and dried under high vacuum to give diethyl(S)-2-(5-(((1,2-dihydro-3-methyl-1-oxobenzo[f]-quinazolin-9-yl)-methyl)amino)-1-oxo-2-isoindolinyl)glutarate (3.27 g). 1H NMR (DMSO-d6, 300 MHz, δ: 1.10 (t, J=7 Hz, 3H, ester CH3), 1.15 (t, J=7 Hz, 3H, ester CH3), 1.93-2.33 (m, 4H, glu CH2CH2), 2.43 (s, 3H, C3—CH3), 3.87-4.03 (m, 2H, ester CH2), 4.09 (q, J=7 Hz, 2H, ester CH2), 4.25 (very strongly coupled AB pair, 2H, glu NCH2Ar), 4.58 (d, J=6 Hz, 2H, C9—CH2N), 4.74-4.83 (m, 1H, glu CH), 6.71 (br d, J=2 Hz, 1H, Ar), 6.74 (dd, J=8,2 Hz, 1H, Ar), 7.20 (t, J=6 Hz, 1H, ArNH), 7.37 (d, J=8 Hz, 1H, Ar), 7.59 (d, J=9 Hz, 1H, Ar), 7.63 (dd, J=8,2 Hz, 1H, Ar), 8.00 (d, J=8 Hz, 1H, Ar), 8.21 (d, J=9 Hz, 1H, Ar), 9.87 (s, 1H, Ar), 12.54 (s, 1H, N2H). Mass spectrum (CI—CH4) 557 (M+1, 100%). Anal. Calculated for C31H32N4O6: C, 66.89; H, 5.79; N, 10.07. Found: C, 66.80; H, 5.82; N, 10.10.

Workup

  1. temperatureAfter cooling
  2. concentrationconcentrated in vacuo onto silica gel (30 g)
  3. customThe absorbed material was purified by chromatography on silica gel eluting with methanol:methylene chloride (1:24)
  4. customprecipitation of the solid from methylene chloride (˜20 ml) with ethyl acetate (˜45 ml) and methanol (˜5 ml)
  5. filtrationThe white solid was filtered under nitrogen
  6. customdried under high vacuum

Sources & evidence

ORD record
ord-9b3dbac10a0a4f2f94dbef1fd0a7e5d4
Source dataset
uspto-grants-2001_10
Patent number
US06306865B1

Reaction notes

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