Hydrogen Peroxide → (5)-7-(2-Fluoropyridin-3-yl)-3-(neopentyloxy)-5',6'-dihydrospiro[chromeno[2,3-b]pyridine-5,4'-[1,3]oxazin]-2'-amine

Temperature

85 °C

In a 25-mL flask, the (R)-3-bromo-7-(2-fluoropyridin-3-yl)-5′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazin]-2′-amine (0.350 g, 0.793 mmol) was suspended in 1,1-dimethoxy-N,N-dimethylmethanamine (5.29 mL, 39.7 mmol). The reaction mixture was heated to 100° C. for 1 h. The reaction was concentrated, and the residue was taken up in 5% MeOH/DCM (60 mL) and the organic phase was extracted with dilute brine (2×8 mL), then was dried over sodium sulfate and concentrated. The residue was purified by chromatography (3.5% MeOH/DCM) to afford (R,E)-N′-(3-bromo-7-(2-fluoropyridin-3-yl)-5′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazin]-2′-yl)-N,N-dimethylformimidamide (394 mg, 0.793 mmol). Step 2: In a 100-mL resealable vessel, the potassium acetate (0.234 g, 2.381 mmol), PdCl2-dppf-DCM (0.065 g, 0.079 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (0.242 g, 0.953 mmol), (R,E)-N′-(3-bromo-7-(2-fluoropyridin-3-yl)-5′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazin]-2′-yl)-N,N-dimethylformimidamide (0.394 g, 0.794 mmol) was suspended in THF (8 mL). Argon was blown through the vessel, which was then sealed and heated in an 85° C. oil bath for 14 h. The vessel was removed from the oil bath and cooled to 0° C., and aqueous NaOH (2.5 M, 1.905 mL, 4.76 mmol) was added, followed by aqueous 30% hydrogen peroxide (0.811 mL, 7.94 mmol). The ice bath was removed, and the mixture was stirred for 45 min. The mixture was concentrated to remove most of the THF. The residue was taken up in 10% MeOH/DCM (600 mL), and the organic layer was extracted with dilute brine (2×15 mL). The organic layer was dried with magnesium sulfate, filtered, and concentrated. The crude (R,E)-N′-(7-(2-fluoropyridin-3-yl)-3-hydroxy-5′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazin]-2′-yl)-N,N-dimethylformimidamide was used in the next step without further purification. Step 3: In a 35-mL resealable vessel, cesium carbonate (0.621 g, 1.905 mmol), 1-iodo-2,2-dimethylpropane (0.211 mL, 1.587 mmol), and crude (S,E)-N′-(7-(2-fluoropyridin-3-yl)-3-hydroxy-5′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazin]-2′-yl)-N,N-dimethylformimidamide (0.344 g, 0.794 mmol) were taken up in DMF (8 mL). The vessel was sealed and heated in a 100° C. oil bath. After 6 h, the reaction was concentrated. The residue was taken up in 10% MeOH/DCM (120 mL) and the organic layer was extracted with water (2×10 mL). The organic layer was dried over MgSO4, filtered and concentrated. The residue was taken up in dioxane (8 mL), and a dioxane solution of HCl (4 M, 2 mL) was added. The vessel was sealed and heated in a 60° C. oil bath. After 1 h, the reaction was concentrated. The residue was diluted with water (30 mL) and the aqueous phase was extracted with 10% MeOH/DCM (3×50 mL). The organics were dried over magnesium sulfate, filtered, and concentrated. The material was purified by chromatography using 65:35:0.5:1 EtOAc-hexane-MeOH-Et3N to afford (5)-7-(2-fluoropyridin-3-yl)-3-(neopentyloxy)-5′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazin]-2′-amine (4.5 mg, 0.010 mmol). MS (m/z) 449 (M+H)+.

1. customwas then sealed
2. customThe vessel was removed from the oil bath
3. temperaturecooled to 0° C.
4. customThe ice bath was removed
5. concentrationThe mixture was concentrated
6. customto remove most of the THF
7. extractionthe organic layer was extracted with dilute brine (2×15 mL)
8. dry with materialThe organic layer was dried with magnesium sulfate
9. filtrationfiltered
10. concentrationconcentrated
11. customThe crude (R,E)-N′-(7-(2-fluoropyridin-3-yl)-3-hydroxy-5′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazin]-2′-yl)-N,N-dimethylformimidamide was used in the next step without further purification
12. customThe vessel was sealed
13. temperatureheated in a 100° C. oil bath
14. waitAfter 6 h
15. concentrationthe reaction was concentrated
16. extractionthe organic layer was extracted with water (2×10 mL)
17. dry with materialThe organic layer was dried over MgSO4
18. filtrationfiltered
19. concentrationconcentrated
20. additiona dioxane solution of HCl (4 M, 2 mL) was added
21. customThe vessel was sealed
22. temperatureheated in a 60° C. oil bath
23. waitAfter 1 h
24. concentrationthe reaction was concentrated
25. additionThe residue was diluted with water (30 mL)
26. extractionthe aqueous phase was extracted with 10% MeOH/DCM (3×50 mL)
27. dry with materialThe organics were dried over magnesium sulfate
28. filtrationfiltered
29. concentrationconcentrated
30. customThe material was purified by chromatography

ORD record

ord-6de14155e9a642bbadbfc61b93b0ea21

Source dataset

uspto-grants-2015_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09012446B2