1h-Benzimidazole-1-carboxylic acid,4-(azidomethyl)-,1,1-dimethylethyl ester → 2-Chloro-4-[[[[1-[(1,1-dimethylethoxy)carbonyl]benzimidazol-4-yl]methyl]amino]carbonyl]benzoic acid, methyl ester

HRID 393036Notes

Reaction equation

HRID 393036 reaction equation
[N:1]([CH2:4][C:5]1[C:13]2[N:12]=[CH:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:9]=2[CH:8]=[CH:7][CH:6]=1)=[N+]=[N-].[Cl:21][C:22]1[CH:23]=[C:24]([CH:35]=[CH:36][C:37]=1[C:38]([O:40][CH3:41])=[O:39])[C:25](ON1C(=O)CCC1=O)=[O:26]>[Pd].CO.C1C=CC=CC=1>[Cl:21][C:22]1[CH:23]=[C:24]([C:25]([NH:1][CH2:4][C:5]2[C:13]3[N:12]=[CH:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:9]=3[CH:8]=[CH:7][CH:6]=2)=[O:26])[CH:35]=[CH:36][C:37]=1[C:38]([O:40][CH3:41])=[O:39]

Participants

6

Reactant 2

HCID 207147611h-Benzimidazole-1-carboxylic acid,4-(azidomethyl)-,1,1-dimethylethyl esterHCID 235607681-[[3-Chloro-4-(methoxycarbonyl)benzoyl]oxy]-2,5-pyrrolidinedione

Product 1

HCID 865851472-Chloro-4-[[[[1-[(1,1-dimethylethoxy)carbonyl]benzimidazol-4-yl]methyl]amino]carbonyl]benzoic acid, methyl esterYield 66.3%

Reagents, catalysts & solvents 3

HCID 23938PalladiumCatalystHCID 241BenzeneSolventHCID 887MethanolSolvent

Procedure

A mixture of 4-(azidomethyl)benzimidazole-1-carboxylic acid, 1,1-dimethylethyl ester (Example 13; 1.40, 5.1 mmol), 1-[[3-chloro-4-(methoxycarbonyl)benzoyl]oxy]-2,5-pyrrolidinedione (Example 5; 1.62 g, 5.2 mmol), and 10% palladium on charcoal (210 mg) in methanol (40 mL) and benzene (2 mL) was hydrogenated at atmospheric pressure for 105 min and then filtered through Celite. Tlc indicated that the reaction was not complete so more 10% palladium on charcoal (210 mg) was added and the mixture was hydrogenated at atmospheric pressure for 3 h and then shaken at 50 psi of hydrogen for 3 h. The reaction mixture was allowed to stand under hydrogen for 12 h, then filtered through Celite, evaporated, and chromatographed (20-100% ethyl acetate/hexanes) to give 2-chloro-4-[[[[1-[(1,1-dimethylethoxy)carbonyl]benzimidazol-4-yl]methyl]amino]carbonyl]benzoic acid, methyl ester (1.50 g, 66%). A solution of the ester (1.45 g, 3.3 mmol) in methanol (15 mL) and 3 M lithium hydroxide solution (5.5 mL) was stirred at room temperature overnight. A white solid was filtered off and discarded. The filtrate was evaporated to dryness. Water and 1 M HCl (16.6 mL) were added, and the mixture was filtered and washed with water to give 2-chloro-4-[[[(benzimidazol-4-yl)methyl]amino]carbonyl]-benzoic acid (925 mg, 86%).

Workup

  1. filtrationfiltered through Celite
  2. additionwas added
  3. waitthe mixture was hydrogenated at atmospheric pressure for 3 h
  4. waitto stand under hydrogen for 12 h
  5. filtrationfiltered through Celite
  6. customevaporated
  7. customchromatographed (20-100% ethyl acetate/hexanes)

Sources & evidence

ORD record
ord-0e51d088e53d4705836d3825c43f3b9f
Source dataset
uspto-grants-2004_10
Patent number
US06803384B2

Reaction notes

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