Hydrochloric Acid → Benzo[h]quinazolin-4(1H)-one

HRID 334337Notes

Reaction equation

HRID 334337 reaction equation
ClC1N=CC(C[C:9]2[CH:10]=[C:11]3[C:16](=[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=24)[N:15]=[CH:14][N:13]([C@H]2CCCC[C@@H]2O)[C:12]3=[O:30])=CC=1.ClC1N=CC(CC2C=C3C(=C4C=CC=CC=24)N=CN([C@H]2CCCC[C@@H]2NC(=O)OC(C)(C)C)C3=O)=CC=1.Cl>CO>[N:15]1[C:16]2[C:11](=[CH:10][CH:9]=[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]3=2)[C:12](=[O:30])[NH:13][CH:14]=1

Participants

5

Reactant 3

HCID 313Hydrochloric AcidHCID 46208126HCID 46208126, compoundHCID 46208971tert-butyl{(1S,2S)-2-[6-[(6-chloropyridin-3-yl)methyl]-4-oxobenzo[h]quinazolin-3(4H)-yl]cyclohexyl}carbamate

Product 1

HCID 135465824Benzo[h]quinazolin-4(1H)-one

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Conditions

Temperature
60 °C

Procedure

1-Amino-N-[(1S,2S)-2-aminocyclohexyl]-4-bromo-2-naphthamide was prepared by the procedure described for the synthesis of 1-amino-4-bromo-N-[(1S,2S)-2-hydroxycyclohexyl]-2-naphthamide in Example 1. To a solution of 1-amino-N-[(1S,2S)-2-aminocyclohexyl]-4-bromo-2-naphthamide (0.460 g, 1.27 mmol) in 20 mL of dichloromethane was added di-tert-butyl dicarbonate (0.305 g, 1.40 mmol). The mixture was stirred at rt for 4 h and then purified via silica gel chromatography, eluting with 0-20% ethyl acetate in hexanes, to provide tert-butyl {(1S,2S)-2-[(1-amino-4-bromo-2-naphthoyl)amino]cyclohexyl)carbamate that gave a mass ion (ES+) of 463.9 for [M+H]+. The above prepared compound was converted to provide tert-butyl {(1S,2S)-2-[6-[(6-chloropyridin-3-yl)methyl]-4-oxobenzo[h]quinazolin-3(4H)-yl]cyclohexyl}carbamate by the procedure described for the synthesis of 6-[(6-chloropyridin-3-yl)methyl]-3-[(1S,2S)-2-hydroxylcyclohexyl]benzo[h]quinazolin-4(3H)-one in Example 2. To a solution of tert-butyl {(1S,2S)-2-[6-[(6-chloropyridin-3-yl)methyl]-4-oxobenzo[h]quinazolin-3(4H)-yl]cyclohexyl}carbamate (0.080 g, 0.15 mmol) in 2 mL of methanol was added hydrochloric acid (0.15 mL, 6 N aqueous, 0.92 mmol). The reaction was heated at 60° C. for 2 h, cooled to ambient temperature and concentrated in vacuo. The residue was concentrated twice with toluene. The residue was purified via preparative reverse phase HPLC to provide 3-[(1S,2S)-2-aminocyclohexyl]-6-[6-chloropyridin-3-yl)methyl]benzo[h]quinazolin-4(3H)-one that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 419.0 for [M+H]+: 1H NMR (400 MHz, d6-DMSO) δ 9.10-9.08 (m, 1H), 8.56 (br s, 1H), 8.27 (s, 1H), 8.14-8.12 (m, 1H), 8.04 (s, 1H), 7.80-7.75 (m, 3H), 7.43-7.36 (m, 1H), 4.60 (s, 2H), 2.31-2.24 (m, 2H), 2.12-1.94 (m, 4H), 1.70-1.56 (m, 4H). To a solution of the above prepared compound (0.025 g, 0.055 mmol) in 2 mL of dichloromethane at 0° C. was added triethylamine (0.023 mL, 0.16 mmol) and acetic anhydride (0.0078 mL, 0.082 mmol). The mixture was stirred at 0° C. for 2 h, diluted with dichloromethane and washed with water and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 10-100% ethyl acetate in hexanes, to provide the title compound that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 460.9 for [M+H]+: 1H NMR (400 MHz, CDCl3) δ 9.11-9.08 (m, 1H), 8.38 (s, 1H), 8.02 (s, 1H), 7.93-7.91 (m, 1H), 7.72-7.68 (m, 2H), 7.41-7.39 (m, 1H), 7.20-7.17 (m, 1H), 5.76-5.74 (m, 1H), 4.94-4.88 (m, 1H), 4.47 (s, 2H), 4.29-4.24 (m, 1H), 2.28-2.21 (m, 1H), 2.16-2.02 (m, 1H), 2.00-1.82 (m, 3H) 1.72 (s, 3H), 1.60-1.41 (m, 3H).

Workup

  1. temperaturecooled to ambient temperature
  2. concentrationconcentrated in vacuo
  3. concentrationThe residue was concentrated twice with toluene
  4. customThe residue was purified via preparative reverse phase HPLC

Sources & evidence

ORD record
ord-b4e791832b0740aa917d83cf70597227
Source dataset
uspto-grants-2014_11
Patent number
US08883810B2

Reaction notes

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