Process for the Preparation of Umeclidinium Bromide

• Main Authors: LOURENÇO, Nuno Torres, SANTOS, Maria, SOBRAL, Luis, ANTUNES, Rafael, ESPADINHA, Margarida
• Format: Patent
• Language: English
• Published: 29.08.2019
• Subjects: CHEMISTRY; HETEROCYCLIC COMPOUNDS; HUMAN NECESSITIES; HYGIENE; MEDICAL OR VETERINARY SCIENCE; METALLURGY; ORGANIC CHEMISTRY; PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES

The present invention discloses processes comprising a) reacting ethyl isonipecotate with 1-bromo-2-chloroethane in the presence of an organic base in a solvent to form ethyl 1-(2-chloroethyl)piperidine-4-carboxylate (II) or a salt thereof. Process step a) may be included in a process for preparing umeclidinium bromide that comprises further process steps: b) reacting ethyl 1-(2-chloroethyl)piperidine-4-carboxylate (II) or a salt thereof with lithium diisopropylamide in a solvent to form ethyl 1-azabicyclo[2.2.2]octane-4-carboxylate (III); c) reacting ethyl 1-azabicyclo[2.2.2]octane-4-carboxylate (III) with phenyl lithium in a solvent to form 1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (IV); and d) reacting 1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (IV) with ((2-bromoethoxy)methyl) benzene in a solvent to form 4-[hydroxyl(diphenyl)methyl]-1-[2-(phenylmethyl)oxy]ethyl]-1-azoniabicyclo[2.2.2]octane bromide (I), umeclidinium bromide. A process comprising d) reacting 1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol with ((2-bromoethoxy)methyl) benzene in a solvent to form 4-[hydroxyl(diphenyl)methyl]-1-[2-(phenylmethyl)oxy]ethyl]-1-azoniabicyclo[2.2.2]octane bromide (I), umeclidinium bromide, wherein the solvent is selected from cyclic ethers such as tetrahydrofuran, aromatic solvents, such as toluene, ketones such as acetone and protic solvents such as water or combinations thereof, optionally wherein the solvent is water is also disclosed. Umeclidinium bromide obtainable from the disclosed processes, ethyl 1-(2-chloroethyl)piperidine-4-carboxylate (II) and pharmaceutical compositions are also disclosed.