Potassium Carbonate → N-(3-chloro-4-fluorophenyl)-6-(3-((1R,5S)-1-(dimethylamino)-3-azabicyclo[3.1.0]hexan-3-yl) propoxy)-7-methoxyquinazolin-4-amine

HRID 712395Notes

Reaction equation

HRID 712395 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:21][CH3:22])=[C:17]([OH:20])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].C([O-])([O-])=O.[K+].[K+].Cl[CH2:30][CH2:31][CH2:32][N:33]1[CH2:38][C@H:37]2[C@:35]([N:39]([CH3:41])[CH3:40])([CH2:36]2)[CH2:34]1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:21][CH3:22])=[C:17]([O:20][CH2:30][CH2:31][CH2:32][N:33]4[CH2:38][C@H:37]5[C@:35]([N:39]([CH3:41])[CH3:40])([CH2:36]5)[CH2:34]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]

Participants

5

Reactant 3

HCID 11430Potassium CarbonateHCID 104712174-[(3-Chloro-4-fluorophenyl)amino]-7-methoxyquinazolin-6-olHCID 86729465(1R,5S)-3-(3-chloropropyl)-N,N-dimethyl-3-azabicyclo[3.1.0]hexan-1-amine

Product 1

HCID 71573149N-(3-chloro-4-fluorophenyl)-6-(3-((1R,5S)-1-(dimethylamino)-3-azabicyclo[3.1.0]hexan-3-yl) propoxy)-7-methoxyquinazolin-4-amineYield 67.7%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent2×

Conditions

Temperature
80 °C

Procedure

To a mixture of 4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-ol (136 mg, 0.42 mmol, 1.0 eq) and anhydrous K2CO3 (290 mg, 2.10 mmol, 5.0 eq) in DMF (3 mL) was added a solution of (1R,5S)-3-(3-chloropropyl)-N,N-dimethyl-3-azabicyclo[3.1.0]hexan-1-amine (103 mg, 0.52 mmol, 1.2 eq) in DMF (2 mL) at room temperature. The reaction mixture was heated at 80° C. for 11 h and cooled to room temperature. Then the reaction mixture was quenched with water (5 mL) and diluted with EtOAc (10 mL). The organic phase was separated from the mixture, and the water phase was extracted with EtOAc (5 mL×3). The combined organic phases were, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo, and the residue was purified by a silica gel column chromatography (10:1 (v/v)CH2Cl2/CH3OH) to give the crude product, which was then recrystallized from CH2Cl2/PE to afford title compound as a yellow solid (138 mg, 67.7%), HPLC: 96.5%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 486.2 (M+1); 1H NMR (400 MHz, CDCl3) δ: 0.81 (1H, m), 1.11 (1H, m), 1.26 (1H, br s), 1.52 (1H, m), 2.38 (6H, s), 2.65-2.81 (3H, m), 3.11 (2H, m), 3.42 (1H, br s), 3.98 (3H, s), 4.18 (2H, t, J=6.8 Hz), 7.14 (1H, t, J=8.8 Hz), 7.25 (1H, d, J=14.4 Hz), 7.41 (1H, s), 7.66 (1H, m), 7.98 (1H, dd, J=5.2, 6.8 Hz), 8.64 (1H, s) ppm.

Workup

  1. temperaturecooled to room temperature
  2. customThen the reaction mixture was quenched with water (5 mL)
  3. additiondiluted with EtOAc (10 mL)
  4. customThe organic phase was separated from the mixture
  5. extractionthe water phase was extracted with EtOAc (5 mL×3)
  6. dry with materialdried over anhydrous Na2SO4
  7. filtrationfiltered
  8. concentrationThe filtrate was concentrated in vacuo
  9. customthe residue was purified by a silica gel column chromatography (10:1 (v/v)CH2Cl2/CH3OH)
  10. customto give the crude product, which
  11. customwas then recrystallized from CH2Cl2/PE

Sources & evidence

ORD record
ord-b23cdb76f94f43f0be142b097ebff072
Source dataset
uspto-grants-2015_11
Patent number
US09181277B2

Reaction notes

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