Yield: 99.8%

Reaction Conditions:

Stage #1:2-hydroxy-5-(trifluoromethyl)pyridine with bromine;sodium acetate in acetic acid at 20 - 80; for 2.5 h;
Stage #2: with sodium hydrogencarbonate in water; pH=8

Steps:

5.A-1 4-[((1R,3S)-3-Isopropyl-3-{[3-(trifluoromethyl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl]carbonyl}cyclopentyl)amino]-1-(1,3-thiazol-2-yl)cyclohexanol
To a solution of 5-(trifluoromethyl)pyridin-2-ol (10.52 g, 62 mmol) and sodium acetate (5.29 g, 64 mmol) in glacial acetic acid (38 mL) was added bromine (3.36 mL, 65 mmol) at room temperature. The white cloudy solution slowly turned into a clear brown solution, which was heated at 80° C. for 2.5 h. The mixture was allowed to cool to room temperature and then evaporated under reduced pressure. The residue was neutralized with saturated NaHCO₃ solution to pH=8. The resulting solution was extracted with EtOAc three times. The combined extracts were dried over MgSO₄, filtered, and evaporated in vacuo to yield 15.1 g (99.8%) of the crude product (15.1 g, 98.8%) as a white solid. LC-MS calculated for C₆H₃BrF₃NO: (M+H)⁺241.9; found 241.9/243.9. Step A-2

References:

Xue, Chu-Biao;Zheng, Changsheng;Cao, Ganfeng;Feng, Hao;Xia, Michael;Anand, Rajan;Glenn, Joseph;Metcalf, Brian W. US2005/267146, 2005, A1 Location in patent:Page/Page column 22-23