Pivalic anhydride → N-(7-(4-cyanoanilino)-1,2-dihydro-1-oxobenzo[f]quinazolin-3-yl)pivalamide

HRID 1654402Notes

Reaction equation

HRID 1654402 reaction equation
[C:1]([C:3]1[CH:31]=[CH:30][C:6]([NH:7][C:8]2[C:21]3[CH2:20][CH2:19][C:18]4[N:17]=[C:16]([NH:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[NH:15][C:14](=[O:29])[C:13]=4[C:12]=3[CH:11]=[CH:10][CH:9]=2)=[CH:5][CH:4]=1)#[N:2].C(OC(=O)C(C)(C)C)(=O)C(C)(C)C>[Pd].COCCOCCOC>[C:1]([C:3]1[CH:31]=[CH:30][C:6]([NH:7][C:8]2[C:21]3[CH:20]=[CH:19][C:18]4[N:17]=[C:16]([NH:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[NH:15][C:14](=[O:29])[C:13]=4[C:12]=3[CH:11]=[CH:10][CH:9]=2)=[CH:5][CH:4]=1)#[N:2]

Participants

5

Reactant 2

HCID 15234Pivalic anhydrideHCID 135838113N-(7-(4-cyanoanilino)-1,2,5,6-tetrahydro-1-oxobenzo[f]quinazolin-3-yl)pivalamide

Product 1

HCID 135838112N-(7-(4-cyanoanilino)-1,2-dihydro-1-oxobenzo[f]quinazolin-3-yl)pivalamideYield 57.6%

Reagents, catalysts & solvents 2

HCID 23938PalladiumCatalystHCID 8150DiglymeSolvent2×

Procedure

To a solution of sodium ethoxide, prepared by reacting sodium (0.28 g, 12 mmol) with ethanol (6 ml), was added guanidine hydrochloride (1.2 g, 12 mmol) and the mixture was briefly stirred at reflux. A solution of methyl 5-(N-(4-cyanophenyl)-2,2,2-trifluoroacetamido)-3,4-dihydro-2-hydroxy-1-naphthalene carboxylate (0.63 g, 1.5 mmol) in ethanol (6 ml) was added and the reaction mixture was stirred at reflux under nitrogen for 18 hours. The solution was diluted with water (50 ml), neutralized with acetic acid, and the resulting precipitate filtered and dried at 110° C. under reduced pressure. A solution of the solid in pivalic anhydride (10 ml) was refluxed for ~5 minutes and then concentrated under high vacuum. The residue was eluted on silica gel (30 g) with ethyl acetate:methylene chloride (1:9) and the resulting solid recrystallized from diethyl ether, the slurry diluted with hexane, filtered, and the solid dried at 100° C. under reduced pressure to give N-(7-(4-cyanoanilino)-1,2,5,6-tetrahydro-1-oxobenzo[f]quinazolin-3-yl)pivalamide (0.48 g). 1H NMR (DMSO-d6, 200 MHz) δ: 1.23 (s, 9H, t-butyl), 2.67 (s, 4H, ArCH2 's), 6.68 (d, J=9 Hz, 2H, Ar), 7.10 (d, J=8 Hz, 1H, Ar), 7.26 (t, J=8 Hz, 1H, Ar), 7.50 (d, J=9 Hz, 2H, Ar), 8.38 (d, J=8 Hz, 1H, Ar), 8.53 (s, 1H, C7 --NH), 11.28 (br s, 1H, N2H), 12.16 (br s, 1H, C3 --NH). A solution of the pivalamide (0.15 g) and 10 % palladium on carbon (70 mg) in diglyme (5 ml) was stirred at reflux under nitrogen for 10 hours. Pivalic anhydride (2×0.5 ml, 4.9 mmol) was added at 5 and 9 hours. The solution was diluted with diglyme (15 ml), filtered hot through celite, and concentrated under high vacuum. The residue was purified by chromatography on silica gel (15 g) eluting with ethyl acetate:methylene chloride (1:9) and then recrystallization from methanol. The solid was filtered and dried at 90° C. under reduced pressure to give N-(7-(4-cyanoanilino)-1,2-dihydro-1-oxobenzo[f]quinazolin-3-yl)pivalamide (86 mg). 1H NMR (DMSO-d6, 200 MHz) δ: 1.26 (s, 9H, t-butyl), 6.85 (d, J=9 Hz, 2H, Ar), 7.49-7.60 (m, 4H, Ar), 7.72 (t, J=8 Hz, 1H, Ar); 8.29 (d, J=9 Hz, 1H, Ar); 9.07 (s, 1 H, C7 --NH), 9.61 (d, J=9 Hz, 1H, Ar), 11.25 (br s, 1H, N2H), 12.32 (br s, 1H, C3 --NH). Mass spectrum (CI-CH4) 412 (M+1, 100%). Anal. Calculated for C24H21N5O2.17/100H2O: C, 69.54; H, 5.19; N, 16.89. Found: C, 69.56; H, 5.23; N, 16.88.

Workup

  1. temperatureat reflux under nitrogen for 10 hours
  2. filtrationfiltered hot through celite
  3. concentrationconcentrated under high vacuum
  4. customThe residue was purified by chromatography on silica gel (15 g)
  5. washeluting with ethyl acetate:methylene chloride (1:9)
  6. customrecrystallization from methanol
  7. filtrationThe solid was filtered
  8. customdried at 90° C. under reduced pressure

Sources & evidence

ORD record
ord-3cf3b3765b0147fabb41209ed0a3cc96
Source dataset
uspto-grants-1995_04
Patent number
US05405851

Reaction notes

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