Acetic Acid → 2-Isopentyl-9-[4-methoxy-3-(trifluoromethyl)benzoyl]-4-phenyl-5-oxa-2,9-diazaspiro[5.5]undecan-3-one

HRID 713133Notes

Reaction equation

HRID 713133 reaction equation
[OH-].[Na+].F[C:4](F)(F)[C:5]([N:7]([CH2:13][C:14]1([OH:34])[CH2:19][CH2:18][N:17]([C:20](=[O:33])[C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([C:29]([F:32])([F:31])[F:30])[CH:22]=2)[CH2:16][CH2:15]1)[CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])=[O:6].C[C:38]([CH3:41])([O-])[CH3:39].[K+].[CH3:43][C:44](O)=O.[CH3:47]O>C1COCC1.C(O)(C)(C)C>[CH2:8]([N:7]1[C:5](=[O:6])[CH:4]([C:39]2[CH:38]=[CH:41][CH:43]=[CH:44][CH:47]=2)[O:34][C:14]2([CH2:15][CH2:16][N:17]([C:20](=[O:33])[C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([C:29]([F:30])([F:31])[F:32])[CH:22]=3)[CH2:18][CH2:19]2)[CH2:13]1)[CH2:9][CH:10]([CH3:12])[CH3:11]

Participants

8

Reactant 5

HCID 176Acetic AcidHCID 887MethanolHCID 14798Sodium HydroxideHCID 23665647Potassium tert-butoxideHCID 866724832,2,2-trifluoro-N-[[4-hydroxy-1-[4-methoxy-3-(trifluoromethyl)benzoyl]-4-piperidyl]methyl]-N-isopentyl-acetamide

Product 1

HCID 665485302-Isopentyl-9-[4-methoxy-3-(trifluoromethyl)benzoyl]-4-phenyl-5-oxa-2,9-diazaspiro[5.5]undecan-3-oneYield 45%

Reagents, catalysts & solvents 2

HCID 6386tert-ButanolSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
65 °C

Procedure

Sodium hydroxide (1.4 mL of 0.2 M, 0.29 mmol) was added to a solution of 2,2,2-trifluoro-N-[[4-hydroxy-1-[4-methoxy-3-(trifluoromethyl)benzoyl]-4-piperidyl]methyl]-N-isopentyl-acetamide (72 mg, 0.14 mmol) in MeOH (722 μL) and the reaction mixture was heated to 65° C. for 16 hours. The solution was partitioned between water (5 mL) and EtOAc (5 mL) and the aqueous layer was extracted with EtOAc (3×5 mL). The combined organics were dried over Na2SO4, filtered, and concentrated in vacuo to provide the crude amine as a clear oil (54 mg, 92%). ESI-MS m/z calc. 402.4. found 403.7 (M+1)+; Retention time: 1.34 minutes (3 min run). The residue was taken up in THF (480 μL) and added dropwise to a solution of potassium tert-butoxide (36 mg, 0.32 mmol) in tert-butanol (480 μL) and the reaction mixture was heated at 83° C. for 20 minutes. The solution was neutralized with AcOH, and partitioned between water (2 mL) and EtOAc (2 mL), the aqueous layer was extracted with EtOAc (3×2 mL). The combined organics were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was dissolved in MeOH (3 mL) and purified by reverse phase HPLC (Gilson) 20-99% water/MeOH to provide 2-isopentyl-9-[4-methoxy-3-(trifluoromethyl)benzoyl]-4-phenyl-5-oxa-2,9-diazaspiro[5.5]undecan-3-one (39 mg, 45%) as a white foam. ESI-MS m/z calc. 518.6. found 519.5 (M+1)+; Retention time: 2.03 minutes (3 min run).

Workup

  1. customThe solution was partitioned between water (5 mL) and EtOAc (5 mL)
  2. extractionthe aqueous layer was extracted with EtOAc (3×5 mL)
  3. dry with materialThe combined organics were dried over Na2SO4
  4. filtrationfiltered
  5. concentrationconcentrated in vacuo
  6. customto provide the crude amine as a clear oil (54 mg, 92%)
  7. customRetention time: 1.34 minutes (3 min run)
  8. temperaturethe reaction mixture was heated at 83° C. for 20 minutes
  9. custompartitioned between water (2 mL) and EtOAc (2 mL)
  10. extractionthe aqueous layer was extracted with EtOAc (3×2 mL)
  11. dry with materialThe combined organics were dried over Na2SO4
  12. filtrationfiltered
  13. concentrationconcentrated in vacuo
  14. dissolutionThe residue was dissolved in MeOH (3 mL)
  15. custompurified by reverse phase HPLC (Gilson) 20-99% water/MeOH

Sources & evidence

ORD record
ord-19f69a7255e24e26a2c445681fe9a3ed
Source dataset
uspto-grants-2015_11
Patent number
US09181273B2

Reaction notes

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