Diisopropylethylamine → (R)-3-((3S,4R)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one

HRID 1507268Notes

Reaction equation

HRID 1507268 reaction equation
[F:1][C@H:2]1[C@@H:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][NH:4][CH2:3]1.CCN(C(C)C)C(C)C.CS(O[C@H:29]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=2)[C:30]1=[O:42])(=O)=O>CC#N>[F:1][C@H:2]1[C@@H:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C@@H:29]2[CH2:33][CH2:32][N:31]([CH2:34][C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)[C:30]2=[O:42])[CH2:3]1

Participants

5

Reactant 3

HCID 81531DiisopropylethylamineHCID 118207340(5)-1-(4-Methylbenzyl)-2-oxopyrrolidin-3-yl methanesulfonateHCID 118207461cis-4-(3-Fluoropiperidin-4-yl)phenol

Product 1

HCID 118207538(R)-3-((3S,4R)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-oneYield 28.7%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent2×

Conditions

Temperature
80 °C

Procedure

To a solution of cis-4-(3-fluoropiperidin-4-yl)phenol (60 mg, 0.31 mmol) in 1.0 mL of CH3CN and DIPEA (0.2 mL, 1.2 mmol) at 80° C. was added a solution of (S)-1-(4-methylbenzyl)-2-oxopyrrolidin-3-yl methanesulfonate (87 mg, 0.3 mmol) in 0.5 mL of CH3CN over 1.5 h. The mixture was then stirred at 80° C. for 16 h. The mixture was allowed to cool to rt and then concentrated. The residue was purified via silica gel chromatography (4 g of silica) eluting with a gradient of 0-100% EtOAc in hexanes to give a mixture of two diastereomers, which were further separated via chiral HPLC under the following conditions: Chiralcel OD column (21×250 mm, 10μ) eluting with an isocratic mixture of 30% B where solvent A=0.1% diethylamine in n-heptane and solvent B=100% ethanol. The absolute stereochemistry of the 2 products has not been assigned and is shown and named for convenience. The first eluting isomer (Example 112, P-1) was (R)-3-((3S,4R)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one (33.8 mg, 0.086 mmol, 28% yield). 1H NMR (500 MHz, methanol-d4) δ 7.21-7.07 (m, 6H), 6.78-6.68 (m, 2H), 4.70 (d, J=48.8 Hz, 1H), 4.41 (dd, J=58.0, 14.5 Hz, 2H), 3.61 (t, J=8.8 Hz, 1H), 3.30-3.03 (m, 5H), 2.77-2.60 (m, 1H), 2.51 (t, J=11.1 Hz, 1H), 2.32 (s, 3H), 2.31-2.15 (m, 2H), 2.01 (dq, J=13.2, 8.4 Hz, 1H), 1.69 (dd, J=13.1, 2.6 Hz, 1H), (M+H)+=383.25. HPLC RT under separation conditions=8.87 min. The second eluting isomer (Example 112, P-2) was (R)-3-((3R,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one (35.2 mg, 0.084 mmol, 27.3% yield), 1H NMR (500 MHz, methanol-d4) δ 7.19-7.08 (m, 6H), 6.74 (d, J=8.4 Hz, 2H), 4.66 (d, J=47.9 Hz, 1H), 4.41 (dd, J=53.7, 14.8 Hz, 2H), 3.58 (t, J=8.8 Hz, 1H), 3.42 (t, J=10.8 Hz, 1H), 3.30-3.14 (m, 2H), 3.05-2.88 (m, 2H), 2.79-2.51 (m, 2H), 2.33 (s, 3H), 2.31-2.13 (m, 2H), 2.06-1.90 (m, 1H), 1.67 (d, J=10.8 Hz, 1H), (M+H)+=383.25. HPLC RT under separation conditions=11.97 min.

Workup

  1. temperatureto cool to rt
  2. concentrationconcentrated
  3. customThe residue was purified via silica gel chromatography (4 g of silica)
  4. washeluting with a gradient of 0-100% EtOAc in hexanes
  5. customto give
  6. additiona mixture of two diastereomers, which
  7. customwere further separated via chiral HPLC under the following conditions
  8. washChiralcel OD column (21×250 mm, 10μ) eluting with an isocratic mixture of 30% B where solvent A=0.1% diethylamine in n-heptane and solvent B=100% ethanol

Sources & evidence

ORD record
ord-bb5527b6ffb1469ba39caf3509d636e1
Source dataset
uspto-grants-2015_12
Patent number
US09221796B2

Reaction notes

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