Regioselective oxidation of terfenadine with Cunninghamella blakesleeana

The regioselective oxidation of terfenadine with the fungi Cunninghamella blakesleeana was studied as a biochemical alternative for the chemical synthesis of the antihistaminic drug fexofenadine. It was demonstrated that C. blakesleeana oxidises the tert-butyl group of terfenadine to the corresponding alcohol 1-[4-(1,1-dimethyl-2-hydroxyethyl)phenyl]-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-butanol. A continuous process for regioselective oxidation of terfenadine was developed. Terfenadine was supplied micro-crystalline due to the low solubility in water. Optimum reaction conditions with respect to medium composition, temperature, pH, pO2, co-substrate and feeding rates were found by means of reaction engineering studies. A cross-flow microfiltration unit was operated in a by-pass of a lab-scale stirred tank reactor for retention of the biocatalysts and the micro-crystalline substrate. The alcohol was continuously removed with the filtrate to minimise product inhibition. Continuous biotransformation of micro-crystalline terfenadine with C. blakesleeana in the membrane reactor system with a dilution rate of 33 h at co-substrate concentrations of about 1 up to 3 g/l glycerol in the reactor resulted in a space–time yield of 145 mg of alcohol/l/day and an alcohol yield of 71%. The produced alcohol was easily isolated from the filtrate by adsorption on XAD-4 resin followed by eluation with methanol (concentration factor 7).