Dimethyl Sulfoxide → 4-(5-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)benzaldehyde

A 50 mL round bottom flask was flame dried and cooled under a stream of dry nitrogen. DCM (25 mL) followed by oxalyl chloride (6.79 mL, 13.59 mmol) (2M in DCM) were added to the flask and it was cooled in an acetone/dry ice bath. Dimethyl sulfoxide (1.47 mL, 20.71 mmol) was added dropwise. After 10 minutes, (4-(5-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)phenyl)methanol (2.5 g, 6.47 mmol) was added in small portions over 5-10 minutes providing a pale yellow slurry. After stirring for 5 minutes, DIPEA (9.27 mL, 53.1 mmol) was added dropwise. The cloudy mixture began to clear up, then became cloudy again with the color fading from pale yellow to off-white during the course of the addition. After 5 minutes, the cooling bath was removed and the reaction was allowed to slowly warm to room temperature. After stirring at room temperature for 3 hours the solvents were evaporated and the residue was partitioned between EtOAc (100 mL) and 0.5 N KHSO4 (70 mL). The EtOAc phase was washed with 50 mL each 1N HCl, water, sat. aq. NaHCO3, water and brine, then dried over MgSO4, filtered and evaporated. The solid was slurried in hexanes (with ˜5% EtOAc) with sonication and heating, then cooled to room temperature and filtered. The solids were washed with hexanes, air dried and placed under vacuum to afford 4-(5-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)benzaldehyde (1.55 g). The compound had an HPLC retention time=2.04 min.−Column: PHENOMENEX® Luna 5u C18 4.6×30 mm (2 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. LC/MS M+1=385.17.

1. temperatureA 50 mL round bottom flask was flame
2. customdried
3. temperaturecooled under a stream of dry nitrogen
4. additionwere added to the flask and it
5. temperaturewas cooled in an acetone/dry ice bath
6. customproviding a pale yellow slurry
7. additionoff-white during the course of the addition
8. waitAfter 5 minutes
9. customthe cooling bath was removed
10. stirringAfter stirring at room temperature for 3 hours the solvents
11. customwere evaporated
12. customthe residue was partitioned between EtOAc (100 mL) and 0.5 N KHSO4 (70 mL)
13. washThe EtOAc phase was washed with 50 mL each 1N HCl, water, sat. aq. NaHCO3, water and brine
14. dry with materialdried over MgSO4
15. filtrationfiltered
16. customevaporated
17. customThe solid was slurried in hexanes (with ˜5% EtOAc) with sonication
18. temperatureheating
19. temperaturecooled to room temperature
20. filtrationfiltered
21. washThe solids were washed with hexanes, air
22. customdried

ORD record

ord-1ba55d760d414672a907090c91a06bf4

Source dataset

uspto-grants-2013_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08389509B2