Microbial Oxidation of Non-activated C-H Bond

It was found that the fungus, C. blakesleeana, was not able to perform the complete oxidation of terfenadine to fexofenadine, because the reactimi stopped at the level of the prim-alcohol. Since the prim-alcohol cannot be selectively oxidized with strong agents, such as RuCls or HslOe, but rather this occurs with the secondary hydroxy group, the result was disappointing for the scale-up process. 

Further progress was made by Buisson et al. [40]. These authors screened a series of micro-organisms for their abiUty to oxidize the ieri-butylphenyl group in terfenadine. They defined the culture conditions required to increase the formation of the carboxylic acid and to avoid the formation of alcohols and other side products. Table 10.4 shows the products detected in crude extracts after 96 h incubation [40]. 

Micro-organisms Culture medium Terfenadine Fexofenadine Alcohol 

Two strains of bacteria and three strains of filamentous fungi were selected and cultivated in a culture medium supplemented (YMS) or not (YM) with soybean peptones (Table 10.1). Soybean peptones obtained by proteolytic digestion [43] are well known nutrient media for growing bacteria and fungi. They were found to induce oxidative activity in all strains tested. 

The best results were obtained with Absidia corymbifera cultured in YMS, with which complete transformation of terfenadine to fexofenadine was achieved. The preparative experiments carried out in 1 L of YMS and 200 mg of terfenadine led to 193 mg (93% yield) of fexofenadine. Some variation of the protocol for microbial oxidation to fexofenadine by A. corymbifera was recently reported by the same author, but no significant improvement in productivity was achieved [44]. 

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