Stille reaction

2-Bromo-5-fluoropyridine (13.0 g, 73.9 mmol), copper(I) iodide (2.10 g, 11.1 mmol) and dichlorobis(triphenylphosphine) palladium(II) in anhydrous acetonitrile (100 ml) was added tributyl(l-ethoxyvinyl)stannane (27.5 ml, 81.3 mmol). The reaction mixture was heated at reflux. After heating for 70 hours, 1.5 M aqueous HCl (20 ml) was added to quench the reaction and the mixture was heated at reflux for 1 hour. After cooling to room temperature, the reaction mixture was neutralized with saturated sodium bicarbonate and extracted with ether (3x100 ml). The combined organic layers were dried over dried over sodium sulfate, and concentrated. After removal of solvent, the resulted residue was purified by column chromatography (hexane: ether = 5:1) to give the title compound as a clear oil [11.3 g (75% pure), 82%].


Patent reference: WO2010020810 (astrazeneca)

To a solution of {(R)-5-[benzyl-(3-bromo-5-trifluoromethyl-benzenesulfonyl)-amino]- 5,6,7,8-tetrahydro-naphthalen-1 -yloxy}-acetic acid tert-butyl ester (1.0 g, 1.53 mmol) in λ/,λ/-dimethylformamide (8 mL) was added tris(dibenzylideneacetone)dipalladium(0) (175 mg, 0.19 mmol), triphenylarsine (175 mg, 0.572 mmol), and 1-ethoxy-vinyltributyltin (1 mL, 2.86 mmol). After being stirred at 80 °C for 2 hours under an argon atmosphere, the reaction mixture was cooled to room temperature, and then treated with 4N hydrochloric acid (1 mL), and stirred at room temperature for 20 minutes. The resulting mixture was poured into water (40 mL) and extracted with ethyl acetate (3 * 20 mL). The combined organic layers were washed with water (20 mL) and brine (20 mL), then concentrated in vacuo. The residue was purified by flash column chromatography (gradient elution: 15-30% ethyl acetate in petroleum ether) to afford {(f?)-5-[(3-acetyl-5-trifluoromethyl- benzenesulfonyl)-benzyl-amino]-5,6,7,8-tetrahydro-naphthalen-1-yloxy}-acetic acid te/t-butyl ester as a yellow oil (815 mg, 86.4%).


Patent reference: WO2010018112 (Roche)