MXPA98008790A - Process for the preparation of a magnesium salt of a heterocicle of sulfinyl sustitu - Google Patents

Abstract

A novel process for the preparation of a magnesium salt of the formula (I) of a substituted sulfinyl heterocyclic compound containing an imidazole portion. The process is carried out by mixing the substituted heterocycle of the formula (I) with a weak base and a magnesium source. The magnesium base and source are selected to result in residues that are easily removed during the reaction. The invention also relates to the use of the compounds produced in the measurement

Description

* •% PROCESS FOR THE PREPARATION OF A MAGNESIUM SALT OF A SUBSTITUTE SULPHINIL HETEROCIDE FIELD OF THE INVENTION The present invention relates to a novel process for the preparation of magnesium salts of heterocyclic substituted sulfinyl compounds containing a portion of imidazole, as well as 10 as well as the use of magnesium salts produced in medicine. More particularly, the present invention relates to the preparation of magnesium salts of substituted benzimidazoles such as the magnesium salts of omeprazole and its 15 simple enantiomers.

BACKGROUND OF THE INVENTION AND PREVIOUS TECHNIQUE Substituted benzimidazoles such as, for example, compounds with the generic names omeprazole, lansoprazole, pantoprazole, pariprazole and leminoprazole have properties that form compounds useful as inhibitors of gastric acid secretion. This class of compounds is known as proton pump inhibitors or inhibitors.

REF: 28563 of H + K + ATPase. There are a large number of patents and patent applications that describe such proton pump inhibitors and processes for their preparation. There is a general need in the industry that pharmaceutically acceptable compounds must be produced by means of processes that give products with properties that make them suitable for pharmaceutical preparations, in such a way that they are easy to handle in a large scale production and that they have good storage stability. WO 95/01977 discloses a magnesium-novel salt of omeprazole with a specific degree of crystallinity which makes the product suitable for pharmaceutical formulations. The novel product is prepared by a process comprising the following steps; reacting omeprazole with magnesium alcoholate; separating inorganic salts from the reaction mixture; crystallize the magnesium salt of omeprazole and isolate the product. Magnesium alcoholate is formed from metallic magnesium that requires special process conditions. The use of magnesium alcoholate in the process constitutes a potential difficulty with the formation of relatively insoluble magnesium salts, such as magnesium hydroxide. Filtration of such magnesium hydroxide is complicated due to extremely small gelling and particle size. The above process is quite complicated, it is sensitive to water and requires special conditions. The above process also has a need for large equipment in the form of three reaction vessels and a separator. Therefore, there is a need for a more efficient process which results in short manufacturing time, lower reaction equipment and higher yield per volume. The present invention provides improvements: on the process described in WO 95/01977 for the preparation of the magnesium salts of omeprazole and other substituted benzimidazoles. The process for the preparation of certain salts of the simple enantiomers of omeprazole, such as the magnesium salts, and processes for their preparation are described in EP 94917244.9. As discussed in WO 95/01783, the magnesium salts of proton pump inhibitors, such as the magnesium salt of omeprazole, are especially suitable for the manufacture of pharmaceutical formulations, such as tablets. Magnesium salts are stable, can be easily purified by crystallization, and are easy to handle in pharmaceutical processes and processes.

BRIEF DESCRIPTION OF THE INVENTION The present invention provides a novel process for the preparation of magnesium salts of substituted sulfinyl heterocycles containing a portion of imidazole and especially substituted benzimidazole derivatives. The process results in high yield per volume, requires less equipment, consumes less time, does not harm the environment and is more economically efficient than the processes described in the patent applications mentioned in the above. According to the novel process, a magnesium salt of a substituted sulfinyl heterocycle containing an imidazole portion is prepared by mixing the substituted sulfinyl heterocycle containing a portion of imidazole with a weak base, preferably an amine or ammonia, and a magnesium source, such as an organic or inorganic magnesium salt or a combination of such salts. The formation of magnesium hydroxide is avoided by means of the novel process of the present invention, for example in the preparation of the magnesium salt of omeprazole. Alternatively, the process can also be used to prepare other salts of a substituted sulfinyl heterocycle containing an imidazole moiety, for example multiple valence salts, such as calcium salts.

DETAILED DESCRIPTION OF THE INVENTION The present invention provides a novel method for preparing a magnesium salt of a substituted sulfinyl heterocycle containing an imidazole moiety with the following formula I. where Z is and X is wherein N within the benzene ring of the benzimidazole moiety means that one of the carbon atoms substituted by R7-R? 0 can optionally be exchanged for a nitrogen atom without any substituents; Ri, R2 and R3 are the same or different and are selected from hydrogen, alkyl, alkylthio, alkoxy optionally substituted by fluorine, alkoxyalkoxy, dialkylamino, piperidino, morpholino, halogen, phenylalkyl and phenylalkoxy; wherein the alkyl and alkoxy groups may be branched or linear and may comprise cyclic alkyl groups such as cycloalkylalkoxy groups; R and R5 are the same or different and are selected from hydrogen, alkyl and aralkyl; Rβ is hydrogen, halogen, trifluoromethyl, alkyl and alkoxy; R7-R10 are the same or different and are selected from hydrogen, alkyl, alkoxy, halogen, haloalkoxy, alkylcarbonyl, alkoxycarbonyl, oxazolyl, trifluoroalkyl, or the adjacent groups of R7-R10 form ring structures that can be further substituted; R11 is hydrogen or forms an alkylene chain together with R3; and R12 and R13 are the same or different and are selected from the groups hydrogen, halogen, alkyl or alkoxy, wherein the alkoxy groups may be linear or branched C1-C9 chains and the alkyl and alkoxy groups may comprise cyclic alkyl groups, example cycloalkylalkyl. Preferably, the substituted sulfinyl heterocyclic compound containing an imidazole moiety prepared by the novel method is a magnesium salt of the formula I '. where Ar is and Ri-Rn are as defined in the foregoing in relation to formula I.

More preferably, the compounds prepared by the novel process are any of the formulas a to Ih.

The substituted sulfinyl heterocycle of Formula I is mixed / reacted with a weak base and a magnesium source and optionally in the presence of an organic solvent. After the reaction is complete, the mixture is clarified, if necessary. The product of preference is precipitated from the filtrate, optionally, by the addition of an appropriate solvent, for example water or acetone, which facilitates the precipitation of the product. As an additional benefit, when water is used, the solubility of the inorganic salts is improved resulting in less impurities in the form of inorganic salts in the product obtained. The product obtained in addition can be processed by means of recrystallization. The novel process according to the present invention can be exemplified by the following reaction scheme showing a reaction between a substituted beneimidazole (HA) and a weak base (B) in the presence of a magnesium source (MgmXn). 1 HOUR? + 1B "^ M ^ <J¡faaßS ..? In the above formula, wherein HA is a substituted benzimidazole, H means the most acidic proton in the compound, B is a weak base and X is a counter ion for Mg2 + in the magnesium source (MgmXn). The base used in the reaction should not be toxic or should only have a low toxicological effect. Preferably it should be a weak base to minimize the precipitation of poorly soluble inorganic magnesium salts, such as magnesium hydroxide during the reaction sequence. Such precipitation of, for example, magnesium hydroxide - is normally difficult to eliminate during the process and in the final product. By "weak base" is meant a base with a lower pKa than the alkoxides and hydroxides, but greater than the substituted sulfinyl heterocycles of the present invention, preferably with a pKa of 7-12. Most preferably the weak base is an organic amine or ammonia. With regard to environmental aspects, the base should preferably be one that results in waste in the form of ammonium salts that can easily be isolated, for example, by filtration or centrifugation, to minimize the effluent of nitrogen-based contaminants, such as ammonia. The magnesium source can be an organic as well as an inorganic magnesium salt, such as magnesium acetate, nitrate. magnesium, magnesium sulfate, magnesium carbonates and magnesium chloride, preferably magnesium sulfate. If one solvent is used in the reaction, one that can be used throughout the entire process is preferred. In such a way a solvent is preferably an alcohol, for example methanol. The process is not sensitive to temperature and can be carried out at room temperature. Of course, the temperature and time of the process can be adjusted with respect to the quality and yield of the obtained product. The recent process according to. the present invention can be exemplified more generally by the manufacture of the magnesium salt of omeprazole. The magnesium salt of omeprazole can be formed according to the invention by treating a weight amount of omeprazole with heavy amounts of aqueous ammonia and magnesium sulfate in methanol.

The procedure of loading the different reagents is not critical to the processed product.

A specific procedure may be preferred over the equipment currently used in the industry. The temperature can be from -10 ° C to + 50 ° C and preferably between 0 ° C and room temperature. After completion of the reaction, the resulting inorganic magnesium salts are separated in a suitable equipment, such as a centrifuge or a pressure filter. The temperature of the clear solution is adjusted from -10 ° C to + 40 ° C, preferably from 10 ° C to 35 ° C. The solution can be seeded with crystals of magnesium salt of omeprazole and an amount of water is added to start the precipitation. The amount of water is not critical, but it can be equal to or less than the volume of the solution; preferably the last one. The crystalline product formed is separated from the mother liquor (filtrate), for example by centrifugation or filtration. Other suitable procedures can be used to separate the product. The produced crystalline product is washed with aqueous methanol and dried under reduced pressure and heat.

The process according to the present invention is described in more detail by way of the following examples, which are not intended to limit the scope of the invention.

Eg emplos Example 1. Preparation of the magnesium salt of 5-methoxy-2- [[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] -sulfinyl] -lH-benzimidazole. 5-Methoxy-2- [[(4-methoxy-3,5- "dimethyl-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazole (31.6 kg, 91.6 moles) is added together with aqueous NH3 (7.4 kg, 107 moles) to methanol (212 1) MgSO x 7 H20 (17.6 kg, 69.9 moles) was added to the obtained mixture at room temperature After the reaction was complete, the inorganic salts were removed by filtration. add water to the filtrate, clarify the mixture and add water (91 1) .The mixture is stirred to crystallize the product.The product obtained is centrifuged and washed with a mixture of MeOH / water. reduced pressure at 40 ° C. Yield: 71% (Mg content: found 3.47%, Theoretically calculated 3.41%) The% crystallinity of the product obtained is measured with powder X-ray diffraction (XRD) as described in next: A thin layer of the crushed sample is smeared on an individual silicone glass cut from a zero-entry support ual is rotated during the measurement. Radiation and Cu Ka constant or automatic antidispersion and divergence slots are used to obtain a diffractogram of 1 or 2 ° 2? to at least 35 °. The% crystallinity is calculated with the formula of crystallinity = 100 * C / (A + C; C = the area of the peaks in the diffractogram ("the area of crystallinity"), A = the area between the peaks and the introduction ("the amorphous area"). Area calculations are carried out between 4-33 ° 2T. The value of. The lowest intensity found in this range is chosen as the input constant and subtracted from area A. When the constant slots are used, the input is increased at low angles, due to the influence of the primary light beam, it is also subtracted from the area A. The crystallinity was measured to be 80 ± 5% (calculation interval 4-33 °).

Example 2. Preparation of the magnesium salt of 5-methoxy-2- [[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] -sulfinyl] -1H-benzimidazole. 5-Methoxy-2- [[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazole is added (25 g, 72.4 mmol) together with isopropylamine (7.4 ml, 86.9 mmol) to methanol (100 ml). MgS0 x 7 -H20 (8.85 g, 35.9 mmol) was added to the mixture obtained at room temperature. After the reaction is complete, the inorganic salts are removed by filtration. Water is added to the filtrate, the mixture is clarified and water (100 ml) is added dropwise. The product is filtered off and washed with a MeOH / water mixture (50 ml, 1: 1). The product is dried under reduced pressure overnight. Yield: 95%. (Mg content: 3.41; Calculated theoretically 3.41.) Example 3. Preparation of the magnesium salt of 5-methoxy-2- [[(4-methoxy-3,5-dimethyl-2-pyridinyl) ethyl] -sulfinyl] -lH-benzimidazole. 5-Methoxy-2- [[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl] -lH-benzimidazole is added (25 g, 72.4 mmol) together with isopropylamine (7.4 ml, 86. 9 mmol) to methanol (100 ml). Add to the obtained mixture Mg (0Ac) 2 x 4 H20 (9.34 g, 43.6 mmol) at room temperature. After the reaction is complete, the inorganic salts are removed by filtration. Water is added to the filtrate, the mixture is clarified and water (100 ml) is added dropwise. The product obtained is extracted by filtration and washed with a mixture of MeOH / water (50 ml, 1: 1). The product is dried under reduced pressure overnight. Yield: 92%. (Mg content: 3.42; Calculated theoretically 3.41.) Example 4. Preparation of the magnesium salt of 5-methoxy-2 - [[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] -sulfinyl] -lH-ben? imidazole 5-Methoxy-2- [[(4-methoxy-3,5-dimethyl-2-pyridinyl) ethyl] sulfinyl] -lH-benzimidazole is added (25 g, 72.4 mmol) together with isopropylamine (7.4 ml, 86.9 mmol) to methanol (100 ml). Mg (N03) 2 x 6 H20 (11.2 g, 43.7 mmol) is added to the mixture at room temperature. After the reaction is complete, the inorganic salts are removed by filtration. Water is added to the filtrate, the mixture is filtered and the filter cake is washed with methanol (10 ml). Water (100 ml) is added dropwise to the combined organic layers. The product is removed by filtration and washed with a MeOH / water mixture (50 ml, 1: 1). The product is dried overnight. Performance: 89%. (Mg content: 3.39; Calculated theoretically 3.41.) Example 5. Preparation of the magnesium salt of 5-methoxy- * 2- [[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] -sulfinyl] -lH-benzimidazole. 5-Methoxy-2- [[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl] -lH-bene imidazole (1.0 g, 2.9 mmol) is added along with diethylamine (0.35 ml, 3.4 mmol) ) to methanol (9 ml). MgCl 2 (142 mg ', 1.5 mmol) in methanol (2 ml) was added to the obtained mixture at room temperature. Water (6.5 ml) is added in drops. The product obtained is extracted by filtration and washed with a mixture of MeOH / water (20 ml, 1: 1). Yield: 76%. (Mg content: 3.38, theoretically calculated 3.41.) Example 6. Preparation of the magnesium salt of (-) - 5-fluoro-2- [[(4-cyclopropylmethoxy-2-pyridinyl) methyl] -sulfinyl] -lH -benzimidazole. (-) -5-Fluoro-2- [[(4-cyclopropyl-methoxy-2-pyridinyl) ethyl] sulfinyl] -lH-benzimidazole is added (20 g, 57.9 mmol) together with NH3 (7.5 mL, 100.2 mmol) to methanol (80 mL). MgSO4 x 7 H20 (11.4 g, 45.3 mmol) is added to the mixture at room temperature. The mixture is clarified. Water (8 ml) is added dropwise during rapid stirring. Another portion of water (72 ml) is added in drops for 75 minutes. The mixture is stirred for 50 minutes while the product is precipitated. The product is removed by filtration and washed with a mixture of MeOH / water (2 ml, 1: 1). The product is dried under reduced pressure at 35 ° C overnight. Yield: 61%. (Mg content: 3.40, calculated theoretically 3.41.) Example 7. Preparation of the magnesium salt of 5-fluoro-2 - [[(4-cyclopropylmethoxy-2-pyridinyl) methyl] -sulfinyl] -lH-benzimidazole. 5-Fluoro-2- [[(4-cyclopropylmethyl-2, -pyridinyl) methyl] sulfinyl] -lH-ben cimidazole (10 g, 28. 9 mmol) together with isopropylamine (1.71 g, 28.9 mmol) to methanol (40 ml). MgCl 2 (1.35 g, 14 mmol) was added to the obtained mixture at room temperature. The excess amine is evaporated. The mixture is clarified and water is added dropwise (56.5 ml). The mixture is cooled to 20 ° C and the product is filtered off and washed with a MeOH / water mixture. (20 ml, 3: 1). The product obtained is dried under reduced pressure at 50 ° C overnight. Performance: 86%.

(Mg content: 3.42, calculated theoretically 3.41.) Example 8. Preparation of the magnesium salt of 5-fluoro-2- [[(4-cyclopropylmethoxy-2-pyridinyl) methyl] -sulfinyl] -1H-benzimidazole. 5-Fluoro-2- [[(4-cyclopropylmethoxy-2-pyridinyl) methyl] sulfinyl] -lH-benzimidazole (690 g) is added, 1.97 mmole) together with aqueous NH3 (140 ml, 2.17 mol) to methanol (2.4 1). MgCl 2 (105.2 g, 1.08 mol) in methanol (940 ml) is added to the obtained mixture. The mixture is clarified and water (350 ml) is added during rapid stirring. Another portion of water is added (3.15 1) and the mixture is stirred overnight. The product is extracted by filtration and washed with a mixture of MeOH / water (11: 4: 1). Yield: 91%. (Mg Content: 3.46; calculated theoretically 3.41.) Example 9. Preparation of the magnesium salt of. (-) - 5-methoxy-2- [[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] -sulfinyl] - lH-benCimidazole. (-) -5-Methoxy-2- [[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl] -lH-benzimidazole is added (10.6 g, 29 mmol) together with aqueous ammonia (3.8 ml of 25%, 50 mmol) to methanol (40 ml). It is added to. MgS04 x 7 H20 solution (5.7 g, 23 mmol). After stirring for 10 minutes the mixture is filtered and the filtrate is diluted with methanol (60 ml). Acetone (150 ml) is added and the solution is seeded with crystals while stirring. After 14 hours, the product is isolated by filtration and the crystals are washed with methanol / acetone (50 ml). The product is dried overnight. Yield: 41%. (Mg content: found 3.33%, Calculated for (C17H18N303S) 2Mg 3.41%.) Example 10. Preparation of the magnesium salt of 5-difluoromethoxy-2- [[(3,4-dimethoxy-2-pyridinyl) methyl] -sulfinyl] -lH-benz imidazole. 5-Difluoromethoxy-2- [[(3,4-dimethoxy-2-pyridinyl) methyl] sulfinyl] -lH-benz imidazole is added (11.1 g, 29 mmol) together with aqueous ammonia (3.8 ml of 25%, 50 mmol) to methanol (60 ml). The solution MgS0 x 7 H20 (5.7 g, 23 mmol) is added. After stirring for 3 minutes the mixture is filtered. Water (40 ml) is added dropwise to the filtrate while stirring. After 30 minutes the product is isolated by filtration and the crystals are washed with methanol / water (25 ml). The product is dried under reduced pressure. Performance: 67%. (Mg content: found 3.07%, Calculated for (C? 6H? 4N.304S) 2Mg 3.08%.) The best way to practice the invention in the present is by the process described in Example 1. It is noted that with In relation to this date, the best method known by the applicant to carry out the aforementioned invention is that which is clear from. the present description of the invention. Having described the invention as above, property is claimed as contained in the following:

Claims (11)

1. A process for the preparation of a magnesium salt of a heterocyclic compound. of substituted sulfinyl containing an imidazole portion according to Formula I characterized because Ar is Z is and X is where N within the benzene ring of the benzimidazole moiety means that one of the carbon atoms substituted by R7-R? or optionally can be exchanged for a nitrogen atom without any substituents; Ri, R2 and R3 are the same or different and are selected from hydrogen, alkyl, alkylthio, alkoxy optionally substituted by fluorine, alkoxyalkoxy, dialkylamino, piperidino, morpholino, halogen, phenylalkyl and phenylalkoxy; wherein the alkyl and alkoxy groups may be branched or linear and may comprise cyclic alkyl groups such as cycloalkylalkoxy groups; R and R5 are the same or different and are selected from hydrogen, alkyl and aralkyl; Re is hydrogen, halogen, trifluoromethyl, alkyl and alkoxy; R-R? O are the same or different and are selected from hydrogen, alkyl, alkoxy, halogen, haloalkoxy, alkylcarbonyl, alkoxycarbonyl, oxazolyl, trifluoroalkyl, or the adjacent groups of R7-R? Or form ring structures which can be further substituted; Rn is hydrogen or forms an alkylene chain together with R3; and R12 and R13 are the same or different and are selected from the groups hydrogen, halogen, alkyl or alkoxy, wherein the alkoxy groups may be linear or branched C1-C9 chains and the alkyl and alkoxy groups may comprise alkyl groups cyclic, for example cycloalkylalkyl, wherein the substituted sulfinyl heterocycle of Formula I is mixed together with a weak base and a magnesium source.

2. A process according to claim 1, characterized in that the weak base is selected. of the group of organic amines and ammonia.

3. A process according to claim 1, characterized in that the weak base is ammonia.

4. A process according to claim 1, characterized in that the magnesium source is selected from the group of the organic and inorganic magnesium salts.

5. A process according to claim 1, characterized in that the magnesium source is selected from the group of magnesium acetate, magnesium nitrate, magnesium sulfate, magnesium carbonates and magnesium chloride, preferably magnesium sulfate.

6. A process according to claim 1, characterized in that the reaction is carried out in the presence of a solvent.

7. A process according to claim 1, characterized in that the reaction is carried out in the presence of an aqueous organic solvent.

8. A process according to claim 1, characterized in that the weak base and the magnesium source are selected to give an ammonium salt which can be removed by means of filtration during the process.

9. The magnesium salt of 5-methoxy-2- [[(4-methoxy-3,5-dimethyl-1-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazole prepared by a process according to any of the claims 1 -8.

10. The magnesium salt of (-) - 5-methoxy-2- [[(4-methoxy-3,5-dimethyl-2-pyridinium) methyl] sulfinyl] -lH-benzimidazole prepared by a process in accordance with any of claims 1-8.

11. A pharmaceutical composition characterized in that it comprises a magnesium salt of a substituted sulfinyl heterocycle of the formula I prepared by a process according to any of claims 1-8 as an active ingredient and a pharmaceutically acceptable carrier.