Triethylamine → 2,2,2-trifluoro-N-[[4-hydroxy-1-[4-methoxy-3-(trifluoromethyl)benzoyl]-4-piperidyl]methyl]-N-isopentyl-acetamide

HRID 73046Notes

Reaction equation

HRID 73046 reaction equation
C([N:8]1[CH2:13][CH2:12][C:11]([CH2:15][N:16]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])([OH:14])[CH2:10][CH2:9]1)C1C=CC=CC=1.C(N(CC)CC)C.[CH3:35][O:36][C:37]1[CH:45]=[CH:44][C:40]([C:41]([OH:43])=O)=[CH:39][C:38]=1[C:46]([F:49])([F:48])[F:47].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CC(O)C.CN(C=O)C.[Pd]>[F:21][C:18]([F:19])([F:20])[C:17]([N:16]([CH2:15][C:11]1([OH:14])[CH2:10][CH2:9][N:8]([C:41](=[O:43])[C:40]2[CH:44]=[CH:45][C:37]([O:36][CH3:35])=[C:38]([C:46]([F:49])([F:48])[F:47])[CH:39]=2)[CH2:13][CH2:12]1)[CH2:23][CH2:24][CH:25]([CH3:26])[CH3:27])=[O:22]

Participants

8

Reactant 4

HCID 8471TriethylamineHCID 27752954-Methoxy-3-(trifluoromethyl)benzoic acidHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 86672482N-[(1-benzyl-4-hydroxy-4-piperidyl)methyl]-2,2,2-trifluoro-N-isopentyl-acetamide

Product 1

HCID 866724832,2,2-trifluoro-N-[[4-hydroxy-1-[4-methoxy-3-(trifluoromethyl)benzoyl]-4-piperidyl]methyl]-N-isopentyl-acetamideYield 56.7%

Reagents, catalysts & solvents 3

HCID 23938PalladiumCatalystHCID 3776IsopropanolSolventHCID 6228DimethylformamideSolvent2×

Procedure

Palladium (50.8 mg, 0.48 mmol) 10% on activated carbon and N-[(1-benzyl-4-hydroxy-4-piperidyl)methyl]-2,2,2-trifluoro-N-isopentyl-acetamide (112 mg, 0.29 mmol) in propan-2-ol (3 mL) was stirred under an atmosphere of hydrogen for 18 hours. The catalyst was filtered through Celite® and washed with MeOH. The organics were concentrated in vacuo to provide a clear oil. To the oil was added DMF (2 mL) and triethylamine (40 μL, 0.29 mmol) and this solution was added dropwise to a solution 4-methoxy-3-(trifluoromethyl)benzoic acid (64 mg, 0.29 mmol) and HATU (110 mg, 0.29 mmol) in DMF (1 mL). The reaction mixture was stirred for 16 hours. The solution was partitioned between water and EtOAc and the layers were separated. The aqueous layer was extracted with EtOAc (3×100 mL). The combined organics were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was taken up in MeOH and purified by reverse phase HPLC (Gilson 20-99% water/MeOH) to give 2,2,2-trifluoro-N-[[4-hydroxy-1-[4-methoxy-3-(trifluoromethyl)benzoyl]-4-piperidyl]methyl]-N-isopentyl-acetamide (82 mg, 56%). ESI-MS m/z calc. 498.5. Found 499.5 (M+1)+; Retention time: 1.86 minutes (3 min run).

Workup

  1. filtrationThe catalyst was filtered through Celite®
  2. washwashed with MeOH
  3. concentrationThe organics were concentrated in vacuo
  4. customto provide a clear oil
  5. customThe solution was partitioned between water and EtOAc
  6. customthe layers were separated
  7. extractionThe aqueous layer was extracted with EtOAc (3×100 mL)
  8. dry with materialThe combined organics were dried over Na2SO4
  9. filtrationfiltered
  10. concentrationconcentrated in vacuo
  11. custompurified by reverse phase HPLC (Gilson 20-99% water/MeOH)

Sources & evidence

ORD record
ord-9552caf01e954472b9a79a15702d0085
Source dataset
uspto-grants-2014_09
Patent number
US08828996B2

Reaction notes

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