Zusammenfassung
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-(hydroxydiphenylmethy
l)-1-piperidinyl1-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, pO(2),
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). (C) 2000 Elsevier Science B.V. All rights
reserved.
Nutzer
