FORM 2
THE PATENTS ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10 and rulel3)
1. TITLE OF THE INVENTION:
"PROCESS FOR PREPARATION OF CETIRIZINE/LEVOCETIRIZINE AND PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF"


2. APPLICANT(S):
(a) NAME: IPCA LABORATORIES LTD.
(b) NATIONALITY: Indian Company incorporated under the Indian
Companies ACT, 1956
(c) ADDRESS: 48, Kandivali Industrial Estate, Mumbai-400 067, Maharashtra,
India.
3. PREAMBLE TO THE DESCRIPTION:
The following specification describes the invention.


FIELD OF INVENTION:
The present invention relates to a process for preparation of antihistamine drug, cetirizine or levocetirizine or a pharmaceutically acceptable salts thereof. More particularly, the invention relates the preparation of cetirizine or levecetirizine or salts thereof by racemizing and recycling of enantiomer of compound having the formula-I.

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.
Levocetirizine is the R enantiomer of cetirizine, chemically known as [2-[(4-chlorophenyl)phenylmethyl]-l-piperazinyl]ethoxy] acetic acid, 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.
An optical resolution method of an optically active 1-[(substituted phenyl)phenylmethyl]piperazine is disclosed in GB 2225321, which method comprises
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reacting racemic l-[(4-chlorophenyl)phenylmethyl]piperazine with an optically active tartaric acid to form a salt. Further the optically active 1-[(substituted phenyl)phenylmethyl]piperazine is converted to levo/dextro cetirizine.
Indian application 501/MUM/2004 and PCX application WO2009078627 disclosed resolution of l-[(4-chlorophenyl)phenylmethyl]piperazine. Another PCT application, WO2006/94648 disclosed resolution of 2-[4-(4-chlorobenzhydryl)piperazin-l-yl] ethoxyacetamide. Yet another PCT application disclosed resolution of alkyl esters of cetirizine. However, an Indian application, 2130/MUM/2007 filed by us disclosed racemization of methyl ester of S-cetirizine during the preparation of Levocetirizinedihydrochloride. Since the undesired isomers obtained after resolution are discarded/incinerated leading to increase in cost of production and causing environmental pollution as well.
Consequently there is a need to recycle and reuse of the undesired isomer of Formula -I to get maximum yield of cetirizine/levocetirizine to make economically viable process.
Therefore, the object of the invention is to provide recycling/racemisation of undesired isomer of Formula-I in the preparation of cetirizine or levocetirizine.
SUMMARY OF INVENTION:
These objects are achieved by studying various conditions of process and surprisingly found that racemization of compound formula-I which ameliorates most of the problems associated with undesired isomers and the process can easily be translated to industrial application.
According to one aspect of the invention, there is provided a recycling process for the preparation of cetirizine or levocetirizine or pharmaceutically acceptable salts thereof. The recycling process comprises:


a) reacting S enantiomer of compound of Formula-I with a base to obtain racemic compound of Formula-1

wherein R is H, ethoxy acetamide, N-monoalkyl or N,N, dialklyl ethoxyacetamide, t-butoxycarbonyl, ethyoxyacetonitrile, lower alkyl, substituted alkyl, and b) converting the racemic l-[(4-chlorophenyl)phenylmethyl]-piperazine of Formula-I to cetirizine or levocetirizine or pharmaceutically acceptable salts thereof.
According to another aspect of the invention, there is provided a process for racemization of R or S isomer of compound of Formula-I which comprises reacting the R or S isomer of compound of Formula-I with a base to obtain racemic compound of Formula-I.
In one preferred embodiment the racemization reaction is carried out in a solvent selected from water, C1-C6 alcohols, dipolar aprotic solvents, nitriles and/or ethers or mixtures thereof.
DETAILED DESCRIPTION OF THE INVENTION:
Unless specified otherwise, all technical and scientific terms used herein 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 here in can be used in the practice or testing of the 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 the appended claims.
The term "pharmaceuticaily acceptable salts" as used herein refers not only to addition salts with pharmaceuticaily 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.
The terms "enantiomer", "S" and "R", as used herein, unless specified otherwise, refer to stereoisomer resulting from the spatial 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 present inventors provide a recycling and recemization process of Formula -I in the preparation of cetirizine or levocetirizine or a pharmaceuticaily acceptable salts thereof. The recycling process comprises:
a) reacting S enantiomer of compound of Formula-I with a base to obtain racemic compound of Formula-1 and



Formula -I b) converting the racemic l-[(4-chlorophenyl)phenylmethyl]-piperazine of Formula-I to cetirizine or levocetirizine or pharmaceutically acceptable salts thereof.
R in the Formula -I represents H, ethoxy acetamide, N-monoalkyl or N,N, dialklyl ethoxyacetamide, t-butoxycarbonyl, ethyoxyacetonitrile, lower alkyl, substituted alkyl, however preferred group is H.
The following scheme-I illustrates the invention.

Preferably, the base is an 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 potassium hydroxide and potassium methoxide or tertiary.butoxide. Most preferably, the base is potassium hydroxide or potassium tertiary butoxide. The base is conveniently used in an amount, although not limited to, equal or greater than molar equivalents relative to the starting S-


enantiomer of Formula-I, preferably in a range between 1.0 to 4.0 moles, more preferably between 2.0 to 2.6 moles.
In a preferred embodiment of the present invention, the process of racemization is performed in a solvent selected from water, C1-C6 alcohols, polar aprotic solvents, nitriles and/or ethers or mixtures thereof. Preferred solvents include dimethyl sulphoxide, dimethyl formamide, Tetrahydrofuran, diisopropyl ether or diethyl ether or mixtures thereof. Most preferred solvents are dimethyl sulphoxide, tetrahydrofuran or mixtures thereof. Typically the reaction is conducted in the range of 0°C to the boiling temperature of the solvent used. Preferably, the reaction is performed in the temperature range of about 50-90°C. Most preferred temperature range is about 60-85°C. Usually time taken for completion of reaction varies from 1-12 hours. The reaction can be monitored by chiral HPLC for completion.
After completion of reaction, work up to isolate the racemic compound of Formula-1 is done by distillation of solvent followed by addition of water and water immiscible organic solvent such as Methylene dichloride. The methylene dichloride layer is further washed with water and concentrated to obtain the racemic compound of Formula -I.
According to another aspect of the invention, there is provided a process for racemization of R or S enantiomer of compound of Formula-I which comprises reacting the R or S isomer of compound of Formula-I with a base to obtain racemic compound of Formula-I.
The R or S isomers are reacted with base in the conditions as explained above for obtaining racemic compound of Formula -I.
The compound of Formula -1 is utilized for preparation of cetirizine or levocetirizine or pharmaceutically acceptable salts thereof by the art known in the literature. When the starting material is racemic compound of Formula -I, it will convert to cetirizine and if the starting compound is R-enantiomer, it will convert to levocetirizine.


In case of preparation of levocetirizine dihydrochloride, the racemic compound of Formula -I is resolved using a chiral acid such as dibenzoyl-D-tartaric acid in methanol-water solvent system to obtain diasteromric salt of R-isomer of Formula-I leaving undesired enriched (S)-enantiomer of Formula -I in the filtrate. The filtrate is either directly subjected to racemization or first concentrated to dryness and the residue obtained is then subjected to racemization. The racemization can be conveniently carried out by following the process described earlier.
The enriched (S)-enantiomer in the filtrate may vary from 100 to 60 % and the (R) enantiomer may vary from 0 to 40% i.e., the ratio of S:R may vary from 100: 0 to 60:40.
This way the undesired S-enantiomer is racemized and the obtained racemic compound is subjected for resolution. Thus the undesired S-enantiomer which does not have any significant value is put in to use. Hence this recmization & recycling process decreases the cost of production significantly.
Typical procedure for preparation of levocetirizine dihydrochloride from the compound of Formula-I, wherein R is H, is as follows:
The racemic compound of Formula -I is resolved using a chiral acid such as dibenzoyl-D-tartaricacid in methanol-water solvent system to obtain diasteromric salt of R-enantiomer of Formula-I. The diasteromeric salt is further, optionally, purified using methanol and then treated with ammonia in water to free the R-enantiomer of l-[(4-chlorophenyl)phenylmethyl]piperazine.
The R-enantiomer of l-[(4-chlorophenyl)phenylmethyl]piperazine is reacted with 2-chloroethanol using an aromatic hydrocarbon solvent such as toluene in the presence of a base such as triethylamine at about 105-108°C. Usually time taken for completion of the reaction is 16-18 hours. Reaction mass is worked up after completion of reaction by water wash followed by distillation of toluene under vacuum. The product, (R) 2-[4-[(4-chlorophenyl)phenylmethyl]-l-piperazinyl]ethanol, is isolated as an oil.


Further, the (R) 2-[4-[(4-chlorophenyl)phenylmethyl]-l-piperazinyl]ethanol is taken in a polar aprotic solvent, for example, dimethylsulphoxide and added a base such as potassium hydroxide. After stirring for 10-15 minutes, sodium monochloroacetate is added slowly. Reaction may be performed in the range from 0°C to 40°C. However, preferred temperature is 26-32°. Usually reaction completes in 6-10 hours of maintenance. After completion of reaction, water is added and pH is adjusted to 9.6-9.8 using concentrated hydrochloric acid. The reaction mass is washed with water immiscible solvent such as ethyl acetate or methylene dichloride to remove starting material/impurities. The aqueous reaction mass is subjected for distillation to remove traces of the solvent. Further, the mass is acidified with dilute hydrochloric acid up to pH 4.0 - 4.5 and extracted with a suitable water immiscible solvent such as methylene dichloride. The extract is distilled under vacuum to thick syrupy/sticky mass, which may be converted into pharmaceutically acceptable salts.
The thick syrupy/sticky mass is converted in to mono/dihydrochloride salt of levocetirizine by dissolving in a suitable solvent such as acetone followed reaction with concentrated hydrochloric acid at ambient temperature to 55°C. The product formed is separated by conventional methods such filtration or centrifugation.
The mono/dihydrochloride of cetirizine/levocetirizine obtained by the process of the present invention, may be formulated into a suitable dosage forms such as tablets, capsules etc., by combining with one or more pharmaceutically acceptable excepients using known techniques. The dosage form may include a suitable amount of the active ingredient and other pharmaceutical agents. The dosage forms prepared by the process of the present invention may be administered to a mammal in need, for the treatment of allergic rhinitis with asthma.
The following examples, which include preferred embodiments, is intended to illustrate the practice of this invention, it being understood that the particulars shown are by way of example and for purpose of illustrative discussion of preferred embodiments of the invention.
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EXAMPLE -1:
Preparation of levo l-[(4-chlorophenyl)phenylmethyl] piperazine:
60gm of Dibenzoyl-D-tartaric acid is added to a solution of lOOgm racemic l-[(4-chlorophenyl)phenylmethyl]piperazine in 2 lit methanol at reflux (at 65 °C). To the reaction mass, further added 500ml of methanol along with 500ml water at same condition. Refmxing the reaction mass is continued for further 45 minutes to complete reaction. Then the reaction mass is allowed to cool to 40°C and added seeds of pure product. The obtained reaction mass, in slurry form, is further stirred at room temperature for 3hours and filtered the solids obtained. Cake is washed with methanol and dried under vacuum at 50°C. Dry wt of product: 40 gm.
The crude is taken in 680 mL methanol and refluxed for 30 minutes. Then the mass is cooled to 30°C, filtered, washed with methanol and dried to get pure levo l-[(4-chlorophenyl)phenylmethyl] piperazine. dibenzoyl-D-tartaric acid salt. Dry wt: 32gm
The purified salt is taken in 100 mL water and basified with 56 mL of ammonia to
liberate free base. The base is extracted with 150 mL of methylene dichloride and
separated layers. The methylene dichloride layer is concentrated under vacuum to get the
levo l-[(4-chlorophenyl)phenylmethyl] piperazine base.
Wt: 18 gm.
Optical Rotation: -13.50°
Chiral purity: 99.78%
EXAMPLE-2:
Racemization of enantiomerically enriched (S)-l-[(4-
chlorophenyl)phenylmethyl]piperazine (S:R::66.49::33.51):


To a solution of lOOgm l-[(4-chlorophenyl)phenylmethyl] piperazine (Enantiomeric purity S:R::66.49::33.51%) in 200ml DMSO, added 42.98gm KOH and heated the reaction mass to 80-85°C for 4hr till completion of racemization. After completion of reaction, DMSO is distilled out under vacuum at 80-85°C. Added water 250ml water & 500ml methylene dichloride and stirred for 15 minuets. Separated methylene dichloride layer followed by water wash. Distilled the methylene dichloride layer to get concentrated mass as an oil. Oil obtained :- 93gm(% Yield-93%) S:R:: 50.58::49.42
EXAMPLE-3:
Racemization of enantiomerically enriched (S)-l-[(4-
chlorophenyl)phenylmethyl]piperazine (S:R::66.49:33.51) in Dimethylsulphoxide & Sodium ethoxide :-
To a solution of lOOgm l-[(4-chlorophenyl)phenylmethyl]piperazine (S:R:: 66.49::33.51) in 200ml Dimethylsulphoxide, added 52.2gm Sodium ethoxide. Heated the reaction mass under stirring to 80-85°C and maintained for 4 hours to complete reaction. After completion of reaction, DMSO is distilled out completely under vacuum at 80-85°C and then introduced 250ml water & 500ml methylene dichloride to form two layers. Separated layers, washed the methylene dichloride layer with water & distilled methylene dichloride to get product as oil. Oil obtained :- 55gm(% Yield-55%) S: R: 50.58::49.42
EXAMPLE-4:
Racemisation of enantiomerically enriched (S)-l-[(4-
chlorophenyl)phenylmethyl]piperazine (S:R::66.49::33.51) in Tetrahydrofuran & Potassium-tert-butoxide: -


To a solution of lOOgm (S)-l-[(4-chlorophenyl)phenylmethyl]piperazine (S:R::
66.49::33.51) in 200ml tetrahydrofuran, added 101.82gm Potassium-tertiary-butoxide.
Heated the reaction mass to 60-65 °C and stirred for 8hr to complete the reaction. After
completion of reaction, THF is distilled under vacuum at 50-55°C and product as
mentioned in example-2&3.
Oil obtained:- 94gm(% Yield-94%)
S:R: 50.68::49.32%
EXAMPLE-5:
Preparation of (R) -2-[4-[(4-chlorophenyl)phenylmethyl]-l-piperazinyl]ethanol:
Added lOOgm levo l-[(4-chlorophenyl)phenylmethyl]piperazine into a solution of 1000ml of toluene and 91.83gm triethyl amine. To the mixture, added 59 gm of 2-chloroethanol at 60°C under stirring, heated the reaction mass to 105-108°C and maintained for 18hrs till completion of reaction. After completion of reaction, 1000 mL water is added, stirred and separated toluene layer. One more water wash given to the toluene layer and then distilled the toluene layer to get concentrated mass as an oil. Oil obtained:- 106gm(% Yield-91.8%). HPLC purity: 98.28%
EXAMPLE-6:
Preparation of Levocetirizine dihydrochloride:
Dissolved lOOgm of (R)-2-[4-[(4-chlorophenyl)phenylmethyl]-l-piperazinyl]ethanol in 400ml of DMF. The obtained solution is cooled to 0-5°C, added 50.83gm ground potassium hydroxide and maintained the reaction mixture for 1 hour at 0-5°C. Then added sodium monochloroacetate, slowly, in 3 lots. The reaction mass is maintained for 6 hours to complete the reaction. After completion, 400ml DM water is added, pH of reaction mass is adjusted to 9.6-9.8 using concentrated hydrochloricacid. Reaction mass is washed with ethyl acetate and then the reaction mass is subjected for distillation to remove traces of ethyl acetate. Aqueous hydrochloride (1:1) is added slowly in to the

reaction mass to adjust the pH of reaction mass to 4.3-4.5. Then the aqueous reaction mass is extracted with 800ml methylene dichloride, separated methylene dichloride layer and the methylene dichloride is distilled to get 82.5gm sticky mass.
Dissolved lOOgm of sticky mass in 1000ml acetone, added 2.0gm charcoal and heated the mass to 50°C. Maintained the mass for 30 minutes and filtered the mass through hyflow bed & micron filtration. To the filtrate added 61.5ml concentrated HC1 slowly at 30°C, heated to 50±5°C and maintained for another 1 hour. The reaction mass in slurry form is cooled down to 0-5°C. Filtered the solids, washed with acetone and dried at 70±5°C. Dry wt: 89.1gm (% Yield:- 75%), HPLC purity: 99.78%, Chiral purity: 99.43% Optical Rotation: +13.038°


We claim:
1) A process for recycling of compound of Formula -I in the preparation of cetirizine or levocetirizine or a pharmaceutically acceptable salt thereof which comprises:
a) reacting S enantiomer of compound of Formula-I with a base to obtain racemic compound of Formula-1

wherein R is H, ethoxy acetamide, N-monoalkyl or N,N, dialkyl ethoxyacetamide,
t-butoxycarbonyl, ethyoxyacetonitrile, lower alkyl, substituted alkyl, and
b) converting the racemic l-[(4-chlorophenyl)phenylmethyl]-piperazine of
Formula-I to cetirizine or levocetirizine or pharmaceutically acceptable salt
thereof.
2) A process for racemisation of R or S isomer of compound of Formula-I which comprises reacting the R or S isomer of compound of Formula-I with a base to obtain racemic compound of Formula-I.
3) The process as claimed in claim 1 step a) or claim 2, wherein the reaction is performed in a solvent selected from water, C1-C6 alcohols, polar aprotic solvents, nitriles and/or ethers or mixtures thereof.
4) The process as claimed in claim 2, wherein the organic solvent is Dimethylsulphoxide or Tetrahydrofuran or mixtures thereof.


5) The process as claimed in claim 1 step a) or claim 2, wherein the base is alkali metal hydroxide, alkali metal alkoxides, or carbonates.
6) The process as claimed in claim 5, wherein the base is potassium hydroxide or potassiumtertiarybutoxide.
7) The process as claimed in claim 3, wherein the reaction is performed in the range of 0°C to reflux temp of solvent used.
8) The process as claimed in claim 5-6, wherein the base is used in the range of 1 to 4 moles on the substrate.
9) The process as claimed in claim 1, wherein the pharmaceutically acceptable salt of cetirizine or levocetirizine is monohydrochloride or dihydrochloride salt.
10) The process as claimed in claim 9, monohydrochloride or dihydrochloride salt of cetirizine or levocetirizine is incorporated in a pharmaceutical composition.

Dated this 01st day of October, 2009