UPSCALING ENZYMATIC PROCESSES IN NON-AQUEOUS MEDIA

The present work covers the use of various enzymes in organic media as catalysts for the synthesis of pharmacologically valuable materials, on both a laboratory and a commercial scale. Several enzymatic processes, using continuous-flow bioreactors have been developed and upscaled for the continuous production of the pharmaceutically important intermediates such as (R)-1-aminoindan and its derivatives and of the chiral resolving agent (R)-1-(1-naphthy1)ethylamine. The processes consist of the subtilisin catalyzed stereoselective aminolysis of the racemic primary amines with active esters in organic solvents while suppressing competing nonenzymatic reactions. Appropriate choice of, e.g., solvents and reactant's concentration are described as well as using immobilization to enhance the enzymatic activity and to facilitate isolation of the reaction products and reprocessing the excess raw materials and recycling the solvents. The present work also covers the synthesis and enzymatic resolution of lactams, carboxylic acids, unnatural amino acids, amino amides, amino esters.