Methanol → 1-(4-Chloro-3-fluoro-2-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2-methoxymethypropan-1-one

HRID 1191616Notes

Reaction equation

HRID 1191616 reaction equation
[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2([C:13]([F:16])([F:15])[F:14])C[O:11]2)=[O:9])=[C:4]([O:17][CH3:18])[C:3]=1[F:19].[C:20](=O)([O-])[O-].[Cs+].[Cs+].[CH3:26][OH:27]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:9])[C:10]([OH:11])([CH2:26][O:27][CH3:20])[C:13]([F:16])([F:15])[F:14])=[C:4]([O:17][CH3:18])[C:3]=1[F:19]

Participants

4

Reactant 3

HCID 887MethanolHCID 10796Cesium carbonateHCID 86630563(4-Chloro-3-fluoro-2-methoxyphenyl)[2-(trifluoromethyl)oxiranyl]methanone

Product 1

HCID 687619191-(4-Chloro-3-fluoro-2-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2-methoxymethypropan-1-one

Procedure

285 mg (0.95 mmol) (4-Chloro-3-fluoro-2-methoxyphenyl)[2-(trifluoromethyl)oxiranyl]methanone are stirred with 622 mg (1.9 mmol) caesium carbonate in 6.7 ml methanol. The reaction is quenched by addition of water after one day. The aqueous layer is extracted with ethyl acetate, the combined organic phases are washed with brine, dried over sodium sulphate and then evaporated to yield 262 mg 1-(4-chloro-3-fluoro-2-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2-methoxymethypropan-1-one. To 27 mg (0.15 mmol) 5-Amino-7-fluoro-1H-quinolin-2-one and 50 mg (0.15 mmol) 1-(4-chloro-3-fluoro-2-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2-methoxymethypropan-1-one in 0.45 ml toluene and 0.13 ml 1,4-dioxane are added 33 μl acetic acid and 0.12 ml tetra butyl orthotitanate. The mixture is heated over 20 hours to 110° C., cooled to room temperature and poured into aqueous ammonium fluoride solution. Ethyl acetate is added and the mixture is stirred vigorously for 30 minutes. Phases are separated and two times extracted with ethyl acetate. The combined organic phases are concentrated to yield quantitatively 5-{[1-(4-chloro-3-fluoro-2-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2-methoxymethylpropylidene]amino}-7-fluoro-1H-quinolin-2-one. The raw imine in 4.2 ml methanol is cooled to 5° C. and 120 mg sodium boron hydride are added in multiple portions over the period of 72 hours. The reaction is quenched by addition of saturated ammonium chloride solution and diluted with water and ethyl acetate. The phases are separated, the aqueous layer is extracted with ethyl acetate, the combined organic phases are washed with brine and dried over sodium sulphate. After removal of the solvent preparative thin layer chromatography on silica gel (acetone in methylene chloride, 30%) yields 9.5 mg of the title compound.

Workup

  1. customThe reaction is quenched by addition of water after one day
  2. extractionThe aqueous layer is extracted with ethyl acetate
  3. washthe combined organic phases are washed with brine
  4. dry with materialdried over sodium sulphate
  5. customevaporated

Sources & evidence

ORD record
ord-0b7d5f0ec8754303b87e0272fa66757a
Source dataset
uspto-grants-2014_03
Patent number
US08680117B2

Reaction notes

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