The Story of Lescol:  From Research to Production

Process R&D transformed a research synthesis of fluvastatin into a commercial process. The major hurdle in the synthesis was the stereoselectivity of the syn -diol formation. The problem was attacked and solved from three directions. First, a method was developed that separated the syn and anti isomers that did not require chromatography. Second, a new, totally stereoselective synthesis, starting with phloroglucinol, was designed to produce the side-chain containing the syn -diol. And third, a new and general stereoselective reaction was invented for the reduction of β-hydroxy ketones to syn -diols. The 99% syn -selectivity of this reaction was achieved with sodium borohydride as the reducing agent, diethylmethoxyboron as the chelating agent, and tetrahydrofuran and methanol as solvents in a 4:1 ratio, at −70 °C. The final process was only six steps long, entirely stereoselective in both the E -olefin and syn -diol formation, and required no chromatography. The cost of the synthesis was thus reduced by a factor of 14.