Sulfuric Acid → (+/-)-(4R,5R)-5-ethoxycarbonyl-1-methyl-4-(4-hydroxyphenyl)pyrrolidin-2-one

HRID 1837975Notes

Reaction equation

[CH2:1]([O:3][C:4]([C@@H:6]1[N:10]([CH3:11])[C:9](=[O:12])[CH2:8][C@@H:7]1[C:13]1[CH:18]=[CH:17][C:16](N)=[CH:15][CH:14]=1)=[O:5])[CH3:2].N([O-])=[O:21].[Na+].OS(O)(=O)=O>[H+].[B-](F)(F)(F)F.O>[CH2:1]([O:3][C:4]([C@@H:6]1[N:10]([CH3:11])[C:9](=[O:12])[CH2:8][C@@H:7]1[C:13]1[CH:18]=[CH:17][C:16]([OH:21])=[CH:15][CH:14]=1)=[O:5])[CH3:2]

Participants

Conditions

Temperature: 90 °C

Procedure

A 2° C. solution of (±)-(4R*,5R*)-5-ethoxycarbonyl-1-methyl-4-(4-aminophenyl)pyrrolidin-2-one (prepared according to the procedure for Intermediate U, 3.25 g, 12.4 mmol) in 42% aqueous HBF4 (6 mL) and water (6 mL) was treated dropwise with a solution of NaNO2 (856 mg, 12.4 mmol) in water (6 mL), keeping the reaction temperature below 10° C. The reaction mixture was stirred for 35 min, then poured in one portion into a 90° C. solution of H2SO4 (24 mL) in water (360 mL). The resulting solution was heated at 90° C. for 45 min, cooled to room temperature, diluted with ice (200 g) and extracted with CH2Cl2. The organic layer was dried (MgSo4) and concentrated under reduced pressure to yield (±)-(4R*,5R*)-5-ethoxycarbonyl-1-methyl-4-(4-hydroxyphenyl)-pyrrolidin-2-one (2.90 g, 89%) as an orange oil: 1H NMR (DMSO-d6) δ 0.76 (t, J=6.4 Hz, 3H), 2.41-2.67 (m, 5H), 3.59-3.87 (m, 3H), 4.38 (d, J=8.5 Hz, 1H), 6.63-6.68 (m, 2H), 6.97-7.02 (m, 2H), 9.30 (s, 1H).

Workup

customthe reaction temperature below 10° C
temperaturecooled to room temperature
extractionextracted with CH2Cl2
customThe organic layer was dried (MgSo4)
concentrationconcentrated under reduced pressure

Sources & evidence

ORD record: ord-c34ab66fed5c4526aec15b7b2ff4d765
Source dataset: uspto-grants-2004_08
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US06784167B2

Reaction notes

Loading…