Methanol → (7R)-1-[(3,4-dichlorophenyl)methyl]-2-(1-methylethyl)-4,5,6,7-tetrahydro-1H-benzimidazol-7-ol

HRID 1946544Notes

Reaction equation

HRID 1946544 reaction equation
Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH2:10][N:11]2[C:15]3[C:16](=[O:20])[CH2:17][CH2:18][CH2:19][C:14]=3[N:13]=[C:12]2[CH:21]([CH3:23])[CH3:22])[CH:6]=[CH:7][C:8]=1[Cl:9].B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@H]2N1CCC2.B.CO>O1CCCC1>[Cl:2][C:3]1[CH:4]=[C:5]([CH2:10][N:11]2[C:15]3[C@H:16]([OH:20])[CH2:17][CH2:18][CH2:19][C:14]=3[N:13]=[C:12]2[CH:21]([CH3:23])[CH3:22])[CH:6]=[CH:7][C:8]=1[Cl:9]

Participants

6

Reactant 4

HCID 887MethanolHCID 6331BoraneHCID 2734713(3aS)-1-methyl-3,3-diphenyl-hexahydropyrrolo(1,2-c)(1,3,2)oxazaboroleHCID 674352173-[(3,4-dichlorophenyl)methyl]-2-(1-methylethyl)-3,5,6,7-tetrahydro-4H-benzimidazol-4-one hydrochloride

Product 1

HCID 58460177(7R)-1-[(3,4-dichlorophenyl)methyl]-2-(1-methylethyl)-4,5,6,7-tetrahydro-1H-benzimidazol-7-ol

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
0 °C

Procedure

Intermediate 85 (900 g, 1.0 eq, 1.0 wt) was charged to a solution of (S)-(−)-2-methyl-CBS-oxazaborolidine (198 g, 0.3 eq, 0.22 wt) in tetrahydrofuran (3.6 L, 4 vol) at 20° C., followed by a line rinse with tetrahydrofuran (0.9 L, 1 vol). The suspension was cooled to 0° C. and chilled (0° C.) 1M borane in tetrahydrofuran solution (4.82 L, 2 eq 5.35 vol) was added over 1 hour 35 minutes at <3° C. The mixture was stirred at 0° C. for 1 hour 20 minutes when complete dissolution was observed and sampled for completion by HPLC. Reaction was complete. The mixture was added into chilled (0° C.) methanol (3.6 L, 4 vol) at <5° C. over 40 minutes, followed by a line rinse with methanol (0.9 L, 1 vol). The mixture was warmed to 20° C. and stirred at this temperature for 1 hour 15 minutes when effervescence had ceased. Water (2.7 L, 3 vol) was added, followed by the addition of 5M aqueous hydrochloric acid (0.9 L, 1 vol) at <10° C. over 10 minutes. The mixture was warmed to 20° C. and stirred at this temperature for 1 hour when effervescence had ceased. To the mixture was added 48% w/w aqueous sodium hydroxide (0.99 L, 1.1 vol) at <30° C. over 15 minutes and the mixture stirred vigorously for 10 minutes at 20° C. The basic aqueous layer was separated. The organic phase was diluted with isopropylacetate (3.6 L, 4 vol) and washed with water (2.7 L, 3 vol). The aqueous phase was separated and the organic phase was concentrated by vacuum (100-200 mbar) distillation to 3.6 L/4 vol at 25° C. To the mixture was added isopropylacetate (5.4 L, 6 vol), followed by water (6 L, 6.7 vol) and the mixture stirred vigorously for 10 minutes at 20° C. The aqueous phase was separated and the organic phase was concentrated by vacuum distillation on a rotary evaporator. The solids were slurried in heptane (9 L, 10 vol) on the rotary evaporator at 40 C for 1 hour and stirred at this temperature for 16 hours. The solids were collected by vacuum filtration, washed with heptane (2×0.9 L, 2×1 vol) and dried in vacuo at 40° C. for 23 hours 30 minutes. Yield of the title compound obtained was 739 g/90% theory yield/82% w/w yield.

Workup

  1. washrinse with tetrahydrofuran (0.9 L, 1 vol)
  2. additionwas added over 1 hour 35 minutes at <3° C
  3. dissolutionwhen complete dissolution
  4. aliquotsampled for completion by HPLC
  5. customReaction
  6. additionThe mixture was added
  7. washrinse with methanol (0.9 L, 1 vol)
  8. temperatureThe mixture was warmed to 20° C.
  9. stirringstirred at this temperature for 1 hour 15 minutes when effervescence
  10. additionWater (2.7 L, 3 vol) was added
  11. additionfollowed by the addition of 5M aqueous hydrochloric acid (0.9 L, 1 vol) at <10° C. over 10 minutes
  12. temperatureThe mixture was warmed to 20° C.
  13. stirringstirred at this temperature for 1 hour when effervescence
  14. additionTo the mixture was added 48% w/w aqueous sodium hydroxide (0.99 L, 1.1 vol) at <30° C. over 15 minutes
  15. stirringthe mixture stirred vigorously for 10 minutes at 20° C
  16. customThe basic aqueous layer was separated
  17. additionThe organic phase was diluted with isopropylacetate (3.6 L, 4 vol)
  18. washwashed with water (2.7 L, 3 vol)
  19. customThe aqueous phase was separated
  20. concentrationthe organic phase was concentrated by vacuum (100-200 mbar) distillation to 3.6 L/4 vol at 25° C
  21. additionTo the mixture was added isopropylacetate (5.4 L, 6 vol)
  22. stirringthe mixture stirred vigorously for 10 minutes at 20° C
  23. customThe aqueous phase was separated
  24. concentrationthe organic phase was concentrated by vacuum distillation on a rotary evaporator
  25. customThe solids were slurried in heptane (9 L, 10 vol) on the rotary evaporator at 40 C for 1 hour
  26. stirringstirred at this temperature for 16 hours
  27. filtrationThe solids were collected by vacuum filtration
  28. washwashed with heptane (2×0.9 L, 2×1 vol)
  29. customdried in vacuo at 40° C. for 23 hours 30 minutes

Sources & evidence

ORD record
ord-100f1d5c92134654ba59cb7576e643d4
Source dataset
uspto-grants-2013_03
Patent number
US08399444B2

Reaction notes

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