Synthesis of Fexofenadine via Rhodium-Catalyzed Hydroaminomethylation

Abstract

Rhodium-catalyzed hydroaminomethylation is employed in a new synthesis of the anti-histamines, Terfenadine and Fexofenadine. Linear selective hydroformylation is performed using a homogeneous Rh-bisphosphite catalyst, followed by reductive amination under H 2 /CO. The reaction can be performed without protection of the hydroxyl substituent in the starting olefins.

Hydroaminomethylation Beyond Carbonylation: Allene–Imine Reductive Coupling by Ruthenium‐Catalyzed Transfer Hydrogenation

“…However, in the last 15 years, due in large part to the elegant work of Eilbracht,4 hydroaminomethylation has been intensively investigated1 and utilized for the preparation of diverse pharmaceutical ingredients,5 including cinacalcet (Sensipar, Mimpara),5, 6a ibutilide (Corvert),5, 6b and fexofenadine (Allegra, Fexidine, Telfast, Fastofen, Tilfur, Vifas, Telfexo, Allerfexo) 5. 6c Recent advances in hydroaminomethylation include the use of ammonia as a reactant,4c, 7 regioselective reactions of terminal8a and internal [8b alkenes through ligand control8 or the use of directing groups,9 the evolution from rhodium‐based to ruthenium‐based catalysts,10 and the emergence of noncarbonylative strategies, including hydroaminoalkylation11 [Scheme , Eq. (2)] and photoredox catalysis [Scheme , Eq.…”

Applications of Rhodium-Catalyzed Hydroformylation in the Pharmaceutical, Agrochemical, and Fragrance Industries

“…Heterocyclic allylic amines undergo hydroaminomethylation to form pharmaceutically active diamines, such as etymemazine [22]. Ibutilide and fexofenadine have been prepared by hydroaminomethylation of 1-arylallyl alcohols in the presence of the requisite amines [23,24]. Although none of these reactions has been developed into a commercial process, the widespread utility of the hydroaminomethylation reaction makes it likely that it will be used commercially…”

Recent Advances in Amine Synthesis by Catalytic Hydroaminomethylation of Alkenes

“…Synthesis of chiral polyaminoalcohols by a two-step procedure. [33] The best reaction conditions led to at least a 98 % yield of the final isolated tetrahydroquinolines (Scheme 12). [37] Access to 1,2,3,4-tetrahydroquinolines, which are of great interest for the preparation of pharmaceuticals and agrochemicals, is possible by means of the catalyzed intramolecular hydroaminomethylation of 2-isopropenylanilines.…”

“…Very recently, Whiteker also published the synthesis of the two other structurally related antihistamine drugs, Terfenadine 29 and Fexofenadine [33,34] 30 (Scheme 10), under similar reaction conditions. The use of the diphosphite ligand 25 leads to high regioselectivities in the linear product, higher than those Scheme 6.…”

“…[37] Access to 1,2,3,4-tetrahydroquinolines, which are of great interest for the preparation of pharmaceuticals and agrochemicals, is possible by means of the catalyzed intramolecular hydroaminomethylation of 2-isopropenylanilines. [33] The best reaction conditions led to at least a 98 % yield of the final isolated tetrahydroquinolines (Scheme 12). However, this synthesis requires a large catalyst load of 5-7.5 mol % and significant reaction times of 48 h. The second series of target molecules, whose synthesis the authors were interested in, are the seven-membered-ring 2-benzazepines and 1-benzazepines, [34,38] which have proven to be interesting for their biological activity.…”