Trifluoroacetic acid → 2-(2-(3-(4-((S)-2,3-dihydroxypropoxy)-3,5-dimethylphenyl)-1,2,4-oxadiazol-5-yl)ethyl)-2-(4-fluorophenyl)cyclohexanone

関与物質

反応手順

A solution of 3-(1-(4-fluorophenyl)-2-oxocyclohexyl)propanoic acid (30 mg, 0.114 mmol, Preparation 1B) and (R)-4-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-N-hydroxy-3,5-dimethylbenzimidamide (33.4 mg, 0.114 mmol) in dichloromethane (900 μL) was treated with N,N′-diisopropylcarbodiimide (19 μL, 0.125 mmol). The reaction mixture was stirred at room temperature for 1.5 h and concentrated. The residue was dissolved in acetonitrile (900 μL) and treated with a solution of 1N tetra-n-butylammonium fluoride in THF (57 μL, 0.057 mmol). After 2.5 h, additional 1N tetra-n-butylammonium fluoride solution in THF (28 μL, 0.028 mmol) was added and stirring was continued for 16 h. The reaction mixture cooled to 0° C. and treated with TFA (1.5 mL). After 1 min, the ice bath was removed and stirring was continued for additional 55 min. The reaction mixture was concentrated and the residue was purified by reversed-phase autoprep HPLC (Phenomenex S10 30×100 mm, 40 min gradient time, Detection Wave length 220 nm, Starting solvent: 10% aq. MeOH—0.1% TFA; Final solvent: 90% aq. MeOH—0.1% TFA) to obtain 2-(2-(3-(4-((S)-2,3-dihydroxypropoxy)-3,5-dimethylphenyl)-1,2,4-oxadiazol-5-yl)ethyl)-2-(4-fluorophenyl)cyclohexanone (23.2 mg, 34% yield) as a white solid. LC/MS: m/e 483.16 (M+H)+. 1H NMR (400 MHz, CD3OD): δ ppm 7.59 (s, 2H), 7.20-7.23 (m, 2H), 7.06-7.10 (m, 2H), 3.91-3.99 (m, 1H), 3.82-3.89 (m, 1H), 3.74-3.81 (m, 1H), 3.59-3.72 (m, 2H), 2.75-2.86 (m, 1H), 2.33-2.2 (m, 2H), 2.56-2.74 (m, 2H), 2.30-2.42 (m, 2H), 2.29 (s, 6H), 2.19-2.26 (m, 1H), 2.00-2.12 (m, 1H), 1.90-2.00 (m, 1H), 1.63-1.85 (m, 4H).

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