Fexofenadine synthesis

Scheme 4. The McGill synthesis of fexofenadine (3) involving a Sonogashira reaction.

In 1996, a group from Sandoz (now part of Novartis) reported their synthesis of fexofenadine (3). Cbz protection of commercially available ethyl piperidine-4-carboxylate (34) was achieved using Af-(benzyloxycarbonyloxy)succinimide to afford 35. Treatment of 35 with three equivalents phenyl magnesium bromide led to tertiary alcohol... 

The Sonogashira reaction has been explored on laboratory scale towards the synthesis of fexofenadine and terbinafin. One of the key intermediates, arylalkyn-ol 40 for the synthesis of Fexofenadine (major metabolite of terfenadine) was achieved by the Sonogashira coupling reaction of 4-bromophenylacetic acid (39) and 3-butync-l-ol catalyzed by Pd(PPh3)4 [108]. 

Case Study 8 Fexofenadine (Scheme 23.12) is an important antihistaminic agent. The keto compound (35, Scheme 23.13), is a key intermediate in the synthesis of... 

Reductive amination of aldehydes prepared from hydrofonnylation is a useful route to amines. Botteghi, et al. reported the synthesis of racemic Tolterodine by sequential hydroformylation-reductive amination [18]. Hydroaminomethylation (tandem hydroformylation/reductive amination) has recently been used to prepare a wide variety of pharmaceutical compounds [19]. Representative examples are shown in Fig. 5. Hydroaminomethylation of 1,1-diarylethenes leads to l-(3, 3-diaiylpropyl)amines, such as fenpiprane [20, 21]. Heterocyclic aUyUc amines undergo hydroaminomethylation to form pharmaceutically active diamines, such as etymemazine [22]. Ibutilide and fexofenadine have been prepared by hydroamino-methylatiOTi of 1-aiylallyl alcohols in the presence of the requisite amines [23,24]. Although none of these reactirais has been developed into a commercial process, the widespread utility of the hydroaminomethylation reaction makes it likely that it will be used commercially... 

Whiteker GT (2010) Synthesis of fexofenadine via rhodium-catalyzed hydroaminomethylation. Top Catal 53 1025-1030... 

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. 

This synthesis of fexofenadine uses either the ester (6) or salt (13) of 4-bromo-2,2-dimethylphenylacetic acid as the Cio building block. However, neither this nor the parent 2,2-dimethylphenylacetic acid is an easily available compound. An original approach to synthesis of the 2,2,-dimethylphenylacetic acid unit was taken by Di Giacomo et al. (Scheme 10.6) [31]. In the key step, skeletal rearrangement was made of the a-halo-isopropylmethyl ketone 15 to the methyl ester of the corresponding phenylalkanoic acid 16. 

Scheme 10.5 Arylation of aldehyde in the last step of the convergent synthesis of fexofenadine...

With the availability of the intermediary acid 23, the authors achieved synthesis of racemic fexofenadine 1, as outlined in Scheme 10.8 [32]. 

According to retrosynthetic analysis (3), the C-C bond to the benzylic C atom can be formed from the suitably selected couple, the Grignard reagent of an alkyl bromide and aryl aldehyde. This is the key step in the synthesis of fexofenadine, as reported by Fang et al. [33] (Scheme 10.9). 

In this context, it is interesting that a patent claimed by Aventis Pharmaceuticals, directed towards the development of a novel method for asymmetric reduction of ketones catalyzed by Cp2TiH, was used in the preparation of intermediates in the synthesis of fexofenadine [34]. 

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...

Although of considerable interest as examples of approaches to enantioselective synthesis, these creative reactions on the route to enantiomerically pure fexofenadine remain chemical curiosities unless a way is fotmd to make them economically viable. Perhaps this may prove to be the case with a future improvement on the fexofenadine molecule. 

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