Hovione Scientia Limited

Hovione International Limited

Rafael Antunes

Luis Sobral

Nuno Torres Lourenço

Margarida Espadinha

Maria Santos

Marcio Temtem

Ana Paula Filipe

Bruna Nunes

Livia Santana De Arruda

Margarida Figueiredo

Susana Saldanha

Antonio Parreira

Sara Sequeira

Nuno Torres LOURENÇO

Temtem Marcio

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.

Process for the preparation of umeclidinium bromide

A tetracycline salt comprising a tetracycline and an organic acid wherein the organic acid is oxalic acid or maleic acid is provided. The tetracycline is preferably doxycycline, minocycline, sancycline, lymecycline, tetracycline or demeclocycline, and preferred salts include oxycycline maleate, minocycline oxalate, tetracycline oxalate, demeclocycline maleate, demeclocycline oxalate, sancycline maleate, lymecycline maleate, or lymecycline oxalate. A pharmaceutical formulation comprising a tetracycline salt according to the invention is also provided, as is a medical device having coated thereon a salt or pharmaceutical formulation according to the invention. A salt of the invention, or a formulation of the invention are also provided for use as medicaments, particularly for use in the treatment or prevention of an inflammation and/or an infection. There is also provided a method of preparing a tetracycline salt, which method comprises reacting a tetracycline base with an excess of an organic acid in a solvent.

Salts of tetracyclines

The present invention relates to a novel process for the preparation of tiotropium bromide there is provided a process for preparing tiotropium bromide comprising (i) reacting scopine oxalate with diethylamine in an inert solvent to form scopine; (ii) reacting scopine and methyl di-(2-dithienyl)glycolate (MDTG) in the presence of an inorganic base, and in an inert solvent to form N-demethyltiotropium; (iii) reacting N-demethyltiotropium with bromomethane in an inert solvent to form tiotropium bromide; (iv) crystallizing tiotropium bromide in a mixture of methanol and acetone, and optionally thereafter, (v) micronizing the tiotropium bromide so formed.

Process for preparing tiotropium bromide

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Setúbal, Portugal

Rafael Antunes