NO172342B - PROCEDURE FOR THE PREPARATION OF 2- (2- (4 - ((4-CHLORPHENYL) -PHENYLMETHYL) -1-PIPERAZINYL) -ETHOXY) -DETIC ACID AND ITS DIHYDROCHLORIDE, AND INTERMEDIATE PRODUCT FOR USE BY FRAME - Google Patents

Abstract

New process for the preparation of 2- [2- [4 - [(4-chlorophenyl) -phenylmethyl] -1-piperazinyl] -ethoxy] -acetic acid and its dihydrochloride, wherein 2- [2- [4 - [(4-chlorophenyl) ) -phenylmethyl] -1-piperazinyl] -ethoxy] -acetonitrile is hydrolyzed in an aqueous, alcoholic or aqueous-alcoholic medium with a base or with an acid, and the acid thus obtained, if desired, is transferred to its dihydrochloride.

Description

The present invention relates to a new process for the production of 2-[2-[4-[(4-chlorophenyl)-phenylmethyl]-1-piperazinyl]-ethoxy]-acetic acid with the formula:

in the levorotatory form, in the dextrorotatory form or in the form of a mixture of the levorotatory and dextrorotatory forms, and its dihydrochloride. In the formula, the star indicates the molecule's center of asymmetry.

The invention also relates to an intermediate product used in the method.

The dihydrochloride of 2-[2-[4-[(4-chlorophenyl)-phenyl-methyl]-1-piperazinyl]-ethoxy]-acetic acid, which is also known by the common name cetirizine, has recently been introduced as a new drug for the treatment of allergic syndromes, such as chronic and acute allergic rhinitis, allergic conjunctivitis, pruritus, urticaria, etc.

European patent document no. 58 146 describes a synthesis for the production of 2-[2-[4-[(4-chlorophenyl)-phenyl-methyl]-1-piperazinyl]-ethoxy]-acetic acid and its dihydrochloride. In this synthesis, the starting material is 1-[(4-chlorophenyl)-phenylmethyl]-piperazine, and this is reacted with methyl-(2-chloro-ethoxy)-acetate, whereby methyl-2-[2-[4-[( 4-chloro-phenyl)-phenylmethyl]-1-piperazinyl]-ethoxy-acetate in a yield of 27.8%. This methyl ester is then subjected to hydrolysis with an inorganic base (potassium or sodium hydroxide), whereby the sodium or potassium salt is obtained, which is easily transferred to the free acid, which is then transferred to cetirizine dihydrochloride.

The biggest disadvantage of this synthesis is that the total yield of 2-[2-[4-[(4-chlorophenyl)-phenylmethyl]-1-piperazinyl]-ethoxy]-acetic acid dihydrochloride is only 10.6%, calculated on the amount of 1-[(4-chlorophenyl)-phenyl-methyl]-1-piperazine used.

With the present invention, a new method is now provided which enables the production of 2-[2-[4-[(4-chlorophenyl)-phenylmethyl]-1-piperazinyl]-ethoxy]-acetic acid in the forms stated above, and the compound's dihydrochloride , in better dividends.

The new method is characteristic in that l-[(4-chlorophenyl)-phenylmethyl]-1-piperazine with the formula:

in the levorotatory form, in the dextrorotatory form or in the form of a mixture of the levorotatory and dextrorotatory forms, is reacted, in the presence of an acid acceptor, with a 2-haloethoxyacetonitrile of the formula: where X is a halogen atom, and the resulting 2-[2-[4-[(4-chlorophenyl)-phenylmethyl]-1-piperazinyl]-ethoxy]-acetonitrile with the formula:

in the levorotatory form, in the dextrorotatory form or in the form of a mixture of the dextrorotatory and levorotatory forms, is hydrolyzed in an aqueous, alcoholic or aqueous-al-

alcoholic medium with a base or with an acid, and that the thereby obtained acid of formula I is, if necessary, transferred to its dihydrochloride.

The invention also relates to the 2-[2-[4-[(4-chlorophenyl)-phenyl-methyl]-1-piperazinyl)-ethoxy]-acetonitrile of formula II, which is obtained as an intermediate by the new process, in the left-handed form , in the right-handed form or in the form of a mixture of the left-handed and right-handed forms.

The compound of formula II is obtained according to the equation:

where X denotes a halogen atom.

This reaction is carried out in the presence of an acid acceptor, such as e.g. 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 (eg n-butanol, etc.), preferably at a temperature close to the reflux temperature.

When an optically active 1-[(4-chlorophenyl)-phenylmethyl]-piperazine of formula III is used in this reaction instead of the racemate, the enantiomer used as starting material can be obtained by optical cleavage of the corresponding racemic compound

these according to methods known in and of themselves.

Among the optically active acids that can be used in this optical cleavage, tartaric acid is preferred.

As regards the 2-haloethoxyacetonitrile of the formula IV, and especially 2-chloroethoxyacetonitrile, these compounds can be prepared according to 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]-1-piperazinyl]-ethoxy]-acetic acid of formula I is obtained by hydrolysis of 2-[2-[4-[(4-chlorophenyl)-phenylmethyl] ]-1-piperazinyl]-ethoxy]-acetonitrile of the formula II according to the equation:

This hydrolysis can be carried out in two ways, namely in a basic medium and in an acidic medium. 1. Hydrolysis of the nitrile in a basic medium The nitrile with the formula II is heated in the presence of an inorganic base, such as e.g. an alkali metal hydroxide, in an aqueous, alcoholic or aqueous-alcoholic medium (methanol, ethanol, etc.), at a temperature between 60°C and the reflux temperature of the reaction mixture.

The formed acid of formula I is present in the reaction mixture in the form of its alkali metal salt, from which the acid is liberated by acidifying the reaction mixture with an inorganic acid (e.g. hydrochloric acid). The acid of formula I is then extracted with an organic solvent (dichloromethane, toluene, etc.) and isolated by crystallization. Finally, the acid of formula I is transferred to the dihydrochloride in a manner known per se.

2. Hydrolysis of the nitrile in an acidic medium

The nitrile of 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 the reaction mixture. The formed acid of formula I is then extracted from the reaction mixture with an organic solvent (dichloromethane, toluene, etc.) and purified by crystallization. The free acid of formula I is then transferred to the dihydrochloride in a manner known per se.

The new method gives cetirizine dihydrochloride in total yields, calculated on the amount of 1-[(4-chloro-phenyl)-phenylmethyl]-piperazine used, of 60% or more by acid hydrolysis and 65% or more by basic hydrolysis. Moreover, very high yields of the optically active forms of this compound can be obtained by this method, e.g. a yield of 57% or more of cetirizine dihydrochloride in the dextrorotatory form, calculated on the amount of 1-[(4-chlorophenyl)-phenyl-methyl]-piperazine in the levorotatory form used. These higher yields, which are obtained by starting with 1-[(4-chlorophenyl)-phenyl-methyl]-piperazine, represent a significant technical advance compared to the method described in European Patent Document No. 58 146.

The following examples illustrate the invention.

Example

Preparation of racemic 2-[2-[4-[(4-chlorophenyl)-phenylmethyl]-1-piperazinyl]-ethoxy]-acetic acid dihydrochloride of formula I.

1. Racemic 2-[2-[4-[(4-chlorophenyl)-phenylmethyl]-1-piperazinyl]-ethoxy]-acetonitrile of formula II

200 ml n-butanol, 43.05 g (0.15 mol) racemic l-[(4-chlorophenyl)-phenylmethyl]-piperazine, 24 g (0.174 mol) 2-chloroethoxyacetonitrile, 26.1 g (0.246 mol) sodium carbonate and 0.78 g (0.0047 mol) of potassium iodide are introduced in turn 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 eleven hours with stirring, cooled, filtered and evaporated in a

rotary evaporator. 60 g of a yellow-brown oil is isolated and

is chromatographed in a column containing 1 kg of silica, using a mixture containing 98 vol% dichloromethane and 2 vol% methanol. The desired nitrile is collected in two fractions, from which the solvents are removed. The purity of the fractions is measured by high-performance liquid chromatography. (HP).

Racemic 2-[2-[4-[(4-chlorophenyl)-phenylmethyl]-1-pipe-razinyl]-1-ethoxy]-acetonitrile is thereby obtained in two fractions, one of 33.6 g with a purity of 100 % and the other of 14.4 g with a purity of 97.4%.

Yield: 86.4%.

The compound obtained can be identified in the form of its dihydrochloride prepared from an ethanolic solution of gaseous hydrogen chloride.

Melting point: 201-202°C.

Analysis for C21H24C1N30- 2HC1 in %

calculated: C 56.96 H 5.91 N 9.48 Cl' 16.01 Cl<tot-> 24.02 found: C 57.21 H 6.00 N 9.49 Cl" 15.78 Cl<tot- > 23.76. 2. Racemic 2-f2-T4-I" (4-chlorophenyl)-phenylmethyl 1-1-piperazinyl-ethoxy]-acetic acid of formula I (by hydrolysis in a basic medium).

250 g ethanol, 23 g (0.062 mol) racemic 2-[2-[4-[(4-chlorophenyl)-phenylmethyl]-1-piperazinyl]-ethoxy]-acetonitrile and 31 ml of a 4N ethanolic solution of potassium hydroxide in are introduced in turn into a three-necked round-bottomed flask equipped with a mechanical stirrer, a condenser and a thermometer. The reaction mixture is boiled under reflux for 10 hours with stirring. The reaction mixture is allowed to cool and its pH is brought to 6 by the addition of 37% concentrated hydrochloric acid. The ethanol is evaporated, and the 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 evaporated in a rotary evaporator. An oil is obtained, which is allowed to crystallize hot by the addition of 100 ml of 2-butanone. The solid formed is filtered off, washed and dried. 18.9 g of racemic 2-[2-[4-[(4-chlorophenyl)-phenylmethyl]-1-piperazinyl]-ethoxy]-acetic acid are thereby obtained.

18.9 g of the acid obtained is resuspended in 150 ml of water, and the pH value is adjusted to 0.8 by adding concentrated hydrochloric acid. The aqueous solution is concentrated in a rotary evaporator, after which the residue is diluted by adding 75 ml of 2-butanone and concentration is carried out again. By adding 150 ml of 2-butanone to the thus obtained residue, crystallization of racemic 2-[2-[4-[(4-chlorophenyl)-phenylmethyl]-1-piperazinyl]-ethoxy]-acetic acid dihydrochloride takes place. The crystals are filtered off and dried. 21.7 g of the desired compound are obtained.

Yield: 75.9%. Melting point: 220.15°C. (Differential Scanning Calorimetry; DSC) (decomposes on melting).

Analysis for C21H25C1N203- 2HC1 in %

calculated: C 54.56 H 5.84 N 6.06 Cl" 15.37 Cl<tot-> 23.05 found: C 54.60 H 5.86 N 6.02 Cl' 15.33 Cl<tot- > 23.26

The total yield of the dichloride of 2-[2-[4-[(4-chlorophenyl)-phenylmethyl]-1-piperazinyl]-ethoxy]-acetic acid, calculated on the amount of 1-[(4-chlorophenyl)-phenylmethyl] used -piperazine, is 65.6%. 3. Racemic 2-f2-f4-f(4-chlorophenyl)-phenylmethyl]-1-piperazin-yl 1-ethoxy]-acetic acid of formula I (by hydrolysis in an acidic medium). 45.3 g (0.123 mol) of racemic 2-[2-[4-[(4-chlorophenyl)-phenylmethyl]-1-piperazinyl]-ethoxy]-acetonitrile is introduced into a reactor equipped with a mechanical stirrer, a condenser, a thermometer and a dropping funnel and heated to 45°C while stirring. 41 ml of 37% concentrated hydrochloric acid is then added drop by drop. The temperature of the reaction mixture increases to 92°C. The reaction mixture is heated at 95°C for 90 minutes with stirring. The reaction mixture is allowed to cool and evaporated in a rotary evaporator. The residue is taken up in 150 ml of toluene, and the reaction mixture is re-evaporated in a rotary evaporator. The residue is dissolved in 200 ml of water, and the resulting aqueous solution is adjusted to pH 5 by adding sodium hydroxide. The solution is extracted three times with 300 ml of dichloromethane. The organic phases are combined, and the solvent is removed in a rotary evaporator. The oil thus obtained is allowed to crystallize hot by dispersing it in 250 ml of 2-butanone.

The mixture is cooled and filtered, and the crystals are dried. 34 g of racemic 2-[2-[4-[(4-chlorophenyl)-phenylmethyl]-1-piperazinyl]-ethoxy]-acetic acid are thereby obtained. 34 g of the acid thus obtained is resuspended in 300 ml of water, and the pH value is adjusted to 0.8 by adding concentrated hydrochloric acid. The aqueous solution is evaporated in a rotary evaporator, and the residue is diluted by adding 150 ml of 2-butanone, after which the mixture is evaporated again. By adding 300 ml of 2-butanone to the residue thus obtained, crystallization of racemic 2-[2-[4-[(4-chloro-phenyl)-phenylmethyl]-1-piperazinyl]-ethoxy]-acetic acid dihydrochloride is effected. The crystals are filtered off and dried, whereby 39.7 g of the desired compound are obtained.

Yield: 70%. Melting point: 227.02°C. (DSC) (decomposes on melting).

Analysis for C21H25C1N203- 2HC1 in %

calculated: C 54.56 H 5.84 N 6.06 Cl" 15.37 Cl<tot-> 23.05 found: C 54.30 H 5.88 N 6.83 Cl" 15.56 Cl<tot- > 23.06

The total yield of 2-[2-[4-[(4-chlorophenyl)-phenyl-methyl]-1-piperazinyl]-ethoxy]-acetic acid dihydrochloride, calculated on the amount of 1-[(4-chlorophenyl)- phenylmethyl]-piperazine, is 60.5%.

Example 2

Preparation of dextrorotatory 2-[2-[4-[(4-chlorophenyl)-phenyl-methyl]-1-piperazinyl]-ethoxy]-acetic acid dihydrochloride of formula I

1. Levorotatory 1-[(4-chlorophenyl)-phenylmethyl]-piperazine of formula III

A solution of 300 g (2 mol) (2R,3R)-tartaric acid in 2 1 ethanol is heated at 72-74°C, and a solution of 286.5 g (1 mol) racemic 1-[(4-chlorophenyl)- phenylmethyl]-piperazine and ethanol are added with stirring. The mixture is refluxed for 5 minutes and then allowed to cool to room temperature with stirring (the desired salt begins to crystallize as the temperature approaches 57°C). The salt obtained is filtered off and recrystallized three times one after the other, first in a mixture of 2 1 ethanol and 0.8 1 methanol, then in ethanol and finally in a mixture of 0.5 1 ethanol, 65 ml methanol and 5 ml water. After filtering off and drying, 118 g of diastereoisomeric impure 1-[4-chlorophenyl)-phenylmethyl]-piperazine (2R,3%)-tartrate are obtained. Melting point 170, 4°C

(DSC).

[a]^<5> : + 7.8° (c = 1, methanol).

This salt is then cleaved by adding a solution of 22 g (0.55 mol) of sodium hydroxide in 750 ml of water. The left-handed 1-[(4-chlorophenyl)-phenylmethyl]-piperazine thereby released is extracted several times with dichloromethane. The combined organic phases are dried over sodium sulphate, filtered and evaporated in a rotary evaporator. 80 g of optically impure, levorotatory 1-[(4-chlorophenyl)-phenylmethyl]-piperazine are obtained. This compound is purified by successive recrystallizations from hexane, whereby 18.2 g of levorotatory 1-[(4-chlorophenyl)-phenylmethyl]-piperazine are finally obtained. Melting point: 90-92°C. Melting point: 90.35°C (DSC);

[a]^<5> : 19.4° (c = 1, toluene).

Dividend: 12.7%.

2. Levorotatory 2-[2-[4-[(4-chlorophenyl)-phenylmethyl]-1-pipe-razinyl]-ethoxy]-acetonitrile of formula II

100 ml n-butanol, 20 g (0.07 mol) levorotatory 1-[(4-chlorophenyl)-phenylmethyl]-piperazine, 11.2 g (0.0937 mol) 2-chloroethoxyacetonitrile, 12.18 g (0.115 mol ) of sodium carbonate and 0.36 g (0.002 mol) of potassium iodide are introduced in turn 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 seven hours with stirring, after which it is cooled, filtered and evaporated in a rotary evaporator. 26 g of a yellow-brown oil is isolated and chromatographed over a column containing 1 kg of silica using a mixture containing 98 vol% dichloromethane and 2 vol% methanol. 17.8% levorotatory 2-[2-[4-[(4-chlorophenyl)-phenylmethyl]-1-piperazinyl]-ethoxy]-acetonitrile is obtained in the form of an oil.

[αjgg: +31.8° (c = 1, methanol). Yield: 69%.

The compound can be identified in the form of its dihydrochloride prepared from an ethanolic solution of hydrogen chloride gas. Melting point 211-212°C.

[α]365: +7'18° (° = 1'methanol).

Analysis for C21<H>24C1N30- 2HC1 in %

calculated: C 56.96 H 5.91 N 9.49 Cl" 16.01 Cl<tot-> 24.02 found: C 56.92 H 5.93 N 9.33 Cl" 15.76 Cl<tot- > 23.65

3. dextrorotatory 2-[2-[4-[(4-chlorophenyl)-phenylmethyl]-1-piperazinyl]-ethoxy]-acetic acid dihydrochloride of formula I

9.42 g (0.0255 mol) mol) of levorotatory 2-[2-[4-[(4-chlorophenyl)-phenylmethyl]-1-piperazinyl]-ethoxy]-acetonitrile is introduced into a reactor equipped with a mechanical stirrer, a condenser, a thermometer and a dropping funnel and heated to 45°C with stirring. 15 ml of 37% concentrated hydrochloric acid is then added. The temperature of the reaction mixture increases to 92°C. The reaction mixture is heated at 60°C for 60 minutes with stirring. The reaction mixture is allowed to cool and evaporate in a rotary evaporator, and the residue is taken up in 50 ml of water. The pH of the reaction mixture is adjusted to 5 by adding sodium hydroxide, and the mixture is extracted with several successive fractions of dichloromethane. The organic phases are combined and dried over magnesium sulfate, and the solvent is removed in a rotary evaporator. 9.6 g of the free acid of formula I is thereby obtained in the form of a beige-coloured powder. The acid is transferred to the dihydrochloride using a solution of hydrogen chloride in acetone, and the dihydrochloride is crystallized. After filtering off 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 compound, as measured by high performance liquid chromatography with a chiral stationary phase of o 2 -AGP (from LKB Company) is 95% with respect to the dextrorotatory enantiomer.

Melting point 199-201°C. Melting point 224.4°C (DSC).

[a]365: +9'4° (°= 1' water).

Yield 83%

Analysis for C21H25C1N203- 2HC1 in %

calculated: C 54.56 H 5.84 N 6.06 Cl" 15.37 Cl<tot-> 23.05 found: C 54.00 H 5.88 N 5.91 Cl" 15.55 Cl<tot- > 23.13

The total yield of dextrorotatory 2-[2-[4-[( 4-chlorophenyl)-phenylmethyl]-1-piperazinyl]-ethoxy]-acetic acid dihydrochloride, calculated on the amount of levorotatory 1-[(4-chloro-phenyl )-phenylmethyl]-piperazine, is 57.3%.

Example 3

Preparation of levorotatory 2-[2-[4-[(4-chlorophenyl)-phenyl-methyl]-1-piperazinyl]-ethoxy]-acetic acid dihydrochloride of formula I

This compound is obtained according to the method described in Example 2, although it is started with dextrorotatory 1-[(4-chlorophenyl)-phenylmethyl]-piperazine. The latter compound was prepared as described in Example 2.1, by treating the racemate with (2S,3S)-tartaric acid.

The levorotatory acid dihydrochloride of formula I is obtained in a yield and with a purity close to that obtained for the dextrorotatory acid dihydrochloride. The purity was thus 95%, as measured by high performance liquid chromatography, with a chiral stationary phase of ^-AGP (from LKB Company).

Melting point: 198-200°C. Melting point: 220.7°C (DSC) (decomposes on melting).

Claims (3)

1. Process for the production of 2-[2-[4-[(4-chloro-phenyl)-phenylmethyl]-1-piperazinyl]-ethoxy]-acetic acid with the formula: in the levorotatory form, in the dextrorotatory form or in the form of a mixture of the levorotatory and dextrorotatory forms, and its dihydrochloride, characterized in that 1-[(4-chlorophenyl)-phenyl-methyl]-1-piperazine with the formula: in the levorotatory form, in the dextrorotatory form or in the form of a mixture of the levorotatory and the dextrorotatory form, is reacted, in the presence of an acid acceptor, with a 2-haloethoxyacetonitrile of the formula: where X is a halogen atom, and the resulting 2-[2-[4-[(4-chlorophenyl)-phenylmethyl]-1-piperazinyl]-ethoxy]-acetonitrile of the formula: in the levorotatory form, in the dextrorotatory form or in the form of a mixture of the dextrorotatory and left-rotating form, is hydrolyzed in an aqueous, alcoholic or aqueous-alcoholic medium with a base or with an acid, and that the thereby obtained acid of formula I , if necessary, is transferred to its dihydrochloride. 2. Method 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. 3 - 2-[2-[4-[(4-chlorophenyl)-phenylmethyl]-1-piperazinyl]-ethoxy]-acetonitrile with the formula and its dihydrochloride, in the levorotatory or dextrorotatory form or in the form of a mixture of the levorotatory form and the dextrorotatory form.