Water → 4-(8-methoxy-1-(1-methoxypropan-2-yl)-2-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]quinolin-7-yl)-3,5-dimethylisoxazole

HRID 2178585Notes

Reaction equation

HRID 2178585 reaction equation
[CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[C:15]3[C:10]([C:11]([NH:26][CH:27]([CH3:31])[CH2:28][O:29][CH3:30])=[C:12]([NH:17][C:18]([CH:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=O)[CH:13]=[N:14]3)=[CH:9][C:8]=2[O:32][CH3:33])=[C:5]([CH3:34])[O:4][N:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[CH3:33][O:32][C:8]1[C:7]([C:6]2[C:2]([CH3:1])=[N:3][O:4][C:5]=2[CH3:34])=[CH:16][C:15]2[N:14]=[CH:13][C:12]3[N:17]=[C:18]([CH:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[N:26]([CH:27]([CH3:31])[CH2:28][O:29][CH3:30])[C:11]=3[C:10]=2[CH:9]=1

Participants

6

Reactant 4

HCID 962WaterHCID 6101p-Toluenesulfonic acid2×HCID 516892Sodium BicarbonateHCID 71259078N-(7-(3,5-dimethylisoxazol-4-yl)-6-methoxy-4-((1-methoxypropan-2-yl)amino)quinolin-3-yl)tetrahydro-2H-pyran-4-carboxamide

Product 1

HCID 712589164-(8-methoxy-1-(1-methoxypropan-2-yl)-2-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]quinolin-7-yl)-3,5-dimethylisoxazole

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Procedure

A mixture of N-(7-(3,5-dimethylisoxazol-4-yl)-6-methoxy-4-((1-methoxypropan-2-yl)amino)quinolin-3-yl)tetrahydro-2H-pyran-4-carboxamide (for a preparation see Intermediate 3) (11.95 g, 25.5 mmol) and p-toluenesulfonic acid (1.2 g, 25.5 mmol) in toluene (250 ml) was heated under nitrogen at reflux using a Dean-Stark apparatus for 3 days. Further p-toluenesulfonic acid (0.2 g, 4.3 mmol) was added and heating continued overnight. Water (750 ml) was added, and the mixture basified to pH 8 using saturated aqueous sodium hydrogen carbonate solution. The aqueous was extracted with ethyl acetate (3×750 ml), the organic layers combined, dried (hydrophobic frit) and evaporated under reduced pressure. The residual solid was triturated in ether (˜200 ml), sonicated briefly. The majority of the solid appeared to be a fine powder. The fine powder suspended in the ether was decanted, the solid isolated by filtration, and dried in a vacuum oven to give crude 4-(8-methoxy-1-(1-methoxypropan-2-yl)-2-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]quinolin-7-yl)-3,5-dimethylisoxazole (6.3 g). This material was triturated in ether (˜100 ml), sonicated briefly, and stood overnight at room temperature. The solid was isolated by filtration and dried in a vacuum oven 4-(8-methoxy-1-(1-methoxypropan-2-yl)-2-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]quinolin-7-yl)-3,5-dimethylisoxazole (4.9 g, 10.88 mmol, 42.6% yield). LCMS (formate): Rt 0.75 min, MH+451.

Workup

  1. temperaturewas heated under nitrogen
  2. temperatureat reflux
  3. customfor 3 days
  4. temperatureheating continued overnight
  5. extractionThe aqueous was extracted with ethyl acetate (3×750 ml)
  6. customdried (hydrophobic frit)
  7. customevaporated under reduced pressure
  8. customThe residual solid was triturated in ether (˜200 ml)
  9. customsonicated briefly
  10. customwas decanted
  11. customthe solid isolated by filtration
  12. customdried in a vacuum oven

Sources & evidence

ORD record
ord-1aca99ec64284c6fb6d41b0f21a41380
Source dataset
uspto-grants-2015_06
Patent number
US09067936B2

Reaction notes

Loading…