Nitrogen → 4-(4-Ethyl-2-trifluoromethyl-oxazolidin-3-yl)-3-fluoro-benzonitrile

HRID 2199403

Reaction equation

HRID 2199403 reaction equation
N#N.[F:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[NH:12][CH:13]([CH2:16][OH:17])[CH2:14][CH3:15])[C:7]#[N:8].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O[CH:32](O)[C:33]([F:36])([F:35])[F:34])C>C1(C)C=CC=CC=1>[CH2:14]([CH:13]1[CH2:16][O:17][CH:32]([C:33]([F:36])([F:35])[F:34])[N:12]1[C:11]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[F:3])[CH3:15]

Participants

6

Reactant 4

HCID 947NitrogenHCID 6101p-Toluenesulfonic acidHCID 9897Ethanol, 1-ethoxy-2,2,2-trifluoro-HCID 436571613-Fluoro-4-(1-hydroxymethyl-propylamino)-benzonitrile

Product 1

HCID 695197144-(4-Ethyl-2-trifluoromethyl-oxazolidin-3-yl)-3-fluoro-benzonitrileYield 82.4%

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent2×

Conditions

Temperature
125 °C

Procedure

A 25 mL round bottom flask fitted with a Dean-Stark trap, reflux condenser, and N2 line was charged with 245.3 mg (1.17 mmol) of 3-Fluoro-4-(1-hydroxymethyl-propylamino)-benzonitrile. p-Toluenesulfonic acid (27.4 mg, 0.144 mmol) was then added, along with trifluoroacetaldehyde ethyl hemiacetal (859.2 mg, 5.96 mmol) in 4 mL toluene. Toluene was then added to the Dean-Stark trap and the reaction was heated in an oil bath at 125° C. overnight. The reaction was cooled to room temperature, poured onto water, and the water extracted with EtOAc (2×). The organic layers were combined, washed with brine, dried (MgSO4), and concentrated. The resulting residue was purified via silica gel chromatography (10% EtOAc/Hexanes) to afford 277.8 mg (82%) of 4-(4-Ethyl-2-trifluoromethyl-oxazolidin-3-yl)-3-fluoro-benzonitrile as a mixture of diastereomers. This was dissolved in 8 mL CHCl3 (8 mL) and Et3SiH (0.62 mL, 3.88 mmol) was then added via syringe and the resulting solution was cooled to −78° C. TiCl4 (1M in dichloromethane, 1.95 mL) was then added dropwise via syringe. The reaction was slowly warmed to room temperature and stirred for 18 hours. The reaction mixture was poured onto water, and the water extracted with EtOAc (2×). The organic layers were combined, washed with brine, dried (MgSO4), and concentrated. The resulting residue was purified via silica gel chromatography (gradient from 5% EtOAc/Hexanes to 15% EtOAc/Hexanes followed by 50% EtOAc/Hexanes) to afford 99.8 mg (36% yield) of 4-(N-(2,2,2-trifluoroethyl)-N-(1-hydroxybut-2-yl)-amino)-3-fluorobenzonitrile. 1H NMR (CDCl3, 500 MHz) δ: 7.39-7.34 (m, 2H), 7.32 (m, 1H), 4.05 (m, 1H), 3.83 (m, 1H), 3.73 (m, 1H), 3.65 (m, 1H), 3.46 (m, 1H), 1.96 (m, 1H), 1.55 (m, 2H), 0.94 (t, J=7.4 Hz, 3H).

Workup

  1. customA 25 mL round bottom flask fitted with a Dean-Stark trap
  2. temperaturereflux condenser
  3. temperatureThe reaction was cooled to room temperature
  4. additionpoured onto water
  5. extractionthe water extracted with EtOAc (2×)
  6. washwashed with brine
  7. dry with materialdried (MgSO4)
  8. concentrationconcentrated
  9. customThe resulting residue was purified via silica gel chromatography (10% EtOAc/Hexanes)

Sources & evidence

ORD record
ord-eea3e31d41c44c06b6186e0facb29960
Source dataset
uspto-grants-2016_06
Patent number
US09359285B2

Linked notes

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