Title of Invention

A NEW PROCESS FOR PREPARATION OF HYDROXYZINE

Abstract The invention provides a process for preparation of hydroxyzine, which process includes reacting haloethoxyethanol with piperazine derivative of formula II or its salts in an aqueous phase.
Full Text FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule l3)
1. TITLE OF THE INVENTION: "A new process for preparation of hydroxyzine"
2. APPLICANT (S)
(a) NAME: IPCA 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 describes the invention and the manner in which it is
to be performed.

Technical field:
The present invention relates to a process for the production of hydroxyzine and its pharmaceutically acceptable salts, which are useful as medications for the treament of allergic reactions in mammals.
Background of the Invention
Hydroxyzine (shown in Formula I) is an antihistamine with anti-cholinergic (drying) and sedative properties that is used to treat allergic reactions. Histamine is released by the body during several types of allergic reactions and — to a lesser extent — during some viral infections, such as the common cold. When histamine binds to its receptors on cells, it causes changes within the cells that lead to sneezing, itching, and increased mucus.-production. Antihistamines compete with histamine for cell receptors; however, when they bind to the receptors they do not stimulate the cells. In addition, they prevent histamine from binding and stimulating the cells. After ingestion, the molecule of hydroxyzine is changed slightly, and this changed hydroxyzine that also binds to cells (this active metabolite is known as cetirizine, which is also marketed. The use of this • compound in these therapies demands high purity of the final compound in a manufacturing operation. The hydroxyzine is also useful as a penultimate intermediate for cetirizine.
Hydroxyzine, its preparation and its therapeutic use were first described in US2899436. There are only few literatures available for the preparation of hydroxyzine exploring. various synthetic methodologies.
One such report GB 1174810 make use of the following synthetic scheme -1 where the dihalodiethylether is reacted with piperazine derivative of Formula II in presence of a base followed by hydrolysis to yield hydroxyzine.
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Hydroxizine Formula I
Another method (scheme - 2) employs reaction of chloroethyoxyethanol (B) and piperazine derivative of Formula II Although, this reaction is pretty straight forward in the condensation of right building blocks, the reaction process according to the literature does not yield the product of good quality in good yields. In US2899436 patent, this reaction is carried out in neat conditions (solvent free) and upon reproduction by the. present inventors, the product is found to be contaminated with starting piperazine due to incomplete conversion. Heating the mass for prolonged period leads to charring/degradation of the reagents/reactants and dark coloration of product. Thus, the method is not suitable not only due to incomplete conversions but also due to manuering such viscous reactions on large scale.

Formula II Scheme 2
This reaction found to be carried out in organic solvents like benzene, xylene etc., but not found suitable at least due to incomplete conversions. The reaction in benzene was found to give better results than neat process. However, the reaction in this case also found to be incomplete and contaminate the product with starting piperazine derivative. The removal of piperazine starting material pose another technical challenge to the purification chemist to devise methods to remove the same due to amino-functionality in both product and impurity. For driving the reaction to completion by incorporation of catalysts such as phase-transfer catalysts or metal iodides does not yield satisfactory conversions under the reported conditions, which is surprising. Also, the removal of solvent like benzene -a known carcinogen from the final product is practically difficult.
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The reactions in polar protic or aprotic solvents also not found to give only less than 80-85% conversion of the staring piperazine. It is surprising to note that consumption/use of excess reactant chloroethyoxyethanol is also not found useful in complete conversion of piperazine derivative, and is also not very attractive owing to the economy of the process. Thus, the objective of the present invention is to provide an economical process for production of hydroxyzine or its salts with minimal use of reactants and reagents.
Summary of the Invention
The present inventors had discovered that the prior art processes present substantial difficulties in producing hydroxyzine in a consistent and reliable manner. The invention, therefore, aims to provide an improved process for making hydroxyzine. In accordance -with one aspect, the invention provides a process for preparation of hydroxyzine, which process includes reacting haloethoxyethanol with piperazine derivative of formula II or its salts in an aqueous phase. The aqueous phase comprises water alone; or water and water miscible solvents; or water and water immiscible solvents. In one embodiment of "the present invention, the reaction is in the presence of a base compound. The base may be selected from organic or inorganic bases commonly used for this purpose. Especially preferred bases include metal carbonates such as sodium carbonate or bicarbonate, metal hydroxides like sodium hydroxides or potassium hydroxide etc. Further, in a second embodiment of the present invention, the reaction is in the presence of a catalyst. The catalyst may be selected from a phase-transfer catalyst or metal iodide or a combination of these catalysts.
Detailed Description of the Invention
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
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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.
" Hydroxyzine dihydrochloride" is a hydrochloride salt of 1 -chlorobenzhydryl-4-[2-(2-hydroxy-ethoxy)-ethyl]piperazine. It has the structural formula:






"Hydroxyzine" is a free species of l-chlorobenzhydryl-4-[2-(2-hydroxy-ethoxyl-ethyl]piperazine. It has the formula:







It should be understood that there exists an equilibrium between a free species and salt form of a compound capable of forming salt with bases/acids (e.g., by virtue of having an-amino-functionality in the molecule).
The inventors of the present invention had found that the use of organic solvents whether polar or apolar and catalysts like PTC in the reaction of chloroethoxy ethanol with piperazine derivative of formula II do not provide a reliable, consistent methodology to prepare hydroxyzine. The inventors had recognized that in using these methodologies lead to contamination of the desired hydroxyzine with starting piperazine among other reaction by-products/impurities. The inventors, on exploring various process alternatives, for a reliable process solution have found that the use of aqueous reaction medium
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permits reliable preparation of hydroxyzine by the reaction of 2-chloroethoxyethanol and piperazine derivative of Formula II.
Thus, according to the present invention, there is provided a process for preparation of hydroxyzine, said process comprises reacting 2-chloroethoxyethanol and piperazine derivative of Formula II in an aqueous medium. The aqueous medium comprises water alone or water miscible organic solvents or water immiscible organic solvent or any • similar cross combinations. Especially preferred aqueous media is water. The reaction is performed with almost compete conversion with Water in 0.1 volume to 20 volume found satisfactory completion of reaction. Water miscible organic solvents, one can choose from a variety of organic solvents including alcohols, ketones, amides, sulphoxides, cyclic ethers etc. However, the proportion of organic solvents increases, the reaction becomes sluggish. It has been found that the presence of 1 to 10 % of organic solvents does not. alter the reaction profile and almost complete reaction between compounds II & B can be achieved. Especially preferred organic solvents are isopropanol, acetone, dimethyl formamide, dimethyl sulphoxide or tetrahydrofuran. The water immiscible solvents are also found useful in the reaction in combination with water. Although the proportions of water immiscible solvents are not critical to the success of the process, it is preferred to -be in the range of 1 to 60%. The water immiscible solvents can be selected from hydrocarbons including chlorinated hydrocarbons aromatic or aliphatic extensively. Especially preferred solvents are cyclohexane, toluene, xylene, methylenedichloride and ethylenedichloride, from an industrial and environment safety view point, non-chlorinated hydrocarbons are preferred. It is very surprising to find that the reaction completes in aqueous medium and therefore the invention is very attractive from economical and _ environmental perspective because the process permits no other solvent than water as the reaction medium. For haloethoxyethanol, reference can be made to chloroethoxyethanol and bromoethoxyethanol, wherein chloroethoxyethanol is especially preferred.
In a further embodiment of the invention, the reaction is preferably in the presence of a. base. As the basic compound, known ones from organic or inorganic bases can be used extensively. Examples thereof include inorganic bases such as sodium hydroxide, potassium hydroxide, cesium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate, sodium hydrogen carbonate, potassium
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hydrogen carbonate, and the like; alcoholates such as sodium methylate, sodium ethylate and the like; metallic salts of organic acids such as sodium acetate and the like; Among these bases, inorganic bases such as sodium carbonate, potassium carbonate, or potassium hydrogen carbonate are particularly preferred. Organic bases like amines can be also used in the invention especially preferred organic bases are trialkyl amine like triethyl amine & diisopropylethyl amine. Especially preferred base for this application is those selected from metal carbonates or metal hydroxides such as sodium carbonate, potassium bicarbonate/carbonate, sodium hydroxide and potassium hydroxide. The base may be used in catalytic amounts to equimolar amounts or in excess. It is preferred to use the base in slight excess and in molar amounts ranging from 0.5 to 2 moles relative to the piperazine derivative.
In a further embodiment of the invention, the reaction is preferably in the presence of a
catalyst. The catalyst may be selected from among the phase-transfer catalyst or metal"
iodide. The selection or presence of said catalysts accelerate the reaction and reduces the
time cycle. However, the same results are obtained in its absence, however, owing to the
economy of the process it is preferred to be used. Sodium or potassium iodide is
especially preferred among the metal iodides. As the phase transfer catalyst, mention can
be made of, for example, quaternary ammonium salts substituted with a residue selected
from the group consisting of straight or branched chain alkyl group having 1-18 carbon
atoms, phenyl lower alkyl group and phenyl group, such as tetrabutylammonium chloride,
tetrabutylammonium bromide, tetrabutylammonium fluoride, tetrabutylammonium
iodide, tetrabutylammonium hydroxide, tetrabutylammonium hydrogen sulfate,
tributylmethylammonium chloride, tributylbenzylammonium chloride,
tetrapentylammonium chloride, tetrapentylammonium bromide, tetrahexylammoniunv
chloride, benzyldimethyloctylammonium chloride, methyltrihexylammonium chloride,
benzylmethyloctadecanylammonium chloride, methyltridecanylammonium chloride,
benzyltripropylammonium chloride, benzyltriethylammonium chloride,
phenyltriethylammonium chloride, tetraethylammonium chloride, tetramethylammonium chloride and the like; phosphonium salts substituted with a residue selected from the group consisting of straight or branched chain alkyl groups having 1-18 carbon atoms such as tetrabutylphosphonium chloride and the like; and pyridinium salts substituted
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with a straight or branched chain alkyl group having 1-18 carbon atoms such as 1-dodecanylpyridinium chloride and the like or from a crown ether.
Among these phase transfer catalysts, quaternary ammonium salts substituted with a straight or branched chain alkyl group having 1-18 carbon atoms such as tetrabutylammonium bromide are particularly preferred.
The reaction is carried out usually at a temperature not lower than ambient temperature ■ and not higher than 110 °C. Preferably the reaction is carried out under heating at a temperature from ambient temperature to reflux temperature of the solvent. Especially preferred temperature for reaction is 90-100[deg.] C. The reaction time is usually from about 2 hours to about 10 hours.
It is recommended to use the haloethoxyethanol in equimolar amounts or in slight excess,. usually in an amount of at least 1.0 mol and preferably 1.10 to 1.5 mol per mol of the piperazine derivative (II), to use the base usually in an amount of 0.5 to 2 mol per mol of the piperazine derivative(II), and to use the phase transfer catalyst usually in an amount of 0.01-1.0 mol and preferably 0.1-0.25 mol per mol of the piperazine derivative (II)., and to use the metal iodide in an amount of 0.1 to 1.0 mole and preferably in 0.1 to 0.3 mole per . mol of the piperazine derivative (II).
Once the reaction is completed the product may be isolated by conventional methods such as filtration, centrifugation, extraction or similar unit operations as exemplified in the accompanying illustrative examples. The hydroxyzine obtained according to the process of the present invention is then transformed into pharmaceutically acceptable salts, especially hydrochloride salt by any conventional method known in the art.
The starting piperazine derivative (II) may be obtained by following any known process disclosed in the literature. Commercial chloroethoxyethanol may be used or can be prepared by known methods.
The examples provided below are illustrative and are not intended to limit the scope of the claimed invention.
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Examples.
Example 1
In a round bottom flask, water(100 ml), 100 gm piperazine (Formula II), 18 gm sodium carbonate and 2 gm sodium iodide were mixed well for 5 minutes and then 48 gm 2-chlrooethoxyethanol was added. The mixture was slowly heated to 100°C and maintained for 6 to 7 hours. When the compound A content is less than 0.5% (as per HPLC analysis) the mass was cooled to room temperature and added water 500 ml and extracted with 1000 ml toluene. The organic layer was dried over sodium chloride and treated with charcoal. Toluene solution filtered and evaporated to give hydroxyzine free base (120 gm), yield = 92%, HPLC purity = 99.0%.
Example 2
In a round bottom flask, water(50 ml), 100 gm piperazine (Formula II), 18 gm sodium carbonate, 2 gm sodium iodide and 2 gm tetrabutylammonium bromide (PTC) were* mixed well for 5 minutes and then 48 gm 2-chlrooethoxyethanol was added. The mixture was slowly heated to 100°C and maintained for 6 to 7 hours. When the compound A content was less than 0.5% (as per HPLC analysis) the mass was cooled to room temperature and added water 500 ml and extracted with 1000 ml toluene. The organic layer was dried over sodium chloride and treated with charcoal. Toluene solution filtered and evaporated to give hydroxyzine free base (120 gm) , yield = 92%, HPLC purity = 99.2%.
Example 3
In a round bottom flask, water (50 ml), 100 gm piperazine (Formula II), 18 gm sodium carbonate, 2 gm sodium iodide and 2 gm tetrabutylammonium bromide (PTC) were-' mixed well for 5 minutes and then 48 gm 2-chlrooethoxyethanol and 50 ml toluene were added. The mixture was slowly heated to 100°C and maintained for 6 to 7 hours. When the compound A content was less than 0.5% (as per HPLC analysis) the mass was cooled to room temperature and added water 500 ml and extracted with 1000 ml toluene. The organic layer was dried over sodium chloride and treated with charcoal. Toluene solution filtered and evaporated to give hydroxyzine free base (120 gm) , yield = 92%, HPLC purity 99.0%.
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Example 4
In a round bottom flask, water (100 ml), 100 gm piperazine (Formula II), 18 gm triethyl amine, 2 gm sodium iodide and 2 gm tetrabutylammonium bromide (PTC) were mixed-, well for 5 minutes and then 48 gm 2-chlrooethoxyethanol was added. The mixture was slowly heated to 100°C and maintained for 6 to 7 hours. When the compound A content was less than 0.5% (as per HPLC analysis) the mass was cooled to room temperature-and added water 500 ml and extracted with 1000 ml toluene. The organic layer was dried over sodium chloride and treated with charcoal. Toluene solution filtered and evaporated to give hydroxyzine free base (118 gm), yield = 90%, HPLC purity = 99.0%
Example 5
In a reaction flask, the hydroxyzine free base (100 gm) was dissolved in 100 ml isopropyl alcohol and to this solution, IPA.HCL solution (195 gm, 15% HC1) was added drop-wise. After complete addition, the solution is heated to reflux and maintained for 10 minutes.. The solution is then gradually cooled to room temperature, further chilled to 0 degrees. The precipitated crystals were filtered, washed with chilled isopropanol, and dried to give 108 gm hydroxyzine dihydrochloride (yield 90%). HPLC purity = 99.7%
Example 6
In a reaction flask, the hydroxyzine free base (100 gm) was dissolved in 100 ml isopropyl alcohol and to this solution, IPA.HCL solution (195 gm, 15% HC1) was added drop-wise. After complete addition, the solution is heated to reflux and maintained for 10 minutes. To this solution diisopropylether (10 vol) is added to precipitate dihydrochloride salt and maintained the slurry for 30 minutes. The precipitated crystals were filtered, washed with chilled isopropanol, and dried to give 110 gm hydroxyzine dihydrochloride (yield 90%). HPLC purity = 99.8%.
It will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative examples and that the present invention may be embodied in other specific forms without departing from the essential attributes thereof, and it is therefore desired that the present embodiments and examples be considered in all respects
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as illustrative and not restrictive, reference being made to the appended claims, rather than to the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.
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We claim,
1. A process for preparation of compound of Formula I or its salts comprising reacting a piperazine compound of Formula II with haloethoxyethanol in presence of an aqueous medium.

2. A process as claimed in claim 1, wherein the reaction is in presence of base substance.
3. The process as claimed in claim 1, wherein the reaction is in presence of a catalyst.
4. A process as claimed in claim 1 to 3, wherein the process is in presence of a phase-transfer catalyst.
5. The process as claimed in claim 1 to 3, wherein the reaction is in presence of a metal iodide.
6. The process as claimed in claim 1 to 3, wherein the reaction is in presence of a phase-transfer catalyst and a metal iodide.
7. The process as claimed in claim 1 to 6, wherein the aqueous solvent is water.
8. The process as claimed in claim 1 to 7, wherein the reaction further comprises organic solvent.
9. The process as claimed in claim 8, wherein the organic solvent is a water miscible polar solvent.
10. The process as claimed in claim 9, wherein the ratio of organic solvent is not more than 10% by weight of water.
11. The process as claimed in claim 8, wherein the organic solvent is a water immiscible solvent.
12. The process as claimed in claim 11, wherein the water immiscible solvents comprises not more than 60% by weight of water.
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13. The process as claimed in claim 8 to 9, wherein the water miscible organic solvents are selected from the group of alcohols, ketones, nitriles, amides, sulphoxides, and ethers, especially methanol, ethanol, isopropanol, acetone, dimethyl formamide, dimethyl sulphoxide or tetrahydrofuran.
14. The process as claimed in claim 13, wherein the organic solvent is isopropanol.
15. The process as claimed in claim 11 to 12, wherein the water immiscible solvent* includes aliphatic or aromatic hydrocarbons or chlorinated hydrocarbons.
16. The process as claimed in claim 15, wherein the solvents are cyclohexane, toluene, methylene dichloride and ethylene dichloride.
17. The process as claim in claim 2, or 4 to 16, wherein the base substance is selected from organic or inorganic base.
18. The process as claimed in claim 17, wherein the organic bases are selected from trialkylamine such as triethyl amine or diisopropylamine.
19. The process as claimed in claim 17, wherein the base compound is a metal carbonate/bicarbonate or metal hydroxide.
20. The process as claimed in claim 19, wherein the base is sodium carbonate, potassium carbonate or potassium bicarbonate.
21. The process as claimed in claim 4 to 16, wherein the phase-transfer catalyst is selected from quaternary ammonium salts substituted with a residue selected from the group consisting of straight or branched chain alkyl group having 1-18 carbon atoms, phenyl lower alkyl group and phenyl group or from a crown ether.
22. The process as claimed in claim 5 to 16, wherein the metal iodide is sodium iodide or potassium iodide.

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ABSTRACT:
The invention provides a process for preparation of hydroxyzine, which process includes reacting haloethoxyethanol with piperazine derivative of formula II or its salts in an aqueous phase.
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Documents:


Patent Number 246916
Indian Patent Application Number 1383/MUM/2007
PG Journal Number 12/2011
Publication Date 25-Mar-2011
Grant Date 21-Mar-2011
Date of Filing 18-Jul-2007
Name of Patentee IPCA LABORATORIES LIMITED
Applicant Address 48, KANDIVILI INDUSTRIAL ESTATE, CHARKOP, KANDIVILI (W), MUMBAI
Inventors:
# Inventor's Name Inventor's Address
1 KUMAR, ASHOK 123/AB, CRD, IPCA LABORATORIES LTD., KANDIVILI INDUSTRIAL ESTATE, CHARKOP, KANDIVILI (W), MUMBAI-400067
2 SINGH, DHARMENDRA 123/AB, CRD, IPCA LABORATORIES LTD., KANDIVILI INDUSTRIAL ESTATE, CHARKOP, KANDIVILI (W), MUMBAI-400067
3 MAHALE, GANESH DEVIDAS 123/AB, CRD, IPCA LABORATORIES LTD., KANDIVILI INDUSTRIAL ESTATE, CHARKOP, KANDIVILI (W), MUMBAI-400067
4 SAWANT, UTTAMRAO ARJUNRAO 123/AB, CRD, IPCA LABORATORIES LTD., KANDIVILI INDUSTRIAL ESTATE, CHARKOP, KANDIVILI (W), MUMBAI-400067
5 KHARADE MAHESH VASANT 123/AB, CRD, IPCA LABORATORIES LTD., KANDIVILI INDUSTRIAL ESTATE, CHARKOP, KANDIVILI (W), MUMBAI-400067
PCT International Classification Number C07D295/088
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA