Sulfur Dioxide → 2-(4-(4-((6-Chloro-5-fluoro-3-pyridinyl)sulfonyl)-2-(1-propyn-1-yl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol

Participants

Reaction Conditions

Reaction Steps

A 50-mL round-bottomed flask solution was cooled to −78° C. and charged with 5-bromo-2-chloro-3-fluoropyridine (259 mg, 1.23 mmol, Asymchem Laboratories, Inc., Morrisville, N.C.) and diethylether (10 mL). n-BuLi (0.49 mL, 2.5M solution in hexanes, 1.23 mmol) was added and after 5 min. Sulfur dioxide (52.5 mg, 0.819 mmol, Sigma-Aldrich, St. Louis, Mo.) was then bubbled through the cold solution for 1 min. The mixture was then allowed to warm to room temperature and concentrated. To this was solid was added CH2Cl2 (10 mL) and NCS (152 mg, 1.15 mmol, Alfa Aesar, Ward Hill, Mass.) added. After 20 min, 1,1,1,3,3,3-hexafluoro-2-(4-(2-(1-propyn-1-yl)-1-piperazinyl)phenyl)-2-propanol (300 mg, 0.819 mmol, Example 241, Step 3) and triethylamine (0.457 mL, 3.28 mmol) were added to the reaction mixture. After a further 10 min at room temperature, the reaction was quenched with water (50 mL) and extracted with EtOAc (3×100 mL). The combined organics were dried (Na2SO4), filtered, and concentrated to give an oil that was purified via column chromatography on silica gel (0 to 100% EtOAc in hexanes) to give 2-(4-(4-((6-chloro-5-fluoro-3-pyridinyl)sulfonyl)-2-(1-propyn-1-yl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (165 mg) as a mixture of two isomers

Provenance & Evidence