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

HRID 1922129Notes

Reaction equation

HRID 1922129 reaction equation
[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

Participants

8

Reactant 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

Product 1

HCID 67458143{3-[4-(5-Cyclopropylisoxazol-4-yl)benzyl]-4-difluoromethoxy-2-ethyl-8-fluoroquinolin-5-yloxy}acetic acid methyl esterYield 17.6%

Reagents, catalysts & solvents 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 962WaterSolvent2×HCID 80711,2-DimethoxyethaneSolvent

Conditions

Temperature
85 °C

Procedure

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).

Workup

  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)

Sources & evidence

ORD record
ord-86f7f5ac01794e98badd5bfdbdb08304
Source dataset
uspto-grants-2012_05
Patent number
US08173812B2

Reaction notes

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