Sodium Bicarbonate → 2-(3-{[2,2-Difluoro-2-(4-fluoronaphthyl)ethyl]amino]-6-chloro-2-fluorophenyl)ethanol

HRID 1060223Notes

Reaction equation

HRID 1060223 reaction equation
[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=O)[C:10]([F:23])([F:22])[C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([F:21])=[CH:13][CH:12]=2)=[C:4]([F:25])[C:3]=1[CH2:26][CH2:27][OH:28].B.C1COCC1.C([O-])(O)=O.[Na+]>C1COCC1.O>[F:23][C:10]([F:22])([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([F:21])=[CH:13][CH:12]=1)[CH2:9][NH:8][C:5]1[C:4]([F:25])=[C:3]([CH2:26][CH2:27][OH:28])[C:2]([Cl:1])=[CH:7][CH:6]=1

Participants

6

Reactant 3

HCID 516892Sodium BicarbonateHCID 2723981Borane;tetrahydrofuranHCID 22475325N-[4-chloro-2-fluoro-3-(2-hydroxyethyl)phenyl]-2,2-difluoro-2-(4-fluoronaphthyl)acetamide

Product 1

HCID 224753262-(3-{[2,2-Difluoro-2-(4-fluoronaphthyl)ethyl]amino]-6-chloro-2-fluorophenyl)ethanolYield 44%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Procedure

To a solution of N- [4-chloro-2-fluoro-3-(2-hydroxyethyl)phenyl]-2,2-difluoro-2-(4-fluoronaphthyl)acetamide (1.9 g, 4.6 mmol), as prepared in the preceding step, in THF (19 mL) at 0° C. was added dropwise a solution of BH3.THF complex (19.4 mL, 19.4 mmol, 1.0 M in THF) over a period of 20 minutes, and the reaction mixture continued to stir until the ice bath expired. The mixture was then heated at reflux in an oil bath at 75° to 80° C. for 3 hours, and continued to stir at ambient temperature overnight. A solution of NaHCO3 (1.63 g, 19.4 mmol) in H2O (20 mL) was added, the THF was evaporated, and the resulting mixture was extracted with DCM twice. The extracts were combined, washed with H2O and brine, dried over Na2SO4, concentrated, and flash chromatographed on silica gel eluting with EtOAc/DCM (0, 1, 1.5%) to give the title compound (805 mg, 44% yield) as a white solid. 1H-NMR (400 MHz, CDCl3) δ 8.24-8.19 (m, 2H), 7.70-7.61 (m, 3H), 7.14 (t, J=9.3 Hz, 1H), 6.90 (dd, J=8.7, 1.6 Hz, 1H), 6.42 (t, J=8.9 Hz, 1H), 4.22-4.16 (m, 1H), 4.00 (dt,J=13.4, 6.8 Hz, 2H), 3.82 (dd, J=12.1, 6.4 Hz, 2H), 3.02 (dt, J=6.8, 2.3 Hz, 2H), 1.39 (br s, 1H). Mass spectrum (LCMS, ESI) calc'd for C20H17ClF4NO (M+H): 398.1. Found: 398.3.

Workup

  1. temperatureThe mixture was then heated
  2. temperatureat reflux in an oil bath at 75° to 80° C. for 3 hours
  3. customthe THF was evaporated
  4. extractionthe resulting mixture was extracted with DCM twice
  5. washwashed with H2O and brine
  6. dry with materialdried over Na2SO4
  7. concentrationconcentrated
  8. customflash chromatographed on silica gel eluting with EtOAc/DCM (0, 1, 1.5%)

Sources & evidence

ORD record
ord-d74b9c19a7a548779f8d721f9f864fb4
Source dataset
uspto-grants-2003_02
Patent number
US06521663B2

Reaction notes

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