Potassium Carbonate → (S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyano-3-fluorophenoxy)-2-hydroxy-2-methylpropanamide

HRID 1631189Notes

Reaction equation

HRID 1631189 reaction equation
Br[NH-].Br[CH2:4][C@@:5]([OH:22])([CH3:21])[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[C:11]([C:17]([F:20])([F:19])[F:18])[CH:10]=1)=[O:7].C([O-])([O-])=O.[K+].[K+].[F:29][C:30]1[CH:37]=[C:36]([OH:38])[CH:35]=[CH:34][C:31]=1[C:32]#[N:33]>CC(C)=O.CC(O)C.O>[C:15]([C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[C@:5]([OH:22])([CH3:21])[CH2:4][O:38][C:36]2[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[C:30]([F:29])[CH:37]=2)=[CH:10][C:11]=1[C:17]([F:20])([F:19])[F:18])#[N:16]

Participants

8

Reactant 4

HCID 11430Potassium Carbonate2×HCID 27346752-Fluoro-4-hydroxybenzonitrileHCID 10450565(2R)-3-bromo-N-[4-cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-2-methylpropanamideHCID 86618840Bromoamide

Product 1

HCID 16045149(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyano-3-fluorophenoxy)-2-hydroxy-2-methylpropanamideYield 23%

Reagents, catalysts & solvents 3

HCID 180AcetoneSolventHCID 962WaterSolventHCID 3776IsopropanolSolvent

Procedure

A mixture of bromoamide ((2R)-3-bromo-N-[4-cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-2-methylpropanamide (2.0 g, 5.70 mmol), anhydrous K2CO3 (2.4 g, 17.1 mmol) in 50 mL of acetone was heated to reflux for 2 h and then concentrated under reduced pressure to give a solid. The resulting solid was treated with 2-fluoro-4-hydroxybenzonitrile (1.2 g, 8.5 mmol) and anhydrous K2CO3 (1.6 g, 11.4 mmol) in 50 mL of 2-propanol, was heated to reflux for 3 h, and then concentrated under reduced pressure to give a solid. The residue was treated with 100 mL of H2O and then extracted with EtOAc (2×100 mL). The combined EtOAc extracts were washed with 10% NaOH (4×100 mL) and brine, successively. The organic layer was dried over MgSO4 and then concentrated under reduced pressure to give an oil which was crystallized from CH2Cl2/hexane to give 0.5 g (23%) of (S)—N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyano-3-fluorophenoxy)-2-hydroxy-2-methylpropanamide as a colorless solid. 1H NMR (CDCl3/TMS) δ 1.63 (s, 3H, CH3), 3.34 (bs, 1H2OH), 4.08 (d, J=9.17 Hz, 1H, CH), 4.50 (d, J=9.17 Hz, 1H, CH), 6.74-6.82 (m, 2H, ArH), 7.50-7.55 (m, 1H, ArH), 7.81 (d, J=8.50 Hz, 1H, ArH), 7.97 (q, J=2.03, 8.50 Hz, 1H, ArH), 8.11 (d, J=2.03 Hz, 1H, ArH), 9.12 (s, 1H, NH). Calculated Mass: 407.1, [M+Na]+430.0. Mp: 124-125° C.

Workup

  1. temperaturewas heated
  2. temperatureto reflux for 2 h
  3. concentrationconcentrated under reduced pressure
  4. customto give a solid
  5. temperaturewas heated
  6. temperatureto reflux for 3 h
  7. concentrationconcentrated under reduced pressure
  8. customto give a solid
  9. extractionextracted with EtOAc (2×100 mL)
  10. washThe combined EtOAc extracts were washed with 10% NaOH (4×100 mL) and brine
  11. dry with materialThe organic layer was dried over MgSO4
  12. concentrationconcentrated under reduced pressure
  13. customto give an oil which
  14. customwas crystallized from CH2Cl2/hexane

Sources & evidence

ORD record
ord-f6e4098a18054537a556a3e7baab6bf6
Source dataset
uspto-grants-2014_07
Patent number
US08791158B2

Reaction notes

Loading…