Potassium Carbonate → 3,4-Dihydro-2H-1,3-benzoxazine

Temperature

80 °C

A mixture of 8-bromo-3,6-di-tert-butyl-3,4-dihydro-2H-benzo[e][1,3]oxazine (Intermediate 1) (2.0 g, 6.13 mmol), 2-(trifluoromethyl)pyridine-5-boronic acid [purchased from Frontier Scientific] (1.17 g, 6.13 mmol) and potassium carbonate (1.27 g, 9.20 mmol) in dimethoxyethane (15 mL) and water (5 mL) was purged with nitrogen for 20 minutes. Tetrakis(triphenylphosphine)palladium(0) (354.2 mg, 0.31 mmol) was then added and the mixture heated at 80° C. in a sealed vial for 24 hours. The cooled reaction mixture was then partitioned between ethyl acetate (80 mL) and 1M aqueous sodium hydroxide (80 mL). The organic phase was separated, washed with water (80 mL) and saturated brine (80 mL), dried (MgSO4), filtered and concentrated under reduced pressure to give an orange syrup. The product was purified using flash chromatography on silica eluting with a solvent gradient of 0 to 30% ethyl acetate in hexanes to give the intermediate 3,4-dihydro-2H-benzo[e][1,3]oxazine (1.875 g, 78% yield) as a yellow syrup. The 3,4-dihydro-2H-benzo[e][1,3]oxazine (1.875 g, 4.78 mmol) was dissolved in ethanol (135 mL), 1.0 M aqueous hydrochloric acid (45 mL) added and the reaction mixture stirred at room temperature for 4 days. The reaction mixture was then concentrated under reduced pressure and the residue partitioned between ethyl acetate (100 mL) and 10% w/v aqueous sodium carbonate solution (100 mL). The organic phase was separated, washed with water (100 mL) and saturated brine (100 mL), dried (MgSO4), filtered and concentrated under reduced pressure to give a yellow syrup. The product was purified using flash chromatography on silica eluting with a solvent gradient of 0 to 30% ethyl acetate in hexanes to give the product as a yellow syrup that partially crystallized (1.435 g). The product was dissolved in absolute ethanol (50 mL), 1.0 M aqueous hydrochloric acid (15.1 mL, 15.1 mmol) added, the mixture stood for 20 minutes then concentrated under reduced pressure and the product azeotroped with absolute ethanol (3×60 mL) to give a cream solid. Diethyl ether (50 mL) and absolute ethanol (10 mL) were added and the resulting suspension stirred vigorously overnight then filtered to afford 4-(tert-butyl)-2-((tert-butylamino)methyl)-6-(6-(trifluoromethyl)pyridin-3-yl)phenol hydrochloride (1.083 g, 54% yield) as a white solid.

1. customwas purged with nitrogen for 20 minutes
2. customThe cooled reaction mixture
3. customwas then partitioned between ethyl acetate (80 mL) and 1M aqueous sodium hydroxide (80 mL)
4. customThe organic phase was separated
5. washwashed with water (80 mL) and saturated brine (80 mL)
6. dry with materialdried (MgSO4)
7. filtrationfiltered
8. concentrationconcentrated under reduced pressure
9. customto give an orange syrup
10. customThe product was purified

ORD record

ord-542af5a25e354287afdaf06c1ecbfcd2

Source dataset

uspto-grants-2016_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09409893B2