The invention refers further to a sulfoxide component hav- ing the formula (I).

The invention concerns further a method for preparing a salt of a compound (I), that salt having the formula (IV) The invention finally concerns a pharmaceutical formula- tion comprising that salt (IV).

Pyridine benzimidazole sulfoxides, and in particular the salts of these compounds are useful as pharmaceuticals for treating ulcer diseases.

Well-known members of this pyridine benzimidazole sulfox- ide compounds are omeprazole, esomeprazole, lansoprazole, pan- toprazole, and rabeprazole.

A common way to prepare the pyridine benzimidazole sulfox- ide compound (I) is to oxidize the respective pyridine benzimi- dazole sulfide (or thioether) compound (II).

During that oxidation step, the sulfone compound (III) is produced as an undesired by-product.

The reaction scheme can be described as follows: Ri N R2 R3 N Rz Rs oxidation agent solvent N R1 0 Rz R3 overoxidation AI S U) undesired N R1 N 0 R2 3 A su N N-- N Many attempts have been made to solve this problem of the undesired overoxidation to the sulfone compound (III).

WO 03 062223 A of the applicant describes a method and a treatment of the semi-pure and sulfone contaminated product (I) with solid K2CO3 in an aqueous ethyl alcohol solution at ele- vated temperatures.

EP 1 000 943 A describes the formation of an acetone com- plex with the desired pyridine benzimidazole sulfoxide compound (I) for separating it from the undesired sulfone by-product.

The common oxidation agent is m-chloroperbenzoic acid, but other oxidation agents are useful, such as monoperoxyphthalate, hydrogene peroxide (with or without catalysts), permanganates, N-chloro or N-bromosucchinimide, 1, 3-dibromo-5,5- dimethylhydantoin, 2-hydroxyperoxyhexafluoro-2-propanol, oxygen (with or without catalysts), ozone, peroxymonosulfate, rutheni- umtetroxid, perborate and the like. The different oxidation agents nevertheless lead to the respective sulfone compound as an undesired by-product.

This undesired sulfone by-product has the disadvantage that this impurity in the final product will accelerate color- ing of the product in long term.

It is therefore an object of the invention, to provide a method for reducing the amount of undesired sulfone by-product during manufacturing of the sulfoxide compound.

The further object of the present invention is, to provide a salt of the sulfoxide component and a pharmaceutical composi- tion containing that salt which is of high purity and of long- term stability.

Within a method for preparing the pyridine benzimidazole sulfoxide compound, this object is achieved by stopping said oxidation step prior to the amount of pyridine benzimidazole sulfone compound (III) exceeds 1 %-by weight based on the en- tire amount of compounds of (I), (II), and (III).

It was noted when studying the oxidation reaction in fur- ther detail that the tendency to form undesired sulfone by- products accelerates at the end of the oxidation reaction. With the method of stopping the oxidation prior the amount of unde- sired sulfone compound exceeds a threshold value (1 %) leads to a crude sulfoxide compound having only a very small amount of undesired sulfoxide impurities. This facilitates or makes un- necessary a later purification step for removing the sulfone compound by known methods.

If the crude sulfoxide product is subsequently transferred into the respective salt, no additional purification step may be necessary, since during the later purification steps of the crude salt of the sulfoxide compound, the respective undesired sulfone compound is further reduced.

If the sulfoxide compound is not subsequently transferred to the respective salt, a removal of the sulfone impurity may be performed, but which is, due to the small amount of not exceeding 1 %-by weight, easier to perform, than with sulfoxide products, having higher contents of sulfone impurities.

In a further embodiment of the invention, the stopping of the oxidation step is performed prior the amount of sulfone compound exceeds 0,7 % or 0,5 %-by weight.

This measure has the advantage, that the amount of unde- sired by-product sulfone compound is so low, allowing a long- term storage without further purification steps, or if a subse- quent transfer to the respective salt is performed, allowing the manufacturing of a high purity salt.

In an embodiment of the invention, the method is performed by monitoring the amount of sulfone compound (III) in the reac- tion medium and stopping addition of the oxidation agent when the amount of undesired sulfone compound (III) reaches a threshold value.

This measure has the advantage that it opens a simple way to control the oxidation reaction, and in particular to control the time the stopping has to take place depending on the amount of undesired sulfone compound (III) to be tolerated, i. e. at the upper limit of 1 %, or at a lower contents like 0,7 or 0,5 %. The monitoring of the oxidation reaction can be per- formed for example by HPLC or the like. The oxidation reaction usually needs some time, i. e. several hours, and the oxidation agent is slowly added step by step. The monitoring allows a simple control and, if a desired threshold value is achieved, the oxidation reaction is stopped.

In a further embodiment of the invention, the method com- prises the step of extracting the desired sulfoxide compound (I) together with the undesired sulfone compound (III) from the reaction mixture and recovering remaining sulfide compound (II) for use in a further oxidation step.

Since the method of the invention uses a stopping of the oxidation step, the reactant, i. e. the starting sulfide com- pound is not yet entirely consumed. The recovering of not yet used sulfide compound (II) is easy to perform and results in a very economic process, since this recovered sulfide product is used as a reactant in a subsequent oxidation reaction.

In a further embodiment of the invention, the method con- tains the steps of treating the extracted compounds (I) and (III) with solid K2CO3 for further reducing the content of undesired sulfone compound (III).

This method is easy to perform and is disclosed in more detail in the earlier application WO 03 062223 A of the appli- cant.

The object of the invention is further achieved by a pyri- dine benzimidazole sulfoxide compound having the formula (I), which contains less than 0,2 %-by weight of the respective sulfone compound (III) and/or less than 0,5 %-by weight of the respective sulfide compound (II).

These pyridine benzimidazole sulfoxide compounds (I) show a low content of impurities (II) and (III) and can be stored as bulkware for a long term.

The object is further achieved by a salt of the pyridine benzimidazole sulfoxide compound (I), that salt having the general formula (IV) That salt is characterized by containing less than 0,2 %- by weight of the respective sulfone compound (III) salt as an impurity and/or containing less than 0,1 %-by weight of the respective sulfide compound (II) salt as an impurity. In a particular preferred embodiment, these impurities are less than 0,15 %-by weight of the sulfone compound salt, and/or less than 0,05 %-by weight of the respective sulfide compound salt.

In particular preferred embodiment of the invention, the salt is the sodium salt of pantoprazole in the form of a ses- quihydrate.

That high purity salt is characterized by a melting point in the range of 140-145°C, a water content of 6,0-6, 5 % and is crystallized in the form of needles from acetonitrile.

This salt is a high purity product with low impurity of sulfide and sulfone compounds and with a water content which is close to the sesquihydrate. In other words, if such a sesqui- hydrate form is dried further, a loss of water is less than 0,5 %. Extra humidity besides the crystal water will affect the long-term stability of the product, because of the known humid- ity sensitivity of the pantoprazole sodium salt.

The final sulfoxide product according to the invention al- lows to prepare pharmaceutical formulations of long stability, since the content of sulfide and sulfone impurities is very small. Further, the water content is close to the stoichiomet- rical sesquihydrate content, therefore, none of the undesired effects of the sulfide or sulfone impurities nor the effects of humidity can develop.

In the above given formulas, the meaning of the substitu- ents are identical for all of the above-mentioned compounds (I), (II), (III), and (IV).

A means, that the 6-ring in the benzimidazole moiety may optionally be substituted by a substituent selected from halo- gen, Ci7 alkyl, cyano, carboxy, alkoxycarbonyl having 1 to 4 carbon atoms in the alkoxy moiety, alkoxycarbonylalkyl having 1 to 4 carbon atoms in each of its alkoxy and alkyl moieties, carbamoyl, carbamoylalkyl having 1 to 4 carbon atoms in its alkyl moiety, hydroxy, ci-, alkoxy, C17 hydroxyalkoxy, CI-7 halo- genated alkyl, C14 halogenated alkoxy, C14 acyl, carbamoyloxy, nitro, C14 acyloxy, aryl, aryloxy, C16 alkylthio and C16 alkyl- sulfinyl.

R1 is hydrogen or an N-protecting group. The N-protecting group is preferably used, if during the oxidation procedure N- oxides may be formed.

If R1 is an N-protecting group, it may be selected from an alkyl group, a carbamoyl group, an alkylcarbamoyl group, an acyl group, a carboalkoxy group, a dialkylcarbomoyl group, an alkylsulfinyl group, an alkoxycarbonylmethyl group, or an al- kylcarbonylmethyl group.

Each of R2, R3, and R4 are, independently from another, hy- drogen, C14 alkyl group which may be optionally be substituted by halogen atom (s), Cig alkoxy group which may optionally be substituted by halogen atom (s) or with further C14 alkoxy groups.

M means alkali metal atoms, alkaline earth metals, ammo- nium salts, amines, basic amino acids.

The invention is now illustrated in further detail with help of the following examples, which do not limit the scope of the invention.

General procedure for preparation of Prazole-Na-salts of the formula (IVa) Step l : Preparation of the sulfide compound (II) A 2-Chloromethyl-pyridyne HC1 is reacted with a 2- mercaptobenzimidazole in the presence of a base, preferably sodium hydroxide in aqueous alcohol, preferably ethyl alcohol, at room temperature. Obtained crystals are filtered, firstly washed with 0,1 N sodiumhydroxyde solution, to remove any unre- acted starting materials, and then with plenty of water, till the washing waters are neutral to litmus.

The sulfide crystals (compound II) are then dissolved in methylene chloride and extracted with water. Organic solution is filtered and transferred into a brine-cooled vessel of the oxidation reaction.

Step 2A: Preparation of the sulfoxide compound (I) from sul- fide compound (II) The above-mentioned vessel content is cooled to below - 20°C. 5 % w/w solution of m-chloroperoxy benzoic acid and methylene chloride is added dropwise to the vessel content maintaining the reaction temperature always below-20°C.

The course of the oxidation reaction is carefully moni- tored with HPLC analysis. At the beginning, formation of sul- fone (III) is negligible, but towards the end of oxidation, that is when 8 to 15 % of the thioether (II) left unreacted, sulfone tends to exceed 0,5 to 0,7 % in the reaction medium.

Addition of more m-chloroperoxy benzoic acid is stopped at this stage. 25 % w/w solution of potassium carbonate in water is added to the reaction medium. pH is adjusted to above 10 with more 25 % potassium carbonate solution, if necessary. Methylene chloride is separated from aqueous layer and washed with water.

Aqueous extracts are combined and washed with methylene chlo- ride. Separated organic extracts are combined, filtered over celite, and distilled to dryness obtaining a residue.

Step 2B: Removal of sulfone by-product (III) from the crude product Removal is optional To the residue remaining in the vessel, 90% v/v aqueous ethanol is added. Vessel content is heated to 45 to 65°C, pref- erably to 55 to 60°C, and is kept at this temperature for 20 to 30 minutes to obtain a solution. To this solution solid K2CO3 crystals are added.

Amount of K2CO3 which should be added will be 2 to 4 % of the weight of the sulfide compound (II) charged for oxidation on dry basis. The slurry is aged for 15 to 20 minutes while maintaining the above temperature. The mixture is filtered over celite as hot in order to get rid of the insolubles mainly consisting of undissolved K2CO3 crystals.

Filter and lines are washed with 90 % ethyl alcohol as hot. The hot filtrate is distilled under reduced pressure until an oily residue in the form of a monohydrate and monoalcoholyte is obtained.

Step 2C: Removal of sulfide compound (II) from the crude sulfoxide product (I) Acetonitrile is added to the oily residue to precipitate the product after cooling to below 0°C. Vessel content is kept under stirring for several hours, preferably 4 hours in order to complete the precipitation. The slurry is filtered and the cake is washed with ice-cold acetonitrile.

Product is analyzed by HPLC to determine sulfone and sul- fide compound contents.

Due to the high solubility of the sulfide compound (II), most of this compound is in the acetonitrile solution. The amount of sulfide compound (II) remaining in the wet product may be negligible.

Anyhow, any sulfide compound (II) that might possibly re- main in the product (I) is well eliminated in a later step, when converting to its sodium salt in aqueous acetonitrile.

Step 2D: Recovery of sulfide compound (II) from mother liquor The sulfide compound (II) dissolved in the mother liquor of Step 2C of the filtered product is recovered as follows: Mother liquor containing 8 to 15 % unreacted sulfide com- pound (II) dissolved in acetonitrile is distilled to dryness under vacuum. Methylene chloride and water are added to the residue. pH is adjusted to. 12,5 to 13 with aqueous sodium hy- droxide solution. Phases are separated. The methylene chloride layer containing the sulfide compound (II) is treated with active carbon and filtered over celite and is kept as it is to be used together in the next batch's oxidation reaction, or can be oxidized alone in another batch. Aqueous phase containing the undesired sulfone component (III) as a sodium salt is dis- carded.

Step 3A: Obtaining of crude sodium salt Crude sulfoxide product is charged into acetonitrile five times weight of its own weight. Mixture is slowly heated to 40 to 45°C to obtain a solution. Equimolar amount of sodium hy- droxide dissolved in 20 % w/w solution in water is added over the acetonitrile solution and the reaction medium is kept at 40 to 45°C under agitation for about 15 to 20 minutes followed by cooling to 0°C. The slurry is kept stirring for 3 to 4 hours under ice-cooling. Slurry is filtered and washed with cold acetonitrile.

Step 3B: Obtaining pure product Crude sodium salt product is dissolved in ethanol, then filtered to eliminate insolubles. Water is added to the fil- trate and the solution is distilled to complete dryness under vacuum. The residue is cooled to room temperature. 90 % aqueous acetonitrile is added over the cooled residue and the mixture is agitated at a temperature of 20 to 25°C until precipitation starts. Then the slurry is cooled to-5/-10°C and kept under stirring in order to obtain complete crystallization for about 4 to 5 hours. Then vessel content is filtered and the wet cake is washed with cold acetonitrile several times. The wet cake is dried at 50°C under vacuum up to a constant weight. Crystal water of the product is determined by K. F. analysis. Loss on drying test is applied to the dry product.

EXAMPLE Preparation of Pantoprazole-Na-salt of the formula (V) Obtaining 5-difluoromethoxy-2-rr (3, 4-dimethoxv-2- pyridinvl) methvllthio-1-H-benzimidazole Reaction vessel was charged with 1050 kg water, 1050 li- ters of ethyl alcohol and 15.2 kg of sodium hydroxide flakes.

19.5 kg of 2-mercapto-5-difluoromethoxybenzimidazole was added to the vessel followed by addition of 20 kg 2-chloromethyl-3,4- dimethoxypyridine. HCl. The mixture was stirred at room tempera- ture for 4 hours. HPLC analysis should confirm the total con- sumption of 2-chloromethyl-3,4-dimethoxypyridine. HCl. 500 li- ters of water were added to the vessel and the mixture was stirred for additional 1 hour at room temperature. Mixture was centrifuged. Centrifuge was first washed with 500 liters of 0,1 N sodium hydroxide and then with plenty of water till the wash water was neutral to litmus.

Wet cake was charged another vessel containing 500 liters of methylene chloride and stirred till a clear solution was obtained. 200 liters of water were added to the vessel and stirred for 30 minutes. Organic phase was decanted, filtered over celite and transferred to a vessel equipped with brine cooling system. 26 kg of sulfide product on dry basis was ob- tained from this step.

Obtaining 5-(Difluoromethoxv)-2-r r (3, 4-dimethoxv-2- pvridinvl) methyl1sulfinvl1lH-benzimidazole (Pantoprazole) The solution of the above-mentioned product in methylene chloride is cooled to below-20°C with brine. In the meantime 11.3 kg 3-chloroperoxybenzoic acid is dissolved in 210 kg of dichloromethane. This oxidizing agent is added to vessel con- tent dropwise by keeping the reaction temperature below-20°C over 8 hours. Reaction is monitored by HPLC very carefully.

Sulfonic impurity is formed towards the end of the reaction faster. When the amount of sulfone as detected by HPLC reached 0,7 % in the reaction medium, the same sample was analyzed for its unreacted sulfide content and was found to be 12.2 %. Addi- tion of m-chloroperbenzoic acid is stopped and to the reaction mixture 200 liters of 25 % w/w K2CO3 was charged followed by heating to room temperature. After stirring the mixture at room temperature for about 30 minutes, pH of the aqueous layer was measured as 11.3.

Dichloromethane was separated and extracted with 200 li- ters of water. Aqueous phases were collected and extracted with 100 liters of methylenechloride twice. Combined organic ex- tracts were treated with activated carbon and filtered over celite. After distillation of the dichloromethane to dryness under reduced pressure, 200 liters 90 % v/v ethanol was charged on to the residue followed by heating at 60 °C for about 15 minutes. To the obtained solution 0.8 kg of solid K2CO3 was added and the mixture was stirred for 20 minutes at a tempera- ture of 55 to 60°C. The cloudy solution was then filtered over celite, vessel and the lines rinsed with 50 liters of 90 % ethylalcohol and transferred to the crystallization vessel and combined with the main solution. Solvent was distilled to dry- ness under vacuum and to the oily residue cooled to room tem- perature 100 liters of acetonitrile was charged. The mixture was cooled to below 0°C and keeping temperature below 0 °C, the obtained slurry was kept under stirring for 3 hours and centri- fuged. The centrifuge content was washed with 20 liters of ice- cooled acetonitrile. 20 kg of pantoprazole was obtained on dry basis.

HPLC test results for related impurities was as follows: Sulfone content < 0.2 %-by weight Sulfide content < 0.5 %-by weight Wet cake of pantoprazole may optionally be dried or can be used as wet for the next step.

Recovery of 5-difluoromethoxv-2-r r (3, 4-dimethoxy- pvridinvl) methvllthio-1-H-benzimidazole from the mother liquor Mother liquor obtained from centrifugation of crude panto- prazole contained 12 % unreacted sulfide dissolved in acetoni- tril and some amount of sulfone.

This liquor was distilled under vacuum till dryness. 150 liters of methylene chloride and 100 liters of water were added to the residue and pH of the mixture adjusted to 12.5 to 13.5 by adding 50 % NaOH solution. Methylene chloride containing unreacted sulfide was separated. Aqueous phase was washed with 50 liters of methylene chloride once more and organic phases were collected. Aqueous phase containing sulfone impurity was discarded. Combined organic phases was treated with active carbon and filtered over celite. This could be added to the next batch's oxidation reaction.

Obtaining 5-(Difluoromethoxv)-2-r r (3, 4-dimethoxy-2- pyridinvl) methvllsulfinvll-1-H-benzimidazole sodium salt (Pan- toprazole-Na) 20 kg of dry pantoprazole was charged to 100 liters of acetonitrile followed by warming to 40°C to get a clear solu- tion. To this solution 2.1 kg of sodium hydroxide dissolved in 4 kg of water was added. Solution was stirred for 20 minutes at 40 to 45°C, which then cooled the room temperature slowly and stirred for 1 hour. The mixture was then cooled to about 0 °C and aged for 2 hours under ice-cooling.

Precipitated product was centrifuged and washed with 20 liters of ice-cold acetonitrile. Centrifuge content was spun to dryness. 21 kg of wet cake was obtained. This product was optionally dried under vacuum or could directly be used in the purification process.

Obtaining pure Pantoprazole sesquihvdrate Crude sodium salt of pantoprazole was dissolved in 400 li- ters of ethylalcohol. The cloudy solution was filtered over celite to remove the insolubles. To thus obtained clear solu- tion 400 liters of water was added. Alcohol-water mixture was distilled to dryness under vacuum. The residue inside the ves- sel was cooled to 20 to 25°C. 100 liters of 90 % v/v aqueous acetonitrile was added over the residue in order to precipitate the product. The mixture was stirred at room temperature until precipitation started and then cooled to-5/-10°C and aged for 3 hours.

Slurry was centrifuged and washed with 20 liters of ice- cooled acetonitrile and spun to dryness. Pure product was dried at 50°C under vacuum to constant weight.

Loss on drying test of the product: 0.12 %-by weight Total water content, determined by K. F.: 6.13 %-by weight Sulfone content 0,15 %-by weight Sulfide content 0,05 %-by weight Melting point 137°C to 145°C Crystallinity Needles