Trifluoroacetic acid → 2-{4-[2-(2,3-dihydro-6-nitrospiro[imidazo[2,1-b]oxazole-2,4'-piperidin]-1'-yl)-2-oxoethyl]piperazin-1-yl}-N-[4-trifluoromethylphenyl]acetamide

HRID 856377Notes

Reaction equation

HRID 856377 reaction equation
[N+:1]([C:4]1[N:5]=[C:6]2[N:31]([CH:32]=1)[CH2:30][C:8]1([CH2:13][CH2:12][N:11]([C:14](=[O:29])[CH2:15][N:16]3[CH2:21][CH2:20][N:19]([C:22](OC(C)(C)C)=O)[CH2:18][CH2:17]3)[CH2:10][CH2:9]1)[O:7]2)([O-:3])=[O:2].FC(F)(F)C(O)=O.BrC[C:42]([NH:44][C:45]1[CH:50]=[CH:49][C:48]([C:51]([F:54])([F:53])[F:52])=[CH:47][CH:46]=1)=[O:43].C(N(CC)CC)C>C(Cl)Cl.O>[N+:1]([C:4]1[N:5]=[C:6]2[N:31]([CH:32]=1)[CH2:30][C:8]1([CH2:9][CH2:10][N:11]([C:14](=[O:29])[CH2:15][N:16]3[CH2:21][CH2:20][N:19]([CH2:22][C:42]([NH:44][C:45]4[CH:46]=[CH:47][C:48]([C:51]([F:52])([F:53])[F:54])=[CH:49][CH:50]=4)=[O:43])[CH2:18][CH2:17]3)[CH2:12][CH2:13]1)[O:7]2)([O-:3])=[O:2]

Participants

7

Reactant 4

HCID 6422Trifluoroacetic acidHCID 8471TriethylamineHCID 27732524-(Trifluoromethyl)-alpha-bromo-acetanilideHCID 69480722Tert-butyl 4-[2-(2,3-dihydro-6-nitrospiro[imidazo[2,1-b]oxazol-2,4'-piperidin]-1'-yl)-2-oxoethyl]piperazine-1-carboxylate

Product 1

HCID 694802082-{4-[2-(2,3-dihydro-6-nitrospiro[imidazo[2,1-b]oxazole-2,4'-piperidin]-1'-yl)-2-oxoethyl]piperazin-1-yl}-N-[4-trifluoromethylphenyl]acetamideYield 75%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6344DichloromethaneSolvent

Procedure

Tert-butyl 4-[2-(2,3-dihydro-6-nitrospiro[imidazo[2,1-b]oxazol-2,4′-piperidin]-1′-yl)-2-oxoethyl]piperazine-1-carboxylate prepared in Example 653 (300 mg, 0.67 mmol) was dissolved in methylene chloride (5 ml). To the solution, trifluoroacetic acid (10 ml) was added followed by stirring at room temperature for 6 hours. The reaction mixture was concentrated under reduced pressure. To the residue, methylene chloride (1 ml) and triethylamine (1 ml) were added followed by stirring at room temperature for 5 minutes, and then the solution was concentrated under reduced pressure. The residue was dissolved in DMF (10 ml). To the solution, 2-bromo-N-(4-trifluoromethylphenyl)acetamide (207 mg, 0.73 mmol) and triethylamine (0.28 ml, 2.0 mmol) were added followed by stirring at 100° C. for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic phase was washed with a saturated saline solution, dried over magnesium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride/methanol=100/1) and crystallized from methylene chloride-diisopropyl ether to afford 2-{4-[2-(2,3-dihydro-6-nitrospiro[imidazo[2,1-b]oxazole-2,4′-piperidin]-1′-yl)-2-oxoethyl]piperazin-1-yl}-N-[4-trifluoromethylphenyl]acetamide (275 mg, yield 75%) as a white powder.

Workup

  1. concentrationThe reaction mixture was concentrated under reduced pressure
  2. additionTo the residue, methylene chloride (1 ml) and triethylamine (1 ml) were added
  3. stirringby stirring at room temperature for 5 minutes
  4. concentrationthe solution was concentrated under reduced pressure
  5. dissolutionThe residue was dissolved in DMF (10 ml)
  6. stirringby stirring at 100° C. for 2 hours
  7. extractionextracted with ethyl acetate
  8. washThe organic phase was washed with a saturated saline solution
  9. dry with materialdried over magnesium sulfate
  10. filtrationfiltered
  11. concentrationThe resulting filtrate was concentrated under reduced pressure
  12. customthe residue was purified by silica gel column chromatography (methylene chloride/methanol=100/1)
  13. customcrystallized from methylene chloride-diisopropyl ether

Sources & evidence

ORD record
ord-a2c9861480424dc9890950a456736d64
Source dataset
uspto-grants-2007_08
Patent number
US07262212B2

Reaction notes

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