Trifluoromethanesulfonic anhydride → (S)-2-(3,5-dichlorophenyl)morpholine

Temperature

-20 °C

Synthesized according to General procedure 31, Method A. A stirring suspension of ((R)-4-fluoro-N-(4-(3-hydroxy-2-oxopyrrolidin-1-yl)phenylsulfonyl)-N-(thiazol-2-yl)benzenesulfonamide (1.07 g, 2.15 mmol), N,N-diisopropylethylamine (1.15 mL, 6.50 mmol), and CH2Cl2 (10.0 mL), under N2, was cooled to −20° C. Triflic anhydride (545 μL, 3.25 mmol) was added dropwise over 10 minutes. The suspension was stirred at −20° C. for 1 hour. A solution of (S)-2-(3,5-dichlorophenyl)morpholine (500 mg, 2.15 mmol) [this enantiomer of 2-(3,5-dichlorophenyl)morpholine was obtained by preparative SFC separation of its racemic mixture: Chiralpak AD-H column (2×15 cm), 50% ethanol (0.1% DEA)/CO2, 50 mL/min)] and CH2Cl2 (2.0 mL) was added dropwise over 5 minutes. The mixture was stirred at −20° C. for 1.5 hours. Morpholine (375 μL, 4.30 mmol) was added dropwise over 5 minutes. The mixture was stirred at −20° C. for 2 hours. The solution was allowed to warm to room temperature and concentrated to dryness under reduced pressure. The residue was purified via silica gel chromatography using 2% MeOH in CH2Cl2 to obtain the desired lactam as a white solid (814 mg, 1.48 mmol, 69% yield). 1H-NMR (400 MHz, DMSO) δ 7.85-7.78 (m, 4H), 7.54 (t, J=1.9 Hz, 1H), 7.42 (d, J=1.8 Hz, 2H), 7.25 (d, J=4.6 Hz, 1H), 6.82 (d, J=4.6 Hz, 1H), 4.53 (dd, J=1.9, 9.9 Hz, 1H), 3.97 (d, J=9.9 Hz, 1H), 3.80-3.65 (m, 4H), 3.01-2.89 (m, 2H), 2.70-2.65 (m, 1H), 2.51-2.45 (m, 1H), 2.27-2.22 (m, 1H), 2.12-2.07 (m, 1H). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=553.3; tR=1.44 min. SFC (Chiralpak AS-H, (0.46×25 cm), 55% methanol (1% DEA)/CO2, 3 mL/min): tR=6.8 min.

1. customSynthesized

ORD record

ord-ea0817a56eff42ccb0fa6434a39ba0fc

Source dataset

uspto-grants-2014_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08841282B2