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

Temperature

-78 °C

300 mL of DCM was cooled to −78° C., then oxalyl chloride (0.475 mL, 5.42 mmol) was added and the mixture was stirred at −78° C. for 10 min. DMSO (0.586 mL, 8.26 mmol) was added and the mixture was stirred at −78° C. for 15 min. A solution of (4-(5-(1-(pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)phenyl)methanol (1 g, 2.58 mmol) in 60 mL of DCM was added dropwise over 10 minutes into the reaction mixture, with the SM flask being rinsed with another 10 mL of DCM which was also added into the reaction dropwise. The reaction was kept at −78° C. for 40 min, then Hunig's Base (3.61 mL, 20.66 mmol) was added over 10 minutes. Stirring at −78° C. continued for 10 min, then the dry ice bath was removed and the reaction flask gradually warmed to room temperature. A 0.5 N KHSO4 solution (70 mL) was added and the mixture was extracted twice with DCM (50 mL). The organics were combined, dried with Na2SO4, and concentrated. Diethyl ether (100 mL) was added to the product, with the mixture being stirred overnight, then filtered and the solids washed with diethyl ether to afford 4-(5-(1-(pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)benzaldehyde (700 mg, 1.74 mmol). The compound had an HPLC retention time=3.69 min.−Column: CHROMOLITH® SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.2% H3PO4; Solvent B=90% MeOH, 10% H2O, 0.2% H3PO4. LC/MS M+1=386.01. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.69 (ddd, J=0.8 Hz, 5.0 Hz, 7.4 Hz, 1H), 7.90 (d, J=8.0 Hz, 1H), 8.15 (d, J=8.3 Hz, 2H), 8.20 (dt, J=1.9 Hz, 7.7 Hz, 1H), 8.32 (d, J=8.3 Hz, 2H), 8.67 (dd, J=1.9 Hz, 4.7 Hz, 1H), 8.76 (s, 1H), 10.13 (s, 1H)

1. stirringthe mixture was stirred at −78° C. for 15 min
2. washbeing rinsed with another 10 mL of DCM which
3. additionwas also added into the reaction dropwise
4. waitThe reaction was kept at −78° C. for 40 min
5. stirringStirring at −78° C.
6. waitcontinued for 10 min
7. customthe dry ice bath was removed
8. temperaturethe reaction flask gradually warmed to room temperature
9. additionA 0.5 N KHSO4 solution (70 mL) was added
10. extractionthe mixture was extracted twice with DCM (50 mL)
11. dry with materialdried with Na2SO4
12. concentrationconcentrated
13. additionDiethyl ether (100 mL) was added to the product, with the mixture
14. stirringbeing stirred overnight
15. filtrationfiltered
16. washthe solids washed with diethyl ether

ORD record

ord-fcb9849d08ac44b592ff869c99790169

Source dataset

uspto-grants-2013_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08389509B2