1,4-Dioxane → 1-((3R,4R)-3-(6-hydroxy-4-methylquinolin-2-ylamino)-4-methoxypyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanone

HRID 1666622Notes

Reaction equation

HRID 1666622 reaction equation
Cl[C:2]1[CH:11]=[C:10]([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:13])[CH:8]=2)[N:3]=1.[NH2:14][C@H:15]1[C@H:19]([O:20][CH3:21])[CH2:18][N:17]([C:22](=[O:35])[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]([F:34])([F:33])[F:32])=[CH:26][CH:25]=2)[CH2:16]1.O1CCOCC1.CC(C)([O-])C.[Na+]>C(OCC)(=O)C.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[OH:13][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:14][C@H:15]1[C@H:19]([O:20][CH3:21])[CH2:18][N:17]([C:22](=[O:35])[CH2:23][C:24]3[CH:25]=[CH:26][C:27]([O:30][C:31]([F:32])([F:33])[F:34])=[CH:28][CH:29]=3)[CH2:16]1)[CH:11]=[C:10]2[CH3:12]

Participants

8

Reactant 4

HCID 312751,4-DioxaneHCID 7663822-Chloro-4-methyl-quinolin-6-olHCID 23676156Sodium t-butoxide2×HCID 579701661-((3R,4R)-3-amino-4-methoxypyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanone

Product 1

HCID 579702171-((3R,4R)-3-(6-hydroxy-4-methylquinolin-2-ylamino)-4-methoxypyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanoneYield 17.1%

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalyst2×HCID 962WaterSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
65 °C

Procedure

To a mixture of 2-chloro-6-hydroxy-4-methylquinoline (0.153 g), Pd2(dba)3 (0.036 g), (±)-BINAP (0.073 g), 1-((3R,4R)-3-amino-4-methoxypyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanone (0.25 g), and 1,4-dioxane (7 mL) was added sodium t-butoxide (0.241 g) under nitrogen atmosphere, and the mixture was stirred at 65° C. for 3 h. Pd2(dba)3 (0.036 g), (±)-BINAP (0.073 g), and sodium t-butoxide (0.241 g) were further added, and the mixture was stirred at 65° C. for 5 h. The reaction mixture was diluted with ethyl acetate and water, then the interlayer was removed by Celite filtration, and the organic layer washed with saturated brine. The organic layer was dried with anhydrous magnesium sulfate, the desiccant was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (silica gel, chloroform/methanol and NH silica gel, ethyl acetate) to obtain colorless amorphous 1-((3R,4R)-3-(6-hydroxy-4-methylquinolin-2-ylamino)-4-methoxypyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanone (0.064 g).

Workup

  1. stirringthe mixture was stirred at 65° C. for 5 h
  2. customthe interlayer was removed by Celite filtration
  3. washthe organic layer washed with saturated brine
  4. dry with materialThe organic layer was dried with anhydrous magnesium sulfate
  5. customthe desiccant was removed by filtration
  6. concentrationthe filtrate was concentrated under reduced pressure
  7. customthe residue was purified by silica gel column chromatography (silica gel, chloroform/methanol and NH silica gel, ethyl acetate)

Sources & evidence

ORD record
ord-63ef79ff1f8c4176ba55f51a60c5a080
Source dataset
uspto-grants-2011_10
Patent number
US08044068B2

Reaction notes

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