Potassium Phosphate, Tribasic → (S)-3-chloro-7-(2-fluoropyridin-3-yl)-2',6'-dihydrospiro[chromeno[2,3-c]pyridine-5,3'-[1,4]oxazin]-5'-amine

Participants

Reaction Conditions

Reaction Steps

A vial was charged with (S)-7-bromo-3-chloro-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-5′-amine (546.36 mg, 1.435 mmol), 2-fluoropyridin-3-ylboronic acid (303 mg, 2.153 mmol), potassium phosphate (914 mg, 4.31 mmol), and bis[di-tert-butyl(4-dimethylaminophenyl)phosphine]dichloropalladium(II) (50.8 mg, 0.072 mmol). The vial was flushed with Ar (g), then dioxane (5383 μL) and water (1794 μL) were added in sequence. The vial was sealed and heated in a Biotage Initiator microwave reactor for 20 min at 90° C. The mixture was diluted with water and extracted with EtOAc (3×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography (0-100% EtOAc/Hexane) to give (S)-3-chloro-7-(2-fluoropyridin-3-yl)-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-5′-amine (510.4 mg, 95% purity) as an off-white solid. Step 2: A vial was charged with (S)-3-chloro-7-(2-fluoropyridin-3-yl)-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-5′-amine (60.4 mg, 0.152 mmol), 4,4-difluoropiperidine hydrochloride (27.7 mg, 0.228 mmol), and X-Phos Precatalyst (25.2 mg, 0.030 mmol). The vial was flushed with Ar (g), then capped with a septum. Lithium bis(trimethylsilyl)amide (1M in THF) (533 μL, 0.533 mmol) was added in one portion at rt. After 30 min. the reaction mixture was diluted with saturated aq. ammonium chloride solution and extracted with EtOAc (3×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography (30% of a 90:10:1 mixture of DCM/MeOH/NH4OH in DCM) to give 43 mg of an oil. The oil was further purified by reverse-phase HPLC (15-90% CH3CN/H2O with 0.1% TFA). Fractions containing product were combined and washed with saturated aq. sodium bicarbonate solution. The mixture was extracted with DCM (3×). The combined organic extracts were dried over sodium sulfate, and concentrated to give (S)-3-(4,4-difluoropiperidin-1-yl)-7-(2-fluoropyridin-3-yl)-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-5′-amine as a white solid. MS m/z=482.1 [M+H]+.

Provenance & Evidence