p-Toluenesulfonic acid → 8-Chloro-3-{3-[3-(4-chloro-phenyl)-3,8-diaza-bicyclo[3.2.1]oct-8-yl]-propyl}-1h-quinazoline-2,4-dione

HRID 1266983노트

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HRID 1266983 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].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:30][CH:29]3[NH:31][CH:26]([CH2:27][CH2:28]3)[CH2:25]2)=[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:31]1[CH:29]3[CH2:28][CH2:27][CH:26]1[CH2:25][N:24]([C:21]1[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][CH:20]=1)[CH2:30]3)[C:7]2=[O:16]

참가 물질

7

반응물 4

HCID 6101p-Toluenesulfonic acidHCID 8471TriethylamineHCID 98159123-(4-Chloro-phenyl)-3,8-diaza-bicyclo[3.2.1] octaneHCID 114590268-chloro-3,4-dihydro-2H-1-oxa-4a,9-diaza-anthracen-10-one

생성물 1

HCID 98903958-Chloro-3-{3-[3-(4-chloro-phenyl)-3,8-diaza-bicyclo[3.2.1]oct-8-yl]-propyl}-1h-quinazoline-2,4-dione수율 83.3%

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 (6.18g, 26.02 mmol), 3-(4-Chloro-phenyl)-3,8-diaza-bicyclo[3.2.1] octane (HCl salt) (5.62 g, 21.68 mmol), triethylamine (3.6 ml, 26.02 mmol), p-toluene sulfonic acid (0.74 g, 3.90 mmol) were combined in dimethyl acetamide (38 ml) and heated at 120° C. for 15 hours. The reaction was cooled to room temperature, diluted with H2O and filtered the tan precipitate. Dissolved the tan solid in chloroform (400 ml), dried over magnesium sulfate, and concentrated to an off-white solid. Silica gel flash chromatography using 5% methanol/chloroform as the eluent yielded 8-Chloro-3-{3-[3-(4-chloro-phenyl)-3,8-diaza-bicyclo[3.2.1]oct-8-yl]-propyl}-1H-quinazoline-2,4-dione (8.3 g, 83.3%) as an off-white solid; Mp. 194-196° C. Maleate salt was formed by dissolving the solid in chloroform (100 ml) and maleic acid (2.52 g, 1.2 eq) in ethyl acetate (20 ml) was added. The mix was concentrated and the off-white solid was washed with ethyl acetate to yield maleate salt (8.95 g). A portion was recrystallized from acetonitrile yielding off-white crystalline solid which had the following properties: Mp. 186-188° C.; 1H NMR DMSO-d6 δ: 11.07 (brd s, 1H), 9.50 (brd s, 1H), 7.92 (dd, J=1.2, 6.6 Hz, 1H, 7.79 (dd, J=1.2, 6.6 Hz, 1H), 7.26-7.17 (m, 3H), 6.89 (d, J=9.1 Hz, 2H), 6.00 (s, 2H), 4.09 ( brd s, 2H), 3.99 (t, J=6.6 Hz, 2H), 3.70-3.65 (m, 2H), 3.17-2.98 (m, 4H), 2.20-2.00 (m, 4H), 1.95-1.86 (m, 2H). 13C NMR DMSO-d6 δ: 167.87, 162.14, 150.76, 149.18, 137.06, 136.53, 129.338, 127.26, 123.85, 119.35, 116.84, 116.63, 61.11, 52.08, 49.48, 38.43, 24.28, 23.88. IR (KBr): 3399, 3367, 32223, 3161, 3074, 2967, 2839, 2410, 1904, 1722, 1656, 1615, 1598, 1499, 1458, 1407, 1351, 1314, 1242, 1234, 1169, 1109, 1098, 1086,1059, 1032, 1003, 982, 945, 922, 863, 829, 814, 774, 756, 731, 691, 663, 580, 532, 513, 495, 480, 468, 445, 426, 407, (cm−1). Analysis calculated for C23H24Cl2N4O2.C4H4O4: C, 56.36; H, 4.90; N, 9.74; Found: C, 56.10; H, 5.06; N, 9.83

후처리

  1. temperatureThe reaction was cooled to room temperature
  2. filtrationfiltered the tan precipitate
  3. dissolutionDissolved the tan solid in chloroform (400 ml)
  4. dry with materialdried over magnesium sulfate
  5. concentrationconcentrated to an off-white solid

출처 및 근거

ORD 기록
ord-715f7871d5d44ebbb0fd394fcac1828a
출처 데이터셋
uspto-grants-2003_04
특허 번호
US06552015B2

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