FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
A process for the preparation of Hydroxyzine
2. APPLICANT (S)
(a) NAME: Enaltec Labs Pvt. Ltd.
(b) NATIONALITY:
An Indian Company incorporated under the Indian Companies ACT 1956
(c) ADDRESS:
Enaltec Labs Pvt. Ltd., 17th Floor, Kesar Solitaire, Plot No. 5, Sector 19, Sanpada, Navi Mumbai- 400705, Maharashtra, India.
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed

Technical field of the invention:
The present invention relates to a process for the preparation of hydroxyzine represented by compound of Formula I and its pharmaceutically acceptable salts. The present invention further relates to the pamoate (Compound of Formula II) or hydrochloride (compound of Formula III) salt of hydroxyzine. Preferably the present invention further related to process for the preparation of Hydroxyzine Pamoate represented by compound of Formula II.

Background of the invention:
Hydroxyzine (compound of formula I) is chemically known as (2-(2- {4-[(4-chlorophenyl)(phenyl)methyl]piperazin-1-yl}ethoxy)ethanol. Also chemically known as (±)-2-[2-[4-(p-Chloro-a-phenylbenzyl)-1-piperazinyl]ethoxy]ethanol or l-(p-chlorobenzhydryl)4-[2-(2-hydroxyethoxy)ethyl]diethylenediamine represented by compound of Formula I.
Hydroxyzine is a first-generation antihistamine, of the piperazine class that is an H1 receptor antagonist. It is used primarily for the treatment of itches and irritations, an antiemetic for the reduction of nausea, and as an anxiolytic for the treatment of anxiety.
Hydroxyzine pamoate (Formula II) approved by USFDA with brand name Vistarir' and designated chemically as l-(p-chlorobenzhydryl)4-[2-(2-hydroxyethoxy)

ethyljdiethylenediamine salt of 1,1 '-methylene bis (2 hydroxy-3-naphthalene carboxylic acid) (Formula II).
Hydroxyzine hydrochloride (Formula III) approved by USFDA with brand name Atarax® and has the chemical name of 2-[2-[4-(p-Chloro-a-phenylbenzyl)-1-piperazinyl]ethoxy]ethanol dihydrochloride (Formula III).

Vistaril® or Atarax© indicated for symptomatic relief of anxiety and tension associated with psychoneurosis and as an adjunct in organic disease states in which anxiety is manifested. Also useful in the management of pruritus due to allergic conditions such as chronic urticaria and atopic and contact dermatoses, and in histamine-mediated pruritus.
US2899436 patent discloses piperazine ethers including hydroxyzine, its preparation and its therapeutic use.
US2899436 patent discloses preparation of hydroxyzine using piperazine compound of formula (IV) and chloroethyoxyethanol (wherein X is Cl) by heating at 150°C, followed by distillation. This method associated drawback such as not complete conversion, contamination of the product with starting piperazine material. Also, practically difficult is associated with the removal of solvent like benzene -a known carcinogen from the final product.


There are only few literatures available for the preparation of hydroxyzine.
Indian patent application 1383/MUM/2007 discloses preparation of hydroxyzine (I) by reacting a piperazine compound of Formula IV with haloethoxyethanol in the presence of phase transfer catalyst (PTC) in an aqueous medium. For isolation of product uses large quantity of hazardous solvents and reagents such as sodium iodide.
Similarly, PCT/IN2009/000509 application also discloses water based process for the preparation of diphenylmethyl piperazines compound (I) by reacting compound of formula IV with haloethoxyethanol in the presence of phase transfer catalyst (PTC) in an aqueous medium.
Indian patent application 1976/MUM/2008 and PCT/IN2009/000509 discloses water based process for the preparation of substituted diphenylmethyl piperazines, using phase transfer catalyst but said method associated with drawback such as degradation of starting material, low yield and tedious workup.
Accordingly there is need to develop a prior art process of preparing hydroxyzine compound of formula I, which is simple, economic, safe and industrially viable and providing the better yield and purity of the final hydroxyzine. This will improve economic feasibility, industrial applicability in the synthesis of hydroxyzine pamoate (Compound of Formula II) or hydroxyzine hydrochloride (compound of Formula III) salts of hydroxyzine.

Object of the invention:
An object of the invention is to provide a simple, economic, safe and industrially viable process for preparation of Hydroxyzine the compound represented by structural formula I or pharmaceutically acceptable salt thereof:

Another object of the present invention is to provide a simple, economic, safe and industrially viable process for preparation of Hydroxyzine Pamoate represented by compound of Formula II:

Another object of the present invention is to provide a simple, economic, safe and industrially viable process for preparation of Hydroxyzine Hydrochloride represented by compound of Formula III:


It is further object of the present invention to provide a commercially viable process for the production of diphenylmethyl piperazines of Formula IV and pharmaceutically acceptable salts.

Another object of present invention is to provide a process for preparation of the compound represented by structural formula I or compound of formula II or III comprising
a) converting (4-chlorophenyl)(phenyl)methanol (Formula V) to compound of formula VI (wherein X is OTs/OMs);
b) reacting compound of formula (VI) with piperazine compound of formula (VII);
c) converting compound formula (VIII) to compound of formula IV,
d) reacting compound of formula IV with compound of formula IX to give compound for formula I;
e) optionally converting compound of formula (I) to compound of formula (II) or compound of formula (III).
Another object of present invention is to provide a process for preparation of the compound represented by structural formula I or compound of formula II or III comprising,

i) reacting piperazine (Formula XI) with compound of XII (wherein X is
OTs/OMs and R is Boc, Benzyl, Acetyl, Cbz, H) to give compound of
formula XIII;
ii) reacting compound of formula (XIII) with compound of formula (VI) to
give compound of formula XIV; iii) converting compound formula (XIV) to compound of formula I; iv) Optionally converting compound of formula (I) to compound of formula
(II) or compound of formula (III),
Further object of the present invention is to provide a process for preparation of Hydroxyzine represented by compound of Formula I, Hydroxyzine Pamoate represented by compound of Formula II or Hydroxyzine Hydrochloride represented by compound of Formula III the compound represented by structural formula I/II/III which avoids the yield loss due to purification of intermediate providing Hydroxyzine the compound represented by structural formula I with better yield and purity.
Summary of the invention:
In accordance with the aspect of the present invention is to provide a simple, economic, safe and industrially viable process for preparation of Hydroxyzine the compound represented by structural formula I or pharmaceutically acceptable salt thereof:



According to another aspect of the present invention, a process for preparation of the compound represented by structural formula I or compound of formula II or III,
According to another aspect of the present invention, a process for preparation of the compound represented by structural formula I or compound of formula II or III comprising,
a) converting (4-chlorophenyl)(phenyl)methanol (Formula V) to compound of formula VI (wherein X is OTs/OMs);
b) reacting compound of formula (VI) with piperazine compound of formula (VII);
c) converting compound formula (VIII) to compound of formula IV,
d) reacting compound of formula IV with compound of formula IX to give compound for formula I;
e) optionally converting compound of formula (I) to compound of formula (II) or compound of formula (III).
Another aspect of the present invention is to provide a process for preparation of the compound represented by structural formula I or compound of formula II or III comprising,
i) reacting piperazine (Formula XI) with compound of XII (wherein X is
OTs/OMs and R is Boc, Benzyl, Acetyl, Cbz, H) to give compound of formula XIII;
ii) reacting compound of formula (XIII) with compound of formula (VI) to give compound of formula XIV;

iii) converting compound formula (XIV) to compound of formula I; iv) Optionally converting compound of formula (I) to compound of formula (II) or compound of formula (III),
Detail description of the invention:
The present invention relates to a simple, economic, safe and industrially viable process for preparation of Hydroxyzine the compound represented by structural formula I comprising:
a) converting (4-chlorophenyl)(phenyl)methanol (Formula V) to compound of formula VI (wherein X is OTs/OMs);
b) reacting compound of formula (VI) with piperazine compound of formula
(VII);
c) converting compound formula (VIII) to compound of formula IV,
d) reacting compound of formula IV with compound of formula IX to give compound for formula I;
e) optionally converting compound of formula (I) to compound of formula (II)
or compound of formula (III),
Scheme -I


In an embodiment of the present invention, the conversion of (4-chlorophenyl)(phenyl)methanol (Formula V) to compound of formula VI (wherein X is OTs/OMs) can be carried out by reacting compound of formula (V) with methane sulfonyl chloride (MsCl/ mesyl chloride) or p-toluene sulfonyl chloride (TsCl/ tosyl Chloride) in the presence of base in suitable solvent.
In another embodiment of the present invention, the conversion of (4-chlorophenyl)(phenyl)methanol (Formula V) to compound of formula VI (wherein X is OTs/OMs) can be carried by reacting compound of formula (V) with methane sulfonyl chloride (MsCl/ mesyl chloride) or p-toluene sulfonyl chloride (TsCl/ tosyl Chloride) in the presence of base selected from triethylamine (TEA), tributylamine, diisopropylethylamine (DIPEA), imidazole, pyridine, 4-dimethylaminopyridine, and morpholine or any combination thereof; in the solvent is selected from methylene chloride (MDC), tetrahydrofuran (THF), acetonitrile, dioxane, toluene, N,N-dimethylformamide or any combination thereof.
In another embodiment of the present invention, the compound of Formula (VI) reacted with piperazine compound of formula (VII) wherein R is Boc (tert-

butyloxycarbonyl) or Cbz (carboxybenzyl) protecting groups, in the presence of catalyst and base in suitable solvent give compound of formula (VIII).
The catalyst may be selected from tetrabutylammonium bromide,
tetrabutylammonium chloride, tetrabutylammonium fluoride,
tetrabutylammoniumiodide, tributylmethylammonium chloride,
tributylbenzylammonium chloride, tetrapentylammonium chloride,
tetrapentylammonium bromide, or any combination of thereof.
The suitable base selected from aq. Ammonia, triethyl amine, disopropyl ethyl amine sodium hydroxide, sodium carbonate, and sodium bicarbonate or any combination thereof.
The suitable solvent selected from dichloromethane, chloroform, tetrahydrofuran (THF) or aqueous medium comprises water alone or water miscible organic solvents.
The water miscible organic solvents, one can choose from a variety of organic solvents including alcohols, ketones, amides, sulphoxides or any combination thereof.
The compound of Formula (VI) reacted with piperazine compound of formula (VII) wherein R is Boc (tert-butyloxycarbonyl) in the presence of potassium carbonate in the presence of tetrabutyl ammonium bromide (TBAB) in tetrahydrofuran (THF) to give compound of formula (VIII).
The compound of formula VIII may be isolated or not isolated.
In another embodiment of the present invention, compound formula (VIII) is converted to compound of formula IV via de-protection reaction. This reaction may be performed using a suitable de-protecting agent in a suitable solvent depending on the nature of the protecting group itself.
In a preferred embodiment, compound of Formula VIII (wherein R- is Boc) is treated with p-toluenesulfonic acid or HBr in acetic acid or aqueous HC1 or HC1 in dioxane

or trifluoroacetic acid followed by neutralization with base to give compound of formula IV.
The base is an inorganic base selected from ammonia, alkali metal hydroxides, carbonates and bicarbonates. Preferable alkali metal is sodium or potassium. Preferred base is aq. Ammonia, triethyl amine, disopropyl ethyl amine sodium hydroxide, sodium carbonate, or sodium bicarbonate.
In another embodiment, compound of Formula VIII (wherein R- is Cbz) is treated with H2 Pd/C in methanol to give compound of IV.
In another embodiment of the present invention, the compound of Formula (IV) reacted with compound of formula (IX) wherein X is OTs/OMs in the presence of catalyst and base in suitable solvent to give compound of formula (I).
The catalyst may be selected from tetrabutylammonium bromide,
tetrabutylammonium chloride, tetrabutylammonium fluoride,
tetrabutylammoniumiodide, tributylmethylammonium chloride,
tributylbenzylammonium chloride, tetrapentylammonium chloride,
tetrapentylammonium bromide, or any combination of thereof.
The base is an inorganic base selected from ammonia, alkali metal hydroxides, carbonates and bicarbonates. Preferable alkali metal is sodium or potassium. Preferred base is aq. Ammonia, triethyl amine, disopropyl ethyl amine sodium hydroxide, sodium carbonate, or sodium bicarbonate.
The suitable solvent selected from dichloromethane, chloroform, tetrahydrofuran (THF) or aqueous medium comprises water alone or water miscible organic solvents.
The water miscible organic solvents, one can choose from a variety of organic solvents including alcohols, ketones, amides, sulphoxides or any combination thereof.

The compound of Formula (IV) reacted withpiperazine compound of formula (IX) wherein R is Boc (tert-butyloxycarbonyl) in the presence of potassium carbonate in the presence of tetrabutyl ammonium bromide (TBAB) in (THF) to give compound of formula (VIII).
In another embodiment of the present invention, the compound of Formula (IV) reacted with compound of formula (IX) wherein X is Cl in the optional presence of catalyst and base in suitable solvent to give compound of formula (I). The catalyst, base and solvent as described above.
In another aspect of present invention, the process for preparation of Hydroxyzine the compound represented by structural formula I comprising:
i) reacting piperazine (Formula XI) with compound of XII (wherein X is
OTs/OMs and R is Boc, Benzyl, Acetyl, Cbz, H) to give compound of
formula XIII; ii) reacting compound of formula (XIII) with compound of formula (VI) to give
compound of formula XIV; iii) converting compound formula (XIV) to compound of formula I; iv) Optionally converting compound of formula (I) to compound of formula (II)
or compound of formula (III),
Scheme -II


In an embodiment of the present invention, the piperazine (Formula XI) reacted with compound of XII (wherein X is OTs/OMs and R is Boc, Benzyl, Acetyl, Cbz, H) in the presence of base in suitable solvent such as dichloromethane, chloroform, tetrahydrofuran (THF) to give compound of formula (XIII).
The compound of formula XIII may be isolated or not isolated.
In another embodiment of the present invention, the piperazine (Formula XI) reacted with compound of XII (wherein X is Cl/Br/OTs/OMs and R is Boc, Benzyl, Acetyl, Cbz, H) in the presence of base in suitable solvent such as dichloromethane, chloroform, tetrahydrofuran (THF) to give compound of formula (XIII),
In another embodiment of the present invention, the piperazine (Formula XIII) reacted with compound of IV (wherein X is OTs/OMs) in the presence of base in suitable solvent such as dichloromethane, chloroform, tetrahydrofuran (THF) to give compound of formula (XIV).

In another embodiment of the present invention, the piperazine (Formula XIII) reacted with compound of IV (wherein X is Cl/Br/OTs/OMs) in the presence of base in suitable solvent such as dichloromethane, chloroform, tetrahydrofuran (THF) to give compound of formula (XIV).
In another embodiment of the present invention, compound formula (XIV) is converted to compound of formula (I) via deportation reaction. This reaction may be performed using a suitable de-protecting agent in a suitable solvent depending on the nature of the protecting group itself.
In a preferred embodiment, compound of Formula XIV (wherein R- is Boc) is treated with p-toluenesulfonic acid or HBr in acetic acid or aqueous HC1 or HC1 in dioxane or trifluoroacetic acid followed by neutralization with base to give compound of formula (I).
The base is an inorganic base selected from ammonia, alkali metal hydroxides, carbonates and bicarbonates. Preferable alkali metal is sodium or potassium. Preferred base is aq. Ammonia, triethyl amine, disopropyl ethyl amine, sodium hydroxide, sodium carbonate, or sodium bicarbonate.
In another embodiment, compound of Formula XIV (wherein R- is Cbz/benzyl) is treated with H2 Pd/C in methanol to give compound of I.
In another embodiment, step € or step (iv) optionally converting compound of formula (I) to compound of formula (II) or compound of formula (III) comprises:
Treating compound of formula I with pamoic acid or hydrochloric acid in suitable solvent to give compound of formula II or III, respectively.


In another embodiment , compound of formula (I) treated with pamoic acid to give compound of formula II.
In another embodiment , compound of formula (I) converted to the compound of formula III, by treating compound of structural formula (I) with alcoholic hydrochloride solution in above mentioned polar pro tic solvent for a period of 30 minutes to 6 hours to get compound of structural formula III.
The examples of alcoholic hydrochloride solution may include methanolic hydrochloric acid, ethanolic hydrochloric acid or isopropanolic hydrochloric acid.
The alcoholic hydrochloride solution may contain hydrochloric acid in the range of 5% weight /weight to 30% weight / weight.
In another embodiment, compound of formula (XIV) wherein R is Boc is converted to the compound of formula III, by treating compound of structural formula (XIV) with alcoholic hydrochloride solution in above mentioned polar protic solvent for a period of 30 minutes to 6 hours to get compound of structural formula (III).
The compound of structural formula I may be converted in to compound of structural formula (II) by reacting compound of structural formula (I) with Pamoic acid in above mentioned non-polar organic solvent.
The compound of structural formula (II) or (III) may be isolated by the steps of filtration, centrifugation, washing, drying or the combinations thereof.
The isolated compound of formula (II) or (III) may be further purified filtration, washing, drying or any combinations thereof.

Example:
In the following example, the preferred embodiments of the present invention are described only by way of illustrating the process of the invention. However, these are not intended to limit the scope of the present invention in any way.
Example-1: Preparation of (4-Chlorophenyl)(phenyl)methyl 4-
methylbenzenesulfonate (compound of formula VI, wherein X is OTs)

A mixture of 10g of (4-chlorophenyl)(phenyl)methanol and 50ml dichloromethane was added 10.5g of para-Toluenesulfonyl chloride under stirring at 10-15°C followed by slow addition of 6g triethylamine. The reaction mass was stirred for 5hr at ambient temperature. Reaction was monitored by thin layer chromatography. The reaction mass was then worked up by washing with water followed by concentration of the organic layer under vacuum to get 14g of the title compound.
Example-2: Preparation of Tert-Butyl 4-((4-
chlorophenyl)(phenyl)methyl)piperazine-l-carboxylate (compound of formula VIII, wherein R is Boc/N-tert-Butyloxycarbonyl)


10g of (4-chlorophenyl)(phenyl)methyl 4-methylbenzenesulfonate was added to 50ml of tctrahydrofuran. To this mixture were added 6g of N-tert-Butyloxycarbonylpiperazine and 7.46g of potassium carbonate followed by 0.2g of tetrabutyl ammonium bromide. The reaction mass was refluxed for lOhr and conversion was monitored by thin layer chromatography followed by concentration of reaction mass under vacuum. The product was extracted with ethyl acetate and washed with aqueous sodium bicarbonate followed by water. Concentration of the organic layer afforded 7.5g of the title compound which may be optionally purified with suitable organic solvent.
Example-3: Preparation of l-((4-Chlorophenyl)(phenyl)methyl)piperazine (Compound of formula IV)

6g of Tert-Butyl 4-((4-chlorophenyl)(phenyl)methyl)piperazine-l-carboxylate was treated with 60ml solution of hydrogen chloride in isopropanol. The reaction mass was stirred at ambient temperature for 5hr. Reaction was monitored by thin layer chromatography. The reaction mass was then concentrated under vacuum and basified with aqueous sodium bicarbonate. The product was extracted with dichloromethane, washed with water and dried over sodium sulfate. Concentration of the organic layer under vacuum afforded 4g of the title compound which may be optionally purified with suitable organic solvent.
Example-4: Preparation of 2-(2-(4-((4-chlorophenyl)(phenyl)methyl)piperazin-l-yl)ethoxy)ethanol (Hydroxyzine/Compound of formula I)


Procedure 1: 9.1g of Potassium carbonate was added into the mixture of lOg of l-((4-chlorophenyl)(phenyl)methyl) piperazine and 50ml water under stirring followed by 0.4g of tetra-butyl ammonium bromide. Then 9.1g of 2-(2-hydroxyethoxy)ethyl 4-methylbenzenesulfonate was added into the reaction mass. The reaction mass was heated to 95-100°C and stirred for 8hr. Reaction was monitored by thin layer chromatography. The reaction mass was then cooled to room temperature and product was extracted with ethyl acetate. Organic layer was washed with water and concentrated under vacuum to get 11.5g of the title compound which is the free base of Hydroxyzine.
Procedure 2: 9.1g of Potassium carbonate was added into the mixture of 10g of l-((4-Chlorophenyl)(phenyl)methyl) piperazine and 50ml water under stirring. Then 9.1g of 2-(2-hydroxyethoxy)ethyl 4-methylbenzene sulfonate was added into the reaction mass. The reaction mass was heated to 95-100°C and stirred for 8hr. Reaction was monitored by thin layer chromatography. The reaction mass was then cooled to room temperature and product was extracted with ethyl acetate. Organic layer was washed with water and concentrated under vacuum to get 11.5g of the title compound which is the free base of Hydroxyzine.
Example-5: Preparation of Hydroxyzine Pamoate (compound of formula II)


5g of Hydroxyzine free base was treated with 5.2g of Pamoic acid in 50ml of isopropanol. The reaction mass was heated to reflux and stirred for 2hr. The reaction mass was then partially concentrated under vacuum and cooled to 50°C. 30ml of methyl tert-butyl ether was slowly added to the reaction mass and cooled to 0-5°C. Filtration of the reaction mass afforded 7.5g Hydroxyzine Pamoate.
Example-6: Preparation of Hydroxyzine Hydrochloride (Compound formula III)

5g of Hydroxyzine free base was dissolved in 10ml isopropanol. 5ml solution of hydrogen chloride in isopropanol (20% weight/volume) was added slowly under stirring into the reaction mass. The reaction mass was heated to 80-85°C and stirred for 20min. The reaction mass was then cooled to 0-5°C and stirred for 4 hr. Filtration of the reaction mass afforded 5g Hydroxyzine hydrochloride.

We Claim:
1. A process for preparation of Hydroxyzine the compound represented by
structural formula (I) comprising:

a) converting (4-chlorophenyl)(phenyl)methanol (Formula V) to compound of formula VI (wherein X is OTs/OMs);
b) reacting compound of formula (VI) with piperazine compound of formula (VII);
c) converting compound formula (VIII) to compound of formula IV,
d) reacting compound of formula IV with compound of formula IX to give compound for formula I;
e) optionally converting compound of formula (I) to compound of formula (II)
or compound of formula (III).
2. A process for preparation of the compound represented by formula II or
formula III comprising:
a) converting (4-chlorophenyl)(phenyl)methanol (Formula V) to compound of formula VI (wherein X is OTs/OMs);
b) reacting compound of formula (VI) with piperazine compound of formula (VII);

c) converting compound formula (VIII) to compound of formula IV,
d) reacting compound of formula IV with compound of formula IX to give compound for formula I;
e) converting compound of formula (I) to compound of formula (II) or compound of formula (III).

3. The process as claimed in claim 1 or 2, wherein the conversion of (4-chlorophenyl)(phenyl)methanol (Formula V) to compound of formula VI (wherein X is OTs/OMs) carried out by reacting compound of formula (V) with methane sulfonyl chloride (MsCl/ mesyl chloride) or p-toluene sulfonyl chloride (TsCl/ tosyl Chloride) in the presence of in the presence of base selected from triethylamine (TEA), tributylamine, diisopropylethylamine (DIPEA), imidazole, pyridine, 4-dimethylaminopyridine, and morpholine or any combination thereof; in solvent is selected from methylene chloride (MDC), tetrahydrofuran (THF), acetonitrile, dioxane, toluene, N,N-dimethylformamide or any combination thereof.
4. The process as claimed in claim 1 or 2, wherein compound of Formula (VI) reacted with piperazine compound of formula (VII) in the presence of potassium carbonate in the presence of tetrabutyl ammonium bromide (TBAB) in tetrahydrofuran (THF) to give compound of formula (VIII).
5. The process as claimed in claim 1 or 2, wherein compound formula (VIII) is converted to compound of formula IV via de-protection reaction using p-toluenesulfonic acid or HBr in acetic acid or aqueous HC1 or HC1 in dioxane or trifluoroacetic acid followed by neutralization with base selected from aq. Ammonia, triethyl amine, disopropyl ethyl amine sodium hydroxide, sodium carbonate, and sodium bicarbonate or any combination thereof.
6. The process as claimed in claim 1 or 2, wherein the compound of Formula (IV) reacted with compound of formula (IX) wherein X is OTs/OMs in the presence of catalyst selected from tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium fluoride, tetrabutylammoniumiodide, tributylmethylammonium chloride, tributylbenzylammonium chloride,

tetrapentylammonium chloride, tetrapentylammonium bromide, or any combination of thereof; in presence of base selected from aq. Ammonia, triethyl amine, disopropyl ethyl amine sodium hydroxide, sodium carbonate, and sodium bicarbonate or any combination thereof; in
solvent selected from dichloromethane, chloroform, tetrahydrofuran (THF) or aqueous medium comprises water alone or water miscible organic solvents.
7. The process as claimed in claim 1 or 2, wherein compound of formula (I) converted to compound of formula (II) by treating with pamoic acid.
8. The process as claimed in claim 1 or 2, wherein compound of formula (I) converted to compound of formula (II) by treating with alcoholic hydrochloride solution selected from methanolic hydrochloric acid, ethanolic hydrochloric acid or isopropanolic hydrochloric acid.
9. A process for preparation of Hydroxyzine the compound represented by structural formula I comprising:

i. reacting piperazine (Formula XI) with compound of XII (wherein X is OTs/OMs and R is Boc, Benzyl, Acetyl, Cbz, H) to give compound of formula XIII;

ii. reacting compound of formula (XIII) with compound of formula (VI) to give
compound of formula XIV; iii. converting compound formula (XIV) to compound of formula I; iv. optionally converting compound of formula (I) to compound of formula (II) or compound of formula (III).
10. A process for preparation of the compound represented by compound of formula II or III comprising:
i) reacting piperazine (Formula XI) with compound of XII (wherein X is OTs/OMs and R is Boc, Benzyl, Acetyl, Cbz, H) to give compound of formula XIII; ii) reacting compound of formula (XIII) with compound of formula (VI) to give
compound of formula XIV; iii) converting compound formula (XIV) to compound of formula (I); iv) converting compound of formula (I) to compound of formula (II) or compound of formula (III).