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 1266983Notes

Reaction equation

HRID 1266983 reaction equation
[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]

Participants

7

Reactant 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

Product 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-dioneYield 83.3%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 31374DimethylacetamideSolvent

Conditions

Temperature
120 °C

Procedure

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

Workup

  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

Sources & evidence

ORD record
ord-715f7871d5d44ebbb0fd394fcac1828a
Source dataset
uspto-grants-2003_04
Patent number
US06552015B2

Reaction notes

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