Process for the manufacture of R-6-hydroxy-8-[1-hydroxy-2-[2-(4-methoxyphenyl)-1,1-dimethylethylaminoethyl]-2H-1,4-benzoxazin-3(4H)-one hydrochloride
Inventors
Capdevila Urbaneja, Enric • Huguet Clotet, Juan • Dalmases Barjoan, Pere
Assignees
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Publication Number
US-10800748-B2
Publication Date
2020-10-13
Expiration Date
Abstract
The present invention provides an improved process for the manufacture (R)-6-hydroxy-8-[1-hydroxy-2-[2-(4-methoxyphenyl)-1,1-dimethyl-ethylamino-ethyl]-2H-1,4-benzoxazin-3(4H)-one, in high purity and high yield, through the use of 1,1-dimethyl-2-(4-methoxyphenyl)ethyl amine L-tartrate salt, 1,1-dimethyl-2-(4-methoxyphenyl)ethyl amine maletate salt or the camphorsulfonate salt of intermediate (4). The invention also relates to said salts, to processes for preparing them and to their use for the manufacture of (R)-6-hydroxy-8-[1-hydroxy-2-[2-(4-methoxyphenyl)-1,1-dimethyl-ethylamino-ethyl]-2H-1,4-benzoxazin-3(4H)-one or a pharmaceutically acceptable salt thereof.
Core Innovation
The document describes an improved industrial process for manufacturing olodaterol, particularly the (R)-enantiomer and the hydrochloride salt, by using purified intermediates formed as specific amine salts. The process addresses limitations of prior-art routes by targeting impurity reduction and by increasing chemical/enantiomeric purity and yield during industrial manufacture.
A key element is the preparation and use of a camphorsulfonate salt of advanced intermediate (4), where the hydroxyl protecting group (PG) is selected from aralkyl groups. The intermediate (4) and camphorsulfonic acid are used with a defined molar ratio of 1:1, with specific PG aralkyl options such as benzyl and p-methoxybenzyl, to reduce specific dimer/isomer impurities (IMP-1/IMP-2) that otherwise carry through into olodaterol.
The document further specifies solid forms and analytical characteristics for the intermediate (4) camphorsulfonate salt, including crystalline and optionally non-crystalline forms, with characterization using DSC thermograms and/or IR absorption bands. It also describes using particular amine salts in the downstream impurity-control strategy, including 1,1-dimethyl-2-(4-methoxyphenyl)ethyl amine L-tartrate and 1,1-dimethyl-2-(4-methoxyphenyl)ethyl amine maleate, to reduce or eliminate impurities associated with hydrochloride salt issues.
Claims Coverage
The patent family includes one independent claim covering a camphorsulfonate salt of intermediate (4) with a defined PG selection and a defined 1:1 molar ratio to camphorsulfonic acid. Dependent claims further refine the allowed PG, specify crystalline/non-crystalline solid forms, and add analytical constraints (DSC onset and/or IR bands), as well as specific salt-preparation and conversion dependents relevant to olodaterol manufacture.
Camphorsulfonate salt of intermediate (4) with aralkyl PG and 1:1 molar ratio
A camphorsulfonate salt of intermediate (4), wherein PG is a hydroxyl protecting group selected from aralkyl groups, and wherein molar ratio of intermediate (4) to camphorsulfonic acid is 1:1.
Specific PG aralkyl substitution and crystalline solid form
A camphorsulfonate salt of intermediate (4), wherein PG is a hydroxyl protecting group selected from aralkyl groups, and wherein the salt is in crystalline solid form.
Crystalline solid characterized by DSC onset and/or IR absorption bands
A crystalline solid form of the camphorsulfonate salt characterized either by a DSC endothermic peak with an onset at 163–166°C or by an IR spectrum with specified absorption bands.
Preparation by camphorsulfonic acid treatment and isolation
A process for preparing the camphorsulfonate salt by treating the intermediate of formula (4) with camphorsulfonic acid in the presence of a solvent or a mixture of solvents, and then isolating the resulting camphorsulfonate salt.
Two-step route from amine/epoxide precursors to camphorsulfonate salt
A process for obtaining the camphorsulfonate salt of intermediate (4) by reacting an amine of formula (3) or a salt thereof with an epoxide of formula (2) in an organic solvent, then treating intermediate (4) with camphorsulfonic acid in the presence of a solvent or solvent mixture.
Stereochemical specification of the (R)-camphorsulfonate salt
The process is specified such that the camphorsulfonate salt of intermediate (4) used in step a) is the (R)-(-)-camphorsulfonate salt.
Overall, claim coverage centers on a camphorsulfonate salt of advanced intermediate (4) defined by an aralkyl PG selection and a 1:1 molar ratio to camphorsulfonic acid, with dependent refinements that define crystalline solid forms and analytical criteria (DSC onset and/or IR bands), and additional dependents that specify related preparation routes and (R)-(-) camphorsulfonate use in downstream processing.
Stated Advantages
increases chemical/enantiomeric purity and yield during industrial manufacture of olodaterol
reduces specific dimer/isomer impurities (IMP-1/IMP-2) carried through into olodaterol
reduces impurities (A/B) associated with hydrochloride salt carry-forward issues
reduces or eliminates impurities associated with hydrochloride salt issues
Produces the corresponding amine L-tartrate salt in high purity and/or high yield with low impurities (A/B).
Provides good stability.
Provides non-hygroscopic handling.
Camphorsulfonic acid improves chemical/enantiomeric purity of advanced intermediate (4) for purification.
Documented Applications
Manufacturing olodaterol, including the (R)-enantiomer and the hydrochloride salt, using purified intermediates formed as specific amine salts and characterized camphorsulfonate intermediates.
Industrial process routes for impurity reduction during olodaterol manufacture (e.g., targeting dimer/isomer impurities and hydrochloride-related impurity carry-forward).
Use in COPD therapy context via olodaterol products (e.g., Striverdi Respimat®) as referenced in the document.
Salt-based manufacturing to convert intermediate forms into olodaterol, including conversion to olodaterol hydrochloride (preferably the R-enantiomer) using camphorsulfonate salt of intermediate (4) and related downstream steps described in the disclosure.
A synthetic route to olodaterol (and salts), including preparation of the R-enantiomer of olodaterol hydrochloride via intermediate (4) camphorsulfonate salt formation and subsequent removal of the hydroxyl protecting group by hydrogenation.
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