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Triethylamine → 4-Amino-5-cyclobutyloxy-6,7-dimethoxy-2-[4-(4-morpholinecarbonyl)-1,4-diazepan-1-yl]quinazoline

HRID 1004015
Notes
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Reaction equation

HRID 1004015 reaction equation
[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:19][CH3:20])=[C:9]([O:17][CH3:18])[C:10]=2[O:12][CH:13]2[CH2:16][CH2:15][CH2:14]2)[N:5]=[C:4](Cl)[N:3]=1.Cl.[N:23]1([C:29]([N:31]2[CH2:37][CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[O:30])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.C(N(CC)CC)C>C(O)CCC>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:19][CH3:20])=[C:9]([O:17][CH3:18])[C:10]=2[O:12][CH:13]2[CH2:16][CH2:15][CH2:14]2)[N:5]=[C:4]([N:34]2[CH2:35][CH2:36][CH2:37][N:31]([C:29]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)=[O:30])[CH2:32][CH2:33]2)[N:3]=1
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

5

Reactant 3

HCID 8471TriethylamineHCID 184706574-Amino-2-chloro-5-cyclobutyloxy-6,7-dimethoxyquinazolineHCID 227070621-(4-Morpholinecarbonyl)-1,4-diazepane hydrochloride

Product 1

HCID 184706584-Amino-5-cyclobutyloxy-6,7-dimethoxy-2-[4-(4-morpholinecarbonyl)-1,4-diazepan-1-yl]quinazolineYield 386.7%

Reagents, catalysts & solvents 1

HCID 263
1-Butanol
Solvent

Procedure

4-Amino-2-chloro-5-cyclobutyloxy-6,7-dimethoxyquinazoline (184 mg, 0.00059 mol) was added to a solution of 1-(4-morpholinecarbonyl)-1,4-diazepane hydrochloride (163 mg, 0.00065 mol) and triethylamine (184 μl, 0.0013 mol) in n-butanol (6 ml) and the reaction stirred at reflux for 2 hours. On cooling, the reaction was concentrated under reduced pressure and the residue partitioned between ethyl acetate (20 ml) and water (20 ml). The aqueous layer was further extracted with ethyl acetate (2×20 ml), the combined organic extracts dried (MgSO4), filtered and evaporated under reduced pressure. The crude product was purified on silica gel eluting with a solvent gradient of methanol:dichloromethane (0:100 to 7:93 v/v) to give the title compound as a white foam (1110 mg, 38%). MS m/z=487 (MH)+. 1H-NMR (CDCl3): δ=1.53 (1H, m), 1.76 (1H, m), 2.04 (2H, m), 2.25 (2H, m), 2.38 (2H, m), 3.20 (4H, t), 3,36 (2H, t), 3.55 (2H, t), 3.66 (4H, t), 3.80 (3H, s), 3.85 (3H, m), 3.94 (6H, m), 4.86 (1H, m), 6.62 (1H, s). Found: C, 58.09; H, 6.96; N, 16.69; C24H34N6O5 0.15CH2Cl2, requires C, 58.09; H, 6.92; N, 16.83%

Workup

  1. temperatureat reflux for 2 hours
  2. temperatureOn cooling
  3. concentrationthe reaction was concentrated under reduced pressure
  4. customthe residue partitioned between ethyl acetate (20 ml) and water (20 ml)
  5. extractionThe aqueous layer was further extracted with ethyl acetate (2×20 ml)
  6. dry with materialthe combined organic extracts dried (MgSO4)
  7. filtrationfiltered
  8. customevaporated under reduced pressure
  9. customThe crude product was purified on silica gel eluting with a solvent gradient of methanol:dichloromethane (0:100 to 7:93 v/v)

Sources & evidence

ORD record
ord-a47f8a7ec80e46fb8b4dc4c2fc7b8190
Source dataset
uspto-grants-2000_04
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US06048864

Reaction notes

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On this pageParticipantsProcedureWorkupSources & evidenceReaction notes