N-methyl-2-pyrrolidone → (4S)-3-{(2S)-2-[(S)-[3,5-bis(trifluoromethyl)phenyl](hydroxy)methyl]but-3-enoyl}-4-phenyl-1,3-oxazolidin-2-one

Temperature

-40 °C

To (4S)-3-[(2E)-but-2-enoyl]-4-phenyl-1,3-oxazolidin-2-one (13.8 g, 59.7 mmol) in DCM (100 mL) was added TiCl4 (1M in DCM, 59.7 mL, 59.7 mmol) at −10° C. The resulting reaction solution was transferred by cannula to a flask containing DIPEA (11.26 mL, 64.5 mmol) and DCM (100 mL) at 10° C. NMP (11.49 mL, 119 mmol) was added via a syringe and the reaction mixture was aged for 1 hour before cooling to −40° C. 3,5-Bis(trifluoromethyl)benzaldehyde (17.3 g, 71.6 mmol) in DCM (25 mL) was added via a syringe and the reaction was allowed to warm to 0° C. over 1.5 hr. The reaction was quenched by addition of acetic acid (15 mL), saturated Rochelle's salt (50 mL) and HCl (1.0 M, 200 mL). The organic was separated and the aqueous was back extracted with DCM (50 mL). The organics were combined, washed with HCl (1.0 M, 100 mL), dried over sodium sulfate, filtered and concentrated. The resultant oil was purified by column chromatography to give (4S)-3-{(2S)-2-[(5)-[3,5-bis(trifluoromethyl)phenyl](hydroxy)methyl]but-3-enoyl}-4-phenyl-1,3-oxazolidin-2-one (20 g, 42.3 mmol) as crystalline solid. 1H NMR (500 MHz, CDCl3) δ7.86 (s, 2H), 7.83 (s, 1H), 7.4 (m, 5H), 5.7 (m, 1H), 5.4 (m, 1H), 5.31 (d, J=10.3 Hz, 1H), 5.28 (d, J=3.9 Hz, 1H), 5.10 (d, J=17.3 Hz, 1H), 4.8 (m, 1H), 4.7 (t, J=9.0 Hz, 1H), 4.3 (m, 1H).

1. customThe resulting reaction solution
2. customwas transferred by cannula to a flask
3. temperatureto warm to 0° C. over 1.5 hr
4. customThe reaction was quenched by addition of acetic acid (15 mL), saturated Rochelle's salt (50 mL) and HCl (1.0 M, 200 mL)
5. customThe organic was separated
6. extractionthe aqueous was back extracted with DCM (50 mL)
7. washwashed with HCl (1.0 M, 100 mL)
8. dry with materialdried over sodium sulfate
9. filtrationfiltered
10. concentrationconcentrated
11. customThe resultant oil was purified by column chromatography

ORD record

ord-196ecbc232434604ac29e23d666146c4

Source dataset

uspto-grants-2016_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09346825B2