Acetic Acid → N-[4-chloro-2-fluor-3-(2-hydroxyethyl)phenyl]-2,2-difluoro-2-phenylacetamide

HRID 2184191Notes

Reaction equation

HRID 2184191 reaction equation
N[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:19])[C:10]([F:18])([F:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:4]([F:20])[C:3]=1[CH2:21][CH2:22][OH:23].N([O-])=O.[Na+].C(O)(=O)C.[ClH:32]>O.Cl[Cu]>[Cl:32][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:19])[C:10]([F:18])([F:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:4]([F:20])[C:3]=1[CH2:21][CH2:22][OH:23]

Participants

7

Reactant 4

HCID 176Acetic AcidHCID 313Hydrochloric Acid3×HCID 22475328N-[4-amino-2-fluoro-3-(2-hydroxyethyl)phenyl]-2,2-difluoro-2-phenylacetamideHCID 23668193Sodium Nitrite

Product 1

HCID 22475352N-[4-chloro-2-fluor-3-(2-hydroxyethyl)phenyl]-2,2-difluoro-2-phenylacetamideYield 48%

Reagents, catalysts & solvents 2

HCID 62652Cuprous chlorideCatalystHCID 962WaterSolvent

Procedure

A suspension of N-[4-amino-2-fluoro-3-(2-hydroxyethyl)phenyl]-2,2-difluoro-2-phenylacetamide (1.63 g, 5.00 mmol), as prepared according to the procedure of the preceding step, in 6N HCl (9 mL) was cooled in an ice-bath, and then a solution of NaNO2 (434 mg, 6.30 mmol) in H2O (2.4 mL) was added over a period of 5 minutes. After 30 minutes, acetic acid (2.9 mL) and concentrated HCl (2.9 mL) were added and the reaction mixture stirred for 1 hour. To this mixture was added a solution of CuCl (848 mg, 8.55 mmol) in concentrated HCl (5 mL) over a period of 20 minutes. After stirring in an ice-bath for 3 hours, the reaction mixture was extracted with EtOAc (200 mL×3). The extracts were combined, washed with H2O (2 times) and brine, dried over Na2SO4, concentrated, and flash chromatographed on silica gel eluting with EtOAc/DCM (0, 2.5, and 5%) to deliver the title compound (0.845 g, 48% yield) as a pale orange oil. 1H-NMR (400 MHz, CDCl3)δ 8.31 (s, 1H), 8.14 (t, J=8.6 Hz, 1H), 7.68-7.66 (m, 2H), 7.54-7.46 (m, 3H), 7.19 (dd, J=8.9, 1.7 Hz, 1H), 3.86 (dd, J=12.6, 6.5 Hz., 2H), 3.09 (dt, J=6.7, 2.3 Hz, 2H), 1.58 (t, J=5.7 Hz, 1H). Mass spectrum (LCMS, ESI) calc'd for C16H14ClF3NO2 (M+H): 344.1. Found: 344.2.

Workup

  1. customas prepared
  2. temperaturewas cooled in an ice-bath
  3. stirringAfter stirring in an ice-bath for 3 hours
  4. extractionthe reaction mixture was extracted with EtOAc (200 mL×3)
  5. washwashed with H2O (2 times) and brine
  6. dry with materialdried over Na2SO4
  7. concentrationconcentrated
  8. customflash chromatographed on silica gel eluting with EtOAc/DCM (0, 2.5, and 5%)

Sources & evidence

ORD record
ord-28964717102c439c9b539958cb586c22
Source dataset
uspto-grants-2005_05
Patent number
US06900231B2

Reaction notes

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