Umeclidinium bromide

Description

Umeclidinium bromide is a long-acting muscarinic acetylcholine antagonist developed by GlaxoSmithKline and approved by the US FDA at the end of 2013 for use in combination with vilanterol, a b2 agonist, for the treatment of chronic obstructive pulmonary disease. Due to umeclidinium’s poor oral bioavailability, the drug is administrated by inhalation as dry powder.

The Uses of Umeclidinium bromide

Umeclidinium Bromide is considered as a potentially long-acting antimuscarinic agent.

Definition

ChEBI: A quaternary ammonium salt that is the bromide salt of umeclidinium. Used in combination with vilanterol for long-term maintenance treatment of airflow obstruction in patients with chronic obstructive pulmonary disease.

Synthesis

Commercially available ethyl isonipecotate (278) was alkylated with 1-bromo-2-chloroethane in the presence of K2CO3 in acetone to give ethyl 1-(2-chloroethyl)piperidine-4-carboxylate (279). This material was then treated with lithium diisopropylamine (LDA) in THF to affect a transannular substitution reaction resulting in the cyclized quinuclidine 280 in 96% yield. Excess of phenyllithium was added to ester 280 in THF starting at low temperature then gradually warming to room temperature to give tertiary alcohol 281 in 61% yield. Amine 281 was finally alkylated with benzyl 2- bromoethyl ether (282) in MeCN/CHCl3 at elevated temperatures to afford umeclidinium bromide (XXXV) in 69% yield.

References

[1] salmon m, luttmann m a, foley j j, et al. pharmacological characterization of gsk573719 (umeclidinium): a novel, long-acting, inhaled antagonist of the muscarinic cholinergic receptors for treatment of pulmonary diseases. journal of pharmacology and experimental therapeutics, 2013, 345(2): 260-270.