WO2022079194A1

WO2022079194A1 - Process for the production of glycopyrronium tosylate

Info

Publication number: WO2022079194A1
Application number: PCT/EP2021/078506
Authority: WO
Inventors: Frédéric CLUET
Original assignee: Pcas
Priority date: 2020-10-14
Filing date: 2021-10-14
Publication date: 2022-04-21

Abstract

The present disclosure relates to a process for the production of glycopyrronium tosylate. The disclosed process comprises the steps of: a) generating p-toluenesulfonic acid salt by reacting p-toluene sulfonic acid and a base in a first single-phase aqueous medium, and 5 b) reacting glycopyrronium bromide with p-toluenesulfonic acid salt in a second single-phase aqueous medium and isolating the resulting glycopyrronium tosylate.

Description

PROCESS FOR THE PRODUCTION OF GLYCOPYRRONIUM TOSYLATE

FIELD OF THE INVENTION

The present invention relates to a process for the production of glycopyrronium tosylate.

BACKGROUND OF THE INVENTION

Glycopyrronium is a quaternary ammonium cation of the muscarinic anticholinergic group. Glycopyrronium, typically in bromide form, has been used in the treatment of various conditions, including diarrhea, urinary incontinence, and anxiety.

Recently, the US Food and Drug Administration has approved glycopyrronium tosylate for the topical treatment of primary axillary hyperhidrosis in adults and children aged 9 years and older. Hyperhidrosis is a condition characterized by excessive sweat production beyond which is physiologically necessary for thermal regulation. Glycopyrronium tosylate has been found to reduce sweat production by blocking the activation of acetylcholine receptors in peripheral sweat glands.

Different methods have been proposed to prepare glycopyrronium tosylate. US2016/052879 describes a method of producing glycopyrronium tosylate which comprises the step of contacting glycopyrrolate base with methyl tosylate in an organic solvent, such as acetone or ethyl acetate. US2013/0211101 describes the transformation of glycopyrronium bromide directly into glycopyrronium tosylate by ion exchange with silver tosylate or via glycopyrronium acetate, the glycopyrronium acetate being obtained by reacting glycopyrronium bromide with silver acetate and then converting the obtained glycopyrronium acetate into glycopyrronium tosylate using p-toluene sulfonic acid in isopropanol. The problem of these approaches is the cost of the silver salts which is prohibitive for an industrial route of synthesis.

More recently, in WO2018/167776, another process for the preparation of glycopyrronium tosylate directly from glycopyrronium bromide was disclosed. The disclosed process comprises reacting p-toluene sulfonic acid, a base (NaOH) and glycopyrronium bromide in a bi-phasic system in presence or absence of a phase transfer catalyst. The glycopyrronium tosylate is extracted in the organic layer, the generated sodium bromide being in the aqueous layer. Glycopyrronium tosylate is then recovered by solvent exchange with cyclohexane. A further process for directly converting glycopyrronium tosylate from glycopyrronium bromide is disclosed in WO2019/021290. The disclosed process comprises the step of reacting glycopyrronium bromide with p-toluene sulfonic acid in the presence of hydrogen peroxide and cyclopentene, butene, pentene, cyclohexene, styrene, phenol or combinations thereof. In the same manner, WO 2020/095322 describes a process for preparing glycopyrronium tosylate directly from glycopyrronium bromide. Sodium tosylate is first prepared by reacting tosylic acid and sodium methoxide in a non-polar organic solvent. Sodium tosylate is then reacted with glycopyrronium bromide in the presence of water to obtain glycopyrronium tosylate.

Although different routes have been made available, a need remains for an efficient, simple, safe and cost competitive process for producing glycopyrronium tosylate at industrial scale.

SUMMARY OF THE INVENTION

The invention relates to a process for the production of glycopyrronium tosylate starting from glycopyrronium bromide which comprises the steps of: a) generating a p-toluenesulfonic acid salt by reacting p-toluene sulfonic acid and a base in a first single-phase aqueous medium, and b) reacting glycopyrronium bromide with p-toluenesulfonic acid salt in a second single-phase aqueous medium and isolating the resulting glycopyrronium tosylate.

Further aspects of the invention are as disclosed herein and in the claims.

DEFINITIONS

Glycopyrronium tosylate designates 3-[(2-cyclopentyl-2-hydroxy-2-phenylacetyl)oxy]-1 , 1-dimethylpyrrolidin-1-ium 4-methylbenzene-1 -sulfonate hydrate.

Glycopyrronium bromide designates 3-[2-Cyclopentyl(hydroxy)phenylacetoxy]-1 , 1-dimethylpyrrolidinium bromide.

The term “p-toluenesulfonic acid salt” as used herein means that p-toluenesulfonic acid is in the form of a salt comprising its conjugate base p-toluenesulfonate and a cation. The term “monoacidic base” (monobase) as used herein means that when one molecule of the base undergoes complete ionization, it produces one hydroxide ion.

The term “diacidic base” (dibase) as used herein means that when one molecule of the base undergoes complete ionization, it produces two hydroxide ions.

The term “about” means in the context of the present invention that the concerned value may be lower or higher by 10%, especially by 5%, in particular by 1 %, than the indicated value. The term “about” encompasses the indicated value and values that may be lower or higher by 10%, especially by 5%, in particular by 1 %, than the indicated value. As a matter of examples, when a range is said to vary from about X to about Y, it includes the range from X to Y and values that may be lower by 10%, especially by 5%, in particular by 1 %, than X and values that may be higher by 10%, especially by 5%, in particular by 1 % than Y.

The term “single-phase aqueous medium” as used herein shall mean a medium consisting of water and a water-miscible solvent, in which the volume of water is predominant, i.e., superior to 50 vol.%. The single-phase aqueous medium may consist of from 75 vol.% to 100 vol. % of water and from 0 vol.% to 25 vol.% of a water-miscible organic solvent. The term “water-miscible” is intended to have its conventional meaning. In particular, an organic solvent having a solubility in water lower than 1 g/L a 25°C is considered herein as being not water-miscible.

The term “reaction medium” as used herein designates the reactants (i.e., base, p-toluene sulfonic acid, glycopyrronium bromide or p-toluenesulfonic acid salt such as sodium p-toluenesulfonate) and the single-phase aqueous medium. It will be readily be understood that the composition of the reaction medium evolves along the course of the reaction. At the beginning of the reaction, it consists of the reactants and the single-phase aqueous medium. Shortly after the reactants are contacted, the reaction medium further comprises the reaction/conversion product (i.e., p-toluenesulfonic acid salt for step a) or glycopyrronium tosylate for step b)). The reaction medium is then in the form of a suspension in step b).

Percentage by weight, percentage by mole and percentage by volume are respectively abbreviated herein as wt.%, mol.% and vol.%. DESCRIPTION OF THE INVENTION

The present invention relates to a process for the production of glycopyrronium tosylate from glycopyrronium bromide.

The process comprises the steps of: a) generating p-toluenesulfonic acid salt by reacting p-toluene sulfonic acid and a base in a first single-phase aqueous medium, and b) reacting glycopyrronium bromide with p-toluenesulfonic acid salt, in particular with sodium p-toluenesulfonate, in a second single-phase aqueous medium and isolating the resulting glycopyrronium tosylate.

The first and/or second single-phase aqueous medium may independently consist of from 75 vol.% to 100 vol. % of water and from 0 vol.% to 25 vol.% of a water-miscible organic solvent, preferably from 80 vol.% to 100 vol. % of water and from 0 vol.% to 20 vol.% of a water-miscible organic solvent, or from 90 vol.% to 100 vol. % of water and from 0 vol.% to 10 vol.% of a water-miscible organic solvent. In some embodiments, the single-phase aqueous medium may consist of from 95 vol.% to 100 vol. % of water and from 0 vol.% to 5 vol.% of a water-miscible organic solvent, preferably from 98 vol.% to 100 vol. % of water and from 0 vol.% to 2 vol.% of a water-miscible organic solvent. Examples of suitable water-miscible organic solvents include, but are not limited to, methanol, ethanol, dimethylformamide, tetrahydrofuran, acetone, acetonitrile, isopropylalcohol, propan-1 -ol and mixtures thereof.

In particular, the first and/or second single-phase aqueous medium may consist in water. More particularly, the first and second single-phase aqueous medium may consist in water.

Step a: generating p-toluenesulfonic acid salt p-toluenesulfonic acid salt is generated in step a) by reacting p-toluene sulfonic acid and a base in a first single-phase aqueous medium.

The base is typically a mineral base. The base is preferably chosen from a hydroxide, a bicarbonate or a carbonate, such as an alkali metal hydroxide, an alkali metal bicarbonate or an alkali metal carbonate. More preferably, the base is selected from the group consisting of lithium hydroxide (LiOH), sodium hydroxide (NaOH), potassium hydroxide (KOH), lithium bicarbonate (LiHCO₃), sodium bicarbonate (NaHCO₃, potassium bicarbonate (KHCO3), lithium carbonate (Li₂CO₃), sodium carbonate (Na₂CO₃) and potassium carbonate (K₂CO₃). Advantageously, the base is sodium hydroxide.

The base can be used as a powder or as an aqueous solution. As a powder, it can be in its anhydrous form or in a hydrate form. p-toluenesulfonic acid can be purchased commercially. It can be anhydrous or be in a monohydrate form. p-toluenesulfonic acid salt is preferably chosen from sodium, potassium or lithium salt of p-toluenesulfonic acid. Preferably, p-toluenesulfonic acid salt is sodium salt of p-toluenesulfonic acid, i.e., sodium p-toluenesulfonate.

Typically, p-toluenesulfonic acid is reacted with from 0.9 to 1 .5 equivalents of a monoacidic base (for example hydroxide or bicarbonate) or from 0.45 to 1 .5 equivalents of a diacidic base (for example carbonate). In particular, p-toluenesulfonic acid is reacted with from 0.9 to 1.1 equivalents of a monoacidic base (for example hydroxide or bicarbonate) or from 0.45 to 1.1 equivalents of a diacidic base (for example carbonate).

In particular, sodium p-toluenesulfonate may be prepared using p-toluenesulfonic acid and a base such as sodium hydroxide, preferably sodium hydroxide 1M. Typically, equimolar amounts of p-toluenesulfonic acid and sodium hydroxide 1 M are reacted to provide the required amount of sodium p-toluenesulfonate.

The first single-phase aqueous medium is as disclosed herein above. Preferably, the first single-phase aqueous medium is water (i.e., water only).

Step b: reacting qlycopyrronium bromide with p-toluenesulfonic acid salt

Glycopyrronium bromide is reacted with p-toluenesulfonic acid salt in a second single-phase aqueous medium and the resulting glycopyrronium tosylate is isolated.

Glycopyrronium bromide and p-toluenesulfonic acid salt, such as sodium p-toluenesulfonate, are typically reacted in 3 to 5 volumes of the second single-phase aqueous medium, preferably in 4 volumes of the second single-phase aqueous medium. One volume means 1 mL per 1 gram of glycopyrronium bromide. The second single-phase aqueous medium is as disclosed herein above. Preferably, the second single-phase aqueous medium is water (i.e., water only). In some embodiments, glycopyrronium bromide and p-toluenesulfonic acid salt, such as sodium p-toluenesulfonate, are reacted in 3 to 5 volumes of water, preferably in 4 volumes of water.

Glycopyrronium bromide is typically reacted with from 0.9 to 1.1 equivalents of p-toluenesulfonic acid salt, such as sodium p-toluenesulfonate, preferably with from 0.95 to 1.05 equivalents of p-toluenesulfonic acid salt, such as sodium p-toluenesulfonate, relative to the glycopyrronium bromide. In some embodiments, glycopyrronium bromide is reacted with 1.01 or 1.03 equivalents of p-toluenesulfonic acid salt, such as sodium p-toluenesulfonate, relative to the glycopyrronium bromide.

Glycopyrronium bromide can be purchased commercially or prepared by well-known methods, such as disclosed in W02006/092617 or WO2010/115937. Any isolated glycopyrronium bromide isomer (i.e., (3R, 2S), (3S, 2R), (3S, 2S), (3R, 2R)) or any mixture of isomers may be used in the process of the present invention. In some embodiments, a mixture of (3R, 2S) and (3S, 2R) glycopyrronium bromide isomers is reacted with p-toluenesulfonic acid salt, such as sodium p-toluenesulfonate, thus providing glycopyrronium tosylate as a mixture of (3R, 2S) and (3S, 2R) isomers. The mixture of (3R, 2S) and (3S, 2R) glycopyrronium bromide isomers may be in any isomeric ratios and notably as a racemic mixture.

Step b) is typically performed under stirring, e.g., under mechanical stirring, for a period of at least about 3 hours, typically for a period ranging from about 3 hours to about 15 hours. It is to be noted that shortly after glycopyrronium bromide and p-toluenesulfonic acid salt, such as sodium p-toluenesulfonate, are contacted, glycopyrronium tosylate crystallizes. The reaction medium is then in the form of a suspension.

In step b), the reaction of glycopyrronium bromide with p-toluenesulfonic acid salt, such as sodium p-toluenesulfonate, is typically performed at a temperature ranging from about 20°C to about 65°C, preferably under stirring, e.g., under mechanical stirring, preferably for a period of at least about 3 hours, typically for a period ranging from about 3 hours to about 15 hours.

In some embodiments, the reaction of glycopyrronium bromide with p-toluenesulfonic acid salt, such as sodium p-toluenesulfonate, is performed at room temperature, i.e., 20 to 25°C, preferably under stirring, e.g., under mechanical stirring, preferably for a period of at least about 3 hours, typically for a period ranging from about 3 hours to about 15 hours. In some embodiments, the reaction of glycopyrronium bromide with p-toluenesulfonic acid salt, such as sodium p-toluenesulfonate, comprises heating glycopyrronium bromide with p-toluenesulfonic acid salt, such as sodium p-toluenesulfonate, in the second single-phase aqueous medium at about 60°C. Such a heating step may facilitate the solubilization of the reactants. The reaction medium is then filtered via hot filtration and allowed to cool to room temperature (i.e., 20 to 25°C), thereby causing glycopyrronium tosylate to crystallize. The cooled reaction medium (suspension) is then stirred for a period ranging from about 3 hours to about 15 hours. Glycopyrronium tosylate is then collected.

The step of isolating the resulting glycopyrronium tosylate may be performed by any conventional means, such as by filtration or centrifugation.

The isolated glycopyrronium tosylate may then be washed, preferably with water, dried and, if desired, further purified. Purification may be performed by any suitable known conventional methods.

Concomitant steps a) and b)

In some embodiments, steps a) and b) are concomitant, i.e., steps a) and b) are not performed sequentially but at the same time. In these embodiments, at the beginning of the process, the reaction medium comprises p-toluene sulfonic acid, a base, glycopyrronium bromide and the single-phase aqueous medium. In other terms, in these embodiments, p-toluenesulfonic acid salt is generated in situ and reacts concomitantly with glycopyrronium bromide. The first and second aqueous media are then the same. There is only one reaction medium.

In these embodiments, glycopyrronium bromide is typically reacted with from 0.9 to 1.1 equivalents, or from 0.95 to 1.05 equivalents, or 1.01 equivalent, or 1.03 equivalents, of p-toluenesulfonic acid relative to the glycopyrronium bromide and either about 1 equivalent of monoacidic base relative to the p-toluenesulfonic acid or from 0.45 to 1.1 of diacidic base relative the p-toluenesulfonic acid.

In some embodiments, glycopyrronium bromide is reacted with from 0.9 to 1.1 equivalents, or from 0.95 to 1.05 equivalents, or 1.01 equivalent, or 1.03 equivalents, of p-toluenesulfonic acid relative to the glycopyrronium bromide and 1 equivalent of sodium hydroxide 1 M relative to the p-toluenesulfonic acid.

In particular, sodium p-toluenesulfonate may be prepared using p-toluenesulfonic acid and a base, such as sodium hydroxide, preferably sodium hydroxide 1 M. Thus, in some embodiments, the process of the present invention comprises the step of reacting glycopyrronium bromide with p-toluenesulfonic acid and a base, e.g., sodium hydroxide, in a single-phase aqueous medium.

Typically, equimolar amounts of p-toluenesulfonic acid and sodium hydroxide 1 M are reacted to provide the required amount of sodium p-toluenesulfonate.

In these embodiments, the reaction conditions (e.g., volume of the single-phase aqueous medium, stirring, temperature, time) are as disclosed in connection with step b).

Sequential steps a) and b)

In some embodiments, step a) and b) are sequential, i.e. , step b) is performed after step a).

In some embodiments, the first single-phase aqueous medium is evaporated at the end of step a). The process comprises then a step of evaporating the first single-phase aqueous medium between steps a) and b). A solid form of p-toluenesulfonic acid salt is then obtained. Step b) is then performed.

The step of reacting glycopyrronium bromide with p-toluenesulfonic acid salt, such as sodium p-toluenesulfonate, in a second single-phase aqueous medium may then be performed by adding p-toluenesulfonic acid salt, such as sodium p-toluenesulfonate, to the glycopyrronium bromide previously dissolved in the second single-phase aqueous medium. In some embodiments, the step of reacting glycopyrronium bromide with p-toluenesulfonic acid salt, such as sodium p-toluenesulfonate, is performed by adding p-toluenesulfonic acid salt, such as sodium p-toluenesulfonate, to glycopyrronium bromide previously dissolved in water.

Alternatively, the step of reacting glycopyrronium bromide with p-toluenesulfonic acid salt, such as sodium p-toluenesulfonate, may be performed by adding the second single-phase aqueous medium, typically water, to the p-toluenesulfonic acid salt, such as sodium p-toluenesulfonate, and glycopyrronium bromide (in solid forms).

Alternatively, the step of reacting glycopyrronium bromide with p-toluenesulfonic acid salt, such as sodium p-toluenesulfonate, may be performed by adding p-toluenesulfonic acid salt, such as sodium p-toluenesulfonate previously dissolved in the second single-phase aqueous medium to glycopyrronium bromide either in solid form or previously dissolved in the second single-phase aqueous medium.

Further aspects of step b) may be as disclosed herein above.

In these embodiments, the second single-phase aqueous medium may be identical to, or different from, the first single-phase aqueous medium. In some embodiments, the first single-phase aqueous medium is not evaporated at the end of step a). In these embodiments, glycopyrronium bromide may be directly added to the reaction medium (i.e., in the first single-phase aqueous medium) obtained at the end of step a). Glycopyrronium bromide may be added in solid form to the first single-phase aqueous medium (the second single-phase aqueous medium then consist in the first single-phase aqueous medium) or in a solubilized form, i.e., solubilized in the second single-phase aqueous medium, for instance an aqueous solution, which may be identical or different from the first single-phase aqueous medium.

Alternatively, the reaction medium obtained at the end of step a) may be added to glycopyrronium bromide. Glycopyrronium bromide may be in solid form or in a solubilized form, i.e., solubilized in the second single-phase aqueous medium, for instance an aqueous solution, which may be identical or different from the first single-phase aqueous medium.

The process according to the present invention allows preparing glycopyrronium tosylate with good reaction % yields, i.e., yields of at least 65%, typically higher than 70%.

Advantageously, the process according to the present invention allows to readily isolate glycopyrronium tosylate, in particular when compared to the process disclosed in WO2018/167776 which allows recovering glycopyrronium tosylate after performing an organic extraction, evaporating the solvent and recrystallisation. Hence, the process according to the present invention is a simple and economical process for the preparation of glycopyrronium tosylate at industrial scale which does not require the use of potentially toxic organic solvents and which makes it possible to obtain glycopyrronium tosylate with yields equivalent, or even greater than those achieved in WO2018/167776 or WO 2020/095322. Advantageously, the process of the present invention does not require the use of phase transfer catalysts which may be costly.

Embodiments of the present invention will now be described by way of the following examples which are provided for illustrative purposes only, and not intended to limit the scope of the disclosure. EXAMPLES

In the below examples, a racemic mixture of (3R, 2S) and (3S, 2R) glycopyrronium bromide isomers was used as reactant.

Example 1 (concomitant steps a) and b))

In a 250mL flask were introduced 114 mL (114 mmol, 1.01 eq) of 1 M NaOH, 21.70 g (114 mmol, 1.01 eq) of p-toluene sulfonic acid monohydrate and 45g (113 mmol) of glycopyrronium bromide and 67.5 mL water. The solution crystallizes few minutes later. The suspension was stirred for 3 hours at room temperature, then filtered and washed by 4x 45 mL of water (AgNO₃ test on mother liquor until no trace of bromide). The cake was then dried at 50°C in a ventilated oven. 43.51g (76%) of glycopyrronium tosylate as white powder were thus obtained.

¹H NMR (400MHz, DMSO-d₆) : d-1.15 (m,1 H), 1.20 (m,1 H), 1.40 (m,1 H), 1.50 (m,2H), 1.60 (m,1 H), 2.05 (m,1 H), 2.30 (s,3H), 2.65 (m,1 H), 2.90 (m,1 H), 3.05 (s,3H), 3.15 (s,3H), 3.50 (m,1 H), 3.60 (d,1 H), 3.70 (m,1 H), 3.80 (dd,1 H), 5.37 (m,1 H), 5.82 (s,1 H),7.10 (d,2H), 7.27 (t,1 H), 7.35 (t,1 H), 7.47 (d,2H), 7.59 (d,2H)

Example 2 (step b))

In a 25mL flask were introduced 2g (5.02 mmol) of glycopyrronium bromide in 8 mL of water and 0,98 g of sodium p-toluenesulfonate (5.07 mmol, 1.01 eq). The solution crystallizes few minutes later. The suspension was stirred for 3 hours at room temperature, then filtered and washed by 4x 3 mL of water (AgNO₃ test on mother liquor until no trace of bromide). The cake was dried at 50°C in a ventilated oven. 1.87g (73%) of glycopyrronium tosylate as white powder were thus obtained.

¹H NMR (400 MHz, DMSO-d₆) : d-1.15 (m,1 H), 1.20 (m,1 H), 1.40 (m,1 H), 1.50 (m,2H), 1.60 (m,1 H), 2.05 (m,1 H), 2.30 (s,3H), 2.65 (m,1 H), 2.90 (m,1 H), 3.05 (s,3H), 3.15 (s,3H), 3.50 (m,1 H), 3.60 (d,1 H), 3.70 (m,1 H), 3.80 (dd,1 H), 5.37 (m,1 H), 5.82 (s,1 H),7.10 (d,2H), 7.27 (t,1 H), 7.35 (t,1 H), 7.47 (d,2H), 7.59 (d,2H) Example 3 (step b))

In a 500 mL flask were introduced under mechanical stirring 100g (251.05 mmol) of glycopyrronium bromide, 50 g (257.49 mmol, 1.03 eq) of sodium p-toluenesulfonate and then 400 mL (4 vol.) of water at 20°C. The mixture was then heated to 60°C and hot filtered under vacuum. The filtrate was then cooled down to 20°C over a period of 1 hour. The solution crystallizes. The suspension was stirred for 12 hours at room temperature, then filtered and washed by 4x 160 mL of water (AgNO₃ test on mother liquor until no trace of bromide). The cake was dried at 50°C in a ventilated oven. 95.2g (75%) of glycopyrronium tosylate as white powder were thus obtained.

Example 4 (step b))

Glycopyrronium tosylate was prepared in accordance with step b) of Example 2, except that a mixture consisting of water and a water-miscible organic solvent was used as solvent. Results are presented in the below table.

Exemple 5

In a 10mL flask were introduced a base, 2 mL of water, 241 mg (1 ,40 mmol) of p-toluene sulfonic acid monohydrate and 500g (1 ,26 mmol) of glycopyrronium bromide. The solution crystallizes few minutes later. The suspension was stirred for 3 hours at room temperature, then filtered and washed with water until no trace of bromide is detected. The cake was then dried at 50°C in a ventilated oven. Results are presented in the below table according to the base introduced.

Claims

1 . A process for the production of glycopyrronium tosylate starting from glycopyrronium bromide comprising the steps of: a) generating p-toluenesulfonic acid salt by reacting p-toluene sulfonic acid and a base in a first single-phase aqueous medium; and b) reacting glycopyrronium bromide with p-toluenesulfonic acid salt in a second single-phase aqueous medium and isolating the resulting glycopyrronium tosylate.

2. The process according to claim 1 wherein glycopyrronium bromide is reacted with p-toluenesulfonic acid salt in 3 to 5 volumes of the second single-phase aqueous medium.

3. The process according to claim 1 or 2 wherein glycopyrronium bromide is reacted with from 0.9 to 1.1 eq of p-toluenesulfonic acid salt relative to the glycopyrronium bromide.

4. The process according to any one of the preceding claims wherein glycopyrronium bromide is reacted with from 0.95 to 1.05 eq of p-toluenesulfonic acid salt relative to the glycopyrronium bromide.

5. The process according to any one of the preceding claims wherein the base is a mineral base, preferably chosen from a hydroxide or a carbonate, more preferably selected from the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, lithium carbonate, sodium carbonate and potassium carbonate.

6. The process according to any of claims 1 to 5 wherein steps a) and b) are concomitant.

7. The process according to any one of claims 1 to 5 wherein steps a) and b) are sequential.

8. The process according to claim 7 wherein glycopyrronium bromide is directly added to the reaction medium at the end of step a).

9. The process according to claim 8 wherein the step of reacting glycopyrronium bromide with p-toluenesulfonic acid salt is performed by adding glycopyrronium bromide in a solubilized form to the reaction medium at the end of step a) or by adding the reaction medium at the end of step a) to glycopyrronium bromide in a solubilized form.

10. The process according to any one of the preceding claims wherein glycopyrronium bromide is reacted with p-toluenesulfonic acid salt under stirring for a period ranging from about 3 hours to about 15 hours.

11 . The process according to any one of the preceding claims wherein glycopyrronium bromide is reacted with p-toluenesulfonic acid salt at a temperature ranging from about 20°C to about 65°C.

12. The process according to any one of the preceding claims wherein the step of reacting glycopyrronium bromide with p-toluenesulfonic acid salt comprises heating glycopyrronium bromide with p-toluenesulfonic acid salt in the single-phase aqueous medium at about 60°C, filtering via hot filtration the reaction medium, allowing the filtered reaction medium to cool to about 20-25°C and stirring the reaction medium for a period ranging from about 3 hours to about 15 hours.

13. The process according to any one of the preceding claims wherein the glycopyrronium tosylate is collected by filtration or centrifugation.

14. The process according to any one of the preceding claims further comprising the step of washing the collected glycopyrronium tosylate.

15. The process according to claim 14 further comprising the step of drying the collected washed glycopyrronium tosylate.

16. The process according to any one of the preceding steps wherein the first and second single-phase aqueous medium is water. 15

17. The process according to any one of the preceding steps wherein p-toluenesulfonic acid salt is sodium p-toluenesulfonate.