Hydrochloric Acid → 3-[(3,4-dichlorophenyl)methyl]-2-(1-methylethyl)-3,5,6,7-tetrahydro-4H-benzimidazol-4-one hydrochloride

HRID 1946543Notes

Reaction equation

HRID 1946543 reaction equation
Cl.[CH3:2][CH:3]([C:5]1[NH:9][C:8]2[CH2:10][CH2:11][CH2:12][C:13](=[O:14])[C:7]=2[N:6]=1)[CH3:4].[Cl:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH2:19]Br.[OH-].[Na+].Cl.CC(O)C>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[ClH:15].[Cl:15][C:16]1[CH:17]=[C:18]([CH2:19][N:6]2[C:7]3[C:13](=[O:14])[CH2:12][CH2:11][CH2:10][C:8]=3[N:9]=[C:5]2[CH:3]([CH3:2])[CH3:4])[CH:21]=[CH:22][C:23]=1[Cl:24]

Participants

8

Reactant 5

HCID 313Hydrochloric AcidHCID 3776IsopropanolHCID 14798Sodium HydroxideHCID 6397264-(Bromomethyl)-1,2-dichlorobenzeneHCID 1317303002-(1-methylethyl)-1,5,6,7-tetrahydro-4H-benzimidazol-4-one, hydrochloride

Product 1

HCID 674352173-[(3,4-dichlorophenyl)methyl]-2-(1-methylethyl)-3,5,6,7-tetrahydro-4H-benzimidazol-4-one hydrochloride

Reagents, catalysts & solvents 2

HCID 74236Tetrabutylammonium BromideCatalystHCID 1140TolueneSolvent

Conditions

Temperature
20 °C

Procedure

To a mixture of Intermediate 84 (1000 g, 1.0 eq, 1.0 wt) and tetrabutylammonium bromide (300 g, 0.2 eq, 0.3 wt) in toluene (9.5 L, 9.5 vol) was added 3,4-dichlorobenzyl bromide (0.71 L, 1.05 eq, 0.71 vol), followed by a line rinse with toluene (0.5 L, 0.5 vol). 5M sodium hydroxide (5 L, 5.36 eq, 5 vol) was added and the biphasic mixture was stirred vigorously for 4 hours 30 minutes at 20° C. and sampled for completion by HPLC. Reaction was complete at 3 hours 30 minutes. The mixture was settled and separated. The aqueous phase was back-extracted with toluene (5 L, 5 vol). The combined organic phases were washed with water (2×2 L, 2×2 vol) and concentrated by atmospheric distillation to 3.4 L/3.4 vol. The mixture was cooled to 20° C. over 30 minutes and diluted with propan-2-ol (10 L, 10 vol). 5-6M hydrochloric acid in propan-2-ol (1.4 L, 1.5 eq, 1.40 vol) was added over 10 minutes at 55° C. The solution was stirred at 60° C. for 20 minutes and seeded with a sample of the title compound (0.4 g, 0.0004 wt). The slurry was aged at 60° C. for 30 minutes, cooled to 3° C. over 3 hours 15 minutes and stirred at this temperature for 1 hour 30 minutes. Solids were collected by vacuum filtration, washed with chilled (5° C.) propan-2-ol/toluene (6 L, 5:1 v/v, 6 vol), followed by tert-butylmethylether (2×5 L, 2×5 vol) and dried in vacuo at 40° C. for 16 hours 30 minutes. Yield of the title compound obtained was 1497 g/86% theory yield/150% w/w yield.

Workup

  1. washrinse with toluene (0.5 L, 0.5 vol)
  2. aliquotsampled for completion by HPLC
  3. customReaction
  4. waitwas complete at 3 hours 30 minutes
  5. customseparated
  6. extractionThe aqueous phase was back-extracted with toluene (5 L, 5 vol)
  7. washThe combined organic phases were washed with water (2×2 L, 2×2 vol)
  8. concentrationconcentrated by atmospheric distillation to 3.4 L/3.4 vol. The mixture
  9. temperaturewas cooled to 20° C. over 30 minutes
  10. additiondiluted with propan-2-ol (10 L, 10 vol)
  11. stirringThe solution was stirred at 60° C. for 20 minutes

Sources & evidence

ORD record
ord-fefa511c5aa242ada5938cd5af60c6eb
Source dataset
uspto-grants-2013_03
Patent number
US08399444B2

Reaction notes

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