WO2006100243A1

WO2006100243A1 - Process for the preparation of pantoprazole

Info

Publication number: WO2006100243A1
Application number: PCT/EP2006/060917
Authority: WO
Inventors: Francisco Palomo Nicolau; Andrés Molina Ponce
Original assignee: Química Sintética, S. A.
Priority date: 2005-03-22
Filing date: 2006-03-21
Publication date: 2006-09-28
Also published as: ES2273564B1; ES2273564A1

Abstract

The present invention is related to a new process for the preparation of pantoprazole (I) and pharmaceutical acceptable salts thereof, with a good yield and a high purity. In said process, the introduction of the methoxy group is carried over the position 4 of the piridine ring of compound (IV) by substitution of the chlorine atom, by the reaction with an alkaline methoxide in a mixture of methanol and an aprotic polar solvent. Also an aspect of the invention is an isolating process that includes a method for the purification of pantoprazole, and a process for the preparation of compound (IV), which is used as starting product for the preparation of pantoprazole.

Description

Process for the preparation of pantoprazole

The present invention relates to a new process for the preparation of pantoprazole and pharmaceutically acceptable salts thereof.

BACKGROUND ART

Pantoprazole is the International Non-proprietary Name (INN) of the compound 5-difluoromethoxy-2-[[(3,4-dimethoxy-2-pyridyl)methyl]sulfinyl]-1/-/- benzimidazole of formula (I):

(I)

Pantoprazole is part of a group of antiulcerative agents which comprises, among others, also the compounds: omeprazole, rabeprazole and lansoprazole. Usually, pantoprazole is used as the sodium salt thereof (II):

The product was first disclosed in the european patent application EP-A-0166287, wherein several processes for the preparation of compounds defined by a general formula, including pantoprazole, were also disclosed. Said processes have a common final step, which consists in the generation of the sulfoxide group by the oxidation of the corresponding sulfide group. One of the inconvenients of this process for the preparation of pantoprazole is the fact that, at the oxidation step, some overoxidized subproducts are formed, such as the sulfone and the sulfoxide N-oxide, which can be removed only after additional costly steps of purification. The difficulties of this oxidation step are made obvious by the large number of alternatives that have been disclosed to carry out said step. As an example, several alternative oxidation processes disclosed in EP-A-0302720, WO-A- 91/18895, EP-A-0533264, and EP-A-0484265 can be cited. Despite the introduction of modifications in the oxidation step, none of them has achieved to resolve positively the problem of the formation of impurities and the difficulty of removing them.

The synthesis strategy disclosed in the patent application WO-A-02/28852 is a different technical solution. In this case, the oxidation of the sulfide group is carried out over derivate (III), and not in the last step of the synthesis:

Thus, the formation of non-desired products in the oxidation step is substantially reduced, and compound (IV) is obtained with a good yield:

(IV)

In said sinthesys strategy, pantoprazole (I) is obtained by means of the nucleofilic substitution of the chlorine atom in position 4 of the piridine ring of compound (IV) by a methoxy group.

As described in WO-A-02/28852, this nucleophilic substitution is carried out by reacting compound (IV) with an alkaline hydroxide, or with a mixture of an alkaline hydroxide and methanol, in a polar solvent, preferably an aprotic solvent.

One disadvantage of this process is that pantoprazole is obtained in low yields, mainly due to the formation of a considerable amount of impurities. Most of them are very insoluble, and they are difficult to remove by means of conventional crystallization processes.

When reproducing literally Example 6 disclosed in the patent application WO- A-02/28852, at the end of the reaction, a reaction mixture has been obtained with a content about 8% of impurities that are difficult to remove. Having carried out the purifications disclosed in said example, pantoprazole is finally obtained with yielding about 50%, far from the disclosed 67%. Even after the purification, the purity of the product is 98%, still containing a 1.5% of difficult to remove impurities. This percentage is still too high for allowing pantoprazole to be used as an active substance in pharmaceutical formulations. The same synthesis strategy for the preparation of omeprazole, lansoprazole and pantoprazole is described in the patent application WO-A-03/097606, but using a different system of solvents.

Example 6 of said patent application discloses the methoxylation reaction to obtain omeprazole using sodium methoxide in methylene chloride and methanol, and hexadecyltributylphosphonium bromide as catalyst. Omeprazole is obtained yielding not more than 60%, which is qualified as a moderate yield in the very summary of the invention. Data related to the purity of the obtained product are not provided. Then, there is the need of having at one's disposal an improved process for the preparation of pantoprazole suitable for the preparation of the product with improved yield and with a suitable purity to use pantoprazole as an active compound in the preparation of pharmaceutical formulations.

The authors of this invention have discovered a new process for the preparation of pantoprazole and salts thereof, which is based on the selection of the solvents wherein the substitution reaction is carried out, so that the yield is higher and the product is obtained with a lower content of impurities.

OBJECT OF THE INVENTION

The object of the invention is a new process for the preparation of pantoprazole and pharmaceutically acceptable salts thereof with a good yield and a low content of impurities.

A further aspect of the invention is to provide a new process for the preparation of pantoprazole and pharmaceutically acceptable salts thereof which includes one isolation step wherein the content of impurities is further reduced. Another aspect of the invention is to provide a new process for the preparation of pantoprazole wherein the starting compound is prepared with a good yield and a high purity grade. DETAILED SUMMARY OF THE INVENTION

The process for the preparation of pantoprazole and pharmaceutically acceptable salts thereof, which is the object of the invention, comprises reacting compound (IV)

(IV)

with an alkaline methoxide in a mixture of solvents which comprises methanol and a polar aprotic solvent, so that the volume/volume ratio of methanol to said solvent is comprised from 10:90 to 60:40, isolating the obtained product, and, if desired, transforming it into a pharmaceutically acceptable salt. It has been observed that, generally, when a nucleophilic substitution reaction of methoxylation is carried over compound (IV), difficult to remove impurities are formed in addition to the formation of pantoprazole. Although this invention is not linked to a certain theory explaining the formation of said impurities, the applicant considers said impurities as the possible result of the nucleophilic substitution of a fluorine atom of the difluoro group of pantoprazole (I) by a methoxy group to form ,at first, the monofluorinated compound (V). The monofluorinated compound could experience additional transformations at the conditions of the process, and/or during the isolation of the product, and become compound (Vl) by the elimination of methyl formate, as shown in the following diagram:

The presence of compound (Vl) and its possible precursor (V), which is substantially transformed into compound (Vl) during the isolation of pantoprazole, is detected in the reaction mixtures obtained by the process of the invention and from the literal reproduction of Example 6 of WO-A-02/28852.

It has been also observed that compound (Vl) is very insoluble and it is difficult to remove by means of recrystallization processes.

Through this specification, those impurities comprising compound (Vl) and its precursor (V) are denominated as difficult to remove impurities.

The selection of the elements of the process of the invention makes possible the preparation of pantoprazole with a lower content of said impurities.

Said process comprises a methoxylation reaction, which consists in the nucleophilic substitution of the chlorine atom in position 4 of the pyridine ring of compound (IV), by a methoxyl group.

The methoxylant agent used in the process of the invention is an alkaline methoxide, preferably sodium methoxide or potassium methoxide.

A molar excess of alkaline methoxide with regard to compound (IV) can be used to raise the reaction speed. Preferably, the excess is comprised from 2 to

7 mol of alkaline methoxide with regard to each mol of compound (IV), more preferably, from 3 to 6 mol.

The alkaline methoxide can be used as a solid with a content about the 95% by weight, or as a methanolic solution with a concentration comprised from 20% to

30% by weight. In the process of the invention, a mixture of solvents comprising methanol and a polar aprotic solvent is used with a volume/volume ratio of methanol to the polar aprotic solvent comprised from 10:90 to 60:40, preferably from 20:80 to 45:55. Polar aprotic solvents are organic solvents with some polarity, making them suitable for the solution of polar organic substances, but lacking of dissociable hydrogen atoms, so they are suitable for carrying out organic reactions wherein the presence of said hydrogen atoms is not recomended. In the process of the invention, the polar aprotic solvent is selected from the group consisting of tetrahydrofuran, acetonitrile, dioxane, dimethyl sulfoxide, dimethylformamide, and mixtures thereof.

Preferably, the polar aprotic solvent is selected from tetrahydrofuran, acetonitrile, and mixtures thereof. More preferably, the solvent used is tetrahydrofuran. The process of the invention can be carried out at a temperature comprised from room temperature to 75° C, preferably from 45° C to 65° C. When a mixture of solvents comprising methanol and THF, or methanol and acetonitrile is used, the reaction can be carried out at the reflux temperature of the mixture of both solvents. The course of the reaction can be quantitatively monitored by the determination of the residual content in compound (IV) in the reaction medium by chromatographic techniques well known by the person skilled in the art, such as HPLC. The reaction can be considered as finished when there is remaining less than the 0.2% in weight of compound (IV) with regard to the initial weight of compound (IV).

The use of an alkaline methoxide and the selection of the mixture of solvents in the provided proportions makes possible to obtain a final reaction mixture with a higher content of pantoprazole and a lower content of impurities with regard to the reaction mixture obtained by the processes disclosed in the state of the art, as for example in WO-A-02/28852.

For instance, when the process of the invention is carried out according to one of the preferred embodiments of the invention, using sodium methoxide and a mixture of methanol and tetrahydrofuran with a (v/v) ratio of methanol to tetrahydrofuran of 33/67, the reaction mixture obtained has a pantoprazole content, determined by HPLC, comprised from 90% to 96%, and a content of difficult to remove impurities comprised from 1.8% to 3.1%. The literal reproduction of Example 6 of patent application WO-A-02/28852 resulted in a reaction mixture containing about an 82% of pantoprazole quantified by HPLC, and about an 8% of difficult to remove impurities. Therefore, inside the reaction mass obtained according to the process of the invention there is more pantoprazole and fewer impurities in comparison to the reaction mass obtained according to the process disclosed in Example 6 of patent application WO-A-02/28852, so that it is possible to isolate the pantoprazole with both higher yield and purity.

Pantoprazole can be isolated from the reaction mass by means of conventional techniques well known by the person skilled in the art, which include, for instance, distillation of the solvents used in the reaction, dissolution in water of the distillation residue and extractions with water in a system formed by water and a water-immiscible solvent at different pH values, decoloration with activated carbon, filtration and drying. The water-immiscible organic solvent used to isolate pantoprazole can be selected from the group of non-chlorinated solvents, such as toluene, and from the group of chlorinated solvents, such as methylene chloride. In a preferred embodiment of the process of the invention, the isolation of pantoprazole includes a purification method which comprises:

a) distilling the solvents used in the reaction until a residue is obtained, b) adding water to the obtained residue and heating the mixture to a temperature comprised from 40° C to 50° C for a period comprised from 1 to 4 hours, and later cooling down at room temperature, c) extracting repeatedly the obtained aqueous solution with an organic solvent which is immiscible in water at a pH comprised from 7.5 to 8.5, and discarding the aqueous phase, d) filtering the organic phase and washing repeatedly the filtered organic phase with water maintaining the pH at a value comprised from 9.5 to 10.5, and discarding the aqueous phase, e) extracting the obtained organic phase with water maintaining the pH of the mixture at a value not lower than 13, and discarding the organic phase, and f) adding methanol to the obtained aqueous phase, and precipitating the pantoprazole from this hydroalcoholic solution by adjusting the solution to a pH comprised from 7.5 to 8.5.

As already said, once the reaction is finished, the solvents are distilled and a residue is obtained including the alkali salt of pantoprazole and the impurities formed through the reaction course, the difficult to remove impurities among them.

It has been observed that the treatment described in step b) substantially transforms precursor of formula (V) into impurity of formula (Vl).

The aqueous solution obtained in said step b) has a strong basic pH due to the alkalinity of the alkaline methoxide used.

The aqueous solution obtained after treatment on step b), is extracted with a water-immiscible organic solvent at the conditions of step c). pH is adjusted with an acid since the aqueous solution had initally an alkaline pH, as said before.

At these pH conditions, pantoprazole is in the organic phase, and the hydrosoluble impurities are removed with the aqueous phase, which is discarded. Preferably, the extractions of step c) are carried out at a temperature comprised from 15° C to 30° C.

Next, said organic phase containing pantoprazole, is treated according to the conditions of step d). The precipitate formed in the organic phase is filtered according the conventional methods, and following steps are performed with the filtered organic phase. The pH can be alkalinized, for example with an alkaline hydroxide.

Preferably, the extractions on step d) are carried out at a temperature comprised from 0° C to 10° C.

With this purification method the amount of impurities in pantoprazole is considerably reduced, specially the amount of the impurity of formula (Vl). The impurity content can be quantitatively monitored by chromatographic techniques, for example HPLC.

Eventually, the organic phase is decoloured by means of activated carbon.

Next, water is added to the organic phase containing pantoprazole, and the pH of the mixture is adjusted to a value not lower than 13, for example with an alkaline hydroxide. At these conditions, pantoprazole is transformed into the alkali salt, and it is extracted in the aqueous phase, so that the organic phase is discarded.

Before proceeding with the precipitation of pantoprazole, the phases are separated and, preferably, the remaining organic solvent present in the aqueous phase is removed by distillation of said solvent at a temperature not above 40° C. Next, methanol is added to the aqueous phase and pantoprazole is precipitated from the hydroalcoholic solution by adjusting the pH at a value comprised from 7.5 to 8.5. pH is adjusted with an acid, for example acetic acid. Preferably, pantoprazole is precipitated from a hydroalcoholic solution comprising equal volumes of methanol and water.

Eventually, to accelerate the precipitation, crystals of pantoprazole can be spread over the hydroalcoholic solution during the adjustment of the pH. The white solid is isolated by means of filtering and drying. According to the process of the invention, the yield of the preparation of high purity pantoprazole is generally higher than 75%, perceptively superior values than those obtained according to the processes disclosed in the state of the art. The literal reproduction of Example 6 disclosed in the patent application WO-A- 02/28852 resulted in the preparation of pantoprazole yielding 51%, and with 98% of purity, still containing a 1.5% of difficult to remove impurities. The yield disclosed in the patent application is 67%, but there are no data about the purity of the obtained product, and said yield has not been reproduced in the preparation of the product of the required purity.

Surprisingly, the process object of the invention makes possible the preparation of pantoprazole with a high yield, with purity above 99%, and with all the impurities below 0.1 % by weight, that makes it suitable for its use as active substance of pharmaceutical formulations.

Pharmaceutical acceptable salts of pantoprazole can be prepared by well known processes for the person skilled in the art, as are described in the european patent application EP-A-0166287. For example, to prepare the sesquihydrate of the sodium salt of pantoprazole, a solution of pantoprazole and a stoichiometric amount of aqueous sodium hydroxide can be prepared in a solvent, and let the product to precipitate, or accelerate the crystallization by means of spreading crystals of the sesquihydrate of the sodium salt of pantoprazole. Finally, to complete the crystallization, a solvent which reduces the salt solubility can be added.

Compound (IV), wich is used as starting material in the process of the invention, can be prepared, for example, according to the process described in Example 5 of the patent application WO-A-02/28852. In a preferred embodiment, compound (IV) is prepared by a process comprising the reaction of compound (III), previously defined, with peracetic acid in presence of an inorganic base in a mixture of solvents comprising at least a halogenated solvent and a d-C₄ alcohol, and isolating the obtained product.

Compound (III) can be prepared, for example, according to the process disclosed in Example 4 of the patent application WO-A-02/28852. Peracetic acid is the oxidative agent used to oxidize compound (III). Said peracid is commercially available as a solution in acetic acid in a concentration of 36% by weight. Preferably, the amount of peracetic acid used in the oxidation reaction is comprised from 95% to 105% of the stoichiometric amount of peracetic acid with regard to compound (III). More preferably, a substantially stoichiometric amount of peracetic acid with regard to compound (III) is used. The oxidation reaction is carried out in presence of an inorganic base.

Preferably, the inorganic base is selected from the group comprising sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, and/or mixtures thereof. The mixture of solvents wherein the oxidation reaction is carried out comprises at least a halogenated solvent and a CrC₄ alcohol.

The halogenated solvent is selected from the group comprising methylene chloride, chloroform, carbon tetrachloride, 1 ,1 ,1-trichloroethane, 1 ,1-dichloroethane, 1 ,2-dichloroethane, and/or mixtures thereof. The CrC₄ chained alcohol can be linear or branched and it is selected from the group comprising methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, and/or mixtures thereof. Preferably, a mixture of isopropanol and methylene chloride is used, wherein the (w/w) ratio of the CrC₄ chained alcohol to the halogenated solvent is comprised from 5:95 to 25:75. Preferably, the oxidation reaction is carried out at a temperature comprised from 0° C to 30° C, more preferably from 0° C to 5° C.

To carry out the oxidation reaction, the starting compound (III) is dissolved in said mixture of solvents, and it is maintained at a temperature inside said range.

Next, an inorganic base in solid form is added to said solution, and it is kept as a suspension by means of stirring. Peracetic acid is slowly added over the heterogeneous mixture maintaining it inside the same interval of temperature. The reaction between the peracetic acid and the starting compound (III) is almost instantaneous and its course can be conveniently monitored by means of thin film chromatography or HPLC. The addition of peracetic acid finishes when the amount of said acid is approximately stoichiometric. Compound (IV) is isolated in the form of a white powder by means of conventional techniques which are well known by the person skilled in the art as, for example, extractions with water/methylene chloride, evaporation of the organic solvent, precipitation from a suitable solvent, for example acetonitrile, and drying in a furnace.

As an example, when the process of the invention is carried out according to a preferred embodiment, employing a 100% of the stoichiometric amount of peracetic acid, with sodium bicarbonate as a base, into a mixture of methylene chloride an isopropanol in a (w/w) ratio of 85:15, only a 3% of the overoxidized sulfone impurity is formed, which is easily removed by means of a single crystallization in acetonitrile. Finally, compound (IV) is obtained yielding 85% and containing a 0.1% of sulfone.

The compound (IV) obtained according to the process of the invention can be used as starting product for the preparation of pantoprazole and pharmaceutically acceptable salts thereof, as said before.

EXAMPLES

Example 1- Preparation of the starting compound (IV)

250 g of monohydrated compound (III), with a water content of 4.6%, which correspond to 238.5 g (0.641 mol) of anhydrous compound (III), were mixed with 2650 g of methylene chloride and 471 g of isopropanol in a 5 I four neck flask, furnished with mechanic stir, thermometer, tap funnel and nitrogen atmosphere. It was stirred until complete solution, and it was cooled down at a temperature comprised from 0° C to 5° C. 538.8 (6.41 mol) of sodium bicarbonate were added over the cold solution and maintained as a suspension by stirring.

135.51 g (0.641 mol) of peracetic acid with 36% by weight of acetic acid were added by means of the tap funnel.

The addition of the oxidative agent was carried out slowly, so that the temperature of the mixture remained from 0° C to 5° C. Once the reaction was finished, 2 I of water were added over the reaction mixture and the pH of the aqueous phase was adjusted to a value comprised from 7.5 to 8.5 with 30% by weight sodium hydroxide, and the mixture was filtered through a layer of diatomaceous earth.

The phases were separated and the upper aqueous phase was extracted with methylene chloride. The gathered organic phases were evaporated to dryness, until a residue crystallized in acetonitrile was obtained. 298 g of a wet white solid were obtained and resulted in 211 g of product (IV) by means of drying at a temperature of 40° C in a vacuum furnace. The yield of the oxidation reaction was 85%, and the product contained a 0.1% of sulfone impurity.

Example 2- Preparation of pantoprazole

209 g of compound (IV) (0.538 mol), obtained according to Example 1 , were suspended in 929 g (1045 ml) of tetrahydrofurane into a 3 I four neck flask, furnished with mechanical stir, condenser, thermometer, tap funnel and nitrogen atmosphere.

582 g of sodium methoxide, 30% by weight in methanol, which equals to 174.6 g (3.23 mol) of sodium methoxide and 407.4 g (515 ml) of methanol, were added over the resulting suspension.

The resulting mixture was stirred and the obtained solution was refluxed for 3-4 hours.

At the moment the reaction was over, the reaction mass contained a 96% of pantoprazole, quantified by means of HPLC, and a 2.8% of dificult to remove impurities. The resulting suspension was cooled down to 20° C-3O⁰ C, about 1 I of water was added, and the organic solvents (methanol and tetrahydrofuran) were vacuum distilled. About 1.5 I of water were added over the resulting residue, and it was heated to 40° C - 45° C for about 2 hours. The resulting solution was cooled down below 30° C and extracted with methylene chloride previously pH had been adjusted with acetic acid to a value comprised from 8.0 to 8.5.

The gathered organic phases, which contained pantoprazole, were filtered through diatomaceous earth, and they were repeatedly washed with water at a temperature comprised from 0° C to 5° C at pH 10.

The washed organic phase was extracted with aproximately 1 I of water maintaining the pH value at 13 with 30% by weight sodium hydroxide, and the organic phase was discarded.

Activated carbon and about 1 I of methanol were added over the aqueous phase containing the product as sodium salt, and it was filtered through diatomaceous earth.

The resulting solution was ajusted to pH 7.5-8.5 with acetic acid, pantoprazole was spreaded over the solution and it was stirred at 20° C-3O⁰ C, until an abundant precipitate appeared. The suspension was cooled to 0° C-5° C to complete the precipitation of pantoprazole. Next, the solid was filtered and it was washed with water/methanol.

187.1 g of wet pantoprazole were obtained, which led to 157.2 g of pantoprazole after vacuum drying at 40° C in a furnace. Pantoprazole was obtained according to the process of the invention yielding

76%, with purity above 99% and all the impurities below 0.1%, being a suitable product to be used as active compound in pharmaceutical formulations.

Examples 3 to 5- Preparation of pantoprazole

Pantoprazole was prepared according to the same process of Example 2, wherein methanol and tetrahydrofuran were used as solvents at a (v/v) ratio of 33:67, and 6 equivalents of sodium methoxide (MeONa), but modifying the nature of the solvents and their proportions, as well as the equivalents of sodium methoxide, as shown in Table 1. TABLE 1

Pantoprazole was always obtained yielding more than 75%, with purity above 99% and all the impurities below 0.1% in weight.

Example 6- Preparation of the sesquihvdrate of the sodium salt of pantoprazole

A solution containing 80 g of pantoprazole (I), prepared in Example 2, 160 ml of isopropanol and an aqueous solution of sodium hydroxide (8,35 g in 11.3 ml of water) was prepared in a 2 I flask furnished with a thermometer, a tap funnel and nitrogen atmosphere.

Crystals of the sesquihydrate of the sodium sat of pantoprazole were spread over the solution to facilitate the precipitation.

The mixture was stirred at room temperature for at least 1 hour. Next, 800 ml of the methyl tert-butyl ether were added, the solution was cooled down to a temperature comprised from 0 ⁰C to 5 ⁰C and it was maintained for at least one hour.

The solid was filtered and, after drying, 85.7 g of the sesquihydrate of the sodium salt of pantoprazole were obtained, yielding 95%. Comparative example 1 - Preparation of pantoprazole using methanol as the sole solvent

Pantoprazole was prepared according to the same process disclosed in Example 2 using methanol as the sole solvent and 6 equivalents of sodium methoxide, in such a case as a solid.

In such a case, the reaction required 50 hours under refluxing to be completed. At the moment the reaction was finished, the reaction mass contained a 78% of pantoprazole, quantified by HPLC, and a 7.8% of difficult to remove impurities.

Comparative example 2 - Literal reproduction of Example 6 disclosed in the patent application WO-A-02/28852

The reaction conditions and amounts disclosed in Example 6 of the patent application WO-A-02/28852 were literally reproduced. In table 2, data relative to purity of the reaction mixture at the moment of finishing the reactions of comparative examples are compared to the purity values from Examples 2 to 5 of the invention. The content of difficult to remove impurities quantified by HPLC is shown as a purity marker, which as said before includes compound of formula (IV) and its precursor of formula (V).

TABLE 2

As shown in Table 2, the content of difficult to remove impurities formed in the methoxylation reaction in the Examples of the invention is from 2.5 to 4 times lower than the content obtained in the comparative examples. In Comparative example 2, pantoprazole was prepared yielding 51% with regard to compound (IV), with 98% of purity, and 1.5% of difficult to remove impurities.

In Example 2, according to the process of the invention, pantoprazole was prepared yielding 76%, with purity above 99%, and all the impurities below 0.1%. Thus, It is demonstrated that, by the process of the invention, pantoprazole is prepared yielding 1.5 times more than in Comparative example 2, and with a higher purity, since the content of difficult to remove impurities is 15 times lower than in Comparative example 2.

Claims

1.- Process for the preparation of pantoprazole and its pharmaceutically acceptable salts characterised in that it comprises reacting the compound (IV)

(IV)

with an alkaline methoxide in a mixture of solvents which comprises methanol and a polar aprotic solvent, so that the volume/volume ratio of methanol to said solvent is comprised from 10:90 to 60:40, isolating the obtained product, and, if desired, transforming it into a pharmaceutically acceptable salt.

2.- The process according to claim 1 , characterised in that the alkaline methoxide used is sodium methoxide or potassium methoxide.

3.- The process according to claims 1-2, characterised in that an excess of alkaline methoxide comprised from 2 to 7 mol of alkaline methoxide is used for each mol of compound (IV).

4.- The process according to claims 1-3, characterised in that the polar aprotic solvent is selected from the group consisting of tetrahydrofuran, acetonitrile, dioxane, dimethyl sulfoxide, dimethylformamide, and mixtures thereof.

5.- The process according to claim 4, characterised in that the aprotic solvent is selected from the group consisting of tetrahydrofuran, acetonitrile, and mixtures thereof.

6.- The process according to claims 1 to 5, characterised in that volume/volume ratio of methanol to the polar aprotic solvent is comprised from 20:80 to 45:55.

7.- The process according to claims 1 to 6, characterised in that the isolation of pantoprazole includes a purification method which comprises:

a) distilling the solvents used in the reaction until a residue is obtained, b) adding water to the obtained residue and heating the mixture to a temperature comprised from 40° C to 50° C for a period comprised from 1 to 4 hours, and later cooling down at room temperature, c) extracting repeatedly the obtained aqueous solution with an organic solvent which is not miscible in water at a pH comprised from 7.5 to 8.5, and discarding the aqueous phase, d) filtering the organic phase and washing repeatedly the filtered organic phase with water maintaining the pH at a value comprised from 9.5 to 10.5, and discarding the aqueous phase, e) extracting the obtained organic phase with water maintaining the pH of the mixture at a value not lower than 13, and discarding the organic phase, and f) adding methanol to the obtained aqueous phase, and precipitating the pantoprazole from this hydroalcoholic solution by adjusting it to a pH comprised from 7.5 to 8.5.

8.- The process according to claim 7, characterised in that the extractions of step c) are carried out at a temperature comprised from 15° C to 30° C, and the extractions on step d) at a temperature comprised from 0° C to 10° C.

9.- The process according to claims 7 and 8, characterised in that pantoprazole is precipitated from a hydroalcoholic solution which comprises equal volumes of methanol and water.

10.- The process according to claims 1 to 9, characterised in that the starting compound (IV) is obtained by a process which comprises the reaction of compound (III),

with peracetic acid in the presence of an inorganic base in a mixture of solvents which comprises at least an halogenated solvent and a CrC₄ alcohol, and isolating the obtained product.

11.- The process according to claim 10, characterised in that it is used an amount of peracetic acid comprised from 95% to 105% of the stoichiometric amount of peracetic acid related to compound (III).

12.- The process according to claim 11 , characterised in that is used an amount substantially stoichiometric of peracetic acid related to compound (III).

13- The process according to claims 10 to 12, characterised in that the inorganic base is selected from the group consisting of sodium bicarbonate, potassium bicarbonate, calcium carbonate, potassium carbonate, and mixtures thereof.

14.- The process according to claims 10 to 13, characterised in that the halogenated solvent is selected from the group consisting of methylene chloride, chloroform, carbon tetrachloride, 1 ,1 ,1-trichloroethane, 1 ,1-dichloroethane, 1 ,2-dichloroethane, and mixtures thereof.

15.- The process according to claims 10 to 14, characterised in that the CrC₄ alcohol is selected from the group consisting of methanol, ethanol, n- propanol, isopropanol, n-butanol, isobutanol, te/f-butanol, and mixtures thereof.

16.- The process according to claims 10 to 15, characterised in that a mixture of isopropanol and methylene chloride is used.

17.- The process according to claims 10 to 16, characterised in that the (w/w) ratio of the CrC₄ chained alcohol to the halogenated solvent is comprised from 5:95 to 25:75.