Acetic Acid → 5-{[1-(4-Chloro-3-fluoro-2-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2-methoxymethylpropylidene]amino}-7-fluoro-1h-quinolin-2-one

HRID 1191617Notes

Reaction equation

HRID 1191617 reaction equation
[NH2:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:13])[NH:7]2.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=O)[C:22]([OH:30])([CH2:27][O:28][CH3:29])[C:23]([F:26])([F:25])[F:24])=[C:17]([O:32][CH3:33])[C:16]=1[F:34].C(O)(=O)C.[F-].[NH4+]>C1(C)C=CC=CC=1.O1CCOCC1.CCCCO.CCCCO.CCCCO.CCCCO.[Ti].C(OCC)(=O)C>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[N:1][C:2]2[CH:11]=[C:10]([F:12])[CH:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][C:6](=[O:13])[NH:7]3)[C:22]([OH:30])([CH2:27][O:28][CH3:29])[C:23]([F:26])([F:25])[F:24])=[C:17]([O:32][CH3:33])[C:16]=1[F:34]

Participants

9

Reactant 4

HCID 176Acetic AcidHCID 25516Ammonium fluorideHCID 669694385-amino-7-fluoroquinolin-2(1H)-oneHCID 687619191-(4-Chloro-3-fluoro-2-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2-methoxymethypropan-1-one

Product 1

HCID 875556265-{[1-(4-Chloro-3-fluoro-2-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2-methoxymethylpropylidene]amino}-7-fluoro-1h-quinolin-2-one

Reagents, catalysts & solvents 4

HCID 521701TetrabutoxytitaniumCatalystHCID 1140TolueneSolventHCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

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. temperatureThe mixture is heated over 20 hours to 110° C.
  2. customPhases are separated
  3. extractiontwo times extracted with ethyl acetate
  4. concentrationThe combined organic phases are concentrated

Sources & evidence

ORD record
ord-4606b28005b84a0faf7246de28121a04
Source dataset
uspto-grants-2014_03
Patent number
US08680117B2

Reaction notes

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