Expedient Synthesis of Mequitazine an Antihistaminic Drug by Palladium Catalyzed Allylic Alkylation of Sodium Phenothiazinate

Abstract

The synthesis of therapeutically important drugs remains a major focus of attention among organic chemists in the academic world as well as in pharmaceutical companies. Particularly appealing is the notion of using green, short and scalable mild processes that rely on atom economy transformations.2-4) Importantly, a large number of synthetic bioactive molecules possess the 3-substituted quinuclidine moiety that exhibits a broad pharmacological profile (Fig. 1). [5][6][7][8][9][10] Mequitazine 1, is a potent H 1 -receptors selective antihistaminic drug widely studied and used for allergic disorders such as hay fever and urticaria. This molecule is also one of the earliest second-generation antihistamines on the market, sold as the trade name Primalan ® , which is beneficial in the symptomatic treatment of allergic rhinitis.11) Recent studies have demonstrated its potential use for the treatment of allergic conjunctivitis, and for its possible sedative properties. 12)As a consequence the development of efficient synthesis of 1 is of prime importance for clinical evaluations, and more importantly for the elucidation of the mechanism of action with different biological targets and receptors. The existing strategies for the preparation of mequitazine 1, most of which have been patented, rely mainly on the construction of the C9-N bond, either by alkylation or acylation of phenothiazine using appropriate 3-substituted quinuclidine electrophiles. [13][14][15][16][17][18] However, these approaches are plagued by severe drawbacks such as, the rapid formation of large amount of the elimination product arising from 3-halomethyl-quinuclidine electrophiles, or the degradation of the sensitive 3-acyl-quinuclidine halide derivative. As part of our ongoing program on medicinal chemistry, 16) we wish to describe a new strategic approach that circumvents these limitations in developing a reliable synthetic route for an expedient synthesis of racmequitazine. The key step of our approach is based on the palladium catalyzed allylic alkylation of sodium phenothiazinate. As shown in Chart 1, we first started with the preparation of the key allyl acetate 8. The treatment of the known epoxide 19,20) 5 with lithium diethylamide in ether under reflux conditions, resulted in a remarkably clean conversion to the corresponding allyl alcohol 6. [21][22][23] To the best of our knowledge, this selective epoxide rearrangement has never been reported earlier for bicyclo[2,2,2]heterocycles containing epoxides. [24][25][26][27][28][29] While three type of products could be obtained, allyl alcohols, aldehyde and saturated alcohols, arising most likely by carbenoid insertion processes, 24-26) the transformation was highly selective and afforded the desired crucial allyl alcohol 6 exclusively, in 96% of isolated yield (see Experimental).Alternatively, we have also discovered that 6 could be efficiently generated via the Shapiro reaction, [30][31][32] by the known trisylhydrazone 7 with excess n-BuLi followed by quenching the nucleophilic vinyllithium ...

Asymmetric Synthesis of (+)-Mequitazine from Quinine

“…Also, nucleophilic attack of a phenothiazine anion on epoxide 3 , followed by elimination of the resulting tertiary alcohol and double bond hydrogenation, allowed the multistep synthesis of mequitazine . The most recent synthetic route reported to date for the synthesis of mequitazine is from the group of Baati who described the palladium catalyzed alkylation of phenothiazine by allylic acetate 4 . The latter was prepared starting either from epoxide 3 by β-elimination or by using the Shapiro reaction.…”