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 1945126노트

반응식

HRID 1945126 반응식
[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]

참가 물질

9

반응물 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

생성물 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

시약·촉매·용매 4

HCID 521701Tetrabutoxytitanium촉매HCID 1140Toluene용매HCID 8857Ethyl Acetate용매HCID 312751,4-Dioxane용매

실험 절차

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.

후처리

  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

출처 및 근거

ORD 기록
ord-f74a0f82e234492d9a639c18c985e450
출처 데이터셋
uspto-grants-2013_03
특허 번호
US08394958B2

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