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

HRID 334337Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 334337
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

Komponenten

5

Edukt 3

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

Produkt 1

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

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 887MethanolLösungsmittel

Reaktionsbedingungen

Temperatur
60 °C

Versuchsvorschrift

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).

Aufarbeitung

  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

Quellen und Nachweise

ORD-Eintrag
ord-b4e791832b0740aa917d83cf70597227
Quelldatensatz
uspto-grants-2014_11
Patentnummer
US08883810B2

Notizen zur Reaktion

Wird geladen…