Methanol → Benzoic acid, 4-hydroxy-3-nitro-, methyl ester

Temperature

80 °C

To a solution of 4-hydroxy-3-nitrobenzoic acid (10.0 g) in methanol (100 ml), concentrated sulfuric acid (1 ml) was added and stirred at 80° C. for 19.5 hours. After the reaction mixture was concentrated, saturated aqueous sodium bicarbonate and ethyl acetate were added to the resulting residue. This mixture was stirred and the aqueous layer was then separated. The separated aqueous layer was diluted with 1M aqueous hydrochloric acid and extracted with ethyl acetate. The organic layer was washed sequentially with water and brine, and then dried over anhydrous sodium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure to give methyl 4-hydroxy-3-nitrobenzoate (10.9 g) as a yellow solid. To a solution of methyl 4-hydroxy-3-nitrobenzoate thus obtained (10.9 g) in tetrahydrofuran:methanol (1:1, 100 ml), 10% palladium on activated carbon (550 mg) was added and stirred overnight under a hydrogen atmosphere at room temperature. After the reaction mixture was filtered through celite, the solvent was distilled off under reduced pressure to give methyl 3-amino-4-hydroxybenzoate (9.1 g) as a light-brown solid. To a solution of methyl 3-amino-4-hydroxybenzoate thus obtained (9.1 g) in N,N-dimethylformamide (80 ml), potassium carbonate (37.3 g) and 1,2-dibromoethane (14 ml) were added and stirred at 130° C. for 2 hours and then stirred overnight at room temperature. After insoluble materials were filtered off, the filtrate was diluted with ethyl acetate and washed with water. The organic layer was extracted with 6M aqueous hydrochloric acid, and the resulting aqueous layer was diluted with 8M aqueous sodium hydroxide and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then filtered to remove the desiccant, followed by distilling off the solvent under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluting solvent: n-hexane:ethyl acetate=10:1 to 5:1) to give the titled compound, i.e., methyl 3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate (7.10 g) as a pink solid.

1. concentrationAfter the reaction mixture was concentrated
2. additionsaturated aqueous sodium bicarbonate and ethyl acetate were added to the resulting residue
3. stirringThis mixture was stirred
4. customthe aqueous layer was then separated
5. additionThe separated aqueous layer was diluted with 1M aqueous hydrochloric acid
6. extractionextracted with ethyl acetate
7. washThe organic layer was washed sequentially with water and brine
8. dry with materialdried over anhydrous sodium sulfate
9. filtrationAfter the desiccant was filtered off
10. distillationthe solvent was distilled off under reduced pressure

ORD record

ord-7655ef70f9df465393241579ddfb4092

Source dataset

uspto-grants-2012_07

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08222417B2