FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
PROVISIONAL PECIFICATION
(See section 10 and rule l3)
1. TITLE OF THE INVENTION:
"ENANTIOMER RESOLUTION AND RACEMIZATION PROCESS
2. APPLICANT (S)
(a) NAME: IPC A LABORATORIES LTD.
(b)NATIONALITY: Indian Company incorporated under the Indian Companies ACT, 1956
(c) ADDRESS: 48, Kandivli Industrial Estate, Mumbai-400 067
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention.

Field of invention:
The present invention relates to new compounds, process for preparing the compounds of the present invention that are useful for preparing optically active cetirizine; process for preparing optical isomers of cetirizine or its pharmaceutical salts; and process to racemize & recycle the optical isomers of cetirizine or its derivatives.
Background of the invention:
Cetirizine is referred to the racemate of [2- [4- [ (4 chlorophenyl) phenylmethyl]-l-piperazinyl] ethoxy]-acetic acid and its dihydrochloride salt, are known compounds and is effective in the treatment of most of the allergies like chronic and acute allergic rhinitis, allergic conjunctivitis, pruritus, urticaria, and the like. Cetirizine is an orally active, long-acting, antihistamine falls in histamine HI receptor antagonist. Antihistamines, such as cetirizine, block the effect of histamines that are released by allergic reactions in the body. Advantages of cetirizine include less sedation, low anticholinergic activity, and longer duration of action.
Cetirizine has an asymmetric center in the molecule, as represented in the structure formula I (marked by an asterisk), and, thus can exist as optical isomers for example levorotatory and dextrorotatory enantiomers. These isomers are also designated as (R) and (S)-isomers. Levocetirizine is the R enantiomer of cetirizine which has a potential anti-inflammatory effect in the treatment of allergic rhinitis with asthma. Levocetirizine is believed to have a two-fold higher affinity for human HI receptors than the racemic cetirizine.
The dextrocetirizine is the (S)- enantiomer of cetirizine which has a potential application in the treatment of asthma exacerbation which are believed to be absent or not significant with Levocetirizine isomer. Therefore it is important to separate both the enantiomers from a racemic cetirizine.
Processes for preparing cetirizine or its salts, the individual optical isomers thereof or a pharmaceutically acceptable salt thereof have been described in Patents, EP0058146, GB 2225320, GB2225321, US5478941, EP0601028, EP0801064, WO9406429,
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W097/37982, WO2004000823, WO2004050647, Indian Application No. 501/MUM/2004, US6803465, WO2005073207, WO2006094648. However, in most of the reported processes for the optical isomers of cetirizine, it has been found either using a stereoselective synthesis or resolution of an early intermediate (2-chlorophenyl)methylphenylpiperazine.
Attempts were reported for resolution of the racemic cetirizine or its precursor, for example in WO2005073207, WO2006094648, US20020128275, and US7199241, either by chiral chromatographic separation or fractional crystallization. However, the workable resolving agents used in these reports are selected from optical pyrrolidone-5-carboxylic acid or sulfonylated derivative of optically active glutamic acid. Optical resolution of racemic cetirizine or its derivatives remains a great challenge to a synthetic chemist, because even repeated fractional crystallization does not yield a chiral purity acceptable to pharmaceutical application in an economical way. Therefore the object of the present invention is to seek better resolving agents for resolving cetirizine or its precursor compounds in high enantiomeric purity.
In order to get the maximum yield in the preparation of commercialized Levocetirizine, there is a need in the art for an efficient synthetic process for continuous production that efficiently recycles the (S)-cetirizine.
Summary of the invention:
The present invention discloses new compounds of formula I given below:

aryl group, preferably C1-C4 alkyl group, and R" refers to an alkyl, or aryl group. The compounds of formula I, in which the carbon marked with an asterisk refers to chiral
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centre, and in the present case it may be racemic, or optically enriched in one enatiomer, or pure chiral isomer.
The present invention provides a process for preparing the compound of formula I, comprising combining preferably a racemic cetirizine ester with optically active tartaric acid or its derivative in a suitable solvent, like aqueous or organic or their combinations, and recovering the title compounds, preferably in enantiomerically enriched or optical diastereomeric form. The preferred optically active tartaric acid are 0,O-dibenzoyltartaric acid, or 0,0-ditoluoyltartaric acid, preferably it is 0,0-dibenzoyltartaric acid.
The compounds of the present invention are useful for producing optically active cetirizine.
The present invention thus provides process for optically active cetirizine by fractional crystallization of compound of Formula I, wherein carbon marked asterisk is partially optically enriched or optical isomer form, from an aqueous or organic solvent, followed by hydrolysis of the obtained optically active tartarate salt. In one embodiment, the fractional crystallization of each isomer is effected preferably in solvents such as, esters like ethyl acetate, acetonitrile, C1-C6 alcohols (straight chain or branched) such as methanol, ethanol, isopropyl alcohol, ethers like di-isopropyl ether, ketones like acetone, acetonitrile-water, methanol-water, ethanol-water, acetonitrile-methanol, acetone-water, isopropanol-water and their combinations.
The compounds of the present invention can be prepared by treating a racemic or enantiomerically enriched compound of formula II with a tartaric acid derivative in a suitable solvent. The compound I-may be directly isolated in optically active form from the above mentioned solvents used during preparation.
In a second aspect, the present invention provides process for the racemization of enantiomerically enriched (S)-Cetirizine ester or (R)-Cetirizine ester comprising combining enantiomerically enriched Cetirizine ester with an alkali in a suitable solvent selected from the group consisting of a C1-6 alcohol, water, dipolar aprotic solvent such as DMSO, acetonitrile, ethers like tertrahydrofuran and mixtures thereof. The present
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racemization process is useful to recycle the unwanted isomer of cetirizine into the Levocetirzine or vise versa.
Detailed description:
Unless specified otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art, to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are described. To describe the invention, certain terms are defined herein specifically as follows.
Unless stated to the contrary, any of the words "including," "includes," "comprising," and "comprises" mean "including without limitation" and shall not be construed to limit any general statement that it follows to the specific or similar items or matters immediately following it. Embodiments of the invention are not mutually exclusive, but may be implemented in various combinations. The described embodiments of the invention and the disclosed examples are given for the purpose of illustration rather than limitation of the invention as set forth in the appended claims.
The term "levocetirizine" as used herein means the (R)-[2- [4- [ (4 chlorophenyl) phenylmethyl]-l-piperazinyl] ethoxy]-acetic acid, also designated as (R)-Cetirizine. More precisely, it means that the active substance comprises at least 90% by weight, preferably at least 95% by weight, of one individual optical isomer of cetirizine and at most 10% by weight, preferably at most 5% by weight, of the other individual optical isomer of cetirizine.
The term "pharmaceutically acceptable salts" as used herein refers not only to addition salts with pharmaceutically acceptable non-toxic organic and inorganic acids, such as acetic, citric, maleic, succinic, ascorbic, hydrochloric, hydrobromic, sulfuric, and phosphoric acids and the like, but also its metal salts (for example sodium or potassium salts) or ammonium salts, the amine salts and the aminoacid salts. Preferably the salt is hydrochloride, or dihydrochloride.
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The terms "S" and "R", as used herein, unless specified otherwise, refer to stereoisomer resulting from the spacial arrangement of groups at a chiral centre, and in the present context, the person of ordinary skill will appreciate that the groups attached with the carbon marked with an asterisk represents the plane for purposes of determining the configuration.
The term "alkyl" refers to a straight or branched alkyl group having from 1 to 6 carbon atoms. Exemplary alkyl groups include but are not limited to methyl, ethyl, n-propyl, iso-propyl, n-butyl, and iso-butyl.
The term "aryl" refers to an aromatic, optionally fused, carbocycles having from 6 to 20 carbon atoms. Examples of C6-12-aryl include but are not limited to phenyl and napthyl. The term "alkylaryl" or 'aralkyl' refers to an alkyl substituted with one or more aromatic residues, and optionally with substituents. Examples of alkylaryl include, but are not limited to, benzyl.
The present invention is directed to new compounds represented in the formula (I),

aryl group, preferably C1-C6 alkyl group, and R" refers to alkyl, or aryl group. The compounds of formula I, in which the carbon marked with an asterisk refers to chiral centre, and in the present case it may be racemic, or optically enriched in one enatiomer, or pure chiral isomer.
In particular, the compounds are diastereomer salts of optically active tartaric acids of formula II,
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III may exists in a racemic, optically enriched with one enantiomer, or pure chiral enantiomer form.
In one embodiment, the present invention provides a process to prepare the compound of Formula I, which comprises contacting a compound of formula III with an optically active tartaric acid of Formula II, wherein the groups are as defined above in a suitable solvent, followed by fractional crystallization of compound of Formula I, wherein the carbon marked with Asterisk is in partially enriched from or optically active enantiomeric form, from an aqueous or organic solvent. The fractional crystallization of corresponding isomer is effected preferably in solvents, but not limited to, esters, ethers, ketone, nitrile, C1-C6 alcohol like methanol, ethanol, and their cross combinations with water. The preferred optically active tartaric acid compound II is 0,0-d\benzoyl tartaric acid, or 0,0-ditoluoyl tartaric acid, preferably the 0,0-dibenzoyl tartaric acid.
According to the invention, the compounds of the formula I may be prepared in any suitable solvent or in the solvent used for fractional crystallization. In the case the salt forming solvent is different from fractional crystallizing solvent, then it is preferably removed from the reaction by any conventional means such as distillation. The first solvents may be selected from any inert organic or aqueous solvent, particularly preferred solvents are alcohol, ethers, esters, hydrocarbons etc.
In a preferred embodiment of the present invention the process comprises contacting compound of Formula III with optically active tartartic acid of Formula III, wherein the groups are as defined above, in solvents selected from esters like ethyl acetate,
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acetonitrile, C1-C6 alcohols (straight chain or branched) such methanol, ethanol, isopropyl alcohol, ethers such as di-isopropyl ether, ketones such as acetone, acetonitrile-water, methanol-water, ethanol-water, acetonitrile-methanol, acetone-water, isopropanol-water or any such cross combinations, at a temperature from room temperature to reflux temperature to form a solution, followed by cooling the obtained solution to precipitate out the compound of Formula I, preferably compound of Formula-I in either single diastereomer, or enantimerically enriched form. Preferably the solution is cooled to room temperature or below room temperature to complete the crystallization of the diastereomer salt.
The process may further comprise purifying the compound of Formula I by crystallization/slurrification from the above solvents, one or more times to receive the optically pure diastereomeric salt.
The tartaric acid of Formula 11 may be used in molar ranges from 0.5 to 1.2 moles, preferably in equi-molar amounts relative to the compound of formula III.
When the compound of formula I is obtained by contacting the compound of Formula III with tartaric acid O-ester in the solvent other than the fractional crystallization solvent, then preferably the compound is obtained in racemic form or slightly enriched form by eliminating the solvent. . The concentrated reaction mixture is then combined with the fractionating crystallization solvent at suitable temperature, followed by recovery of the optically active cetirizine tartarate salt.
The present compounds are useful for preparation of optically active cetirizine, either in (R)-form or (S)-form, or an enantiomerically enriched form. The process for preparation of cetirizine comprises hydrolysis of compound of formula I in acidic or alkaline condition. The hydrolysis may be conducted in a single step or break-up to form compound of Formula III in optically active form followed by an acid or base assisted ester hydrolysis. The hydrolysis in the first step is preferably carried out in alkaline condition. Hydrolysis is preferably conducted in aqueous solvent which includes water and its combinations with water miscible organic solvents such as alcohols, aprotic dipolar solvents etc. The hydrolytic reaction is carried out at a temperature, for example from room temperature to reflux temperature, preferably carried under heating above room temperature. Lower temperature results in long reaction times and a suitable
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temperature range is chosen depending on the stability/decomposition of the compound & the base or acid used..
Preferably, the base is an organic or inorganic base. The bases are preferably a metal carbonate, or hydroxides or alkoxides, amines, exemplary bases are sodium hydroxide, potassium hydroxide, sodium carbonate or bicarbonate. Preferably, the acid is an organic or inorganic acid. Exemplarary mineral acids are hydrochloric acid, HBr, HI, phosphoric acids, sulphuric acid etc, and organic acids are acetic acid, sulphonic acids etc.
To improve the efficiency of recovery of optically active cetirizine from the racemic cetirizine, the present invention also provides process for the racemization of enantiomerically pure or enriched (S)-Cetirizine ester or (R)-Cetirizine ester of formula III. The process comprises combining enantiomerically enriched Cetirizine ester, with an alkali in a suitable solvent. The solvent may be selected from the group consisting of a Ci-6 alcohol, dipolar aprotic solvent such as DMSO, acetonitrile, ethers such as tetrahydrofuran and mixtures thereof. The present racemization process is useful to recycle the unwanted isomer of cetirizine into the preparation/resolution of Levocetirzine or vise versa.
The process of racemization is preferably effected under heating, for example at a temperature ranging from above room temperature to reflux temperature of the solvent. Preferably, the base is an organic or inorganic base. More preferably, the base is selected from the group consisting of: alkali metal hydroxide, alkali metal alkoxides, and carbonates. Even more preferably, the base is selected from the group consisting of KOH and potassium methoxide or tert.butoxide. Most preferably, the base is KOH.
The optically active cetirizine ester either (R)- isomer or (S)-isomer or its free form is recovered after hydrolysis in a conventional manner. Preferably, the product is extracted in an additional organic solvent. Preferably, the additional organic solvent is an ester, or chlorinated hydrocarbon solvent, more preferably, dichloromethane.
The present invention further comprises preparing a pharmaceutical salt of cetirizine, preferably levocetirizine hydrochloride or levocetirizine dihydrochloride. The process
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further comprises a method to manufacture pharmaceutical composition, by incorporating said leveocetirizine or pharmaceutical^ acceptable salts in a unit dosage form, including tablet, capsule, injectible etc.
The starting cetirizine ester of Formula III may be obtained by any conventional esterification, preferably in the presence of an acid catalyst. The optically active tartaric acid of formula II, is commercially available, or can be prepared in a known manner per se.
Having described the invention with reference to certain preferred embodiments, other embodiments will become apparent to one skilled in the art from consideration of the specification. The invention is further defined by reference to the following examples describing in detail the methods of preparation and use of the invention. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention.
Examples:
Example 1: Preparation of (R)-Cetirizine methyl ester - (9,0-dibenzoyl-D-tartaric acid salt
A solution of 100 g of (±)-Cetirizine methyl ester in 600 ml ethyl acetate was heated to reflux, and a solution of 59.7 gm (0.67 mole) (9,0-dibenzoyl-D-tartaric acid in 200 ml ethyl acetate was added and then refluxed for 30 minutes. The solution was then cooled to room temperature, 30 ml water was added to precipitate solids, and maintained for 1 hour. The precipitated solids were filtered, washed with 100 ml ethyl acetate. The solids were then taken in 128 ml acetonitrile, heated to reflux and maintained for 30 minutes until clear solution is obtained. The solution was then allowed to cool to room temperature, and maintained for 1 hour. The precipitated solids filtered out, washed with chilled acetonitrile, and dried to obtain (R)-Cetirizine methyl ester-O.O-dibenzoyltartaric acid salt
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Example -2: Preparation of (R)-Cetirizine methyl ester.
32 gm (R)-Cetirizine methyl ester - 0,0-dibenzoyltartaric acid salt obtained in example-1 was mixed with 200 ml dichloromethane. To this mixture, a solution of 6.6 gm sodium hydroxide in 100 ml water was added, stirred for 30 minutes, organic layer was separated, washed with water, and distilled dichloromethane under vacuum to obtain title product as an oil.
Example-3. Racemization of enantiomerically enriched (S)-Cetirizine 100 gm Cetirizine methyl ester (70% (S)-isomer & 30 % R-Isomer) was dissolved in 500 ml dimethyl sulphoxide. To this mixture 84.4 gm sodium ethoxide (5 mole) was added and heated to 100 degree for 3 hours. The reaction mass was found to be racemic. 500 ml water was added to the reaction mass and extracted with 250 ml dichloromethane (2 times). The dichloromethane layer was washed with water, and distilled dichloromethane to obtain 98.0 gm racemic cetirizine methyl ester as an oil.


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