FORM2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2006
PROVISIONAL SPECIFICATION
(See section 10; rule 13)
1. Title of the invention. -"Novel Water Based Process for the Preparation of Substituted
Diphenylmethyl Piperazines".


2. Applicant(s)
(a) NAME: CALYX CHEMICALS AND PHARMACEUTICALS LTD.
(b) NATIONALITY: An Indian Company
(c) ADDRESS: 2, Marwah *s Complex, Marwah Estate, Saki Vihar Road, Sakinaka.
Andheri (East). Mumbai 400 072. Maharashtra, India.
3. PREAMBLE TO THE DESCRIPTION
The following specification describes the invention.


FIELD OF INVENTION
The present invention relates to a novel water based process for the preparation of racemic, levorotatory or dextrorotatory diphenylmethyl piperazines of Formula I and pharmaceutically acceptable salts thereof
R
6

Formula I
wherein X] and X2 represent independently a hydrogen, a halogen, a straight or branched chain lower alkyl, alkoxy or a hydroxyl radical and R is selected from groups such as alkyl, alkenyl, aralalkyl, aralalkenyl, hydroxyalkyl, aryloxyalkyl, alkoxyalkyl, aminoalkyl or its derivatives.
BACKGROUND OF THE INVENTION
Substituted diphenylmethyl piperazines are known for their valuable pharmacological properties. It is well known that [bis(substituted and /or unsubstituted aryl)methyl]piperazin-l-yl compounds are used as antiasthamatics and antiallergics that inhibit leukotriene release.
US 4525358 discloses (2-[2-[4-[(4-Chlorophenyl)phenylmethyl]-l-
piperazinyljethoxyacetic acid) and its amides as antiallergic, spasmolytic and antihistamine agents.
JP 7138230 discloses 4-arIakyI-I-piperazinyI unsaturated carboxyiic acid derivatives useful as antiallergic agents for the treatment of asthma and rhinitis.
2

WO 97/23466 describes the preparation of N-diarylmethylpiperazines as
analgesics. US6451801 explains the dual activity of these compounds as
possessing both lipoxygenase inhibition properties as well as antihistaminergic
properties. Piperazine moieties with lipophilic substituents are often present in
cardiovascular drugs also. For example, 2-(4-diphenylmethyI-l-piperazinyI)ethyl
methyl l,4-dihydro-2,6-dimethyI-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate
dihydrochloride has been selected as a potent and long-acting antihypertensive drug from a series of analogues with piperazinylalkyl ester side chains. Detailed description on the activity as well as the chemistry of some of the molecules containing diphenylmethyl piperazine is cited below,
Cetirizine of Formula la (2-[2-[4-[(4-ChlorophenyI)phenylmethyl]-l-piperazinyljethoxyacetic acid) and its dihydrochloride salt are well established as drugs for the treatment of allergic syndromes, such as chronic and allergic rhinitis, allergic conjunctivitis and urticaria.

Formula la
Meclizine of Formula lb (l-[(4-chlorophenyl)-phenyl-methyl]-4- [(3-methylphenyl)methyl]piperazine) is an antihistamine considered to be an antiemetic and is most commonly used to inhibit nausea and vomiting.

ci-
Formula lb
3

Hydroxyzine of Formula Ic (2-(2-{4-[(4-chlorophenyl)(phenyI)methyl]piperazin-l-yl}ethoxy)ethanol) is a first-generation antihistamine, of the piperazine class that is an Hi receptor antagonist. It is used primarily for the treatment of itches and irritations, an antiemetic for the reduction of nausea, as a weak analgesic by itself and as an opioid potentiator, and as an anxiolytic for the treatment of anxiety.
0

Formula Ic
Compound of Formula Id (2-{4-[(4-chIorophenyl)(phenyImethyl]piperazin-l-yl}ethanol) is an important intermediate for the preparation of several valuable drugs such as Cetirizine of Formula la.

Formula Id
Several methods for the preparation of substituted diphenylmethyl piperazines of Formula I a dihydrochloride is known in the literature.
US 4525358 describes a process for the preparation of Cetirizine of Formula la by reacting l-(diphenylmethy)-piperazine of Formula III with a compound of Formula IV in an inert solvent such as benzene, toluene or xylene at reflux in presence of a base in which X is a halogen and R is OR' or NH2 wherein R' is a lower alkyl radical, which is followed by hydrolysis.
4


Formula III Formula IV Formula la
The reaction is carried out at a temperature and requires a longer reaction period of 40 hours and the resulting 2-[2-[4-[(4-ChIorophenyl)phenylmethyI]-l-piperazinyl]ethoxyacetate obtained is only 27.8 % after column chromatography.
GB 2225321 discloses the preparation of Cetirizine of formuala la by reacting 1-(diphenylmethy)-piperazine of Formula III with 2-haloethoxyacetonitrile in which X is a halogen in an inert organic solvent such as alcohol followed by the hydrolysis of the resulting nitrile using an acid or base. The reaction is carried out at a temperature of 110°C for 11 hours and the resulting 2-[2-[4-[(4-Chlorophenyl)phenylmethyl]-l-piperazinyl]ethoxyacetonitrile is separated by column chromatography.

Formula III Formula la
US 6239277 discloses the process for the preparation of Cetirizine of Formula la involves the reaction of l-(diphenylmethyl)-piperazine of Formula III and an alkoxy ester of Formula V, in which X is a leaving group and R' is C3 to C12 branched alkyl or a cation, in an inert solvent such as dimethylformamide or 2-butanone at reflux in presence of a base.
5

Formula III Formula V

Formula la

GB 2225320, GR 99100135 and WO 2004103982 disclose a process for the preparation of 2-{4-[(4-chlorophenyl)(phenylmethyl]piperazin-l-yl}ethanol of Formula Id by reacting compound of Formula III with 2-haloethanol in which the halogen is selected from chlorine or bromine in an organic solvent such as toluene.


Formula III Formula Id

The process described in US 2899436 and BE 523901 involves heating a compound of Formula III directly with CI(CH2)20(CH2)2OH at 150°C for 3 hours in the absence of a solvent.
o
N'
US 2709169 disclose the process for the preparation of Meclizine of Formula lb by reacting Formula III with 3-methyl benzylchloride in an organic solvent such as benzene or toluene at reflux for 3 hours.



+
CI

Formula III

Formula lb

US6255487 describes a process for the preparation of racemic cetirizine of Formula la by reacting piperazine of Formula VI with Cl-CH2-CH2-0-CH2C02H to get the intermediate of Formula VII followed by reacting the said intermediate with benzhydryl halide to give compound of Formula la. First reaction is carried out in water for 27 hours with only 12% yield and after lengthy work up procedure involving treatment with ion exchange resin followed by elution with water and evaporation of water under reduced pressure. The product is isolated by sublimation. The process is thus tedious and not commercially viable.
Formula VI

Formula la
All the processes described in the prior art involve either heating the reaction mixture in an organic solvent at high temperature and/or tedious work-up and purification procedures like column chromatography which in turn leads to the use of a large amount of organic solvents making the process economically expensive. Also in most of the prior art processes, the reaction requires longer time periods
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and end up with lower yield of the final product. All the processes require organic solvents which are not eco-friendly.
The environmental impact and cost of solvents in drug manufacturing processes is becoming a worldwide concern. These costly, hazardous, and polluting solvents are then disposed of through environmentally unfriendly waste-disposal processes, often contributing to global warming, substantial energy consumption, ground water contamination, etc.
In view of the adverse impacts of organic solvents to the environment and human health, there is a continuous need to develop an environment friendly and economical process for the preparation of racemic, levorotatory or dextrorotatory diphenyl methyl piperazines of Formula I in high yield and purity
The inventors of the present invention have surprisingly found out an environment friendly and cost effective process for the preparation of racemic, levorotatory or dextrorotatory diphenylmethyl piperazines of Formula I from a racemic, levorotatory or dextrorotatory compound of Formula II using water as a solvent in presence of a catalyst and a base.
OBJECT OF THE INVENTION
It is an object of the present invention to provide a novel process for the preparation of racemic, levorotatory or dextrorotatory diphenylmethyl piperazines of Formula I and pharmaceutically acceptable salts thereof.
It is another object of the present invention to provide a water based process for the preparation of racemic, levorotatory or dextrorotatory diphenylmethyl piperazines of Formula I from a racemic, levorotatory or dextrorotatory compound of Formula II.
8

It is another object of the present invention to provide an environment friendly process for the preparation of racemic, levorotatory or dextrorotatory diphenylmethyl piperazines of Formula I and pharmaceutical^ acceptable salts thereof by avoiding the use of hazardous organic solvents.
It is yet another object of the present invention to provide a cost effective process for the preparation of racemic, levorotatory or dextrorotatory diphenylmethyl piperazines of Formula I and pharmaceutical^ acceptable salts thereof in good yield and with high purity.
It is further object of the present invention to provide a commercially viable process for the production of racemic, levorotatory or dextrorotatory diphenylmethyl piperazines of Formula I and pharmaceutical^ acceptable salts.
SUMMARY OF INVENTION
According to an aspect of the present invention there is provided a novel process for the preparation of racemic, levorotatory or dextrorotatory diphenylmethyl piperazines of Formula I and pharmaceutically acceptable salts thereof

wherein Xi and X2 represent independently a hydrogen, a halogen, a straight or branched chain lower alkyl, alkoxy or a hydroxyl radical and R is selected from groups such as alkyl, alkenyl, aralalkyl, aralalkenyl hydroxyalkyl, aryloxyalkyl, alkoxyalkyl, aminoalkyl or its derivatives comprising the steps:
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(a) reacting a racemic, levorotatory or dextrorotatory compound of Formula II with a compound of formula R-X using water as a solvent in presence of a catalyst and a base at 25-100°C;
H
a
N


Formula II
(b) continuing the reaction at 25-100°C for 0.5-10 hours;
(c) isolating the product either by separation or by extraction using an organic solvent;
(d) optionally converting the product of Formula I to its pharmaceutically acceptable salt.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a novel water based process for the preparation of racemic, levorotatory or dextrorotatory diphenylmethyl piperazines of Formula I and pharmaceutically acceptable salts thereof.
R
6

N
Formula I
wherein Xj and X2 represent independently a hydrogen, a halogen, a straight or branched chain lower alkyl, alkoxy or a hydroxyl radical and R is selected from groups such as alkyl, alkenyl, aralalkyl, aralalkenyl, hydroxyalkyl, aryloxyalkyl, alkoxyalkyl, aminoalkyl or its derivatives comprising,
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(a) reacting a racemic, Ievorotatory or dextrorotatory compound of Formula II, with a compound of formula R-X using Water as a solvent, in presence of a catalyst and a base, at 25-\00°C;

Formula II
(b) continuing the reaction at 25-100°C for 0.5- 10 hours;
(c) isolating the product either by separation or by extraction using an organic solvent;
(d) optionally converting the product of Formula I to its pharmaceutically acceptable salts;
In particular, the present invention relates to a novel process for the preparation of racemic, Ievorotatory or dextrorotatory diphenylmethyl piperazines of Formula I by reacting a racemic, Ievorotatory or dextrorotatory compound of Formula II wherein Xi and X2 are as defined above, with R-X wherein X is a halogen and R is as defined above using water as solvent, in presence of a catalyst and a base, at a temperature of 25-100°C for 0.5-10 hours. The reaction is shown in Scheme I.

Formula II Formula I
Scheme I
The racemic, Ievorotatory or dextrorotatory compound of Formula II is prepared by well known prior art processes.
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The term 'aralalkyi' denotes linear or branched alkyl radicals containing substituted or unsubstituted aryl group, the term 'aralalkenyl' denotes linear or branched alkenyl radicals containing substituted or unsubstituted aryl group, the term 'hydroxyalkyP denotes linear or branched alkyl radical substituted with one or more hydroxyl groups the term 'aryloxyalkyl' denotes alkyl radical containing substituted or unsubstituted aryloxy groups wherein the substituents include groups such as -OH, -OR, -COOH, -CONH2, -CONHR, -CONR2, -COOR _NH2) -NHR, NR2, -OCOR etc., the term 'alkoxyalkyl' means alkyl radical containing substituted or unsubstituted alkoxy groups wherein the substituents include groups such as -OH, -OR, -COOH, -CONH2, -CONHR, -CONR2, -COOR _NH2, -NHR, NR2, -OCOR etc, the term 'aminoalkyl' refers to alkyl radical containing monosubstituted, disubstituted or unsubstituted amino groups.
Especially, preferred compounds of Formula I include,
1. (±)-[2-[4-[(4-Chlorophenyl)phenylmethyl]-l-piperazinyl]ethoxy]acetic acid dihydrochloride
2. (R)-2-[2-[4-[ 1 -(4-ChIorophenyl)-1 -phenylmethyl]piperazin-1 -yl]ethoxy]acetic acid dihydrochloride
3. 2-[2-[4-[(4-Chlorophenyl)phenylmethyl]-l-piperazinyl]ethoxy]ethanol
4. l-[(4-Chlorophenyl)phenylmethyl]-4-[(3-rnethylphenyl)methyl]piperazine
5. l-[(4-Chlorophenyl)phenylmethyl]-4-[[4-(l,l-dimethylethyl)phenyl]methyl]piperazine
6. l-[(4-Chlorophenyl)phenylmethyl]-4-methylpiperazine
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7. l-(Diphenylmethyl)-4-(3-phenyl-2-propenyl)piperazine
8. 1 -Diphenylmethyl-4-methylpiperazine
9. l-(Diphenylmethyl)-4-[3-(2-phenyl-J,3-dioxolan-2-yI)propyl]piperazine
10. 2-[2-[2-[4-[(4-Chlorophenyl)phenylmethyl]-l-piperazinyl]ethoxy]ethoxy]ethanol
11. 1 -[(4-Chlorophenyl)phenylmethyl]-4-(3-phenyt-2-propenyl)piperazine
12. l-[3-[4-(Diphenylmethyl)-l-piperazinyI]propyl]-l,3-dihydro-2H-benzimidazol- 2-one
13. l,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid 2-[4-(diphenylmethyl)-l-piperazinyl]ethyl methyl ester
14. l-[Bis(4-fluorophenyl)methyl]-4-[(2,3,4-trimethoxyphenyl)m ethyl] pi perazine
15. (J£)-l-[Bis(4-fluorophenyI)methyl]-4-(3-phenyl-2-propenyI)piperazine
16. 4-[3-[4-(Diphenylmethyl)piperazin-l-yl]-2-hydroxypropoxy]-lH-indole-2-carbonitrile
17. 2-[2-[4-(4-Chlorobenzhydryl)piperazino]ethoxy]eth yl 2-(3-benzoylphenyl)propionatedimaleate
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18. (±)-l -(3,4-Dimethoxyphenyl)-2-(4-diphenylmethyI-1 -piperazinyl)ethanol dihydrochloride
19. 2,6-Dimethyl-3-nitro-4-[2-(4-diphenylmethyl-l -piperazinyl)ethylamino]pyridine
20. 2-[4-[4-(diphenyImethyl)piperazin-l-yl]phenyl]ethyl methyl diester dihydrochloride
21. 2-[2-[4-[Bis(4-fluorophenyl)methyl]piperazin-l-yl]ethoxy]acetic acid
22. 4-[4-[4-(DiphenyImethyl)piperazin-l-yl]butoxy]-2,3,6-trimethylphenol dihydrochloride
23. 4-Benzyl-1 -(4 -tert-buty 1-3 '-hydroxy benzhydry l)piperazine dihydrochloride

24. 4-(DiphenyImethyl)-l-[3-phenylprop-2(E)-enyI]-l-(phosphonooxymethyl)piperazin-1 -ium trifluoroacetate
25. N-[4-[4-[2-[4-[l(R)-(4-Chlorophenyl)-I-phenylmethyl]piperazin-l-yl]ethoxy]phenyI]butyl]-N-hydroxyurea
26. 5-[4-(N-Carbamoyl-N-hydroxyamino)-I-butynyl]-2-[2-[4-[l(R)-(4-chlorophenyl)-l-phenylmethyl]p)perazin-l-yl]ethoxy]Benzamide
27. N-[4-[4-[4-[4-[Bis(4-fluorophenyl)methyl]piperazin-I-yI]butoxy]phenyl]-3-butynyl]-N-hydroxyureaand
28. 1 -Allyl-4-(diphenylmethyl)piperazine dihydrochloride.
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Detailed description of the process for some of these molecules is given below. In an aspect of the present invention there is provided a cost effective process for the preparation of the Cetirizine of Formula la and pharmaceutical ly acceptable salts thereof such as Cetirizine dihydrochloride

Formula la
by reacting a racemic, levorotatory or dextrorotatory compound of Formula III with Cl(CH2)20CH2CONH2 using water as a solvent in presence of a catalyst and a base at a temperature of 25-100°C for 0.5-10 hours followed by hydrolysis using known methods.
In another aspect of the present invention there is provided a cost effective process for the preparation of the Meclizine of Formula lb and pharmaceutical ly acceptable salts thereof such as Meclizine dihydrochloride

Formula lb
by reacting a compound of Formula III with CICH2C6H5CH3 using water as a solvent in presence of a catalyst and a base at a temperature of 25-100°C for 0.5-10 hours.
Yet another aspect of the present invention is to provide a cost effective process for the preparation of the Hydroxyzine of Formula Ic and pharmaceutical ly acceptable salts thereof such as Hydroxyzine dihydrochloride, pamoate etc.
15

ft
N

Formula Ic
by reacting a compound of Formula III with 0(CH2)20(CH2)20H using water as a solvent in presence of a catalyst and a base at a temperature of 25-100°C for 0.5-10 hours.
Another aspect of the present invention is to provide a cost effective process for the preparation of an intermediate of Formula Id and pharmaceutical ly acceptable salts thereof
|^OH

Formula Id by reacting a compound of formula III with C1(CH2)20H using water as a solvent in presence of a catalyst and a base, at a temperature of 25-100°C for 0.5-10 hours.
In an embodiment of the present invention, the amount of water used as solvent ranges from 2 -5 volumes, preferably from 2-3 volumes based on the compound of Formula II.
In an another embodiment of the present invention, R-X is employed in an amount ranging from 1 to 1.75 molar equivalents, preferably between 1 to 1.5 molar
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equivalents, more preferably between 1.1 to 1.25 molar equivalents based on the compound of Formula II.
In yet another embodiment of the present invention, the reaction is carried out at temperature between 25 -100°C, preferably between 30 -90 °C, more preferably between 60 -80°C.
In yet another embodiment of the present invention the reaction time varies from 0.5- 10 hours, preferably between 1 to 7 hours, more preferably between 2 to 5 hours.
In one more embodiment of the present invention, the catalyst used is selected from a phase transfer catalyst or an alkali metal halide. Suitable phase transfer catalyst used herein include, but are not limited to, quaternary 'onium' salt of nitrogen or phosphorous, substituted with a residue such as alkyl or aralalkyl group, preferably tetraalkylammonium halide or trialkylaryl ammonium halide. The preferred alkali metal halide is potassium iodide.
In yet another embodiment of the present invention, the catalyst used is in an amount ranging from 0.1 to 1 wt % based on the compound of Formula II and preferably between 0.1 to 0.5 wt %; more preferably between 0.25 to 0.5 wt %.
In another embodiment of the present invention, the base used is selected from inorganic or organic bases. The inorganic base is selected from alkali metal carbonate or alkaline earth metal carbonate, such as potassium carbonate or sodium carbonate, and the preferred organic base is triethylamine. When the counter ion of the phase transfer catalyst is basic, the use of base like potassium carbonate can be avoided.
17

In yet another embodiment of the present invention, the solvent used for extraction is selected from aromatic hydrocarbons, ethers, esters, halogenated hydrocarbons or alcohols.
The present invention is illustrated below by way of examples. Details of the invention provided in the following examples are given by the way of illustration only and should not be construed to limit the scope of the present invention.
Example I
(±)2-(2-{4-[(4-chIorophenyJ)(phenyI)methyl]piperazin-l-yJ}ethoxy)ethanol dihydrochloride (Hydroxyzine dihydrochloride)
N-(4-Chloro benzhydril) piperazine (lOOgm, 0.35mol) was taken in water (150 ml) and stirred at 25°C. Potassium carbonate (96.6gm, 0.7mol), and tetrabutyl ammonium bromide (0.5g) were added in sequence into the reaction mixture while stirring it. 2-(2-chIoroethoxy) ethanoi (64.9gm, 0.52mol) dissolved in water (150 ml) was then added into the reaction mixture. The reaction mixture was heated while stirring at 80°C for 5h. It was cooled to room temperature and extracted with ethyl acetate (100 ml). The ethyl acetate layer was washed with water. The ethyl acetate layer was concentrated to obtain the hydroxyzine free base (128.0g, Yield 98%, purity by HPLC: 99%), which was converted to its dihydrochloride salt by usual procedure.
IR(neat): 3356, 2285, 1602, 1496 cm"1
*H NMR(400MHz, D20)5 ppm: 7.57-7.52 (m, 4H), 7.48-7.39 (m. 5H), 5.23 (s, 1H), 3.83 (t, J=4Hz, 2H), 3.71-3.68 (m, 2H), 3.65-3.55 (m, 6H), 3.47 (t, J=4Hz, 2H), 3.4-3.3 (brs, 4H)
Example II
(±) l-[(4-chlorophenyl)- phenyl-methyl]-4- [(3-methylphenyl)methyl] piperazine dihydrochloride (Meclizine dihydrochloride)
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N-(4-ChIorobenzhydril) piperazine (lOOgm, O.35mol) was taken in water (300ml) and stirred at 25°C. Potassium carbonate (33.75gm, 0.24mol), tetrabutyl ammonium bromide (0.05g) were added in sequence into it while stirring. 3-methyl benzyl chloride (59.0gm, 0.42mol) was then added into the reaction mixture while stirring. The reaction mixture was heated at 60°C for 2h. It was cooled to room temperature and extracted with ethyl acetate (100ml). The ethyl acetate layer was washed with water. The ethyl acetate layer was concentrated to obtain Meclizine free base. Yield: Quantitative. Purity by HPLC: 98%. This was converted to hydrochloride salt by usual procedure.
IR (neat): 2391, 2289, 1490 cm"1
IHNMR(400MHz, CDC13)5 ppm: 13.7 (s, 1H, HCI), 13.23 (s, 1H, HCI), 7.86(s, 4H), 7.46-7.36(m, 7H), 7.34-7.22 (m, 2H), 5.11(s, 1H), 4.4-4.15 (m, 4H), 4.1-3.9(m, 2H), 3.52-3.33 (m, 4H), 2.35 (s, 3H)
Example III
(±)2-[2-[4-[(4-ChlorophenyI)phenylmethyl]-l-piperazinyl]ethoxyaceticacid
dihydrochloride (Citrizine dihydrochloride):
N-(4-Chloro benzhydril) piperazine (10gm, 34.9mmol) was taken in water (30ml) and stirred at 25°C. Potassium carbonate (3.37gm, 24.4mmol), tetrabutyl ammonium bromide (0.05g) were added in sequence into it while stirring. 2-(2-chloroethoxy)acetamide (5.21gm, 37.8mmol) was then added into the reaction mixture while stirring. The reaction mixture was heated at 80°C. After the reaction is over (tic), it was cooled to room temperature and extracted with toluene (20 ml). The toluene layer was washed with brine solution and dried. The organic layer was concentrated to obtain the 12.8g compound. Yield: 95%. This was converted to cetirizine hydrochloride by hydrolysis of amide followed by formation of hydrochloride salt by usual procedure.
IR(neat):2983(br), 2389, 2291, 1739 cm'1
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'HNMR (400MHZ, D20)8 ppm: 7.53(d, J=8Hz, 2H), 7.49-7.39(complex m, 5H), 7.35-7.34(m, 2H), 5.31(s, 1H), 4.15(s, 2H), 3.84(t, J=4Hz, 2H), 3.65(br s, 4H), 3.46(t, J=4Hz, 2H), 3.42(br s, 4H)
Example IV
(±)2-{4-[(4-chlorophenyl)(phenylmethyl]piperazin-l-yl}ethanoI dihydrochloride
N-(4-Chloro benzhydril) piperazine (lOgm, 34.9mmol) was taken in water (30ml) and stirred at 25°C. Potassium carbonate (9.65gm, 69.9mmoI), tetrabutyl ammonium bromide (0.05g) were added in sequence into it while stirring. Then 2-chloroethanol (4.1gm, 50.9mmol) was added into the reaction mixture while stirring. The reaction mixture was heated at 80°C. After the reaction is over (tic), it was cooled to room temperature and extracted with ethyl acetate (20 ml). The ethyl acetate layer was washed with brine solution and dried. The organic layer was concentrated to obtain the I lg compound. Yield: 94%. This was converted to corresponding hydrochloride salt by usual procedure. IR (neat): 3300,2287, 1597,1494, 1440 cm'1
lHNMP(400MHz,D2O)S ppm: 7.53-7.32 (complex m, 9H), 5.27(s, 1H), 3.85(t, J=4Hz, 2H), 3.59-3.52(m, 4H), 3.39-3.34(m, 6H).
Dated this 17th day of September 2008
Poonam Kolhe Of S. Majumdar & Co Agents for the Applicant
u
20