Ethyl Acetate → 3-Methoxy-4-(2-methyl-1,3-oxazol-5-yl)benzoic acid

Temperature

120 °C

Under a nitrogen atmosphere, a mixture of zinc cyanide(II) (41.3 g), 5-(4-bromo-2-fluorophenyl)-2-methyl-1,3-oxazole (150 g), tris(dibenzylideneacetone)dipalladium(0) (10.8 g), 1,1′-bis(diphenylphosphino)ferrocene (13.0 g), zinc powder (4.60 g) and N,N-dimethylacetamide (600 mL) was stirred at 120° C. for 1 hr. The reaction mixture was diluted with ethyl acetate (1.4 L), aqueous ammonia (20%, 100 mL) and water (700 mL) were added, and the mixture was filtered through celite. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. To a mixture of the residue in DMF (880 mL) was added dropwise sodium methoxide (28% methanol solution, 170 g) at 0° C., the mixture was stirred at room temperature for 4 hr, and ice water (300 g) was added. The resulting solid was collected by filtration, washed with water, and added to 6N hydrochloric acid (1.3 L). The reaction mixture was heated under reflux for 2 days, and allowed to cool to room temperature. The resulting solid was collected by filtration, washed with water, subjected to azeotropic distillation with toluene and dried under reduced pressure to give the title compound (93.0 g).

1. additionwere added
2. filtrationthe mixture was filtered through celite
3. customThe organic layer was separated
4. extractionthe aqueous layer was extracted with ethyl acetate
5. washThe combined organic layers were washed with water and saturated brine
6. dry with materialdried over anhydrous sodium sulfate
7. customthe solvent was evaporated under reduced pressure
8. additionTo a mixture of the residue in DMF (880 mL)
9. additionwas added dropwise sodium methoxide (28% methanol solution, 170 g) at 0° C.
10. stirringthe mixture was stirred at room temperature for 4 hr
11. additionice water (300 g) was added
12. filtrationThe resulting solid was collected by filtration
13. washwashed with water
14. additionadded to 6N hydrochloric acid (1.3 L)
15. temperatureThe reaction mixture was heated
16. temperatureunder reflux for 2 days
17. temperatureto cool to room temperature
18. filtrationThe resulting solid was collected by filtration
19. washwashed with water
20. distillationsubjected to azeotropic distillation with toluene
21. customdried under reduced pressure

ORD record

ord-5da1c72d43434c898a0e9cf220e3af48

Source dataset

uspto-grants-2014_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08822699B2