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p-Toluenesulfonic acid → 8-Chloro-3-{3-[5-(4-fluoro-phenyl)-2,5-diaza-bicyclo[2.2.2]oct-2-yl]-propyl}-1H-quinazoline-2,4-dione

HRID 1266993
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HRID 1266993 반응식
[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:15]=1[N:14]=[C:13]1[N:8]([CH2:9][CH2:10][CH2:11][O:12]1)[C:7]2=[O:16].[F:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH:28]3[CH2:30][CH2:31][CH:25]2[CH2:26][NH:27]3)=[CH:20][CH:19]=1.C(N(CC)CC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(N(C)C)=O.O>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:15]=1[NH:14][C:13](=[O:12])[N:8]([CH2:9][CH2:10][CH2:11][N:27]1[CH2:26][CH:25]3[CH2:31][CH2:30][CH:28]1[CH2:29][N:24]3[C:21]1[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=1)[C:7]2=[O:16]
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참가 물질

7

반응물 4

HCID 6101p-Toluenesulfonic acidHCID 8471TriethylamineHCID 114590268-chloro-3,4-dihydro-2H-1-oxa-4a,9-diaza-anthracen-10-oneHCID 120525482-(4-Fluorophenyl)-2,5-diazabicyclo[2.2.2]octane

생성물 1

HCID 101143138-Chloro-3-{3-[5-(4-fluoro-phenyl)-2,5-diaza-bicyclo[2.2.2]oct-2-yl]-propyl}-1H-quinazoline-2,4-dione수율 32.8%

시약·촉매·용매 2

HCID 962Water용매HCID 31374Dimethylacetamide용매

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온도
120 °C

실험 절차

8-Chloro-3,4-dihydro-2H-1-oxa-4a,9-diaza-anthracen-10-one (0.35, 1.49 mmol), 2-(4-Fluoro-phenyl)-2,5-diaza-bicyclo[2.2.2]octane (HCl salt) (0.30g, 1.24 mmol), triethylamine (0.21 ml, 1.49 mmol), p-toluene sulfonic acid (0.036 g, 0.187 mmol) were combined in dimethyl acetamide (2 ml) and heated at 120° C. for 15 hours. The reaction was cooled to room temperature, diluted with H2O (200 mL) and extracted with ethyl acetate (3×100 mL). The pooled organic layers were washed with water (3×200 mL),dried over magnesium sulfate, and concentrated to a brown semi-solid. Silica gel flash chromatography using 5% methanol/chloroform as the eluent yielded 8-Chloro-3-{3-[5-(4-fluoro-phenyl)-2,5-diaza-bicyclo[2.2.2]oct-2-yl]-propyl}-1H-quinazoline-2,4-dione (0.18 g, 32.7%) as an light brown solid Maleate salt was formed by dissolving the solid in hot ethyl acetate (5 ml) and maleic acid (0.57 g, 1.2 eq) in ethyl acetate (4 ml) was added. Upon cooling the white solid was filtered to yield the maleate salt (0.12 g) which had the following properties: Mp. 186-188° C.; 1H NMR DMSO-d6 δ: 11.04 (brds, 1H), 9.40 (brd s, 1H), 7.91 (d, J=7.9 Hz, 1H), 7.79 (d, J=7.9 Hz, 1H), 7.20 (t, J=7.9 Hz, 1H), 6.68 (brds, 2H), 6.02 (s, 2H), 4.11 (brds, 1H), 4.02-3.92 (m, 2H), 3.80-3.52 (m, 3H), 3.44-3.17 (m, 4H), 2.18-1.65 9m, 6H). IR(KBr): Analysis calculated for C23H24ClFN4O2* C4H4O4: C, 56.40; H, 4.91; N, 9.74;

후처리

  1. temperatureThe reaction was cooled to room temperature
  2. extractionextracted with ethyl acetate (3×100 mL)
  3. washThe pooled organic layers were washed with water (3×200 mL),dried over magnesium sulfate
  4. concentrationconcentrated to a brown semi-solid

출처 및 근거

ORD 기록
ord-a309de205d894148bce9d0d49b5d150e
출처 데이터셋
uspto-grants-2003_04
DOI
10.6084/m9.figshare.5104873.v1
특허 번호
US06552015B2

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