Trifluoroacetic acid → (S)-[4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazin-1-yl]-[4-(4-trifluoromethylphenyl)piperidin-1-yl]methanone

HRID 856332Notes

Reaction equation

HRID 856332 reaction equation
[CH3:1][C@@:2]1([CH2:13][N:14]2[CH2:19][CH2:18][N:17]([C:20](OC(C)(C)C)=[O:21])[CH2:16][CH2:15]2)[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1.FC(F)(F)C(O)=O.C(N(CC)CC)C.C(=O)([O-])[O-].[K+].[K+].[F:47][C:48]([F:65])([F:64])[C:49]1[CH:54]=[CH:53][C:52]([CH:55]2[CH2:60][CH2:59][N:58](C(Cl)=O)[CH2:57][CH2:56]2)=[CH:51][CH:50]=1>CN(C=O)C.O.C(Cl)Cl>[CH3:1][C@@:2]1([CH2:13][N:14]2[CH2:15][CH2:16][N:17]([C:20]([N:58]3[CH2:59][CH2:60][CH:55]([C:52]4[CH:53]=[CH:54][C:49]([C:48]([F:47])([F:64])[F:65])=[CH:50][CH:51]=4)[CH2:56][CH2:57]3)=[O:21])[CH2:18][CH2:19]2)[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1

Participants

9

Reactant 5

HCID 6422Trifluoroacetic acidHCID 8471TriethylamineHCID 11430Potassium CarbonateHCID 230815264-(4-Trifluoromethylphenyl)-piperidine-1-carbonylchlorideHCID 69635111tert-butyl (S)-4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazine-1-carboxylate

Product 1

HCID 69479825(S)-[4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazin-1-yl]-[4-(4-trifluoromethylphenyl)piperidin-1-yl]methanoneYield 33.1%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent

Procedure

A mixture of tert-butyl (S)-4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)-piperazine-1-carboxylate prepared in Example 393 (1.17 g, 3.32 mmol), trifluoroacetic acid (5 ml) and methylene chloride (10 ml) was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in methylene chloride (10 ml). To the resulting solution, triethylamine (5 ml, 35.87 mmol) was added followed by stirring at room temperature for 10 minutes. The solution was concentrated under reduced pressure, the residue was dissolved in DMF (15 ml). To the mixture, potassium carbonate (920 mg, 6.64 mmol) and a solution of 4-(4-trifluoromethylphenyl)-piperidine-1-carbonylchloride (1.07 g, 3.65 mmol) in DMF (10 ml) was added slowly with cooling on ice-bath followed by stirring at room temperature overnight. To the reaction mixture, water was added followed by extraction with ethyl acetate. The extract was washed with water three times and a saturated saline solution, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride/methanol=30/1) to afford (S)-[4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazin-1-yl]-[4-(4-trifluoromethylphenyl)piperidin-1-yl]methanone (575 mg, yield 33%) as a white powder.

Workup

  1. concentrationThe reaction mixture was concentrated under reduced pressure
  2. dissolutionthe residue was dissolved in methylene chloride (10 ml)
  3. stirringby stirring at room temperature for 10 minutes
  4. concentrationThe solution was concentrated under reduced pressure
  5. dissolutionthe residue was dissolved in DMF (15 ml)
  6. temperaturewith cooling on ice-bath
  7. stirringby stirring at room temperature overnight
  8. extractionfollowed by extraction with ethyl acetate
  9. washThe extract was washed with water three times
  10. dry with materiala saturated saline solution, dried over sodium sulfate
  11. filtrationfiltered
  12. concentrationThe filtrate was concentrated under reduced pressure
  13. customthe residue was purified by silica gel column chromatography (methylene chloride/methanol=30/1)

Sources & evidence

ORD record
ord-4996a99965a049828fd534e4d1b38d1d
Source dataset
uspto-grants-2007_08
Patent number
US07262212B2

Reaction notes

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