CY1671A - A process for the preparation of 2-(2-(4-((4-chlorophenyl)phenylmethyl)-1-piperazinyl)ethoxy)-acetic acid and its dihydrochloride - Google Patents

A process for the preparation of 2-(2-(4-((4-chlorophenyl)phenylmethyl)-1-piperazinyl)ethoxy)-acetic acid and its dihydrochloride Download PDF

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CY1671A
CY1671A CY1671A CY167193A CY1671A CY 1671 A CY1671 A CY 1671A CY 1671 A CY1671 A CY 1671A CY 167193 A CY167193 A CY 167193A CY 1671 A CY1671 A CY 1671A
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chlorophenyl
formula
phenylmethyl
ethoxy
piperazinyl
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CY1671A
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Ucb Sa
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Description

2225321 »•««>
A process for the preparation of 2-f2-T4-r(4-chlorophenvl)phenylmethvn-l-oiperazinvnethoxv]-acetic acid and its dihydrochloride.
The present invention relates to a new process for the preparation of 2-[2-[4-J(4-chlorophenyl)phenylinethy1]-l-piperazinyl]ethoxy-acetic acid of the formula
5 in wich the asterisk indicates the centre of asymmetry of the molecule, and its dihydrochloride.
The compound of the formula I may exist in the levorotatory form, the dextrorotatory form or a mixture of the levorotatory and dextrorotatory forms.
10 The present invention relates to the synthesis of the compound of the formula I in these various forms;
The dihydrochloride of 2-[2-[4-[(4-chlorophenyl)pheny lmethyl]-l-piperazinyl]ethoxy]-acetic acid, also known by the generic name of cetirizine, has recently been introduced as a new medicament for the 15 treatment of allergic syndromes,' such as chronic and acute allergic rhinitis, allergic conjunctivitis, pruritus, urticaria etc..
European Patent No.58,146 in the name of the Applicant describes the synthesis of 2-[2-[4-[(4-chlorophenyl)phenylmethyl]-l-piperazinyl]ethoxy-acetic acid and its dihydrochloride. In this 20 synthesis, the starting substance is 1-[(4-chlorophenyl)pheny lmethyl]-
piperazine, which is reacted with methyl (2-chloroethoxy)-acetate to give methyl 2-[2-[4-[(4-chlorophenyl)pheny lmethyl]-l-piperazinyl]ethoxy]-acetate in a yield of 27.82. This methyl ester is then subjected to hydrolysis with an inorganic base (sodium or potassium hydroxide} to give 25 the sodium or potassium salt, which is easily converted into the free acid, and then into cetirizine dihydrochloride.
1
BNSDOCID: <GB 2225321A_L>
The major disadvantage of this synthesis is that the overall yield of 2-[ 2-[4-chlorophenyl)phenylmethyl]-l-piperazinyl]ethoxy]-acetic acid dihydrochloride is only 10.62, based on the amount of l-[(4-chlorophenyl)-phenylmethyl]-piperazine employed.
5 According to the present invention, a new process for the synthesis is provided, which enables 2-[2-[4-[(4-chlorophenyl)phenylmethyl]-l-piperazinyl]ethoxy)-acetic acid and its dihydrochloride to be prepared with better yields.
According to the present invention, 2-[2-[4-[(4-10 chlorophenyl) pheny lmethyl]-l-piperazinyl] ethoxy] -acetic acid of the formula
CH-N^ ^N-(CH2)2-0-CH2-CQ0H (I)
15
and its dihydrochloride are prepared by a process which is characterized in that 2-[2-[4-[(4-chlorophenyl)phenylmethyl]-l-piperazinyl]ethoxy]-acetonitrile of the formula
CH-N N-(CH,),-0-CH,-CN
\ / 22 2
(II)
is hydrolysed in an aqueous, alcoholic or aqueous-alcoholic medium by a base or by an acid, and in that, if desired, the acid of the formula I thus obtained is converted into its dihydrochloride.
20 2- [2- [ 4- [ (4-Chlorophenyl) pheny lmethyl ] -l-piperazinyl ] ethoxy ] -
acetonitrile of the formula II used as the starting material is a new compound which is easily obtained by reacting l-[(4-
2
BNSDOCID: <GB 2225321A_I_>
i chlorophenyl)pheny lmethyl ]-piperazine of the formula III with 2-haloethoxyacetonitrile of the formula IV in accordance with the equation:
CI
c o7
CH-N
/"A
(III)
H-K
(IV)
(III
10
15
in which X represents a halogen atom.
This reaction is carried out in the presence of an acid acceptor, such as an alkali metal carbonate, and optionally in the presence of a small amount of an alkali metal iodide to accelerate the reaction, in an inert organic solvent, such as an alcohol {for example n-butanol etc.), preferably at a temperature close to the reflux temperature.
When an optically active l-[ (4-chlorophenyl)phenylmethyl]-piperazine of the formula III instead of the racemate is used in this reaction, the starting enantiomer can be obtained by resolution of the corresponding racemic compound by methods which are known per se.
Of the optically active acids which can be used for this resolution, tartaric acid is preferably used.
As regards the 2-haloethoxyacetonitriles of the formula IV, and more .particularly 2-chloroethoxyacetonitrile, these products can be prepared in accordance with the method described by E.J. SALMI et al., Suomen Kemistilehti, 17B,(1944),17-19 (Chem. Abstr. 40,(1946),6491).
The 2-[2-[4-[ (4-chlorophenyl)phenylmethyl]-l-piperazinyl]ethoxy]-
3
BNSDOCID: <GB 2225321 A_l_>
acetic acid of the formula I is obtained by hydrolysis of 2-[2-[4-[(4-chlorophenyl) pheny lmethyl ] -l-piperazinyl ] ethoxy ] -acetonitrile of the formula II in accordance with the equation:
*2' 2
r\
CH-N N-(CH,, ),,-0-CH -CN
W
(II)
(I)
5 This hydrolysis can be carried out by two operating methods, one in a basic medium and the other in an acid medium.
1. Hydrolysis of the nitrile in a basic medium
The nitrile of the formula II is heated in the presence of an inorganic base, such as an alkali metal hydroxide, in an aqueous, 10 alcoholic or aqueous-alcoholic medium (methanol, ethanol etc.), at a temperature between CCC and the reflux temperature of the reaction mixture.
The acid of the formula I formed is present in the reaction mixture in the form of its alkali metal .salt, from which the acid is liberated by 15 acidification of the reaction mixture by means of an inorganic acid
(such as hydrochloric acid). The acid of the formula I is then extracted by means of an organic solvent (dichloromethane, toluene etc.) and crystallized for isolation.
Finally, the acid of the formula I is converted into the 20 dihydrochloride by a process which is known per se.
2. Hydrolysis of the nitrile in an acid medium
The nitrile of the formula II is heated in the presence of an inorganic acid, such as hydrochloric acid, preferably in an aqueous medium, at a temperature between 60°C and the reflux temperature of 25 the reaction mixture. The acid of the formula I formed is then extracted from the reaction mixture by means of an organic solvent (dichloromethane, toluene etc.) and purified by crystallization. The free acid of the formula I is then converted into the dihydrochloride by a process which is known per se.
30 This new synthesis process gives yields of cetirizine dihydrochloride.
4
BNSDOCID: <GB 2225321 A_l_:
calculated with respect to the amount of l-[(4-
chlorophenyl)phenylmethyl]-piperazine employed, of 60Z or more by acid hydrolysis and 651 or more by basic hydrolysis. Moreover, very high yields of the optically active forms of this compound can be obtained by this process. These higher yields starting from l-[4-chlorophenyl)phenylmethyl]-piperazine constitute a considerable technical advance with respect to the process described in European Patent No.58,146.
The following examples are given for the purpose of illustrating the invention.
Example 1. Preparation of racemic 2-T2-T4T(4-chlorophenyl)-
phenyImethylT-l-piperazinyl 1 ethoxy!-acetic dihydrochloride of the formule I.
1. Racemic 2- f 2- f 4- \ (4-chlorophenyl)phenylmethyl 1 -l-piperazinyl 1 ethoxy 1 -acetonitrile of the formula II.
200 ml of n-butanol, 43.05 g (0.15 mole) of racemic l-[(4-chlorophenyl)phenylmethyl]-piperazine, 24 g (0.174 mole) of 2-chloroethoxyacetonitrile, 26.1 g (0.246 mole) of sodium carbonate and 0.78 g (0.0047 mole) of potassium iodide are introduced successively into a three-necked round-bottomed flask equipped with a mechanical stirrer, a condenser and a thermometer. The mixture is heated at 110°C for 11 hours while stirring, cooled, filtered and concentrated on a rotary evaporator. 60 g of a yellcrw-brown oil are isolated and are chromatographed over a column containing 1 kg of silica using a mixture containing, by volume, 982 dichloromethane and 22 methanol.
This desired nitrile is collected in two fractions, from which the solvents are removed and the purity of which is measured by high performance liquid chromatography.
Racemic 2-[2-{4-[(4-chlorophenyl)phenylmethyl]-l-piperazinyl]ethoxy]-acetonitrile is thus obtained in two fractions, one of which of 33.6 g has a purity of 1002 and the other of which of 14.4 g has a purity of 97.4Z.
Yields 86.42
The product obtained can be characterized in the form of its dihydrochloride prepared from an ethanolic solution of gaseous hydrochloric acid.
M.P.: 201-202°C.
Analysis for C_,H_,C1N.0.2HC1 in 2 21 24 3
calc.i C 56.96 H 5.91 N 9.48 Ci" 16.01 CI 24.02 found: C 57.21 H 6.00 N 9.49 Cl" 15.78 Clt0t' 23.76
5 2. Racemic 2-f2-[4-\(4-chlorophenyl)phenylmethyl1-l-piperazinyl1ethoxy]-acetic acid of the formula I (by hydrolysis in a basic medium) 250 ml of ethanol, 23 g (0.062 mole) of racemic 2-[2-[4-[(4-chlorophenyl) pheny lmethyl ] -l-piperazinyl ] ethoxy ] -acetonitr ile and 31 ml of a 4N ethanolic solution of potassium hydroxide are introduced 10 successively into a three-necked round-bottomed flask equipped with a mechanical stirrer, a condenser and a thermometer. The reaction mixture is refluxed for 10 hours, while stirring. The reaction mixture is allowed to cool and its pH is brought to 6 by addition of 37Z concentrated hydrochloric acid. The ethanol is evaporated and the 15 reaction mixture is diluted with 100 ml of water and extracted three times with 200 ml of dichloromethane. The organic phases are combined, dried over magnesium sulphate, filtered and concentrated in a rotary evaporator. An oil is obtained and is allowed to crystallize by addition of 100 ml of 2-butanone, while hot. The solid formed is 20 filtered, washed and dried. 18.9 g of racemic 2-{2-[4-{(4-
chlorophenyl)phenylmethyl]-l-piperazinyl]ethoxy]-acetic acid are thus, obtained.
18.9 g of the acid thus obtained are resuspended in 150 ml of water; the pH is brought to 0.8 by addition of concentrated hydrochloric 25 acid. The aqueous solution is concentrated on a rotary evaporator and the residue is then diluted by addition of 75 ml of 2-butarione and concentrated again. The addition of 150 ml of 2-butanone to the residue thus obtained causes crystallization of racemic 2-[2-[4-[(4-chloropheny 1)phenyImethyl]-l-piperaziny 1 ]ethoxy]-acetic acid 30 dihydrochloride. The crystals are filtered off and dried, 21.7 g being obtained.
Yield: 75.9Z. M.P.:220.15°C (Differential Scanning Calorimetry; DSC)
(decomposition on melting)
Analysis for C H C1N?0 .2HC1 in Z 35 Calc. : C 54.56 H 5,84 N 6.06 Cl" 15.37 Cl ' 23.05
found: C 54.60 H 5.86 N 6.02 Cl" 15.33 Clt0t' 23.26 The overall yield of dihydrochloride of the 2-[2-[4-[(4-chlorophenyl) pheny lmethyl ] -l-piperazinyl ] ethoxy ] -acetic acid,
BNSDOCID: <GB 2225321A_J_>
calculated with respect to the amount of l-[(4-chlorophenyl)-phenylmethyl]-piperazine employed, is 65.6Z.
3. Racemic 2- f2-T4- F (4-chlorophenyl)phenylmethyl 1-l-piperazinyl 1 ethoxy 1-acetic acid of the formula I (by hydrolysis in an acid medium) 45.3 g (0.123 mole) of racemic 2- [2-[4-[(4-chlorophenyl) pheny lmethyl) -l-piperazinyl]ethoxy)-acetonitrile are introduced into a reactor equipped with a mechanical stirrer, a condenser, a thermometer and a dropping funnel and are heated to 45°C, while stirring. 41 ml of 37Z concentrated hydrochloric acid are then introduced dropwise. The temperature of the reaction mixture rises to 92 °C; the reaction mixture is heated at 95°C for 90 minutes, while stirring. The reaction mixture is allowed to cool and is concentrated on a rotary evaporator, the residue is taken up in 150 ml of toluene and the reaction mixture is concentrated again on a rotary evaporator. The residue is dissolved in 200 ml of water and the aqueous solution obtained is brought to pH 5 by addition of sodium hydroxide. The solution is extracted three times with 300 ml of dichloromethane. The organic phases are combined and the solvent is removed on a rotary evaporator. The oil thus obtained is allowed to crystallize by being dispersed in 250 ml of 2-butanone, while hot.
The mixture is cooled and filtered and the crystals are dried. 34 g of racemic 2-[2-[4-[(4-chlorophenyl)phenylmethyl)-l-piperazinyl]ethoxy]-acetic acid are thus isolated.
34 g of the acid thus obtained are resuspended 'in 300 ml of water; the pH is brought to 0.8 by addition of concentrated hydrochloric acid. The aqueous solution is concentrated on a rotary evaporator, the residue is then diluted by addition of 150 ml of 2-butanone and the mixture is concentrated again. The addition of 300 ml of 2-butanone to the residue thus obtained causes crystallization of racemic 2-[2-[4-[ (4-chlorophenyl)phenylmethyl]-l-piperazinyl]ethoxy]-acetic acid dihydrochloride. The crystals are filtered off and dried, 39.7 g being obtained.
Yields 70Z. M.P.: 227.02°C (DSC) (decomposition on melting).
Analysis for C21H25C1N203.2HC1 in Z
Calc.s C 54.56 h 5.84 N 6.06 Cl" 15.37 Clt0t* 23.05 found: C 54.30 H 5.88 N 6.83 Cl" 15.56 Clt0t* 23.06 The overall yield of 2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]-acetic acid dihydrochloride, calculated with
respect to the amount of 1-[4-chlorophenylJphenylmethyl]-piperazine employed, is 60.52.
Example 2. Preparation of dextrorotatory 2-f 2-f 4-F(4-
chloropheny1)phenylmethyl1-l-piperazinyl1ethoxy1-acetic acid dihydrochloride of the formula I.
1. Levorotatory 1-f (4-chlorophenvl)phenvlmethvH-piperazine of the formula III.
A solution of 300 g (2 moles) of (2R,3R)-tartaric acid in 2 litres of ethanol is heated at 72-74°C and a solution of 286.5 (1 mole) of racemic l-[(4-chlorophenyl)phenylmethyl]-piperazine in 1 litre of ethanol is added, while stirring. The mixture is refluxed for 5 minutes and then allowed to return to room temperature, while stirring (the desired salt starts to crystallize towards 57°C). The salt obtained is filtered off and recrystallized three times in succession, first in a mixture of 2 litres of ethanol and 0.8 litre of methanol, then in 1 litre of ethanol, and finally in a mixture of 0.5 litre of ethanol, 65 ml of methanol and 5 ml of water. After filtrati'on and drying, 118 g of diastereoisomerically impure l-[4-chlorophenyl)phenylmethyl]-piperazine (2R, 3B.)-tartrate are obtained. M.P.: 170.4°C (DSC), [a]25 : + 7.8° (c - 1, methanol).
This salt is then decomposed by addition of a solution of 22 g (0.55 mole) of sodium hydroxide in 750 ml of water. Levorotatory l-[(4-chlorophenyl)phenylmethylJ-piperazine thus liberated is extracted several times with dichloromethane. The combined organic phases are dried over sodium sulphate, filtered and concentrated on a rotary evaporator. 80 g of optically impure levorotatory l-[(4-chlorophenylJphenylmethyl]-piperazine are obtained; this product is purified by successive recrystallizations from hexane, to give finally 18.2 g of levorotatory l-[(4-chlorophenyl)phenylmethyl]-piperazine. M.P.: 90-92°C.. M.P.s 90.35°C (DSC) [a]25 : -19,4° (c - 1, toluene).
Yield: 12.72
2. Levorotatory 2-f2-f4-T(4-chlorophenyl)phenylmethyll-l-piperazinyl1-ethoxy 1-acetonitrile of the formula II.
100 ml of n-butanol, 20 g (0.07 mole) of levorotatory l-[(4-chlorophenyl)phenylmethyl]-piperazine, 11.2 g (0.0937 mole) of 2-chloroethoxyacetonitrile, 12.18 g (0.115 mole) of sodium carbonate
8
and 0.36 g (0.002 mole) of potassium iodide are introduced successively into a three-necked round-bottomed flask equipped with a mechanical stirrer, a condenser and a thermometer. The mixture is heated at 110°C for 7 hours, while stirring, then cooled, filtered and concentrated on a rotary evaporator. 26 g of a yellow-brown oil are isolated and are chromatographed over a column containing 1 kg of silica using a mixture containing by volume, 98Z dichloromethane and 22 methanol. 17.8 g of levorotatory 2-[2-[4-[(4-chlorophenyl)-phenylmethyl]-l-piperazinyl]ethoxy]-acetonitrile are obtained in the form of an oil.
tal365s "31,8° (c " lt methanol). Yield: 692.
The product can be characterized in the form of its dihydrochloride prepared from an ethanolic solution of gaseous hydrochloric acid. M.P.: 211-212°C +7.18° (c - 1, methanol)
Analysis for C21H2/,C1N30.2HC1 in 2
Calc.: C 56.96 H 5.91 N 9.49 Cl" 16.01 Clt0t' 24.02 found: C 56.92 H 5.93 N 9.33 Cl" 15.76 Clt0t" 23.65
Dextrorotatory 2-f2-f4-f(4-chlorophenyl-phenvlmethyll-l-pjperazinyll-ethoxyl-acetic acid dihydrochloride of the formula I.
9.42 g (0.0255 mole) of levorotatory 2-[2-[4-[(4-chlorophenyl)phenylmethyl]-l-piperazinyl]ethoxy]-acetonitrile are introduced into a reactor equipped with a mechanical stirrer, a condenser, a thermometer and a dropping funnel and are heated to 45°C, while stirring. 15 ml of 372 concentrated hydrochloric acid are then added. The temperature of the reaction mixture rises to 92°C. The reaction mixture is heated at 60°C for 60 minutes, while stirring. The reaction mixture is allowed to cool and is concentrated on a rotary evaporator, and the residue is taken up in 50 ml of water. The pH of the reaction mixture is brought to 5 by addition of sodium hydroxide and the mixture is extracted with several successive fractions of dichloromethane. The organic phases are combined and dried over magnesium sulphate and the solvent is removed on a rotary evaporator. 9.6 g of the free acid of the formula I are thus obtained in the form of a beige powder and are converted into the dihydrochloride by means of a solution of hydrochloric acid in acetone, and the dihydrochloride is crystallized. After filtration and drying, 9.8 g of dextrorotatory 2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-
piperazinyl]ethoxy]-acetic acid dihydrochloride are obtained. The purity of this product, measured by high performance liquid chromatography with a chiral stationary phase of ot^-AGP (from the LKB Company) is 95Z with respect to the dextrorotatory enantiomer. M.P.: 199-201°C M.P.:224.4eC (DSC). [a]" = +9-48 (c - 1, water)
Yield: 83Z
Analysis for c2iH25C1N2°3.2HC1 in Z
calc.: C 54.56 H 5.84 N 6.06 Cl" 15.37 Clt0t* 23.05
found: C 54.00 H 5.88 N 5.91 Cl" 15.55 Clt0t* 23.13
The overall yield of dextrorotatory 2-[2-[4-[(4-
chl orophenyl) phenylmethyl ] -1-piperaainyl ] ethoxy ] -acetic acid dihydrochloride, calculated with respect to the amount of levorotatory l-[4-chlorophenyl-phenylmethyl]-piperazine employed, is 57.3Z.
Example 3. Preparation of levorotatory 2-r2-T4-f(4-
chlorophenvl)phenylmethyl1-l-piperazinyl1ethoxy1-acetic acid dihydrochloride of the formula I.
This product is obtained by the method described in example 2, but starting from dextrorotatory l-[ (4-chlorophenyl)phenylmethyl]-piperazine, the latter being obtained as in example 2.1 by treating the racemate with (2S,3S)-tartaric acid.
The levorotatory acid dihydrochloride of the formula I is obtained in yields and with a purity very close to those obtained for the dextrorotatory acid dihydrochloride: 95Z measured by high performance liquid chromatography with a chiral stationary phase of oc^-AGP (from the LKB Company).
M.P.: 198-200°C M.P.: 220.7 (DSC) (decomposition on melting).
10
2225321 A_l_>

Claims (3)

CLAIMS. f
1. A process for the preparation of 2-[2-[4-[(4-
chlorophenyl)phenylmethyl]-l-piperazinyl]ethoxy]-acetic acid of the formula
Cl.
w r~\
CH-N N-(CH„) -Q-CH -C00H
\ / A 2 2
(I)
and its dihydrochloride, characterized in that 2-[2-[4-[(4-chlorophenyl)phenylmethyl]-l-piperazinyl]ethoxy]-acetonitrile of the formula
Cl
\j)\
CH-N
\ f
M-(CH2)2-0-CH2-CN
(II)
v\ I
is hydrolysed in an aqueous, alcoholic or aqueous-alcoholic medium by 10 a base or by an acid, and in that, if desired, the acid of the formula
I thus obtained is converted into its dihydrochloride.
2. A process according to claim 1, characterized in that the hydrolysis is carried out at a temperature between 60°C and the reflux temperature of the reaction mixture.
15
3. A process according to any of claims 1 and 2, characterized in that the 2-[2-[4-[(4-chlorophenyl)phenylmethyl ]-l-piperazinylJethoxy]-acetic acid of the formula I is in the levorotatory or dextrorotatory form or in the form of a mixture of the levorotatory and u
BNSDOCID: <GB 2225321 A_l_>
dextrorotatory forms.
4. A process according to any of claims 1 to 3, characterized in that the 2-[2- [ 4- [(4-chlorophenylJ phenylmethyl]-l-piperazinyl]ethoxy]-acetonitrile of the formula II is in the levorotatory or
5 dextrorotatory form or in the form of a mixture of the dextrorotatory and levorotatory forms.
5. 2-[2-[4-[(4-chlorophenyl}pheny lmethylJ-l-piperazinyl]ethoxy]-acetonitrile of the formula
\
CH-N N-(CH_),-0-CH -CN (II)
\ / Z22
//
10 and its dihydrochloride in the levorotatory or dextrorotatory form or in the form of a mixture of the levorotatory and dextrorotatory forms.
€. A process for the preparation of 2-(2-(4-((4-chlorophenyl)-phenylmethyl)-l-piperazinyl)ethoxy)-acetonitrile as claimed in claim 5 comprising reacting l-((4-chlorophenyl)phenylmethyl) -piperazine of the formula III
C1<j\
CH-N .N-H
/=\/ (III)
with a 2-haloethoxyacetonitrile of formula X-(CH2)2~0-CH^-CN, in which x represents a halogen atom.
7. A process as claimed in Claim 6 wherein the reaction is carried out in the presence of an acid acceptor such as an alkali
. metal carbonate and optionally, in the presence of an alkali metal iodide in an inert organic solvent such as an alcohol.
8. A process substantially as hereinbefore described in any one of examples 1-3.
12
Published 1S90 at'ihe jPateutCi&ce.State House, 66/71 High Holborn, LondonWC1R4TP. Further c cries maybe obtesnes&cnr. The Paten*, Office. CID GB 2^321 ^ar3r Cray, Orpington, Kent BUS 3RD. Printed by Multiplex techniques ltd, St Mary Cray, Kent, Con. 1/67
CY1671A 1988-11-23 1993-05-14 A process for the preparation of 2-(2-(4-((4-chlorophenyl)phenylmethyl)-1-piperazinyl)ethoxy)-acetic acid and its dihydrochloride CY1671A (en)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DK0661975T3 (en) * 1992-09-24 1999-09-27 Sepracor Inc Transdermal treatment of hives using optically pure (+) - cetirizine
AU703690B2 (en) * 1992-09-24 1999-04-01 Sepracor, Inc. Methods for treating allergic disorders using optically pure (+)cetirizine
EP0950412A3 (en) * 1992-09-24 2001-05-16 Sepracor, Inc. Compositions for treating allergic disorders using (-) cetirizine
GB9305282D0 (en) * 1993-03-15 1993-05-05 Ucb Sa Enantiomers of 1-(4-chlorophenyl)phenylmethyl)-4-(4-methylphenyl)sulphonyl)piperazine
US6469009B1 (en) 1996-04-08 2002-10-22 Ucb, S.A. Pharmaceutical compositions for the treatment of rhinitis
BE1010095A3 (en) * 1996-04-10 1997-12-02 Ucb Sa METHOD OF PREPARATION OF ACID 2- [2- [4 - [(4-Chlorophenyl) phenylmethyl] -1-PIPERAZINYL] ETHOXY] acetic acid AND ITS SALTS.
BE1010094A3 (en) * 1996-04-10 1997-12-02 Ucb Sa NEW [2- (1-piperazinyl) ethoxy] SUBSTITUTED.
JP3476475B2 (en) 1997-06-04 2003-12-10 株式会社アズウェル Method for producing piperazine sulfonamide derivative and salt thereof
EP0919550A1 (en) 1997-11-26 1999-06-02 Ucb, S.A. Pseudopolymorphic forms of 2-2-4-bis(4-fluorophenyl)methyl-1-piperazinyl-ethoxy acetic acid dihydrochloride
IL124195A (en) * 1998-04-23 2000-08-31 Chemagis Ltd Process for the preparation of esters of 2-¬4-¬4-chlorophenyl¾phenylmethyl¾-1-piperazinyl¬ethoxy¾acetic acid
GR990100135A (en) * 1999-04-22 2000-12-29 Genepharm �.�. Method of preparation 2-(2-{4-[(4-chlorophenyl)(phenyl)methhyl]piperasine}-ethoxy)acetic acid and its bihydrochloric salt
JP2002249487A (en) 2001-02-22 2002-09-06 Sumitomo Chem Co Ltd A 4- (tert-butoxycarbonyl) piperazine derivative, an optically active acid addition salt thereof, a method for producing them, and a method for producing optically active 1-[(substituted phenyl) phenylmethyl] piperazine using the same.
US7199241B1 (en) 2001-05-29 2007-04-03 Ucb, S.A. Process for preparing (S) and (R)-2-[4-(4-chlorobenzhydryl)piperazin-1-yl]-ethoxyacetamide
US6977301B1 (en) 2001-05-29 2005-12-20 Ucb, S.A. Process for preparing (S) and (R)—2-[4-(4-chlorobenzhydryl)piperazin-1-yl]-ethoxyacetamide
CN100378086C (en) * 2003-01-23 2008-04-02 Ucb法奇姆股份有限公司 Piperazine derivatives and their use as synthetic intermediates
KR100503443B1 (en) 2004-02-02 2005-07-22 한림제약(주) Processes for preparing an optically active cetirizine or its salt
MX2007010455A (en) * 2005-03-03 2007-11-08 Ucb Farchim Sa Pyroglutamate salts and their use in the optical resolution of intermediates for the synthesis of dextrocetirizine and levocetirizine.
HU227325B1 (en) * 2005-12-08 2011-03-28 Egis Gyogyszergyar Nyrt Process for the production of an intermediate of (dextro- and levo)- cetirizine
WO2008110586A2 (en) 2007-03-12 2008-09-18 Krka, Tovarna Zdravil, D.D., Novo Mesto New process for the preparation of levocetirizine and intermediates thereof
SI22489A (en) * 2007-03-12 2008-10-31 Krka, Tovarna Zdravil, D.D., Novo Mesto New procedure for preparation of levocetirizine and its intermediates
WO2008152650A1 (en) 2007-06-15 2008-12-18 Symed Labs Limited Process for preparation of substantially optically pure levorotatory and dextrorotatory enantiomers of cetirizine using novel intermediates
WO2009062036A2 (en) * 2007-11-09 2009-05-14 Dr. Reddy's Laboratories Ltd. Processes for preparing levocetirizine and pharmaceutically acceptable salts thereof
EP2062881B1 (en) 2007-11-21 2011-02-23 Synthon B.V. Process for making N-(diphenylmethyl)piperazines
US7989623B2 (en) 2007-11-21 2011-08-02 Synthon Bv Process for making n-(diphenylmethyl)piperazines
AU2009254959B2 (en) 2008-06-02 2014-01-30 Cipla Limited Processes for the synthesis of levocetirizine and intermediates for use therein
WO2009150147A1 (en) * 2008-06-11 2009-12-17 Krka, Tovarna Zdravil, D.D., Novo Mesto New process for the preparation of levocetirizine and intermediates thereof
KR100998067B1 (en) 2008-09-08 2010-12-03 주식회사 삼오제약 Bis (1-[(4-chlorophenyl) phenylmethyl] piperazin) -2,3-dibenzoyl tartaric acid novel intermediate salt and optically pure 1-[(4-chlorophenyl) phenylmethyl] piperazin using the same How to separate
US20110172425A1 (en) 2008-09-17 2011-07-14 Calyx Chemicals And Pharmaceuticals Pvt. Ltd. Novel water based process for the preparation of substituted diphenylmethyl piperazines
WO2010107404A1 (en) 2009-03-16 2010-09-23 Mahmut Bilgic Stable pharmaceutical combinations
TR201007652A2 (en) 2010-09-20 2012-04-24 Bi̇lgi̇ç Mahmut Synergistic effect.
TR201009398A2 (en) 2010-11-11 2012-05-21 Bi̇lgi̇ç Mahmut Tablet formulations with improved physical properties
WO2012101475A1 (en) 2011-01-27 2012-08-02 Jubilant Life Sciences Limited An improved process for the preparation of antihistaminic drugs via a novel carbamate intermediate
CN103044355A (en) * 2011-10-13 2013-04-17 湖南九典制药有限公司 Key intermediate for synthesizing levocetirizine and preparation method thereof
KR101418404B1 (en) 2012-01-06 2014-07-10 한미약품 주식회사 Stable pharmaceutical formulation for oral administration comprising levocetirizine or a pharmaceutically acceptable salt thereof, and montelukast or a pharmaceutically acceptable salt thereof
KR102226833B1 (en) 2013-06-28 2021-03-12 한미약품 주식회사 Complex granule formulation having improved stability comprising levocetirizine and montelukast
CN104045607B (en) * 2014-05-21 2016-04-13 丽珠医药集团股份有限公司 A kind of purification process of cetrizine hcl
CN105924409B (en) * 2016-05-12 2019-01-08 浙江永宁药业股份有限公司 The method for splitting of one kind (R) -1- ((2- chlorphenyl)-(phenyl)-methyl)-piperazine
CN111205247B (en) * 2020-04-22 2020-08-14 湖南九典宏阳制药有限公司 Preparation method of levocetirizine

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DK154078C (en) * 1981-02-06 1989-05-22 Ucb Sa METHOD OF ANALOGUE FOR THE PREPARATION OF 2- (2- (4- (DIPHENYL-METHYL) -1-PIPERAZINYL) ETHOXY) -ACETAMIDES OR ACID ADDITION SALTS.

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