Ethyl Acetate → 3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylphenyl)pyrrolidin-2-one

HRID 1507233Notes

Reaction equation

HRID 1507233 reaction equation
FC(F)(F)C(O)=O.[F:8][C@@H:9]1[C@@H:14]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[CH2:13][CH2:12][NH:11][CH2:10]1.C([O-])([O-])=O.[K+].[K+].Br[CH:29]1[CH2:33][CH2:32][N:31]([C:34]2[CH:39]=[CH:38][C:37]([CH3:40])=[C:36]([F:41])[CH:35]=2)[C:30]1=[O:42].CCOC(C)=O>CN(C=O)C>[F:8][C@@H:9]1[C@@H:14]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[CH2:13][CH2:12][N:11]([CH:29]2[CH2:33][CH2:32][N:31]([C:34]3[CH:39]=[CH:38][C:37]([CH3:40])=[C:36]([F:41])[CH:35]=3)[C:30]2=[O:42])[CH2:10]1

Participants

6

Reactant 4

HCID 8857Ethyl AcetateHCID 11430Potassium CarbonateHCID 637889133-Bromo-1-(3-fluoro-4-methylphenyl)pyrrolidin-2-oneHCID 1182075694-((3R,4R)-3-fluoropiperidin-4-yl)phenol trifluoroacetate

Product 1

HCID 1182074163-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylphenyl)pyrrolidin-2-one

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
60 °C

Procedure

To a solution of 4-((3R,4R)-3-fluoropiperidin-4-yl)phenol trifluoroacetate, from step B (120 mg, 0.39 mmol) in DMF (2.0 mL) was added K2CO3 (134 mg, 0.97 mmol) and racemic 3-bromo-1-(3-fluoro-4-methyl-phenyl)pyrrolidin-2-one (106 mg, 0.39 mmol, from step C). The mixture was heated to 60° C. and stirred for 30 min. It was then allowed to cool to rt and stirred overnight, followed by the addition of 50 mL of EtOAc, which induced precipitation of a solid. The solid was removed by filtration and discarded, and the filtrate was concentrated in vacuo. The residue was purified via silica gel chromatography eluting with a gradient of 0-100% ethyl acetate/hexanes to give 110 mg of (R and S) 3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylphenyl)pyrrolidin-2-one) as a mixture of two diastereomers. A portion (35 mg) of the diastereomer mixture was separated (chiral HPLC method H) into homochiral example 49 P-1 (14 mg) and P-2 (14 mg). Data for P-1 (S)-3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylphenyl)-pyrrolidin-2-one: Chiral HPLC (method H-2) RT 6.97 min, 98% AP; 1H NMR (500 MHz, methanol-d4) δ 7.60-7.52 (m, 1H), 7.32-7.22 (m, 2H), 7.12 (d, J=8.5 Hz, 2H), 6.76 (d, J=8.5 Hz, 2H), 4.72-4.65 (m, 1H), 4.63-4.55 (m, 1H), 3.84 (d, J=9.2 Hz, 4H), 3.51-3.44 (m, 1H), 2.87-2.80 (m, 1H), 2.76-2.68 (m, 1H), 2.64-2.54 (m, 1H), 2.53-2.46 (m, 1H), 2.37-2.30 (m, 1H), 2.26 (d, J=1.4 Hz, 3H), 2.24-2.18 (m, 1H), 1.84 (br s, 3H). Data for P-2 (R)-3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)-piperidin-1-yl)-1-(3-fluoro-4-methylphenyl)-pyrrolidin-2-one: Chiral HPLC (method H-2) RT 8.84 min, 99.3% AP; 1H NMR (500 MHz, methanol-d4) δ 7.56 (dd, J=12.0, 1.9 Hz, 1H), 7.32-7.23 (m, 2H), 7.12 (d, J=8.4 Hz, 2H), 6.80-6.73 (m, 2H), 4.70-4.63 (m, 1H), 4.60-4.54 (m, 1H), 3.88-3.77 (m, 5H), 3.23-3.17 (m, 2H), 3.07 (d, J=10.7 Hz, 2H), 2.75-2.68 (m, 2H), 2.64-2.48 (m, 4H), 2.33 (dd, J=6.6, 2.4 Hz, 2H), 2.26 (d, J=1.5 Hz, 5H), 2.21 (dd, J=12.7, 9.6 Hz, 2H), 1.90-1.83 (m, 4H).

Workup

  1. temperatureto cool to rt
  2. stirringstirred overnight
  3. customprecipitation of a solid
  4. customThe solid was removed by filtration
  5. concentrationthe filtrate was concentrated in vacuo
  6. customThe residue was purified via silica gel chromatography
  7. washeluting with a gradient of 0-100% ethyl acetate/hexanes

Sources & evidence

ORD record
ord-bc042c82e27d478daf5b4f74d8657d46
Source dataset
uspto-grants-2015_12
Patent number
US09221796B2

Reaction notes

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