Patent Description:
Umeclidinium bromide is an effective anticholinergic agent and has been used in the treatment of respiratory diseases such as asthma or chronic obstructive pulmonary disease (COPD). It is used for preparing pharmaceutical compositions to be administrated as a dry powder for oral inhalation at once-daily micrograms dose. New compositions, combinations, forms of administration (e.g. metered-dose inhalers) and dosages using umeclidinium bromide are being developed.

The compound umeclidinium bromide of molecular structure (I) depicted below is a long-acting muscarinic antagonist used in the treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema.

The synthesis of umeclidinium bromide has been claimed in <CIT> involving four steps as follows:
<CHM>.

The key intermediate ethyl <NUM>-(<NUM>-chloroethyl)piperidine-<NUM>-carboxylate of formula (II) is synthesized by reacting <NUM>-bromo-<NUM>-chloroethane and ethyl isonipecotate in the presence of potassium carbonate in acetone. However, the compound of formula (II) is prepared in very low yields (<NUM>%), due to the formation of a dimer by-product, diethyl <NUM>,<NUM>'-(ethane-<NUM>,<NUM>-diyl)bis(piperidine-<NUM>-carboxylate) (V), which must be separated from the primary compound by chromatographic techniques.

In order to overcome the dimerization issue and consequent low yields, <CIT> claims an alternative two-step process for the preparation of the compound of formula (II) in better yield (<NUM>%) as follows:
<CHM>.

There is no doubt that such synthetic alternative can lead to better yields, but the need for two reaction steps, instead of a single one as described in <CIT>, is not the best solution for an industrial application. Additionally, <CIT> discloses the use of a high temperature in the first step and the use of a highly corrosive and toxic reagent in the second step, namely thionyl chloride that produces environmentally unfriendly SOx by-products. Three major disadvantages when compared to the mild conditions described in <CIT>.

Alternatively, <CIT> claims a one-step process for the preparation of compound of formula (II) which comprises the reaction of ethyl isonipecotate with halogenated-acetaldehyde in a mixture of methanol:acetic acid together with a reducing agent as follows:
<CHM>.

Although leading to better yields (<NUM>%) in comparison to those described in <CIT> and <CIT>, the synthesis requires the use of methanolic-aqueous acidic solutions, which can degrade the ester moiety to some extent, prior to the reaction with the reductive agents.

<CIT> describes an alternative process to prepare umeclidinium bromide through the use of different intermediates as follows:
<CHM>
wherein P is a protecting group; R is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycle, aryl and heteroaryl; and X and Y are leaving groups, provided that X and Y are different.

However, this process is more complex than the process disclosed in <CIT> because it encompasses a longer synthetic route and includes extra protection-deprotection steps.

Unsolvated crystalline forms of umeclidinium bromide have been disclosed as polymorphs of the active pharmaceutical ingredient (<CIT>, <CIT>), showing that the compound may give rise to a variety of solids having distinct physical properties. The preparation of pure umeclidinium bromide in a single crystalline form has been a challenge for the industry as umeclidinium bromide is highly susceptible to forming solvates. Umeclidinium bromide solvates include a methanol solvate (<CIT>), and ethanol, <NUM>-propanol, <NUM>-methylpropan-<NUM>-ol, chlorobenzene and p-xylene solvates have been disclosed (<CIT>, <CIT>). <NUM>-Propanol has been used as the solvent in the final process step to minimize solvate formation (<CIT>) avoiding the resuspension of the compound in ethyl acetate, methanol and water, which was previously required (example <NUM>, Method B, <CIT>).

In order to fulfill the umeclidinium bromide market demand, there is a need to develop more efficient processes. Namely, processes that offer advantages over those previously disclosed in <CIT>, <CIT>, <CIT> and <CIT>. There is also a need to provide processes that prepare umeclidinium bromide in a single, pure crystalline form with a consistent level of crystallinity and chemical purity.

According to the present invention, there is provided a process comprising:.

The present invention also relates to a process for preparing umeclidinium bromide comprising:.

Also disclosed herein but not claimed are ethyl <NUM>-(<NUM>-chloroethyl)piperidine-<NUM>-carboxylate (II) obtainable by the processes of the present invention, umeclidinium bromide obtainable by the process outlined above, and pharmaceutical compositions comprising said umeclidinium bromide.

Surprisingly, it has been found that step a) of the present invention affords the key intermediate ethyl <NUM>-(<NUM>-chloroethyl)piperidine-<NUM>-carboxylate (II) in higher yields (<NUM>%) than the process disclosed in <CIT> without needing to increase the number of process steps (such as protection-deprotection steps), without needing to use high temperatures and without needing to use undesirable reagents (such as corrosive reagents, toxic reagents or methanol/aqueous acidic systems). Step a) of the present invention controls the formation of undesirable by-products such as diethyl <NUM>,<NUM>'-(ethane-<NUM>,<NUM>-diyl)bis(piperidine-<NUM>-carboxylate) (V). Ethyl <NUM>-(<NUM>-chloroethyl)piperidine-<NUM>-carboxylate (II) obtained during step a) of the present invention can be either purified or used directly in the process steps that follow without purification (e.g. purification by chromatography). The processes of the present invention enable a telescoped (or one-pot) synthesis of umeclidinium bromide, whereby the starting material is subjected to successive chemical reactions. Such a synthesis is in great demand because it improves chemical reaction efficiency by avoiding separation and purification of intermediates, thereby saving time and resources whilst increasing chemical yield.

One advantage of step a) of the present invention is that use of the ethyl <NUM>-(<NUM>-chloroethyl)piperidine-<NUM>-carboxylate (II) intermediate obtained from this process step allows the preparation of umeclidinium bromide in a single, pure crystalline form with a consistent level of crystallinity and chemical purity. Consequently, the present invention discloses processes for the preparation of umeclidinium bromide which afford a single, pure crystalline form with a consistent level of crystallinity and chemical purity.

Finally, the processes of the present invention enables the production of umeclidinium bromide with a particle size suitable for inhalation.

The present invention provides a process comprising: a) reacting ethyl isonipecotate with <NUM>-bromo-<NUM>-chloroethane in the presence of an amine in a solvent to form ethyl <NUM>-(<NUM>-chloroethyl)piperidine-<NUM>-carboxylate (II) or a salt thereof; wherein the amine is selected from the group consisting of <NUM>,<NUM>-diazabicyclo [<NUM>. <NUM>]undec-<NUM>-ene, triethylamine, pyridine, N,N-diisopropylethyl amine, <NUM>-(dimethylamino)pyridine.

The present invention also provides a process comprising the following steps:.

Steps a) to e) may be combined in the absence of step f). Steps a) to d) and f) may be combined in the absence of step e).

Step a) of the present invention may be carried out as follows:.

The solvent used in step a) may be selected from the group consisting of ketones such as acetone.

The amine used in step a) is selected from the group consisting of triethylamine, pyridine, N,N-diisopropylethylamine, <NUM>-(dimethylamino)pyridine, <NUM>,<NUM>-diazabicyclo[<NUM>. <NUM>]undec-<NUM>-ene. Preferably the organic base is triethylamine. Upon completion of the reaction of step a), solvent exchange may be performed, triethylamine salts can be removed by aqueous extraction, and the resulting solution can be concentrated to isolate the ethyl <NUM>-(<NUM>-chloroethyl)piperidine-<NUM>-carboxylate (II). By using triethylamine as the organic base, it is possible to obtain ethyl <NUM>-(<NUM>-chloroethyl)piperidine-<NUM>-carboxylate (II) in yields up to <NUM>% with a residual content of diethyl <NUM>,<NUM>'-(ethane-<NUM>,<NUM>-diyl)bis(piperidine-<NUM>-carboxylate) (V) below <NUM>%. In contrast, by performing the innovator's procedure disclosed in <CIT>, the formation of by-product diethyl <NUM>,<NUM>'-(ethane-<NUM>,<NUM>-diyl)bis(piperidine-<NUM>-carboxylate) (V) reached <NUM>%.

Step a) may be carried out at a temperature between about <NUM> and about <NUM>, preferably between about <NUM> and about <NUM>, more preferably the reaction is performed at a temperature between about <NUM> and about <NUM>. At temperatures higher than <NUM> more significant amounts of the byproduct diethyl <NUM>,<NUM>'-(ethane-<NUM>,<NUM>-diyl)bis(piperidine-<NUM>-carboxylate) (V) are obtained yielding ethyl <NUM>-(<NUM>-chloroethyl)piperidine-<NUM>-carboxylate (II) in lower yield (<NUM>%) Step a) may be carried out for a time period of between about <NUM> and about <NUM>.

After any salts (e.g. triethylamine salts) have been removed by aqueous extraction, the resulting solution can be acidified with inorganic or organic acids, preferably using hydrochloric acid, acetic acid, succinic acid or oxalic acid or solutions thereof, and the product ethyl <NUM>-(<NUM>-chloroethyl)piperidine-<NUM>-carboxylate (II) can be isolated as a salt, preferably by filtration and drying.

As disclosed above, step a) may comprise exchanging the reaction solvent. The exchange solvent may comprise one or more alkanes, such as n-heptane or a mixture of heptanes.

As also disclosed above, step a) may comprise removing the dimer by filtration. The reaction mixture may be cooled prior to filtration, optionally being cooled down to about -<NUM> and maintained at that temperature for about <NUM> to about <NUM>, optionally for about <NUM>.

Step b) of the present invention may be carried out as follows:
b) reacting ethyl <NUM>-(<NUM>-chloroethyl)piperidine-<NUM>-carboxylate (II) or a salt thereof with lithium diisopropylamide in a solvent, preferably at a temperature between about -<NUM> and about <NUM> to form ethyl <NUM>-azabicyclo[<NUM>. <NUM>]octane-<NUM>-carboxylate (III) or a salt thereof; and preferably thereafter removing any salts formed from the reaction mixture, preferably by basic aqueous extraction, and performing solvent distillation and solvent exchange.

The solvent used in step b) may be selected from the group consisting of cyclic ethers such as tetrahydrofuran (THF).

Step c) of the present invention may be carried out as follows:
c) reacting ethyl <NUM>-azabicyclo[<NUM>. <NUM>]octane-<NUM>-carboxylate (III) or a salt thereof with phenyl lithium in a solvent, preferably at a temperature between about -<NUM> to about <NUM> to form <NUM>-azabicyclo[<NUM>. <NUM>]oct-<NUM>-yl(diphenyl)methanol (IV) or a salt thereof; preferably treating the reaction mixture containing <NUM>-azabicyclo[<NUM>. <NUM>]oct-<NUM>-yl(diphenyl)methanol (IV) or a salt thereof with water and concentrating the resulting solution, and preferably thereafter adding a suitable anti-solvent to effect precipitation, and isolating the product so formed, preferably by filtration and drying, with a purity of ≥<NUM>% by HPLC.

The solvent used in step c) may be selected from the group consisting of cyclic ethers such as THF.

Step d) of the present invention may be carried out as follows:
d) reacting <NUM>-azabicyclo[<NUM>. <NUM>]oct-<NUM>-yl(diphenyl)methanol (IV) with ((<NUM>-bromoethoxy)methyl) benzene in a solvent, at a temperature between about <NUM> and about solvent reflux temperature, preferably at a temperature between about <NUM> about solvent reflux temperature to form <NUM>-[hydroxyl(diphenyl)methyl]-<NUM>-[<NUM>-(phenylmethyl)oxy]ethyl]-<NUM>-azoniabicyclo[<NUM>. <NUM>]octane bromide (I), umeclidinium bromide, and preferably cooling down the reaction mixture to a temperature between about -<NUM> and about <NUM>, preferably stirring the suspension at a temperature between about -<NUM> and about <NUM> for about <NUM>. Thereafter, the resulting product can be isolated, preferably by filtration and dried at a temperature of between about <NUM> and about <NUM>° C, preferably under vacuum, with a purity of ≥<NUM>% by HPLC, in a single crystalline form.

The solvent used in step d) may be selected from the group consisting of cyclic ethers such as THF, aromatic solvents, such as toluene, ketones such as acetone, and protic solvents such as water. Step d) may be carried out at a temperature between about <NUM> and about <NUM>, preferably optionally between about <NUM> and about <NUM>. Preferably the reaction is carried out in water at a temperature between about <NUM> to about <NUM>. Step d) may be carried out for a time period of between about <NUM> to about <NUM>. When the reaction is complete, cooling down the reaction allows umeclidinium bromide to be obtained in yields up to <NUM>%. The purity of the product obtained by following the procedure described is typically ≥<NUM>% by HPLC, in a single crystalline form. The crystalline form of the isolated umeclidinium bromide is an unsolvated form of umeclidinium bromide.

Step e) of the present invention may be carried out as follows:
e) recrystallizing the umeclidinium bromide in a solvent, at a temperature between about <NUM> to about solvent reflux temperature, preferably at a temperature between about <NUM> to about <NUM> to obtain <NUM>-[hydroxyl(diphenyl)methyl]-<NUM>-[<NUM>-(phenylmethyl)oxy]ethyl]-<NUM>-azoniabicyclo [<NUM>. <NUM>]octane bromide (I), umeclidinium bromide, and preferably cooling down the reaction mixture to a temperature between about -<NUM> and about <NUM>, preferably stirring the suspension at a temperature between about -<NUM> and about <NUM> for about <NUM>. Thereafter, the resulting product is isolated, preferably by filtration and dried at a temperature of between about <NUM> and about <NUM>, preferably under vacuum, to provide a product with a purity of ≥<NUM>% by HPLC and in a single crystalline form.

Umeclidinium bromide obtained according to the step d) of the present invention can be recrystallized. The recrystallization solvents may be selected from the group consisting of alcohols, such as <NUM>-propanol, protic solvents such as water or mixtures of both classes of solvents. Preferably recrystallization is carried out in water, optionally by suspending the material in water at a temperature between about <NUM> to about solvent reflux temperature, preferably at a temperature between about <NUM> and about <NUM>° C. The resulting solution may be cooled to a temperature between about -<NUM> and about <NUM> and the resulting suspension may be stirred at a temperature between about -<NUM> and about <NUM> for about <NUM> hours. Preferably, umeclidinium bromide is isolated (optionally by filtration), washed with water (optional) and then dried. The umeclidinium bromide may be dried under vacuum at a temperature between about <NUM> and about <NUM>. The dried product typically has a purity ≥<NUM>% by HPLC and exhibits a single crystalline form.

The X-Ray Powder Diffraction (XRPD) diffractogram, the Differential Scanning Calorimetry (DSC) thermogram, the Thermogravimetric Analysis (TGA) thermogram and HPLC chromatogram of a product obtained according to the present invention are presented in <FIG>.

Umeclidinium bromide obtained from the present invention is preferably micronized to obtain material with a particle size suitable for inhalation. Therefore, the present invention also provides a micronization process for tailoring the particle size whilst maintaining the crystalline form of umeclidinium bromide.

The following examples are provided to illustrate the process of the present invention and are not intended to be construed as limitations of the present invention; minor variations may be resorted to without departing from the spirit and scope of the present invention.

Triethylamine (<NUM>, <NUM> mmol) was added to a solution of ethyl isonipecotate (<NUM>, <NUM> mmol) in acetone (<NUM>) followed by <NUM>-bromo-<NUM>-chloroethane (<NUM>, <NUM> mmol). The reaction mixture was stirred for <NUM> at <NUM> and then concentrated under vacuum. The resulting residue was treated with water (<NUM>) and extracted with ethyl acetate (<NUM> x <NUM>). The combined organic layers were dried with MgSO<NUM>, filtered and concentrated under vacuum. The purification of the crude product was performed by flash chromatography on silica gel (gradient <NUM>:<NUM> n-hexane/ethyl acetate to <NUM>:<NUM> ethyl acetate/methanol) resulting in the desired compound (colorless liquid, <NUM>, <NUM>%) and the respective dimer (<NUM>, <NUM>%).

Ethyl <NUM>-(<NUM>-chloroethyl)-<NUM>-piperidine-<NUM>-carboxylate (II): <NUM>H-NMR (<NUM>, CDCl<NUM>) δ <NUM> (q, J = <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (t, J=<NUM>, <NUM>), <NUM> (dt, J = <NUM>, <NUM>, <NUM>), <NUM> (td, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>); <NUM>C-NMR (<NUM>, CDCl<NUM>) δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>. MS (ESI) m/z calculated for C<NUM>H<NUM>ClNO<NUM>: <NUM>, found <NUM> [M + H]+.

Diethyl <NUM>,<NUM>'-(ethane-<NUM>,<NUM>-diyl)bis(piperidine-<NUM>-carboxylate) (V): <NUM>H-NMR (<NUM>, CDCl<NUM>) δ <NUM> (q, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>); <NUM>C-NMR (<NUM>, CDCl<NUM>) δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>. MS (ESI) m/z calcd for C<NUM>H<NUM>N<NUM>O<NUM>: <NUM>, found <NUM> [M + H]+.

Triethylamine (<NUM>, <NUM> mmol) was added to a solution of ethyl isonipecotate (<NUM>, <NUM> mmol) in acetone (<NUM>) followed by <NUM>-bromo-<NUM>-chloroethane (<NUM>, <NUM> mmol). The reaction mixture was stirred for <NUM> at <NUM>. n-heptane (<NUM>) was then added and the acetone was removed under vacuum. To the resultant mixture, n-heptane (<NUM>) was added again and more acetone was removed under vacuum to obtain a volume of <NUM>. Water (<NUM>) was added to the mixture and extracted with n-heptane (<NUM> x <NUM>). The combined organic layers were dried with MgSO<NUM>, filtered and concentrated under vacuum. Further n-heptane was added (<NUM>) and the solution was placed at <NUM> for <NUM> and cooled down to -<NUM> for <NUM>. The solution was filtered to remove dimer (diethyl <NUM>,<NUM>'-(ethane-<NUM>,<NUM>-diyl)bis(piperidine-<NUM>-carboxylate) (V)) and then concentrated under vacuum. The purification of the crude product was performed by flash chromatography on silica gel (gradient <NUM>:<NUM> n-hexane/ethyl acetate to <NUM>:<NUM> ethyl acetate/methanol) resulting in the desired compound (colorless liquid, <NUM>, <NUM>%) and the respective dimer (<NUM>, <NUM>%).

A solution of ethyl isonipecotate (<NUM>, <NUM> mmol) and triethylamine (<NUM>, <NUM> mmol) in acetone (<NUM>) was slowly added over <NUM> to a solution of <NUM>-bromo-<NUM>-chloroethane (<NUM>, <NUM> mmol) in acetone (<NUM>) at <NUM>. The reaction mixture was stirred for <NUM> at <NUM> and then concentrated under vacuum. The resulting residue was treated with water (<NUM>) and extracted with diethyl ether (<NUM> x <NUM>). The combined organic layers were dried with MgSO<NUM>, filtered and concentrated under vacuum. The purification of the crude product was performed by flash chromatography on silica gel <NUM>:<NUM> n-hexane/ethyl acetate) resulting in the desired compound (colorless liquid, <NUM>, <NUM>%) and the respective dimer.

A solution of ethyl isonipecotate (<NUM>, <NUM> mmol) and triethylamine (<NUM>, <NUM> mmol) in acetone (<NUM>) was slowly added over <NUM> to a solution of <NUM>-bromo-<NUM>-chloroethane (<NUM>, <NUM> mmol) and potassium iodide (<NUM>%, <NUM> mmol, <NUM>) in acetone (<NUM>) at room temperature. The reaction mixture was stirred for <NUM> at <NUM> and then concentrated under vacuum. The resulting residue was treated with water (<NUM>) and extracted with diethyl ether (<NUM> x <NUM>). The combined organic layers were dried with MgSO<NUM>, filtered and concentrated under vacuum. The purification of the crude product was performed by flash chromatography on silica gel (<NUM>:<NUM> n-hexane/ethyl acetate) resulting in the desired compound (colorless liquid, <NUM>, <NUM>%) and the respective dimer.

N,N-diisopropylethylamine (DIPEA) (<NUM>, <NUM> mmol) was added to a solution of ethyl isonipecotate (<NUM>, <NUM> mmol) in acetone (<NUM>) followed by <NUM>-bromo-<NUM>-chloroethane (<NUM>, <NUM> mmol). The reaction mixture was stirred for <NUM> at <NUM>. Water (<NUM>) was then added, the pH was neutralized with HCl (<NUM>) and the aqueous phase was extracted with diethyl ether (<NUM> x <NUM>). The combined organic layers were dried with MgSO<NUM>, filtered and concentrated under vacuum. The crude product (<NUM>) was analyzed by <NUM>H-NMR resulting in a <NUM>:<NUM> ethyl <NUM>-(<NUM>-chloroethyl)-<NUM>-piperidine-<NUM>-carboxylate (II) to dimer.

<NUM>-dimethylaminopyridine (DMAP) (<NUM>, <NUM> mmol) was added to a solution of ethyl isonipecotate (<NUM>, <NUM> mmol) in acetone (<NUM>) followed by <NUM>-bromo-<NUM>-chloroethane (<NUM>, <NUM> mmol). The reaction mixture was stirred for <NUM> at <NUM>. Water (<NUM>) was then added, the pH was neutralized with HCl (<NUM>) and the aqueous phase was extracted with diethyl ether (<NUM> x <NUM>). The combined organic layers were dried with MgSO<NUM>, filtered and concentrated under vacuum. The crude product (<NUM>) was analyzed by <NUM>H-NMR resulting in a <NUM>:<NUM> ethyl <NUM>-(<NUM>-chloroethyl)-<NUM>-piperidine-<NUM>-carboxylate (II) to dimer.

<NUM>,<NUM>-diazabicycloundec-<NUM>-ene (DBU) (<NUM>, <NUM> mmol) was added to a solution of ethyl isonipecotate (<NUM>, <NUM> mmol) in acetone (<NUM>) followed by <NUM>-bromo-<NUM>-chloroethane (<NUM>, <NUM> mmol). The reaction mixture was stirred for <NUM> at <NUM>. Water (<NUM>) was then added, the pH was neutralized with HCl (<NUM>) and the aqueous phase was extracted with diethyl ether (<NUM> x <NUM>). The combined organic layers were dried with MgSO<NUM>, filtered and concentrated under vacuum. The crude product (<NUM>) was analyzed by <NUM>H-NMR and the dimer was not detected.

Pyridine (<NUM>, <NUM> mmol) was added to a solution of ethyl isonipecotate (<NUM>, <NUM> mmol) in acetone (<NUM>) followed by <NUM>-bromo-<NUM>-chloroethane (<NUM>, <NUM> mmol). The reaction mixture was stirred for <NUM> at <NUM>. n-heptane (<NUM>) was then added and the acetone was removed under vacuum. To the resultant mixture, n-heptane (<NUM>) was added again and more acetone was removed under vacuum to obtain a volume of <NUM>. Water (<NUM>) was added to the mixture and extracted with n-heptane (<NUM> x <NUM>). The combined organic layers were dried with MgSO<NUM>, filtered and concentrated under vacuum. The crude product (<NUM>) was analyzed by <NUM>-NMR resulting in <NUM>:<NUM> ratio of ethyl <NUM>-(<NUM>-chloroethyl)-<NUM>-piperidine-<NUM>-carboxylate (II) to dimer.

To a solution of ethyl <NUM>-(<NUM>-chloroethyl)-<NUM>-piperidine-<NUM>-carboxylate (II) (<NUM>) in ethyl acetate (<NUM>) was added hydrogen chloride (<NUM>) in ethanol (<NUM>), drop by drop, at room temperature. The solvent was removed under vacuum, resulting in a crystalline white solid.

A solution of ethyl <NUM>-(<NUM>-chloroethyl)-<NUM>-piperidine-<NUM>-carboxylate (II) (<NUM>, <NUM> mmol) in tetrahydrofuran (THF, <NUM>) was cooled down to -<NUM> under nitrogen. LDA (<NUM> in heptane/THF/ethyl benzene, <NUM>, <NUM> mmol) was added to the solution at -<NUM> over <NUM> mins. The reaction mixture was allowed to warm up to room temperature over <NUM>. The reaction was quenched with saturated aqueous K<NUM>CO<NUM> (<NUM>) and extracted with diethyl ether (<NUM> x <NUM>). The combined organic layers were dried with MgsO<NUM>, filtered and concentrated under vacuum. The resulting orange liquid was co-evaporated three times with dichloromethane to remove excess ethyl benzene, resulting in an orange oil (<NUM>, <NUM>%).

Ethyl <NUM>-azabicyclo[<NUM>. <NUM>]octane-<NUM>-carboxylate (III): <NUM>H-NMR (<NUM>, CDCl<NUM>) δ <NUM> (t, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>).

A solution of phenyllithium (<NUM> in <NUM> cyclohexane/<NUM> ether, <NUM>, <NUM> mmol) was cooled down to -<NUM> under nitrogen. A solution of ethyl <NUM>-azabicyclo[<NUM>. <NUM>]octane-<NUM>-carboxylate (III, <NUM>, <NUM> mmol) in THF (<NUM>) was slowly added to the reaction mixture at -<NUM> over <NUM> mins. The reaction mixture was allowed to warm up to room temperature over <NUM>. The reaction was quenched with water (<NUM>) and then evaporated to dryness under vacuum. Water (<NUM>) and ethyl acetate (<NUM>) were added, causing a white solid to crash out. This solid was filtered off under vacuum, to give a white powder (<NUM>, <NUM>%).

<NUM>-azabicyclo[<NUM>. <NUM>]oct-<NUM>-yl(diphenyl)methanol (IV): <NUM>H-NMR (<NUM>, CDCl<NUM>) δ <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>). MS (ESI) m/z calcd for C<NUM>H<NUM>NO: <NUM>, found <NUM> [M + H]+.

To a solution of <NUM>-azabicyclo[<NUM>. <NUM>]oct-<NUM>-yl(diphenyl)methanol (IV, <NUM>, <NUM> mmol) in THF (<NUM>) was added ((<NUM>-bromoethoxy)methyl)benzene (<NUM>, <NUM> mmol). The solution was stirred for <NUM> at <NUM>. Then the solution was cooled down to <NUM> and concentrated under vacuum, forming a white solid. The product was filtered and washed with ethyl acetate (5x20. <NUM>) and n-hexane (5x20. <NUM>) under vacuum. The white solid was then dried under vacuum (<NUM>, <NUM>%).

<NUM>-[hydroxyl(diphenyl)methyl]-<NUM>-[<NUM>(phenylmethyl)oxy]ethyl}-<NUM>-azoniabicyclo[<NUM>. <NUM>] octane bromide (I): <NUM>H-NMR (<NUM>, DMSO-d<NUM>) δ <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (b, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (bt, J=<NUM>, <NUM>). MS (ESI) m/z calcd for C<NUM>H<NUM>NO<NUM>: <NUM>, found <NUM> [M + H]+.

To a suspension of <NUM>-azabicyclo[<NUM>. <NUM>]oct-<NUM>-yl(diphenyl)methanol (IV, <NUM>, <NUM> mmol) in acetone (<NUM>) was added ((<NUM>-bromoethoxy)methyl)benzene (<NUM>, <NUM> mmol). The reaction mixture was stirred for <NUM> at <NUM><NUM>C. Then the reaction mixture was cooled down to <NUM> and concentrated under vacuum, forming a white solid. The product was filtered and washed with ethyl acetate (<NUM> x <NUM>) and n-hexane (<NUM> x <NUM>) under vacuum. The white solid was then dried under vacuum (<NUM>, <NUM>%).

To a suspension of <NUM>-azabicyclo[<NUM>. <NUM>]oct-<NUM>-yl(diphenyl)methanol (IV, <NUM>, <NUM> mmol) in toluene (<NUM>) was added ((<NUM>-bromoethoxy)methyl)benzene (<NUM>, <NUM> mmol). The reaction mixture was stirred for <NUM> at <NUM>. Then the solution was cooled down to <NUM> and concentrated under vacuum, forming a white solid. The product was filtered and washed with ethyl acetate (<NUM> x <NUM>) and n-hexane (<NUM> x <NUM>) under vacuum. The white solid was then dried under vacuum (<NUM>, <NUM>%).

To a suspension of <NUM>-azabicyclo[<NUM>. <NUM>]oct-<NUM>-yl(diphenyl)methanol (IV, <NUM>, <NUM> mmol) in toluene (<NUM>) was added ((<NUM>-bromoethoxy)methyl)benzene (<NUM>, <NUM> mmol). The reaction mixture was stirred for <NUM> under reflux. Then the reaction mixture was slowly cooled down to a temperature between <NUM><NUM>C and <NUM><NUM>C wherein a white solid precipitated. The product was filtered and washed with ethyl acetate (<NUM> x <NUM>) and n-hexane (<NUM> x <NUM>) under vacuum. The white solid was then dried under vacuum (<NUM>, <NUM>%).

To a suspension of <NUM>-azabicyclo[<NUM>. <NUM>]oct-<NUM>-yl(diphenyl)methanol (IV, <NUM>, <NUM> mmol) in water (<NUM>) was added ((<NUM>-bromoethoxy)methyl)benzene (<NUM>, <NUM> mmol). The reaction mixture was stirred for <NUM> under reflux. Then the reaction mixture was slowly cooled down to a temperature between <NUM><NUM>C and <NUM><NUM>C wherein a white solid precipitated. The product was filtered and washed with ethyl acetate (<NUM>) and n-hexane (<NUM> x <NUM>) under vacuum. The white solid was then dried under vacuum (<NUM>, <NUM>%).

To a suspension of <NUM>-azabicyclo[<NUM>. <NUM>]oct-<NUM>-yl(diphenyl)methanol (IV, <NUM>, <NUM> mmol) in water (<NUM>) and acetone (<NUM>) was added ((<NUM>-bromoethoxy)methyl)benzene (<NUM>, <NUM> mmol). The reaction mixture was stirred for <NUM> at <NUM><NUM>C. Then the reaction mixture was slowly cooled down to a temperature between <NUM><NUM>C and <NUM><NUM>C wherein a white solid precipitated. The product was filtered and washed with ethyl acetate (<NUM>) and n-hexane (<NUM> x <NUM>) under vacuum. The white solid was then dried under vacuum (<NUM>, <NUM>%).

To a suspension of <NUM>-azabicyclo[<NUM>. <NUM>]oct-<NUM>-yl(diphenyl)methanol (IV, <NUM>, <NUM> mmol) in water (<NUM>) was added ((<NUM>-bromoethoxy)methyl)benzene (<NUM>, <NUM> mmol). The reaction mixture was stirred for <NUM> at <NUM>. Then the reaction mixture was slowly cooled down to a temperature between <NUM> and <NUM> and stirred for <NUM> at a temperature between <NUM> and <NUM>. The product was filtered and washed with ethyl acetate (<NUM>) and n-hexane (<NUM> x <NUM>) under vacuum. The white solid was then dried under vacuum (<NUM>, <NUM>%).

Triethylamine (<NUM>, <NUM> mmol) was added to a solution of ethyl isonipecotate (<NUM>, <NUM> mmol) in acetone (<NUM>) followed by <NUM>-bromo-<NUM>-chloroethane (<NUM>, <NUM> mmol). The reaction mixture was stirred for <NUM> at <NUM>. n-heptane (<NUM>) was then added and the acetone was removed under vacuum. To the resultant mixture, n-heptane (<NUM>) was added again and more acetone was removed under vacuum to obtain a volume of <NUM>. Water (<NUM>) was added to the mixture and extracted with n-heptane (<NUM> x <NUM>). The combined organic layers were dried with MgSO<NUM>, filtered and concentrated under vacuum. This first crude product (<NUM>) was analyzed by <NUM>H-NMR resulting in <NUM>:<NUM> ratio of ethyl <NUM>-(<NUM>-chloroethyl)-<NUM>-piperidine-<NUM>-carboxylate (II) to dimer. Further n-heptane (<NUM>) was added to the crude product and the solution was placed at <NUM> for <NUM> and cooled down to -<NUM> for <NUM>. The solid was filtered to remove dimer and then the solution of ethyl <NUM>-(<NUM>-chloroethyl)-<NUM>-piperidine-<NUM>-carboxylate (II) was concentrated under vacuum. This second crude product (<NUM>) was analyzed by <NUM>H-NMR resulting in a <NUM>:<NUM> ratio of ethyl <NUM>-(<NUM>-chloroethyl)-<NUM>-piperidine-<NUM>-carboxylate (II) to dimer.

A solution of the second crude product (ethyl <NUM>-(<NUM>-chloroethyl)-<NUM>-piperidine-<NUM>-carboxylate (II) <NUM>) in THF (<NUM>) was cooled down to -<NUM> under nitrogen. LDA (<NUM> in hexanes/THF <NUM>, <NUM> mmol) was added to the solution at -<NUM> over <NUM> mins. The reaction mixture was allowed to warm up to room temperature over <NUM>. The reaction was quenched with saturated aqueous solution of K<NUM>CO<NUM> (<NUM>) and extracted with ethyl acetate (<NUM> x <NUM>). The combined organic layers were dried with MgSO<NUM>, filtered and concentrated under vacuum, to give crude ethyl <NUM>-azabicyclo[<NUM>. <NUM>]octane-<NUM>-carboxylate (III) as an orange oil (<NUM>).

A solution of phenyllithium (<NUM> in <NUM> cyclohexane/<NUM> ether, <NUM>, <NUM> mmol) was cooled down to -<NUM>, under nitrogen. A solution of the crude ethyl <NUM>-azabicyclo[<NUM>. <NUM>]octane-<NUM>-carboxylate (III, <NUM>) in THF (<NUM>) was slowly added to the reaction mixture at -<NUM> over <NUM> mins. The reaction mixture was allowed to warm up to room temperature over <NUM>. The reaction was quenched with water (<NUM>) and then evaporated to dryness under vacuum (result: yellow solid). Water (<NUM>) and ethyl acetate (<NUM>) were added, causing a white solid to crash out. This solid was filtered off under vacuum, to give crude <NUM>-azabicyclo[<NUM>. <NUM>]oct-<NUM>-yl(diphenyl)methanol (IV) as a white powder (<NUM>, three steps yield: <NUM>%).

To a suspension of the crude <NUM>-azabicyclo[<NUM>. <NUM>]oct-<NUM>-yl(diphenyl)methanol (IV, <NUM>, <NUM> mmol) in water (<NUM>) was added ((<NUM>-bromoethoxy)methyl)benzene (<NUM>, <NUM> mmol). The reaction mixture was stirred for <NUM> under reflux. Then the reaction mixture was slowly cooled down to a temperature between <NUM> and <NUM> and stirred for <NUM> at a temperature between <NUM> and <NUM>. The product was filtered under vacuum and excess bromide was removed by washing the compound with heptane (<NUM>). The white solid was then dried under vacuum (<NUM>, final step yield <NUM>%).

A suspension of <NUM>-[hydroxyl(diphenyl)methyl]-<NUM>-[<NUM>(phenylmethyl)oxy]ethyl}-<NUM>-azoniabicyclo[<NUM>. <NUM>] octane bromide (I, <NUM>) in water (<NUM>) was heated up <NUM>. The solution was stirred for <NUM> then slowly cooled down to a temperature between <NUM> and <NUM> and stirred for <NUM> at a temperature between <NUM> and <NUM>. The solid was filtered and dried under vacuum (<NUM>, <NUM>%).

<NUM>-[hydroxyl(diphenyl)methyl]-<NUM>-[<NUM>(phenylmethyl)oxy]ethyl}-<NUM>-azoniabicyclo[<NUM>. <NUM>] octane bromide (I, <NUM>) was fed to a fluid energy jet mill at <NUM>/h, operated with N<NUM> at a pressure of <NUM> bar for the venturi and a pressure of <NUM> bar for the ring.

The isolated product presented an XRPD identical to that of the starting material with a particle size distribution of Dv10=<NUM>; Dv50=<NUM>; Dv90=<NUM>; span= <NUM>, as depicted in <FIG>.

<NUM>-[hydroxyl(diphenyl)methyl]-<NUM>-[<NUM>(phenylmethyl)oxy]ethyl}-<NUM>-azoniabicyclo[<NUM>. <NUM>] octane bromide (I, <NUM>) was suspended in water (<NUM>) and stirred until a uniform suspension was obtained. The uniform suspension was fed to a lab scale High Pressure Homogenization equipment operated at a pressure of <NUM> bar for <NUM> cycles in total. After the homogenisation step the suspension was transferred to a holding vessel. The homogenised suspension was fed to a lab scale spray dryer whilst stirring at a feed rate of <NUM>/min and at a drying temperature of <NUM>° C (T out).

The isolated product presented an XRPD identical to that of the starting material with a particle size distribution of Dv10=<NUM>; Dv50= <NUM>; Dv90=<NUM>; span= <NUM>, as depicted in <FIG>.

<NUM>H and <NUM>C NMR spectra were recorded on a Bruker <NUM> Avance at <NUM> (<NUM>H-NMR) and <NUM> (<NUM>C-NMR).

MS experiments were performed on Micromass® Quattro Micro triple quadrupole (Waters®, Ireland) with an electrospray in positive ion mode (ESI+), ion source at <NUM>, capillary voltage of <NUM> kV and source voltage of 30V.

The HPLC analysis was conducted using a Waters® model Alliance/<NUM> and <NUM> detector (dual A) system under the following conditions:.

The X-ray powder patterns were recorded using the PANalytical X'Pert PRO X-ray diffraction system equipped with a copper source (Cu/Kα-<NUM>Å).

DSC experiments were performed on DSC Q200, Ramp <NUM>/min to <NUM>.

Claim 1:
A process comprising:
a) reacting ethyl isonipecotate with <NUM>-bromo-<NUM>-chloroethane in the presence of an amine in a solvent to form ethyl <NUM>-(<NUM>-chloroethyl)piperidine-<NUM>-carboxylate (II) or a salt thereof; wherein the amine is selected from the group consisting of <NUM>,<NUM>-diazabicyclo [<NUM>.<NUM>]undec-<NUM>-ene, triethylamine, pyridine, N,N-diisopropylethyl amine, <NUM>-(dimethylamino)pyridine.