Methyl {(2S,4R)-1-[(1S)-4-methyl-1-(3-methylbutyl)pent-4-en-2-yn-1-yl]-2-[4-(trifluoromethyl)phenyl]piperidin-4-yl}acetate → methyl {(2S,4R)-1-[4-methyl-1-(3-methylbutyl)pentyl]-2-[4-(trifluoromethyl)phenyl]piperidin-4-yl}acetate

HRID 1942294Notes

Reaction equation

HRID 1942294 reaction equation
[CH3:1][C:2](=[CH2:32])[C:3]#[C:4][C@@H:5]([N:11]1[CH2:16][CH2:15][C@@H:14]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH2:13][C@H:12]1[C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=1)[CH2:6][CH2:7][CH:8]([CH3:10])[CH3:9]>CO.[Ni]>[CH3:9][CH:8]([CH3:10])[CH2:7][CH2:6][CH:5]([N:11]1[CH2:16][CH2:15][C@@H:14]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH2:13][C@H:12]1[C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:24][CH:23]=1)[CH2:4][CH2:3][CH:2]([CH3:1])[CH3:32]

Participants

4

Reactant 1

HCID 59201188Methyl {(2S,4R)-1-[(1S)-4-methyl-1-(3-methylbutyl)pent-4-en-2-yn-1-yl]-2-[4-(trifluoromethyl)phenyl]piperidin-4-yl}acetate

Product 1

HCID 59201267methyl {(2S,4R)-1-[4-methyl-1-(3-methylbutyl)pentyl]-2-[4-(trifluoromethyl)phenyl]piperidin-4-yl}acetateYield 72.5%

Reagents, catalysts & solvents 2

HCID 935NickelCatalystHCID 887MethanolSolvent

Procedure

A solution of methyl {(2S,4R)-1-[(1S)-4-methyl-1-(3-methylbutyl)pent-4-en-2-yn-1-yl]-2-[4-(trifluoromethyl)phenyl]piperidin-4-yl}acetate (Example 1, Step 1, 8.4 g, 18.9 mmol) in MeOH (250 ml) was hydrogenated over Raney Nickel (˜6 g) at 50 psi for 18 hrs. The catalyst was removed by filtration—washing with CH2Cl2. The filtrate was evaporated and the residue was partitioned between CH2Cl2/H2O. The aqueous layer was extracted with CH2Cl2 (×1). The combined extracts were dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography (silica, 3% EtOAc/isohexane) to give the alkane (6.24 g) as an oil. 1H NMR (500 MHz, CDCl3): δ 0.64-0.74 (1H, m), 0.81 (6H, t J 6.5), 0.85 (6H, t, J 6.8), 0.93-0.97 (3H, m), 1.19-1.42 (7H, m), 1.52-1.58 (1H, m), 1.72-1.78 (2H, m), 1.86-1.94 (1H, m), 2.11-2.27 (4H, m), 2.92 (1H, brd, J 11.6), 3.58 (1H, dd, J2.6, 11.1), 3.64 (3H, s), 7.40 (2H, brs), 7.54 (2H, d, J 8.2). Further chromatography of mixed fractions (silica 2.5% EtOAc/isohexane) gave the cis alkene: methyl{(2S,4R)-1-[(1S,2Z)-4-methyl-1-(3-methylbutyl)pent-2-en-1-yl]-2-[4-(trifluoromethyl)phenyl]piperidin-4-yl}acetate (415 mg) as an oil. 1H NMR (500 MHz, CDCl3): δ 0.68 (3H, d, J 6.6), 0.77 (3H, d, J 6.5) 0.83-0.86 (6H, m), 1.02-1.30 (4H, m), 1.37-1.43 (1H, m), 1.51-1.63 (3H, m), 1.71-1.78 (2H, m), 1.83-1.91 (1H, m), 2.13-2.27 (2H, m), 2.37-2.43 (1H, m), 3.02-3.06 (1H, m), 3.20 (1H, q, J 7.8), 3.42 (1H, dd, J 2.9, 11.1), 3.63 (3H, s), 5.20-5.28 (2H, m), 7.44 (2H, brd, J 7.5), 7.54 (2H, d, J 8.2).

Workup

  1. customThe catalyst was removed
  2. washby filtration—washing with CH2Cl2
  3. customThe filtrate was evaporated
  4. customthe residue was partitioned between CH2Cl2/H2O
  5. extractionThe aqueous layer was extracted with CH2Cl2 (×1)
  6. dry with materialThe combined extracts were dried (Na2SO4)
  7. filtrationfiltered
  8. customevaporated
  9. customThe residue was purified by chromatography (silica, 3% EtOAc/isohexane)

Sources & evidence

ORD record
ord-07186230de14462f86ee61c9ecd3dc28
Source dataset
uspto-grants-2013_03
Patent number
US08389547B2

Reaction notes

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