1,8-Diazabicyclo(5.4.0)undec-7-ene → FK-614

HRID 48252Notes

Reaction equation

HRID 48252 reaction equation
[Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[C:11]([C:14]([OH:16])=O)[CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[CH3:17].[CH2:23]([S:28]([NH2:31])(=[O:30])=[O:29])[CH2:24][CH2:25][CH2:26][CH3:27].C1CCN2C(=NCCC2)CC1>CN(C)C=O>[Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[C:11]([C:14]([NH:31][S:28]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])(=[O:30])=[O:29])=[O:16])[CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[CH3:17]

Participants

5

Reactant 3

HCID 811841,8-Diazabicyclo(5.4.0)undec-7-eneHCID 109206961-PentanesulfonamideHCID 225088211-(2,4-Dichlorobenzyl)-2-methyl-1H-benzo[d]imidazole-6-carboxylic acid

Product 1

HCID 9869229FK-614

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
40 °C

Procedure

A mixture of 3-(2,4-dichlorobenzyl)-2-methyl-3H-benzimidazole-5-carboxylic acid (34.1 g, 102 mmol), N,N′-carbonyldiimidazole (21.4 g) and N,N-dimethylformamide (122.7 g) was stirred for one hour at 35° C., into which 1-pentanesulfonamide (20.0 g) and 1,8-diazabicyclo[5.4.0]-7-undecene (20.1 g) were then added, and stirred for 6 hours at 40° C. After the reaction, a portion of N,N-dimethylformamide (62.9 g) was distilled off in vacuo, and, to the residue were added methanol (227.8 g) and water (227.8 g). This solution contained 1,8-diazabicyclo[5.4.0]-7-undecene and imidazole generated from N,N′-carbonyldiimidazole as the bases. This solution was filtered to remove insoluble materials, and the filtrate was heated to 50° C., and conc. hydrochloric acid (20.4 g) was added drop-wise thereto over one hour. After the dropping, crystal form B of 3-(2,4-dichlorobenzyl)-2-methyl-N-(pentylsulfonyl)-3H-benzimidazole-5-carboxamide (119 mg) was added as seed crystal, and the mixture was allowed to be ripen for 2 hours. After the ripening, conc. hydrochloric acid (15.5 g) was further added drop-wise thereto over 2 hours. The slurry was ripened for one hour at 50° C. and cooled down to 30° C., and then the crystals were collected by filtration. The crystals were washed with a mixed solvent of methanol (120 g) and water (120 g), and vacuum-dried to obtain crystal form B of 3-(2,4-dichlorobenzyl)-2-methyl-N-(pentylsulfonyl)-3H-benzimidazole-5-carboxamide.

Workup

  1. additionwere then added
  2. customAfter the reaction
  3. distillationa portion of N,N-dimethylformamide (62.9 g) was distilled off in vacuo
  4. additionto the residue were added methanol (227.8 g) and water (227.8 g)
  5. filtrationThis solution was filtered
  6. customto remove insoluble materials
  7. temperaturethe filtrate was heated to 50° C.
  8. additionconc. hydrochloric acid (20.4 g) was added drop-wise
  9. waitover one hour
  10. additionAfter the dropping, crystal form B of 3-(2,4-dichlorobenzyl)-2-methyl-N-(pentylsulfonyl)-3H-benzimidazole-5-carboxamide (119 mg) was added as seed crystal
  11. waitto be ripen for 2 hours
  12. additionAfter the ripening, conc. hydrochloric acid (15.5 g) was further added drop-wise
  13. waitover 2 hours
  14. waitThe slurry was ripened for one hour at 50° C.
  15. temperaturecooled down to 30° C.
  16. filtrationthe crystals were collected by filtration
  17. washThe crystals were washed with a mixed solvent of methanol (120 g) and water (120 g)
  18. customvacuum-dried

Sources & evidence

ORD record
ord-5cdfee7b8f034ebebcc2352ffdfb02eb
Source dataset
uspto-grants-2004_03
Patent number
US06703410B1

Reaction notes

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