Triethylamine → (+/-)-rel-3-((3R,4R)-3-hydroxy-4-(4-methoxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one

HRID 1507243Notes

Reaction equation

HRID 1507243 reaction equation
Br[CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[C:3]1=[O:15].[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([C@@H:24]2[CH2:29][CH2:28][NH:27][CH2:26][C@H:25]2[OH:30])=[CH:20][CH:19]=1.C(N(CC)CC)C>>[OH:30][C@@H:25]1[C@@H:24]([C:21]2[CH:22]=[CH:23][C:18]([O:17][CH3:16])=[CH:19][CH:20]=2)[CH2:29][CH2:28][N:27]([CH:2]2[CH2:6][CH2:5][N:4]([CH2:7][C:8]3[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=3)[C:3]2=[O:15])[CH2:26]1

Participants

4

Reactant 3

HCID 8471TriethylamineHCID 637890883-Bromo-1-(4-methylbenzyl)pyrrolidin-2-one2×HCID 96770188(+/-) trans-4-(4-Methoxyphenyl)-piperidin-3-ol

Product 1

HCID 118207300(+/-)-rel-3-((3R,4R)-3-hydroxy-4-(4-methoxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-oneYield 63.4%

Conditions

Temperature
60 °C

Procedure

A mixture of 3-bromo-1-(4-methylbenzyl)pyrrolidin-2-one (Intermediate 2, 450 mg, 1.68 mmol), (±)-rel-(3S,4S)-4-(4-methoxyphenyl)piperidin-3-ol (313 mg, 1.5 mmol) and triethylamine (23 mL, 16.8 mmol) was stirred at 60° C. for 1 h, followed by heating at 85° C. for 1 h, 120° C. for 1 h and at 140° C. for 1 h. The mixture was cooled and then quenched with 40 mL of water and extracted with 3×50 mL of chloroform. The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified via silica gel chromatography (24 g column, gradient of 0-80% ethyl acetate/petroleum ether) to yield 375 mg of (±)-rel-3-((3R,4R)-3-hydroxy-4-(4-methoxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one as a mixture of four diastereomers. LCMS (method F) RT 1.84 min (74% AP), m/z 395.2 (M+H+); 1H NMR (300 MHz, DMSO-d6) δ ppm 7.31-7.41 (m, 8H) 6.86 (d, J=9.07 Hz, 2H) 4.66 (s, 1H) 3.73 (s, 3H) 3.49 (s, 2H) 2.59 (d, J=10.58 Hz, 2H) 2.32-2.47 (m, 3H) 1.89 (td, J=12.65, 4.53 Hz, 2H) 1.56 (d, J=11.71 Hz, 2H).

Workup

  1. temperatureby heating at 85° C. for 1 h, 120° C. for 1 h and at 140° C. for 1 h
  2. temperatureThe mixture was cooled
  3. customquenched with 40 mL of water
  4. extractionextracted with 3×50 mL of chloroform
  5. dry with materialThe combined organic layers were dried over Na2SO4
  6. filtrationfiltered
  7. concentrationconcentrated under vacuum
  8. customThe residue was purified via silica gel chromatography (24 g column, gradient of 0-80% ethyl acetate/petroleum ether)

Sources & evidence

ORD record
ord-ea4a04e9536c490cb32b8d8c2018b6cf
Source dataset
uspto-grants-2015_12
Patent number
US09221796B2

Reaction notes

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