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

HRID 73047노트

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HRID 73047 반응식
[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]

참가 물질

8

반응물 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

생성물 1

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

시약·촉매·용매 2

HCID 6386tert-Butanol용매HCID 8028Tetrahydrofuran용매

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온도
65 °C

실험 절차

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).

후처리

  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

출처 및 근거

ORD 기록
ord-a3c03c4fcc7e4790b1abe5ea7187fd6e
출처 데이터셋
uspto-grants-2014_09
특허 번호
US08828996B2

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