Triethylamine → (R)-N-(1-(5-(5-chloro-3-fluoro-2-(2-methyl-2H-tetrazol-5-yl)phenyl)-3-fluoropyridin-2-yl)ethyl)-4,4-difluoro-1-hydroxycyclohexanecarboxamide

Participants

Reaction Steps

To a mixture of the compound of Reference Example 4 (0.192 g, 0.547 mmol), 4-fluoro-1-hydroxycyclohex-3-ene-1-carboxylic acid (0.114 g, 0.71 mmol), (1H-1,2,3-benzotriazol-1-yloxy)[tris-(dimethylamino)]phosphonium hexafluorophosphate (0.339 g, 0.77 mmol) in 5 mL of dichloromethane was added triethylamine (0.138 g, 1.37 mmol). The reaction mixture was allowed to stir at ambient temperature for 1 hour. After the reaction was judged complete by LC/MS analysis, the volume of the reaction was reduced in vacuo. The residue was taken up in EtOAc and washed in succession with water, 0.25 N HCl and saturated aqueous sodium bicarbonate solution prior to drying over sodium sulfate. Filtration and solvent removal provided material which was subjected to chromatography on silica gel eluting with 0-50% EtOAc in hexanes to yield a mixture of diastereomers of N-((1R)-1-{5-[5-chloro-3-fluoro-2-(2-methyl-2H-tetrazol-5-yl)phenyl]-3-fluoropyridin-2-yl}ethyl)-4-fluoro-1-hydroxycyclohex-3-ene-1-carboxamide, which gave a proton NMR spectrum consistent with theory and a mass ion (ES+) of 493.1 for M+H+: 1H NMR (500 MHz, CDCl3) δ 8.12 (s, 1H), 8.03 (bd, J=7.1 Hz, NH), 7.35 (d, J=8.9 Hz, 1H), 7.28-7.25 (m, 2H), 5.43 (quint, J=6.7 Hz, 1H), 5.16 (d, J=13.4 Hz, 1H), 4.35 (s, 3H), 2.79 (d, J=17.8 Hz, 1H), 2.68 (s, OH), 2.43 (m, 1H), 2.26 (m, 1H), 2.21-2.10 (m, 2H), 1.91 (m, 1H), 1.45 (d, J=6.8 Hz, 3H).

Provenance & Evidence