An improved manufacturing process for fluvastatin

An improved manufacturing process for fluvastatin 1 has been developed by performing the condensation reaction of E-[3-(4-fluorophenyl)-1-(1-methylethyl)-1H-indol-2-yl]-2-propenal, 4, with the dianion of tert-butyl acetoacetate and the subsequent low-temperature reduction to 7-[3-(4-fluorophenyl)-1-(1-methylethyl)-1H-indol-2-yl]-3,5-dihydroxy-6-heptenoic acid-1,1-dimethylethylester, 2, without isolation of the intermediate 7-[3-(4-fluorophenyl)-1-(1-methylethyl)-1H-indol-2-yl]-5-hydroxy-3-oxo-6-heptenoic acid-1,1-dimethylethylester, 3. To be successful, a crucial selectivity problem in the conversion of aldehyde 4 to aldol 3 had to be understood and solved. The improved process allows the omission of two solvents, and the manufacture of fluvastatin at considerably lower cost and in higher throughput.