Dimethylformamide → 4-Trifluromethylbenzyl 4-[2-(2,3-dihydro-6-nitrospiro[imidazo[2,1-b]oxazole-2,4'-piperidin]-1'-yl)-2-oxoethyl]piperazine-1-carboxylate

HRID 856374Notes

Reaction equation

HRID 856374 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]([O:24]C(C)(C)C)=[O:23])[CH2:18][CH2:17]3)[CH2:10][CH2:9]1)[O:7]2)([O-:3])=[O:2].[F:33][C:34]([F:44])([F:43])[C:35]1[CH:42]=[CH:41][C:38]([CH2:39]O)=[CH:37][CH:36]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.CN(C=O)C>C(Cl)Cl.FC(F)(F)C(O)=O.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]([C:22]([O:24][CH2:39][C:38]4[CH:37]=[CH:36][C:35]([C:34]([F:33])([F:43])[F:44])=[CH:42][CH:41]=4)=[O:23])[CH2:18][CH2:17]3)[CH2:12][CH2:13]1)[O:7]2)([O-:3])=[O:2]

Participants

8

Reactant 4

HCID 6228DimethylformamideHCID 676844-(Trifluoromethyl)benzenemethanolHCID 682631,1'-CarbonyldiimidazoleHCID 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 694814184-Trifluromethylbenzyl 4-[2-(2,3-dihydro-6-nitrospiro[imidazo[2,1-b]oxazole-2,4'-piperidin]-1'-yl)-2-oxoethyl]piperazine-1-carboxylateYield 88%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6344DichloromethaneSolventHCID 6422Trifluoroacetic acidSolvent

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 (5 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. The reaction mixture was stirred at room temperature for 5 minutes and concentrated under reduced pressure, and the residue was dissolved in DMF (15 ml). To the solution, a mixture of 4-trifluoromethylbenzyl alcohol (293 mg, 1.67 mmol), 1,1′-carbonyldiimidazole (270 mg, 1.67 mmol) and DMF (5 ml) stirred at room temperature for 3 hours was added followed by stirring at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate, and the organic phase was washed with a saturated saline solution and dried over magnesium sulfate. After filtration, the resulting filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/methanol=200/1) and crystallized from methylene chloride-isopropyl ether to afford 4-trifluromethylbenzyl 4-[2-(2,3-dihydro-6-nitrospiro[imidazo[2,1-b]oxazole-2,4′-piperidin]-1′-yl)-2-oxoethyl]piperazine-1-carboxylate (324 mg, yield 88%) as a light pink powder.

Workup

  1. additionwas added
  2. concentrationThe reaction mixture was concentrated under reduced pressure
  3. additionTo the residue, methylene chloride (1 ml) and triethylamine (1 ml) were added
  4. stirringThe reaction mixture was stirred at room temperature for 5 minutes
  5. concentrationconcentrated under reduced pressure
  6. dissolutionthe residue was dissolved in DMF (15 ml)
  7. stirringstirred at room temperature for 3 hours
  8. additionwas added
  9. stirringby stirring at room temperature overnight
  10. extractionextracted with ethyl acetate
  11. washthe organic phase was washed with a saturated saline solution
  12. dry with materialdried over magnesium sulfate
  13. filtrationAfter filtration
  14. concentrationthe resulting filtrate was concentrated under reduced pressure
  15. customThe residue was purified by silica gel column chromatography (methylene chloride/methanol=200/1)
  16. customcrystallized from methylene chloride-isopropyl ether

Sources & evidence

ORD record
ord-ec624471163b48e69fca219aeadfc9a6
Source dataset
uspto-grants-2007_08
Patent number
US07262212B2

Reaction notes

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