1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 z Organic & Supramolecular Chemistry An Efficient and Scalable Synthesis of Fexofenadine Hydrochloride Michele Castaldi, [a, b] Marco Baratella, [b] Mauro Gaboardi, [b] Graziano Castaldi, [b] and Giovanni B. Giovenzana* [a] Allergic rhinitis (AR) is an important allergic inflammatory disease, affecting 30-60 million people annually in the USA. The most important class of drug used in the treatment of AR is second-generation H 1 -antihistamines (highly selective and non- sedating drugs) like levocetirizine, desloratadine and fexofena- dine. Different synthetic strategies are reported for the preparation of fexofenadine hydrochloride, but these ap- proaches involve the formation of byproducts, either toxic or difficult to remove. The aim of this work is to find a new, efficient and scalable synthetic approach for the preparation of fexofenadine hydrochloride. The final product was assembled from methyl 2-(4-bromophenyl)-2-methylpropanoate, 3-butyn- 1-ol and azacyclonol, cheap and commercially available raw materials. A key step allows to build the central oxygenated-C 4 - moiety through a key 5-membered intermediate, avoiding toxic or expensive reagents and catalysts. The 8-step synthesis is competitive with existing protocols, leading to fexofenadine hydrochloride in 59% overall yield. Introduction Allergic rhinitis (AR) is an allergic inflammatory disease, affecting 10-25% of people worldwide, [1] with 30 to 60 million people being affected annually in the United State. [2] The main symptoms are nasal obstruction and congestion, itching, sneezing and rhinorrea. Nasal congestion has negative effects on quality and duration of sleep and impairs the quality of life, emotional functioning, ability to perform daily activities and work/school productivity. [1] AR is commonly caused by aller- gens, which include airborne dust mite fecal particles, molds, pollens and animal danders. [2] Allergens, which penetrate the epithelial layer of the respiratory tract, are processed by antigen presenting cells and presented to histocompatibility complex molecules resulting in the development of specific TH 2 -cell clones, followed by the production of allergen-specific IgE. The IgE-mediated response is characterized by the degranulation of basophils and mast-cells which release some mediators that are able to provoke the typical symptoms of AR. [3] Histamine is the principal mediator and the AR symptoms arise following the interaction of histamine with its receptor H 1 . This receptor increase vascular and epithelial permeability in the nasal mucosa and mediate vasodilatation, resulting in congestion of the capacitance vessels and plasma extravasa- tion. [1,4,5] For these reasons a class of oral H 1 -blockers, called H 1 - antihistamines, was developed. Thus, H 1 -antihistamines are not receptor antagonist but are inverse agonists: they produce the opposite effect on the receptor to histamine. [6] First-generation antihistamines (e.g. chlorpheniramine, diphenhydramine, prom- ethazine) are no longer the preferred therapy for AR because of their adverse-effects profiles, including somnolence/sedation and anticholinergic effects. Second-generation antihistamines (e.g. fexofenadine, levocetirizine, desloratadine) have become the treatment of choice for AR. These drugs are non-sedative, selective for H 1 -receptor (no anticholinergic effects) and have longer duration of action, that allow once-daily dosing. [1] Fexofenadine hydrochloride (1) is a very important drug for the treatment of AR because is a potent, non-sedating and selective antihistamine with proven efficacy in patients affected by allergic rhinitis. Fexofenadine is highly selective for periph- eral H 1 -receptors (no interaction with muscarinic receptors, avoiding adverse cardiac effects) and does not cross the blood- brain barrier (non sedative antihistamine), being also well tolerated in children aged 2-5 years. [3] The aim of this work is to find a new, efficient and scalable synthetic approach for the preparation of fexofenadine hydrochloride. Results and Discussion The molecule of fexofenadine (Scheme 1) includes an aromatic ring (α,α-dimethylphenylacetic acid), bearing in para position an aliphatic 4-carbon aliphatic chain, terminating with azacy- clonol (2, α,α-diphenyl-4-piperidinemethanol) and carrying a hydroxyl group at the carbon atom directly connected to the aromatic ring (stereocenter, racemic in the commercial prod- uct). Retrosynthetic approaches to fexofenadine rely on a highly conserved disconnection of the azacyclonol residue, the latter being introduced as such, due to the availability of this cheap heterocyclic starting material. This allows to limit the synthetic approaches to the preparation of intermediates 3 and 4, consisting of the aralkyl portion and bearing a terminal reactive [a] Dr. M. Castaldi, Prof. G. B. Giovenzana DSF – Università del Piemonte Orientale Largo Donegani 2/3 - I-28100 - Novara - Italy E-mail: giovannibattista.giovenzana@uniupo.it [b] Dr. M. Castaldi, Dr. M. Baratella, Dr. M. Gaboardi, G. Castaldi Chemelectiva srl Strada due Ponti 12, I-28100 - Novara - Italy Supporting information for this article is available on the WWW under https://doi.org/10.1002/slct.201802808 Communications DOI: 10.1002/slct.201802808 428 ChemistrySelect 2019, 4,428–431 © 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim