BACKGROUND OF THE INVENTION In light of the versatility of 2- {2- [4- [ (4-chlorophe- nyl) phenylmethyl]-l-piperazinyl] ethoxy} acetic acid in the form of its dihydrochloride-also known by the generic name of cetirizine-as a powerful drug for the treatment of allergic diseases, a new, cheap, easy to perform and high yielding process for its preparation is in great need.

EP Patent No. 58 146 (UCB, S. A.) describes a process for the synthesis of i. a. 2- {2- [4- (diphenylmethyl)-l-pipera- zinyl] ethoxy} acetic acid compounds which comprises react- ing a 1- (diphenylmethyl) piperazine compound with methyl (2-chloroethoxy) acetate or 2- (2-chloroethoxy) acetamide to form a methyl 2- {2- [4- (diphenylmethyl)-l-piperazinyl]- ethoxy} acetate or a 2- {2- [4- (diphenylmethyl)-l-piperazi- nyl] ethoxy} acetamide, respectively. The formed methyl es- ter or acetamide is then subjected to basic hydrolysis followed by acidification and isolation of the free car- boxylic acid which is eventually transformed into its di- hydrochloride. The main problem concerning this approach is that the overall yield of cetirizine dihydrochloride

based on 1- [ (4-chlorophenyl) phenylmethyl] piperazine is only 10.6%.

A development of this process is the subject of EP Patent Application No. 801 064 (UCB, S. A.) according to which 1- [ (4-chlorophenyl) phenylmethyl] piperazine is reacted with 2-chloroethoxyacetic acid in an inert solvent in the presence of an acid acceptor such as potassium carbonate and optionally in the presence of a small amount of an alkali metal iodide to accelerate the reaction. The reac- tion is generally effected by heating at between 80 and 150 °C during several hours. The process is stated to be more simple and easy to perform than that of EP Patent No. 58 146, but nothing is said about the yield.

A process similar to that of EP Patent No. 58 146 is pre- sented in GB Patent No. 2 225 321 (UCB, S. A.) according to which 1- [ (4-chlorophenyl) phenylmethyl] piperazine is reacted with a 2-haloethoxyacetonitrile. The resulting 2- {2- [4- [ (4-chlorophenyl) phenylmethyl]-1-piperazinyl]- ethoxy} acetonitrile is then subjected to either basic or acidic hydrolysis resulting in 2- {2- [4- [ (4-chlorophenyl)- <BR> <BR> <BR> <BR> phenylmethyl]-1-piperazinyl] ethoxy} acetic acid in 65.6% yield overall. As this process involves the use of 1.4 equivalents of haloethoxyacetonitrile, which is not com- mercially available, and furthermore requires column chromatography for purification, it is not feasible for large scale production.

GB Patent No. 2 225 320 (UCB, S. A.) describes a process wherein 2-f4- [ (4-chlorophenyl) phenylmethyl]-1-piperazi- nyl} ethanol is reacted with an alkali metal haloacetate and potassium tert. butoxide. By a rather complicated procedure involving continuous addition of the haloace- tate and the tert. butoxide a yield of 55.5 % of 2- {2- [4- [ (4-chlorophenyl) phenylmethyl]-1-piperazinyl] ethoxy} ace-

tic acid is obtained. Although the yield is better than in the process of EP Patent No. 58 146, the method and especially the continuous addition of reactants during the reaction is somewhat difficult to handle. In addi- tion, alkali metal haloacetate and potassium tert. butox- ide are used in a 1.66 fold excess, which adds to the cost of the process.

PL Patent No. 163 415 (Warszawskie Zaklady Farmaceutyczne "POLFA") describes a process for the synthesis of 2- {2- <BR> <BR> <BR> [4- [ (4-chlorophenyl) phenylmethyl]-1-piperazinyl] ethoxy}- acetic acid using the same starting materials as in GB Patent No. 2 225 320, but a different set of reaction conditions. By refluxing a two-phase system consisting of 2- {4- [ (4-chlorophenyl) phenylmethyl]-l-piperazinyl} ethanol and an alkali metal haloacetate in toluene as one phase, and solid alkali metal hydroxide as the other phase, a yield of 60 % of 2- {2- [4- [ (4-chlorophenyl) phenylmethyl]- 1-piperazinyl] ethoxy} acetic acid was isolated. Although this procedure gives a somewhat better yield than the one used in GB Patent No. 2 225 320, alkali metal haloacetate is still used in rather large quantities, e. g. 1.5 fold excess.

The international Patent Application WO 97/37982 (UCB, S. A.) describes certain piperazinylethoxyacetic acid de- rivatives and their utilization for the preparation of i. a. cetirizine by reaction with diphenylmethylhalogeni- des. By refluxing (4-chlorophenyl) phenylmethylchloride and potassium 2- (1-piperazinyl) ethoxyacetate in acetoni- trile for 16 hours cetirizine is obtained in a yield of 48.5%.

The international Patent Application WO 98/02425 (APOTEX INC.) describes the synthesis of 2- {2- [4- [ (4-chlorophe- nyl) phenylmethyl]-l-piperazinyl] ethoxy} acetic acid by

oxidation of 2- {2- [4- [ (4-chlorophenyl) phenylmethyl]-l-pi- perazinyl] ethoxy} ethanol with an oxidation agent. Two em- bodiments are described therein. The first one comprises reacting 2- {2- [4- [ (4-chlorophenyl) phenylmethyl]-l-pipera- zinyl] ethoxy} ethanol with Jones'reagent: chromium triox- ide and sulfuric acid. A very tedious workup process is therefore needed in order to remove any chrome from the product. In addition, the use of large amounts of chrome in a given synthesis can only be considered a serious en- vironmental hazard. The other embodiment involves the use of oxygen and platinum dioxide on carbon. As oxygen in the presence of an organic solvent (here dioxane) consti- tutes a serious safety hazard, this preparation is proba- bly not feasible for the synthesis of larger amounts of cetirizine than the 0.51 g produced in this example.

Thus, there is a need for a new economical and high yielding process for the synthesis of cetirizine.

SUMMARY OF THE INVENTION The present invention provides a process for the manufac- ture of compounds of the general formula I:

<BR> wherein R¹ and R² independently represent a hydrogen atom, a halogen atom, a lower alkoxy radical or a trifluoromethyl radical. The halogen atom is Br, Cl, F or I.

According to the process of the invention a 2- [4- (diphe- nylmethyl)-l-piperazinyl] ethanol (II) is first reacted with a 2-substituted acetaldehyde dialkylacetal (III) in the presence of a proton acceptor in an inert solvent:

<BR> where R¹ and R² are as defined above, R³ represents a leaving group e. g. Cl, Br, I, or a sulfuric ester group; and R4 and R5 independently represent a lower alkyl radi- cal, or R4 and R5 together form an alkylene chain of 2-4 carbon atoms.

As the proton acceptor sodium hydride seems to work best, but in principle any proton acceptor known to those skilled in the art can be used, e. g. other alkali metal hydrides, alkali metal hydroxides, alkali metal alkoxides such as sodium or potassium tert butoxide and free alkali metals. As the solvent any chemically inert solvent such as aliphatic and aromatic hydrocarbons, ethers, amides and alcohols of low reactivity can be used. Examples of such solvents are hexane, toluene, dimethoxyethane (DME), tetrahydrofurane (THF), dimethylformamide (DMF) and tert- butanol. The reaction is generally carried out at a tem-

perature between room temperature and the boiling point of the chosen solvent.

The resulting diphenylmethylpiperazinoethoxyacetaldehyde dialkylacetal (IV) is then hydrolysed to the correspond- ing aldehyde, catalysed by a proton donor e. g. hydrochlo- ric acid or formic acid, whereafter the aldehyde is oxi- dised to the acid (I) by means of a suitable oxidation agent. If desired, the acid (I) is converted into a salt thereof.

Suitable oxidation agents are e. g. reagents based on met- als such as chromium, manganese, nickel, selenium etc., oxygen as well as oxo acids of halogens, e. g. sodium hy- pochlorite, or, even better, peroxides, e. g. hydrogen peroxide, potassium peroxodisulfate, potassium peroxo- monosulfate ("Oxone@@) and peracids like m-chloroperoxy- benzoic acid. The reaction is usually conducted in an al- coholic/aqueous solution or an aqueous suspension, but any solvent known to those skilled in the art can be used.

The diphenylmethylpiperazinoethoxyacetaldehyde dialkyl- acetal compounds of the general formula IV above and the corresponding free aldehydes (IVa) which are intermedi- ates in the process of the invention are novel compounds.

The most interesting compound to be prepared by the proc- ess of the invention is at present 2- {2- [4- [ (4-chloro- phenyl) phenylmethyl]-l-piperazinyl] ethoxy} acetic acid in the form of its dihydrochloride known by the generic name of cetirizine.

DETAILED DESCRIPTION OF THE INVENTION The first step in the synthesis of cetirizine comprises reacting 2- 4- [ (4-chlorophenyl) phenylmethyl]-1-piperazi-

nyl} ethanol with a haloacetaldehyde derivative. Quite a lot of haloacetaldehyde derivatives are now commercially available, but for large scale processes, a stable, reac- tive, and fairly cheap haloacetaldehyde derivative must be used. The far cheapest one is chloroacetaldehyde di- methylacetal, but when this derivative was used, very long reaction times were required, and furthermore the quality of the resulting product was rather low. We have found that this reaction gives both excellent yield and excellent quality of the resulting product when the leav- ing group is bromine, and for the sake of reducing cost, we have thus used bromoacetaldehyde diethylacetal.

The choice of solvent for this reaction was also governed by both reaction time and quality of the product. We found that THF was an excellent solvent for this reac- tion. The main reasons for this observation is that a rather small volume is required, and that the quality of the 2- {2- [4- [ (4-chlorophenyl) phenylmethyl]-l-piperazi- nyl] ethoxy} acetaldehyde diethylacetal produced, is sur- prisingly high. As proton acceptor we have chosen sodium hydride, as this base is both easy to handle and very cheap. Thus, by using the above mentioned set of reac- tants, a yield of 2- {2- [4- [ (4-chlorophenyl) phenylmethyl]- l-piperazinyl] ethoxy} acetaldehyde diethylacetal above 95 % with a HPLC purity of about 98 % can easily be accom- plished. Even more surprisingly, no trace of an N-alky- lated product can be detected on HPLC.

The next step starts with the hydrolysis of 2- {2- [4- [ (4- chlorophenyl) phenylmethyl]-l-piperazinyl] ethoxy} acetalde- hyde diethylacetal. This can be accomplished in many ways (Theodora W. Greene, PROTECTIVE GROUPS IN ORGANIC SYNTHE- SIS, second edition, John Wiley & Sons, Inc. pp 178-210), but the most convenient way in this context is simply to hydrolyse in hot dilute hydrochloric acid. We have found

have found that at 60 °C this is both a very fast and clean reaction, thereby producing 2- {2- [4- [ (4-chlorophe- nyl) phenylmethyl]-l-piperazinyl] ethoxy} acetaldehyde dihy- drochloride in quantitative yield. The hydrolysis can, however, be accomplished at lower temperatures, down to 0 °C or below, as well as at higher temperatures, up to the boiling point of the solution, thereby only increasing or reducing the reaction time required. The preferred temperatures for practical reasons are in the range of 50-80 °C, more preferably about 60 °C.

The aldehyde then needs only to be oxidised, and again there are several ways of accomplishing this (Milos Hud- licky, OXIDATIONS IN ORGANIC CHEMISTRY, American Chemical Society, Washington, D. C., 1990). In view of the demands for ecological sound procedures in large scale chemical processes, we do not wish to use oxidizing agents which could imply environmental problems. Thus, although re- agents based on chromium, manganese, nickel, selenium etc are known to effect oxidation of an aldehyde to the cor- responding acid in high yield, we prefer to use hydrogen peroxide for this conversion. The main reasons for this choice are that hydrogen peroxide is very cheap and that it only gives water when reduced. Of course, any peroxide could in principle be used. However, we have tried to use m-chloroperoxybenzoic acid and oxygen as oxidants, but found that hydrogen peroxide is a far superior oxidant for this aldehyde.

Surprisingly, with hydrogen peroxide, the conversion takes place under very mild conditions when the suspen- sion is buffered (preferably in the pH range of 4 to 8).

Conducting the oxidation at a pH below 4 requires a fairly long reaction time and, in addition thereto, rather large amounts of 2- {4- [ (4-chlorophenyl) phenyl- methyl]-l-piperazinyl} ethanol is produced during the re-

action. We believe that this is a consequence of a- hydroxylation of the aldehyde (via its enol form) thereby producing a hemiacetal which is subsequently hydrolysed in situ to 2- {4- [ (4-chlorophenyl) phenylmethyl]-l-pipera- zinyl} ethanol. The oxidation of the aldehyde to the acid is very fast at pH > 7, but, not surprisingly, it results in large amounts of N-oxide formation. The N-oxide has to be reduced in situ as it is somewhat difficult to sepa- rate from the 2- {2- [4- [ (4-chlorophenyl) phenylmethyl]-l- piperazinyl] ethoxy} acetic acid formed. The pH of the re- action is usually maintained at appr. 6,5 by addition of concentrated sodium hydroxide solution, but the intervals of addition can be reduced if a buffer is present, e. g. acetic acid/acetate buffer.

The present invention will probably be better understood from the following examples which only serve to illus- trate the invention and therefore should not be taken to limit the scope thereof.

EXAMPLES Example 1 A. 2- {2-r 4- [ (4-chlorophenyl) phenylmethyl1-1-piperazi- nyl]acetaldehyde diethylacetal To a stirred solution of 2- {4- [ (4-chlorophenyl) phenyl- methyl]-l-piperazinyl} ethanol (50.9 g, 0.154 mol) in 200 ml dry THF under dry nitrogen was added sodium hydride (6 g 80% in mineral oil, 0.20 mol). The temperature was raised to 50 °C and the solution was stirred for 20 min- utes whereafter bromoacetaldehyde diethylacetal (35.5 g, 0.18 mol) was added. The bath temperature was raised to 90 °C and the reaction left for 5 hours. Additional so- dium hydride (1 g, 0.033 mol) and bromoacetaldehyde di- ethylacetal (3 g, 0.015 mol) was added, and the solution

was left for another 5 hours. The reaction mixture was quenched with water (a total of 40 ml was used) and hex- ane (100 ml) was added in order to ease the separation.

The organic phase was isolated, washed with water (40 ml) and brine/water (1: 1,40 ml). The combined aqueous solu- tions were extracted with toluene (20 ml) and the toluene extract was added to the THF/hexane solution. The com- bined organic phases were washed with brine (40 ml), fil- tered and evaporated in vacuo, ending up with a pressure of 0.5 mbar and a temperature of 70 °C. The yield of crude material was 68 g, but this material also contains mineral oil from the sodium hydride (1.4 g), thereby re- ducing the yield to 66.6 g (96.7 %). HPLC (nucleosil C18, MeOH/H20 9: 1, buffer: phosphate buffer pH 7, flow = 0.9 ml/min, 230 nm), Rf = 7.94 (98.2 %). 1H NMR (CDC13,250 MHz) 8 ppm: 7.2 (m, 9H); 4.6 (t, 1H); 4.2 (s, 1H); 6.6 (m, 8H); 2.5 (m, 10 H); 1.2 (t, 6H).

B. 2-f2- [4- (4-chlorophenyl) phenylmethyl]-1-piperazi- nyl] ethoxylacetic acid 2- {2- [4- [ (4-chlorophenyl) phenylmethyl]-1-piperazinyl]- ethoxy} acetaldehyde diethylacetal (18.2 g of the crude product from A above, 0.0413 mol), water (20 ml) and conc. hydrochloric acid (8.3 ml, 0.1 mol) were mixed, heated for 30 min at 60 °C and then cooled to room tem- perature. Ethanol (20 ml) was added, and the solution was brought to pH ca. 7 with conc. sodium hydroxide solution (appr. 7 ml). To the cooled suspension (20 °C) hydrogen- peroxide (4.0 ml 35 %, 0.041 mol) was added, and the re- sulting suspension was stirred at room temperature keep- ing the pH of the solution at appr. 6.5 by addition of concentrated sodium hydroxide solution. The reaction was monitored by means of HPLC (nucleosil C18, MeOH/H20 9: 1, buffer: phosphate buffer pH 7, flow = 0.9 ml/min, 230 nm), and when the aldehyde (Rf = 5.39) was almost con-

sumed, pH was adjusted to 9 with concentrated sodium hy- droxide solution and the reaction was freed of peroxide with sodium dithionite (1.0 g, 0.0057 mol). The ethanol was evaporated in vacuo leaving an aqueous suspension which was diluted with water (250 ml). pH was adjusted to 9.5 with concentrated sodium hydroxide solution and the aqueous solution was extracted with butyl acetate/THF 5: 1 (2 x 40 ml) at 50 °C. pH was adjusted to 1.5 with concen- trated hydrochloric acid and the aqueous solution was ex- tracted at 50 °C with butyl acetate (2 x 30 ml) and fi- nally with cyclohexane (40 ml). The aqueous solution was cooled to room temperature, pH adjusted to 4.5 with con- centrated sodium hydroxide solution, and the solution was extracted with dichloromethane (2 x 70 ml). The combined organic phases were washed with water (20 ml), dried (MgS04) and evaporated in vacuo leaving a colourless foam (14.4 g). The foam was taken up in toluene (75 ml), heated to appr. 70 °C, and cyclohexane (25 ml) was added.

Cooling overnight caused crystallisation, and the formed solid was filtered off and washed with toluene/cyclo- hexane 1: 1 (40 ml). After drying in vacuo 13.7 g (85.3 %) of 2- {2- [4- [ (4-chlorophenyl) phenylmethyl]-l-piperazinyl]- ethoxy} acetic acid was obtained. M. P. 135-138 °C. 1H NMR (CDCl3,300 MHz) 5 ppm: 7.1 (m, 9H); 4.20 (s, 1H); 3.95 (s, 2H); 3.70 (m, 2H); 3.00 (s, 4 H); 2.85 (m, 2H); 2.60 (s, 4H).

C. 2- {2-f 4-r (4-chlorophenyl) phenylmethyl1-1-piperazi- nylethoxyacetic acid dihydrochloride 2- {2- [4- [ (4-chlorophenyl) phenylmethyl]-1-piperazinyl]- ethoxy} acetic acid from B above (13.4 g, 0.034 mol) was suspended in acetone (150 ml), heated to 50 °C and con- centrated hydrochloric acid (6.2 ml, 0.078 mol) was added with vigorous stirring. The resulting almost clear solu- tion was stirred at room temperature for 2 hours after

which a fine white precipitate of 2- {2- [4- [ (4-chlorophe- nyl) phenylmethyl]-l-piperazinyl] ethoxy} acetic acid dihy- drochloride had formed. The solution was filtered, washed with acetone (50 ml) and dried in vacuo leaving 13.8 g (87.9 %) of 2- {2- [4- [ (4-chlorophenyl) phenylmethyl]-1- piperazinyl] ethoxy} acetic acid dihydrochloride. M. P.

224-226 °C.

Example 2 <BR> <BR> <BR> <BR> <BR> 2-{2-f4-[(4-chlorophenyl)phenylmethyl1-1-piperazinyl1-<BR > <BR> <BR> ethoxylacetaldehyde dihydrochloride In order to characterize the above intermediate concen- trated hydrochloric acid (1 ml, 0,0125 mol) and water (4 ml) was added to 2- {2- [4- [ (4-chlorophenyl) phenylmethyl]- l-piperazinyl] ethoxy} acetaldehyde diethylacetal (2 g of the crude product obtained under A in Example 1,0.0045 mol), and the mixture was heated for 20 minutes at 50 °C.

Acetone (20 ml) was added, and the mixture was treated with active carbon, heated to reflux and filtered. The solution was evaporated in vacuo until a colourless foam appeared. Acetone (50 ml) was added, and the suspension was stirred for two hours, after which a colourless pre- cipitate had formed. This was filtered off, washed with acetone and dried in vacuo. The yield of 2- {2- [4- [ (4- chlorophenyl) phenylmethyl]-l-piperazinyl] ethoxy} acetalde- hyde dihydrochloride was 1.32 g (78 %).