Hydrochloric Acid → 2-bromo-5-(1,3-oxazol-2-yl)benzaldehyde

Temperature

60 °C

A 1 L round bottom flask was charged with 2-[4-bromo-3-(dibromomethyl)-phenyl]-5-methoxy-oxazoline (27.8 g, 67.1 mmol), DBU (24.1 mL, 161.2 mmol) and morpholine (56.4 mL, 646.7 mmol). The mixture was heated at 60° C. for 2.5 hours. HPLC indicated the starting material had disappeared. The reaction mixture was cooled to −10° C. to 0° C. in an ice/acetone bath. The stirring stopped. Potassium tert-butoxide (1 M in THF, 350 mL) was added dropwise in 0.5 hours. The stirring started after ˜20 mL of potassium tert-butoxide THF solution was added. The reaction mixture was warmed up to RT and stirred at RT for 5 hours. It was put aside in a −40° C. freezer for 13 hours and then was stirred at RT for another 2 hours. The reaction mixture was cooled to −10° C. to 0° C. in an ice/acetone bath. HCl (6N, cold, 214 mL) was added dropwise in 15 minutes. The mixture was stirred at 0° C. to RT in 0.5 hours. It was transferred to a 2 L separatory funnel, diluted with EtOAc (300 mL) and water (300 mL). The aqueous layer was separated and extracted with EtOAc (300 mL×2). The organic layers were combined and the combined organic phase was washed with brine/1N HCl mixture (200 mL/30 mL ), brine/water mixture (200 mL/30 mL×2) and brine (230 mL×2). It was dried over MgSO4 (50 g) for 0.5 hours and concentrated to 21.3 g of semi solid. The crude semi solid was dissolved in warm THF (60 mL). The THF solution was added dropwise to a mixture of refluxing cyclohexane (600 mL) and charcoal (3.6 g). The mixture was stirred without heat for 0.5 hours and was heated to reflux. It was filtered through a celite pad and the pad was washed with a hot mixture of cyclohexane/THF (90 mL/9 mL×3). The filtrate was concentrated to 14.1 g of yellowish white solid. The charcoal treated crude product was dissolved in cyclohexane (300 mL) at reflux. Crystallization occurred upon cooling to RT. The mixture was stirred at RT for 4 hours and then at 4° C. for 13 hours. The 2-[4-Bromo-3-(formyl)-phenyl]oxazole was collected by filtration and was suction dried at RT for 13 h. It was obtained as an off-white solid in 72.3% yield, HPLC area percent 99.8. The 1H NMR and mass spectra were consistent with the assigned structure.

1. temperatureThe reaction mixture was cooled to −10° C. to 0° C. in an ice/acetone bath
2. additionwas added
3. temperatureThe reaction mixture was warmed up to RT
4. waitIt was put aside in a −40° C. freezer for 13 hours
5. stirringwas stirred at RT for another 2 hours
6. temperatureThe reaction mixture was cooled to −10° C. to 0° C. in an ice/acetone bath
7. stirringThe mixture was stirred at 0° C. to RT in 0.5 hours
8. customIt was transferred to a 2 L separatory funnel
9. customThe aqueous layer was separated
10. extractionextracted with EtOAc (300 mL×2)
11. washthe combined organic phase was washed with brine/1N HCl mixture (200 mL/30 mL ), brine/water mixture (200 mL/30 mL×2) and brine (230 mL×2)
12. dry with materialIt was dried over MgSO4 (50 g) for 0.5 hours
13. concentrationconcentrated to 21.3 g of semi solid
14. dissolutionThe crude semi solid was dissolved in warm THF (60 mL)
15. additionThe THF solution was added dropwise to a mixture of refluxing cyclohexane (600 mL) and charcoal (3.6 g)
16. stirringThe mixture was stirred
17. temperaturewithout heat for 0.5 hours
18. temperaturewas heated to reflux
19. filtrationIt was filtered through a celite pad
20. washthe pad was washed with a hot mixture of cyclohexane/THF (90 mL/9 mL×3)
21. concentrationThe filtrate was concentrated to 14.1 g of yellowish white solid
22. additionThe charcoal treated crude product
23. dissolutionwas dissolved in cyclohexane (300 mL)
24. temperatureat reflux
25. customCrystallization
26. temperatureupon cooling to RT
27. stirringThe mixture was stirred at RT for 4 hours
28. waitat 4° C. for 13 hours
29. filtrationThe 2-[4-Bromo-3-(formyl)-phenyl]oxazole was collected by filtration
30. customdried at RT for 13 h
31. customIt was obtained as an off-white solid in 72.3% yield, HPLC area percent 99.8

ORD record

ord-c5ec029248f3426b96e2d19e54ba1106

Source dataset

uspto-grants-2003_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06639082B2