FI91862B - Process for the preparation of 2- [2- [4 - / (4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] acetic acid and its dihydrochloride - Google Patents

Description

91862 Process for the preparation of 2- [2- [4 - [(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] acetic acid and its dihydrochloride For the preparation of 2- [2- [4 - [(4-chlorophenyl)] The present invention relates to a new process for the preparation of 2- [2- [4 - [(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] -acetic acid ci ~ 0 \ CH - f / \ j - (CH2) 2-O-CH2-COOH (i) <y left or right rotating form or a mixture thereof or its dihydrochloride.

2- [2- [4 - [(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] acetic acid, also known as the generic “I” cetirizine, dihydrochloride, has recently been introduced as a new treatment for allergic syndromes such as chronic and as a medicament for the treatment of acute allergic rhinitis, allergic conjunctivitis, pruritus urticaria, etc.

2 91862

The European patent no. 58,146 describes the synthesis of 2- [2- [4 - [(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] acetic acid and its dihydrochloride. The starting material for this synthesis is 1 - [(4-chlorophenyl) phenylmethyl) piperazine, which is reacted with methyl (2-chloroethoxy) acetate to give methyl 2- [2- [4 - [(4-chlorophenyl) phenylmethyl ] -1-piperazinyl] ethoxy] acetate in 27.8% yield. This methyl ester is then hydrolyzed with an inorganic base (sodium or potassium hydroxide) to give the sodium or potassium salt, which can be easily converted to the free acid and then to cetirizine dihydrochloride.

The main disadvantage of this method is that the yield of 2- [2 - [(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] acetic acid dihydrochloride is only 10.6%, based on the 1 - [(4-chlorophenyl) phenylmethyl] piperazine-number.

According to the present invention, there is provided a novel synthetic process for the preparation of 2- [2 - [(4-chlorophenyl) -phenylmethyl] -1-piperazinyl] -ethoxy] -acetic acid, a mixture thereof, or a dihydrochloride thereof. with better yields.

According to the present invention there is provided a 2- [2 - [(4-chlorophenyl) -phenylmethyl] -1-piperazinyl] -ethoxy] -acetic acid of the formula I CH-N N 1 (CH 2) j -O-CH 2 -COOH (I)

/ W

<y right or left rotating form, a mixture thereof or its dihydrochloride by a process characterized in that the 2- [2- [4 - [(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] acetonitrile of formula II CH-NN - (CH2) 2-O-CH.-CN (I3 :) c / w the dextrorotatory or dextrorotatory form or a mixture thereof is hydrolysed with a base or an aqueous-alcoholic medium and, if desired, the acid of formula I thus obtained is converted into its dihydrochloride.

! The 2- [2- [4 - [(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] acetonitrile of formula II used as a starting material is a novel compound which can be easily obtained by reacting 1 - [(4-chlorophenyl) phenylmethyl] of formula III. ] -piperazine to react with a 2-haloethoxyacetonitrile of formula IV according to the following scheme: 4 91862 “Οχ π CH-N NH X- (CH2) 2-O-CH2-CN> n / w Y _ // (III) (IV ) ciO \ ^

CH-N N- (CH2) 2-O-CH2-CN

O7 w where X is a halogen atom.

This reaction is carried out in the presence of an acid acceptor such as an alkali metal carbonate and in the presence of a small amount of time metal iodide to accelerate the reaction in an inert organic solvent such as an alcohol (e.g. n-butanol, etc.), preferably at a temperature close to reflux.

When optically active 1 - [(4-chlorophenyl) phenylmethyl] piperazine of formula III is used in this reaction instead of a racemate, the starting enantiomer can be obtained by resolution of the corresponding racemic compound by methods known per se.

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Of the optically active acids that can be used in this separation, tartaric acid is preferably used.

As for the 2-haloethoxyacetonitriles of formula IV, and in particular 2-chloroethoxyacetonitrile, these products can be prepared by E.J. SALMEN et al. by the method described, Suomen Kemistilehti, 17B (19441.17-19 (Chem.

Abstr. 40. (1946). 6491).

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] formula of formula II. 1-piperazinyl] ethoxy] -acetonitrile according to the following scheme: <k \ / \ ca-N n- (ch2) 2-o-ch2-cn-> cd q /

(ID

This hydrolysis can be performed in two ways, one in the base medium and the other in the acid medium.

1. Hydrolytic nitrile in basic medium

The nitrile of formula II is heated in the presence of an inorganic base such as an early 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.

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The acid of formula I formed is present in the reaction mixture as its alkali metal salt, from which the acid is liberated by acidifying the reaction mixture with an inorganic acid (such as hydrochloric acid). The acid of formula I is then extracted with an organic solvent (dichloromethane, toluene, etc.) and isolated by crystallization.

a

Finally, the acid of formula I is converted into its dihydrochloride by a method known per se.

2. Hydrolysis of nitrile in acid 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 acid of formula I formed 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 converted to the dihydrochloride by a method known per se.

This new synthetic method yields cetirizine dihydrochloride in yields of 60% or more by acid hydrolysis and 65% or more by base hydrolysis, based on the amount of 1 - [(4-chlorophenyl) phenylmethyl] piperazine used. In addition, optically active compounds of this compound can be obtained by this method in very high yields. These higher yields starting from 1 - [(4-chlorophenyl) phenyl] methyl] piperazine are a significant technical advantage over the process described in European Patent No. 58,146.

The following examples are provided to illustrate the invention.

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Example 1. Preparation of racemic 7- [2- [4] - [4-chlorophenyl] -n-phenylmethyl] -1-piperazinylethyloxyacetic acid dihydrochloride of formula I.

1 · Racemic 2-Γ2-Γ4-Γ (4-chlorophenyl) phenylmethyl 1-piperazinyl of formula II 1- [1]: acetonitrile.

200 ml of n-butanol, 43.05 g (0.15 mol) of racemic 1 - [(4-chlorophenyl) phenylmethyl] piperazine, 24 g (0.174 mol) of 2-chloroethoxyacetonitrile, 26.1 g (0.246 mol) of sodium carbonate and 0.78 g (0.0047 mol) of potassium iodide is added successively to a three-necked round-bottomed flask equipped with a mechanical stirrer, condenser and thermometer. The mixture is heated at 110 ° C for 11 hours with stirring, cooled, filtered and concentrated on a rotary evaporator. Isolate 60 g of a tan oil and chromatograph on a column containing 1 kg of silica, using a mixture of 98% by volume of dichloromethane and 2% of 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] -1-piperazinyl] ethoxy] acetonitrile is thus obtained in two fractions, one of which, 33.6 g, is 100% pure and the other, 14.4 g, is 97.4% pure. .

Yield: 86.4% The product thus obtained can be characterized as its dihydrochloridine prepared from an ethanolic solution of gaseous hydrochloric acid.

M.p .: 201-202 ° C.

Analysis for C21H24ClN3O.2HCl as% calculated: C 56.96 H 5.91 N 9.48 Cl '16.01 Cltot. 24.02 91862 2. Racemic 2-Γ2-Γ4-Γ (4-chlorophenyl-1-methyl-1-piperazinyl) ethoxy 1-acetic acid (by hydrolysis in a basic medium) 250 ml of ethanol, 23 g (0.062 mol) of racemic 2- [2 - [4 - [(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] acetonitrile and 31 ml of 4N ethanolic potassium hydroxide solution

• I

is added successively to a three-necked round-bottomed flask equipped with a mechanical stirrer, condenser and thermometer. The reaction mixture is refluxed for 10 hours with stirring. The reaction mixture is allowed to cool and its pH is adjusted to 6 by adding 37% concentrated hydrochloric acid. The ethanol is evaporated off 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 concentrated on a rotary evaporator. The oil obtained is allowed to crystallize by adding 100 ml of 2-butanone while still hot. The solid formed is filtered, washed and dried.

18.9 g of racemic 2- [2- [4 - [(4-chlorophenyl) phenylmethyl] -1-piperazinylethoxy] acetic acid are thus obtained.

18.9 g of the acid thus obtained are resuspended in 150 ml of water: the pH is adjusted to 0.8 by adding concentrated hydrochloric acid. The aqueous solution is evaporated on a rotary evaporator and then the residue is diluted by adding 75 ml of 2-butanone and reconcentrated. Racemic 2- [2- [4 - [(4-chlorophenyl) phenyl] methyl] -1-piperazinyl] ethoxy] acetic acid dihydrochloride is crystallized by adding 150 ml of n-butanone to the residue thus obtained. The crystals are filtered off and dried to give 2.17 g of product.

Yield: 75.9%. M.p .: 220.15 ° C (Differential Scanning

Calorimetry: DSC) (decomposes on melting) 9 91862

Analysis for C21H25ClN2O3.2HCl

Calcd: C 54.56 H 5.84 N 6.06 Cl "15.37 Cl 2 Ot. 23.05 Found: C 54.60 H 5.86 N 6.02 Cl" 15.33 Cltot. 23.26 The total yield of 2- [2- [4 - [(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] acetic acid dihydrochloride, based on the amount of 1 - [(4-chlorophenyl) phenylmethyl] piperazine used, is 65.6%.

3. Racemic 2- [2- [4- (4-chlorophenyl) phenyl] methyl] -1-piperazinyl] ethoxy 1 -acetic acid (by hydrolysis in acid medium) 45.3 g (0.123 mol) of racemic 2- [2 - [4 - [(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] acetonitrile is added to a reactor equipped with a mechanical stirrer, condenser, thermometer and dropping funnel and heated to 45 ° C with stirring. Then 41 ml of 37% concentrated hydrochloric acid are added dropwise. The temperature of the reaction mixture rises to 92 ° C and the reaction mixture is heated at 95 ° C for 90 minutes with stirring. The reaction mixture is allowed to cool and concentrated on a rotary evaporator, the residue is taken up in 150 ml of toluene and the reaction mixture is reconcentrated on a rotary evaporator. The residue is dissolved in 200 ml of water and the aqueous solution obtained 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 on a rotary evaporator. The oil thus obtained is allowed to crystallize by dispersing it while still hot 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 thus isolated. 34 g of the acid thus obtained are resuspended in 300 ml of water: the pH is adjusted to 0.8 by adding concentrated hydrochloric acid. The aqueous solution is concentrated on a rotary evaporator, then the residue is diluted with 150 ml of 2-butanone and the mixture is reconcentrated. When 300 ml of 2-butanone is added to the residue thus obtained, racemic 2- [2- [4 - [(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] acetic acid dihydrochloride is crystallized. The crystals are filtered off and dried to give 39.7 g of product.

Yield: 70%. M.p .: 227.02 ° C (DSC) (decomposes on melting)

Analysis for C21H25ClN2O3.2HCl as%

Calculated: C 54.56 H 5.84 N 6.06 Cl "15.37 23.05 Found: C 54.30 H 5.88 N 6.83 Cl" 15.56 Cltot · 23.06 2- [ The total yield of 2- [4 - [(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] acetic acid dihydrochloride, based on the amount of 1 - [(4-chlorophenyl) phenylmethyl] piperazine used, is 60.5%.

Example 2. Preparation of dextrorotatory 2- (-2-Γ4-ΓΜ-chlorophenyl) phenylmethyl-1-pioerazinyl-acetic acid dihydrochloride.

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

A solution of 300 g (2 mol) of (2R, 3R) -tartaric acid in 2 liters of ethanol is heated at 72-74 ° C and a solution containing 286.5 g (1 mol) of racemic 1 - [(4 mol) -chlorophenyl) phenylmethyl] -piperazine in 1 liter of ethanol. The mixture is refluxed for 5 minutes and then allowed to return to room temperature with stirring (the desired salt begins to crystallize near 57 ° C). The salt thus obtained is filtered off and recrystallized three times in succession, first in a mixture of 2 l of ethanol and 0.8 l of methanol, then in 1 liter of ethanol and finally in a mixture of 11 91862 containing 0.5 l of ethanol, 65 ml of methanol and 5 ml of water. After filtration and drying, 118 g of diastereoisomerically impure 1 - [(4-chlorophenyl) phenyl] methyl] piperazine (2R, 3R) -tartrate are obtained. M.p .: 170.4 ° C (DSC). [α] 25 D: + 7.8 ° (c = 1, methanol).

This salt is then decomposed by adding a solution of 22 g (0.55 mol) of sodium hydroxide in 750 ml of water. The levorotatory 1 - [(- 4-chlorophenyl) phenylmethyl] piperazine thus released is extracted several times with dichloromethane. the combined organic phases are dried over sodium sulfate, filtered and concentrated on a rotary evaporator. 80 g of optically impure levorotatory 1 - [(4-chlorophenyl) phenylmethyl] piperazine are obtained: This product is purified by successive recrystallization from hexane to finally give 18.2 g of levorotatory 1 - [(4-chlorophenyl) phenyl] methyl]. ] piperazine.

M.p .: 90-92 ° C. . M.p .: 90.35 <> C (DSC) [o] 2Sd; -19.4 ° (c = 1, toluene).

Yield: 12.7% 2. Left-turning 2-Γ2-Γ4-Γ (4-chlorophenyl) -phenylmethyl-1-pinerazinyl-1-ethoxy-1-acetonitrile of formula II. 1100 ml of n-butanol, 20 g (0.07 mol) of levorotatory Ι Ε (4-chlorophenyl) phenylmethyl] piperazine, 11.2 g (0.0937 mol) of 2-chloroethoxyacetonitrile, 12 18 g (0.115 mol) of sodium carbonate and 0.36 g (0.002 mol) of potassium iodide are added successively to 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 with stirring and then cooled, filtered and concentrated on a rotary evaporator. 26 g of a tan oil are isolated and chromatographed on a column of 1 kg of silica using a mixture of 98% by volume of 12,91862 dichloromethane and 2% methanol. 17.8 g of levorotatory 2- [2- [4 - [(4-chlorophenyl) phenylmethyl] -1-piperazinyl ethoxy] acetonitrile are obtained in the form of an oil.

[A] 25 365 '. -31.8® (c = 1, methanol). Yield: 69%.

The product can be characterized as its dihydrochloridine prepared from an ethanolic solution of gaseous hydrochloric acid.

M.p .: 211-2i2 ° C [α] 2536 s: + 7.18 ° (c = 1, methanol)

Analysis for C21H24ClN3O.2HCl as%

Calc .: C 56.96 H 5.91 N 9.49 Cl ~ 16.01 Clt ° t. 24.02 Found: C 56.92 H 5.93 N 9.33 Cl- 15.76 Cl1®1 · 23.65 3. The dextrorotatory 2-Γ2-Γ4-Γ (4-chlorophenyl) -phenylmethyl1- 1-piperatsinvvli1-etoksi1-acetic acid dihydrochloride.

9.2 g (0.0255 mol) of levorotatory 2- [2- [4 - [(4-chlorophenyl) phenyl] methyl] -1-piperazinyl] ethoxy] acetonitrile are charged to a reactor equipped with a mechanical stirrer, condenser, thermometer and dropping funnel. , and heated to 45 ° C with stirring.

15 ml of 37% 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 6C minutes with stirring. The reaction mixture

allow to cool, concentrate on a rotary evaporator and take up the residue in 50 ml of water. The pH of the reaction mixture is adjusted to 5 by adding sodium hydroxide and the mixture is extracted several times successively with dichloromethane fractions. The organic phases are combined, dried over magnesium sulphate and the solvent is removed on a rotary evaporator. This gives 9.6 g of the free formula I

the acid as a beige powder which is converted into the dihydrochloride with 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] -1H-piperazinyl] ethoxy] -acetic acid dihydrochloride are obtained. 95% as measured by high performance liquid chromatography with a chiral stationary phase of α1-AGP (1K3 Company).

M.p .: 199-201 ° C M.p .: 224.4 ° C (DSC). [α] 25 365: + 9.4® (c = 1, water) Yield: 83%

Analysis calculated for C 21 H 25 ClN 2 O 3 .2HCl: C 54.56 H 5.84 N 6.06 Cl "15.37 Cltot. 23.05 Found: C 54.00 H 5.88 N 5.91 Cl" 15, 55 Cltot. 23.13

The total yield of dextrorotatory 2- [2- [4 - [(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] acetic acid dihydrochloride is 57.3% based on the amount of dextrorotatory 1- [4-chlorophenylphenylmethyl] piperazine used.

Example 3. Preparation of levorotatory 2--2-Γ4-Γ (4-chlorophenyl) phenylmethyl-1-piperazinylmethoxy 1-acetic acid dihydrochloride of formula I.

This product is obtained by the method described in Example 2, but starting from the dextrorotatory 1 - [(4-chlorophenyl) phenyl]. style] -piperazine obtained according to Example 2.1 by treating the racemate (2S, 3S) -tartaric acid.

The dextrorotatory acid dihydrochloride of formula I is obtained in yields and purities very close to the values obtained for dextrorotatory acid dihydrochloride11e:: 95% measured by high performance liquid chromatography with a chiral stationary phase of al-AGP (LKB Company).

M.p .: 198-200 ° C M.p .: 220.7 (DSC) (decomposes on melting).

Claims (2)

91862 A process for the preparation of 2- [2- [4 - [(4-chloro-phenyl) -phenylmethyl] -1-piperazinyl] -ethoxy] -acetic acid of the formula I-CH-N N - (CH2) -O-CH -C00H (U <yw the levorotatory form or a mixture thereof or a dihydrochloride thereof, characterized in that 2- [2- [4 - [(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy of formula II] - the right- or left-turning form of acetonitrile CH-N N - (CHjJj-O-CHj-CN (II) <yw or a mixture thereof is hydrolysed with a base or an acid in an aqueous, alcoholic or aqueous-alcoholic medium and, if desired, the acid of formula I thus obtained is converted to a dihydro -kloridikseen. 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. Il 91862 3. 2- [2- [4 - [(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] acetonitrile of formula II X / Λ CH-n N - (CH 2 -O-CH 2 -CN ( II) <yw and its dihydrochloride in dextrorotatory or dextrorotatory form or as a mixture of levorotatory and dextrorotatory forms.