CA1320732C - Process for the preparation of 2-¬2-¬4-¬(4-chlorophenyl)-phenylmethyl|-1-piperazinyl| ethyoxy|-acetic acid and its dihydrochloride - Google Patents
Process for the preparation of 2-¬2-¬4-¬(4-chlorophenyl)-phenylmethyl|-1-piperazinyl| ethyoxy|-acetic acid and its dihydrochlorideInfo
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- CA1320732C CA1320732C CA000614708A CA614708A CA1320732C CA 1320732 C CA1320732 C CA 1320732C CA 000614708 A CA000614708 A CA 000614708A CA 614708 A CA614708 A CA 614708A CA 1320732 C CA1320732 C CA 1320732C
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- Canada
- Prior art keywords
- chlorophenyl
- alkali metal
- phenylmethyl
- piperazinyl
- reaction
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
-
- 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
Abstract
A B S T R A C T
A process for the preparation of 2-[2-[4[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]-acetic acid and its dihydrochloride, wherein 2-[4-[(4-chlorophenyl-phenylmethyl]-1-piperazinyl]-ethanol is reacted with an alkali metal halogenoacetate in the presence of an alkali metal alcoholate, the alkali metal salt thus obtained is converted into the corresponding acid and, if appropriate, into its dihydrochloride.
A process for the preparation of 2-[2-[4[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]-acetic acid and its dihydrochloride, wherein 2-[4-[(4-chlorophenyl-phenylmethyl]-1-piperazinyl]-ethanol is reacted with an alkali metal halogenoacetate in the presence of an alkali metal alcoholate, the alkali metal salt thus obtained is converted into the corresponding acid and, if appropriate, into its dihydrochloride.
Description
16 39(2) ~ 3 (~ ~ rj ~ ~
A process for the pre~aration of 2-~2-~4--~(4-chlorophenyl)phenylmethyll-l-piperazinyl]ethoxyl-acetic acid and lts dihy~_ochloride.
The present invention relates to a new process for the preparation of 2-[2-[4-[(4-chlorophenyl)phenylmethyl3-1-piperazinyl]ethoxy]-acetic acid and its dihydrochloride.
The dihydrochloride of 2-[2--[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]-acetic acid also known by the generic name of cetirizine, has recently been introduced as a new medicament for the treatment of allergic syndromes, such as chronic and acute allergic rhinitis, allergic conjunctivitis, pruritus, urticaria etc. When used in therapy, this product has proved to be remarkably free from side effects on the central nervous system, such as drowsiness, reduced mentai performance etc.(c.f. D.P.TASHKIN et al., Annals of Allergy, Part II, 59, (1987),49-52, and F.M. GENG0 et al., Annals of Allergy, Part II, 59, t1987),53_57).
European Patent No.58,146 in the name of the Applicant describes the 15 synthesis of 2-[2-[4-[(4-chlorophenyl)phenylmethyl~-1-piperazinyl]ethoxy]-acetic acid and its dihydrochloride. In this synthesis, the starting substance is l-[(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 a yield of 27.8Z. This methyl ester is then subjected to hydrolysis with an inorganic base (potassium or sodium hydro~ide) 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 25 of 2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]-acetic acid dihydrochloride is only 10.6%, based on the amount of 1-[(4-chlorophenyl)phenylmethyl]-piperazine employed.
According to the present invention, a new process for the synthesis is provided, which enables 2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxyj-acetic acid and its dihydrochloride to be prepared with better yields.
According to the present invention, 2-[2-[4-[(4-chlorophenyl) ' '~ ''' ~
.~
~3~3~
phenylmethy~ -piperazinyl~ethoxy]-acetic acid and its dihydrochloride are prepared by a process wherein an alkali metal alcoholate and an alkali metal haloacetate are alternately and repeatedly added to a reaction medium comprising 2-[4~[~4-chlorophenyl)phenylmethyl]-1-piperazinyl]-ethanol, so that the latter reacts with the alkali metal haloacetate, in the presence of the alkali metal alcoholate, to form an alkali metal salt o~ the subject acid and said alkali metal salt is converted either into the subject acid or into its dihydrochloride.
The 2-[4-[(4-chlorophenyl)phenylmethyl-1-piperazinyl)-ethanol used as the starting substance in the process oE the invention is a product which is known per se. Its synthesis by reaction of 1-piperazineethanol with (4-chlorophenyl)phenylmethyl chloride has already been described in U.S. Patent No.2,899,436. This product can also be prepared in a higher yield (9OZ) by reaction of 1-[~4-chlorophenyl)phenylmethyl~-piperazine with a 2-haloethanol in the presence of an acid acceptor, such as an inorganic base (for example sodium or potassium carbonate) or a tertiary organic base (for example triethylamine), in an inert solvent, such as toluene, xylene or another aromatic solvent.
In accordance with the invention, 2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]-acetic acid is obtained by reaction of 2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]-ethanol and an alkali metal haloacetate, such as sodium chloroacetate. This reaction is generally carried out by heating at between 60 and 100C for several hours in the presence of an alkali metal alcoholate, such as, for example, potassium tert-butoxide, and in an organic solvent, preferably an aliphatic alcohol of low reactivity, such as, for example, tert-butanol.
To achieve optimum yields, its is advisable to use potassium tert-butoxide and tert-butanol and to resupply the reaction medium regularly with the two reactants (alkali metal alcoholate and alkali metal haloacetate) in smaller and smaller amounts and-at regular intervals until the reaction is as complete as possible.
By way of example, each reactant can be added to the reaction mixture every half hour for a total duration of four hours. Each of the total molar amounts of alcoholate and haloacetate used is advantageously 25 to 75~ higher than the molar amount oE the starting 2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]-ethanol.
For reasons of economy, it is of interest to recover and recycle the starting alcohol. To this effect, the solvent is removed from the reaction medium, the latter is taken up in acidified water (to bring the pH to a weakly basic value) and ~he starting alcohol is extracted with diethyl ether. The 2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]-acetic acid which is formed in the course of the 7 ~ .~
reaction i9 present in the reaction mixture ln the form oE an alkali metal salt. After the reaction mixture is acidiEied to pH 5 by addition of an inorganic acid (such as hydrochloric acid), the corresponding acid can be recovered from the reaction mixture by extraction by means of an organic solvent (dichloromethane, toluene etc.). The desired acid can also be isolated in the form of well-crystallized salts. This acid can be converted into the corresponding dihydrochloride of the acid by a conventional process.
This new synthesis process gives yields of 44% or more of cetirizine dihydrochloride, calculated on the basis of the 1-[(4-chlorophenyl)phenylmethyl]-l-piperazine employed. With recycling of the 2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]-ethanol in the reaction, the overall yield can even reach values close to 50~. This higher yield starting from 1-[(4-chlorophenyl)phenylmethyl]-1-piperazine constitutes a considerable technical advance with respect to the process described in European Patent No.58,146.
The following example is given fo} the purpose of illustrating the invention.
Example. Preparation of 2-~Z- r 4-~(4-chlorophenyl)~henYlme_hyl~
piperazinyll hoxyl-acetic acid.
1. 2-~4-~4-chlorophenyl)~henylmethyll-1-piperaæinyll-ethanol.
325 ml of dry toluene, 131.2 g (0.458 mole) of 1-[(4-chlorophenyl)phenylmethyl]-piperazine and 125 ml (0.9 mole) of triethylamine are introduced successively into a three-necked round-bottomed flask of 2 litres capacity equipped with a mechanical stirrer, a condenser and a -thermometer. 41.5 g (0.516 mole) of 2-chloroethanol are added to this solution and the mixture is brought to the reflux temperature, while stirring. After heating for six hours, a further 20 g (0.248 mole~ of 2-chloroethanol are added and reflux is maintained for an additional six hours.
The reaction mixture is cooled and filtered and the filtrate is concentrated under a vacuum on a rotary evaporator. 146.5 g of 2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]-ethanol are thus isolated in the form of a yellow oil in a yield of 96.8%.
50 g of the alcohol obtained are distilled at 220C under reduced pressure (0.0065 mbar) and collected in two separate fractions.
The purity of each fraction is measured by high pressure liquid chromatography. One fractlon of 24.5 g has a purity of 96.6%, ~ s~
whereas the other fraction (of 22.2 g) has a purity of 99.6~. A
yield of pure product of 90.4% is thus obtained.
The alcohol thus obtained can be characterized in the form of its dihydrochloride prepared from an ethanolic solution of gaseous hydrochloric acid.
M.P.: 222C
Analysis for Cl9H23ClN2 ZHCl in %
calc : C 56.50 H 6.19 N 6.94 Cl 17.59 Cl 26.39 found: C 56.63 H 6.28 N 6.86 Cl 17.48 Cl 26.32 2. 2-~2-~4-~(4-chlorophenyl)phenylmethyll-1-piperazinyllethoxyl-acetic acid.
50 g (0.15 mole) of 2-~4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]-ethanol and 225 ml of tert-butanol are introduced into a three-necked round bottomed flask equipped with a mechanical stirrer, a thermometer, a nitrogen inlet and a condenser. The mixture is stirred gently and heated to 45C under a nitrogen atmosphere, and 21 g of potassium tert-butoxide are added. The temperature is raised to 75-80C and the mixture is kept at this temperature. ll g of sodium chloroacetate are then added to the mixture, taking the time of this addition as time zero. Sodium chloroacetate and potassium tert-butoxide are introduced successively into the reaction mixture, the temperature being kept at 75-80C and while stirring under a nitrogen atmosphere, in the following manner: after 45 minutes 11 g of sodium chloroacetate are added after 1 hour and a half 5.2 g of potassium tert-butoxide are added; after 2 hours 5.64 g of sodium chloroacetate are added;
after 2 and a half hours 1.9 g of potassium tert-butoxide are added;
after 3 hours 1.9 g of sodium chloroacetate are added; after 3 and a half hours 0.8 g of potassium tert-bu-~oxide is added; after 4 hours the operation is ended by addition of 1.13 g of sodium chloroacetate. A total of 28.92 g (0.25 mole) of potassium tert-butoxide (97%) and 30.65 g (0.25 mole) of sodium chloroacetate (95%) has thus been added. The reactor is then converted into a distillation apparatus and about 150 ml of tert-butanol are distilled off; 190 ml of water are then added to the reaction mixture and the distillation of tert-butanol in the form of an azeotrope with water is continued until the temperature of the vapours reac:hes 100C.
~ 32~'~3~
The reaction mixture is cooled, diluted with 60 ml of water and brought to pH 8 by addition of about 8 ml concentrated hydrochloric acid. The starting 2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]-ethanol which has not reacted is then carefully extracted with diethyl ether, which enables 7.3 g to be recovered after evaporation of the solvent.
The aqueous phase, which contains the sodium salt of the desired acid, is acidified to pH 5 by addition of hydrochloric acid and extracted three times with 200 ml of dichloromethane. The organic phases of the extraction are comb:ined and dried over magnesium sulphate, filtered and concentrated in a rotary evaporator. An oil is obtained and is allowed to crystallize by addition of 150 ml of 2-butanone, while hot. The solid formed is filtered off and dried.
32.7 g of 2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]-acid are thus isolated.
Yield: 55.5%. M.P.:146-148C.
Y 21 25 lN2O3 in %
calc.: C 64.86 H 6.48 N 7.20 Cl 9.12 found: C 64.67 H 6.46 N 7.19 Cl 9.39 A second crop of product can be obtained by concentration of the mother liquors (7.4 g).
A process for the pre~aration of 2-~2-~4--~(4-chlorophenyl)phenylmethyll-l-piperazinyl]ethoxyl-acetic acid and lts dihy~_ochloride.
The present invention relates to a new process for the preparation of 2-[2-[4-[(4-chlorophenyl)phenylmethyl3-1-piperazinyl]ethoxy]-acetic acid and its dihydrochloride.
The dihydrochloride of 2-[2--[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]-acetic acid also known by the generic name of cetirizine, has recently been introduced as a new medicament for the treatment of allergic syndromes, such as chronic and acute allergic rhinitis, allergic conjunctivitis, pruritus, urticaria etc. When used in therapy, this product has proved to be remarkably free from side effects on the central nervous system, such as drowsiness, reduced mentai performance etc.(c.f. D.P.TASHKIN et al., Annals of Allergy, Part II, 59, (1987),49-52, and F.M. GENG0 et al., Annals of Allergy, Part II, 59, t1987),53_57).
European Patent No.58,146 in the name of the Applicant describes the 15 synthesis of 2-[2-[4-[(4-chlorophenyl)phenylmethyl~-1-piperazinyl]ethoxy]-acetic acid and its dihydrochloride. In this synthesis, the starting substance is l-[(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 a yield of 27.8Z. This methyl ester is then subjected to hydrolysis with an inorganic base (potassium or sodium hydro~ide) 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 25 of 2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]-acetic acid dihydrochloride is only 10.6%, based on the amount of 1-[(4-chlorophenyl)phenylmethyl]-piperazine employed.
According to the present invention, a new process for the synthesis is provided, which enables 2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxyj-acetic acid and its dihydrochloride to be prepared with better yields.
According to the present invention, 2-[2-[4-[(4-chlorophenyl) ' '~ ''' ~
.~
~3~3~
phenylmethy~ -piperazinyl~ethoxy]-acetic acid and its dihydrochloride are prepared by a process wherein an alkali metal alcoholate and an alkali metal haloacetate are alternately and repeatedly added to a reaction medium comprising 2-[4~[~4-chlorophenyl)phenylmethyl]-1-piperazinyl]-ethanol, so that the latter reacts with the alkali metal haloacetate, in the presence of the alkali metal alcoholate, to form an alkali metal salt o~ the subject acid and said alkali metal salt is converted either into the subject acid or into its dihydrochloride.
The 2-[4-[(4-chlorophenyl)phenylmethyl-1-piperazinyl)-ethanol used as the starting substance in the process oE the invention is a product which is known per se. Its synthesis by reaction of 1-piperazineethanol with (4-chlorophenyl)phenylmethyl chloride has already been described in U.S. Patent No.2,899,436. This product can also be prepared in a higher yield (9OZ) by reaction of 1-[~4-chlorophenyl)phenylmethyl~-piperazine with a 2-haloethanol in the presence of an acid acceptor, such as an inorganic base (for example sodium or potassium carbonate) or a tertiary organic base (for example triethylamine), in an inert solvent, such as toluene, xylene or another aromatic solvent.
In accordance with the invention, 2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]-acetic acid is obtained by reaction of 2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]-ethanol and an alkali metal haloacetate, such as sodium chloroacetate. This reaction is generally carried out by heating at between 60 and 100C for several hours in the presence of an alkali metal alcoholate, such as, for example, potassium tert-butoxide, and in an organic solvent, preferably an aliphatic alcohol of low reactivity, such as, for example, tert-butanol.
To achieve optimum yields, its is advisable to use potassium tert-butoxide and tert-butanol and to resupply the reaction medium regularly with the two reactants (alkali metal alcoholate and alkali metal haloacetate) in smaller and smaller amounts and-at regular intervals until the reaction is as complete as possible.
By way of example, each reactant can be added to the reaction mixture every half hour for a total duration of four hours. Each of the total molar amounts of alcoholate and haloacetate used is advantageously 25 to 75~ higher than the molar amount oE the starting 2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]-ethanol.
For reasons of economy, it is of interest to recover and recycle the starting alcohol. To this effect, the solvent is removed from the reaction medium, the latter is taken up in acidified water (to bring the pH to a weakly basic value) and ~he starting alcohol is extracted with diethyl ether. The 2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]-acetic acid which is formed in the course of the 7 ~ .~
reaction i9 present in the reaction mixture ln the form oE an alkali metal salt. After the reaction mixture is acidiEied to pH 5 by addition of an inorganic acid (such as hydrochloric acid), the corresponding acid can be recovered from the reaction mixture by extraction by means of an organic solvent (dichloromethane, toluene etc.). The desired acid can also be isolated in the form of well-crystallized salts. This acid can be converted into the corresponding dihydrochloride of the acid by a conventional process.
This new synthesis process gives yields of 44% or more of cetirizine dihydrochloride, calculated on the basis of the 1-[(4-chlorophenyl)phenylmethyl]-l-piperazine employed. With recycling of the 2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]-ethanol in the reaction, the overall yield can even reach values close to 50~. This higher yield starting from 1-[(4-chlorophenyl)phenylmethyl]-1-piperazine constitutes a considerable technical advance with respect to the process described in European Patent No.58,146.
The following example is given fo} the purpose of illustrating the invention.
Example. Preparation of 2-~Z- r 4-~(4-chlorophenyl)~henYlme_hyl~
piperazinyll hoxyl-acetic acid.
1. 2-~4-~4-chlorophenyl)~henylmethyll-1-piperaæinyll-ethanol.
325 ml of dry toluene, 131.2 g (0.458 mole) of 1-[(4-chlorophenyl)phenylmethyl]-piperazine and 125 ml (0.9 mole) of triethylamine are introduced successively into a three-necked round-bottomed flask of 2 litres capacity equipped with a mechanical stirrer, a condenser and a -thermometer. 41.5 g (0.516 mole) of 2-chloroethanol are added to this solution and the mixture is brought to the reflux temperature, while stirring. After heating for six hours, a further 20 g (0.248 mole~ of 2-chloroethanol are added and reflux is maintained for an additional six hours.
The reaction mixture is cooled and filtered and the filtrate is concentrated under a vacuum on a rotary evaporator. 146.5 g of 2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]-ethanol are thus isolated in the form of a yellow oil in a yield of 96.8%.
50 g of the alcohol obtained are distilled at 220C under reduced pressure (0.0065 mbar) and collected in two separate fractions.
The purity of each fraction is measured by high pressure liquid chromatography. One fractlon of 24.5 g has a purity of 96.6%, ~ s~
whereas the other fraction (of 22.2 g) has a purity of 99.6~. A
yield of pure product of 90.4% is thus obtained.
The alcohol thus obtained can be characterized in the form of its dihydrochloride prepared from an ethanolic solution of gaseous hydrochloric acid.
M.P.: 222C
Analysis for Cl9H23ClN2 ZHCl in %
calc : C 56.50 H 6.19 N 6.94 Cl 17.59 Cl 26.39 found: C 56.63 H 6.28 N 6.86 Cl 17.48 Cl 26.32 2. 2-~2-~4-~(4-chlorophenyl)phenylmethyll-1-piperazinyllethoxyl-acetic acid.
50 g (0.15 mole) of 2-~4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]-ethanol and 225 ml of tert-butanol are introduced into a three-necked round bottomed flask equipped with a mechanical stirrer, a thermometer, a nitrogen inlet and a condenser. The mixture is stirred gently and heated to 45C under a nitrogen atmosphere, and 21 g of potassium tert-butoxide are added. The temperature is raised to 75-80C and the mixture is kept at this temperature. ll g of sodium chloroacetate are then added to the mixture, taking the time of this addition as time zero. Sodium chloroacetate and potassium tert-butoxide are introduced successively into the reaction mixture, the temperature being kept at 75-80C and while stirring under a nitrogen atmosphere, in the following manner: after 45 minutes 11 g of sodium chloroacetate are added after 1 hour and a half 5.2 g of potassium tert-butoxide are added; after 2 hours 5.64 g of sodium chloroacetate are added;
after 2 and a half hours 1.9 g of potassium tert-butoxide are added;
after 3 hours 1.9 g of sodium chloroacetate are added; after 3 and a half hours 0.8 g of potassium tert-bu-~oxide is added; after 4 hours the operation is ended by addition of 1.13 g of sodium chloroacetate. A total of 28.92 g (0.25 mole) of potassium tert-butoxide (97%) and 30.65 g (0.25 mole) of sodium chloroacetate (95%) has thus been added. The reactor is then converted into a distillation apparatus and about 150 ml of tert-butanol are distilled off; 190 ml of water are then added to the reaction mixture and the distillation of tert-butanol in the form of an azeotrope with water is continued until the temperature of the vapours reac:hes 100C.
~ 32~'~3~
The reaction mixture is cooled, diluted with 60 ml of water and brought to pH 8 by addition of about 8 ml concentrated hydrochloric acid. The starting 2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]-ethanol which has not reacted is then carefully extracted with diethyl ether, which enables 7.3 g to be recovered after evaporation of the solvent.
The aqueous phase, which contains the sodium salt of the desired acid, is acidified to pH 5 by addition of hydrochloric acid and extracted three times with 200 ml of dichloromethane. The organic phases of the extraction are comb:ined and dried over magnesium sulphate, filtered and concentrated in a rotary evaporator. An oil is obtained and is allowed to crystallize by addition of 150 ml of 2-butanone, while hot. The solid formed is filtered off and dried.
32.7 g of 2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]-acid are thus isolated.
Yield: 55.5%. M.P.:146-148C.
Y 21 25 lN2O3 in %
calc.: C 64.86 H 6.48 N 7.20 Cl 9.12 found: C 64.67 H 6.46 N 7.19 Cl 9.39 A second crop of product can be obtained by concentration of the mother liquors (7.4 g).
3. 2-r2-~4-~(4-chlorophenyl)phenylmethyll-1-piperazinyllethoxyl-acetic acid dihydrochloride.
32.7 g of 2-[2-[4-[(4-chlorophenyl)phenylmethylJ-l-piperazinyl]ethoxy]-acetic acid are suspended in a mixture of 125 ml of water and 13.8 ml of 37% aqueous hydrochloric acid. This mixture is concentrated on a rotary evaporator. An oil is obtained and is crystallized by addition of 245 ml of 2-butanone. The crystals formed are filtered off, drained and dried. 34.2 g of 2-[2-[4-[(4-chlorophenyl)phenylmethyl]-l-piperazinyl]ethoxy]-acetic acid dihydrochloride are obtained.
Yield: 88%. M.P.: 228.22C (Differential Scanning Calorimetry, DSC) Y 21 25 2 3.2HCl in %
calc.: C 54.56 H 5.84 N 6.06 Cl 15.37 Cl 23.05 found: C 54.28 H 5.86 N 6.15 Cl 15.24 Cl 23.22 A second crop of dihydrochloride can be obtained in the same way starting from the second crop of product obtained above under point 2 (4.5 g).
Taking into account the fact that the 2-[4-[(4-chlorophenyl)phenylmethyl]-l-piperazinyl]-ethanol ls obtained in a yield of 90.4Z from l-[(4-chlorophenyl)phenylmethyl]-piperazine, the 2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyllethoxy]-acetic acid dihydrochloride is thus obtained in three steps in an overall yield of 44.1~ (or more than 48~ if possible recycling of 2-[4-[(4-chlorophenyl)phenylmethyl]-l-piperazinyl]-ethanol which has not reacted is taken into account), which constitutes a marked improvement with respect to the process according to European Patent No. 58,146.
32.7 g of 2-[2-[4-[(4-chlorophenyl)phenylmethylJ-l-piperazinyl]ethoxy]-acetic acid are suspended in a mixture of 125 ml of water and 13.8 ml of 37% aqueous hydrochloric acid. This mixture is concentrated on a rotary evaporator. An oil is obtained and is crystallized by addition of 245 ml of 2-butanone. The crystals formed are filtered off, drained and dried. 34.2 g of 2-[2-[4-[(4-chlorophenyl)phenylmethyl]-l-piperazinyl]ethoxy]-acetic acid dihydrochloride are obtained.
Yield: 88%. M.P.: 228.22C (Differential Scanning Calorimetry, DSC) Y 21 25 2 3.2HCl in %
calc.: C 54.56 H 5.84 N 6.06 Cl 15.37 Cl 23.05 found: C 54.28 H 5.86 N 6.15 Cl 15.24 Cl 23.22 A second crop of dihydrochloride can be obtained in the same way starting from the second crop of product obtained above under point 2 (4.5 g).
Taking into account the fact that the 2-[4-[(4-chlorophenyl)phenylmethyl]-l-piperazinyl]-ethanol ls obtained in a yield of 90.4Z from l-[(4-chlorophenyl)phenylmethyl]-piperazine, the 2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyllethoxy]-acetic acid dihydrochloride is thus obtained in three steps in an overall yield of 44.1~ (or more than 48~ if possible recycling of 2-[4-[(4-chlorophenyl)phenylmethyl]-l-piperazinyl]-ethanol which has not reacted is taken into account), which constitutes a marked improvement with respect to the process according to European Patent No. 58,146.
Claims (12)
1. A process for the preparation of 2-[2-[4 [(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]-aceticacid and its dihydrochloride are prepared by a process wherein an alkali metal alcoholate and an alkali metal haloacetate are alternately and repeatedly added to a reaction medium comprising 2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]-ethanol, so that the latter reacts with the alkali metal haloacetate, in the presence of the alkali metal alcoholate, to form an alkali metal salt of the subject acid and said alkali metal salt is converted either into the subject acid or into its dihydrochloride.
2. A process as claimed in claim 1, wherein the alkali metal alcoholate and the alkali metal haloacetate are added to the reaction medium in decreasing amounts.
3. A process as claimed in claim 1 or 2, wherein the alkali metal alcoholate is potassium tert-butoxide.
4. A process as claimed in claim 1 or 2, wherein the alkali metal alcoholate and the alkali metal haloacetate are added to the reaction medium at regular intervals and until the reaction is as complete as possible.
5. A process as claimed in claim 4, wherein the alkali metal alcoholate is potassium tert-butoxide.
6. A process as claimed in claim 1, 2 or 5, wherein the reaction is carried out in tert-butanol as a solvent.
7. A process as claimed in claim 3, wherein the reaction is carried out in tert-butanol as a solvent.
8. A process as claimed in claim 4, wherein the reaction is carried out in tert-butanol as a solvent.
9. A process according to claim 1, 2, 5, 7 or 8, wherein the reaction is carried out at a temperature between 60°C and 100°C.
10. A process as claimed in claim 3, wherein the reaction is carried out at a temperature between 60°C and 100°C.
11. A process as claimed in claim 4, wherein the reaction is carried out at a temperature between 60°C and 100°C.
12. A process as claimed in claim 6, wherein the reaction is carried out at a temperature between 60°C and 100°C.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB888827390A GB8827390D0 (en) | 1988-11-23 | 1988-11-23 | Process for preparation of 2-(2-(4-((4-chlorophenyl)phenylmethyl)-1-pipera-zinyl)ethoxy)-acetic acid & its dihydrochloride |
| GB8827390 | 1988-11-23 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1320732C true CA1320732C (en) | 1993-07-27 |
Family
ID=10647346
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000614708A Expired - Fee Related CA1320732C (en) | 1988-11-23 | 1989-09-29 | Process for the preparation of 2-¬2-¬4-¬(4-chlorophenyl)-phenylmethyl|-1-piperazinyl| ethyoxy|-acetic acid and its dihydrochloride |
Country Status (17)
| Country | Link |
|---|---|
| KR (1) | KR970009727B1 (en) |
| AT (1) | AT398970B (en) |
| CA (1) | CA1320732C (en) |
| CY (1) | CY1696A (en) |
| DK (1) | DK174289B1 (en) |
| ES (1) | ES2018967A6 (en) |
| FI (1) | FI91861C (en) |
| GB (2) | GB8827390D0 (en) |
| GR (1) | GR1000576B (en) |
| HK (1) | HK45493A (en) |
| HU (1) | HU208002B (en) |
| NO (1) | NO172287C (en) |
| PH (1) | PH26334A (en) |
| PL (1) | PL161374B1 (en) |
| PT (1) | PT92363B (en) |
| RU (1) | RU1838306C (en) |
| SG (1) | SG12793G (en) |
Families Citing this family (17)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ATE170749T1 (en) * | 1992-09-24 | 1998-09-15 | Sepracor Inc | USE OF (-)CETIRIZINE FOR THE TREATMENT OF ALLERGIC RHINITIS AND AND ASTHMA |
| ATE177636T1 (en) * | 1992-09-24 | 1999-04-15 | Sepracor Inc | TRANSDERMAL TREATMENT OF HURTS WITH OPTICALLY PURE (+)-CETIRIZINE |
| BE1010094A3 (en) * | 1996-04-10 | 1997-12-02 | Ucb Sa | NEW [2- (1-piperazinyl) ethoxy] SUBSTITUTED. |
| 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. |
| CA2180993A1 (en) * | 1996-07-11 | 1998-01-12 | Yong Tao | Methods for the manufacture of cetirizine |
| 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 |
| DK176706B1 (en) * | 1999-03-04 | 2009-03-30 | Sandoz As | Process for the preparation of 2- {2- [4- (diphenylmethyl) -1-piperazinyl] ethoxy} -acetic acid compounds or salts thereof |
| US6265579B1 (en) * | 1999-10-29 | 2001-07-24 | Salsbury Chemicals, Inc. | Process for preparing piperazine-substituted aliphatic carboxylates |
| 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 |
| 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 |
| AU2003237394A1 (en) * | 2002-06-05 | 2003-12-22 | Dr. Reddy's Laboratories Limited | Crystalline (2-(4-((4-chlorophenyl)-phenyl methyl)-1-piperazinyl) ethoxy) acetic acid dihydrochloride |
| AU2004205494B2 (en) * | 2003-01-23 | 2009-04-30 | Ucb Farchim Sa | Piperazine derivatives and their use as synthesis intermediates |
| AU2003228011A1 (en) * | 2003-05-21 | 2004-12-13 | Wockhardt Limited | 2-(2-(4-((4-chlorophenyl) phenylmethyl)-1-piperazinyl)ethoxy)acetic acid monohydrochloride as anti-allergenic compound and process for its production |
| 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 |
| 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 |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB817231A (en) * | 1956-01-27 | 1959-07-29 | Henri Morren | New derivatives of n-mono-benzhydryl-piperazine and process for the preparation thereof |
| US3090725A (en) * | 1960-02-29 | 1963-05-21 | Burroughs Wellcome Co | Phosphorylated quaternary ammonium compounds of improved oral absorption |
| 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. |
-
1988
- 1988-11-23 GB GB888827390A patent/GB8827390D0/en active Pending
-
1989
- 1989-09-29 CA CA000614708A patent/CA1320732C/en not_active Expired - Fee Related
- 1989-11-20 GR GR890100771A patent/GR1000576B/en not_active IP Right Cessation
- 1989-11-21 PT PT92363A patent/PT92363B/en not_active IP Right Cessation
- 1989-11-21 GB GB8926242A patent/GB2225320B/en not_active Expired - Lifetime
- 1989-11-22 ES ES8903974A patent/ES2018967A6/en not_active Expired - Lifetime
- 1989-11-22 HU HU896130A patent/HU208002B/en not_active IP Right Cessation
- 1989-11-22 AT AT0266489A patent/AT398970B/en not_active IP Right Cessation
- 1989-11-22 FI FI895563A patent/FI91861C/en not_active IP Right Cessation
- 1989-11-22 NO NO894650A patent/NO172287C/en not_active IP Right Cessation
- 1989-11-22 RU SU894742406A patent/RU1838306C/en active
- 1989-11-22 DK DK198905865A patent/DK174289B1/en not_active IP Right Cessation
- 1989-11-22 PL PL1989282411A patent/PL161374B1/en unknown
- 1989-11-23 PH PH39569A patent/PH26334A/en unknown
- 1989-11-23 KR KR1019890017039A patent/KR970009727B1/en not_active IP Right Cessation
-
1993
- 1993-02-06 SG SG127/93A patent/SG12793G/en unknown
- 1993-05-13 HK HK454/93A patent/HK45493A/en not_active IP Right Cessation
-
1994
- 1994-01-14 CY CY160694A patent/CY1696A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| CY1696A (en) | 1994-01-14 |
| GR890100771A (en) | 1990-12-31 |
| GB8926242D0 (en) | 1990-01-10 |
| DK586589D0 (en) | 1989-11-22 |
| HK45493A (en) | 1993-05-21 |
| GB2225320B (en) | 1992-09-02 |
| NO172287B (en) | 1993-03-22 |
| SG12793G (en) | 1993-04-16 |
| AT398970B (en) | 1995-02-27 |
| HU208002B (en) | 1993-07-28 |
| PH26334A (en) | 1992-04-29 |
| PT92363A (en) | 1990-05-31 |
| GB2225320A (en) | 1990-05-30 |
| FI91861C (en) | 1994-08-25 |
| DK586589A (en) | 1990-05-24 |
| NO894650L (en) | 1990-05-25 |
| KR900007824A (en) | 1990-06-02 |
| PT92363B (en) | 1995-07-18 |
| NO172287C (en) | 1993-06-30 |
| ATA266489A (en) | 1994-07-15 |
| HU896130D0 (en) | 1990-02-28 |
| DK174289B1 (en) | 2002-11-18 |
| KR970009727B1 (en) | 1997-06-17 |
| NO894650D0 (en) | 1989-11-22 |
| GB8827390D0 (en) | 1988-12-29 |
| HUT53626A (en) | 1990-11-28 |
| FI895563A0 (en) | 1989-11-22 |
| ES2018967A6 (en) | 1991-05-16 |
| FI91861B (en) | 1994-05-13 |
| GR1000576B (en) | 1992-08-26 |
| RU1838306C (en) | 1993-08-30 |
| PL161374B1 (en) | 1993-06-30 |
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| MKLA | Lapsed |