Dimethylformamide → (+)-4-Phenyl4-[(1-(3,5-bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)methyl]-1-(2-(pyrrolidinyl)acetamido)piperidine Hydrochloride

HRID 962474

Reaction equation

HRID 962474 reaction equation
[N:1]1([CH2:6][C:7]([OH:9])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:10]C([O-])=O.Cl.[C:15]1([C:21]2([CH2:27][O:28][CH:29]([C:32]3[CH:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=[C:34]([C:42]([F:45])([F:44])[F:43])[CH:33]=3)[CH2:30][OH:31])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].C[N:53](C)C=O>CO.C(N(CC)CC)C>[ClH:10].[C:15]1([C:21]2([CH2:27][O:28][CH:29]([C:32]3[CH:37]=[C:36]([C:38]([F:39])([F:40])[F:41])[CH:35]=[C:34]([C:42]([F:45])([F:43])[F:44])[CH:33]=3)[CH2:30][OH:31])[CH2:26][CH2:25][N:24]([NH:53][C:7](=[O:9])[CH2:6][N:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[CH2:23][CH2:22]2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1

Participants

8

Reactant 5

HCID 6228DimethylformamideHCID 11430Potassium CarbonateHCID 414564Pyrrolidin-1-ylacetic acidHCID 190847004-Phenyl-4-((1-(3,5-bis(trifluoromethyl)phenyl)-2-hydroxyethoxy) methyl)piperidine HydrochlorideHCID 21226386Carbonochloridate

Product 1

HCID 19084703(+)-4-Phenyl4-[(1-(3,5-bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)methyl]-1-(2-(pyrrolidinyl)acetamido)piperidine Hydrochloride

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 8471TriethylamineSolvent

Procedure

(1-Pyrrolidinyl)acetic acid (0.68 g) in dry dimethyl formamide (20 ml) was treated with triethylamine (1.38 ml) and cooled to -30° C. iButyl chloroformate (0.55 ml) was added and the reaction stirred for 10 minutes before adding the compound of Example 1 (1.0 g). The solution was allowed to warm slowly to room temperature then stirred for 16 hours. The solution was concentrated under reduced pressure then ethyl acetate was added and washed with aqueous sodium chloride, then dried and concentrated to give an oil which was dissolved in methanol and stirred with potassium carbonate for 1 hour. The solvent was evaporated and the residue partitioned between ethyl acetate and aqueous sodium chloride. The organic solution was dried (Na2SO4) and concentrated to give a residue which was purified by chromatography on neutral alumina eluting with 1% methanol/dichloromethane. The resulting product was treated with ethereal hydrogen chloride to give a white solid which was recrystallised from ethyl acetate to give the title compound; mp 110°-112° C.; MS (Cl+) 559 (M+H)+ ; 1H NMR (360 MHz, d6 -DMSO) δ 1.78-2.32 (8H, m), 2.96-3.18 (4H, m), 3.29 (1H, d, J=9.1 Hz), 3.38-3.60 (6H, m), 3.80-3.95 (1H, m), 4.24-4.33 (1 H, m), 4.38-4.47 (2H, m), 7.23 (1H. t, J=7.5 Hz), 7.34 (2H, t, J=7.5 Hz), 7.41 (2H, t, J=7.5 Hz), 7.68 (1H, s), 7.70 (1H, s) and 7.96 (1H, s).

Workup

  1. additionwas added
  2. stirringthen stirred for 16 hours
  3. concentrationThe solution was concentrated under reduced pressure
  4. additionethyl acetate was added
  5. washwashed with aqueous sodium chloride
  6. customdried
  7. concentrationconcentrated
  8. customto give an oil which
  9. customThe solvent was evaporated
  10. customthe residue partitioned between ethyl acetate and aqueous sodium chloride
  11. dry with materialThe organic solution was dried (Na2SO4)
  12. concentrationconcentrated
  13. customto give a residue which
  14. customwas purified by chromatography on neutral alumina eluting with 1% methanol/dichloromethane
  15. additionThe resulting product was treated with ethereal hydrogen chloride
  16. customto give a white solid which
  17. customwas recrystallised from ethyl acetate

Sources & evidence

ORD record
ord-06839cc722bc4906bfccbefaf91ac6f2
Source dataset
uspto-grants-1998_06
Patent number
US05760018

Linked notes

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