Guanidine Hydrochloride → N-(diaminomethylene)-1-(2-fluorobenzyl)-2,3-dimethyl-1H-indole-5-carboxamide

HRID 1015452Notes

Reaction equation

HRID 1015452 reaction equation
[CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH3:11])=[CH:8][C:7]([C:12]([O:14]CC)=O)=[CH:6][CH:5]=2.[H-].[Na+].Br[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[F:27].C(=O)(O)[O-].[Na+].Cl.[NH2:34][C:35]([NH2:37])=[NH:36]>CN(C)C=O.O>[NH2:36][C:35]([NH2:37])=[N:34][C:12]([C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[F:27])[C:2]([CH3:1])=[C:10]2[CH3:11])=[O:14]

Participants

8

Reactant 5

HCID 5742Guanidine HydrochlorideHCID 24758Sodium hydride2×HCID 67968alpha-Bromo-o-fluorotolueneHCID 516892Sodium BicarbonateHCID 612460Ethyl 2,3-dimethyl-1H-indole-5-carboxylate

Product 1

HCID 67300777N-(diaminomethylene)-1-(2-fluorobenzyl)-2,3-dimethyl-1H-indole-5-carboxamide

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent2×

Procedure

A 10.9 mg portion of ethyl 2,3-dimethyl-1H-indole-5-carboxylate was dissolved in 0.300 ml of N,N-dimethylformamide, and 2.0 mg of sodium hydride (60% dispersion in oil) was added, followed by stirring at room temperature for 30 minutes. Then, 6.3 mg of 1-(bromomethyl)-2-fluorobenzene was added, followed by overnight stirring at room temperature. A saturated sodium bicarbonate aqueous solution was added to the reaction liquid, followed by extraction with chloroform. The solvent of the organic layer was evaporated under a reduced pressure, and the residue was dissolved in a mixed solvent of 0.50 ml tetrahydrofuran and 0.50 ml methanol. Then, 0.50 ml of a 1 M sodium hydroxide aqueous solution was added, followed by overnight stirring at 60° C. At room temperature, a 1 M hydrochloric acid aqueous solution was added to the reaction liquid to acidify the water layer, followed by extraction with chloroform. The solvent of the organic layer was evaporated under a reduced pressure, and 0.60 ml an N,N-dimethylformamide solution of 12 mg of 1,1′-carbonylbis-1H-imidazole was added to the residue, followed by stirring at 50° C. for 2 hours. A solution prepared by adding 26 mg of guanidine hydrochloride to 0.400 ml of an N,N-dimethylformamide solution of 10 mg of sodium hydride (60% dispersion in oil) and stirring at room temperature for 30 minutes was added to this reaction liquid at room temperature, followed by overnight stirring at room temperature. Water was added to the reaction liquid, followed by extraction with chloroform. The solvent of the organic layer was evaporated under a reduced pressure, and the resulting residue was purified by a fractional high performance liquid chromatography (acetonitrile/a 0.1% trifluoroacetic acid aqueous solution) to obtain 9.5 mg of N-(diaminomethylene)-1-(2-fluorobenzyl)-2,3-dimethyl-1H-indole-5-carboxamide.

Workup

  1. waitfollowed by overnight
  2. stirringstirring at room temperature
  3. extractionfollowed by extraction with chloroform
  4. customThe solvent of the organic layer was evaporated under a reduced pressure
  5. dissolutionthe residue was dissolved in a mixed solvent of 0.50 ml tetrahydrofuran and 0.50 ml methanol
  6. additionThen, 0.50 ml of a 1 M sodium hydroxide aqueous solution was added
  7. waitfollowed by overnight
  8. stirringstirring at 60° C
  9. additionAt room temperature, a 1 M hydrochloric acid aqueous solution was added to the reaction liquid
  10. extractionfollowed by extraction with chloroform
  11. customThe solvent of the organic layer was evaporated under a reduced pressure, and 0.60 ml an N,N-dimethylformamide solution of 12 mg of 1,1′-carbonylbis-1H-imidazole
  12. additionwas added to the residue
  13. stirringby stirring at 50° C. for 2 hours
  14. customA solution prepared
  15. stirringstirring at room temperature for 30 minutes
  16. additionwas added to this reaction liquid at room temperature
  17. waitfollowed by overnight
  18. stirringstirring at room temperature
  19. extractionfollowed by extraction with chloroform
  20. customThe solvent of the organic layer was evaporated under a reduced pressure
  21. customthe resulting residue was purified by a fractional high performance liquid chromatography (acetonitrile/a 0.1% trifluoroacetic acid aqueous solution)

Sources & evidence

ORD record
ord-3747734074274ab791d582bb4492278e
Source dataset
uspto-grants-2011_07
Patent number
US07985764B2

Reaction notes

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