Hydrochloric Acid → N-[4-chloro-2-fluoro-3-(2-hydroxyethyl)phenyl]-2,2-difluoro-2-(4-fluoronaphthyl)acetamide

HRID 2184204Notes

Reaction equation

HRID 2184204 reaction equation
C(ON=O)(C)(C)C.N[C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:31])[C:17]([F:30])([F:29])[C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]([F:28])=[CH:20][CH:19]=2)=[C:11]([F:32])[C:10]=1[CH2:33][CH2:34][OH:35].[ClH:36]>C(#N)C.[Cu](Cl)Cl>[Cl:36][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:31])[C:17]([F:30])([F:29])[C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]([F:28])=[CH:20][CH:19]=2)=[C:11]([F:32])[C:10]=1[CH2:33][CH2:34][OH:35]

Participants

6

Reactant 3

HCID 313Hydrochloric AcidHCID 10906Tert-Butyl nitriteHCID 20792218N-[4-Amino-2-fluoro-3-(2-hydroxyethyl)phenyl]-2,2-difluoro-2-(4-fluoronaphthyl)acetamide

Product 1

HCID 22475325N-[4-chloro-2-fluoro-3-(2-hydroxyethyl)phenyl]-2,2-difluoro-2-(4-fluoronaphthyl)acetamideYield 56%

Reagents, catalysts & solvents 2

HCID 24014Cupric ChlorideCatalystHCID 6342AcetonitrileSolvent2×

Conditions

Temperature
0 °C

Procedure

To a flask charged with copper(II) chloride (1.84 g, 13.7 mmol) was added a solution of tert-butylnitrite (1.46 g, 12.8 mmol, 90%, Aldrich) in acetonitrile (35 mL) under argon atmosphere. The resulting green reaction mixture was cooled in an ice-bath to 0° C., and a solution of N-[4-amino-2-fluor-3-(2-hydroxyethyl)phenyl]-2,2-difluoro-2-(4-fluoronaphthyl) acetamide (3.58 g, 9.13 mmol), as prepared according to the procedure of the preceding step, in acetonitrile (60 mL) was added over a period of 45 minutes. After stirring for an additional 6 hours at 0° C., the resulting brown mixture was allowed to warm up to ambient temperature, then poured into 20% aqueous HCl (160 mL), and extracted with DCM (3 times). The extracts were combined, washed with 20% HCl, H2O, and brine, dried over Na2SO4, concentrated, and flash chromatographed on silica gel eluting with EtOAc/DCM (0 and 2.5%) to deliver the title compound (2.1 g, 56% yield) as a white solid. 1H-NMR (400 MHz, CDCl3) δ 8.31 (br s, 1H), 8.24-8.12 (m, 3H), 7.84 (dd, J=8.2, 5.3 Hz, 1H). 7.68-7.60 (m, 2H), 7.22-7.20 (m, 2H), 3.87 (dd, J=12.6, 6.5 Hz, 2H), 3.09 (dt, J=6.7, 2.2 Hz, 2H), 1.47 (t, J=5.6 Hz, 2H). Mass spectrum (LCMS, ESI) calc'd for C20H15ClF4NO2 (M+H): 412.1. Found: 412.6.

Workup

  1. additionwas added over a period of 45 minutes
  2. temperatureto warm up to ambient temperature
  3. extractionextracted with DCM (3 times)
  4. washwashed with 20% HCl, H2O, and brine
  5. dry with materialdried over Na2SO4
  6. concentrationconcentrated
  7. customflash chromatographed on silica gel eluting with EtOAc/DCM (0 and 2.5%)

Sources & evidence

ORD record
ord-2e4458ae841c440fac98ccfbd3f73cfe
Source dataset
uspto-grants-2005_05
Patent number
US06900231B2

Reaction notes

Loading…