Triethylamine → (R)-[4-(4-Fluorobenzoyl)-1-(3,3,3-trifluoro-2-hydroxy-2-methylpropionyl)piperidine]

HRID 1814797Notes

Reaction equation

HRID 1814797 reaction equation
[F:1][C:2]([F:14])([F:13])[C@@:3]([O:8][Si](C)(C)C)([CH3:7])[C:4](Cl)=[O:5].[F:15][C:16]1[CH:29]=[CH:28][C:19]([C:20]([CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[O:21])=[CH:18][CH:17]=1.C(N(CC)CC)C>CCOC(C)=O>[F:15][C:16]1[CH:17]=[CH:18][C:19]([C:20]([CH:22]2[CH2:27][CH2:26][N:25]([C:4](=[O:5])[C@:3]([OH:8])([CH3:7])[C:2]([F:14])([F:13])[F:1])[CH2:24][CH2:23]2)=[O:21])=[CH:28][CH:29]=1

Participants

5

Reactant 3

HCID 8471TriethylamineHCID 27244404-(4-Fluorobenzoyl)piperidineHCID 10586677(S)-3,3,3-trifluoro-2-trimethylsilyloxy-2-methylpropanoyl chloride

Product 1

HCID 11268023(R)-[4-(4-Fluorobenzoyl)-1-(3,3,3-trifluoro-2-hydroxy-2-methylpropionyl)piperidine]Yield 30%

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent2×

Procedure

A solution of (S)-3,3,3-trifluoro-2-trimethylsilyoxy-2-methylpropanoyl chloride (J. Med. Chem., 1999, 42, 2741-2746) (293 mg, 1.2 mmol) in EtOAc (5 ml) was added to a stirred mixture of 4-(4-fluorobenzoyl)piperidine (207 mg, 1.0 mmol) and triethylamine (0.21 ml, 1.5 mmol) in EtOAc (25 ml). The resultant mixture was stirred at ambient temperature for 2 hours, washed with 1 M hydrochloric acid, saturated sodium hydrogen carbonate solution and brine, dried and evaporated. The residue was dissolved in methanol (10 ml), treated with 1 M hydrochloric acid (2 ml) and the mixture stirred at ambient temperature for 1 hour. The methanol was evaporated, the aqueous layer was extracted with EtOAc (2×25 ml), the EtOAc extracts were washed with saturated sodium hydrogen carbonate solution and brine, dried and evaporated. The residue was chromatographed on silica with 10% EtOA/DCM as eluent to give a solid which was recrystallized from EtOAc/hexane to give the title compound as a solid (104 mg, 0.3 mmol). Mp: 78-79° C.; NMR: 1.7 (s, 3H), 1.8-2.0 (m, 4H), 3.2 (dd, 2H), 3.5 (m, 1H), 4.4 (dd, 2H), 5.25 (s, 1H), 7.15 (dd, 2H), 8.0 (dd, 2H); m/z 346.

Workup

  1. washwashed with 1 M hydrochloric acid, saturated sodium hydrogen carbonate solution and brine
  2. customdried
  3. customevaporated
  4. dissolutionThe residue was dissolved in methanol (10 ml)
  5. additiontreated with 1 M hydrochloric acid (2 ml)
  6. customThe methanol was evaporated
  7. extractionthe aqueous layer was extracted with EtOAc (2×25 ml)
  8. washthe EtOAc extracts were washed with saturated sodium hydrogen carbonate solution and brine
  9. customdried
  10. customevaporated
  11. customThe residue was chromatographed on silica with 10% EtOA/DCM as eluent
  12. customto give a solid which
  13. customwas recrystallized from EtOAc/hexane

Sources & evidence

ORD record
ord-b5f96ae8619845e8b0c7123c3f26c536
Source dataset
uspto-grants-2005_04
Patent number
US06878712B1

Reaction notes

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