Dimethylformamide → 1-{2-[3-(4-Chlorophenyl)-[1,2,4]oxadiazol-5-ylmethyl]-3,3,3-trifluoro-propyl}-3-(3-trifluoromethyl-phenyl)-piperidine hydrochloride

HRID 1051403Notes

Reaction equation

HRID 1051403 reaction equation
[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:35][OH:36])[NH:9][C:10](=O)[CH2:11][CH:12](CN2CCCC(C3C=CC=C(C(F)(F)F)C=3)C2)[C:13]([F:16])([F:15])[F:14])=[CH:4][CH:3]=1.[CH3:37][N:38]([CH:40]=O)[CH3:39].[CH3:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47]>[Cl-].[Na+].O.O.O1CCOCC1>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([CH2:11][CH:12]([C:13]([F:14])([F:15])[F:16])[CH2:40][N:38]3[CH2:37][CH2:42][CH2:43][CH:44]([C:45]4[CH:7]=[CH:2][CH:3]=[C:47]([C:13]([F:16])([F:15])[F:14])[CH:46]=4)[CH2:39]3)[O:36][N:35]=2)=[CH:6][CH:7]=1

Participants

6

Reactant 3

HCID 6228DimethylformamideHCID 8058HexaneHCID 137210851N-((4-chlorophenyl)(hydroxyimino)methyl)-4,4,4-trifluoro-3-((3-(3-(trifluoromethyl)phenyl)piperidin-1-yl)methyl)butanamide

Product 1

HCID 752013751-{2-[3-(4-Chlorophenyl)-[1,2,4]oxadiazol-5-ylmethyl]-3,3,3-trifluoro-propyl}-3-(3-trifluoromethyl-phenyl)-piperidine hydrochlorideYield 41%

Reagents, catalysts & solvents 2

HCID 312751,4-DioxaneSolventHCID 23713072Sodium chloride dihydrateSolvent

Conditions

Temperature
120 °C

Procedure

In a 5 mL sealed tube, N-((4-chlorophenyl)(hydroxyimino)methyl)-4,4,4-trifluoro-3-((3-(3-(trifluoromethyl)phenyl)piperidin-1-yl)methyl)butanamide (30 mg, 56.0 μmol) was combined with DMF (2 ml) and heated at 120° C. for 3 hr. The reaction mixture was diluted with 30 ml of brine/water (1:1) and extracted with ether (2×30 ml). The combined organic layer was washed with brine and water, dried with MgSO4, filtered and concentrated in vacuo to give an oil. This crude material was purified by flash chromatography (silica gel, 12 g, 0% to 30% ethyl acetate in hexanes gradient) to afford an oil. This oil was treated with 4NHCl in dioxane and hexane and concentrated to give 14 mg (41%) of 1-{2-[3-(4-chlorophenyl)-[1,2,4]oxadiazol-5-ylmethyl]-3,3,3-trifluoro-propyl}-3-(3-trifluoromethyl-phenyl)-piperidine hydrochloride as a viscous solid. This solid was a 1:1 mixture of diastereomers by LCMS (MS of each peak showed MH+=518).

Workup

  1. customIn a 5 mL sealed tube
  2. extractionextracted with ether (2×30 ml)
  3. washThe combined organic layer was washed with brine and water
  4. dry with materialdried with MgSO4
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo
  7. customto give an oil
  8. customThis crude material was purified by flash chromatography (silica gel, 12 g, 0% to 30% ethyl acetate in hexanes gradient)
  9. customto afford an oil
  10. concentrationconcentrated

Sources & evidence

ORD record
ord-17847cdcdf834128ba2cfd6d2d83889a
Source dataset
uspto-grants-2016_07
Patent number
US09388172B2

Reaction notes

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