WO2015071824A1 - Process for the preparation of aclidinium bromide - Google Patents

Process for the preparation of aclidinium bromide Download PDF

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Publication number
WO2015071824A1
WO2015071824A1 PCT/IB2014/065952 IB2014065952W WO2015071824A1 WO 2015071824 A1 WO2015071824 A1 WO 2015071824A1 IB 2014065952 W IB2014065952 W IB 2014065952W WO 2015071824 A1 WO2015071824 A1 WO 2015071824A1
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formula
compound
bromide
solvent
aclidinium bromide
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PCT/IB2014/065952
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French (fr)
Inventor
Shekhar Bhaskar Bhirud
Samir Jaivant Naik
Sushanta Kumar MISHRA
Premkumar Ramraj YADAV
Yogesh Baburao Kajale
Lalit Vasant MARATHE
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Glenmark Pharmaceuticals Limited; Glenmark Generics Limited
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Publication of WO2015071824A1 publication Critical patent/WO2015071824A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems

Definitions

  • 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- [(hydroxy di-2- thienylacetyl)oxy]-l-(3-phenoxypropyl)-, bromide, (3i?)-, and has the following structural Formula I:
  • TUDORZA PRESSAIR® is dry powder formulation for oral inhalation only.
  • TUDORZA PRESSAIR® 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.
  • COPD chronic obstructive pulmonary disease
  • 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
  • the processes of the present invention are simple, eco-friendly, cost-effective, reproducible, robust and well suited on commercial scale.
  • the present invention relates to process for the preparation of aclidinium bromide, a compound of formula I:
  • 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.
  • 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.
  • 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.
  • the present invention relates to use of compound of formula III preparation of aclidinium bomide.
  • 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 Example 7.
  • Fig. 3 Thermogravimetric Analysis (TGA) graph of aclidinium bromide prepared by Example 7.
  • the present invention is directed to an improved process for the preparation of aclidinium bromide, a compound of formula I.
  • 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,
  • 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.
  • 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.
  • cycloalkyl as used herein includes a 3- to 8 membered, preferably 3-, 5- or 6 membered cycloalkyl.
  • cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl.
  • aryl 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.
  • alkylaryl refers to an aryl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • alkylaryl include, but are not limited to, benzyl, 2-phenyl ethyl, 3-phenylpropyl, and 2-naphth-2- ylethyl.
  • substituted aryl 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; Ci-C 6 alkyl wherein alkyl refers to methyl, ethyl, n-propyl, isopropyl, n-butyl, sec- butyl, tert- butyl, n-pentyl, isopentyl, neopentyl, n-hexyl and Ci-C 6 alkoxy wherein alkoxy refers to methoxy, ethoxy, propoxy, butoxy.
  • 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 (IP A), 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 diethy
  • 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 ethylamine, triethyl amine, trimethyl amine and the like.
  • the base may be selected from mixture of inorganic base and organic base.
  • 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 HQ), ethyl - dimethylaminopropylcarbodimide, 1 -hydroxybenzotriazole (HOBT) and the like or mixture thereof.
  • condensing agent is carbonyldiimidazole (CDI).
  • 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 ⁇ 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.
  • the present invention provides that above reaction is carried out in the temperature range of about 5°C to about 80°C.
  • the compound of formula ⁇ is reacted with compound of formula III in presence of a base and condensing agent.
  • the hydrogen bromide may be added either in gaseous form or in the form of saturated solution.
  • the hydrogen bromide is added after being dissolved in glacial acetic acid or water.
  • 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
  • the present invention relates to process for the preparation of aclidinium bromide, a compound of formula I,
  • X is selected from chloride, bromide, iodide, sulphate, phosphate, nitrate, methane sulfonate, p-toluene sulfonate, hexachlorophosphate, hexafluorophosphate, with a compound of formula II,
  • 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 present invention provides a 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,
  • the present invention relates to process for the preparation of a compound of formula III,
  • the present invention relates to process for the preparation of a compound of formula Ilia,
  • 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.
  • 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.
  • the present invention provides that above reaction is carried out in the temperature range of about 20°C to about 80°C.
  • the present invention relates to use of compound of formula II in the preparation of aclidinium bomide.
  • R is selected from the group consisting of C 2 -C 6 alkyl, cycloalkyl, alkylaryl, aryl and substituted aryl.
  • the present invention relates to use of compound of formula III in the preparation of aclidinium bomide.
  • the present invention relates to use of compound of formula Ilia in the preparation of aclidinium bomide.
  • X is selected from chloride, bromide, iodide, sulphate, phosphate, nitrate, methane sulfonate, p-toluene sulfonate, hexachlorophosphate, hexafluorophosphate and the like.
  • the desired compounds can be obtained from the reaction mixture by conventional means known in the art.
  • 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.
  • the present invention relates to process for purification of aclidinium bromide, a compound of formula I, comprising:
  • suitable solvent may be selected from polar aprotic solvent for example dimethylsulfoxide, dimethylamide, ethylene glycol monomethyl ether and the like.
  • 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.
  • 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.
  • isolation may be carried out by filtration and method known in the art.
  • the present invention provides drying the isolated purified aclidinum bromide.
  • the drying temperature is between 40°C-80°C, more preferably the drying temperature is between 50°C- 60°C.
  • the present invention provides a process for purification of aclidinium bromide, a compound of formula I, comprising:
  • step b) adding an anti-solvent to the solution obtained in step a) to precipitate the solid aclidinium 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.
  • DMSO dimethylsulfoxide
  • DMF N,N-dimethylformamide
  • DMA dimethylacetamide
  • N-methylpyrrolidinone N-methylpyrrolidinone
  • sulfolane ethylene glycol monomethyl ether and the like.
  • DMSO dimethylsulfoxide
  • 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 halogen
  • Dio, 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.
  • D 10 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 Di 0 , D 50 , D 90 include those using laser light diffraction with equipment sold by Malvern Instruments ltd.
  • the present invention provides aclidinium bromide, compound of formula I, obtained by the processes herein described, having a Di 0 particle size of about ⁇ ⁇ -4 ⁇ , D 50 particle size of about ⁇ -15 ⁇ and D 90 particle size of about 30 ⁇ -50 ⁇ .
  • the present invention provides aclidinium bromide, compound of formula I, obtained by the processes herein described, having a Di 0 particle size of about 2 ⁇ -3 ⁇ , D 50 particle size of about 9 ⁇ -12 ⁇ and D 90 particle size of about 30 ⁇ -40 ⁇ .
  • the present invention provides micronized aclidinium bromide, compound of formula I, obtained by the processes herein described, having a Dio particle size of about ⁇ ⁇ -3 ⁇ , D50 particle size of about 5 ⁇ -8 ⁇ and D90 particle size of about 15 ⁇ -20 ⁇ .
  • the present invention provides a process for purification of aclidinium bromide, a compound of formula I, comprising:
  • step 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.
  • DMSO dimethylsulfoxide
  • step a) polar aprotic solvent is used in combination with other solvent.
  • the anti- solvent is selected from isopropyl alcohol, acetone, water, acetonitrile and ethyl acetate.
  • isopropyl alcohol Preferably, isopropyl alcohol.
  • the present invention provides a process for purification of aclidinium bromide, a compound of formula I, comprising:
  • step 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.
  • anti-solvent is added to solution of aclidinium bromide at room temperature, cooled and isolated by filtration.
  • 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.
  • 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.
  • 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.
  • compound of formula II is absent.
  • 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.
  • 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.
  • DSC 822 Differential Scanning Calorimeter
  • Aclidinium bromide exhibits an endotherm peak at about 229.82°C.
  • 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.
  • 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.
  • TGA thermogravimetric analysis
  • the present invention provides aclidinium bromide, compound of formula I having specific surface area of about 1.0 m 2 /g.
  • the present invention provides aclidinium bromide, compound of formula I having aspect ratio is 5.45.
  • Example 6 Preparation of Aclidinium Bromide, compound of formula I.
  • sodium hydride was added to a mixture of (3i?)-3 -hydroxy- 1 -(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 9 Purification of Aclidinium Bromide, compound of formula I.
  • water was added to a solution of aclidinium bromide in dimethylsulfoxide (DMSO) at about room temperature.
  • DMSO dimethylsulfoxide
  • the precipitated solid was filtered, washed and dried under vacuum at about 50°C -60°C to yield titled compound.
  • Example 10 Purification of Aclidinium Bromide, compound of formula I.
  • acetonitrile was added to a solution of aclidinium bromide in dimethylsulfoxide (DMSO) at about room temperature.
  • DMSO dimethylsulfoxide
  • the precipitated solid was filtered, washed and dried under vacuum at about 50°C -60°C to yield titled compound.
  • Particle size by Malvern d 10 about 2.11 ⁇ , d3 ⁇ 4o about 11.27 ⁇ and d3 ⁇ 4) about 35.95 ⁇ .
  • Micronized particle size d 10 about 1.4 ⁇ , d3 ⁇ 4o about 6.59 ⁇ and d3 ⁇ 4) about 16.12 ⁇ .

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Abstract

The present invention relates to process for the preparation of aclidiunium or intermediates thereof. More particularly, it relates to the preparation of aclidinium bromide.

Description

PROCESS FOR THE PREPARATION OF ACLIDINIUM BROMIDE
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 I VENTION
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- [(hydroxy di-2- thienylacetyl)oxy]-l-(3-phenoxypropyl)-, bromide, (3i?)-, and has the following structural Formula I:
Figure imgf000002_0001
Formula I
Aclidinium bromide is marketed in the United States under the trade name TUDORZA PRESSAIR® 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:
Figure imgf000003_0001
Formula I
comprising: a) reacting (3R)-3-hydroxy-l-(3-phenoxypropyl)-l-azoniabicyclo[2.2.2]octane bromide, a compound of formula III,
Figure imgf000004_0001
Formula III
with a compound of formula II,
Figure imgf000004_0002
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 preparation of aclidinium bomide.
Figure imgf000005_0001
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 Example 7.
Fig. 3 : Thermogravimetric Analysis (TGA) graph of aclidinium bromide prepared by Example 7.
DETAILED DESCRD7TION 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,
Figure imgf000005_0002
Formula I 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,
Figure imgf000006_0001
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-phenyl ethyl, 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; Ci-C6 alkyl wherein alkyl refers to methyl, ethyl, n-propyl, isopropyl, n-butyl, sec- butyl, tert- butyl, n-pentyl, isopentyl, neopentyl, n-hexyl and Ci-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 (IP A), 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, Ν,Ν-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 ethylamine, 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 HQ), 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 Π 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 Π 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.
In one embodiment, the present invention relates to process for the preparation of aclidinium bromide, a compound of formula I,
Figure imgf000009_0001
Formula I
comprising: a) reacting a compound of formula Ilia,
Figure imgf000010_0001
Formula Ilia
wherein X is selected from chloride, bromide, iodide, sulphate, phosphate, nitrate, methane sulfonate, p-toluene sulfonate, hexachlorophosphate, hexafluorophosphate, with a compound of formula II,
Figure imgf000010_0002
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,
Figure imgf000010_0003
Formula I 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,
Figure imgf000011_0001
Formula II
wherein R is Ci-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,
Figure imgf000011_0002
Formula III
comprising: a) reacting 3(R)-hydroxy-l-azabicyclo[2.2.2]octane, a compound of formula V,
Figure imgf000012_0001
Formula V
with 3-phenoxypropyl bromide, a compound of formula IV,
Figure imgf000012_0002
Formula IV
In one embodiment, the present invention relates to process for the preparation of a compound of formula Ilia,
Figure imgf000012_0003
Formula Ilia
wherein X is same as defined above,
comprising: a) reacting 3(R)-hydroxy-l-azabicyclo[2.2.2]octane, a compound of formula V,
Figure imgf000012_0004
Formula V
with 3-phenoxypropyl halide, a compound of formula rVa,
Figure imgf000012_0005
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.
Figure imgf000013_0001
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.
Figure imgf000014_0001
Formula III
In one embodiment, the present invention relates to use of compound of formula Ilia in the preparation of aclidinium bomide.
Figure imgf000014_0002
Formula Ilia
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-80°C, 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 Dio, 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 Di0, 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 Di0 particle size of about Ι μηι -4μηι, D50 particle size of about ΙΟμιτι -15μηι and D90 particle size of about 30μηι -50μηι.
In one embodiment, the present invention provides aclidinium bromide, compound of formula I, obtained by the processes herein described, having a Di0 particle size of about 2μηι -3 μηι, D50 particle size of about 9μηι -12μηι and D90 particle size of about 30μηι -40μηι.
In one embodiment, the present invention provides micronized aclidinium bromide, compound of formula I, obtained by the processes herein described, having a Dio particle size of about Ι μηι -3μηι, D50 particle size of about 5μηι -8μηι and D90 particle size of about 15μηι -20μηι. 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 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 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 (3i?)-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 (3i?)- 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 (3i?)-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 (3i?)- 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 (3i?)-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 (3i?)- 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 (3i?)-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 (3i?)- 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, (3i?)-3 -hydroxy- 1 -(3 -phenoxypropyl)-l-azoniabicyclo [2.2.2] octane Bromide (formula ΙΠ) 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 (3i?)-3 -hydroxy- 1 -(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:
Figure imgf000020_0001
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 clean 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 2.11 μπι, d¾o about 11.27 μπι and d¾) about 35.95 μπι.
Micronized particle size: d10 about 1.4μηι, d¾o about 6.59μπι and d¾) about 16.12μηι.

Claims

Aclid-2014 We Claims:
1. A process for the preparation of aclidinium bromide, a compound of formula I:
Figure imgf000023_0001
Formula I
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,
Figure imgf000023_0002
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 solvent.
4. The process as claimed in claim 1, wherein the reaction is carried out in presence of a base.
5. The process as claimed in claim 1, wherein the reaction is carried out in presence of condensing agent.
6. The process as claimed in claim 1, wherein the compound of formula III,
Figure imgf000024_0001
Formula III
is prepared by a process comprising: a) reacting 3(R)-hydroxy-l-azabicyclo[2.2.2]octane, a compound of formula V,
Figure imgf000024_0002
Formula V
with 3-phenoxypropyl bromide, a compound of formula IV,
Figure imgf000024_0003
Formula IV
7. The process as claimed in claim 6, wherein the reaction is carried out in presence of a solvent selected from the group consisting of alcohol, ester and halogenated hydrocarbon.
8. A 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.
9. The process as claimed in claim 8, wherein the precipitation is carried out by addition of antisolvent.
10. 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.
11. The process as claimed in claim 10, wherein the D50 particle size of aclidinium bromide ranges from 9μηι to 12μηι.
12. The process as claimed in claim 10, wherein the polar aprotic solvent is selected from dimethylsulfoxide, dimethylamide and ethylene glycol monomethyl ether.
13. The process as claimed in claim 10, wherein an anti-solvent is selected from isopropyl alcohol, acetone, water, acetonitrile and ethyl acetate.
14. The process as claimed in claim 10, wherein the polar aprotic solvent is dimethylsulfoxide and an anti-solvent is isopropyl alcohol.
15. The process as claimed in claim 14, wherein the aclidinium bromide obtained in a purity of greater than 98% as determined by HPLC.
16. Use of compound of formula III in the preparation of aclidinium bromide.
Figure imgf000026_0001
Formula III
PCT/IB2014/065952 2013-11-13 2014-11-11 Process for the preparation of aclidinium bromide WO2015071824A1 (en)

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WO2016156836A1 (en) * 2015-03-30 2016-10-06 Hovione Scientia Limited Process for the preparation of aclidinium bromide
CN108586450A (en) * 2017-12-15 2018-09-28 上海方予健康医药科技有限公司 A kind of recrystallization purifying method of choline m receptor anticaking agent

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016156836A1 (en) * 2015-03-30 2016-10-06 Hovione Scientia Limited Process for the preparation of aclidinium bromide
JP2018510189A (en) * 2015-03-30 2018-04-12 ホビオネ サイエンティア リミテッド Method for producing acridinium bromide
US10087177B2 (en) 2015-03-30 2018-10-02 Hovione Scientia Limited Process for the preparation of aclidinium bromide
US10590124B2 (en) 2015-03-30 2020-03-17 Hovione Scienta Limited Process for the preparation of aclidinium bromide
AU2016240289B2 (en) * 2015-03-30 2020-08-27 Hovione Scientia Limited Process for the preparation of aclidinium bromide
JP2020143160A (en) * 2015-03-30 2020-09-10 ホビオネ サイエンティア リミテッド Process for preparation of aclidinium bromide
JP2021020965A (en) * 2015-03-30 2021-02-18 ホビオネ サイエンティア リミテッド Process for preparation of aclidinium bromide
JP7124035B2 (en) 2015-03-30 2022-08-23 ホビオネ サイエンティア リミテッド Method for producing acridinium bromide
CN108586450A (en) * 2017-12-15 2018-09-28 上海方予健康医药科技有限公司 A kind of recrystallization purifying method of choline m receptor anticaking agent
CN108586450B (en) * 2017-12-15 2021-02-19 上海方予健康医药科技有限公司 Recrystallization purification method of choline M receptor anticaking agent

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