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

HRID 1507224Notes

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])=[C:10]([F:15])[CH:9]=2)[C:3]1=[O:16].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C@@H:25]2[CH2:30][CH2:29][NH:28][CH2:27][C@H:26]2[OH:31])=[CH:21][CH:20]=1.C(N(CC)CC)C>C(#N)C.[Cl-].[NH4+]>[F:15][C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][C:11]=1[CH3:14])[CH2:7][N:4]1[CH2:5][CH2:6][CH:2]([N:28]2[CH2:29][CH2:30][C@@H:25]([C:22]3[CH:23]=[CH:24][C:19]([O:18][CH3:17])=[CH:20][CH:21]=3)[C@H:26]([OH:31])[CH2:27]2)[C:3]1=[O:16]

Participants

Conditions

Temperature: 100 °C

Procedure

To a solution of 3-bromo-1-(3-fluoro-4-methylbenzyl)pyrrolidin-2-one (Intermediate 6, 200 mg, 0.7 mmol) and (±)-rel-(3S,4S)-4-(4-methoxyphenyl)piperidin-3-ol (145 mg, 0.7 mmol, from Example 46, step B) in acetonitrile (15 mL) was added triethylamine (0.1 mL, 0.7 mmol) and the resulting mixture was heated in the microwave at 100° C. for 1 h. The cooled reaction mixture was diluted with a saturated ammonium chloride solution and extracted with ethyl acetate (100 mL). The organic layer was separated, dried over Na2SO4, filtered, and evaporated under reduced pressure to give (±)-rel-1-(3-fluoro-4-methylbenzyl)-3-((3S,4S)-3-hydroxy-4-(4-methoxyphenyl)piperidin-1-yl)pyrrolidin-2-one (280 mg, 0.51 mmol, 73% yield, mixture of 4 diaseteroisomers), which was used directly in the next step. LCMS (Method F) RT 1.99 min m/z 413.2 (M+H+).

Workup

customThe cooled reaction mixture
extractionextracted with ethyl acetate (100 mL)
customThe organic layer was separated
dry with materialdried over Na2SO4
filtrationfiltered
customevaporated under reduced pressure

Sources & evidence

ORD record: ord-c92b7ea9cf284e9ab803350a4e40dd0a
Source dataset: uspto-grants-2015_12
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09221796B2

Reaction notes

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