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

HRID 2228503
Notes
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Reaction equation

HRID 2228503 reaction equation
NC1C2C(=CC(OC)=C(OC)C=2OC2CCC2)N=C(Cl)N=1.[NH2:22][C:23]1[C:32]2[C:27](=[CH:28][C:29]([O:40][CH3:41])=[C:30]([O:38][CH3:39])[C:31]=2[O:33][CH:34]2[CH2:37][CH2:36][CH2:35]2)[N:26]=[C:25]([N:42]2[CH2:48][CH2:47][CH2:46][N:45]([C:49]([N:51]3[CH2:56][CH2:55][O:54][CH2:53][CH2:52]3)=[O:50])[CH2:44][CH2:43]2)[N:24]=1.Cl.N1(C(N2CCCNCC2)=O)CCOCC1.C(N(CC)CC)C>C(O)CCC>[NH2:22][C:23]1[C:32]2[C:27](=[CH:28][C:29]([O:40][CH3:41])=[C:30]([O:38][CH3:39])[C:31]=2[O:33][CH:34]2[CH2:35][CH2:36][CH2:37]2)[N:26]=[C:25]([N:42]2[CH2:48][CH2:47][CH2:46][N:45]([C:49]([N:51]3[CH2:52][CH2:53][O:54][CH2:55][CH2:56]3)=[O:50])[CH2:44][CH2:43]2)[N:24]=1
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

5

Reactant 3

HCID 8471TriethylamineHCID 184706624-Amino-5-cyclobutyloxy-6,7-dimethoxy-2-[4-(4-morpholinecarbonyl)-1,4-diazepan-1-yl]quinazoline 4-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 38.3%

Reagents, catalysts & solvents 1

HCID 2631-ButanolSolvent

Procedure

4-Amino-5-cyclobutyloxy-6,7-dimethoxy-2-[4-(4-morpholinecarbonyl)-1,4-diazepan-1-yl]quinazoline 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, 0.00065mol) and triethylamine (184 Π1, 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 (110 mg, 38%). MS m/z=487 (MH)+. 1H-NMR (CDCl3): Γ=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-0094c402f5db4aebb9074913b7cb02d5
Source dataset
uspto-grants-2002_07
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US06417194B1

Reaction notes

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