Pivalic acid → (R)-methyl 5-hydroxy-5-(5-(4-methyl-6-(4-(trifluoromethyl)pyridin-2-ylamino)pyridin-2-yl)thiazol-2-yl)-5,6,7,8-tetrahydronaphthalene-2-carboxylate

Participants

Reaction Steps

A suspension of butyl di-1-adamantylphosphine (5.95 g, 16.59 mmol) and Pd(OAc)2 (1.862 g, 8.29 mmol) in 1,4-dioxane (100 mL) was stirred under nitrogen for 10 minutes and a yellow slurry was formed. 6-Bromo-4-methyl-N-(4-(trifluoromethyl)pyridin-2-yl)pyridin-2-amine (17.39 g, 52.4 mmol), (R)-methyl 5-hydroxy-5-(thiazol-2-yl)-5,6,7,8-tetrahydronaphthalene-2-carboxylate (enantiomer 2, 12 g, 41.5 mmol), cesium fluoride (18.90 g, 124 mmol), pivalic acid (7.22 mL, 62.2 mmol) and 1,4-dioxane (50 mL) were then added. The reaction mixture was vacuum purged with nitrogen 3 times and then heated to reflux under nitrogen for 20 hours. The reaction was cooled to rt and filtered through Celite®, washing through with EtOAc. The organic filtrate was washed sequentially with water and brine, dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 40% ethyl acetate in hexanes to afford the (R)-methyl 5-hydroxy-5-(5-(4-methyl-6-(4-(trifluoromethyl)pyridin-2-ylamino)pyridin-2-yl)thiazol-2-yl)-5,6,7,8-tetrahydronaphthalene-2-carboxylate as a pale yellow solid (18 g, 80% yield). MS ESI calcd for C27H23F3N4O3S [M+H]+ 541, found 541. 1H NMR (500 MHz, DMSO) δ 10.20 (s, 1H), 8.63 (s, 1H), 8.48 (d, J=5.0 Hz, 1H), 8.23 (s, 1H), 7.74 (s, 1H), 7.69 (d, J=8.2 Hz, 1H), 7.36 (s, 1H), 7.23-7.17 (m, 2H), 7.09 (s, 1H), 6.63 (s, 1H), 3.82 (s, 3H), 2.92-2.85 (m, 2H), 2.33-2.30 (m, 4H), 2.15-2.09 (m, 1H), 2.02-1.88 (m, 2H) ppm.

Provenance & Evidence