PREPARATION OF TROSPIUM CHLORIDE

INTRODUCTION

The present patent application relates to an improved process for preparation of substantially pure trospium chloride and its pharmaceutical compositions.

Trospium chloride is the adopted name for a drug compound having a chemical name (1a,3β,5a)-3-[(Hydroxydiphenylacetyl)oxy]spiro[8-azoniabicyclo[3.2.1]octane-8,1'-pyrrolidinium] chloride and represented by structural Formula I.

Formula I

Trospium chloride is antispasmodic and antimuscarinic agent. It is intended to be used for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and urinary frequency. Trospium chloride is marketed in the U.S. market under as SANCTURA® oral tablets containing 20 mg of the drug, and SANCTURA XR® extended release oral capsules containing 60 mg of the drug.

U.S. Patent No. 3,480,626 discloses various azoniaspironortropine derivatives including trospium chloride and processes for preparing them. The process for preparation of trospium chloride disclosed in this patent is as described below:

U.S. Patent No. 4,855,422 discloses two synthetic routes for preparing trospium chloride, which are schematically described below: Route A:

It is observed that, if the 1,4-dichlorobutane involved in the synthesis of trospium chloride in Route A is contaminated with higher levels of 1-bromo-4-chloro and/or 1,4-dibromo compounds, respectively, as impurities, they result in the formation of trospium bromide as an impurity at undesirable levels, which is not acceptable to regulatory authorities. In a trial, when 1,4-dichlorobutane that has 1-bromo-4-chloro butane at a level of 1.73% and 1,4-dibromobutane at a level of 0.37% by gas chromatography (GC) is used for the preparation of trospium chloride, it resulted in trospium chloride that has about 0.96% of trospium bromide by high performance liquid chromatography (HPLC), and the purification of such trospium chloride has not resulted in trospium chloride with reduced level of trospium bromide to meet the desired regulatory agency required quality.

As is known by those skilled in the art, controlling of undesired process related impurities in the final product may be addressed, after properly understanding their chemical structures, synthetic pathways, identifying the route cause for their formation and controlling the parameters that influence the content of those impurities in the final product.

There is a need to provide an improved, easy to handle and environment-friendly process for preparation of substantially pure trospium chloride.

It would be desirable to have an improved process for preparation of substantially pure trospium chloride, which does not involve:

1. chlorinated solvents (non-environment-friendly solvents);

2. isolation of an benzilic-imidazolide intermediate, which is generally unstable;

3. substrates containing high levels of impurities, which may give rise to trospium chloride that is contaminated with the corresponding impurities at higher levels;

4. use of ethyl chloroformate, which provides a poor conversion of tropine of Formula (IV) to nortropine of Formula (III); and/or

5. prolonged reaction times.

SUMMARY

An embodiment of the present application provides an improved process for the preparation of substantially pure trospium chloride; which includes:

(a) demethylating tropine of Formula (IV) to produce nortropine of Formula (III);

(b) reacting nortropine of Formula (III) with substantially pure 1,4-dichloro butane to obtain 3a-hydroxynortropane-8-spiro-1'-pyrrolidinium chloride in the presence of a base in a solvent;

(c) reacting benzilic acid with carbonyl diimidazolide in presence of 4-(dimethylamino)-pyridine to obtain benziloyl imidazolide followed by reacting the resulting benziloyl imidazolide with 3α-hydroxynortropane-8-
spiro-1 '-pyrrolidrnium chloride obtained in step (b) to obtain trospium chloride; and (d) optionally, purifying the trospium chloride by recrystallization from a solvent or mixture of solvents to obtain substantially pure trospium chloride. An aspect of the present application provides pharmaceutical compositions comprising substantially pure trospium chloride and at least one pharmaceutically acceptable carrier.

DETAILED DESCRIPTION

An embodiment of the present application provides an improved process for the preparation of substantially pure trospium chloride, which includes:

(a) demethylating tropine of Formula (IV) to produce nortropine of Formula (III);

(b) reacting nortropine of Formula (III) with substantially pure 1,4-dichloro butane to obtain 3a-hydroxynortropane-8-spiro-1'-pyrrolidinium chloride in the presence of a base in a solvent;

(c) reacting benzilic acid with carbonyl diimidazolide in presence of 4-(dimethylamino)-pyridine to obtain benziloyl imidazolide, followed by reacting the resulting benziloyl imidazolide with 3α-hydroxynortropane-8-spiro-1'-pyrrolidinium chloride obtained in step (b) to obtain trospium chloride;

(d) optionally, purifying the trospium chloride by recrystallization from a solvent or mixture of solvents to obtain substantially pure trospium chloride.

As used herein, unless otherwise defined, the term "substantially pure trospium chloride" refers to trospium chloride containing very low levels of.irapurities. The possible impurities of trospium chloride include trospium bromide of Formula (la), benzilic acid of Formula (lb), nortropine benzilate of Formula (Ic) and desbenziloyi trospium chloride of Formula (Id), in addition to the raw materials used in the preparation of trospium chloride in the present application. These impurities may be identified and quantified using high performance liquid chromatography (HPLC). Very low levels of impurities as used herein, unless otherwise defined, refer to levels of individual impurities less than about 0.3%, or less than about 0.2%, or less than about 0.1%, or non-detectable levels, based on the weight of the trospium chloride. These levels of impurities are contemplated with substantially pure trospium chloride.

As used herein, unless otherwise defined: trospium bromide of Formula (la) refers to (1a,3B,5a)-3-[(hydroxy-diphenylacetyl)oxy]spiro[8-azoniabicyclo[3.2.1]octane-8,1'-pyrrolidinium] bromide; benzilic acid of Formula (lb) refers to hydroxy(diphenyl)acetic acid; nortropine benzilate of Formula (Ic) refers to hydroxy(diphenyl)acetic acid 8-aza-bicyclo[3.2.1]oct-3-yl ester; desbenziloyi trospium chloride of Formula (Id) refers to 3a-hydroxynortropane-8-spiro-1'-pyrrolidinium chloride; exo-trospium chloride of Formula (le) refers to (1a,3a,5a)-3-[(hydroxy-diphenylacetyl)oxy]spiro[8-azoniabicyclo[3.2.1 ]octane-8,1 '-pyrrolidinium] chloride; and these compounds are structurally represented below.

As used herein, unless otherwise defined, substantially pure 1,4-dichlorobutane refers to 1,4-dichlorobutane containing very low levels of impurities. The possible impurities of 1,4-dichlorobutane include 1-bromo-4-chlorobutane and 1,4-dibromobutane, among others. These impurities may be identified and quantified using gas chromatography (GC). Very low levels of impurities as used herein, unless otherwise defined, refers to the levels of individual impurities less than about 1%, or less than about 0.5%, or less than about 0.3%, or less than about 0.2%, or less than about 0.15%, including non-detectable levels, based on the weight of 1,4-dichlorobutane. The said levels of impurities are contemplated with substantially pure 1,4-dichlorobutane.

In a process of the present application, step a) involves demethylating tropine of Formula (IV).
Formula (IV)

Demethylation may be carried out using methods generally known in the art. For example, it may be carried out by reacting tropine of Formula (IV) with an alkyl or aryl haloformate in the presence of a base, in a suitable solvent, to give 8-alkoxycarbonylnortropine or 8-aryloxycarbonylnortropine, followed by hydrolysis withr a base in a solvent or mixture of solvents, in the presence of water, to give nortropine of Formula (III).

Suitable alkyl haloformates which may be used in step a) include, but are not limited to, methyl chloroformate, methyl bromoformate, methyl iodoformate, ethyl chloroformate, ethyl bromoformate, ethyl iodoformate, isopropyl chloroformate, isopropyl bromoformate, isopropyl iodoformate, butyl chloroformate, butyl bromoformate, butyl iodoformate, and the like. Suitable aryl haloformates which may be used in step a) include, but are not limited to, phenyl chloroformate, phenyl bromoformate, phenyl iodoformate, benzyl chloroformate, benzyl bromoformate, benzyl iodoformate, 4-nitrophenyl chloroformate, 4-nitrophenyl bromoformate, 4-nitrophenyl iodoformate, and the like.
Suitable temperatures for the reaction range from about 0°C to about 150°C, or about 20°C or about 100°C, or about 40°C to about 60°C, or any other suitable temperatures.

The resulting 8-alkoxycarbonylnortropine or 8-aryloxycarbonylnortropine may be hydrolyzed, optionally after removal of solvent from the reaction mixture, using a base in a solvent or a mixture of solvents comprising water to obtain nortropine of Formula (III).

Suitable solvents, which may be used in step a), include, but are not limited to: water; alcohols such as methanol, ethanol, isopropyl alcohol, n-propanol, n-butanol, 2-butanol, and the like; halogenated hydrocarbons such as dichloromethane, ethylene dichloride, and chloroform; ketones, such as acetone, ethyl methyl ketone, methyl isobutyl ketone, and the like; hydrocarbons such as toluene, xylene, n-hexane, n-heptane, cyclohexane, and the like; esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate, and the like; ethers such as diethyl ether, diisopropyl ether, methyl t-butyl ether, tetrahydrofuran, dioxane, and the like; polar aprotic solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulphoxide, sulpholane, and N-methylpyrrolidone; nitriles such as acetonitrile, propionitrile, and the like; and any mixtures thereof.

Suitable bases for use in step a) include inorganic bases and organic bases-. Suitable organic bases include, but are not limited to, aliphatic amines such as triethylamine, tributylamine, N-methyl morpholine, N,N-diisopropylethyl amine, N-methylpyrrolidone and the like, and aromatic amines such as pyridine, N,N-dimethylaminopyridine, and the like. Suitable inorganic bases include, but are not limited to, alkali metal carbonates, alkali metal bicarbonates, alkali metal hydroxides, and the like. Suitable alkali metal carbonates include, but are not limited to, sodium carbonate, potassium carbonate, and the like. Suitable alkali metal bicarbonates include, but are not limited to, sodium bicarbonate, potassium bicarbonate, and the like. Suitable alkali metal hydroxides include, but are not limited to, lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like.
The nortropine of Formula (III) may be recovered from the reaction mixture in a conventional manner. For example, it may be extracted from the reaction mixture with a suitable solvent, followed by isolation from the extract in a conventional manner.

Step b) involves reacting nortropine of Formula (III)

Formula (III)

with substantially pure 1,4-dichlorobutane to obtain 3a-hydroxynortropane-8-spiro-T-pyrrolidinium chloride, in the presence of a base in a solvent.

Suitable bases, which may be used in step b), include, but are not limited to, secondary amines such as dimethylamine, diethylamine, diisopropylamine, dicyclohexylamine, and the like, tertiary amines such as trimethylamine, triethylamine, and the like, pyridine, quinoline, and the like.

Suitable solvents that may be used in step b) include, but are notlimited to: water; alcohols such as methanol, ethanol, isopropyl alcohol, n-propanol, n-butanol, 2-butanol and the like; ketones, such as acetone, ethyl methyl ketone, methyl isobutyl ketone, and the like; halogenated hydrocarbons such as dichloromethane; ethylene dichloride, chloroform, and the like; hydrocarbons such as toluene, xylene, n-hexane, n-heptane, cyclohexane and the like; esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate, and the like; ethers such as diethyl ether, diisopropyl ether, methyl t-butyl ether, tetrahydrofuran, dioxane, and the like; polar aprotic solvents such as N.N-dimethylformamide, N,N-dimethylacetamide, dimethylsulphoxide, sulpholane, N-methylpyrrolidone, and the like; nitriles such as acetonitrile, propionitrile, and the like; and any mixtures thereof.

Step c) involves reacting benzilic acid with carbonyl diimidazolide in the-presence of 4-(dimethylamino)pyridine to obtain benziloyl imidazolide followed by reacting the resulting benziloyl imidazolide with 3a-hydroxynortropane-8-spiro-1'-pyrrolidinium chloride of Formula (II) to obtain trospium chloride.

Formula (II)

In step c), benzilic acid may be reacted with carbonyl diimidazolide in a suitable solvent in the presence of 4-(dimethylamino)pyridine. To this reaction mixture, 3a-hydroxynortropane-8-spiro-1'-pyrrolidinium chloride of Formula (II) may be added.

The reaction may be carried out at elevated temperatures, which may range from about 20°C to about 150°C, or about 40°C to about 100°C, or about 60°C to about 90°C, or any other suitable temperatures.

Suitable solvents that may be used in step c) include, but are not limited to: water; alcohols such as methanol, ethanol, isopropyl alcohol, n-propanol, n-butanol, 2-butanol, and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone, and the like; halogenated hydrocarbons such as dichloromethane, ethylene dichloride, chloroform, and the like; hydrocarbons such aa toluene, xylene, n-hexane, n-heptane, cyclohexane, and the like; esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate, and the like; ethers such as diethyl ether, diisopropyl ether, methyl t-butyl ether, tetrahydrofuran, dioxane, and the like; polar aprotic solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulphoxide, sulpholane, N-methylpyrrolidone, and the like nitriles such as acetonitrile, propionitrile, and the like; and any mixtures thereof.

The resulting trospium chloride after the reaction of benziloy imidazolide with 3α-hydroxynortropane-8-spiro-1'-pyrrolidinium chloride of Formula be recovered by conventional methods including decantation, centrifugation, gravity filtration, vacuum filtration, or by adding an anti-solvent, or any other techniques known in the art for the recovery of solids from a reaction mixture. "Anti-solvent" means a solvent that reduces the solubility of the solid in a solution. Suitable anti-solvents include, but are not limited to, aromatic hydrocarbons such as toluene, xylenes and the like; ethers such as diethyl ether, diisopropyl ether and the like; aliphatic hydrocarbons such as hexanes, n-heptane, cyclohexane, and the like; and mixtures thereof.

The recovered solid may be optionally dried. Drying may be suitably carried out using a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer and the like. The drying may be carried out at temperatures from about 25°C to about 250°C, at atmospheric pressure or under reduced pressure, and in the presence or absence of an inert atmosphere such as nitrogen, argon, neon, helium, and the like.

Step d) involves optionally purifying the trospium chloride obtained in step c) by recrystallization from a solvent or mixture of solvents to obtain substantially pure trospium chloride.

Suitable solvents which may be used in step d) include, but are not limited to water; alcohols such as methanol, ethanol, isopropyl alcohol, n-propanol, n-butanol, 2-butanol, and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone, and the like; halogenated hydrocarbons such as dichloromethane, ethylene dichloride, chloroform, and the like; hydrocarbons such as toluene, xylene, n-hexane, n-heptane, cyclohexane, and the like; esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate, and the like; ethers such as diethyl ether, diisopropyl ether, methyl t-butyl ether, tetrahydrofuran, dioxane, and the like; polar aprotic solvents such as N,N-dimethylformamide, N,N-dimethylacetamide,
dimethyl sulphoxide, sulpholane, N-methylpyrrolidone, and the like; nitriles such as
acetonitrile, propionitrile, and the like; and any mixtures thereof.

Suitable temperatures for forming a solution may range from about 25°C to about 150°C, or about the reflux temperature of the solvent used.
The solution obtained may be optionally treated with activated charcoal or any other material such as a resin, which may be desirable to remove some of the undesired impurities and/or to remove any insoluble particles, followed by filtration through a membrane, or a bed of a medium such as a flux calcined diatomaceous earth (Hyflow) to remove the carbon or other insoluble material.

Precipitation of solids from the solution may be promoted by techniques such as concentrating, cooling, seeding, adding an anti-solvent, any combination thereof, and the like. Anti-solvents that may be used include, but are not limited to: aromatic hydrocarbons such as toluene, xylenes, and the like; ethers such as diethyl ether, diisopropyl ether, and the like; aliphatic hydrocarbons such as hexanes, n-heptane, cyclohexane, and the like; and mixtures thereof.

The precipitated solid may be recovered using conventional methods including decantation, centrifugation, gravity filtration, vacuum filtration or other techniques known in the art for the recovery of precipitated solids from a solution.

The recovered solid may be optionally dried. Drying may be suitably carried out using a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer and the like. The drying may be carried out at temperatures of about 25°C to about 250°C, at atmospheric pressure or under reduced pressure, and in the presence or absence of an inert atmosphere such as nitrogen, argon, neon, helium, and the like. The drying may be carried out for any desired time periods to achieve the desired quality of the product and/or to obtain a desired residual solvent content, the times ranging from about 1 to about 20 hours, or longer.

Trospium chloride of Formula (I) may be analyzed using high performance liquid chromatography (HPLC), for example by a method using a C-8 column, 250 х 4.6 mm ID, 5 µm particle size, or equivalent. The other parameters of the method may be as shown in Table 1.

Table 1

Flow rate 10mL/minute
Wavelength 215 nm
Injection load 20.0 µL
Temperature40°C
Elution
Isocratic
Diluent
Mobile Phase
Sample preparation
Mobile phase preparation

30.0 mg of test sample, dissolved and diluted to 10ml with diluent.

Mix 1 volume of triethyl amine and 3 volumes of phosphoric acid with 700 volumes of water, and add 300 volumes of acetonitrile.

Trospium chloride of Formula (I) may also be analyzed by an alternate HPLC method, as shown in Table 2.
Table 2
Flow rate 0.4-0.8 mL/minute
Detector ELSD
Gas flow (Nitrogen) 1.5 mL/minute
Drift tube temperature 70°C
Impactor mode ON
Gain 1
Injection load 5.0 µL
Elution Gradient
Diluent Milli-Q Water
Sample preparation 100.0 mg of test sample dissolved ar ml with diluent.
Mobile phase preparation Buffer: Mix 1 ml of triethylamine and acid with water and dilute to 1000 ml Mobile Phase A: Buffer. Mobile Phase B: BuffenAcetonitrile. 1 ml of formic with water.
Gradient program % of B increased to 70 over a time-span of 20 minutes, held for 15 minutes and then equilibrated the column to initial conditions for 10 minutes.

Trospium chloride of Formula (I) may also be analyzed by an alternate HPLC method, as shown in Table 3.

Table 3

Flow rate 0.8 mL/minute
Wavelength 215 nm
Injection load 5.0 nl_
Temperature 40°C
Elution Gradient
Diluent Buffer: Acetonitrile (7:3)
Sample preparation •30.0 mg of test sample, dissolved and diluted to 10. ml with diluent.
Mobile phase preparation Buffer: Mix 1 volume of triethyl amine and 3 volumes
of 88% of phosphoric acid with 700 volumes of
water.
Mobile Phase A: Buffer: Methanol.
Mobile Phase B: Methanol: Water: Acetonitrile.
Gradient program % of B was increased to 50 over a time-span of 55 minutes with stepwise gradient elution, held for 5 minutes and then equilibrated the column to initial conditions for 13 minutes.

Separately contemplated is substantially pure trospium chloride characterized by containing individual impurities less than about 0.3%, or less than about 0.2%, or less than about 0.1%, or at non-detectable levels, with respect to the total area of all the peaks in a HPLC chromatogram.

An aspect of the present application provides processes for purification of 1,4-dichlorobutane, an embodiment including subjecting 1,4-dichlorobutane having high levels of impurities to high-vacuum distillation (HVD) for any desired time periods at suitable temperatures to obtain pure 1,4-dichlorobutane.

Purity of 1,4-dichlorobutane may be measured by gas chromatography (GC) using a gas chromatograph equipped with flame ionization detector, column G46 or equivalent. The method may be as shown in Table 4.

Table 4

GC Column G46
Detector FID
Make up flow (N2) 30 mL/minute
Detector Temperature 260°C
injector 250°C
Split ratio 1:5
Injection load 1.0 µL
Carrier gas 31 cm/second (average velocity)
Mode Constant pressure
Diluent Methanol
Column oven temperature Oven program is varied from initial 70°C to 250°C, with a heating rate of 15°C per minute.

Separately contemplated is substantially pure 1,4-dichlorobutane containing individual impurities less than about 1%, or less than about 0.5%, or less than about 0.3%, or less than about 0.2%, or less than about 0.15%, or at non-detectable levels, with respect to the total area of all the peaks in a GC chromatogram.

Trospium chloride obtained from a process of the present application may have a particle sizes less than about 250 µm, or less than about 200 µm," or less than about 150 µm, or less than about 100 µm, or less than about 50 µm, or any other desired particle sizes, which may be suitable for use in formulation processes.

An aspect of the present application provides pharmaceutical compositions that include substantially pure trospium chloride with one or more pharmaceutically acceptable excipients.

Substantially pure trospium chloride of the present application may be formulated as solid compositions for oral administration in the form of capsules, tablets, pills, powders or granules. In these compositions, the active ingredient is combined with one or more pharmaceutically acceptable excipients.

Substantially pure trospium chloride of the present application may also be formulated as liquid compositions for oral administration including, for example, solutions, suspensions, syrups, elixirs and emulsions, containing solvents or vehicles -such as water, sorbitol, glycerine, propylene glycol or liquid paraffin.

Substantially pure trospium chloride of the present application may also be formulated as compositions for parenteral administration including suspensions, emulsions or aqueous or non-aqueous, sterile solutions. As a solvent or vehicle, propylene glycol, polyethylene glycol, vegetable oils, especially olive oil, and injectable organic esters, e.g., ethyl oleate, may be employed. These compositions may contain adjuvants, especially wetting, emulsifying and dispersing agents. Sterilization may be carried out in several ways, e.g. using a bacteriological filter, by incorporating sterilizing agents in the composition, by irradiation or by heating. The compositions may be prepared in the form of sterile compositions, which can be dissolved at the time of use in sterile water or any other sterile injectable medium.

Pharmaceutically acceptable excipients that may be used to prepare formulations comprising substantially pure trospium chloride of the present application include, but are not limited to: diluents such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, and sugar; binders such as acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidones, hydroxypropyl celluloses, hydroxypropyl methylcelluloses, pregelatinized starch; disintegrants such as starches, sodium starch glycolate, pregelatinized starch, crospovidones, croscarmellose sodium, colloidal silicon dioxide; lubricants such as stearic acid, magnesium stearate, zinc stearate; glidants such as colloidal silicon dioxide and talc; solubility or wetting enhancers such as anionic or cationic or neutral surfactants; complex-forming agents such as various grades of cyclodextrins and resins; and release rate-controlling agents such as hydroxypropyl celluloses, hydroxymethyl celluloses, hydroxypropyl methylcelluloses, ethylcelluloses, methylcelluloses, various grades of methyl methacrylates, and waxes. Pharmaceutically acceptable excipients further include, but are not limited to, film-formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, and antioxidants.

Certain specific aspects and embodiments are described in further detail by the examples below, which are provided only for the purpose of illustration and are not intended to limit the scope of the application in any manner.

EXAMPLES

EXAMPLE 1: PREPARATION OF NORTROPINE FROM TROPINE.

Tropine (50.0 g), acetone (1900 mL) and NaHC03 (89.2 g) were charged into a round bottom flask under an inert atmosphere and stirred for about 10-20 minutes. The reaction mass was heated to about 40-50°C. A solution of phenyl chloroformate (166.2 g) in acetone (100 mL) was added and the mixture was refluxed for about 1-2 hours. After cooling to 25-30°C, the reaction mass was filtered and washed with acetone (100 mL). Solvent was distilled off under vacuum and cyclohexane (250 mL) was added to the residue. Solvent was distilled off under vacuum and further cyclohexane (1000 mL) was added to the obtained crude and heated to reflux for about 15-30 minutes. After cooling to 25-35°C and stirring for about 30-60 minutes, the separated solid was filtered and washed with cyclohexane (100 mL). The compound was dried and KOH (198.3 g) in water (500 mL) was added. The reaction mass was stirred and heated to reflux for about 10-12 hours. After cooling the reaction mass to 70-80°C, toluene (1000 mL) was added and organic layer and aqueous layers were separated. The aqueous layer was extracted with toluene (3x500 mL). Solvent was distilled off under vacuum from the organic layer. After cooling to 10-15°C and stirring for about 45-90 minutes, the formed solid was filtered and washed with toluene (100 mL). It was then dried at 75-85°C to yield the title compound. Yield: 76.4% of theoretical.

EXAMPLE 2: PREPARATION OF 3a-HYDROXYNORTROPANE-8-SPIRO-1'-PYRROLIDINIUM CHLORIDE.

Nortropine (50.0 g) and dimethylformamide (450 mL) were charged into a round bottom flask and stirred for about 30-60 minutes at 25-35°C. The mass was filtered and washed with dimethylformamide (50 mL). Diethylamine (115.1 g) was added to the filtrate and stirred for about 10-15 minutes. 1,4-dichlorobutane (200.0 g) was to the reaction mass and heated for about 10-12 hours. After cooling to 25-30°C and stirring for about 1-2 hours, the reaction mass was filtered. The solid was washed with dimethylformamide and dried under vacuum. Dichloromethane (435 mL) was added to the residue and refluxed for about 30-40 minutes. The reaction mass was cooled to 25-35°C and stirred for about 1-2 hours. The solid was filtered and washed with dichloromethane (125 mL). It was then dried at 75-85°C to yield the title compound. Yield: 79% of theoretical.

EXAMPLE 3: PREPARATION OF TROSPIUM CHLORIDE (CRUDE).

Benzilic acid (78.9 g), dimethylaminopyridine (14.0 g) and acetonitrile (800 mL) were charged into a round bottom flask and stirred for about 15-30 minutes at 25-35°C. N,N'-carbonyldiimdazile (67.2 g) was added to the reaction mass and stirred for about 30-60 minutes at 25-35°C. 3oc-hydroxynortropane-8-spiro-1'-pyrrolidinium chloride (50.0 g) was added to the reaction mass and heated to reflux
for about 10-12 hours. The reaction mass is cooled to 25-35°C and stirred for about 60-90 minutes. The solid was filtered and washed with acetonitrile (100 ml_). It was then dried at 75-85°C to yield the title compound. Yield: 85.4% of theoretical.

EXAMPLE 4: PURIFICATION OF TROSPIUM CHLORIDE.

Crude trospium chloride (70.0 g) and 1-propanol (700 mL) were charged into a round bottom flask and stirred for about 5-10 minutes at 25-35°C to dissolve. The solution was heated to about 85-95°C for about 60-90 minutes. Acidic carbon (7.0 g) was charged. The hot mixture was filtered through a Hyflow bed and washed with 1-propanol (70 mL). After slowly cooling the solution to about 25-35°C and stirring for about 3-5 hours, the solid was filtered and washed with 1-propanol (70 mL). It was then dried at 60-80°C to yield the title compound. Yield: 71.5% w/w; Purity by HPLC: 99.93%.

In a trial, when trospium chloride was prepared by performing Examples 2, 3 and 4 using 1,4-dichlorobutane having the impurities 1-bromo-4-chlorobutane 1.73% and 1,4-dibromobutane 0.37%, the resulting trospium chloride contained 0.96% of trospium bromide of Formula (la).

EXAMPLE 5: PURIFICATION OF TROSPIUM CHLORIDE.

Crude trospium chloride (10.0 g) and acetonitrile (300 mL) were charged into a round bottom flask and refluxed for about 30-45 minutes to dissolve. The solution was cooled to 25-35°C and stirred for about 60-90 minutes. The formed solid was filtered and washed with acetonitrile (10 mL). This process was repeated until the content of trospium bromide impurity was reduced to desired levels. Yield: 71.5% w/w; Purity by HPLC: 99.79%.

EXAMPLE 6: PURIFICATION OF TROSPIUM CHLORIDE.

Crude trospium chloride (35.0 g) and n-butanol (350 mL) were charged into a round bottom flask and stirred for about 5-10 minutes at 25-35°C to dissolve. The solution was heated to about 90-110°C for about 60-90 minutes, then was filtered through a Hyflow bed and washed with n-butanol (17.5 mL). After cooling the filtrate to 25-30°C and stirring for about 3-5 hours, the formed solid was filtered and washed with n-butanol (17.5 mL). The solid was dried at 70-90°C to yield the title compound.

Yield: 85.7% w/w; Purity by HPLC: 99.95%.
EXAMPLE 7: PURIFICATION OF 1.4-DICHLOROBUTANE.
1,4-dichlorobutane (150.0 g), having 1 -bromo-4-chlorobutane at about 1.73% and 1,4-dibromobutane at about 0.37% by GC, was charged into a round bottom flask and subjected to high vacuum distillation under a reduced pressure of less than 30 mm Hg for about 2-3 hours to obtain highly pure 1,4-dichlorobutane:

Purity by GC:

Fraction I (collected between 48°C to 51 °C; 18% w/w yield):
content of 1-bromo-4-chlorobutane: 0.80% and
content of 1,4-dibromobutane: 0.04%; and

Fraction II (collected between 51°C to 54°C; 26% w/w yield):
content of 1-bromo-4-chlorobutane: 1.01%; and
content of 1,4-dibromobutane: 0.07%.

By optimizing the temperature and pressure conditions and collecting the proper fractions containing substantially pure 1,4-dichlorobutane at proper intervals during high vacuum distillation, purity of 1,4-dichlorobutane can be improved to any desired level.

EXAMPLE 8: PURIFICATION OF TROSPIUM CHLORIDE.
Crude trospium chloride (10.0 g) and 1-propanol (70 mL) were charged into a round bottom flask and stirred for about 30 minutes at 25°C. The solution was heated to about 90-100°C for about 20 minutes. Acidic carbon (1.0 g) was charged to the solution and further stirred for 15 minutes. The hot mixture was filtered through a Hyflow bed and washed with 1-propanol (20 mL). After slowly cooling the solution to about 25-35°C and stirring for about 5 hours, the solid was filtered and washed with 1-propanol (10 mL). It was then dried at 70°C to yield the title compound. Purity by HPLC: 99.89%.

Yield Benzilic Nortropine Desbenziloyl Exo- Bromide
(%) Acid (lb) Benzilate Trospium Trospium Content by
(Ic) Chloride (Id) Chloride (le) GC
77.0 ND* ND ND ND 243 ppm
*ND = not detected.

Trospium chloride prepared according to the procedure described in the present application has the following representative purities.

Trial Yield (%) Purity by HPLC (area-%)

Trospium
Bromide
(la) Benzilic
Acid
(lb) Nortropine
Benzilate
(Ic) DesbenziloyI
Trospium Chloride (Id)
1 74.0 0.02 0.001 ND ND
2 79.6 0.006 ND* ND ND
3 80.2 0.007 ND ND ND
4 77.3 0.01 ND ND ND
5 57.6 0.01 ND ND ND
*ND = not detected.

CLAIMS:

1. A process for preparing trospium chloride, comprising:

a) demethylating tropine of Formula (IV) to produce nortropine of Formula (in);

b) reacting nortropine of Formula (III) with substantially pure 1,4-dichloro butane to obtain 3a-hydroxynortropane-8-spiro-1'-pyrrolidinium chloride, in the presence of a base in a solvent;

c) reacting benzilic acid with carbonyl diimidazolide, in the presence of 4-(dimethylamino)-pyridine, to obtain benziloyl imidazolide, followed by reacting the resulting benziloyl imidazolide with 3a-hydroxynortropane-8-spiro-1'-pyrrolidinium chloride obtained in step b) to obtain trospium chloride; and

d) optionally, purifying the trospium chloride by recrystallization from a solvent or mixture of solvents to obtain substantially pure trospium chloride.

2. The process of claim 1, wherein a demethylating reagent comprises an alkyl or aryl haloformate.

3. The process of claim 1, wherein a demethylating reagent is phenyl chloroformate.

4. The process of any of claims 1-3, wherein a base comprises at least one of dimethylamine, diethylamine, diisopropylamine, dicyclohexylamine, trimethylamine, triethylamine, pyridine, and quinoline.

5. The process of any of claims 1-4, wherein a solvent is at least one of water, an alcohol, a ketone, a halogenated hydrocarbon, a hydrocarbon, an ester, an ether, a nitrile, and a polar aprotic solvent.

6. The process of any of claims 1-4, wherein a solvent is at least one of water, methanol, ethanol, isopropyl alcohol, n-propanol, n-butanol, 2-butanol, acetone, ethyl methyl ketone, methyl isobutyl ketone, dichloromethane, ethylene dichloride, chloroform, toluene, xylene, n-hexane, n-heptane, cyclohexane, ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate, diethyl ether, diisopropyl ether, methyl t-butyl ether, tetrahydrofuran, dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulphoxide, sulpholane, N-methylpyrrolidone, acetonitrile, and propionitrile.

7. The process of any of claims 1-4, wherein a solvent comprises n-propanol, n-butanol, or acetronitrile.

8. The process of any of claims 1-7, providing trospium chloride with a HPLC purity greater than about 99.5%.

9. The process of any of claims 1-7, providing trospium chloride with a HPLC purity greater than about 99.9%.