Tetrahydrofuran → N-[5-chloro-7-(3-methoxyprop-1-yn-1-yl)-1,3-benzodioxol-4-yl]-7-(3-morpholin-4-ylpropoxy)-5-(tetrahydro-2H-pyran-4-yloxy)quinazolin-4-amine

HRID 1785183Notes

Reaction equation

HRID 1785183 reaction equation
C[Si]([N-][Si](C)(C)C)(C)C.[Na+].O1CCCC1.[Cl:16][C:17]1[CH:25]=[C:24]([C:26]#[C:27][CH2:28][O:29][CH3:30])[C:20]2[O:21][CH2:22][O:23][C:19]=2[C:18]=1[NH2:31].Cl[C:33]1[C:42]2[C:37](=[CH:38][C:39]([O:50][CH2:51][CH2:52][CH2:53][N:54]3[CH2:59][CH2:58][O:57][CH2:56][CH2:55]3)=[CH:40][C:41]=2[O:43][CH:44]2[CH2:49][CH2:48][O:47][CH2:46][CH2:45]2)[N:36]=[CH:35][N:34]=1>CN(C=O)C>[Cl:16][C:17]1[CH:25]=[C:24]([C:26]#[C:27][CH2:28][O:29][CH3:30])[C:20]2[O:21][CH2:22][O:23][C:19]=2[C:18]=1[NH:31][C:33]1[C:42]2[C:37](=[CH:38][C:39]([O:50][CH2:51][CH2:52][CH2:53][N:54]3[CH2:55][CH2:56][O:57][CH2:58][CH2:59]3)=[CH:40][C:41]=2[O:43][CH:44]2[CH2:45][CH2:46][O:47][CH2:48][CH2:49]2)[N:36]=[CH:35][N:34]=1

Participants

6

Reactant 4

HCID 8028Tetrahydrofuran2×HCID 2724254Sodium bis(trimethylsilyl)amide2×HCID 210827165-Chloro-7-(3-methoxyprop-1-ynyl)-1,3-benzodioxol-4-amineHCID 866015674-chloro-7-(3-morpholin-4-ylpropoxy)-5-(tetrahydro-2H-pyran-4-yloxy)quinazoline

Product 1

HCID 68882557N-[5-chloro-7-(3-methoxyprop-1-yn-1-yl)-1,3-benzodioxol-4-yl]-7-(3-morpholin-4-ylpropoxy)-5-(tetrahydro-2H-pyran-4-yloxy)quinazolin-4-amineYield 36.2%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
-10 °C

Procedure

A solution of sodium bis(trimethylsilyl)amide (1.28 ml) in tetrahydrofuran (1.0M, 1.28 mmol) was added to a suspension of 5-chloro-7-(3-methoxyprop-1-yn-1-yl)-1,3-benzodioxol-4-amine (0.153 g) and 4-chloro-7-(3-morpholin-4-ylpropoxy)-5-(tetrahydro-2H-pyran-4-yloxy)quinazoline (0.260 g) in DMF (4 ml) that had been cooled to −10° C. and the mixture was stirred for 90 minutes. A further portion of sodium bis(trimethylsilyl)amide (0.64 ml) in tetrahydrofuran (1.0M, 0.64 mmol) was added and the reaction was allowed to warm to room temperature and then stirred for a further 2 hours. The reaction mixture was quenched into water and saturated ammonium chloride solution was added. This was then extracted into dichloromethane and the organic portion was then washed with brine, dried over magnesium sulfate and evaporated. The residue was purified by column chromatography on silica using increasingly polar mixtures of dichloromethane and methanol as eluent. The product material gathered after chromatography as a foam was triturated with diethyl ether giving an off-white solid. This was then re-dissolved into dichloromethane and then evaporated under reduced pressure. The resulting solid was triturated with diethyl ether and air-dried. There was thus obtained the title compound (0.141 g) as a white solid; NMR Spectrum: (CDCl3) 2.00 (m, 4H), 2.23 (m, 2H), 2.48 (m, 4H), 2.54 (t, 2H), 3.46 (s, 3H), 3.63 (dq, 2H), 3.73 (t, 4H), 4.02 (dt, 2H), 4.16 (t, 2H), 4.35 (s, 2H), 4.76 (tt, 1H), 6.11 (s, 2H), 6.51 (d, 1H), 6.85 (d, 1H), 7.06 (s, 1H), 8.52 (s, 1H), 9.26 (s, 1H); Mass Spectrum: M+H+ 611/613.

Workup

  1. temperatureto warm to room temperature
  2. stirringstirred for a further 2 hours
  3. customThe reaction mixture was quenched into water and saturated ammonium chloride solution
  4. additionwas added
  5. extractionThis was then extracted into dichloromethane
  6. washthe organic portion was then washed with brine
  7. dry with materialdried over magnesium sulfate
  8. customevaporated
  9. customThe residue was purified by column chromatography on silica using
  10. temperatureincreasingly polar mixtures of dichloromethane and methanol as eluent
  11. customwas triturated with diethyl ether giving an off-white solid
  12. dissolutionThis was then re-dissolved into dichloromethane
  13. customevaporated under reduced pressure
  14. customThe resulting solid was triturated with diethyl ether
  15. customair-dried

Sources & evidence

ORD record
ord-8ffaa77a8e984dbd916df2b62730caa8
Source dataset
uspto-grants-2009_03
Patent number
US07504408B2

Reaction notes

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