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The Story of Lescol: From Research to Production

2001; American Chemical Society; Volume: 5; Issue: 5 Linguagem: Inglês

10.1021/op0100450

1520-586X

Oljan Repič, Kapa Prasad, George T. Lee,

Microbial Natural Products and Biosynthesis

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.