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.
Uses
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.
