Process Development for the Producton of the (S)-Acid Precursor of a Novel Elastase Inhibitor (L-694,458) through the Lipase-Catalyzed Kinetic Resolution of a β-Lactam Benzyl Ester

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A limited screen of several commercially-available and internally-produced lipases and esterases identified the lipase PS-800 as a suitable biocatalyst for the resolution of a racemic β-lactam benzyl ester to the (S)-acid. This β-lactam is a precursor to the elastase inhibitor L-694,458,an experimental drug targeted for the treatment of cystic fibrosis. Key to the development of a scalable process was the optimization of β-lactam and surfactant (Triton X-100) charges. These optimization studies yielded a 21-fold increase in the volumetric production of the (S)-acid (from 0.38 g/l to 8.0 g/l) and a 10-fold improvement in the initial bioconversion rate (from 17 mg/(l・h) to 170 mg/(l・h)). Additionally, these studies achieved the control of the (S)-acid enantiomeric excess (e.e.) which was improved from less than 65% to greater than 90%. Keys to an economical and high yielding process, both the recycling of the lipase (at levels of 90%) and the use of re-racemized unreacted (R)-benzyl ester in multiple reaction cycles were successfully demonstrated. This process was scaled up in 2.0-l reactors and afforded gram quantities of greater than 90% e.e. (S)-acid, which upon purification was successfully used to synthesize the elastase inhibitor L-694,458.
社団法人日本生物工学会の論文
1997-01-25