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

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Reaction Steps

In a 150-mL resealable flask, potassium carbonate (1.557 g, 11.27 mmol 3-bromo-7-iodo-5′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazin]-2′-amine (intermediate 25 1.97 g, 4.17 mmol), 2-fluoropyridin-3-ylboronic acid (0.441 g, 3.13 mmol), and PdCl2-dppf-dcm (0.225 g, 0.275 mmol) were suspended in dioxane (18 mL) and water (6 mL). Argon was blown through the vessel, which was sealed and heated in an 85° C. oil bath for 2 h. The reaction was concentrated to remove most of the dioxane. The aqueous residue was diluted further with dilute brine (50 mL), and the aqueous phase was extracted with 10% MeOH-DCM (3×100 mL). The organics were combined, washed with dilute brine (30 mL), dried over sodium sulfate and concentrated. The residue was purified by chromatography (4% MeOH/DCM), to afford (3-bromo-7-(2-fluoropyridin-3-yl)-5′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazin]-2′-amine) (1.03 g). MS (m/z) 441/443 (M+H)+. Step 2: Intermediates ((S)-3-bromo-7-(2-fluoropyridin-3-yl)-5′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazin]-2′-amine) (intermediate 26A, 350 mg), and its enantiomer ((R)-3-bromo-7-(2-fluoropyridin-3-yl)-5′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazin]-2′-amine (intermediate 26 B, 500 mg) were obtained from racemic (3-bromo-7-(2-fluoropyridin-3-yl)-5′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazin]-2′-amine) using similar chiral separation conditions as described herein for intermediate 10. MS (m/z) 441/443 (M+H)+.

Provenance & Evidence