FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule13)
1. TITLE OF THE INVENTION:
AN IMPROVED PROCESS FOR THE PREPARATION OF CETIRIZINE OR
SALT THEREOF.
2. APPLICANT (S)
(a) NAME: WOCKHARDT LTD.
(b) NATIONALITY: INDIAN
(c) ADDRESS: Wockhardt Towers, Bandra-Kurla Complex, Bandra
(East), Mumbai-400 051.
3. PREAMBLE TO THE DESCRIPTION
The present invention provides an improved process for the preparation of cetirizine or salt thereof.
The following specification particularly describes the invention and the manner in which it is to be performed.

4. DESCRIPTION
The present invention provides an improved process for the preparation of cetirizine or salt thereof. More particularly present invention provides a process for preparation of cetirizine free base.
Cetirizine dihydrochloride of formula I is chemically known as [2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy] acetic acid, dihydrochloride. It is a non-sedating type histamine H1-receptor antagonist and is used in the treatment of allergic syndromes.

Formula I
US patent No. 4,525,358 describes the process of preparation of cetirizine and its dihydrochloride involving reaction of 1-[(4-chlorophenyl)phenylmethyl] piperazine with methyl (2-chloroethoxy) acetate or 2-(2-chloroethoxy) acetamide.
GB Patent No. 2 225 320 relates to a process for preparing cetirizine and its dihydrochloride by reacting [2-[4-[4-(chlorophenyl)phenylmethyl]-1-piperazinyl]-ethanol with an alkali metal halo acetate.
GB Patent No. 2 225 321 describes a process for preparing cetirizine by reaction of 1-[(4-chlorophenyl) phenylmethyl-piperazine with chloroethoxyacetonitrile to obtain the nitrile derivative that is hydrolized in acidic or alkaline medium to cetirizine and, where appropriate into its dihydrochloride.
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Other methods of preparing cetirizine are disclosed in US 6,046,332; US 6,239,277; US 6,265,579; US 6,908,999.
PCT Application WO 05/073207 describes process for preparation of optically active cetirizine or its salt thereof.
Our co-pending Indian patent application 1793/MUM/2006 describes the process for the preparation of cetirizine dihydrochloride.
The present invention discloses an unknown impurity of formula II formed during the synthesis of cetirizine from the intermediate 2-{4-[(4-chloro-phenyl)-phenyl-methyl]-piperazin-1-yl}-ethanol. The present inventors have also found an improved process for the preparation of the cetirizine from the intermediate 2-{4-[(4-chloro-phenyl)-phenyl-methyl]-piperazin-1-yl}-ethanol to reduce the formation of the impurity of formula II.
Cetirizine is prepared from the intermediate 2-{4-[(4-chloro-phenyl)-phenyl-methyl]-piperazin-1-yl}-ethanol by treating with 1.99 molar equivalents of sodium chloroacetate in the presence powdered potassium hydroxide. During this reaction there is a formation of an unknown impurity in 0.2-0.3 % which is identified and characterized in the present invention as (2-{4-[(4-Chloro-phenyl)-phenyl-methyl]-piperazin-1-yl}-ethoxy)-acetic acid carboxymethyl ester (formula II).
In one of the aspect of the present invention there is provided a process for the preparation of cetirizine dihydrochloride wherein the said process comprises of, a) reacting 2-{4-[(4-chloro-phenyl)-phenyl-methyl]-piperazin-1-yl}-ethanol (formula III) in an organic solvent with sodium chloroacetate in presence of a base, wherein the molar ratio of 2-{4-[(4-chloro-phenyl)-phenyl-methyl]-piperazin-1-yl}-ethanol to sodium chloroacetate is in the range of 1:1.25 to 1:1.4;
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b) washing the reaction mass with suitable organic solvent to remove unreacted 2-{4-[(4-chloro-phenyl)-phenyl-methyl]-piperazin-1-yl}-ethanol;
c) acidifying the aqueous layer with hydrochloric acid to pH 4 to 4.5;
d) isolating the cetirizine free base;
e) dissolving the product obtained in step (d) in acetone and treating with hydrogen chloride;
f) isolating cetirizine dihydrochloride from reaction mass thereof.

The compound of Formula III i.e. 2-{4-[(4-chloro-phenyl)-phenyl-methyl]-piperazin-1-yl}-ethanol, prepared as per the procedure described in our pending Indian patent application 1793/MUM/2006, is dissolved in dimethyl formamide. The solution was treated with powered potassium hydroxide and sodium chloroacetate in a ratio in the range of 1:1.25 to 1:1.4. The reaction mixture was
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stirred at 20-35 °C for 5-8 hours. Then pH is adjusted to around 9-10 in the presence of water with dilute hydrochloric acid solution. The reaction mixture is then washed with ethyl acetate to remove unreacted 2-{4-[(4-chloro-phenyl)-phenyl-methyl]-piperazin-1-yl}-ethanol. The aqueous layer pH is adjusted to 4 to 4.5 with hydrochloric acid solution. The product is extracted with organic solvent such as methylene chloride, chloroform. Removal of organic solvent yields oily mass. The oily mass is dissolved in acetone and treated with concentrated hydrochloric acid to get precipitation of cetirizine dihydrochloride. The reaction mixture is heated at reflux for 16 hours and then cooled to room temperature 20-30° C. The product obtain is filter and dried to get Cetirizine dihydrochloride which is > 99% pure. The impurity (2-{4-[(4-Chloro-phenyl)-phenyl-methyl]-piperazin-1-yl}-ethoxy)-acetic acid carboxymethyl ester (formula II) is found to be in the range of 0.03 to 0.06 %.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
EXAMPLE
Preparation of cetirizine dihydrochloride
2-{4-[(4-chloro-phenyl)-phenyl-methyl]-piperazin-1-yl}-ethanol (122.6 g) in dimethyl formamide (410 ml_) was cooled to 8 to 10°c and added powdered potassium hydroxide (49.8 g) followed by the addition of sodium chloroacetate (63.0 g) in portions. The reaction mass was stirred at 10 -20°C for 1 hour and stirring continued for 1 hour and then at 30-35° C for 4 hours. Then water (1.46 L) was added to the reaction mass and pH of reaction mass was adjusted to 9.4 with aqueous hydrochloric acid solution. The reaction mass was washed with ethyl acetate (2.6 L). The aqueous layer was treated with hydrochloric acid solution to get pH 4 to 4.5. The product was extracted with methylene chloride
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(1.6 L) and distilled under reduced pressure. Then the oily residue (165.0 g) was
dissolved in acetone (1.75 L) and to it concentrated hydrochloric acid (50 mL)
was added to precipitate cetirizine dihydrochloride. The reaction mixture was
heated at reflux for 16 hours and then cooled to room temperature. The product
obtained was filter and dried to get title compound.
Yield = 139 g,
Purity = > 99.5 % by HPLC,
Single largest Impurity of (2-{4-[(4-chloro-phenyl)-phenyl-methyl]-piperazin-1-yl}-
ethoxy)-acetic acid carboxymethyl ester is 0.03%.
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We Claim:
1. (2-{4-[(4-Chloro-phenyl)-phenyl-methyl]-piperazin-1-yl}-ethoxy)-acetic acid carboxymethyl ester.
2. A process for the preparation of cetirizine or salt thereof, wherein the said process comprises of,

a) reacting 2-{4-[(4-chloro-phenyl)-phenyl-methyl]-piperazin-1-yl}-ethanol in an organic solvent with sodium chloroacetate in presence of a base, wherein the molar ratio of 2-{4-[(4-chloro-phenyl)-phenyl-methyl]-piperazin-1-yl}-ethanol to sodium chloroacetate is in the range of 1:1.25 to 1:1.4;
b) washing the reaction mass with suitable organic solvent to remove unreacted 2-{4-[(4-chloro-phenyl)-phenyl-methyl]-piperazin-1-yl}-ethanol;
c) acidifying the aqueous layer with hydrochloric acid to pH 4 to 4.5;
d) isolating cetirizine dihydrochloride thereof.

3. The process of claim 2, wherein the ratio of 2-{4-[(4-chloro-phenyl)-phenyl-methyl]-piperazin-1-yl}-ethanol compound of formula II and sodium chloroacetate is in the range of 1:1.25 to 1:1.4.
4. The process of claim 2, wherein the organic solvent used in step (a) is dimethyl formamide.
5. The process of claim 2, wherein the base used in step (a) is potassium hydroxide.
6. The process of claim 2, wherein cetirizine dihydrochloride obtained is having purity of 99% or more by HPLC.
7. The process of claim 2, wherein the organic solvent used in step (c) is
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methylene chloride or chloroform.
8. The process of claim 2, wherein in the step (d) isolation of cetirizine dihydrochloride comprises of,
a) isolating cetirizine free base;
b) treating cetirizine free base with hydrochloride chloride in an organic solvent;
c) isolating the product from the reaction mass thereof.
9. The process of claim 8, wherein the organic solvent used is acetone.
Dated this 27TH day of Apr, 2007 For Wockhardt Limited