Triethylamine → 8-Chloro-3-{4-[3-(4-chloro-phenyl)-3,8-diaza-bicyclo[3.2.1]oct-8-yl]-butyl}-1H-quinazoline-2,4-dione

HRID 1266987Notes

Reaction equation

HRID 1266987 reaction equation
CO[C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:5]=1[NH2:11].C(N(CC)CC)C.Cl[C:21](Cl)([O:23]C(=O)OC(Cl)(Cl)Cl)Cl.[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([N:39]2[CH2:45][CH:44]3[N:46]([CH2:47][CH2:48][CH2:49][CH2:50][NH2:51])[CH:41]([CH2:42][CH2:43]3)[CH2:40]2)=[CH:35][CH:34]=1>C(Cl)Cl>[Cl:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]2[C:5]=1[NH:11][C:21](=[O:23])[N:51]([CH2:50][CH2:49][CH2:48][CH2:47][N:46]1[CH:44]3[CH2:43][CH2:42][CH:41]1[CH2:40][N:39]([C:36]1[CH:37]=[CH:38][C:33]([Cl:32])=[CH:34][CH:35]=1)[CH2:45]3)[C:3]2=[O:12]

Participants

6

Reactant 4

HCID 8471TriethylamineHCID 94429TriphosgeneHCID 11030511Benzoic acid, 2-amino-3-chloro-, methyl esterHCID 185451914-[3-(4-Chloro-phenyl)-3,8-diaza-bicyclo[3.2.1]oct-8-yl]-butylamine

Product 1

HCID 101402428-Chloro-3-{4-[3-(4-chloro-phenyl)-3,8-diaza-bicyclo[3.2.1]oct-8-yl]-butyl}-1H-quinazoline-2,4-dioneYield 184.3%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Conditions

Temperature
0 °C

Procedure

2-Amino-3-chloro-benzoic acid methyl ester (0.126 g, .681 mmol) and triethylamine (0.22 mL, 1.57 mmol) were dissolved in methylene chloride (3 mL) and cooled to 0° C. Triphosgene (0.067 g, 0.227 mmol) in methylene chloride (1 mL) was added dropwise to the reaction and then stirred in the cold for 1 hour. Next 4-[3-(4-Chloro-phenyl)-3,8-diaza-bicyclo[3.2.1]oct-8-yl]-butylamine (0.20 g, 0.681 mmol) was added in one portion and the reaction was stirred at room temperature for 15 hours. Mix was evaporated to dryness, diluted with toluene (40 mL) and refluxed for 6 hours, cooled, diluted with saturated sodium bicarbonate (200 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (200 mL), dried with magnesium sulfate and concentrated to a light brown solid. Silica gel flash chromatography using 3.5% methanol/chloroform as eluent yielded 8-Chloro-3-{4-[3-(4-chloro-phenyl)-3,8-diaza-bicyclo[3.2.1]oct-8-yl]-butyl}-1H-quinazoline-2,4-dione (0.198 g, 61%) as a white solid. Maleate salt was formed by dissolving the solid in warm chloroform (30 ml) and maleic acid (0.058 g, 1.2 eq) in warm ethyl acetate (20 ml) was added. Cooling yielded the maleate salt (0.196 g) as a white solid which had the following properties: Mp. 235-238° C., 1H NMR DMSO-d6 δ: 11.02 (brd s, 1H), 9.85 (brd s, 1H), 7.91 (d, J=7.1 Hz, 1H), 7.79 (d, J=6.6 Hz, 1H), 7.26-7.18 (m, 3H), 6.90 (d, J=9.1 Hz, 2H), 6.00 (s, 2H), 4.17 (brd s, 2H), 3.98-3.87 (m, 2H), 3.66 (d, J=14.1 Hz, 2H), 3.11-2.93 ( m,4H), 2.19-2.06 (m, 2H), 1.97-1.85 (m, 2H), 1.77-1.6 (m, 4H). IR (KBr): 3355, 3216, 3190, 3161, 3071, 2960, 2849, 2706, 2397, 1717, 1655, 1610, 1500, 1473, 1456, 1435, 1420, 1404, 1365, 1332, 1311, 1269, 1254, 1221, 1185, 1163, 1134, 1101, 1068, 1041, 989, 973, 954, 925, 915, 882, 851, 821, 814, 790, 761, 747, 729, 701, 671, 650, 580, 545, 515, 496, 484, 437, 411, 404, (cm−1). Analysis calculated for C24H26Cl2N4O2.C4H4O4.1½ H2O: C, 54.55; H, 5.39; N, 9.08. Found: C, 54.81; H, 5.06; N, 8.91.

Workup

  1. stirringthe reaction was stirred at room temperature for 15 hours
  2. additionMix
  3. customwas evaporated to dryness
  4. additiondiluted with toluene (40 mL)
  5. temperaturerefluxed for 6 hours
  6. temperaturecooled
  7. additiondiluted with saturated sodium bicarbonate (200 mL)
  8. extractionextracted with ethyl acetate (3×100 mL)
  9. washThe combined organic layers were washed with brine (200 mL)
  10. dry with materialdried with magnesium sulfate
  11. concentrationconcentrated to a light brown solid

Sources & evidence

ORD record
ord-cfb84608b3c549bab8d0b5a6f4a8e3cd
Source dataset
uspto-grants-2003_04
Patent number
US06552015B2

Reaction notes

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