FORM 2
THE PATENTS ACT 1970
(Act 39 of 1970)
&
THE PATENTS RULE 2003
(SECTION 10 and rule 13)
PROVISIONAL SPECIFICATION
"A PROCESS FOR THE SYNTHESIS OF 2-[2-[4-[(4-chlorophenyl) phenyl methyl]-l-piperazinyl] ethoxy acetic acid"
Glenmark Pharmaceuticals Limited
an Indian Company, registered under the Indian company's Act 1957 and having its registered
office at
Glenmark House,
HDO - Corporate Bldg, Wing -A,
B.D. Sawant Marg, Chakala, Andheri (East), Mumbai - 400 099
THE FOLLOWING SPECIFICATION DESCRIBES THE NATURE OF THE INVENTION

FIELD OF THE INVENTION
The present invention relates to a process for the preparation of 2-[2-[4-[(4-chloro phenyl) phenyl methyl]-!-piperazinyl] ethoxy acetic acid of formula (la),

(la)
the asterisk indicates the centre of asymmetry of the molecule and its dihydrochloride. The compound of formula-I may exist in the levorotatory form, the dextrorotatory form or a mixture of the levorotatory and dextrorotatory forms or pharmaceutically acceptable salts thereof The present invention also relates to novel compound of formula-(IIa),

Wherein R, is C1-C4 alkyl,
R2 is aryl or heteroaryl or Ri and R2 together with the carbon to which they are attached form a
C3-C8 cycloalkyl group.
BACKGROUND OF THE INVENTION
The dihydrochloride of 2-[2-[4-[(4-chloro phenyl) phenyl methyl]-1-piperazinyl] ethoxy acetic acid, also known as Cetirizine, is known as a medicament for the treatment of allergic syndromes, such as chronic and acute allergic rhinitis, allergic conjunctivies, pruritus, urticaria etc. Its pharmacological and medicinal properties have been described in the literature, C. De. Vos et. Al., Ann. Allergy 59, 278, 1987; L. Juhlin et. Al, J. Allergy Clin. Immunol., 80, 80,599 (1987).
European Patent No. 58,146 describes the synthesis of 2-[2-[4-[(4-chloro phenyl) phenyl methyl]-1-piperazinyl] ethoxy acetic acid and its dihydrochloride. Patent discloses the synthesis wherein the starting substance l-[(4-Chloro phenyl) phenyl methyl] piperazine is reacted with methyl (2-chloroethoxy) acetate to give methyl-2-[2-[4-[(4-chloro phenyl) phenyl methyl]-l-piperazinyl] ethoxy acetate in a yield 27.8%. This methyl ester is then subjected to hydrolysis with an
2

inorganic base (sodium or potassium hydroxide) to give the sodium or potassium salt, which is easily converted into the free acid, and then into cetirizine dihydrochloride
The major disadvantage of this synthesis is that the overall yield of 2-[2-[4-[(4-chloro phenyl) phenyl methyl]-1-piperazinyl] ethoxy acetic acid dihydrochloride is only 10.6%, based on the amount of l-[(4-Chloro phenyl) phenyl methyl] piperazine
British Patent No. 2,225,321 describes a process for the preparation of the enantiomers of 2-[2-[4-[(4-chloro phenyl) phenyl methyl]-l-piperazinyl] ethoxy acetic acid dihydrochloride. This process is based on the use of levorotatory or dextrorotatory l-[(4-Chloro phenyl) phenyl methyl] piperazine which is obtained by the chemical resolution of racemic form, using conventional methods, in particular, by salt formation with a suitably selected optical isomer of tartaric acid.
The disadvantages of this process are, on one hand, the yield of the resolution step of the racemic l-[(4-Chloro phenyl) phenyl methyl] piperazine is extremely low (only 12.7%) and on the other hand the optical purity of the dextrorotatory and levorotatory enantiomers so obtained is insufficient and does not allow the final product to be prepared with an optical purity greater than 95%.
Thus it is desired to provide new routes for preparing the enantiomers of 2-[2-[4-[(4-chloro phenyl) phenyl methyl]-1-piperazinyl] ethoxy acetic acid with improved optical purity and in better yields.
In order to achieve this objective, it is necessary to find precursors having the correct stereo chemical configuration and thus keeping this in mind, we have discovered a new process to synthesize a new compound 2-[2-[4-[(4-chloro phenyl) phenyl methyl]-1-piperazinyl] ethoxy -1-[N-(l -phenyl ethyl) acetamide (II). This compound shows diastereoisomerism. Thus, unwanted diastereomer can be removed by a simple leaching to this amide (II) with suitable solvent or by solvent mixture to get substantially optically pure diastereomer which can be converted easily and with high yields into the substantially optically pure enantiomers of 2-[2-[4-[(4-chloro phenyl) phenyl methyl]-!-piperazinyl] ethoxy acetic acid.
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SUMMARY OF THE INVENTION
The present invention provides a process for the preparation of 2-[2-[4-[(4-chloro phenyl) phenyl methyl]-1-piperazinyl] ethoxy acetic acid, a compound of formula la, which is either in the levorotatory or dextrorotatory form or a mixture thereof

(la)
The process comprises converting the compound of formula (IIa)
O Rl

N H
R7
(IIa)
by treatment with acid or a base to obtain a compound of formula la wherein Ri is C1-C4 alkyl
R2 is aryl or heteroaryl or Rj and R2 together with the carbon to which they are attached form a C3-C8 cycloalkyl group.
The process as defined above wherein the compound of formula IIa is prepared by a process comprising condensing a compound of formula Villa
X.
N
O R, H
X (Villa)
with a compound of formula IX.

NH,
(IXa)
wherein Ri and R2 are as defined above
The process of preparing the compound of formula VIII comprising chlorination of a compound of formula VII, 2-[N, N-bis (2-hydroxy ethyl) amino] ethoxy -1-[N-(1-phenyl ethyl) acetamide
4

O Rj
OH (Vila)
Wherein R{ and R2 are as defined above.
The process of preparing a compound of formula Vila by the condensation of 2-Chloro-N-(l-phenyl ethyl) acetamide of formula Va
O R,
OV^
II i CI-
H 2 (Va)
with triethanol amine VI.
The process of preparing a compound of formula V by the acylation of Phenyl ethyl amine by 2-chloroacetyl chloride.
In yet another embodiment patent relates to novel intermediate of formula
LI
CI

N R, H
(Ha) Wherein R, and R2 are as stated above. Description of the preferred embodiments;
In one embodiment the present invention provides a process for preparation of the levorotatory isomer, (R)-2-[2-[4-[(4-chloro phenyl) phenyl methyl]-1-piperazinyl] ethoxy acetic acid (I),a compound of formula I, depicted schematically in scheme I below;

5



H2N

Stage-A Cl^X
^•4^
(ill) wvX^cl W
J- I H
(IV)

CI
NH,
(VIII)

(II)
(K)
Stage-E


Stage-F

CI

2HC1
(I)
SCHEME I
wherein X is a suitable leaving group such halo or an activated group such as mesylate, tosylate.
According to the present invention, 2-chloro-N-( 1 -phenyl ethyl) acetamide (V) is prepared by the usual method, an acylation of 1-phenyl ethyl amine by chloroacetylchloride in the presence of the organic or inorganic base.
O R,
H
(V)
R2= aryl or heteroaryl or R] and R2 together with the carbon to which they are attached form a C3-C8 cycloalkyl group.
In one of the embodiment, the solvent used in said stage-A is selected from non-polar hydrocarbon or chlorinated hydrocarbon solvents or aprotic solvent or aromatic solvent or ether solvent. The aromatic solvent used in stage-A may be selected from benzene, toluene, Xylene and
6

the likes thereof, preferably toluene. The chlorinated hydrocarbons used in stage-A may be selected from dichloromethane, dichloroethane, dibromoethane, preferably dichloromethane.
The base used in said stage-A is selected from organic base or inorganic base. Wherein the inorganic base may be selected from sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, preferably sodium carbonate or the organic base may be tert.butyl dimethylamine, triethylamine, diisopropylethylamine, pyridine, morpholine, p-N,N-dimethyl amino pyridine and the likes thereof ,preferably triethylamine.
The acylation reaction is carried out at a temperature range of -15° to +45°C, preferably -5° to 0°C to achieve good yield and quality.
In yet another embodiment invention provides a process for the preparation of 2-[N, N-Bis (2-hydroxy ethyl) amino] ethoxy-l-[N-(l-phenyl ethyl) acetamide (VII) which involves the condensation of 2-chloro-N-(l -phenyl ethyl) acetamide (V) with triethanolamine (VI).

O
OH (VII)
wherein
Ri= C1-C4
R2= aryl or heteroaryl or Ri and R2 together with the carbon to which they are attached form a
C3-C8 cycloalkyl group. The solvent used in said stage-B is selected from aprotic polar solvent or aromatic solvent. The aprotic polar solvent may be selected from N,N-dimethyl formamide, N,N-dimethyl- acetamide, dimethylsulfoxide, N-methyl-2-pyrrolidone and the likes thereof, preferably dimethylsulfoxide or the aromatic solvent may be selected from benzene, toluene, Xylene and the likes thereof , preferably toluene.
The base used in said stage-B is selected from alkali hydrides, hydroxides, carbonates or bicarbonates. The inorganic base may be selected from sodium hydride, lithium hydride, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate ,preferably sodium hydroxide.
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The mole equivalent of triethanolamine (VI) against chloroamide compound (V) in said stage-B may be 1: 1 to 1:15, preferably 1:3. The excess use of triethanol amine can be recovered by conventional method and recycled to increase the productivity.
The condensation reaction performed at the temperature in said stage-B is in between -15° to 130°C, preferably 65° to 80°C to achieve good yield and quality.
According to the present invention, 2-[N, N-Bis (2-hydroxy ethyl) amino] ethoxy-l-[N-(l-phenyl ethyl) acetamide (VII) is converted in to dihalo compound formula-(VIII) by the conventional methods wherein, X is chlorine, bromine or iodine atom or the 4-methylphenyl-sulfonyloxy or methylsulfonyloxy group or 4-bromophenyl-sulfonyloxy group.
O R, \/ N \x \/- N R
X
(VIII) X= CI, Br, I, mesylate, tosylate, brosilate, Ri= Ci-C4alkyl
R2= aryl or heteroaryl or R^ and R2 together with the carbon to which they are attached form a C3-C8 cycloalkyl group.
The solvent used in said stage-C is selected from non-polar hydrocarbon, chlorinated hydrocarbon solvents, aprotic solvent, aromatic solvent, ether solvent. The aromatic solvent may be selected from benzene, toluene, Xylene etc. preferably toluene or the chlorinated hydrocarbons may be dichloromethane, dichloroethane, dibromoethane etc. preferably dichloromethane.
The base used in said stage-C is selected from organic base or inorganic base. The inorganic base may be selected from sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, preferably sodium carbonate or organic base may be triethylamine, diisopropylethylamine, pyridine, morpholine, p-N,N-dimethyl amino pyridine, preferably diisopropylethylamine.
The condensation reaction is carried out at a temperature range of-15° to 55°C, preferably 5° to 15°C.
8

In yet another embodiment the present invention provides a process for the preparation of (R)-2-[2-[4-[(4-chloro phenyl) phenyl methyl]-1-piperazinyl] ethoxy -1-[N-(1 -phenyl ethyl) acetamide (II) which involves the condensation of 2-[N, N-Bis (2-chloro ethyl) amino] ethoxy-1-[N-(1-phenyl ethyl) acetamide (VIII) with R-4-chlorophenyl phenyl methyl amine (IX).

6
(ii)
wherein
Ri= C1-C4alkyl
R2= aryl or heteroaryl or Rj and R2 together with the carbon to which they are attached form a
C3-C8 cycloalkyl group.
The solvent used in said stage-D is selected from aprotic polar solvents may be N,N-dimethyl formamide, N,N-dimethylacetamide, dimethylsulfoxide, N-methyl-2-pyrrolidone, preferably dimethylsulfoxide or organic base as a reaction medium may be selected from triethylamine, diisopropylethylamine, pyridine, morpholine, p-N,N-dimethyl amino pyridine, preferably diisopropylethyl amine.
The base used in stage-D is selected from organic base or inorganic base. The inorganic base may be selected from sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate ,preferably sodium carbonate or the organic base may be selected from triethylamine, diisopropylethylamine, pyridine, morpholine, p-N,N-dimethyl amino pyridine ,preferably diisopropylethyl amine.
The cyclization reaction is carried out at a temperature range of-15° to 130°C, preferably 75° to 80°C to achieve good yield and quality.
In one of the embodiments the hydrolysis of (R)-2-[2-[4-[(4-chloro phenyl) phenyl methyl]-l-piperazinyl] ethoxy -1-[N-(1-phenyl ethyl) acetamide (II) is carried out by conventional methods.
9

o
XK
u
6
(I)
The hydrolysis performed in said stage-E is either acid hydrolysis or alkaline hydrolysis, preferably acid hydrolysis. Acid used for the hydrolysis is selected from a group consisting of aq. Hydrochloric acid, aq. Hydrobromic acid, aq. Sulfuric acid, preferably aq. Hydrobromic acid.
The temperature for hydrolysis in said stage-E may be between -20° to 130°C, preferably 55° to 60°C. The byproduct amino compound obtained by this hydrolysis step can be recovered and recycled to increase the productivity.
In yet another embodiment, the hydrochloride salt of (R)-2-[2-[4-[(4-chloro phenyl) phenyl methyl]-1-piperazinyl] ethoxy acetic acid (I) is prepared by purging or addition of organic solvent saturated with hydrochloric acid gas or by direct purging the hydrochloric acid gas in to the reaction mass.
The solvent used in said stage-F is selected from the ketonic solvent or alcoholic solvent. The ketonic solvent may be selected from acetone, methylethylketone, methyl isobutyl ketone, methyl tert. butyl ketone, preferably acetone.
The levorotatory and dextrorotatory enantiomers of 4-Chlorophenyl-phenyl methyl amine, used as starting materials are known compounds; they can be prepared by chemical resolution of racemic 4-Chlorophenyl-phenyl methyl amine by known methods using tartaric acid. These enantiomers can be prepared with an optical purity of at list 99%.
The enantiomeric purity of levorotatory or dextrorotatory isomer of 2-[2-[4-[(4-chloro phenyl)
phenyl methyl]-1-piperazinyl] ethoxy acetic acid (la) obtained by the above described process has
optical
purity of more than 99.5%.
Example-1: Preparation of 2-Chloro-N-(S-l-phenyl ethyl) acetamide (V)
A mixture of 100.0 g (0.82 mol) S-1-Phenylethyl amine, 135.0 g (1.33 mol) triethylamine and
7500.0 ml dichloromethane is cooled to 0-5°C and added slowly a solution of 108.0 g. (0.95 mol)
of chloroacetylchloride in 250.0 ml of dichloromethane to the reaction mass at 0-5°C within 2-3
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hours time. Stir the reaction mass for 3-4 hours at 5°C. Add 500.0 ml of water into the reaction mass and separate the organic layer. Wash the organic layer by 500.0 ml of brine solution. Distilled out dichloromethane completely. Add 1000.0 ml of diisopropyl ether and stir the mass for 2 hours. Filter the solid and wash the wet cake with 200.0 ml of diisopropyl ether. Dry wt. 129.0 g.
NMR: 3H(d-1.35-1.38ppm); 2H(s-4.06ppm); lH(q-4.85-4.92ppm); 5H(m-7.20-7.30ppm) Mass: 198.35 [M+H]
Example-2: Preparation of 2-[N, N-Bis (2-hydroxy ethyl) amino] ethoxy-l-S-[N-(l-phenyl ethyl) acetamide (VII)
A mixture of 340.0 g (2.20 mol) Triethanol amine and 20.0 g (0.50 mol) sodium hydroxide and 100.0 ml toluene heated up to 120-130°C. Distilled out water and toluene completely. Cool the reaction mass to 100°C. Then add slowly 100.0 g (0.51 mol) 2-Chloro-N-(S-l -phenyl ethyl) acetamide (Example-1) in to the reaction mass. Maintain the mass at the same temperature for 1 hr. Cool the reaction mass to RT. Add 400.0 ml of 50% v/v aq. Hydrochloric acid solution to the reaction mass. Filter the solid and Extract the mother liquor by 500.0 ml Dichloromethane at pH: 8.0. Distilled out the methylene chloride completely. Oil observed.
NMR: 3H(dd-1.50-1.53 ppm); 6H(m-2.70-2.76 ppm); 6H(t-3.55-3.57 ppm); 2H(dt-3.91-4.03 ppm); lH(q-5.14-5.18 ppm); 5H (m-7.24-7.33 ppm) Mass: 311.27 [M+H]
Example-3: Preparation of 2-[N, N-Bis (2-methane sulfinyl ethyl) amino] ethoxy-l-S-[N-(l-phenyl ethyl) acetamide (VIII)
A mixture of 50.0 g (0.16 mol) 2-[N, N-Bis (2-hydroxy ethyl) amino] ethoxy-l-S-[N-(l-phenyl ethyl) acetamide oil (Example-2), 48.8 g (0.48 mol) triethyl amine and 500.0 ml dichloro methane cool to 0-5°C. Add 45.9 g (0.40 mol) methane sulfinyl chloride in to the reaction mass slowly by maintaining the same temperature for 2 hrs. Raise the temperature to 25-30°C and stir for 15 hrs. Distilled out the methylene chloride completely. Oil observed.
Example-4: Preparation of 2-[N, N-Bis (2-chloro ethyl) amino] ethoxy-l-S-[N-(l-phenyl ethyl) acetamide (VIII)
Dissolve 10.0 g (0.03 mol) 2-[N, N-Bis (2-hydroxy ethyl) amino] ethoxy-l-S-[N-(l-phenyl ethyl) acetamide oil (Example-2) in 100.0 ml dichloro methane and 0.5 ml N, N-dimethylformamide. Cool the reaction mass to 0-5°C. Add 15.35 g (0.13 mol) thionyl chloride dropwise in to the reaction mass slowly by maintaining the same temperature for 2 hrs. Raise the temperature to 25-
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30°C and stir for 4 hrs. Quench the reaction mass using 40.0 ml water and 10.0 ml methanol mixture. Stir the mass for 30 mins and separate the aq. Layer and extract the aq. Layer with 25.0 ml of dichloro methane. Combined dichloro methane layer and wash it with 25.0 ml of water. Distilled out the methylene chloride completely. Oil observed.
NMR: 3H(dd-1.37-1.39 ppm); 6H(m-2.72-2.87 ppm); 6H(m-3.49-3.58 ppm); 2H(s-3.89 ppm); lH(q-4.97 ppm); 5H (m-7.28 ppm) Mass: 347.18 [M+H]
Example-5: Preparation of (R)-2-[2-|4-[(4-chloro phenyl) phenyl methyl]-l-piperazinyl] ethoxy -l-S-[N-(l-phenyl ethyl) acetamide (II)
A mixture of 50.0 g 2-[N, N-Bis (2-methane sulfinyl ethyl) amino] ethoxy- 1-S-[N-(1 -phenyl ethyl) acetamide oil (Example-3), 35.0 g (0.16 mol) R-(4-chloro phenyl) phenyl methylamine and 500.0 ml of toluene are heated to 75-80°C for 7 hrs. Add 500.0 ml of water to the reaction mass and separate the organic layer. Extract the product by 1000.0 ml of toluene. Distilled out toluene completely under vacuum. Strip out the residue by 200.0 ml of diisopropyl ether. Add 500.0 ml of diisopropyl ether to the residue and heat the mass to reflux temperature. Maintain the reflux for half an hour and cool the mass to 25-30°C. Filter the white solid. Dry wt. 30.0 g
NMR: 3H(dd-1.48-1.50 ppm); 2H(t-2.04 ppm); 4H(m-2.30-2.34 ppm); 4H(m-2.47-2.55 ppm); 2H(t-3.59 ppm); 2H(s-3.89 ppm); lH(q-4.11 ppm); 14H (m-7.166-7.31 ppm) Mass: 492.71 [M+H]
Example-6: Preparation of (R)-2-[2-[4-[(4-chloro phenyl) phenyl methyl]-l-piperazinyl] ethoxy acetic acid (I)
A mixture of 10.0 g (R)-2-[2-[4-[(4-chloro phenyl) phenyl methyl]-1-piperazinyl] ethoxy -1-S-[N-(1-phenyl ethyl) acetamide (II) (Example-5), 30.0 ml of cone. Hydrobromic acid and 50.0 ml water heat to 90-95°C for 24 hrs. cool the reaction mass to 25-30°C and dilute the reaction mass by adding 50.0 ml water. Extract the aq. Reaction mass by 100.0 ml ethyl acetate followed by adjusting the pH=9.5-10.0 with dilute sodium hydroxide solution. Adjust pH=4.5-5.0 using dilute hydrochloride solution. And then extract the product by 100.0 ml dichloro methane. Distilled out dichloromethane to get oil.
Example-6: Preparation of (R)-2-[2-|4-[(4-chloro phenyl) phenyl methyl]-1 -piperazinyl] ethoxy acetic acid Dihydrochloride
Dissolve 9.0 g (R)-2-[2-[4-[(4-chloro phenyl) phenyl methyl]-1-piperazinyl] ethoxy acetic acid (I) oil (Example-5) in 100.0 ml of acetone and cool it to 0-5°C. Purge hydrogen chloride gas to get
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pH=l.0-2.0 constant. Stir the reaction mass for 4 hrs. at 25-30°C. Filter the solid and wash by 20.0 ml of acetone. Dry wt. 8.0 g
NMR: 6H(t-3.45 ppm); 4H(t-3.66 ppm); 2H(t-3.87 ppm); 2H(s-4.17 ppm); lH(s-5.33 ppm); 9H(m-
7.34-7.55 ppm) Mass: 389.84 [M+H]
The invention is particularly represented by;
A] A process for the preparation of, 2-[2-[4-[(4-chlorophenyl) phenyl methyl]-1-piperazinyl]
ethoxy acetic acid, a compound of formula I

(I)
in the form of levorotatory or dextrorotatory isomer, mixture thereof or pharmaceutically acceptable salt thereof comprising converting the compound of formula II

(H)
by treatment with acid or a base to obtain a compound of formula I wherein Ri is C1-C4alkyl;
R2 is aryl or heteroaryl or Ri and R2 together with the carbon to which they are attached form a C3-C8 cycloalkyl group.
B]The process as defined in "A "above wherein the compound of formula II is prepared by a process comprising condensing a compound of formula VIII
o R,
H ^
X
(VIII)
with a compound of formula IX.
13

NH,
(IX) wherein Ri and R2 are as defined above
C] The process as defined in "B" above wherein the compound of formula VIII is prepared by a
process comprising chlorination of a compound of formula VII, 2-[N, N-bis (2-hydroxy ethyl)
amino] ethoxy -1-[N-(1-phenyl ethyl) acetamide o R,
OH
(VII) wherein Rj and R2 are as defined above.
D] The process as defined in "C" above wherein the compound of formula VII is prepared by the
condensation of 2-Chloro-N-(l-phenyl ethyl) acetamide of formula V
O R,
H
(V) with triethanol amine VI.
E] The process as defined in "D" above wherein the compound of formula V is prepared by the
acylation of phenyl ethyl amine by 2-chloroacetyl chloride.
F] The process, as defined in "A" above, for the preparation of levorotatory isomer, (R)-2-[2-[4-
[(4-chloro phenyl) phenyl methyl]-1-piperazinyl] ethoxy acetic acid, compound of formula I,
comprising the treatment of compound of formula (II) o

)
with an acid or a base to obtain compound of formula I,
o
C1^S ^N-^-O-AOH
N.
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G] The Compound, 2-[2-[4-[(4-chloro phenyl) phenyl methyl]-1-piperazinyl] ethoxy-l-S-N-(l-phenyl ethyl) acetamide

4lhx

15