p-Toluenesulfonic acid → N-(4-Methoxybenzyl)-4-chloro-2-(trifluoroacetyl)aniline

HRID 1838026Notes

Reaction equation

HRID 1838026 reaction equation
O.Cl.[Cl:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[C:6]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH:5]=1.[OH-].[Na+].[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]O)=[CH:23][CH:22]=1.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.O.O.C1(C)C=CC=CC=1>[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH:8][C:7]2[CH:9]=[CH:10][C:4]([Cl:3])=[CH:5][C:6]=2[C:11](=[O:16])[C:12]([F:14])([F:15])[F:13])=[CH:23][CH:22]=1

Participants

8

Reactant 4

HCID 6101p-Toluenesulfonic acidHCID 77384-Methoxybenzyl alcoholHCID 14798Sodium HydroxideHCID 441819891-(2-Amino-5-chlorophenyl)-2,2,2-trifluoroethan-1-one--hydrogen chloride--water (1/1/1)

Product 1

HCID 11089189N-(4-Methoxybenzyl)-4-chloro-2-(trifluoroacetyl)aniline

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 1140TolueneSolventHCID 22272177Toluene waterSolvent

Procedure

To a slurry of 4-Chloro-2-trifluoroacetylaniline, hydrochloride hydrate (40.0 kg, 144 mol) in toluene (140 kg) and water (50 L) was added 30% NaOH (18 kg) to pH 7.0. After removing the aqueous phase, 4-methoxybenzyl alcohol (20 kg, 144 mol) and TsOH (1.0 kg, 5.3 mol) were added. The solution was heated to reflux and the water/toluene azeotrope (30 L) distilled. The solution was cooled to room temperature and washed with saturated brine (80 kg). The organic solution was concentrated in vacuo to a volume of 35-40 L, then diluted with THF (52 kg). The weight percent of the title compound in toluene/THF was calculated by HPLC to be 43%. The yield based on HPLC weight % analysis was 47.7 kg (96%). An analytical sample was obtained by removing the solvent in vacuo and recrystallizing from heptane: mp 82-84° C.; 1H NMR (300 MHz, CDCl3) δ 9.04 (s,1H), 7.74 (d, J=2 Hz, 1H), 7.35 (dd, J=2, 9 Hz), 7.24 (d, J=8 Hz, 2H), 6.91 (d, J=8 Hz, 2H), 6.75 (d, J=9 Hz, 1H), 4.43 (d, J=6 Hz, 2H), 3.79 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 180.5, 159.2, 151.9, 137.4, 130.8, 128.9, 128.4, 119.9,117.0, 114.5, 114.4, 111.3, 55.3, 46.6.

Workup

  1. additionwere added
  2. temperatureThe solution was heated
  3. temperatureto reflux
  4. distillationdistilled
  5. washwashed with saturated brine (80 kg)
  6. concentrationThe organic solution was concentrated in vacuo to a volume of 35-40 L
  7. additiondiluted with THF (52 kg)
  8. customAn analytical sample was obtained
  9. customby removing the solvent in vacuo
  10. customrecrystallizing from heptane

Sources & evidence

ORD record
ord-2dd414432abe44c4907f3f6178e3f64a
Source dataset
uspto-grants-2004_01
Patent number
US06673372B1

Reaction notes

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