Triethylamine → (+/-)-Methyl {(2S*)-2-[4-(trifluoromethyl)phenyl]-1-[4,4,4-trifluoro-1-(3,3,3-trifluoropropyl)butyl]piperidin-4-yl}acetate

HRID 1942310Notes

Reaction equation

HRID 1942310 reaction equation
C[CH:2]([C@@H:6]1[CH2:11][CH2:10][NH:9][C@H:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[CH2:7]1)[C:3]([O-:5])=[O:4].[F:22][C:23]([F:35])([F:34])[CH2:24][CH2:25][C:26](=O)[CH2:27][CH2:28][C:29]([F:32])([F:31])[F:30].[CH2:36](N(CC)CC)C.[BH3-]C#N.[Na+]>C(Cl)Cl.CO.O.C(OCC)(=O)C.Cl[Ti](Cl)(Cl)Cl>[F:21][C:18]([F:19])([F:20])[C:15]1[CH:14]=[CH:13][C:12]([C@@H:8]2[CH2:7][CH:6]([CH2:2][C:3]([O:5][CH3:36])=[O:4])[CH2:11][CH2:10][N:9]2[CH:26]([CH2:27][CH2:28][C:29]([F:32])([F:31])[F:30])[CH2:25][CH2:24][C:23]([F:35])([F:34])[F:22])=[CH:17][CH:16]=1

Participants

10

Reactant 4

HCID 8471TriethylamineHCID 5805611,1,1,7,7,7-Hexafluoro-4-heptanoneHCID 5003444Sodium cyanoborohydrideHCID 86617999(+)-methyl{(2S,4R)-2-[4-(trifluoromethyl)phenyl]piperidin-4-yl}acetate

Product 1

HCID 91443632(+/-)-Methyl {(2S*)-2-[4-(trifluoromethyl)phenyl]-1-[4,4,4-trifluoro-1-(3,3,3-trifluoropropyl)butyl]piperidin-4-yl}acetateYield 20%

Reagents, catalysts & solvents 5

HCID 24193Titanium TetrachlorideCatalystHCID 887MethanolSolventHCID 962WaterSolventHCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
-78 °C

Procedure

Intermediate 2 (301 mg, 1 mmol), 1,1,1,7,7,7-hexafluoroheptan-4-one (500 mg, 2 mmol) and triethylamine (0.8 mL, 6 mmol) were dissolved in CH2Cl2 (4 mL) and the mixture was cooled to −78° C. TiCl4 (2 mL, 1M in CH2Cl2) was added dropwise to give a dark orange mixture. This mixture was allowed to warm to 0° C. for 5 min then re-cooled to −78° C. NaCNBH3 (376 mg, 6 mmol) in methanol (2 mL) was added and the mixture was warmed to room temperature. The mixture was diluted with water and ethyl acetate and was filtered through celite to remove titanium salts. The organic extracts were pooled, washed with brine, dried and evaporated. The residue was purified on silica using 20-50% CH2Cl2 in iso-hexane as eluant to give the product as a crystalline solid (85 mg, 20%) upon evaporation.

Workup

  1. customto give a dark orange mixture
  2. temperatureto warm to 0° C. for 5 min
  3. temperaturethen re-cooled to −78° C
  4. temperaturethe mixture was warmed to room temperature
  5. filtrationwas filtered through celite
  6. customto remove titanium salts
  7. washwashed with brine
  8. customdried
  9. customevaporated
  10. customThe residue was purified on silica using 20-50% CH2Cl2 in iso-hexane as eluant

Sources & evidence

ORD record
ord-fd454cfba9264edcb88ca8eea5a73907
Source dataset
uspto-grants-2013_03
Patent number
US08389547B2

Reaction notes

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