Hydrochloric Acid → {3-[4-(5-Cyclopropylisoxazol-4-yl)benzyl]-4-difluoromethoxy-2-ethyl-8-fluoroquinolin-5-yloxy}acetic acid methyl ester

HRID 1922129Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 1922129
[F:1][CH:2]([F:33])[O:3][C:4]1[C:13]2[C:8](=[C:9]([F:20])[CH:10]=[CH:11][C:12]=2[O:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[N:7]=[C:6]([CH2:21][CH3:22])[C:5]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.Br[C:35]1[CH:36]=[N:37][O:38][C:39]=1[CH:40]1[CH2:42][CH2:41]1.C(=O)([O-])O.[Na+].Cl>O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].COCCOC>[CH3:19][O:18][C:16](=[O:17])[CH2:15][O:14][C:12]1[CH:11]=[CH:10][C:9]([F:20])=[C:8]2[C:13]=1[C:4]([O:3][CH:2]([F:33])[F:1])=[C:5]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:35]3[CH:36]=[N:37][O:38][C:39]=3[CH:40]3[CH2:42][CH2:41]3)=[CH:26][CH:25]=1)[C:6]([CH2:21][CH3:22])=[N:7]2

Komponenten

8

Edukt 4

HCID 313Hydrochloric AcidHCID 516892Sodium BicarbonateHCID 674575914-Bromo-5-cyclopropylisoxazoleHCID 67458287(4-{[4-Difluoromethoxy-2-ethyl-8-fluoro-5-(2-methoxy-2-oxoethoxy) quinolin-3-yl]methyl}phenyl)boronic acid

Produkt 1

HCID 67458143{3-[4-(5-Cyclopropylisoxazol-4-yl)benzyl]-4-difluoromethoxy-2-ethyl-8-fluoroquinolin-5-yloxy}acetic acid methyl esterAusbeute 17,6 %

Reagenzien, Katalysatoren, Lösungsmittel 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)KatalysatorHCID 962WaterLösungsmittel2×HCID 80711,2-DimethoxyethaneLösungsmittel

Reaktionsbedingungen

Temperatur
85 °C

Versuchsvorschrift

A mixture of (4-{[4-difluoromethoxy-2-ethyl-8-fluoro-5-(2-methoxy-2-oxoethoxy)quinolin-3-yl]methyl}phenyl)boronic acid (0.15 g), 4-bromo-5-cyclopropylisoxazole (0.24 g), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (0.027 g), sodium hydrogen carbonate (0.082 g), 1,2-dimethoxyethane (1.0 mL) and water (0.4 mL) was heated at 85° C. for 2 hours. The mixture was cooled to room temperature, diluted with water (5 mL), neutralised by the addition of 1.0 M aqueous hydrochloric acid solution (1.0 mL) and extracted with ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride solution, dried over magnesium sulphate and then concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (1:0 to 7:3 by volume) gave title compound as a colourless oil (0.03 g).

Aufarbeitung

  1. temperatureThe mixture was cooled to room temperature
  2. extractionextracted with ethyl acetate
  3. washThe combined extracts were washed with saturated aqueous sodium chloride solution
  4. dry with materialdried over magnesium sulphate
  5. concentrationconcentrated under reduced pressure
  6. customPurification of the residue by column chromatography on silica gel
  7. washeluting with a mixture of cyclohexane and ethyl acetate (1:0 to 7:3 by volume)

Quellen und Nachweise

ORD-Eintrag
ord-86f7f5ac01794e98badd5bfdbdb08304
Quelldatensatz
uspto-grants-2012_05
Patentnummer
US08173812B2

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