Water → 2-(3-Chloro-4-pyridin-3-ylphenyl)-1,3-benzoxazole

Temperature

75 °C

A suspension of 3-chloro-4-hydroxybenzoic acid (20.0 g, 11.6 mmol) in anhydrous dichloromethane (100 mL) was treated with oxalyl chloride (20 mL, 23.2 mmol) followed by few drops of DMF at 22° C. under argon. After 2 h stirring, the solution became clear, concentrated to dryness, dissolved in dichloromethane (50 mL) and added slowly to a solution of 2-aminophenol (12.6 g, 11.6 mmol) and TEA (9 mL, 11.6 mmol) in anhydrous DMC (50 mL). After 20 min stirring, filtered off salt, concentrated the mixture to afford 4-chloro-3-hydroxy-N-phenylbenzamide as a brown solid. MS (ESI) 264(M+H)+. 4-Chloro-3-hydroxy-N-phenylbenzamide (4 g, 15.2 mmol) was treated with POCl3 (5 mL) at reflux for 1 h. Concentrated and dissolved in dichloromethane (50 mL), washed with sat. NaHCO3 (3×25 mL) and sat. brine (3×25 mL), dried (MgSO4), concentrated in vacuo. The crude residue was chromatographed on silica gel, eluting with 2:1 hexanes:EtOAc to afford 4-(1,3-benzoxazol-2-yl)-2-chlorophenol as a colorless solid. MS (ESI) 246(M+H)+. The solution of 4-(1,3-benzoxazol-2-yl)-2-methoxyphenol (800 mg, 3.3 mmol) in anhydrous DMF (10 mL) was treated with Cs2CO3 (1.1 g, 3.2 mmol) and N-phenyl trifluoromethanesulfonimide (1.2 g, 3.2 mmol) at 22° C. for 30 min. After which time it was quenched with sat. NaHCO3 (20 mL) and diluted with EtOAc (50 mL). The EtOAc solution was washed with sat. brine (3×10 ml), dried (MgSO4), filtered and concentrated in vacuo. The residue was chromatographed on silica gel, eluting with 6:1 hexanes:EtOAc to afford 4-(1,3-benzoxazol-2-yl)-2-chlorophenyl trifluoromethanesulfonate a colorless oil. MS (ESI) 378 (M+H)+. The solution of 4-(1,3-benzoxazol-2-yl)-2-chlorophenyl trifluoromethanesulfonate (150 mg, 0.4 mmol) in 6 mL of 2:1 DMF:H2O was degassed via Argon for 10 min. Then K2CO3 (137 mg, 0.99 mmol), Pd(Ph3P)4 (23 mg, 0.02 mmol), n-Bu4NBr (128 mg, 0.40 mmol) and 3-Pyridylboronic acid (73 mg, 0.60 mmol) were added at 22° C. The resulting mixture was then heated at 75° C. for 1 h under Argon. Cooled the reaction mixture to 22° C., then filtered through a pad of Celite. The filtrate was concentrated under reduced pressure to give after purification by flash chromatography (silica gel, 3:1; hexanes:EtOAc) the desired compound, as a yellow solid. 1H NMR (CDCl3, 300 MHz) δ 8.75 (d, 1H), 6.68 (dd, 1H), 8.42 (d, 1H), 8.24 (dd, 1H), 7.89 (dt, 1H), 7.81 (m, 1H), 7.63 (m, 1H), 7.52 (d, 1H), 7.42 (m, 3H). MS (ESI) 307 (M+H)+.

1. temperatureCooled the reaction mixture to 22° C.
2. filtrationfiltered through a pad of Celite
3. concentrationThe filtrate was concentrated under reduced pressure
4. customto give
5. customafter purification by flash chromatography (silica gel, 3:1; hexanes:EtOAc) the desired compound

ORD record

ord-8d2bf357927e4ef08780c9b0afbd39d0

Source dataset

uspto-grants-2006_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07087601B2