Hydrochloric Acid → HCID 57973988, compound

HRID 2067095Notes

Reaction equation

HRID 2067095 reaction equation
[CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:11]=[CH:10][C:9](N)=[C:8]([O:13][C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Br:21])[CH:15]=2)[C:7]=1[F:22])[CH3:2].C(ON=O)(C)(C)C.[ClH:31].CCOCC>CC#N>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:31])=[C:8]([O:13][C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Br:21])[CH:15]=2)[C:7]=1[F:22])[CH3:2]

Participants

6

Reactant 4

HCID 313Hydrochloric AcidHCID 3283Diethyl EtherHCID 10906Tert-Butyl nitriteHCID 67370940HCID 67370940, compound

Product 1

HCID 57973988HCID 57973988, compound

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Conditions

Temperature
50 °C

Procedure

steps 4 and 5—A suspension of 44a (16.1 g, 37 mmol), Fe powder (8.2 g, 148 mmol, Fisher, electrolytically deposited), and NH4Cl (8.0 g, 148 mmol) in absolute ethanol (700 mL) and H2O (180 mL) was heated to reflux for 4 h. The solution was cooled to RT and filtered through CELITE®. The filter cake was washed with chloroform (2×150 mL). The filtrate was washed with aqueous NaHCO3, water, and brine and dried (K2CO3), filtered and the volatiles removed to afford 14.0 g of [4-amino-3-(3-bromo-5-chloro-phenoxy)-2-fluoro-phenyl]-acetic acid ethyl ester (44b). The aniline 44b (9.7 g, 24.1 mmol) was dissolved in anhydrous MeCN (100 mL) under nitrogen. This solution was added slowly to a mixture of tert-butyl-nitrite (7.1 mL, 60.3 mmol, assay 90%) and CuCl2 (6.5 g, 48.2 mmol) that had been prepared under nitrogen and warmed to 50° C. The reaction temperature was maintained at 50° C. for 15 min, cooled to 0° C. and poured into 5% aqueous HCl solution (80 mL) and Et2O (150 mL). The mixture was extracted with EtOAc (3×150 mL), the combined extracts were washed with brine and dried (MgSO4), filtered and the volatiles were removed. The residual oil was purified by flash SiO2 chromatography eluting with EtOAc/hexanes (0% to 10% EtOAc) to afford 6.25 g of [4-chloro-3-(3-bromo-5-chloro-phenoxy)-2-fluoro-phenyl]-acetic acid ethyl ester (44c) as an oil.

Workup

  1. customhad been prepared under nitrogen
  2. temperatureThe reaction temperature was maintained at 50° C. for 15 min
  3. temperaturecooled to 0° C.
  4. extractionThe mixture was extracted with EtOAc (3×150 mL)
  5. washthe combined extracts were washed with brine
  6. dry with materialdried (MgSO4)
  7. filtrationfiltered
  8. customthe volatiles were removed
  9. customThe residual oil was purified by flash SiO2 chromatography
  10. washeluting with EtOAc/hexanes (0% to 10% EtOAc)

Sources & evidence

ORD record
ord-1a67dee487ec4b5d9515251fb0c9bbd2
Source dataset
uspto-grants-2012_10
Patent number
US08293778B2

Reaction notes

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