PRIORITY
This application claims the benefit to Indian Provisional Application No. 3570/MUM/2013, filed on November 13, 2013, the contents of which are incorporated by reference herein.
FIELD OF THE INVENTION
The present invention relates to an improved process for the synthesis of aclidiunium or intermediates thereof. More particularly the present invention relates to synthesis of aclidinium bromide.
BACKGROUND OF THE INVENTION
Aclidinium bromide is chemically known as l-Azoniabicyclo[2.2.2]octane, 3-[(hydroxydi-2-thienylacetyl)oxy]-l-(3-phenoxypropyl)-, bromide, (3R)-, and has the following structural Formula I;

Formula I
Aclidinium bromide is marketed in the United States under the trade name TUDORZA PRESS AIR® is dry powder formulation for oral inhalation only.
Aclidinium bromide, the active component of TUDORZA PRESSAIR® is an anticholinergic with specificity for muscarinic receptors. TUDORZA PRESSAIR® is indicated for long term maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease (COPD), including bronchitis and emphysema.
United States Patent No. 7,750,226 discloses aclidinium bromide and its process for manufacturing.

United States Patent No. 8,044,205 discloses a process for preparing aclidinium bromide
Present health care reforms and legislation lead to evolving and increasingly rigorous requirements demanded of drug manufacturers. Subsequent therefrom and coupled with prevailing disadvantages, which may be present with the prior art processes, paves opportunities for improved processes for the preparation of aclidinium bromide. There is a need for an improved process for the preparation of aclidinium bromide, which avoids the formation of isomeric and other process-related impurities, while affording the desired aclidinium bromide product with high yield and purity.
The processes of the present invention are simple, eco-friendly, cost-effective, reproducible, robust and well suited on commercial scale.
SUMMARY OF THE INVENTION
In one embodiment, the present invention relates to process for the preparation of aclidinium bromide, a compound of formula I;

Formula I
comprising: a) reacting (3R)-3-hydroxy-l-(3-phenoxypropyl)-l-azoniabicyclo[2.2.2]octane bromide, a compound of formula III,

Formula III

with a compound of formula II,

Formula II
wherein R is selected from the group consisting of alkyl, cycloalkyl, alkylaryl, aryl and substituted aryl, to form a reaction mixture; and,
b) reacting the reaction mixture obtained in step a) with hydrogen bromide.
In one embodiment, the present invention relates to process for the purification of aclidinium bromide, a compound of formula I, comprising:
a) providing a solution of aclidinum bromide in a solvent or a mixture of solvents or their aqueous mixtures;
b) precipitating the solid from the solution; and
c) isolating the pure aclidinum bromide.
In one embodiment, the present invention relates to process for the purification of aclidinium bromide, a compound of formula I, comprising:
a) providing a solution of aclidinum bromide in a polar aprotic solvent;
b) adding an anti-solvent to the solution obtained in step a) to precipitate the solid aclidinium
bromide; and c) isolating the pure aclidinum bromide.

In one embodiment, the present invention relates to use of compound of formula III in the preparation of aclidinium bomide.

Formula III
BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1: X-ray Powder diffraction Pattern (XRPD) of aclidinium bromide prepared by Example 7. Fig. 2: Differential Scanning Calorimetry (DSC) endotherm of aclidinium bromide prepared by
i
Example 7.
Fig. 3: Thermogravimetric Analysis (TGA) graph of aclidinium bromide prepared by Example 7.
DETAILED DESCRIPTION OF INVENTION
As mentioned above, the present invention is directed to an improved process for the preparation of aclidinium bromide, a compound of formula I.
In one embodiment, the present invention relates to process for the preparation of aclidinium bromide, a compound of formula I,

%^
Formula I

Formula III
comprising: a) reacting (3R)-3-hydroxy-l-(3-phenoxypropyl)-l-azoniabicyclo[2.2.2]octane bromide, a compound of formula III,

with a compound of formula II,

Formula II
wherein R is selected from the group consisting of alkyl, cycloalkyl, aryl, alkylaryl and substituted aryl, to form a reaction mixture; and,
b) reacting the reaction mixture obtained in step a) with hydrogen bromide.
The term "alkyl" as used herein includes a straight or branched chain hydrocarbon containing from 1 to 6 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert- butyl, n-pentyl, isopentyl, neopentyl, n-hexyl.
The term "cycloalkyl" as used herein includes a 3- to 8 membered, preferably 3-, 5- or 6 membered cycloalkyl. Representative examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl.

The term "aryl" as used herein, refers to aromatic ring systems, which may include fused rings. Representative examples of aryl include, but are not limited to, phenyl, and naphthyl, anthracenyl, phenant.
The term "alkylaryl" as used herein, refers to an aryl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of alkylaryl include, but are not limited to, benzyl, 2-phenylethyl, 3-phenylpropyl, and 2-naphth-2-ylethyl.
The term "substituted aryl" as used refers to substituent on the aryl is present at one or more positions on the aryl ring, selected from the group consisting of halogen such as chloro, bromo, iodo; nitro; C1-C6 alkyl wherein alkyl refers to methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert- butyl, n-pentyl, isopentyl, neopentyl, n-hexyl and C1-C6 alkoxy wherein alkoxy refers to methoxy, ethoxy, propoxy, butoxy.
In one embodiment, the reaction of a compound of formula III, with a compound of formula II, may be carried out in presence of a suitable solvent.
The suitable solvent may be selected from alcohol for example, methanol, ethanol, isopropanol (IPA), n-propanol, butanol, isobutanol, 2-butanol and the like; ester for example, methyl acetate, ethyl acetate, isopropyl acetate, isobutyl acetate, n-butyl acetate, t-butyl acetate and the like; ether for example, diethyl ether, dimethyl ether, dimethoxymethane, dimethoxypropane, isopropyl ether, diisopropyl ether, methyl tertiary butyl ether (MTBE), tetrahydrofuran (THF), dioxane, furan, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether; nitrile for example, acetonitrile, propionitrile and the like; ketone for example, acetone, methyl ethyl ketone, methyl isobutyl ketone, diethyl ketone and the like; Polar aprotic solvent for example, N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), dimethylacetamide (DMA), N-methylpyrrolidinone, sulfolane and the like; hydrocarbon solvents and halogenated derivatives thereof may include pentane, n-hexane, heptane, cyclohexane, petroleum ether, m-,o-,or p-xylene, dichloromethane (MDC), and the like; acetic acid, formic acid, water or mixture thereof.

In one embodiment, the reaction of a compound of formula III, with a compound of formula II, may be carried out in presence of a base. The base may be selected from an inorganic base or organic base.
The inorganic base may be selected from the group consisting of hydrides such as sodium hydride, potassium hydride; alkoxides such as sodium methoxide, potassium methoxide, sodium tert-butoxide, potassium tert-butoxide; hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide; carbonates such as sodium carbonate, potassium carbonate; bicarbonates such as sodium bicarbonate, potassium bicarbonate; lithium hexamethyldisilazene, sodium hexamethyldisilazene and the like
The organic base may be selected from pyridine, piperidine, dimethyl amino pyridine, picoline, imidazole, diisopropyl ethyl amine, triethyl amine, trimethyl amine and the like.
The base may be selected from mixture of inorganic base and organic base.
In one embodiment, the reaction of a compound of formula III, with a compound of formula II, may be carried out in presence of condensing agent. The condensing agent may be selected from carbonyldiimidazole (CDI), carbonyldi-l,2,4-triazole, dicyclohexylcarbodiimide (DCC), l-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDC HC1), ethyl-dimethylaminopropylcarbodimide, 1-hydroxybenzotriazole (HOBT) and the like or mixture thereof. Preferably condensing agent is carbonyldiimidazole (CDI).
In one embodiment, the present invention provides reaction of compound of formula III with compound of formula II, wherein 1 to 5 molar equivalent of compound of formula II are employed per mole of compound of formula III, preferably 1 to 1.2 molar equivalent of compound of formula II are employed per mole of compound of formula III.
In one embodiment, the present invention provides that above reaction is carried out in the temperature range of about 5°C to about 80°C.
In one embodiment of the process of the present invention in step a) the compound of formula II is reacted with compound of formula III in presence of a base and condensing agent.

In step b), the hydrogen bromide may be added either in gaseous form or in the form of saturated solution. Preferably, the hydrogen bromide is added after being dissolved in glacial acetic acid or water. Preferably, a 33% hydrogen bromide solution in glacial acetic acid may be used.
The present invention provides isolation of compound of formula I by precipitation. The precipitation may be carried out by addition of anti-solvent to a solution of aclidinium bromide. The suitable anti-solvent is selected from group consisting of alcohol such as ethanol, isopropyl alcohol, butanol, isobutanol, 2-butanol, amyl alcohol and the like; ester such as ethyl acetate, isopropyl acetate, isobutyl acetate, n-butyl acetate , tert-butyl acetate and the like; ether such as dimethyl ether, diethyl ether, dimethoxy methane, isopropyl ether, methyl tert-butyl ether, tetrahudrofuran, dioxane and the like; hydrocarbon and halogenated derivatives thereof such as hexane, cyclohexane, petroleum ether, toluene, benzene, m-, o-, p- xylene, methylene chloride, ethylene chloride and the like; nitrile such as acetonitrile, propionitrile and the like; ketone such as acetone, methyl ethyl ketone, ethyl methyl ketone, methyl isobutyl ketone and the like, or water or mixture thereof.

Formula I comprising: a) reacting a compound of formula IIIa,
In one embodiment, the present invention relates to process for the preparation of aclidinium bromide, a compound of formula I,


Formula IIIa
wherein X is selected from chloride, bromide, iodide, sulphate, phosphate, nitrate, methane sulfonate, p-toluehe sulfonate, hexachlorophosphate, hexafluorophosphate, with a compound of formula II,

Formula II
wherein R is selected from the group consisting of alkyl, cycloalkyl, aryl, alkylaryl and substituted aryl, to form a reaction mixture; and,
b) reacting the reaction mixture obtained in step a) with hydrogen bromide.
In one embodiment, the present invention provides a process for the preparation of aclidinium bromide, a compound of formula I,


Formula III
comprising: a) reacting (3R)-3-hydroxy-l-(3-phenoxypropyl)-l-azoniabicyclo[2.2.2]octane bromide, a compound of formula III,

with a compound of formula II,

Formula II wherein R is C1-C6 alkyl to form a reaction mixture; and
b) reacting the reaction mixture obtained in step a) with hydrogen bromide.
In one embodiment, the present invention relates to process for the preparation of a compound of formula III,

Formula III comprising: a) reacting 3(R)-hydroxy-l-azabicyclo[2.2.2]octane, a compound of formula V,


.OH

Formula V with 3-phenoxypropyl bromide, a compound of formula IV,
,Br

Formula IV
In one embodiment, the present invention relates to process for the preparation of a compound of formula IIIa,

Formula IIIa wherein X is same as defined above, comprising: a) reacting 3(R)-hydroxy-l-azabicyclo[2.2.2]octane, a compound of formula V,


OH

Formula V with 3-phenoxypropyl halide, a compound of formula IVa,


Formula IVa
wherein X is same as defined above.
The reaction of compound of formula V, with compound of formula IV or IVa, may be carried out in presence of a suitable solvent. The suitable solvent may selected from group consisting of alcohol such as ethanol, isopropyl alcohol, butanol, isobutanol, 2-butanol, amyl alcohol and the like; ester such as ethyl acetate, isopropyl acetate, isobutyl acetate, n-butyl acetate , tert-butyl acetate and the like; hydrocarbon and halogenated derivatives thereof such as hexane, cyclohexane, petroleum ether, toluene, benzene, m-, o-, p- xylene, methylene chloride, ethylene chloride and the like, or water or mixture thereof.
In one embodiment, the present invention provides reaction of compound of formula V with compound of formula IV or IVa, wherein 1 to 5 molar equivalent of compound of formula IV or IVa are employed per mole of compound of formula V, preferably 1 to 1.5 molar equivalent of compound of formula IV or IVa are employed per mole of compound of formula V.
In one embodiment, the present invention provides that above reaction is carried out in the temperature range of about 20°C to about 80°C.
In one embodiment, the present invention relates to use of compound of formula II in the preparation of aclidinium bomide.

Formula II
wherein R is selected from the group consisting of C2-C6 alkyl, cycloalkyl, alkylaryl, aryl and substituted aryl.
In one embodiment, the present invention relates to use of compound of formula III in the preparation of aclidinium bomide.

Formula III
In one embodiment, the present invention relates to use of compound of Formula IIIa in the preparation of aclidinium bomide.

Formula IIIa
wherein X is selected from chloride, bromide, iodide, sulphate, phosphate, nitrate, methane sulfonate, p-toluene sulfonate, hexachlorophosphate, hexafluorophosphate and the like.
After completion of the reaction, the desired compounds can be obtained from the reaction mixture by conventional means known in the art. For example, the working-up of reaction mixtures, especially in order to isolate desired compounds, follows customary procedures, known to the organic chemists skilled in the norms of the art and steps, e.g. selected from the group comprising but not limited to extraction, neutralization, crystallization, chromatography, evaporation, drying, filtration, centrifugation and the like.
In one embodiment, the present invention relates to process for purification of aclidinium bromide, a compound of formula I, comprising:
a) providing a solution of aclidinum bromide in a solvent or a mixture of solvents or their aqueous mixtures;

b) precipitating the solid from the solution; and
c) isolating the pure aclidinum bromide.
In one embodiment, in step a), suitable solvent may be selected from polar aprotic solvent for example dimethylsulfoxide, dimethylamide, ethylene glycol monomethyl ether and the like.
In one embodiment, in step a), suitable solvent may be selected from polar protic solvent for example methanol, ethanol, isopropanol, n-propanol, formic acid, acetic acid, water or mixture thereof.
Precipitating the solid from the solution may be carried out by removal of solvent for example by by evaporation, distillation, cooling and like or by adding an anti-solvent.
In one embodiment, precipitation of solid form of aclidinium bromide is carried out by addition of an anti-solvent.
The anti-solvent may be selected such that it can cause precipitation of aclidinium bromide from the solution.
In step c), isolation may be carried out by filtration and method known in the art.
The present invention provides drying the isolated purified aclidinum bromide. Preferably the drying temperature is between 40°C-800C, more preferably the drying temperature is between 50°C- 60°C.
In one embodiment, the present invention provides a process for purification of aclidinium bromide, a compound of formula I, comprising:
a) providing a solution of aclidinum bromide in a polar aprotic solvent;
b) adding an anti-solvent to the solution obtained in step a) to precipitate the solid aclidinium bromide; and
c) isolating the pure aclidinum bromide.
The polar aprotic solvent is selected from dimethylsulfoxide (DMSO), N,N-dimethylformamide (DMF), dimethylacetamide (DMA), N-methylpyrrolidinone, sulfolane, ethylene glycol monomethyl ether and the like. Preferably, dimethylsulfoxide (DMSO).

The anti-solvent may be selected from alcohols for example methanol, ethanol, isopropyl alcohol, n-propanol, butanol, isobutanol, 2-butanol, amyl alcohol and the like; ketones for example acetone, methyl ethyl ketone, ethyl methyl ketone, methyl isobutyl ketone and the like; nitriles for example acetonitrile, propionitrile and the like; esters for example ethyl acetate, isopropyl acetate, isobutyl acetate, n-butyl acetate, tert-butyl acetate and the like; ethers for example dimethyl ether, diethyl ether, dimethoxy methane, isopropyl ether, methyl tert-butyl ether, tetrahudrofuran, dioxane and the like; hydrocarbon and halogenated derivatives thereof for example hexane, cyclohexane, petroleum ether, toluene, benzene, m-, o-, p- xylene, methylene chloride, ethylene chloride and the like; water or mixture thereof.
The D10, D50, and D90 values are useful ways for indicating a particle size distribution. D90 is a size value where at least 90 percent of the particles have a size smaller than the stated value. Likewise D10 refers to 10 percent of the particles having a size smaller than the stated value. D50 refers to at least 50 percent of the particles having a size smaller than the stated value. Methods for determining D10, D50, D90 include those using laser light diffraction with equipment sold by Malvern Instruments ltd.
In one embodiment, the present invention provides aclidinium bromide, compound of formula I, obtained by the processes herein described, having a D10 particle size of about 1pm -4pm, D50 particle size of about 10pm -15pm and D90 particle size of about 30pm -50pm.
In one embodiment, the present invention provides aclidinium bromide, compound of formula I, obtained by the processes herein described, having a Dio particle size of about 2pm -3pm, D50 particle size of about 9pm -12pm and D90 particle size of about 30pm -40pm.
In one embodiment, the present invention provides micronized aclidinium bromide, compound of formula I, obtained by the processes herein described, having aD10 particle size of about 1µm -3 µm, D50 particle size of about 5µm -8µm and D90 particle size of about 15µm -20µm.
In one embodiment, the present invention provides a process for purification of aclidinium bromide, a compound of formula I, comprising:
a) providing a solution of aclidinum bromide in dimethylsulfoxide (DMSO);
b) adding an anti-solvent to the solution obtained in step a) to precipitate the solid aclidinium
bromide; and c) isolating the pure aclidinium bromide.

In one embodiment, in step a) polar aprotic solvent is used in combination with other solvent.
In step b), the anti- solvent is selected from isopropyl alcohol, acetone, water, acetonitrile and ethyl acetate. Preferably, isopropyl alcohol.
In one embodiment, the present invention provides a process for purification of aclidinium bromide, a compound of formula I, comprising:
a) providing a solution of aclidinum bromide in a mixture of methanol and dimethyl sulfoxide (DMSO);
b) adding an anti-solvent to the solution obtained in step a) to precipitate the solid aclidinium bromide; and
c) isolating the pure aclidinium bromide.
In one embodiment of the process of the present invention anti-solvent is added to solution of aclidinium bromide at room temperature, cooled and isolated by filtration.
In one embodiment of the process of the present invention anti-solvent is added to solution of aclidinium bromide at 40°C -70°C temperature, cooled and isolated by filtration.
The present invention provides a process for preparing compound of Formula I in greater than 99% purity as determined by high performance liquid chromatography (HPLC). Preferably greater than 99.5%, preferably greater than.99.7%, preferably preferably greater than 99.8% purity as determined by HPLC.
Preferably the purity of the aclidinium bromide, a compound of formula I, is greater than 99%, more preferably greater than 99.8% as determined by HPLC.
In one embodiment, the present invention provides aclidinium bromide wherein the level of compound of formula II is less than 0.1% w/w relative to the amount of aclidinium bromide as determined by HPLC. Preferably, compound of formula II is absent.
In one embodiment, the present invention provides aclidinium bromide wherein the level of compound of formula III is less than 0.1 % w/w relative to the amount of aclidinium bromide as determined by HPLC. Preferably, compound of formula III is absent.

The present invention provides aclidinium bromide with X-ray powder diffraction pattern, which is substantially characterized in Fig 1, X-ray powder were performed on ARL (scanting) X-ray diffractometer model XPERT-PRO (PANalytical) scanning parameters start position [ 2Th.] 2.01 and end position [°2Th.] 49.98.
The present invention provides aclidinium bromide with a differential scanning calorimetry thermogram, which is substantially characterized in Fig 2, is measured by a Differential Scanning Calorimeter (DSC 822, Mettler Toledo) at a scan rate of 10°C per minute with an Indium standard. Aclidinium bromide exhibits an endotherm peak at about 229.82 C. Whereupon, the endotherm measured by a particular differential scanning calorimeter is dependent upon a number of factors, including the rate of heating (i.e., scan rate), the calibration standard utilized, instrument calibration, relative humidity, and upon the chemical purity of the sample being tested. Thus, an endotherm as measured by DSC on the instrument identified above may vary as much as ±1°C or even ± 2°C.
The present invention provides aclidinium bromide with a thermogravimetric analysis (TGA) scan, which is substantially characterized in Fig 3, recorded on TGA Q500 V 20.6 in a platinum pan with a temperature rise of 10°C/ min in the range 30°C to 350 C.
In one embodiment the present invention provides aclidinium bromide, compound of formula I having specific surface area of about 1.0 m2/g.
In one embodiment the present invention provides aclidinium bromide, compound of formula I having aspect ratio is 5.45.
The following examples are provided to enable one skilled in the art to practice the invention and are merely illustrative of the invention. The examples should not be read as limiting the scope of the invention as defined in the features and advantages.

EXAMPLES
Example 1: Preparation of (3R)-3-hydroxy-l-(3-phenoxypropyl)-l-azoniabicyclo[2.2.2) octane bromide, compound of formula III.
In a clean round bottom flask, 1-bromo 3-phenoxypropane was added to a solution of (3R)~ quinuclidin-3-ol in ethyl acetate at about room temperature. The reaction mass was filtered, washed and dried under vacuum to yield titled compound.
Example 2: Preparation of (3R)-3-hydroxy-l-(3-phenoxypropyl)-l-azoniabicyclo[2.2.2] octane bromide, compound of formula III.
In a clean round bottom flask, 1-bromo 3-phenoxypropane was added to a solution of (3R)-quinuclidin-3-ol in methylene chloride at about room temperature. The reaction mass was filtered, washed and dried under vacuum to yield titled compound.
Example 3: Preparation of (3R)-3-hydroxy-l-(3-phenoxypropyl)-l-azoniabicyclo [2.2.2] octane bromide, compound of formula III.
In a clean round bottom flask, 1-bromo 3-phenoxypropane was added to a solution of (3R)-quinuclidin-3-ol in n-propanol at about room temperature. The reaction mass was filtered, washed and dried under vacuum to yield titled compound.
Example 4: Preparation of (3R)-3-hydroxy-l-(3-phenoxypropyl)-l-azoniabicycIo[2.2.2] octane bromide, compound of formula III.
In a clean round bottom flask, 1-bromo 3-phenoxypropane was added to a solution of (3R)-quinuclidin-3-ol in isopropyl alcohol at about room temperature. The reaction mass was filtered, washed and dried under vacuum to yield titled compound.
Example 5: Preparation of Aclidinium Bromide, compound of formula I.
In a clean round bottom flask, (3R)-3-hydroxy-l-(3-phenoxypropyl)-l-azoniabicyclo [2.2.2] octane Bromide (formula III) was added to a mixture of methyl hydroxyl (dithien-2-yl) acetate and carbonyldiimidazole in N, N dimethyl formamide at about room temperature. Imidazole and sodium hydride was added to the obtained reaction mass and stirred and then solution of

hydrogen bromide in glacial acetic acid was added. The reaction mass was filtered, washed and dried under vacuum to yield titled compound. HPLC purity 90%.
Example 6: Preparation of Aclidinium Bromide, compound of formula I.
In a clean round bottom flask, sodium hydride was added to a mixture of (3R)-3-hydroxy-l-(3-phenoxypropyl)-l-azoniabicyclo[2.2.2]octane Bromide , carbonyldiimidazole and imidazole in N, N dimethyl formamide. The reaction mass was stirred and a solution of methyl hydroxyl (dithien-2-yl) acetate in N, N dimethyl formamide was added and then solution of hydrogen bromide in glacial acetic acid was added. The reaction mass was filtered, washed and dried under vacuum to yield titled compound. HPLC purity 88%.
Example 7: Purification of Aclidinium Bromide, compound of formula I.
In a clean round bottom flask, isopropyl alcohol was added to a solution of aclidinium bromide in dimethylsulfoxide (DMSO) at about room temperature. The reaction mass was filtered,washed and dried under vacuum at about 50°C -60°C to yield titled compound. HPLC purity 99.21%.
XRPD peaks of aclidinium bromide:

Pos.
[°2Th.] d-spacing [A] Rel. Int.
[%] Pos.
[°2Th.] d-spacing
[A] Rel. Int.
[%]
7.80 11.33 100.00 25.46 3.49 8.60
8.13 10.86 7.12 25.89 3.44 19.26
10.49 8.42 23.22 26.35 3.82 13.03
11.99 7.37 7.51 27.01 3.30 5.52
12.90 6.85 5.07 27.72 3.21 11.60
13.27 6.67 47.57 28.62 3.11 7.14
13.88 6.37 52.98 28.85 3.09 7.05 '
14.48 6,11 3.37 29.43 3.03 26.71
15.57 5.68 13.56 30.31 2.94 1.92
16.24 5.45 8.08 31.08 2.87 12.47

16.61 5.33 10.87 31.62 2.82 10.94
17.09 5.18 13.36 32.80 2.73 6.60
17.55 5.05 6.13 33.35 2.68 4.92
18.02 4.92 9.11 33.82 2.64 7.04
18.51 4.79 8.79 34.55 2.59 8.12
19.08 4.64 18.41 35.79 2.50 2.23
20.03 4.43 7.43 36.54 2.45 3.17
20.64 4.30 21.12 38.83 2.31 5.50
21.01 4.22 28.80 40.09 2.24 2.84
21.38 4.15 37.48 40.74 2.21 5.78
21.61 4.11 39.73 41.99 2.15 4.12
22.33 3.98 23.54 44.58 2.03 4.00
22.73 3.91 6.52 45.82 1.98 4.86
23.28 3.82 14.55 46.84 4.93 3.12
23.65 3.76 8.60 47.33 1.92 4.05
24.43 3.64 32.58 48.78 1.866 2.26
Example 8: Purification of Aclidinium Bromide, compound of formula I.
In a cJean round bottom flask, acetone was added to a solution of aclidinium bromide in dimethylsulfoxide (DMSO) at about room temperature. The precipitated solid was filtered, washed and dried under vacuum at about 50°C -60°C to yield titled compound. HPLC purity > 99%.
Example 9: Purification of Aclidinium Bromide, compound of formula I.
In a clean round bottom flask, water was added to a solution of aclidinium bromide in dimethylsulfoxide (DMSO) at about room temperature. The precipitated solid was filtered,

washed and dried under vacuum at about 50°C -60°C to yield titled compound. HPLC purity > 99.2%
Example 10: Purification of Aclidinium Bromide, compound of formula I.
In a clean round bottom flask, acetonitrile was added to a solution of aclidinium bromide in dimethylsulfoxide (DMSO) at about room temperature. The precipitated solid was filtered, washed and dried under vacuum at about 50°C -60°C to yield titled compound. HPLC purity > 99.5%
Example 11: Purification of Aclidinium Bromide, compound of formula I.
In a clean round bottom flask, ethyl acetate and water was added to a solution of aclidinium bromide in dimethylsulfoxide (DMSO) at about room temperature. The precipitated solid was filtered, washed and dried under vacuum at about 50°C -60°C to yield titled compound. HPLC purity > 99%
Example 12: Purification of Aclidinium Bromide, compound of formula I.
In a clean round bottom flask, isopropyl alcohol was added to a solution of aclidinium bromide in methanol and dimethylsulfoxide (DMSO) at about 50°C -60°C. The reaction mass was cooled, filtered, washed and dried under vacuum at about 50°C -60°C to yield titled compound. HPLC purity > 98%.
Example 13: Purification of Aclidinium Bromide, compound of formula I.
In a clean round bottom flask, isopropyl alcohol was added to a solution of aclidinium bromide in dimethylsulfoxide (DMSO) at about 50°C -60°C. The reaction mass was cooled, filtered, washed with isopropyl alcohol and dried under vacuum at about 50°C -60°C to yield titled compound. HPLC purity > 99.5%.
Particle size by Malvern: d10 about 2.11µm, d50 about 11.27 µm and d90 about 35.95 µm
Micronized particle size d10 about 1.4µm, d50 about 6.59 µm and d90 about 16.12µm

We Claims:
l. A process for the preparation of aclidinium bromide, a compound of formula I:

Formula I
Formula III
comprising: a) reacting (3R)-3-hydroxy-l-(3-phenoxypropyl)-l-azoniabicyclo[2,2.2]octane bromide, a compound of formula III,

with a compound of formula II,

Formula II
wherein R is selected from the group consisting of alkyl, cycloalkyl, alkylaryl, aryl and substituted aryl,

to form a reaction mixture; and,
b) reacting the reaction mixture obtained in step a) with HBr.
2. The process as claimed in claim 1, wherein R is methyl.
3. The process as claimed in claim 1, wherein the reaction is carried out in presence of a base.
4. The process as claimed in claim 1, wherein the reaction is carried out in presence of
condensing agent.
5. The process as claimed in claim 1, wherein the compound of formula III,

Formula III
is prepared by a process comprising: a) reacting 3(R)-hydroxy-l-azabicyclo[2.2.2]octane, a compound of formula V,
Formula IV
Formula V with 3-phenoxypropyl bromide, a compound of formula IV,


6.. A process for purification of aclidinium bromide, a compound of formula I, comprising:
a) providing a solution of aclidinum bromide in a polar aprotic solvent;
b) adding an anti-solvent to the solution obtained in step a) to precipitate the solid aclidinium bromide; and
c) isolating the pure aclidinum bromide.
7. The process as claimed in claim 6, wherein the D50 particle size of aclidinium bromide ranges
from9µm to 12µm.
8. The process as claimed in claim 6, wherein the polar aprotic solvent is selected from
dimethyl sulfoxide, dimethylamide and ethylene glycol monomethyl ether.
9. The process as claimed in claim 6, wherein an anti-solvent is selected from isopropyl alcohol,
acetone, water, acetonitrile and ethyl acetate.
10. The process as claimed in claim 6, wherein the polar aprotic solvent is dimethylsulfoxide and
an anti-solvent is isopropyl alcohol.