GB2225320A - Process for the preparation of a 1-piperazine-ethoxyacetic acid - Google Patents

Process for the preparation of a 1-piperazine-ethoxyacetic acid Download PDF

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Publication number
GB2225320A
GB2225320A GB8926242A GB8926242A GB2225320A GB 2225320 A GB2225320 A GB 2225320A GB 8926242 A GB8926242 A GB 8926242A GB 8926242 A GB8926242 A GB 8926242A GB 2225320 A GB2225320 A GB 2225320A
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Prior art keywords
phenylmethyl
chlorophenyl
alkali metal
piperazinyl
dihydrochloride
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GB8926242A
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GB8926242D0 (en
GB2225320B (en
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Eric Cossement
Jean Gobert
Guy Bodson
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UCB SA
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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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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

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]1-1ethanol 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

A process for the Preparation of 2-12-r4-r(4-chlorophenyl)phenglmethyll- l-piperazinollethoxYl-acetic acid and its dihydrochioride.
The present invention relates to a new process for the preparation of 2-[2-[4-[ (4.chlorophenyl)phenylmethyl)l-piperazinyl)ethoxy)acetic acid and its dihydrochloride.
The dihydrochloride of 2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1piperazinyl]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 mental performance etc.(c.f. D.P.TASHKIN et al., Annals of Allergy, Part II, 59, (1987),49-52, and F.M. GENGO et al., Annals of Allergy, Part II, 59, (1987),53-57).
European Patent No.58,146 in the name of the Applicant describes the 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 hydroxide) to give the sodium or potassium salt, which is easily converted into the free acid, and then into cetirizine dihydrochloride.
The major disadvantage of this synthesis is that the overall yield of 2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]-acetic acid dihydrochloride is only 10.6X, based on the amount of 1-[(4chlorophenyl)phenylmethyl]-piperazine employed.
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 chlorophenyl )phenylmethyl)-l-piperazinyl)-acetic acid and its dihydrochloride are prepared by a process which is characterized in that 2-[4-[ (4-chlorophenyl)phenylmethyl]-l-piperazinyl]-ethanol is reacted with an alkali metal haloacetate in the presence of an alkali metal 1 alcoholate and in that the alkali metal salt thus obtained is converted into the corresponding acid and, if appropriate, into its dihydrochloride.
The 2-[4-[(4-chlorophenyl)phenylmethyl-1-piperazinyl)-ethanol used as the starting substance in the process of the invention is a product which is known per se. Its synthesis by reaction of l-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 (90Z) 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-[(4chlorophenyl)phenylmethyl]-l-piperazinyl]ethosy]-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 1000C 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, tertbutanol.
To achieve optimum yields, its is advisable to use potassium tertbutoxide 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 75Z higher than the molar amount of the starting 2-[4-[(4 chlorophenyl)phenylmethyl]-l-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 the 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 reaction is present in the reaction mixture in the form of an alkali metal salt. After the reaction mixture is acidified 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 44Z or more of cetirizine dihydrochloride, calculated on the basis of the 1-[(4chlorophenyl)phenylmethyl]-l-piperazine employed. With recycling of the 2-[4-[ (4-chlorophenyl)phenylmethyl)-1-piperazinylj-ethanol in the reaction, the overall yield can even reach values close to 50z. This higher yield starting from l-[ (4-chlorophenyl)phenylmethylj-1-piperazine constitutes a considerable technical advance with respect to the process described in European Patent No.58,146.
The following example is given for the purpose of illustrating the invention.
Example. PreParation of 2- (2- F (4-chloronhenyl )ohenvlmethyl 1-1- piperazinyllethoxyl-acetic acid.
1. 2-r4- r 4-chlorophenol)phenylmethyll-1-Piperazinsll-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 96.8Z.
50 g of the alcohol obtained are distilled at 2200C 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 fraction of 24.5 g has a purity of 96.6X, whereas the other fraction (of 22.2 g) has a purity of 99.6Z. A yield of pure product of 90.4Z 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.: 2220C Analysis for C19H23ClN20.2HCl in Z calc : C 56.50 H 6.19 N 6.94 Cl 17.59 tot 26.39 found: C 56.63 H 6.28 N 6.86 Cl 17.48 C1tot 26.32 2. 2- r 2- r & r (4-chloroDhenol)Whenolmethol1-l-piPerazinollethosYl-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 450C under a nitrogen atmosphere, and 21 g of potassium tert-butoxide are added. The temperature is raised to 75-800C and the mixture is kept at this temperature. 11 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 75-800C 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-butoxide 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 (97Z) and 30.65 g (0.25 mole) of sodium chloroacetate (95Z) 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 reaches 1000C.
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]-l- 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 combined 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: 55.5Z. M.P.:146-1480C.
Analysis for C H gC1N203 in Z 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-[2-[4-[(4-chloronhenyl)phenylmethyl]-1-piperazinyl]ethoxy]-acetic acid dihydrochloride.
32.7 g of 2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1 piperazinyl]ethoxyl-acetic acid are suspended in a mixture of 125 ml of water and 13.8 ml of 37Z 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: 88Z. M.P.: 228.220C (Differential Scanning Calorimetry, DSC) Analysis for C21H25ClN20 3.2HCl in Z calc.: C 54.56 H 5.84 N 6.06 Cl 15.37 Cltot 23.05 found: C 54.28 H 5.86 N 6.15 C1 15.24 C1 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 is obtained in a yield of 90.4Z from 1-[(4-chlorophenyl)phenylmethyl]-piperazine, the 2-[2-[4-[(4chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]acetic acid dihydrochloride is thus obtained in three steps in an overall yield of 44.1X (or more than 48X 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 (5)

WE CLAIM:
1. A process for the preparation of 2-[2-[4-[(4- chlorophenyl)phenylmethyl]-l-piperazinyl]ethoxy]-acetic acid and its dihydrochloride, characterized in that 2-[4-[(4 chlorophenyl )phenylmethyl ]-l-piperazinyl ]-ethanol is reacted with an alkali metal haloacetate in the presence of an alkali metal alcoholate, and in that the alkali metal salt thus obtained is converted into the corresponding acid and, if appropriate, into its dihydrochloride.
2. A process according to claim 1, characterized in that the alkali metal alcoholate is potassium tert-butoxide.
3. A process according to claim 1 or 2, characterized in that the reaction medium is resupplied regularly with the two reactants, the alkali metal alcoholate and the alkali metal haloacetate, in decreasing amounts and at regular intervals, until the reaction is as complete as possible.
4. A process according to any of claims 1 to 3, characterized in that the reaction is carried out at a temperature between 600C and 1000C.
5. A process substantially as hereinbefore described in the foregoing example.
GB8926242A 1988-11-23 1989-11-21 A process for the preparation of 2-(2-(4-((4-chlorophenyl)phenylmethyl)-1-piperazinyl)ethoxy)-acetic acid and its dihydrochloride Expired - Lifetime GB2225320B (en)

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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

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GB8926242A Expired - Lifetime GB2225320B (en) 1988-11-23 1989-11-21 A process for the preparation of 2-(2-(4-((4-chlorophenyl)phenylmethyl)-1-piperazinyl)ethoxy)-acetic acid and its dihydrochloride

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ES (1) ES2018967A6 (en)
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GR (1) GR1000576B (en)
HK (1) HK45493A (en)
HU (1) HU208002B (en)
NO (1) NO172287C (en)
PH (1) PH26334A (en)
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Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5627183A (en) * 1992-09-24 1997-05-06 Sepracor, Inc. Methods for treating urticaria using optically pure (+) cetirizine
EP0801064A1 (en) * 1996-04-10 1997-10-15 U C B, S.A. Process for the preparation of 2-(2-(4((4-chlorophenyl)phenylmethyl)-1-piperazinyl)ethoxy)-acetic acid and their salts
WO1997037982A1 (en) * 1996-04-10 1997-10-16 Ucb S.A. Novel substituted [2-(1-piperazinyl)ethoxy]methyl
US5698558A (en) * 1992-09-24 1997-12-16 Sepracor, Inc. Methods for treating allergic disorders using optically pure (-) cetirizine
WO1998002425A1 (en) * 1996-07-11 1998-01-22 Apotex Inc. 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
US6100400A (en) * 1998-04-23 2000-08-08 Chemiagis, Ltd. Process for the preparation of esters of [2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]-ethoxy]acetic acid
WO2000052000A1 (en) * 1999-03-04 2000-09-08 A/S Gea Farmaceutisk Fabrik A process for the preparation of 2-{2-[4-(diphenylmethyl)-1-piperazinyl]ethoxy}acetic acid compounds or salts thereof
WO2001032641A1 (en) * 1999-10-29 2001-05-10 Salsbury Chemicals, Inc. Process for preparing piperazine-substituted aliphatic carboxylates
WO2003104211A2 (en) * 2002-06-05 2003-12-18 Dr. Reddy's Laboratories Limited Crystalline [2-[4-[(4-chlorophenyl)-phenyl methyl]-1-piperazinyl] ethoxy] acetic acid dihydrochloride
WO2004065360A3 (en) * 2003-01-23 2004-11-11 Ucb Farchim Sa Piperazine derivatives and their use as synthesis intermediates
WO2004103982A1 (en) * 2003-05-21 2004-12-02 Wockhardt Limited 2-[2-[4-[(4-chlorophenyl) phenylmethyl]-1-piperazinyl]ethoxy]acetic acid monohydrochloride as anti-allergenic compound and process for its production
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
WO2010046908A2 (en) 2008-09-17 2010-04-29 Calyx Chemicals And Pharmaceuticals Pvt. Ltd. Novel water based process for the preparation of substituted diphenylmethyl piperazines
WO2013103262A1 (en) 2012-01-06 2013-07-11 Hanmi Pharm. Co., Ltd. Stable pharmaceutical formulation for oral administration comprising levocetirizine or a pharmaceutically acceptable salt thereof, and montelukast or a pharmaceutically acceptable salt thereof
WO2014208915A2 (en) 2013-06-28 2014-12-31 Hanmi Pharm. Co., Ltd. Complex granule formulation having improved stability comprising levocetirizine and montelukast

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US3090725A (en) * 1960-02-29 1963-05-21 Burroughs Wellcome Co Phosphorylated quaternary ammonium compounds of improved oral absorption
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Cited By (32)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5698558A (en) * 1992-09-24 1997-12-16 Sepracor, Inc. Methods for treating allergic disorders using optically pure (-) cetirizine
US5627183A (en) * 1992-09-24 1997-05-06 Sepracor, Inc. Methods for treating urticaria using optically pure (+) cetirizine
US6140501A (en) * 1996-04-10 2000-10-31 Ucb, S.A. Substituted [2-(1-piperazinyl)ethoxy]methyl compounds
EP0801064A1 (en) * 1996-04-10 1997-10-15 U C B, S.A. Process for the preparation of 2-(2-(4((4-chlorophenyl)phenylmethyl)-1-piperazinyl)ethoxy)-acetic acid and their salts
WO1997037982A1 (en) * 1996-04-10 1997-10-16 Ucb S.A. Novel substituted [2-(1-piperazinyl)ethoxy]methyl
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.
US6255487B1 (en) 1996-04-10 2001-07-03 Ucb, S.A. Process of preparing [2-(1-piperazinyl)ethoxy]methyl compounds
EA000831B1 (en) * 1996-04-10 2000-04-24 ЮСиБи С.А. Novel substituted [2-(1-piperazinyle)etoxy]methyl compounds, method for preparing said compounds and the use thereof
WO1998002425A1 (en) * 1996-07-11 1998-01-22 Apotex Inc. Methods for the manufacture of cetirizine
US6046332A (en) * 1996-07-11 2000-04-04 Tao; Yong Methods for the manufacture of cetirizine
US6262057B1 (en) 1997-11-26 2001-07-17 Ucb, S.A. Pseudopolymorphic forms of 2-[2-[4-[Bis(4-fluorophenyl)methyl]-1-piperazinyl]ethoxy]acetic acid dihydrochloride
JP2007224042A (en) * 1997-11-26 2007-09-06 Ucb Sa Pseudopolymorphic forms of 2-[2-[4-[bis (4-fluorophenyl) methyl]-1-piperazinyl]ethoxy]acetic acid dihydrochloride
WO1999028310A1 (en) * 1997-11-26 1999-06-10 Ucb, S.A. Pseudopolymorphic forms of 2-[2-[4-[bis (4-fluorophenyl) methyl]-1-piperazinyl] ethoxy]acetic acid dihydrochloride
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
US6335331B2 (en) 1997-11-26 2002-01-01 Ucb, S.A. Pseudopolymorphic forms of 2-[2-[4-[Bis (4-fluorophenyl) methyl]-1-piperazinyl]ethoxy]acetic acid dihydrochloride
US6100400A (en) * 1998-04-23 2000-08-08 Chemiagis, Ltd. Process for the preparation of esters of [2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]-ethoxy]acetic 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
WO2000052000A1 (en) * 1999-03-04 2000-09-08 A/S Gea Farmaceutisk Fabrik A 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
WO2001032641A1 (en) * 1999-10-29 2001-05-10 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
WO2003104211A3 (en) * 2002-06-05 2004-12-23 Reddys Lab Ltd Dr Crystalline [2-[4-[(4-chlorophenyl)-phenyl methyl]-1-piperazinyl] ethoxy] acetic acid dihydrochloride
WO2003104211A2 (en) * 2002-06-05 2003-12-18 Dr. Reddy's Laboratories Limited Crystalline [2-[4-[(4-chlorophenyl)-phenyl methyl]-1-piperazinyl] ethoxy] acetic acid dihydrochloride
WO2004065360A3 (en) * 2003-01-23 2004-11-11 Ucb Farchim Sa Piperazine derivatives and their use as synthesis intermediates
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PH26334A (en) 1992-04-29
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HK45493A (en) 1993-05-21
NO894650L (en) 1990-05-25
NO172287C (en) 1993-06-30
GR890100771A (en) 1990-12-31
NO894650D0 (en) 1989-11-22
PT92363B (en) 1995-07-18
AT398970B (en) 1995-02-27
DK586589D0 (en) 1989-11-22
HU896130D0 (en) 1990-02-28
SG12793G (en) 1993-04-16
NO172287B (en) 1993-03-22
CA1320732C (en) 1993-07-27
RU1838306C (en) 1993-08-30
FI91861B (en) 1994-05-13
HU208002B (en) 1993-07-28
HUT53626A (en) 1990-11-28
FI895563A0 (en) 1989-11-22
GB8926242D0 (en) 1990-01-10
ES2018967A6 (en) 1991-05-16
KR900007824A (en) 1990-06-02
ATA266489A (en) 1994-07-15
PT92363A (en) 1990-05-31
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GB2225320B (en) 1992-09-02

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