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

HRID 713133Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 713133
[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]

Komponenten

8

Edukt 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

Produkt 1

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

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 6386tert-ButanolLösungsmittelHCID 8028TetrahydrofuranLösungsmittel

Reaktionsbedingungen

Temperatur
65 °C

Versuchsvorschrift

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).

Aufarbeitung

  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

Quellen und Nachweise

ORD-Eintrag
ord-19f69a7255e24e26a2c445681fe9a3ed
Quelldatensatz
uspto-grants-2015_11
Patentnummer
US09181273B2

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