Pivalic acid → HCID 70977363, compound

Participants

Reaction Steps

To a solution of Pd(OAc)2 (45 mg, 0.2 mmol) in 1,4-dioxane (20 mL) was added butyldi-1-adamantylphosphine (143 mg, 0.4 mmol) and the mixture was stirred at under nitrogen for 10 minutes, during which time a yellow slurry developed. Then 6-bromo-N-(4-methoxypyridin-2-yl)-4-methylpyridin-2-amine (410 mg, 1.4 mmol), methyl 5-hydroxy-5-(thiazol-2-yl)-5,6,7,8-tetrahydronaphthalene-2-carboxylate (289 mg, 1 mmol), CsF (456 mg, 3 mmol), pivalic acid (153 mg, 1.5 mmol) and 1,4-dioxane (10 mL) were added. The reaction mixture was vacuum-purged with N2 and then heated to reflux under N2 for 20 hours. After cooling to rt, the reaction was filtered through Celite®, and the organic layer was washed with water and brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a solvent system of 2:1 petroleum ether/EtOAc to afford racemic methyl 5-hydroxy-5-(5-(6-((4-methoxypyridin-2-yl)amino)-4-methylpyridin-2-yl)thiazol-2-yl)-5,6,7,8-tetrahydronaphthalene-2-carboxylate (160 mg, 52% total), which was resolved by supercritical fluid chromatography using a Chiralpak AS-H 150*4.6 mm I.D., 5 um column and a mobile phase of 5 to 40% MeOH (0.05% diethylamine) in CO2 with a flow rate 3 mL/min at a wavelength 220 nm to give two enantiomers. MS ESI calcd for C27H26N4O4S [M+H]+ 503. found 503.

Provenance & Evidence