Sila-fexofenadine

Synthetic highlights Although not feasible from a cost-benefit point of view, racemic switch to the R(+) enantiomer is discussed. Retrosynthetic analysis of the fexofenadine molecule is presented together with some inventive synthetic steps employed. These include ZnBr2-catalyzed transposition (rearrangement) of a-haloketones to terminal carboxylic acids and microbial oxidation of the non-activated C-H bond. The concept of bioisosterism is exemplified by the silicon switch of fexofenadine to sila-fexofenadine. 

Bioisosterism Silicon Switch of Fexofenadine to Sila-Fexofenadine... 

The properties of bioisosteric compounds prompted Tacke et al. to prepare sila-fexofenadine (49) and to study the bioisosterism of this and some related Hi-receptor antagonists [55, 56]. Replacement with a silicon atom of the tert-carbon atom bearing the OH group in fexofenadine was attempted, and the synthesis of sila-fexofenadine was achieved according to Schemes 10.11-10.13. 

Scheme 10.12 Synthesis of the Si-containing building block for sila-fexofenadine...

Scheme 10.13 Final steps in the synthesis of sila-fexofenadine...

There are three key mles to be followed in retrosynthetic analysis disconnection should follow the correct mechanism, allow maximal simplification of the TM and lead to available starting materials. The fexofenadine molecule can be maximally simplified by discormections made at critical bonds (Scheme 10.3). These are disconnections at the CH2-aryl bond (a) and an alternative disconnection of the CH2-CH2Ar bond (b). In addition, disconnection of the N-CH2 bond, after FGI of the amine to an amide group, represents another possibility (c), which can be completed to create a pathway to the sila-bioisostere of fexofenadine, as described in Sect. 10.4.3. 

Two synthons C and D are the result of an alternative disconnection b of the CH2-CH2Ar bond. Finally, retrosynthetic analysis c suggests two functional group interconversions followed by disconnection of the amide N-CO bond, affording synthons E and F. This analysis has been used in the synthesis of the sila-bioisostere of fexofenadine (49), as described in Sect. 10.4.3. 

Finally, both fexofenadine and its sila-bioisostere exhibited similar in vitro pharmacological profiles. Evaluation of the effects in vivo of the C/Si switch, though, was not reported. 

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