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 EFFICIENT 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 efficient 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.
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4. DESCRIPTION
The present invention provides an efficient process for the preparation of cetirizine or salt thereof. More particularly present invention provides a process for preparation of cetirizine dihydrochloride
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 .
UK 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.
UK 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
US Application No. 2005020608 provides crystalline cetirizine monohydrochloride having a specific XRD pattern.
PCT Application WO 05/073207 describes process for preparation of optically active cetirizine or its salt thereof.
The present inventors have found an industrially advantageous process for the preparation of cetirizine dihydrochloride. The process of present invention is easily scalable at commercial scale.
In one of the aspect of the present invention there is provided a process for the preparation chloroethanol adduct intermediate of formula II useful in preparation of cetirizine or salt thereof, wherein the said process comprises of
a) reacting 4-chlorobenzhydryl piperazine with 2.-chloroethanol using organic solvent in presence of a base
,OH

Formula II
b) isolating the chloroethanol adduct compound of formula II from reaction mass thereof.
In another aspect of the present invention there is provided a process for preparation of cetirizine dihydrochloride wherein the said process comprises of, a) reacting compound of formula II in organic solvent with sodium chloroacetate in presence of a base
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b) washing the reaction mass with suitable organic solvent to remove unreacted compound of formula II
c) adding hydrogen chloride to the solution of step (b)
d) isolating cetrizine dihydrochloride from reaction mass thereof
Yet in another aspect of present invention, there is provided a process for the purification of cetrizine dihydrochloride, wherein the said process comprises of,
a) suspending cetrizine dihydrochloride in mixture of organic solvent,
b) isolating the product from the reaction mass thereof.
4-chlorobenzhydryl piperazine, 2-chloroethanol and base like triethyl amine or dicyclohexyl amine is heated in organic solvent such as toluene. The reaction mixture is then cooled to room washed with water. Organic solvent removed under reduced pressure to obtain thick viscous oil of chloroethanol adduct of formula II. The compound of Formula II in dissolved in dimethyl formamide and treated with base like powered potassium hydroxide and sodium chloro acetate. The reaction mixture stirred at 20-35° C for 5-8 hours. Then pH is adjusted to around 10 in presence of water with dilute hydrochloric acid solution. The reaction mixture is then washed ethyl acetate to remove unreacted chloroethanol adduct. The aqueous layer pH is adjusted to 4 to 4.5 with hydrochloric acid solution. The product is extracted with methylene chloride, and then removal of methylene chloride yields oily mass. The oily mass is dissolved in acetone and treated with 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 crude Cetirizine dihydrochloride
The cetirizine dihydrochloride crude is heated with mixture of organic solvent such as dimethyl sulphoxide and acetone at below 100°C. The precipitated product is filtered and wet cake obtained is resuspended in acetone and refluxed
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for 30 min. Then product isolated on cooling to room temperature, washed with acetone and dried to get cetirizine dihydrochloride
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
Stage-I: Preparation of chloroethanol adduct
A mixture of 4-chlorobenzhydryl piperazine (1.035 kg), 2-chloroethanol (418 gm)
and triethyl amine (618 gm) was heated at reflux in toluene (4.63 Litre) for 30-33
Hours. The reaction mass was then cooled to room temperature and washed
with water (2.6 Litre X 3). The toluene was then distilled under reduced pressure
to get thick viscous oil.
Yield = 1.06 Kg,
Purity = 92 to 95% by HPLC
Stage-ll: Preparation of cetirizine dihydrochloride crude
Chloroethanol adduct (1.065 kg) in dimethyl formamide (3.4 kg) was added potassium hydroxide (438.2 gm) was added and followed by the addition of sodium chloroacetate (742.6 gm) in portions. The reaction mass was stirred at 20 -25°C for 1 hour and stirring continued for 4 hours at 30-35° C. Then water (13.4 Litre) was added to 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. The aqueous layer was treated with hydrochloric acid solution to get pH 4 to 4.5. The product was extracted with methylene chloride (16 Litre) and distilled under reduced pressure. Then the oily residue (1.4 kg) was dissolved in acetone (15 Litre) and to it concentrated hydrochloric acid (550 ml) was added to precipitate Cetirizine dihydrochloride. The reaction mixture was heated at reflux
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for 16 hours and then cooled to room temperature. The product obtained was filter and dried to get title compound. Yield = 1.1 to 1.20 Kg, Purity = > 98% by HPLC
Stage-Ill: Purification of cetirizine dihydrochloride
Cetirizine dihydrochloride crude (1.1 kg) was heated with dimethyl sulphoxide (1.77 Litre) at 80°C to get clear solution. The reaction mass was cooled to 50-60°C and acetone (13.3 Litre) was added to reaction mass under stirring and then mass was refluxed at 50-55°C for 1 hour. The reaction mass was cooled to room temperature, filtered and washed with acetone. The wet cake obtained was suspended in acetone (5.0 Litre) and refluxed for 30 min. Then product obtained was cooled to room temperature, filtered, washed with acetone and dried to get the title compound.
Yield = 0.881 Kg
Purity = > 99 % by HPLC
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WE CLAIM:
1. A process for the preparation of chloroethanol adduct intermediate of formula II useful in preparation of cetirizine or salt thereof, wherein the said process comprises of
a) reacting 4-chlorobenzhydryl piperazine with i-chloroethanol using organic solvent in presence of a base

Formula II
b) isolating the chloroethanol adduct compound of formula II from reaction mass thereof.
2. A process of claim 1 wherein the organic solvent is toluene.
3. A process of claim 1 wherein the base is triethyl amine.
4. A process for the preparation of cetrizine dihydrochloride, wherein the said process comprises of,

a) reacting compound of formula II in organic solvent with sodium chloroacetate in presence of a base
b) washing the reaction mass with suitable organic solvent to remove unreacted compound of formula II
c) adding hydrogen chloride to the solution of step (b)
d) isolating cetrizine dihydrochloride from reaction mass thereof.
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5. A process of claim 4 wherein the organic solvent is dimethyl formamide, ethyl acetate, dichloro methane and acetone.
6. A process of claim 4 wherein the base is potassium hydroxide.

7. A process of claim 4 wherein hydrogen choride is hydrochloric acid.
8. A process of purification of cetrizine dihydrochloride, wherein the said process
comprises of
a) suspending cetrizine dihydrochloride in mixture of organic solvent,
b) isolating the product from the reaction mass thereof.
9. A process of claim 1 wherein the organic solvent mixture is dimethylsulphoxide
and acetone
10. A process of claim 1, wherein cetrizine dihydrochloride obtained having purity
of 99% or more by HPLC.
Dated this 30th day of October, 2006 For Wockhardt Limited
(Mandar Kodgule) Authorized signatory
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