Trifluoromethanesulfonic anhydride → (R)-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 (500 mg, 1.00 mmol), N,N-diisopropylethylamine (465 μL, 3.00 mmol), and CH2Cl 2 (5.0 mL), under N2, was cooled to −20° C. Triflic anhydride (220 μL, 1.3 mmol) was added dropwise over 10 minutes. The suspension was stirred at −20° C. for 1 hour. A solution of (R)-2-(3,5-dichlorophenyl)morpholine (248 mg, 1.00 mmol) [this enantiomer of 2-(3,5-dichlorophenyl)morpholine was obtained by preparative SFC separation of its racemic mixture: Chiralpak AD-H column (2×25 cm), 50% ethanol (0.1% DEA)/CO2, 50 mL/min)] and CH2Cl2 (1.0 mL) was added dropwise over 5 minutes. The mixture was stirred at −20° C. for 1.5 hours. Morpholine (174 μL, 2.0 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 (420 mg, 0.76 mmol, 76% yield). 1H-NMR (400 MHz, DMSO) δ 12.71 (s, 1H), 7.84-7.77 (m, 4H), 7.54-7.50 (m, 1H), 7.44 (d, J=1.8 Hz, 2H), 7.24 (d, J=4.6 Hz, 1H), 6.82 (d, J=4.6 Hz, 1H), 4.57 (dd, J=1.7, 9.8 Hz, 1H), 3.97-3.91 (m, 1H), 3.79-3.62 (m, 4H), 3.21-3.17 (m, 1H), 2.95-2.86 (m, 2H), 2.69-2.66 (m, 1H), 2.22-2.12 (m, 2H). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=553.3; tR=1.45 min. SFC (Chiralpak AS-H, (0.46×25 cm), 55% methanol (1% DEA)/CO2, 3 mL/min): tR=5.6 min.

1. customSynthesized

ORD record

ord-653817b72b9e461486db5f3e294faa07

Source dataset

uspto-grants-2011_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07994166B2