Diisopropylamine → 6-methoxy-N-[7-(3-methoxyprop-1-ynyl)-1,3-benzodioxol-4-yl]-7-(3-morpholin-4-ylpropoxy)quinazolin-4-amine

HRID 1785082Notes

Reaction equation

HRID 1785082 reaction equation
C(NC(C)C)(C)C.I[C:9]1[C:14]2[O:15][CH2:16][O:17][C:13]=2[C:12]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([O:31][CH2:32][CH2:33][CH2:34][N:35]4[CH2:40][CH2:39][O:38][CH2:37][CH2:36]4)=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[CH:11][CH:10]=1.[CH2:41]([O:44][CH3:45])[C:42]#[CH:43]>C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[CH3:30][O:29][C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][C:25]=1[O:31][CH2:32][CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1)[N:22]=[CH:21][N:20]=[C:19]2[NH:18][C:12]1[C:13]2[O:17][CH2:16][O:15][C:14]=2[C:9]([C:43]#[C:42][CH2:41][O:44][CH3:45])=[CH:10][CH:11]=1

Participants

7

Reactant 3

HCID 7912DiisopropylamineHCID 693933-MethoxypropyneHCID 68882269N-(7-iodo-1,3-benzodioxol-4-yl)-6-methoxy-7-(3-morpholin-4-ylpropoxy)quinazolin-4-amine

Product 1

HCID 688816576-methoxy-N-[7-(3-methoxyprop-1-ynyl)-1,3-benzodioxol-4-yl]-7-(3-morpholin-4-ylpropoxy)quinazolin-4-amineYield 30.6%

Reagents, catalysts & solvents 3

HCID 83717Copper iodideCatalystHCID 178418476HCID 178418476, compoundCatalystHCID 8857Ethyl AcetateSolvent

Procedure

Bis(Triphenyl-phosphine)palladium(II) chloride (94 mg), copper iodide (19 mg) and diisopropylamine (68 mg) were added to a stirred solution of N-(7-iodo-1,3-benzodioxol-4-yl)-6-methoxy-7-(3-morpholin-4-ylpropoxy)quinazolin-4-amine (200 mg) and methyl propargyl ether (47 mg) in ethyl acetate (5 mls) at −20° C. The reaction was allowed to warm to ambient temperature and stirred over 16 hours. The reaction mixture was partitioned between ethyl acetate and saturated NaHCO3. The organic layer was washed with water and saturated brine and dried over magnesium sulfate. The product was purified by column chromatography on silica using a gradient of 0-10% methanol/methylene chloride as eluent. The resultant yellow gum was dissolved in minimal methylene chloride, diluted with diethyl ether and precipitated as an HCl salt by the addition of 1.0 M ethereal hydrogen chloride. The resultant solid was centrifuged and washed with diethyl ether (3 times) and dried to give the title compound as a yellow solid (55 mg); NMR Spectrum: DMSOd6) 2.29-2.36 (m, 2H); 3.03-3.14 (m, 2H); 3.24 -3.31 (m, 2H), 3.32 (s, 3H), 3.43-3.54 (m, 2H), 3.76-3.86 (m, 2H), 3.94 -4.00 (m, 5H), 4.31 (t, 2H), 4.35 (s, 2H), 6.13 (s, 2H), 6.98 (d, 1H), 7.02 (d, 1H), 7.40 (s, 1H), 8.27 (s, 1H), 8.80 (s, 1H); Mass Spectrum: M+H+ 507.11

Workup

  1. customThe reaction mixture was partitioned between ethyl acetate and saturated NaHCO3
  2. washThe organic layer was washed with water and saturated brine
  3. dry with materialdried over magnesium sulfate
  4. customThe product was purified by column chromatography on silica using a gradient of 0-10% methanol/methylene chloride as eluent
  5. dissolutionThe resultant yellow gum was dissolved in minimal methylene chloride
  6. additiondiluted with diethyl ether
  7. customprecipitated as an HCl salt by the addition of 1.0 M ethereal hydrogen chloride
  8. washwashed with diethyl ether (3 times)
  9. customdried

Sources & evidence

ORD record
ord-1214585e18644ff0b15cadc6b737a489
Source dataset
uspto-grants-2009_03
Patent number
US07504408B2

Reaction notes

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