Boron tribromide → (S)-5-amino-2'-bromo-4'-fluoro-2,6-dihydrospiro[[1,4]oxazine-3,9'-xanthen]-7'-ol

Temperature

0 °C

In a 500-mL flask, (S)-2′-bromo-4′-fluoro-7′-methoxy-2,6-dihydrospiro[[1,4]oxazine-3,9′-xanthen]-5-amine (0.676 g, 1.719 mmol) was suspended in DCM (50 mL). The suspension was cooled to 0° C., and boron tribromide (1.0 M in DCM; 5.16 mL, 5.16 mmol) was added. After 1.5 h, excess boron tribromide was quenched with saturated aqueous NH4Cl (18 mL) and aqueous NH4OH (2 mL). The aqueous phase was separated and extracted further with 5% MeOH-DCM (3×50 mL). The organics were combined, washed with brine (15 mL), dried over sodium sulfate and concentrated to afford 604 mg of (S)-5-amino-2′-bromo-4′-fluoro-2,6-dihydrospiro[[1,4]oxazine-3,9′-xanthen]-7′-ol which was used in the next step without further purification. Step 2: A flask was charged with (S)-5-amino-2′-bromo-4′-fluoro-2,6-dihydrospiro[[1,4]oxazine-3,9′-xanthen]-7′-ol (10 mg, 0.026 mmol) and dioxane (0.6 mL). Triethylamine (10.5 μL, 0.076 mmol) and di-tert-butyl dicarbonate (0.017 g, 0.076 mmol) were added, and the solution was stirred at RT for 14 h. The material was taken up in 1 M aqueous HCl (10 mL) and the aqueous phase was extracted with DCM (3×20 mL). The organics were combined, dried over sodium sulfate and concentrated. The material was purified by chromatography (30% ethyl acetate/hexane) to afford 12 mg of (S)-tert-butyl 2′-bromo-4′-fluoro-7′-hydroxy-2,6-dihydrospiro[[1,4]oxazine-3,9′-xanthene]-5-ylcarbamate. Step 3: A microwave vial was charged with potassium acetate (6.14 mg, 0.063 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (1.77 mg, 2.504 μmol), and 2-fluoropyridin-4-ylboronic acid (4.23 mg, 0.030 mmol). The (S)-tert-butyl 2′-bromo-4′-fluoro-7′-hydroxy-2,6-dihydrospiro[[1,4]oxazine-3,9′-xanthene]-5-ylcarbamate (0.012 g, 0.025 mmol) was added as a solution in 1:1 acetonitrile/dioxane (1 mL). Water (0.1 mL) was added. Argon was blown through the vessel, which was then sealed and heated in a 100° C. oil bath for 6 h. The mixture was cooled, diluted with brine (10 mL), and the aqueous layer was extracted with 10% MeOH-DCM (3×20 mL). The organics were combined, washed with dilute brine (5 mL), dried over sodium sulfate and concentrated. The residue was purified by preparative TLC (20% MeOH in DCM) to afford 3.8 mg of (S)-5-amino-4′-fluoro-2′-(2-fluoropyridin-4-yl)-2,6-dihydrospiro[[1,4]oxazine-3,9′-xanthen]-7′-ol.

1. customexcess boron tribromide was quenched with saturated aqueous NH4Cl (18 mL) and aqueous NH4OH (2 mL)
2. customThe aqueous phase was separated
3. extractionextracted further with 5% MeOH-DCM (3×50 mL)
4. washwashed with brine (15 mL)
5. dry with materialdried over sodium sulfate
6. concentrationconcentrated

ORD record

ord-d1a52e67edd94314b775ea93f27f399d

Source dataset

uspto-grants-2015_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09012446B2