Acetyl chloride → (2S)-1-[(4-fluorophenyl)sulfonyl]-2-(5-methyl-4H-1,2,4-triazol-3-yl)piperidine

HRID 397638Notes

Reaction equation

HRID 397638 reaction equation
[C:1](Cl)(=O)[CH3:2].[F:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][C@H:16]2[C:21](=[NH:25])OCC)(=[O:14])=[O:13])=[CH:8][CH:7]=1.C(N(CC)CC)C.O.[NH2:34][NH2:35]>C1(C)C=CC=CC=1>[F:5][C:6]1[CH:7]=[CH:8][C:9]([S:12]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][C@H:16]2[C:21]2[NH:25][C:1]([CH3:2])=[N:35][N:34]=2)(=[O:13])=[O:14])=[CH:10][CH:11]=1

Participants

6

Reactant 4

HCID 6367Acetyl chlorideHCID 8471TriethylamineHCID 24654Hydrazine hydrate (1:1)HCID 57097015ethyl (2S)-1-[(4-fluorophenyl)sulfonyl]-2-piperidinecarboximidate

Product 1

HCID 178434052(2S)-1-[(4-fluorophenyl)sulfonyl]-2-(5-methyl-4H-1,2,4-triazol-3-yl)piperidine

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Procedure

Acetyl chloride (91 ml) was added to a stirred solution of ethyl (2S)-1-[(4-fluorophenyl)sulfonyl]-2-piperidinecarboximidate (288 mg) [see Preparation 41] and triethylamine (178 ml) in toluene (5 ml). The reaction mixture was stirred at room temperature for 1 hr after which time hydrazine hydrate (62 ml) was added. The mixture was stirred for 18 hrs and then poured into a column containing silica gel, and the product eluted with a solvent gradient of 1:1, by volume, ethyl acetate: hexane followed by 95:5 ethyl acetate:methanol. The fractions containing the product were combined and the solvent removed under reduced pressure, the remaining residue was dissolved in toluene (10 ml) and the reaction mixture was heated to reflux for 1 hr. Tosic acid (5 mg) was then added and the mixture was heated to reflux for a further 18 hrs. The cooled reaction mixture was then purified by column chromatography on silica gel eluting with a solvent gradient of 1:1, changing to 0:100, by volume, hexane:ethyl acetate, in 10% increments, to afford (2S)-1-[(4-fluorophenyl)sulfonyl]-2-(5-methyl-4H-1,2,4-triazol-3-yl)piperidine (60 mg) as a white solid.

Workup

  1. additionwas added
  2. additionpoured into a column
  3. additioncontaining silica gel
  4. washthe product eluted with a solvent gradient of 1:1, by volume, ethyl acetate
  5. additionThe fractions containing the product
  6. customthe solvent removed under reduced pressure
  7. dissolutionthe remaining residue was dissolved in toluene (10 ml)
  8. temperaturethe reaction mixture was heated
  9. temperatureto reflux for 1 hr
  10. additionTosic acid (5 mg) was then added
  11. temperaturethe mixture was heated
  12. temperatureto reflux for a further 18 hrs
  13. customThe cooled reaction mixture
  14. customwas then purified by column chromatography on silica gel eluting with a solvent gradient of 1:1

Sources & evidence

ORD record
ord-9b6669813f3f45df8f49c7cb79a761e3
Source dataset
uspto-grants-2003_08
Patent number
US06610707B1

Reaction notes

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