Lithium Hexamethyldisilazide → (S)-7-(2-fluoropyridin-3-yl)-3-((R)-3-fluoropyrrolidin-1-yl)-2',6'-dihydrospiro[chromeno [2,3-b]pyridine-5,3'-[1,4]oxazin]-5'-amine

A vial was charged with (R)-3-fluoropyrrolidine HCl (0.021 g, 0.170 mmol), (S)-3-bromo-7-(2-fluoropyridin-3-yl)-2′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,3′-[1,4]oxazin]-5′-amine (0.050 g, 0.113 mmol) and RuPhos palladacycle (9.05 mg, 0.011 mmol). THF (1 mL) and LiHMDS (1N in THF; 0.567 mL, 0.567 mmol) were added, and the reaction mixture was allowed to stir at RT overnight. Additional RuPhos palladacycle (9.05 mg, 0.011 mmol) and LiHMDS solution (0.567 mL, 0.567 mmol) were added, and the reaction mixture was heated to 45° C. for 2 hours. The reaction mixture was then quenched with MeOH and concentrated under reduced pressure. Purification of the crude residue by column chromatography [0-100% (90:10:1 DCM/MeOH/NH4OH)/DCM] gave (S)-7-(2-fluoropyridin-3-yl)-3-((R)-3-fluoropyrrolidin-1-yl)-2′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,3′-[1,4]oxazin]-5′-amine (0.018 g, 0.040 mmol, 35.3% yield).

1. temperaturethe reaction mixture was heated to 45° C. for 2 hours
2. customThe reaction mixture was then quenched with MeOH
3. concentrationconcentrated under reduced pressure
4. customPurification of the crude residue by column chromatography [0-100% (90:10:1 DCM/MeOH/NH4OH)/DCM]

ORD record

ord-53db8d6fd0184a74aaa2e1229532e76c

Source dataset

uspto-grants-2013_07

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08497264B2