Diisopropylamine → 1-[3-(6-Chloro-7-{[6-methoxy-7-(3-morpholin-4-ylpropoxy)quinazolin-4-yl]amino}-1,3-benzodioxol-4-yl)prop-2-yn-1-yl]pyrrolidin-2-one

HRID 1785131Notes

Reaction equation

HRID 1785131 reaction equation
[Cl:1][C:2]1[CH:10]=[C:9](I)[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH2:26][CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][N:14]=1.[CH2:35]([N:38]1[CH2:42][CH2:41][CH2:40][C:39]1=[O:43])[C:36]#[CH:37].C(NC(C)C)(C)C>C(OCC)(=O)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[CH:10]=[C:9]([C:37]#[C:36][CH2:35][N:38]2[CH2:42][CH2:41][CH2:40][C:39]2=[O:43])[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH2:26][CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][N:14]=1

Participants

7

Reactant 3

HCID 7912DiisopropylamineHCID 124643131-(Prop-2-yn-1-yl)pyrrolidin-2-oneHCID 68884527N-(5-chloro-7-iodo-1,3-benzodioxol-4-yl)-6-methoxy-7-(3-morpholin-4-ylpropoxy)quinazolin-4-amine

Product 1

HCID 688828751-[3-(6-Chloro-7-{[6-methoxy-7-(3-morpholin-4-ylpropoxy)quinazolin-4-yl]amino}-1,3-benzodioxol-4-yl)prop-2-yn-1-yl]pyrrolidin-2-oneYield 40%

Reagents, catalysts & solvents 3

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 6102075Dichlorobis(triphenylphosphine)palladiumCatalystHCID 8857Ethyl AcetateSolvent

Procedure

N-(5-chloro-7-iodo-1,3-benzodioxol-4-yl)-6-methoxy-7-(3-morpholin-4ylpropoxy)quinazolin-4-amine (250 mg, 0.42 mmol) and 1-prop-2-yn-1-ylpyrrolidin-2-one (103 mg, 0.84 mmol) in ethyl acetate (8 ml) were cooled in ice-methanol, under an atmosphere of nitrogen, then treated with bis(triphenylphosphine) palladium(II) dichloride (30 mg, 10 mol %) followed by copper(I) iodide (8 mg, 10 mol %) and diisopropylamine (84 mg, 0.84 mmol). The reaction was allowed to warm to room temperature and stirred 46 hr. then filtered through Celite and evaporated. The residue was partitioned between dichloromethane and dilute aqueous ammonium chloride solution, the organic layer separated, dried over magnesium sulphate and evaporated then purified by chromatography on silica using increasing concentrations of methanol in dichloromethane as eluent to give the title compound (98 mg, 40%) as a pale brown solid; NMR Spectrum:(CDCl3) 2.12 (m, 4H), 2.44 (t, 2H), 2.49 (m, 4H), 2.57 (t, 2H), 3.55 (t, 2H), 3.72 (m, 4H), 4.00 (s,3H), 4.25 (t,2H), 4.35 (s,2H), 6.08 (s,2H), 7.03 (s,1H), 7.10 (s, 1H), 7.17 (s, 1H), 7.30 (s, 1H), 8.60 (s, 1H); Mass Spectrum: M+H+ 594/596.

Workup

  1. filtrationthen filtered through Celite
  2. customevaporated
  3. customThe residue was partitioned between dichloromethane and dilute aqueous ammonium chloride solution
  4. customthe organic layer separated
  5. dry with materialdried over magnesium sulphate
  6. customevaporated
  7. customthen purified by chromatography on silica using
  8. temperatureincreasing concentrations of methanol in dichloromethane as eluent

Sources & evidence

ORD record
ord-e33abe0006cc49f8b4c1967b0f21ae7b
Source dataset
uspto-grants-2009_03
Patent number
US07504408B2

Reaction notes

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