1-Hydroxybenzotriazole → N-[(4-carbamimidoylphenyl)methyl]-1-(4-fluorophenyl)-2,5-dimethyl-pyrrole-3-carboxamide

HRID 1500188Notes

Reaction equation

HRID 1500188 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[CH:11][C:10]([C:14]([OH:16])=O)=[C:9]2[CH3:17])=[CH:4][CH:3]=1.N=C=N.Cl.[NH2:22][CH2:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([NH2:30])=[NH:29])=[CH:26][CH:25]=1.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl.CS(C)=O>[C:28]([C:27]1[CH:31]=[CH:32][C:24]([CH2:23][NH:22][C:14]([C:10]2[CH:11]=[C:12]([CH3:13])[N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:9]=2[CH3:17])=[O:16])=[CH:25][CH:26]=1)(=[NH:29])[NH2:30]

Participants

8

Reactant 5

HCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 160435CarbodiimideHCID 50082781-(4-Fluorophenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylic acidHCID 21904871HCID 21904871, compound

Product 1

HCID 53258557N-[(4-carbamimidoylphenyl)methyl]-1-(4-fluorophenyl)-2,5-dimethyl-pyrrole-3-carboxamide

Reagents, catalysts & solvents 2

HCID 679Dimethyl SulfoxideSolvent2×HCID 6344DichloromethaneSolvent2×

Procedure

808 mg (4 mmol) of 1-(4-fluorophenyl)-2,5-dimethyl-pyrrole-3-carboxylic acid (Enamine, Kiev, Ukraine) was dissolved in 100 ml methylene chloride and 30 ml dimethyl sulfoxide, and added with stirring to 4 g of PS-carbodiimide (Biotage, Charlotte, N.C., USA), substituted at 1.33 mmol/g, wetted with 40 ml methylene chloride. 892 mg (4 mmol) of 4-(aminomethyl)benzamidine hydrochloride (Astatech, Bristol, Pa., USA), and 540 mg of HOBt were dissolved in 50 ml dimethyl sulfoxide, added to the stirred mixture, followed by 1.4 ml of diisopropylethylamine (Sigma-Aldrich). The mixture was stirred for seven days at room temperature, followed by filtration to remove the consumed resin. 50 ml of water was added to 150 ml of the filtrate, stirred vigorously for 10 minutes, then allowed to settle for 20 minutes to separate aqueous phase from the methylene chloride. The aqueous phase was carefully removed, neutralized by adding Tris base to 20 mM final concentration, then applied to a 20 ml bed volume CM-Sepharose (Sigma-Aldrich) cation-exchange column equilibriated with 20 mM Tris-HCl, pH 8. The column was washed with 40 ml of methanol and then eluted with 40 ml of 5% formic acid in methanol. The target compound was recovered as a yellowish oily solid following removal of the solvent by evaporation. The mass of the compound was verified by LC-MS/MS.

Workup

  1. additionadded to the stirred mixture
  2. filtrationfollowed by filtration
  3. customto remove the consumed resin
  4. addition50 ml of water was added to 150 ml of the filtrate
  5. stirringstirred vigorously for 10 minutes
  6. waitto settle for 20 minutes
  7. customto separate aqueous phase from the methylene chloride
  8. customThe aqueous phase was carefully removed
  9. additionby adding Tris base to 20 mM final
  10. concentrationconcentration
  11. washThe column was washed with 40 ml of methanol
  12. washeluted with 40 ml of 5% formic acid in methanol
  13. customThe target compound was recovered as a yellowish oily solid following removal of the solvent by evaporation

Sources & evidence

ORD record
ord-4c897d4bc5e643c5b53cd739d6c2fc6f
Source dataset
uspto-grants-2015_12
Patent number
US09206123B2

Reaction notes

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