FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
(See sectionlO and rule 13]
1. Title of the invention; "A process for the enantiomeric enrichment of Escitalopram or pharmaceutically acceptable addition salts thereof
2. MacLeods Pharmaceuticals Ltd., an Indian Company, having its Registered Office at 304 - Atlanta Arcade, Opp. Leela Hotel, Marol Church Road, Andheri
3. The following specification particularly describes the invention and the manner in which it is to be performed.


22 SEP 2008

A PROCESS FOR THE ENANTIOMERIC ENRICHMENT OF ESCITALOPRAM OR PHARMACEUTICALLY ACCEPTABLE ADDITION SALTS THEREOF
FIELD OF THE INVENTION
The present invention relates to a process for the enantiomeric enrichment of Escitalopram
or pharmaceutically acceptable addition salts thereof. The process includes
a) precipitating Escitalopram as a salt of (-) isomer of optically active acid from a solution
of non-racemic Citalopram b) converting optically active acid salt of Escitalopram into
Escitalopram base c) optionally converting the Escitalopram base into an acid addition salt
thereof.
BACKGROUND OF THE INVENTION
Escitalopram oxalate is Oxalic acid salt of (+)-l-(3-Dimethylarninopropyl)-l-(4'-fluorophenyl)-l, 3-dihydroisobenzofuran-5-carbonitrile and is disclosed in U.S.Patent No. 4,943,590. Escitalopram oxalate is represented by Formula I.

Formula I
Escitalopram is a valuable antidepressant of the selective serotonin reuptake inhibitor (SSRI) type.
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U.S.Patent No. 4,943,590 describes two processes for the preparation of Escitalopram and both of them are starting with the racemic diol of Formula II.

Formula II
According to the first process, the diol of Formula II is reacted with an enantiomerically pure acid derivative such as an acid chloride, anhydride or labile ester to form a mixture of diastereomeric esters, which are separated by HPLC purification. The purified diastereomeric ester with the right stereochemistry is converted into Escitalopram by stereoselective ring closure reaction with the strong base in an inert organic solvent. This process involves diastereoisomeric separations by means of HPLC technique, which set limits in terms of scalability of the process and reaction yields.
In the second process, the diol of Formula II is separated into the enantiomers by stereoselective crystallisation of a salt with one of the enantiomers of an optically active acid such as tartaric acid, di-benzoyltartaric acid, di-(p-toluoyl) tartaric acid, bisnaphthylphosphoric acid and 10-camphorsulphonic acid. The S-enantiomer of the diol of Formula II is converted into Escitalopram by stereoselective ring closure reaction via a labile ester as e.g. methanesulfonyl, p-toluenesulfonyl, 10-camphorsulfonyl, trifluoroacetyl or trifluoromethanesulfonyl with simultaneous addition of a base in an inert organic solvent at 0°C. Stereoselective ring closure reaction of above mentioned labile ester compounds leads to a chiral perturbation of Escitalopram i.e. increase the amount of
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R-Citalopram in Escitalopram and therefore this process is not suitable at commercial scale.
U.S.Patent No. 7,112,686 describes a process for the preparation of racemic Citalopram free base or an acid addition salt thereof and R-or S-Citalopram as the free base or an acid addition salt thereof from non-racemic Citalopram by precipitating Citalopram as the free base or an acid addition salt thereof, wherein the precipitated Citalopram comprises racemic Citalopram and the mother liquor comprises R- or S-Citalopram. This process involves repeated crystallization step which result into increased cycle time and the cost of production and therefore this process is not suitable at commercial scale.
U.S.Patent No. 7,390,913 describes a process for the preparation of racemic citalopram diol ("racemic-diol") free base or acid addition salt thereon and / or the corresponding R-or S-diol tree base or acid addition salt thereof from an initial non-racemic mixture of R-and S-diol free base or acid addition salt thereof by precipitating a mixture of R- and S~ citalopram diol ("RS-diol") in the form of a free base or acid addition salt thereof from a solution of the initial non-racemic mixture, leaving a final solution phase comprising R- or S-diol free base or acid addition salt thereof. This process involves a repeated crystallization step which leads to a low yield of S-diol and therefore this process is not suitable at commercial scale.
U.S.Patent No. 5,498.752 describes a simulated moving bed (SMB) chromatographic process wherein enantiomers of an optically active compound are separated and the stationary phase comprises silica gel coated with a chiral material.
U.S. Patent Publication No. US 2005/0065207 describes a chromatographic separation of the enantiomers of Citalopram or an intermediate in the production of Citalopram using a chiral stationary phase such as Chiralpak™ or Chiralcel™.
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Above mentioned processes involve the tedious and cumbersome procedures of chromatography and therefore not suitable for the commercial scale production of Escitalopram.
U.S. Patent Publication No. US 2005/0154051 describes a process for the preparation of Escitalopram via the optical resolution of the racemic compound of Formula III.

Formula 111
Wherein X is halogen or any other group that may be converted to a cyano group and Z is OH or a leaving group.
Formula IV
U.S. Patent Publication No. US 2006/0009515 describes a process for the preparation of Escitalopram via the optical resolution of the racemic compound of Formula IV.


Wherein Ac is acetyl group.
Above mentioned processes involve one extra step of cyanation, which makes the process uneconomical and also need extra care for handling cyanide reagents.
U.S. Patent Publication No. US 2007/0129561 describes a process for the preparation of optically active intermediates useful for the preparation of Escitalopram involving selective enzymatic acylation or deacylation.
U.S. Patent Publication No. US 2007/0238887 describes a process for the preparation of Escitalopram and the pharmaceutically acceptable salts therof via enzymatic enantiomeric resolution of a racemic compound of Formula V.

Formula V
Wherein R represents a C1-C4 alkyl radical, or an aryl radical.
Above mentioned enzymatic processes are not commercially viable due to fragile nature of an enzyme.
U.S. Patent Publication No. US 2007/0270599 describes a process for the preparation of Escitalopram by the cyclisation reaction of the compound of Formula VI in the presence
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of an azodicarboxylate, a phosphine and a strong base. However, this process is not suitable on an industrial scale as it involves the use of phosphine which is very hazardous reagent.

Formula VI
U.S. Patent Publication No. US 2008/0177096 describes a process for the preparation of Escitalopram with chiral purity greater than 99.8% by cyclization of ether compound of Formula VII or acid addition salt thereof in the presence of a base.

Formula VII
Wherein R is selected from alkyl, alkenyl, aryl and heteroaryl which my be optionally substituted with electron withdrawing groups and X is selected from F, CI, Br, I, CN OTf
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and OR1, wherein Tf represents trifluoromethanesulfonyl group, and R1 is optionally substituted alkyl, Z is cyano group or a group that may be converted to a cyano group.
In light of the above drawbacks in the prior art processes, there is a need for the development of a simple, convenient and efficient process for the preparation of pure Escitalopram or pharmaceutically acceptable addition salts thereof which is convenient to operate on an industrial scale.
SUMMARY OF THE INVENTION
A first aspect of the present invention is to provide a process for the enantiomeric enrichment of Escitalopram or pharmaceutically acceptable addition salts thereof comprising the steps of:
a) precipitating Escitalopram as a salt of (-) isomer of optically active acid from a solution of non-racemic Citalopram,
b) converting optically active acid salt of Escitalopram into Escitalopram base,
c) optionally converting the Escitalopram base into an acid addition salt thereof.
A second aspect of the present invention is to provide pure Escitalopram or pharmaceutically acceptable addition salts thereof prepared by a process comprising the steps of:
a) precipitating Escitalopram as a salt of (-) isomer of optically active acid from a solution of non-racemic Citalopram,
b) converting optically active acid salt of Escitalopram into Escitalopram base,
c) optionally converting the Escitalopram base into an acid addition salt thereof.
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DETAILED DESCRIPTION OF THE INVENTION
Non-racemic Citalopram used for the present invention may be prepared by any of the processes known in the literature, such as those described in U.S. Pub. Nos. US 4,943590, US 7,112,686, US 2007/0270599 and US 2008/0177096 which are herein incorporated by reference.
Non-racemic Citalopram means mixtures which do not contain R- and S-Citalopram as a 1:1 mixture.
Non-racemic Citalopram may contain 0.25% to 15% of R-Citalopram.
(-) Isomer of optically active acid may be selected from the group comprising of tartaric acid, di-benzoyltartaric acid, di-(p-toluoyl) tartaric acid (as hydrate), bisnaphthylphosphoric acid and 10-camphorsulphonic acid.
As used in this description, precipitating means forming a precipitate in the form of crystals or an amorphous solid from a solvent
The precipitation of Escitalopram as a salt of (-) isomer of optically active acid may be carried out by dissolving the non-racemic Citalopram in an organic solvent, optionally by applying heating, and then allowing the solution to cool.
(-) di-p-toluoyl-L-tartaric acid salt of Escitalopram is the preferred salt.
Example of organic solvent includes alkyl acetate, chlorinated hydrocarbon, alkyl amide and alcohol.
Example of alkyl acetate solvent includes methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, butyl acetate, t-butyl acetate or amyl acetate.
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Example of chlorinated hydrocarbon solvent includes dichloromethane, dichloroethane, chloroform or carbon tetrachloride.
Example of alkyl amide solvent includes N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMA), N, N-diethylacetamide (DEA) or N, N-dimethylpropanamide (DMP).
Example of alcohol solvent includes methanol, ethanol, n-propanol, iso propanol or butanol.
The dissolution of non-racemic Citalopram in an organic solvent may be carried out at a temperature in the range of 25°C to 40°C.
The precipitate of Escitalopram salt of (-) isomer of optically active acid may be isolated by cooling, filtration, washing or a combination thereof.
The precipitate of Escitalopram salt of (-) isomer of optically active acid may be isolated at a temperature in the range of 5°C to 25°C.
The precipitate of Escitalopram salt of (-) isomer of optically active acid may be further purified by recrystallization in a combination of alcohol and alkyl amide solvents.
Example of alcohol solvent includes methanol, ethanol, n-propanol, iso propanol, butanol, diethyl ether, tetrahydrofuran or mixture(s) thereof.
Example of alkyl amide solvent includes N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMA), N, N-diethylacetamide (DEA), N, N-dimethylpropanamide (DMP) or mixture(s) thereof.
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The mother liquid obtained after the precipitation of Escitalopram salt of (-) isomer of optically active acid may be further recycled by the process of the present invention.
As used in this description, mother liquid means filtrate obtained after the isolation of Escitalopram salt of (-) isomer of optically active acid.
Mother liquid obtained after the isolation of Escitalopram salt of (-) isomer of optically active acid may contain 4% to 30% of R-Citalopram.
The optically active acid salt of Escitalopram may be converted into Escitalopram base by reacting optically active acid salt of Escitalopram with inorganic base in chlorinated hydrocarbon solvent at a temperature in the range of 25°C to 30°C.
Example of inorganic base includes alkali metal carbonate and alkali metal bicarbonate.
Example of alkali metal carbonate includes sodium carbonate and potassium carbonate.
Example of alkali metal bicarbonate includes sodium bicarbonate and potassium bicarbonate.
Example of chlorinated hydrocarbon solvent includes dichloromethane, dichloroethane, chloroform, carbon tetrachloride or mixture(s) thereof.
Escitalopram base may be converted into acid addition salts of Escitalopram by reacting Escitalopram with mineral acids or organic acids in ketone solvent at a temperature in the rangeofO°Cto30°C.
Escitalopram base obtained by the present invention may contain 0.05 % to 0.20% of R-Citalopram preferably less than 0.1% of R-Citalopram.
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The acid addition salts of Escitalopram are salts of pharmacologically acceptable non¬toxic acids such as mineral acids, for example, hydrochloric acid, hydrobromic acid, phosphoric acid or sulphuric acid, and organic acids such as acetic acid, tartaric acid, maleic acid, citric acid, oxalic acid, benzoic acid or methane sulphonic acid.
The preferred acid addition salt of Escitalopram is Escitalopram oxalate.
Example of ketone solvent includes acetone, methyl ethyl ketone, methyl isobutyl ketone, diethyl ketone or mixture (s) thereof.
The acid addition salts of Escitalopram may be isolated by cooling, filtration, washing or a combination thereof.
Escitalopram oxalate may be dried at a temperature in the range of 45°C to 60°C under reduced pressure.
Escitalopram oxalate obtained by the present invention may contain 0.05% to 0.20% of R-Citalopram oxalate preferably less than 0.1% of R-Citalopram oxalate.
The particle size of the Escitalopram oxalate obtained by the present invention is having X95 between 20um to 40fim and X50 is less than 20Pm.
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The following non-limiting examples illustrate specific embodiments of the present invention. They are, however, not intended to be limiting the scope of present invention in anyway.
EXAMPLE 1
Preparation of (-) di-p-toluoyl-L-tartaric acid salt of Escitalopram:
(-)-4-(4-dimethylamino)-l-(4'-fluorophenyl)-l-(hydroxybutyl)-3-(hydroxymethyl) benzonitrile, hemi (+)-di-p-toluoyltartaric acid salt (50 gm) was charged in sodium hydroxide solution ( 7.8gm dissolved in 500 ml water). Toluene (500 ml) was added and the resulting solution was stirred for 1 hour, organic layer separated and washed with water (2 x 100 ml). Toluene was distilled out azeotropically at 110-115°C and the resulting residue was cooled to -10°C to -15°C. Di-isopropyl amine (20.5 gm) and methane sulphonyl chloride (11.5 gm) solution in toluene (150 ml) were added at-15°C to -10°C. The reaction mixture was stirred for 1 hour and then quenched with water (100 ml). Organic layer was separated and toluene was distilled out under reduced pressure to get a residue of non-racemic Citalopram (27 gm). A residue of non-racemic Citalopram (27 gm) was dissolved in ethyl acetate (400 ml) and Di-para toluoyl -L-tartaric acid dihydrate (31gm) was added at 25-30°C. The reaction mixture was stirred at 25-30°C for 2 hours and filtered to get crude (-) di-p-toluoyl-L-tartaric acid salt of Escitalopram. The crude (-) di-p-toluoyl-L-tartaric acid salt of Escitalopram was purified by recrystallization in isopropyl alcohol (200ml) and dimethyl formamide (2ml) solvents to get pure (-) di-p-toluoyl-L-tartaric acid salt of Escitalopram. Yield: 43 gm
Chiral Purity: 99.9% (S-isomer) Chemical Purity: 99.9% (By HPLC) Melting point: 124-127°C. [D]D = -70.2° (c=l% Methanol)
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EXAMPLE 2
Preparation of Escitalopram oxalate:
To a solution of (-) di-p-toluoyl-L-tartaric acid salt of Escitalopram (32 gm) in methylene chloride (105 ml) was added 10% sodium carbonate solution (280 ml) and the resulting reaction mixture was stirred for 2.5 hours at 25-30°C. Organic layer was separated and washed with 10% sodium carbonate solution (2 x 140 ml) and water (175 ml). Methylene chloride was distilled out under reduced pressure at 40-45°C to get residue (15.75 gm). The residue was dissolved in acetone (50 ml) and oxalic acid solution (6.7 gm oxalic acid dissolved in 50 ml acetone) was added slowly at 25-30°C. The reaction mixture was stirred for 2 hours at 25-30°C and resulting solid was filtered and dried to get Escitalopram oxalate. Yield: 13gm
Chiral Purity: 99.9% (S-isomer) Chemical Purity: 99.9% (By HPLC) Melting point: 149- 154°C. [D]D = +12.13° (c=l% Methanol)
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WE CLAIM:
1. A process for the enantiomeric enrichment of Escitalopram or pharmaceutically
acceptable addition salts thereof comprising the steps of:
a) precipitating Escitalopram as a salt of (-) isomer of optically active acid from a solution of non-racemic Citalopram,
b) converting optically active acid salt of Escitalopram into Escitalopram base,
c) optionally converting the Escitalopram base into an acid addition salt thereof.
2. A pure Escitalopram or pharmaceutical ly acceptable addition salts thereof prepared by a
process comprising the steps of:
a) precipitating Escitalopram as a salt of (-) isomer of optically active acid from a solution of non-racemic Citalopram,
b) converting optically active acid salt of Escitalopram into Escitalopram base,
c) optionally converting the Escitalopram base into an acid addition salt thereof.

3. The process according to claims 1 or 2, wherein (-) isomer of optically active acid is selected from the group comprising of tartaric acid, di-benzoyltartaric acid, di-(p-toluoyl) tartaric acid (as hydrate), bisnaphthylphosphoric acid and 10-camphorsulphonic acid.
4. The process according to claims 1 or 2, wherein non-racemic Citalopram contain up to 4%ofR-Citalopram.
5. The process according to claims 1 or 2, wherein the precipitation of Escitalopram as a salt of (-) isomer of optically active acid is carried out by dissolving the non-racemic Citalopram in an organic solvent, optionally by applying heating, and then allowing the solution to cool.
6. The process according to claim 5, wherein the organic solvent is selected from the group consisting of alkyl acetate such as methyl acetate, ethyl acetate, n-propyl acetate,
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isopropyl acetate, butyl acetate, t-butyl acetate or amyl acetate; chlorinated hydrocarbon such as dichloromethane, dichloroethane, chloroform or carbon tetra chloride; alcohol such as methanol, ethanol, n-propanol, iso propanol or butanol and alkyl amide such as N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMA), N, N-diethylacetamide (DEA) or N, N-dimethylpropanamide (DMP).
7. The process according to claims 1 or 2, wherein optically active acid salt of
Escitalopram is converted into Escitalopram base by reacting optically active acid salt of
Escitalopram with inorganic base such as sodium carbonate, potassium carbonate, sodium
bicarbonate or potassium bicarbonate in chlorinated hydrocarbon solvent such as
dichloromethane, dichloroethane, chloroform, carbon tetrachloride or mixture(s) thereof at
a temperature in the range of 25°C to 30°C.
8. The process according to claims 1 or 2 wherein Escitalopram base is converted into acid addition salts of Escitalopram by reacting Escitalopram with mineral acids or organic acids in ketone solvent at a temperature in the range of 0°C to 30°C.
9. The process according to claims 1, 2 or 8 wherein acid addition salts of Escitalopram are salts of pharmacologically acceptable non-toxic acids such as mineral acids, for example, hydrochloric acid, hydrobromic acid, phosphoric acid or sulphuric acid, and organic acids such as acetic acid, tartaric acid, maleic acid, citric acid, oxalic acid, benzoic acid or methane sulphonic acid.
10. The process according to claim 8, wherein ketone solvent is selected from the group
consisting of acetone, methyl ethyl ketone, methyl isobutyl ketone, diethyl ketone or
mixture (s) thereof.
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Dated this 19th day of September, 2008

Signature:
Name: Dr. Rajendra Agarwal
To
The Controller of Patents The patent Office, At Mumbai

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