Triethylamine → (2R)-3-bromo-N-[4-cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-2-methylpropanamide

HRID 1631188Notes

Reaction equation

HRID 1631188 reaction equation
S(Cl)(Cl)=O.[Br:5][CH2:6][C@@:7]([OH:12])([CH3:11])[C:8](O)=[O:9].CCN(CC)CC.[NH2:20][C:21]1[CH:22]=[CH:23][C:24]([C:31]#[N:32])=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1>C1COCC1.O>[Br:5][CH2:6][C@@:7]([OH:12])([CH3:11])[C:8]([NH:20][C:21]1[CH:22]=[CH:23][C:24]([C:31]#[N:32])=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:26]=1)=[O:9]

Participants

7

Reactant 4

HCID 8471TriethylamineHCID 24386Thionyl ChlorideHCID 5221704-Amino-2-(trifluoromethyl)benzonitrileHCID 10582468(2R)-3-BROMO-2-HYDROXY-2-METHYLPROPANOIC ACID

Product 1

HCID 10450565(2R)-3-bromo-N-[4-cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-2-methylpropanamideYield 75.7%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent2×

Procedure

Thionyl chloride (46.02 g, 0.39 mol) was added dropwise to a cooled solution (less than 4° C.) of (R)-3-bromo-2-hydroxy-2-methylpropanoic acid (51.13 g, 0.28 mol) in 300 mL of THF under an argon atmosphere. The resulting mixture was stirred for 3 h under the same condition. To this was added Et3N (39.14 g, 0.39 mol) and stirred for 20 min under the same condition. After 20 min, 5-amino-2-cyanobenzotrifluoride (40.0 g, 0.21 mol), 400 mL of THF were added and then the mixture was allowed to stir overnight at room temperature. The solvent was removed under reduced pressure to give a solid which was treated with 300 mL of H2O, extracted with EtOAc (2×400 mL). The combined organic extracts were washed with saturated NaHCO3 solution (2×300 mL) and brine (300 mL). The organic layer was dried over MgSO4 and concentrated under reduced pressure to give a solid which was purified from column chromatography using CH2Cl2/EtOAc (80:20) to give a solid. This solid was recrystallized from CH2Cl2/hexane to give 55.8 g (73.9%) of (2R)-3-bromo-N-[4-cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-2-methylpropanamide as a light-yellow solid. 1H NMR (CDCl3/TMS) δ 1.66 (s, 3H, CH3), 3.11 (s, 1H, OH), 3.63 (d, J=10.8 Hz, 1H, CH2), 4.05 (d, J=10.8 Hz, 1H, CH2), 7.85 (d, J=8.4 Hz, 1H, ArH), 7.99 (dd, J=2.1, 8.4 Hz, 1H, ArH), 8.12 (d, J=2.1 Hz, 1H, ArH), 9.04 (bs, 1H, NH). Calculated Mass: 349.99, [M-H]− 349.0. M.p.: 124-126° C.

Workup

  1. stirringstirred for 20 min under the same condition
  2. waitAfter 20 min
  3. stirringto stir overnight at room temperature
  4. customThe solvent was removed under reduced pressure
  5. customto give a solid which
  6. extractionextracted with EtOAc (2×400 mL)
  7. washThe combined organic extracts were washed with saturated NaHCO3 solution (2×300 mL) and brine (300 mL)
  8. dry with materialThe organic layer was dried over MgSO4
  9. concentrationconcentrated under reduced pressure
  10. customto give a solid which
  11. customwas purified from column chromatography
  12. customto give a solid
  13. customThis solid was recrystallized from CH2Cl2/hexane

Sources & evidence

ORD record
ord-9953a8f26b7c4a74a627f463ff30ccea
Source dataset
uspto-grants-2014_07
Patent number
US08791158B2

Reaction notes

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