3-Chloro-2-methylaniline → N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-nitro-1H-benzimidazole-4-carboxamide

HRID 1505786Notes

Reaction equation

HRID 1505786 reaction equation
[CH3:1][O:2][CH2:3][C:4]1[NH:8][C:7]2[CH:9]=[C:10]([N+:16]([O-:18])=[O:17])[CH:11]=[C:12]([C:13]([OH:15])=O)[C:6]=2[N:5]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:43][C:44]1[C:45]([CH3:51])=[C:46]([CH:48]=[CH:49][CH:50]=1)[NH2:47].C(=O)(O)[O-].[Na+]>CN(C=O)C.C(N(CC)CC)C>[Cl:43][C:44]1[C:45]([CH3:51])=[C:46]([NH:47][C:13]([C:12]2[C:6]3[N:5]=[C:4]([CH2:3][O:2][CH3:1])[NH:8][C:7]=3[CH:9]=[C:10]([N+:16]([O-:18])=[O:17])[CH:11]=2)=[O:15])[CH:48]=[CH:49][CH:50]=1

Participants

7

Reactant 4

HCID 68943-Chloro-2-methylanilineHCID 516892Sodium BicarbonateHCID 2733084Methanaminium, N-((1H-benzotriazol-1-yloxy)(dimethylamino)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 902293352-(methoxymethyl)-6-nitro-1H-benzimidazole-4-carboxylic acid

Product 1

HCID 90229481N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-nitro-1H-benzimidazole-4-carboxamideYield 104.9%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8471TriethylamineSolvent

Procedure

To a suspension of methyl 2-(methoxymethyl)-6-nitro-1H-benzimidazole-4-carboxylate (Example 11, Step 3) (4.8 g) in MeOH (120 mL), were added lithium hydroxide hydrate (4.56 g) and water (54 mL). The mixture was stirred at room temperature for 16 hours. Under ice-cooling, 1N hydrochloric acid was added slowly to the reaction mixture to adjust the pH to about 2. The precipitate was collected by filtration and dried to obtain 2-(methoxymethyl)-6-nitro-1H-benzimidazole-4-carboxylic acid (4.6 g). To the solution of 2-(methoxymethyl)-6-nitro-1H-benzimidazole-4-carboxylic acid (4.6 g) in DMF (90 mL), HBTU (8.23 g), triethylamine (2.19 g) and 3-chloro-2-methylaniline (3.07 g) were added sequentially, and the solution was stirred for 18 hours. The reaction mixture was poured into saturated aqueous sodium bicarbonate and stirred for 1 hour. The precipitate was collected by filtration and washed sequentially with water and ethyl acetate to obtain N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-nitro-1H-benzimidazole-4-carboxamide (7.2 g) as pale yellow powder. To the solution of N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-nitro-1H-benzimidazole-4-carboxamide (7.2 g) in MeOH-THF (1:1, 120 mL), were added 1% platinum+0.1% copper-activated carbon (Degussa type CF105 R/W) (1.4 g). The mixture was stirred under hydrogen atmosphere (3 atm) for 4 hours. The catalyst was filtered off, and the mother liquid was concentrated. The residual solid was washed with ethyl acetate to obtain 6-amino-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide (5.1 g) as pale yellow powder.

Workup

  1. stirringstirred for 1 hour
  2. filtrationThe precipitate was collected by filtration
  3. washwashed sequentially with water and ethyl acetate

Sources & evidence

ORD record
ord-0d4d561c015b4e2aaf10fbd92b8d1ae6
Source dataset
uspto-grants-2015_12
Patent number
US09216968B2

Reaction notes

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