1,2-Dichloroethane → 2-[4-(2,6-difluoro-benzoylamino)-1H-pyrazol-3-yl]-1H-benzimidazole-4-carboxylic acid methyl ester

HRID 1012060Notes

Reaction equation

HRID 1012060 reaction equation
[F:1][C:2]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:3]=1[CH2:4][NH:5][C:6]1[C:7]([C:11](O)=O)=[N:8][NH:9][CH:10]=1.[NH2:19][C:20]1[C:29]([NH2:30])=[CH:28][CH:27]=[CH:26][C:21]=1[C:22]([O:24][CH3:25])=[O:23].C(Cl)CCl.C1C=CC2N([OH:44])N=NC=2C=1>CN(C=O)C>[CH3:25][O:24][C:22]([C:21]1[C:20]2[N:19]=[C:11]([C:7]3[C:6]([NH:5][C:4](=[O:44])[C:3]4[C:2]([F:1])=[CH:17][CH:16]=[CH:15][C:14]=4[F:18])=[CH:10][NH:9][N:8]=3)[NH:30][C:29]=2[CH:28]=[CH:27][CH:26]=1)=[O:23]

Participants

6

Reactant 4

HCID 111,2-DichloroethaneHCID 757711-HydroxybenzotriazoleHCID 5718252,3-Diaminobenzoic acid methyl esterHCID 178524951HCID 178524951, compound

Product 1

HCID 1784975902-[4-(2,6-difluoro-benzoylamino)-1H-pyrazol-3-yl]-1H-benzimidazole-4-carboxylic acid methyl esterYield 40.7%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

A mixture of 4-(2,6-difluorobenzylamino)-1H-pyrazole-3-carboxylic acid (690 mg, 2.6 mmol) Example 16D), methyl 2,3-diaminobenzoate (415 mg, 2.6 mmol), EDC (590 mg, 3.1 mmol) and HOBt (415 mg, 3.1 mmol) in DMF (10 ml) was stirred at ambient temperature for 16 h and then reduced in vacuo. The residue was partitioned between EtOAc and brine and the organic portion dried (MgSO4), filtered, reduced then crystallised from hot EtOH. The amide intermediate (480 mg) was dissolved in AcOH (10 ml) then heated at reflux for 3 h. The reaction mixture was reduced in vacuo and then azeotroped with toluene (2×20 ml) to afford 2-[4-(2,6-difluoro-benzoylamino)-1H-pyrazol-3-yl]-1H-benzimidazole-4-carboxylic acid methyl ester (420 mg) as a fawn coloured solid. (LC/MS: Rt 3.82, [M+H]+ 398).

Workup

  1. customThe residue was partitioned between EtOAc and brine
  2. dry with materialthe organic portion dried (MgSO4)
  3. filtrationfiltered
  4. customreduced then crystallised from hot EtOH
  5. dissolutionThe amide intermediate (480 mg) was dissolved in AcOH (10 ml)
  6. temperaturethen heated
  7. temperatureat reflux for 3 h
  8. customazeotroped with toluene (2×20 ml)

Sources & evidence

ORD record
ord-e90709d967c84be6bdf1f16d4a94039b
Source dataset
uspto-grants-2011_07
Patent number
US07977477B2

Reaction notes

Loading…