Trifluoroacetic acid → 3-Chloro-4-(2-(5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1h-imidazol-2-yl)ethyl)-5-fluorobenzenesulfonic acid

Participants

Reaction Steps

To a solution of tert-butyl 3-chloro-4-(2-(5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-yl)ethyl)-5-fluorophenylcarbamate (230 mg, 0.373 mmol) in DCM (anhyd, 3 mL) at 5° C. was added slowly TFA (3 mL). The flask was removed from the ice bath and stirred at ambient temperature. After 30 min, the deprotection was complete by LCMS and TLC. The mixture was concentrated to minimum volume and diluted with HOAc (1.34 mL). To this flask was added slowly cone HCl (387 μL) and water (231 μL). Then submerged flask in ice bath to attain constant temperature of 5° C. To this acidic mixture added dropwise a solution of sodium nitrite (31.7 mg, 0.458 mmol) in minimum water, while maintaining a temperature of 4-6° C. In another flask a mixture of CuCl2 (10 mg, 0.0746 mmol), HOAc (1 mL) and H2O (4 drops) was sparged with sulfur dioxide at a slow rate for 10 min, then submerged flask in ice bath at 5° C. After diazotization reaction has stirred 30-40 min at 5° C., this mixture was transferred to the second flask in small portions. After stirring 1 h, an aliquot from the mixture showed 90-95% sulfonyl chloride present by LCMS. The mixture was diluted with H2O (5 mL) and extracted with DCM (2×5 mL). Combined extracts were concentrated under reduced pressure and then dissolved in THF (3 mL). To this solution chilled to 5° C. was added dropwise 2N NaOH until the mixture attained pH 8. After stirring 10 min, the reaction mixture was concentrated under reduced pressure, diluted with H2O (3 mL) and acidified with 1N HCl. The aqueous mixture was extracted with DCM (4×5 mL). Combined extracts were washed with brine, dried (Na2SO4) and concentrated. The residue was purified by chromatography (silica, MeOH/DCM, 0-20%) to afford 3-chloro-4-(2-(5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-yl)ethyl)-5-fluorobenzenesulfonic acid (201 mg). 1H NMR (400 MHz, DMSO) δ 7.68 (s, 1H), 7.37 (s, 1H), 7.26-7.19 (m, 2H), 7.11 (d, J=8.4 Hz, 1H), 7.09 (d, J=8.7 Hz, 1H), 6.87-6.81 (m, 2H), 6.55 (d, J=2.0 Hz, 1H), 6.50 (dd, J=8.3, 2.1 Hz, 1H), 3.70 (d, J=8.1 Hz, 3H), 2.84 (t, J=7.2 Hz, 2H), 2.68 (t, J=7.3 Hz, 2H), 1.51 (s, 6H).

Provenance & Evidence