反应详情

温度

0 °C

A 250 ml RBF was charged with 7′-bromo-4′-fluoro-2′-methoxy-2,6-dihydrospiro[[1,4]oxazine-3,9′-xanthen]-5-amine (2.73 g, 6.94 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (0.492 g, 0.694 mmol) and 2-fluoropyridin-3-ylboronic acid (1.467 g, 10.41 mmol). Dioxane (40 mL) and potassium carbonate (1M in water; 20.83 mL, 20.83 mmol) were added and the mixture was flushed with argon and heated at 85° C. for 30 minutes. The mixture was cooled to RT, diluted with EtOAc and the organic layer was separated and concentrated in vacuo to give a yellow residue. After triturating with 10 ml of ethanol the solid was filtered off, washed with EtOH (2×1 ml) and dried on air overnight to afford 4′-fluoro-7′-(2-fluoropyridin-3-yl)-2′-methoxy-2,6-dihydrospiro[[1,4]oxazine-3,9′-xanthen]-5-amine (2.11 g, 5.15 mmol). Step 2: To a suspension of 4′-fluoro-7′-(2-fluoropyridin-3-yl)-2′-methoxy-2,6-dihydrospiro[[1,4]oxazine-3,9′-xanthen]-5-amine (1.668 g, 4.07 mmol) in DCM (12 ml) was added boron tribromide (0.963 mL, 10.19 mmol) at 0° C. The reaction mixture was stirred for 45 hrs at 0° C. The reaction mixture was allowed to warm to RT and was stirred for additional 2 hrs. The reaction mixture was cooled to 0° C. and quenched by addition of saturated aqueous NaHCO3 solution (˜10 mL). The solvent was removed in vacuo, the mixture was diluted with water and filtered. The solid was washed with water and dried under reduced pressure to afford 5-amino-4′-fluoro-7′-(2-fluoropyridin-3-yl)-2,6-dihydrospiro[[1,4]oxazine-3,9′-xanthen]-2′-ol (1.53 g, 3.87 mmol, 95% yield). Step 3: To a suspension of 5-amino-4′-fluoro-7′-(2-fluoropyridin-3-yl)-2,6-dihydrospiro[[1,4]oxazine-3,9′-xanthen]-2′-ol (1.01 g, 2.55 mmol) in DCM (12.77 mL) were added TEA (1.424 mL, 10.22 mmol) and N-(5-chloropyridin-2-yl)-1,1,1-trifluoro-N-(trifluoromethylsulfonyl)methanesulfonamide (1.103 g, 2.81 mmol). After stirring for 2 hours the reaction mixture was washed 3× with 2N NaOH solution followed by brine. The solution was then concentrated. The yellow residue was diluted with DCM (5 ml) and the white precipitate was filtered, washed with DCM and dried under a stream of air to afford 355 mg (26%) of pure product. The filtrate was purified by chromatography (5-40% DCM/MeOH/NH4OH in DCM) to afford 5-amino-5′-fluoro-2′-(2-fluoropyridin-3-yl)-2,6-dihydrospiro[[1,4]oxazine-3,9′-xanthene]-7′-yl trifluoromethanesulfonate (880 mg, 1.668 mmol, 65.3% yield) as a white foam. Total isolated 5-amino-5′-fluoro-2′-(2-fluoropyridin-3-yl)-2,6-dihydrospiro[[1,4]oxazine-3,9′-xanthene]-7′-yl trifluoromethanesulfonate (1235 mg, 2.342 mmol, 92% yield). Step 4: A re-sealable vial was charged with 5-amino-5′-fluoro-2′-(2-fluoropyridin-3-yl)-2,6-dihydrospiro[[1,4]oxazine-3,9′-xanthene]-7′-yl trifluoromethanesulfonate (200 mg, 0.379 mmol), chloro(2-dicyclohexylphosphino-2′,6′-di-isopropoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(II) 1 (27.6 mg, 0.038 mmol) and 0.5 ml of THF. The mixture was stirred at RT until all solids were dissolved. Morpholine (66.1 μL, 0.758 mmol) and LiHMDS (1M in THF) (1138 μL, 1.138 mmol) were added and the vial was sealed and stirred at RT for 20 minutes. The reaction was quenched by addition of water (1 ml) and diluted with EtOAc (2 ml). The organic layer was separated, and the aqueous layer was extracted with EtOAc (2×2 ml). The combined organic fractions were concentrated and purified by chromatography (10-80% DCM/MeOH/NH4OH in DCM) to provide racemic 4′-fluoro-7′-(2-fluoropyridin-3-yl)-2′-morpholino-2,6-dihydrospiro[[1,4]oxazine-3,9′-xanthen]-5-amine (97 mg, 0.209 mmol, 55.1% yield). Step 5: The final compound (S)-4′-fluoro-7′-(2-fluoropyridin-3-yl)-2′-morpholino-2,6-dihydrospiro[[1,4]oxazine-3,9′-xanthen]-5-amine was obtained from racemic 4′-fluoro-7′-(2-fluoropyridin-3-yl)-2′-morpholino-2,6-dihydrospiro[[1,4]oxazine-3,9′-xanthen]-5-amine using similar chiral separation conditions as described herein for intermediate 10.

1. temperatureto warm to RT
2. stirringwas stirred for additional 2 hrs
3. temperatureThe reaction mixture was cooled to 0° C.
4. customquenched by addition of saturated aqueous NaHCO3 solution (˜10 mL)
5. customThe solvent was removed in vacuo
6. additionthe mixture was diluted with water
7. filtrationfiltered
8. washThe solid was washed with water
9. customdried under reduced pressure