Sodium bis(trimethylsilyl)amide → N-[5-fluoro-7-(3-methoxyprop-1-yn-1-yl)-1,3-benzodioxol-4-yl]-6-methoxy-7-(3-morpholin-4-ylpropoxy)quinazolin-4-amine

HRID 1785097Notes

Reaction equation

HRID 1785097 reaction equation
Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[F:24][C:25]1[CH:33]=[C:32]([C:34]#[C:35][CH2:36][O:37][CH3:38])[C:28]2[O:29][CH2:30][O:31][C:27]=2[C:26]=1[NH2:39].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>CN(C=O)C>[F:24][C:25]1[CH:33]=[C:32]([C:34]#[C:35][CH2:36][O:37][CH3:38])[C:28]2[O:29][CH2:30][O:31][C:27]=2[C:26]=1[NH:39][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1

Participants

5

Reactant 3

HCID 2724254Sodium bis(trimethylsilyl)amideHCID 118239414-Chloro-6-methoxy-7-(3-morpholin-4-ylpropoxy)quinazolineHCID 688818145-Fluoro-7-(3-methoxyprop-1-yn-1-yl)-1,3-benzodioxol-4-amine

Product 1

HCID 68881186N-[5-fluoro-7-(3-methoxyprop-1-yn-1-yl)-1,3-benzodioxol-4-yl]-6-methoxy-7-(3-morpholin-4-ylpropoxy)quinazolin-4-amineYield 78%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

4-Chloro-6-methoxy-7-(3-morpholin-4ylpropoxy)quinazoline (201 mg, 0.60 mmol) and 5-fluoro-7-(3-methoxyprop-1-yn-1-yl)-1,3-benzodioxol-4-amine (140 mg, 0.63 mmol) in DMF (3 ml) were cooled in an ice-water bath then treated dropwise, under an atmosphere of nitrogen, with a solution of sodium bis(trimethylsilyl)amide (1.0 M in THF, 1.25 ml). The resulting mixture was stirred at ice temperature for a further 90 minutes before quenching in dilute aqueous ammonium chloride solution and extracting with dichloromethane (containing a small percentage of methanol). The extract was washed with saturated brine, dried over magnesium sulphate and evaporated to an orange oil. The residue was purified by column chromatography on silica using increasing concentrations of methanol in dichloromethane as eluent. There was thus obtained the title compound (245 mg, 78%) as a colourless solid; NMR Spectrum: (DMSOd6) 1.97 (quintet, 2), 2.40 (m, 4H), 2.47 (t, 2H), 3.36 (s, 3H), 3.59 (m, 4H), 3.95 (s, 3H), 4.20 (t, 2H), 4.37 (s, 2H), 6.16 (s, 2H), 6.91 (d, 1H), 7.19 (s, 1H), 7.81 (s, 1H), 8.36 (s, 1H), 9.52 (s, 1H); Mass Spectrum: M+H+ 525.

Workup

  1. custombefore quenching in dilute aqueous ammonium chloride solution
  2. extractionextracting with dichloromethane (
  3. additioncontaining a small percentage of methanol)
  4. washThe extract was washed with saturated brine
  5. dry with materialdried over magnesium sulphate
  6. customevaporated to an orange oil
  7. customThe residue was purified by column chromatography on silica using
  8. temperatureincreasing concentrations of methanol in dichloromethane as eluent

Sources & evidence

ORD record
ord-6dece205276a4b6fab876c8abbd09338
Source dataset
uspto-grants-2009_03
Patent number
US07504408B2

Reaction notes

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