The present invention relates to a process for preparing itopride hydrochloride. State of the art Itopride hydrochloride, characterized by the following formula

.HCI

is a drug capable of activating motor function.

In EP306827 the relative synthesis is described, involving the following steps: 4- hydroxybenzaldehyde is reacted with 2-dimethylaminoethyl chloride in the presence of a weak inorganic base to obtain 4-(2-dimethylaminoethoxy)- benzaldehyde, which is reacted with hydroxylamine hydrochloride to obtain 4-(2- dimethylaminoethoxy)-benzaldoxime, subsequently reduced by catalytic hydrogenation, in particular using Nickel Raney, to 4-(2-dimethylaminoethoxy)- benzylamine, which is subsequently reacted with veratric acid chloride in the presence of a tertiary amine to obtain itopride, which is then salified with an ethanol solution in which gaseous hydrochloric acid is dissolved. This process has a drawback caused by the use, in the reducing step of the oxime to the corresponding amine, of hydrogen, in other words a highly explosive gas and moreover at high pressure (50 kg/cm ² ) for which expensive equipment (autoclaves and hydrogen lines) must be used.

Moreover it is necessary to use a costly and easily flammable catalyst like Nickel Raney, which moreover is highly polluting, and therefore its disposal requires costly and laborious processes for the treatment of waste water.

Summary of the invention

The Applicant has now found that with the process forming the object of the present invention the aforesaid drawbacks can be overcome.

In particular, the process of the present invention differs mainly for the use in reducing step of 4-(2-dimethylaminoethoxy)-benzaldoxime to 4-(2- dimethylaminoethoxy)-benzylamine of powdered Zinc as reducing agent.

Detailed description of the invention

In particular, the process according to the present invention which comprises the following steps: a) Reacting 4-hydroxy-benzaldehyde

with 2-dimethylaminoethyl chloride

in the presence of a weak inorganic base to obtain 4-(2-dimethylaminoethoxy)- benzaldehyde

b) reacting 4-(2-dimethylaminoethoxy)-benzaldehyde with hydroxylamine hydrochloride in an acid environment to obtain 4-(2-dimethylaminoethoxy)- benzaldoxime hydrochloride

c) reducing 4-(2-dimethylaminoethoxy)-benzaldoxime hydrochloride in the presence of a reducing agent to 4-(2-dimethylaminoethoxy)-benzylamine

d) reacting 4-(2-dimethylaminoethoxy)-benzylamine with veratric acid chloride to obtain itopride

e) salifying itopride with hydrochloric acid to obtain itopride hydrochloride, is characterized in that in the reducing step (c) of 4-(2-dimethylaminoethoxy)- benzaldoxime hydrochloride to 4-(2-dimethylaminoethoxy)-benzylamine powdered Zinc is used as reducing agent.

The reducing reaction is preferably carried out in an acidic aqueous solution of an organic acid, preferably concentrated acetic acid, more preferably 80% in weight. According to a particularly preferred solution, the reducing reaction (c) is carried out directly on the reaction mixture obtained from step (b) and not on the previously isolated benzaldoxime.

This represents a further advantage compared to the process described in

EP306827 where the reducing reaction is carried out on the previously isolated benzaldoxime.

Preferably, 4-(2-dimethylaminoethoxy)-benzylamine obtained from reducing reaction (c) is salified with hydrochloric acid to obtain the corresponding dihydrochloride salt. In this way the benzylamine is isolated from the impurities and by-products obtained in the reducing reaction, to obtain an HPLC purity higher than 98%. In this way and unlike the case of the process described in EP306827, the itopride in step (d) is obtained with high purity; therefore, not only is it no longer necessary to purify it through crystallization prior to salification, but wet itopride separated by means of simple centrifugation of the reaction mixture obtained from step (d) of the process of the invention, is actually used as starting reactant during salification step (c). Another preferred embodiment of the process forming the subject of the present invention is based on the fact that in the salification reaction of itopride, to obtain the corresponding itopride hydrochloride, concentrated aqueous hydrochloric acid (37%) in an alcohol solvent, preferably sec-butanol, is used instead of gaseous hydrochloric acid dissolved in an alcohol solvent. In fact, with this type of salification, a product is obtained with a purity higher than 99.8% and which therefore does not require further purification by means of crystallization which cause inevitable decreases of the reaction yield. Therefore, a further subject of the present invention is a salification process of itopride with hydrochloric acid characterized in that concentrated aqueous hydrochloric acid is used in an alcohol solution, in which the alcohol is preferably sec-butanol.

Step (a) is preferably carried out in phase transfer in the presence of a catalyst consisting of a quaternary ammonium salt.

Even more preferably, in step (a) a mixture of ethyl acetate, toluene and water is used as the solvent and the quaternary ammonium salt is tetrabutylammonium bromide.

The following examples of the process to prepare itopride hydrochloride and the relative intermediates according to the present invention are indicated for illustrative and non-limiting purposes. EXAMPLE 1 - Preparation of 4-(2-dimethylaminoethoxy)benzaldehyde 17.5 kg of 2-dimethylaminoethylchloride hydrochloride, 75 kg of deionized water and 2.50 kg of toluene are charged into a batch, 17.5 kg of 30% sodium hydroxide are then dropped into. The mixture obtained is kept under stirring until complete solution of the solid. The aqueous phase is removed while the organic phase is used for the following preparation. 10 kg of 4-hydroxy-benzaldehyde, 12.5 kg of potassium carbonate, 0.27 kg of tetrabutylammonium bromide and 70 kg of ethyl acetate are charged into a reactor. The mixture obtained is heated under reflux and then the aforesaid toluene solution is added dropwise. The mixture is kept under stirring and reflux for at least 5 hours. 50 kg of deionized water are then added, the mixture obtained is stirred for at least 5 minutes, the aqueous phase is removed and the organic phase is distilled, to obtain an oily residue. The residue is cooled to 20-30°C and 35 kg of 80% acetic acid are added dropwise. The reaction mixture is then stirred for 5 minutes until complete solution. A solution containing 13.5 kg of 4-(2-dimethylaminoethoxy)-benzaldehyde is obtained. Reaction yield referred to 4-hydroxybenzaldehyde: 85.33% EXAMPLE 2 - Preparation of 4-(2-dimethylaminoethoxy)-benzylamine 27 kg of 80% acetic acid are charged into a reactor, 5.3 kg of hydroxylamine hydrochloride are added, the mixture is cooled to 0-5 °C and the solution prepared in the previous step containing 13.5 kg of 100% 4-(2-dimethylaminoethoxy)- benzaldehyde in acetic solution is added. The reaction mixture is kept at 0-5°C for at least 2 hours.

When the reaction is complete, 10.8 kg of powdered zinc are added in portions, allowing the temperature to rise up to a maximum of 50 °C.

This mixture is kept under stirring at 45-50°C for at least 5 hours, and then heated to 65-70°C for at least 2 hours. Upon completion of the reaction, the reaction mixture is distilled to obtain a dense but stirrable residue.

20.3 kg of deionized water are then added to the residue thus treated, the mixture thus obtained is cooled to 20-30°C and 54 kg of 30% ammonia are added dropwise. The reaction mixture is then stirred at 20-30°C for at least 10 minutes, the pH is checked to ensure it is above 9.5. The reaction mixture is then extracted at 20-25 °C with 40.5 kg of methylene chloride. The organic phase is separated while the aqueous phase is reextracted with 27 kg of methylene chloride and the mixture is stirred for at least 5 minutes; the organic phase is added to the previous organic phase. Then the solvent is removed until an oily residue is obtained. 54 kg of sec-butanol and 20.3 kg of N, N - dimethylformamide are added. The solution thus obtained contains 11.5 kg of 4-(2-dimethylaminoethoxy)-benzylamine Yield: 84.7%.

EXAMPLE 3 - Preparation of 4-(2-dimethylaminoethoxy)benzylamine dihydrochloride 1 1.5 kg of 4-(2-dimethylaminoethoxy)-benzylamine dissolved in sec-butanol and DMF obtained as described in the previous example are charged into a reactor and 12.7 kg of 37% hydrochloric acid are added dropwise. The pH is checked to ensure it is <1.0 and the precipitated mixture is stirred at 45-50°C for at least 30 minutes. The mixture is cooled to 0-5°C, centrifuged and the precipitate washed with 1 1.5 kg of sec-butanol. It is dried under vacuum at 70-80°C. 13.5 kg of 4-(2- dimethylaminoethoxy)benzylamine dihydrochloride are obtained with HPLC purity higher than 98%. Reaction yield calculated on the 4-(2-dimethylaminoethoxy)- benzylamine 85.8%. EXAMPLE 4 - Preparation of itopride 10.1 kg of veratric acid and 27.0 kg of toluene are charged into a reactor, the mixture is heated under reflux (105-1 15°C) and 7.4 kg of thionyl chloride are added dropwise. The mixture is kept under reflux for at least 2 hours, and is

distilled under vacuum, to obtain an oily residue which 10.1 kg of toluene are added to. The solution is then brought to 20-50°C, and the aforesaid reaction mixture is added dropwise to a stainless steel reactor, which 13.5 kg of 4-(2- dimethylaminoethoxy)-benzylamine dihydrochloride, 81 kg of toluene, 11.5 kg of triethylamine, were previously charged into, at a temperature ranging from 75 to 80°C.

After adding the reaction mixture dropwise, the reaction mixture thus obtained is stirred at 75-80°C for at least two hours. Upon completion of the reaction, 40.5 kg of deionized water are added, 1 1.5 kg of 30% ammonia are added dropwise and the reaction mixture is taken to 55-60°C until complete solution. The aqueous phase is separated and removed. 27.0 kg of deionized water are added and the mixture is cooled to 40-45 °C until obtaining a good degree of precipitation. The mixture is then centrifuged, the precipitate is washed with 10.1 kg of deionized water and the same quantity of toluene. A sample of product is taken and the loss of weight determined; this analysis shows that the wet product contains 16 kg of dry itopride.

Reaction yield compared to 4-(2-dimethylaminoethoxy) benzylamine dihydrochloride: 88.3%. EXAMPLE 5 - Preparation of itopride hydrochloride The equivalent wet product corresponding to 16 kg of dry itopride coming from Example 4 and 56 kg of sec-butanol are charged into a reactor and heated to 50- 55 °C until solution. 4.8 kg of 37% hydrochloric acid are added dropwise, the pH is checked to ensure it is <2.0, and the mixture is stirred at 50-55 °C for at least 30 minutes; it is cooled to 15-25 °C and it is then centrifuged, the precipitate is washed with 16.0 kg of sec-butanol. The product is then dried at 70-80°C. 16.5 kg of itopride hydrochloride with HPLC purity higher than 99.8% are obtained. Reaction yield compared to itopride: 93.7%.