p-Toluenesulfonic acid → Ro4368554

HRID 1005665Notes

Reaction equation

HRID 1005665 reaction equation
[C:1]1([S:7]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)[C:12]=2[NH2:24])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:25]1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[K+].[Cl-].[NH4+]>C(OC)(OC)OC.CCOC(C)=O>[C:1]1([S:7]([C:10]2[C:11]3[C:12](=[C:13]([N:17]4[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]4)[CH:14]=[CH:15][CH:16]=3)[NH:24][CH:25]=2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1

Participants

7

Reactant 4

HCID 6101p-Toluenesulfonic acidHCID 14797Potassium HydroxideHCID 25517Ammonium ChlorideHCID 60108777HCID 60108777, compound

Product 1

HCID 6918682Ro4368554Yield 767.1%

Reagents, catalysts & solvents 2

HCID 8857Ethyl AcetateSolventHCID 9005Trimethyl orthoformateSolvent

Conditions

Temperature
60 °C

Procedure

To a solution of 2.3 g of 2-benzenesulfonylmethyl-6-(4-methyl-piperazin-1-yl)-phenylamine in 20 mL trimethyl orthoformate was added p-toluenesulfonic acid (120 mg). The mixture was heated under reflux in a nitrogen atmosphere for 2 hours. The mixture was cooled to 60° C. and one flake of KOH was added. The mixture was reheated to reflux for 1.5 hours. The heating oil bath was turned off and the mixture stirred overnight under nitrogen. The mixture was treated with 50 mL saturated ammonium chloride solution and 100 mL EtOAc. The purple organic layer was separated from the clear aqueous solution, and washed with water (45 mL) and evaporated to a foam. This foam was dissolved in 80 mL 200 proof EtOH. After dissolution, the freebase crystallized. This mixture was heated under reflux to redissolve the solid, and after removal of the heating, 5 mL of a saturated solution of HCl in ethanol was added to this mixture. The mixture was cooled with stirring to room temperature and seeded to ensue immediate crystallization. The mixture was concentrated to ca. 40 mL and filtered. This collected solid was washed with ca. 3 mL EtOH and vacuum oven dried at 50° C. to give 1.9 g 3-benzenesulfonyl-7-(4-methyl-piperazin-1-yl)-1H-indole (501) mp 160-162° C.

Workup

  1. temperatureThe mixture was heated
  2. temperatureunder reflux in a nitrogen atmosphere for 2 hours
  3. temperatureto reflux for 1.5 hours
  4. customThe purple organic layer was separated from the clear aqueous solution
  5. washwashed with water (45 mL)
  6. customevaporated to a foam
  7. dissolutionThis foam was dissolved in 80 mL 200 proof EtOH
  8. dissolutionAfter dissolution
  9. temperatureThis mixture was heated
  10. temperatureunder reflux
  11. dissolutionto redissolve the solid
  12. customafter removal of the heating, 5 mL of a saturated solution of HCl in ethanol
  13. additionwas added to this mixture
  14. temperatureThe mixture was cooled
  15. stirringwith stirring to room temperature
  16. customcrystallization
  17. concentrationThe mixture was concentrated to ca. 40 mL
  18. filtrationfiltered
  19. washThis collected solid was washed with ca. 3 mL EtOH and vacuum oven
  20. customdried at 50° C.

Sources & evidence

ORD record
ord-4424197ed9454bfe80bd8bf167958a40
Source dataset
uspto-grants-2004_09
Patent number
US06787535B2

Reaction notes

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