Title of Invention	IMPROVED PROCESS FOR PRODUCING S-OMEPRAZOLE MAGNESIUM IN AMORPHOUS FORM
Abstract	The present invention relates to an improved process for the preparation of S-omeprazole magnesium in amorphous form, wherein the process comprises providing alkali or alkaline earth metal salt of S-omeprazole in water, adjusting pH of the reaction mixture to alkaline, contacting the resulting alkali or alkaline earth metal salt solution of S-omeprazole with an organic solvent selected from an alkyl alcohol, adding a source of magnesium and isolating the precipitated solid.

Title of Invention

IMPROVED PROCESS FOR PRODUCING S-OMEPRAZOLE MAGNESIUM IN AMORPHOUS FORM

Abstract

The present invention relates to an improved process for the preparation of S-omeprazole magnesium in amorphous form, wherein the process comprises providing alkali or alkaline earth metal salt of S-omeprazole in water, adjusting pH of the reaction mixture to alkaline, contacting the resulting alkali or alkaline earth metal salt solution of S-omeprazole with an organic solvent selected from an alkyl alcohol, adding a source of magnesium and isolating the precipitated solid.

Full Text	This application is an improvement of the invention claimed in Indian Patent Application No. 1796/DEL/2006 filed on August 8, 2006. FIELD OF THE INVENTION This invention, in general relates to an improved process for producing S-omeprazole magnesium. More particularly, but without restriction to the particular embodiments hereinafter described in accordance with the best mode of practice, the present invention is directed to improved process for the preparation of S-omeprazole magnesium in amorphous form. BACKGROUND OF THE INVENTION Different solid forms of the same drug may exhibit different properties, including characteristics that have functional implications with respect to their use as active ingredients of pharmaceutical products. For example, polymorphs of the same drug may have substantial differences in such pharmaceutically important properties such as dissolution rates and bioavailability. Likewise, different polymorphs may have different processing properties, such as hydroscopicity, flowability, and the like, which could affect their suitability as active pharmaceuticals for commercial production. Differently substituted 2-(2-pyridinylmethyl sulphinyl)-lH-benzimidazoles such as omeprazole, lansoprazole, pantoprazole and rabeprazole are known as gastric acid secretion inhibitors. Omeprazole, chemically known as 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methylsulphinyl-lH-benzimidazole) is useful as an antiulcer agent. These structurally related sulphoxide compounds have a stereogenic center at the sulphur atom and thus exist as enantiomers. Certain salts of single enantiomers of omeprazole and their preparation are disclosed in DE4035455 and W097/27988. There are several methods known in the prior art, which discloses the asymmetric oxidation of prochiral sulfide. US 5,948,789 and Eur. J. Biochem., 166 (1987), 453, describes enantioselective synthesis of substituted sulphoxide. In this process, a prochiral sulphide is oxidized into the corresponding sulphoxide either as a single enantiomer or in an enantiomerically enriched form using oxidizing agent in the presence of chiral titanium complex and in presence of base and organic solvent. Similarly, WO2003089408 describes an enantioselective catalytic oxidation of sulfide with an oxidizing agent in an organic solvent and base and in the presence of titanium or vanadium complex with a chiral monodentate ligand. WO2005054228 describes an enantioselective process for the preparation of substituted benzimidazole by asymmetrically oxidizing substituted prochiral sulphide preferably halo or nitro substituted, in an organic solvent and base with an oxidizing agent and a chiral titanium complex into the corresponding sulphoxide. WO2005080374 describes enantioselective synthesis of sulphoxide compound either as a single enantiomer or in an enantiomerically enriched form by oxidizing prochiral sulphoxide, with an oxidizing agent in an organic solvent at a temperature between 20-40°C and in the presence of chiral titanium complex. WO2006040635 describes synthesis of substituted sulphoxide by oxidizing prochiral sulphoxide in presence of chiral titanium metal complex and a base in the absence of an organic solvent. WO96/02535 discloses a process for the preparation of the single enantiomers of omeprazole and salts thereof, including a sodium salt. W097/41114 discloses an improved process for the preparation of omeprazole magnesium and S-omeprazole magnesium with a low content of inorganic impurities. WO2004/20436 discloses amorphous S-omeprazole magnesium in the form of hydrate and their process of preparation. WO2004/046134 describes an amorphous S-omeprazole magnesium salt in the form of a trihydrate wherein the term trihydrate is used to define a crystalline material in which water molecules are bound in the crystalline lattice. WO2004/037253 discloses amorphous form of the salts of S-omeprazole, their process for preparing the same and their pharmaceutical composition. WO2006/096709 discloses amorphous solid omeprazole magnesium and S-omeprazole magnesium by subjecting a solution of omeprazole magnesium or S-omeprazole magnesium to agitated thin film drier vertical. WO2006/134605 discloses amorphous form of S-omeprazole hydrate, their process of preparation and pharmaceutical composition. WO2007/031845 discloses novel polymorphic forms of S-omeprazole trihydate and their process of preparation. The application also discloses process for the preparation of amorphous form of S-omepraole magnesium and their pharmaceutical compositions. The above mentioned prior art references disclose the process of oxidation which is costly and not an environment friendly. The other disadvantage is requirement of strict reaction conditions during the oxidation and formation of sulphone by-product, which makes the process industrially uneconomical. These problems have been addressed in the parent application no. 1796/DEL/2005. The invention claimed therein is economically viable and eco-friendly process for the preparation of sulphoxide either as a single enantiomer or in an enantiomerically enriched form, which avoids the use of organic solvent and base, the product is free from sulfone by-product and the process of preparation is cost effective and high yielding. Despite the foregoing, there still exists a need for a cost effective and industrially efficient process for making magnesium salt of S-omeprazole in amorphous form, which requires shorter manufacturing time, is easy to prepare on industrial scale with high chemical and optical purity and can be effectively used for different pharmaceutical formulations. Further and other object of the invention will become apparent to those skilled in the art when considering the following summary of the invention and more detailed description of the preferred embodiments and examples contained herein. OBJECTS AND SUMMARY OF THE INVENTION The parent application No. 1796/DEL/2005 is addressed at a process for producing a sulphoxide compound either as a single enantiomer or in an enantiomerically enriched form. The invention also discloses the process for preparation of S-omeprazole magnesium, but with certain disadvantages as stated above. The reference to specification of parent application No. 1796/DEL/2005 is included herein in its entirety for describing the invention disclosed therein. The present invention provides an improved process for producing amorphous form of S-omeprazole magnesium. According to the principal aspect of the present invention, there is provided an improved process for the preparation of S-omeprazole magnesium, in amorphous form having moisture content between 7 to 11% by weight as measured by the karl fischer method and is easy to prepare and convenient to operate on commercial scale. According to one aspect of the present invention, there is provided an improved process for the preparation of S-omeprazole magnesium in amorphous form wherein the process comprises providing alkali or alkaline earth metal salt of S-omeprazole in water, adjusting pH of the reaction mixture to alkaline, contacting the resulting alkali or alkaline earth metal salt solution of S-omeprazole with an organic solvent selected from an alkyl alcohol, adding a source of magnesium and isolating the precipitated solid. According to another aspect of the present invention, there is provided an improved process for the preparation of S-omeprazole magnesium in amorphous form wherein the process comprises providing alkali or alkaline earth metal salt of S-omeprazole in water, adjusting pH of the solution to alkaline using an organic acid, contacting the resulting alkali or alkaline earth metal salt solution of S-omeprazole with an organic solvent selected from alkyl alcohol, adding a source of magnesium and isolating the precipitated solid. According to another aspect of the present invention, there is provided an improved process for the preparation of S-omeprazole magnesium in amorphous form wherein the process comprises providing alkali or alkaline earth metal salt of S-omeprazole in water, adjusting pH of the solution to alkaline using an organic acid, contacting the resulting alkali or alkaline earth metal salt solution of S-omeprazole with an organic solvent selected from alkyl alcohol, adding an organic source of magnesium and isolating the precipitated solid. According to another aspect of the present invention, there is provided an improved process for the preparation of S-omeprazole magnesium in amorphous form wherein the process comprises providing alkali or alkaline earth metal salt of S-omeprazole in water, adjusting pH of the solution to alkaline using an organic acid, contacting the resulting alkali or alkaline earth metal salt solution of S-omeprazole with an organic solvent selected from alkyl alcohol, adding magnesium acetate and isolating the precipitated solid. DESCRIPTION OF THE DRAWING Figure 1 shows a sample X-ray powder diffractogram of amorphous form of S-omeprazole magnesium obtained according to a prior art process. Figure 2 is a sample X-ray power diffractogram of amorphous form of S-omeprazole magnesium prepared by the improved process of the present invention. DETAILED DESCRIPTION OF THE INVENTION While this specification concludes with claims particularly pointing out and distinctly claiming that, which is regarded as the invention, it is anticipated that the invention can be more readily understood through reading the following detailed description of the invention and study of the included examples. The reference herein is made to the specification of parent application No. 1796/DEL/2005, which provides a cost effective and industrial feasible process for the production of sulphoxide compounds wherein said process comprises of asymmetrically oxidizing a prochiral sulphide of Formula II with a selective amount of oxidizing agent in the presence of a chiral transition metal complex without using organic solvent and base and converting the resultant into a salt. The resulting alkali or alkaline earth metal salts of the optically active substituted sulphoxide compound of the Formula [1] is further converted to another pharmaceutical acceptable alkali or alkaline earth metal salts. As further disclosed in the parent application, the invention discloses a process for producing sulphoxide compounds of Formula I either as a single enantiomer or in an enantiomerically enriched form, (Formula Removed) Formula I wherein ring A is a benzene ring optionally having 1 to 3 substituent (s) selected from (a) a halogen atom, (b) a cyano, (c) a nitro, (d) a C1-7 alkyl optionally having 1 to 3 substituent(s) selected from a halogen atom, a hydroxy, a C1-6 alkoxy- a C1-6 alkoxy-carbonyl and carbamoyl, (e) a hydroxy, (f) a C1-6 alkoxy optionally having 1 to 3 substituent(s) selected from a halogen atom, a hydroxy, a C1-6 alkoxy, a C1-6alkoxy-carbonyl and a carbamoyl, (g) a C6-14 aryl (h) a C6-14 aryloxy (i) a carboxy (j) an acyl selected from formyl a C1-6 alkyl-carbonyl, a C1-6 alkoxy-carbonyl, a carbamoyl, an N-C1-6 alkyl an N,N-di C1-6 alkyl-carbamoyl, a C1-7 alkylsulfinyl and a C1.7 alkylsulfonyl, (k) an acyloxy selected from a C1-6 alkyl-carbonyloxy, aC1-6 alkoxy-carbonyloxy, a carbamoyloxy, a C1-6 alkyl-carbamoyloxy, a C1-7 alkylsulfinyloxy and a C1-7 alkylsulfonyloxy and (1) a 5-to 10-membered heterocyclic group, Ri is a hydrogen atom, or a group selected from (A) a C1-6 alkyl group, a C3-14 cycloalkyl group, a C2-6 alkenyl group, a C3-14 cycloalkenyl group and a C2-6 alkynyl group, each of which optionally has 1 to 3 substituent(s) selected from (a) a C1-4 alkylthio group, (b) a halogen, (c) a C1-6 alkoxy group, (d) an acyloxy group selected from a C1-6 alkyl-carbonyloxy group, a C1-6 alkoxy-carbonyloxy group, a C1-6 alkyl-carbamoyloxy group, a C1-7 alkylsulfinyloxy, a C1.7 alkylsulfonyloxy and a C6-14 aryl-carbonyloxy group, (e) a nitro group, (f) a C1-6 alkoxy-carbonyl group, (g) a mono-or di-C1-6 alkylamino group, (h) a C1-6 alkoxyimino group and (i) a hydroxyimino (B) a C6-14 aryl group and a C7-19 aralkyl group, each of which optionally has 1 to 5 substituent (s) selected from (a) a C1-6 alkyl group, (b) a C3-6 cycloalkyl group, (c) a C2-6 alkenyl group, (d) a C2-6 alkynyl group, (e) a C1-6 alkoxy group, (f) an acyl group selected from C1-7 alkanoyl , a C6-14 aryl-carbonyl, a C1-6 alkoxy-carbonyl, a C6-14 aryloxy-carbonyl, a C7-19 aralkyl-carbonyl and a C7-19 aralkyloxycarbonyl, (g) a nitro, (h) an amino, (i) a hydroxy, (j) a cyano, (k) a sulfamoyl, (1) a mercapto, (m) a halogen and (n) a C1-4 alkylthio (C) an acyl group selected from formyl, a Ci_6 alkyl-carbonyl, a C1-6 alkoxy-carbonyl, a carbamoyl, an N-C1-6 alkyl-carbamoyl, an N,N-di-Ci_6 alkyl-carbamoyl, a C1-7 alkylsulfinyl and a C1-7 alkylsulfonyl and (D) an acyloxy group selected from a C1-6 alkyl-carbonyloxy, a C1-6 alkoxy-carbonyloxy, a carbamoyloxy, a C1-6alkyl-carbamoyloxy, a C1-7 alkylsulfmyloxy and a C1-7 alkylsulfanyloxy, R2, R3 and R4 are each a hydrogen atom, a C1-7 alkyl group optionally having 1 to 3 substituent(s) selected from a halogen atom, a hydroxy, a C1-6 alkoxy, a C1-6 alkoxy-carbonyl and a carbamoyl; a C1-6 alkoxy group optionally having 1 to 3 substituent(s) selected from a halogen atom, a hydroxy, a C1-6 alkoxy, a C1-6 alkoxy-earbonyl and a carbamoyl; an amino group; a mono-C1-6 alkylamino; a mono-C6-14 arylamino; a di-C1-6 alkylamino, or a di-C6-H arylamino, X is a nitrogen atom or CH, Y is a nitrogen atom or CH, by asymmetrically oxidizing a prochiral sulphide of the Formula II (Formula Removed) wherein the Ri, R2, R3, R4, are as defined above, with an oxidizing agent in the presence of a chiral transition metal complex without using organic solvent and base. The prochiral sulfide of the Formula II is prepared by various methods known in the art. The prochiral sulfide of the Formula II is obtained as a solution, for example from a reaction mixture resulting directly from a reaction in which it is formed. The process claimed in the parent application further includes the optional step of converting the resulting alkali or alkaline earth metal salts of the optically active sulphoxide compound of Formula I to another alkali or alkaline earth metal salts of these compounds. For example, S-omeprazole potassium is converted into S-omeprazole magnesium, wherein the alkali or alkaline earth metal source may be selected from Na+, Li+, K+, Mg+2, Ca+2 and Ba+2 salts such as bicarbonates, carbonates, hydrides, hydroxides, halides, sulphates, oxides and the like, preferably sodium hydroxide, potassium hydroxide, barium hydroxide, lithium hydroxide, magnesium hydroxide, calcium halide, magnesium halide and barium halide may be used. The present improvement invention provides an improved process for producing magnesium salt of S-omeprazole. According to the present invention the resultant S-omeprazole magnesium in amorphous form having moisture content between 7 to 11% by weight as measured by the karl fischer method is easy to prepare and convenient to operate on commercial scale. The process for the preparation of S-omeprazole magnesium in amorphous form according to the present invention comprises of providing alkali or alkaline earth metal salt of S-omeprazole in water, adjusting pH of the reaction mixture to alkaline, contacting the resulting alkali or alkaline earth metal salt solution of S-omeprazole with an organic solvent selected from alkyl alcohol, adding a source of magnesium and isolating the precipitated solid. The alkali or alkaline earth metal salt of S-omeprazole is prepared by treating neutral form of S-omeprazole with alkali and/or alkaline earth metal source. The alkali or alkaline earth metal source may be selected from Na+, K+, Li+, Mg+2, Ca+2 and Ba+2 salts such as bicarbonates, carbonates, hydrides, hydroxides, halides, sulphates, and oxides, preferably sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, magnesium hydroxide, magnesium halide, calcium halide, barium halide and the like. The pH of the resulting mixture containing alkali or alkaline earth metal salt of S-omeprazole is adjusted between 10-11 using organic acid or weak base. The organic acid is selected from formic acid, acetic acid, propionic acid, butanoic acid and the like. The weak base is selected from ammonium salt such as ammonium chloride, ammonium acetate and the like. According to the present invention, the organic solvent used during the process of the invention is selected from alkyl alcohol preferably selected from C1-C4 alkyl alcohol including but are not limited to straight or branched chain alcohols. Most preferably the solvent is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol and the like. The magnesium source used herein is selected from organic magnesium salt such as magnesium acetate, magnesium methoxide, and the like and mixture thereof. Preferably the magnesium source is magnesium acetate and/or magnesium methoxide. The molar ratio of the magnesium source to the alkali or alkaline earth metal salt of S-omeprazole ordinarily ranges from about 0.3 to about 0.8 and preferably from about 0.4 to 0.6. The process is not temperature sensitive and is carried out at ambient temperature. Suitable temperatures for preparing the magnesium salt of S-omeprazole in the amorphous form range from about 20-40°C preferably of about 20-30°C. The resulting solid is separated from the mother liquor (filtrate) by conventional methods such as by filtration or centrifugation. Other suitable procedure may be used to separate the product. The amorphous product is washed with water, and dried under vacuum at a temperature of about 40°C-60°C, preferably of about 40°C to 50°C to a constant weight. The S-omeprazole magnesium in amorphous form obtained as per the above process is stable and is well suited for pharmaceutical applications. The process of the present invention is simple, non-hazardous and well suited for commercial production. The process provides better yield, better purity and avoids the byproduct generation and multiple steps purification. The main advantage of the use of magnesium acetate as a source of magnesium in comparison to magnesium halides, is that during the conversion of S-omeprazole potassium to S-omeprazole magnesium, inorganic salts like potassium halide is generated as a by product. Removal of the said by product for example potassium halide from the final product require multiple purification steps as compared to the potassium acetate. This is due to reason that potassium halide has low solubility in water as compared to the potassium acetate. This enhanced the purity and yield of the final product. The examples that follow are not intended to limit the scope of the invention as defined herein above or as claimed below. Example 1 Preparation of 5-methoxv-2-[\|"(4-methoxv-3.5-dimethvl-2-pvridinvlVmethvl1 sulfinvl]-lH-benzimidazole potassium salt Titanium isopropoxide (60.4.g) and D- (-) diethyl tartarate (87.6 g) was taken and stirred at room temperature under an inert atmosphere. Temperature was increased up to 55-60°C and 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]thio]-lH-benzimidazole (100 g) was added at the above temperature. The resulting mixture was stirred for 30 minutes at the same temperature. Water (1.4 ml) was added and was stirred for another one hour. The resulting reaction mass was cooled to 5-10°C and cumene hydroperoxide (78 g) was added. The resulting mixture was stirred for 3-4 hours at 5-10°C. After completion of the reaction, toluene, triethylamine and water was added to the resulting reaction mixture. The organic layer was separated and washed with water. The organic layer was then cooled to 10-15°C and methanolic potassium hydroxide (17.9 g dissolved in 145 ml methanol) was added. The resulting mixture was stirred for 30 minutes, seeded with pure potassium S-omeprazole and further stirred for 3-4 hours at room temperature. The resulting solid was filtered off, washed with toluene and methanol and dried under vacuum for 2-3 hours at 45-50°C. The resulting solid was dissolved in water (350 ml) at room temperature. The pH was adjusted to 7.5-8.0 with acetic acid and dichloromethane (500 ml) was added. The organic layer was seperated, washed with brine and distilled off. The resulting oily mass was dissolved in methyl ethyl ketone (350 ml) at room temperature under stirring. The resulting reaction mass was then cooled to 10-15°C and methanolic potassium hydroxide (7.2 g potassium hydroxide in 36 ml methanol) was added. The resuting mixture was stirred for 4-5 hours at room temperature, first and then cooled to 10-15°C under stirring. Solid was filtered off, washed with methyl ethyl ketone and dried under vacuum at 40-45°C for 6-8 hours. Yield: = 45-50 g Sulfone =0.15% HPLC Purity = 99.7% Chiral purity =99.9% Example 2 Preparation of amorphous form of S-omeprazole magnesium S-Omeprazole potassium (100 g) was taken in water (800 ml) and was stirred at room temperature for 10-15 minutes. The pH of the resulting solution was adjusted between 10 to 11 with acetic acid. Methanol (200 ml) was added. Aqueous solution of magnesium acetate tetrahydrate (25.7 g) was then added to the above mixture at room temperature under stirring. The mixture was stirred for 30 minutes at room temperature. The precipitated solid was filtered and washed with water. The resulting solid was dried under reduced pressure at 40- 45°C for 12-15 hours to isolate S-omeprazole magnesium as amorphous solid. Yield: 76-77 g Sulfone: Not detected Chiral purity: 99.9% HPLC Purity: 99.9%. Moisture Content: 8.9%. Example 3 Preparation of amorphous form of S-omeprazole magnesium S-Omeprazole potassium (100 g) was taken in water (800 ml) and was stirred at room temperature for 10-15 minutes. The pH of the resulting solution was adjusted between 10 to 11 with acetic acid. Isopropyl alcohol (200 ml) was added. Aqueous solution of magnesium acetate tetrahydrate (25.7 g) was then added to the above mixture at room temperature under stirring. The mixture was stirred for 30 minutes at room temperature. The precipitated solid was filtered and washed with water. The resulting solid was dried under reduced pressure at 40-45°C for 12-15 hours to isolate S-Omeprazole Magnesium as amorphous solid. Yield: 84-85 g Sulfone: Not detected Chiral purity: 99.9% HPLC Purity: 99.9%. Moisture Content: 9.2% While this invention has been described in detail with reference to certain preferred embodiments, it should be appreciated that the present invention is not limited to those precise embodiments. Rather, in view of the present disclosure, which describes the current best mode for practicing the invention, many modification and variations would present themselves to those skilled in the art without departing from the scope and sprit of this invention. We Claim: 1. An improved process for the preparation of S-omeprazole magnesium in amorphous form, the process comprising: providing alkali or alkaline earth metal salt of S-omeprazole in water; adjusting pH of the reaction mixture to alkaline; contacting the resulting alkali or alkaline earth metal salt solution of S-omeprazole with an organic solvent; adding an organic source of magnesium; and isolating the precipitated S-omeprazole magnesium. 2. The process according to claim 1, wherein the alkali or alkaline earth metal salt is prepared by treating neutral form of S-omeprazole with alkali and/or alkaline earth metal source. 3. The process according to claim 2, wherein alkali or alkaline earth metal source is selected from Na+, K+, Li+, Mg+2, Ca+2 and Ba+2 salts. 4. The process according to claim 1, wherein the pH of the resulting mixture containing salt of S-omeprazole is adjusted between 10 to 11 using an organic acid or a weak base. 5. The process according to claim 4, wherein the organic acid is selected from formic acid, acetic acid, propionic acid, or butanoic acid. 6. The process according to claim 4, wherein the weak base is selected from an ammonium salt. 7. The process according to claim 6, wherein the ammonium salt is selected from ammonium chloride or ammonium acetate. 8. The process according to claim 1, wherein the organic solvent is selected from alkyl alcohol. 9. The process according to claim 8, wherein the alkyl alcohol is selected from C1-C4 alkyl alcohol. 10. The process according to claim 9, wherein the said C1-C4 alkyl alcohol is selected from straight or branched chain isomers. 11. The process according to claim 8, wherein the C1-C4 alkyl alcohol is preferably selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol or a mixture thereof. 12. The process according to claim 1, wherein the source of magnesium is preferably selected from magnesium acetate or magnesium methoxide.

Full Text

This application is an improvement of the invention claimed in Indian Patent Application No. 1796/DEL/2006 filed on August 8, 2006.
FIELD OF THE INVENTION
This invention, in general relates to an improved process for producing S-omeprazole magnesium. More particularly, but without restriction to the particular embodiments hereinafter described in accordance with the best mode of practice, the present invention is directed to improved process for the preparation of S-omeprazole magnesium in amorphous form.
BACKGROUND OF THE INVENTION Different solid forms of the same drug may exhibit different properties, including characteristics that have functional implications with respect to their use as active ingredients of pharmaceutical products. For example, polymorphs of the same drug may have substantial differences in such pharmaceutically important properties such as dissolution rates and bioavailability. Likewise, different polymorphs may have different processing properties, such as hydroscopicity, flowability, and the like, which could affect their suitability as active pharmaceuticals for commercial production.
Differently substituted 2-(2-pyridinylmethyl sulphinyl)-lH-benzimidazoles such as omeprazole, lansoprazole, pantoprazole and rabeprazole are known as gastric acid secretion inhibitors. Omeprazole, chemically known as 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methylsulphinyl-lH-benzimidazole) is useful as an antiulcer agent.
These structurally related sulphoxide compounds have a stereogenic center at the sulphur atom and thus exist as enantiomers. Certain salts of single enantiomers of omeprazole and their preparation are disclosed in DE4035455 and W097/27988.
There are several methods known in the prior art, which discloses the asymmetric oxidation of prochiral sulfide.

US 5,948,789 and Eur. J. Biochem., 166 (1987), 453, describes enantioselective synthesis of substituted sulphoxide. In this process, a prochiral sulphide is oxidized into the corresponding sulphoxide either as a single enantiomer or in an enantiomerically enriched form using oxidizing agent in the presence of chiral titanium complex and in presence of base and organic solvent.
Similarly, WO2003089408 describes an enantioselective catalytic oxidation of sulfide with an oxidizing agent in an organic solvent and base and in the presence of titanium or vanadium complex with a chiral monodentate ligand.
WO2005054228 describes an enantioselective process for the preparation of substituted benzimidazole by asymmetrically oxidizing substituted prochiral sulphide preferably halo or nitro substituted, in an organic solvent and base with an oxidizing agent and a chiral titanium complex into the corresponding sulphoxide.
WO2005080374 describes enantioselective synthesis of sulphoxide compound either as a single enantiomer or in an enantiomerically enriched form by oxidizing prochiral sulphoxide, with an oxidizing agent in an organic solvent at a temperature between 20-40°C and in the presence of chiral titanium complex.
WO2006040635 describes synthesis of substituted sulphoxide by oxidizing prochiral sulphoxide in presence of chiral titanium metal complex and a base in the absence of an organic solvent.
WO96/02535 discloses a process for the preparation of the single enantiomers of omeprazole and salts thereof, including a sodium salt.
W097/41114 discloses an improved process for the preparation of omeprazole magnesium and S-omeprazole magnesium with a low content of inorganic impurities.
WO2004/20436 discloses amorphous S-omeprazole magnesium in the form of hydrate and their process of preparation.

WO2004/046134 describes an amorphous S-omeprazole magnesium salt in the form of a trihydrate wherein the term trihydrate is used to define a crystalline material in which water molecules are bound in the crystalline lattice.
WO2004/037253 discloses amorphous form of the salts of S-omeprazole, their process for preparing the same and their pharmaceutical composition.
WO2006/096709 discloses amorphous solid omeprazole magnesium and S-omeprazole magnesium by subjecting a solution of omeprazole magnesium or S-omeprazole magnesium to agitated thin film drier vertical.
WO2006/134605 discloses amorphous form of S-omeprazole hydrate, their process of preparation and pharmaceutical composition.
WO2007/031845 discloses novel polymorphic forms of S-omeprazole trihydate and their process of preparation. The application also discloses process for the preparation of amorphous form of S-omepraole magnesium and their pharmaceutical compositions.
The above mentioned prior art references disclose the process of oxidation which is costly and not an environment friendly. The other disadvantage is requirement of strict reaction conditions during the oxidation and formation of sulphone by-product, which makes the process industrially uneconomical.
These problems have been addressed in the parent application no. 1796/DEL/2005. The invention claimed therein is economically viable and eco-friendly process for the preparation of sulphoxide either as a single enantiomer or in an enantiomerically enriched form, which avoids the use of organic solvent and base, the product is free from sulfone by-product and the process of preparation is cost effective and high yielding.
Despite the foregoing, there still exists a need for a cost effective and industrially efficient process for making magnesium salt of S-omeprazole in amorphous form, which requires shorter manufacturing time, is easy to prepare on industrial scale with high chemical and optical purity and can be effectively used for different pharmaceutical formulations.

Further and other object of the invention will become apparent to those skilled in the art when considering the following summary of the invention and more detailed description of the preferred embodiments and examples contained herein.
OBJECTS AND SUMMARY OF THE INVENTION
The parent application No. 1796/DEL/2005 is addressed at a process for producing a sulphoxide compound either as a single enantiomer or in an enantiomerically enriched form. The invention also discloses the process for preparation of S-omeprazole magnesium, but with certain disadvantages as stated above. The reference to specification of parent application No. 1796/DEL/2005 is included herein in its entirety for describing the invention disclosed therein.
The present invention provides an improved process for producing amorphous form of S-omeprazole magnesium.
According to the principal aspect of the present invention, there is provided an improved process for the preparation of S-omeprazole magnesium, in amorphous form having moisture content between 7 to 11% by weight as measured by the karl fischer method and is easy to prepare and convenient to operate on commercial scale.
According to one aspect of the present invention, there is provided an improved process for the preparation of S-omeprazole magnesium in amorphous form wherein the process comprises providing alkali or alkaline earth metal salt of S-omeprazole in water, adjusting pH of the reaction mixture to alkaline, contacting the resulting alkali or alkaline earth metal salt solution of S-omeprazole with an organic solvent selected from an alkyl alcohol, adding a source of magnesium and isolating the precipitated solid.
According to another aspect of the present invention, there is provided an improved process for the preparation of S-omeprazole magnesium in amorphous form wherein the process comprises providing alkali or alkaline earth metal salt of S-omeprazole in water, adjusting pH of the solution to alkaline using an organic acid, contacting the resulting alkali or alkaline earth metal salt solution of S-omeprazole with an organic solvent selected from alkyl alcohol, adding a source of magnesium and isolating the precipitated solid.

According to another aspect of the present invention, there is provided an improved process for the preparation of S-omeprazole magnesium in amorphous form wherein the process comprises providing alkali or alkaline earth metal salt of S-omeprazole in water, adjusting pH of the solution to alkaline using an organic acid, contacting the resulting alkali or alkaline earth metal salt solution of S-omeprazole with an organic solvent selected from alkyl alcohol, adding an organic source of magnesium and isolating the precipitated solid.
According to another aspect of the present invention, there is provided an improved process for the preparation of S-omeprazole magnesium in amorphous form wherein the process comprises providing alkali or alkaline earth metal salt of S-omeprazole in water, adjusting pH of the solution to alkaline using an organic acid, contacting the resulting alkali or alkaline earth metal salt solution of S-omeprazole with an organic solvent selected from alkyl alcohol, adding magnesium acetate and isolating the precipitated solid.
DESCRIPTION OF THE DRAWING
Figure 1 shows a sample X-ray powder diffractogram of amorphous form of S-omeprazole magnesium obtained according to a prior art process.
Figure 2 is a sample X-ray power diffractogram of amorphous form of S-omeprazole magnesium prepared by the improved process of the present invention.
DETAILED DESCRIPTION OF THE INVENTION
While this specification concludes with claims particularly pointing out and distinctly claiming that, which is regarded as the invention, it is anticipated that the invention can be more readily understood through reading the following detailed description of the invention and study of the included examples. The reference herein is made to the specification of parent application No. 1796/DEL/2005, which provides a cost effective and industrial feasible process for the production of sulphoxide compounds wherein said process comprises of asymmetrically oxidizing a prochiral sulphide of Formula II with a selective amount of oxidizing agent in the presence of a chiral transition metal complex without using organic solvent and base and converting the resultant into a salt. The resulting alkali or alkaline earth metal salts of the optically active substituted sulphoxide compound of the Formula [1] is further converted to another pharmaceutical acceptable alkali or alkaline earth metal salts.

As further disclosed in the parent application, the invention discloses a process for producing sulphoxide compounds of Formula I either as a single enantiomer or in an enantiomerically enriched form,
(Formula Removed)

Formula I
wherein
ring A is a benzene ring optionally having 1 to 3 substituent (s) selected from (a) a halogen atom, (b) a cyano, (c) a nitro, (d) a C1-7 alkyl optionally having 1 to 3 substituent(s) selected from a halogen atom, a hydroxy, a C1-6 alkoxy- a C1-6 alkoxy-carbonyl and carbamoyl, (e) a hydroxy, (f) a C1-6 alkoxy optionally having 1 to 3 substituent(s) selected from a halogen atom, a hydroxy, a C1-6 alkoxy, a C1-6alkoxy-carbonyl and a carbamoyl, (g) a C6-14 aryl (h) a C6-14 aryloxy (i) a carboxy (j) an acyl selected from formyl a C1-6 alkyl-carbonyl, a C1-6 alkoxy-carbonyl, a carbamoyl, an N-C1-6 alkyl an N,N-di C1-6 alkyl-carbamoyl, a C1-7 alkylsulfinyl and a C1.7 alkylsulfonyl, (k) an acyloxy selected from a C1-6 alkyl-carbonyloxy, aC1-6 alkoxy-carbonyloxy, a carbamoyloxy, a C1-6 alkyl-carbamoyloxy, a C1-7 alkylsulfinyloxy and a C1-7 alkylsulfonyloxy and (1) a 5-to 10-membered heterocyclic group, Ri is a hydrogen atom, or a group selected from (A) a C1-6 alkyl group, a C3-14 cycloalkyl group, a C2-6 alkenyl group, a C3-14 cycloalkenyl group and a C2-6 alkynyl group, each of which optionally has 1 to 3 substituent(s) selected from (a) a C1-4 alkylthio group, (b) a halogen, (c) a C1-6 alkoxy group, (d) an acyloxy group selected from a C1-6 alkyl-carbonyloxy group, a C1-6 alkoxy-carbonyloxy group, a C1-6 alkyl-carbamoyloxy group, a C1-7 alkylsulfinyloxy, a C1.7 alkylsulfonyloxy and a C6-14 aryl-carbonyloxy group, (e) a nitro group, (f) a C1-6 alkoxy-carbonyl group, (g) a mono-or di-C1-6 alkylamino group, (h) a C1-6 alkoxyimino group and (i) a hydroxyimino (B) a C6-14 aryl group and a C7-19 aralkyl group, each of which optionally has 1 to 5 substituent (s) selected from (a) a C1-6 alkyl group, (b) a C3-6 cycloalkyl group, (c) a C2-6 alkenyl group, (d) a C2-6 alkynyl group, (e) a C1-6 alkoxy group, (f) an acyl group selected from C1-7 alkanoyl , a C6-14 aryl-carbonyl, a C1-6 alkoxy-carbonyl, a C6-14 aryloxy-carbonyl, a C7-19 aralkyl-carbonyl and a C7-19 aralkyloxycarbonyl,

(g) a nitro, (h) an amino, (i) a hydroxy, (j) a cyano, (k) a sulfamoyl, (1) a mercapto, (m) a halogen and (n) a C1-4 alkylthio (C) an acyl group selected from formyl, a Ci_6 alkyl-carbonyl, a C1-6 alkoxy-carbonyl, a carbamoyl, an N-C1-6 alkyl-carbamoyl, an N,N-di-Ci_6 alkyl-carbamoyl, a C1-7 alkylsulfinyl and a C1-7 alkylsulfonyl and (D) an acyloxy group selected from a C1-6 alkyl-carbonyloxy, a C1-6 alkoxy-carbonyloxy, a carbamoyloxy, a C1-6alkyl-carbamoyloxy, a C1-7 alkylsulfmyloxy and a C1-7 alkylsulfanyloxy,
R2, R3 and R4 are each a hydrogen atom, a C1-7 alkyl group optionally having 1 to 3 substituent(s) selected from a halogen atom, a hydroxy, a C1-6 alkoxy, a C1-6 alkoxy-carbonyl and a carbamoyl; a C1-6 alkoxy group optionally having 1 to 3 substituent(s) selected from a halogen atom, a hydroxy, a C1-6 alkoxy, a C1-6 alkoxy-earbonyl and a carbamoyl; an amino group; a mono-C1-6 alkylamino; a mono-C6-14 arylamino; a di-C1-6 alkylamino, or a di-C6-H arylamino, X is a nitrogen atom or CH, Y is a nitrogen atom or CH,
by asymmetrically oxidizing a prochiral sulphide of the Formula II
(Formula Removed)

wherein the Ri, R2, R3, R4, are as defined above, with an oxidizing agent in the presence of a chiral transition metal complex without using organic solvent and base.
The prochiral sulfide of the Formula II is prepared by various methods known in the art. The prochiral sulfide of the Formula II is obtained as a solution, for example from a reaction mixture resulting directly from a reaction in which it is formed.
The process claimed in the parent application further includes the optional step of converting the resulting alkali or alkaline earth metal salts of the optically active sulphoxide compound of Formula I to another alkali or alkaline earth metal salts of these compounds. For example,

S-omeprazole potassium is converted into S-omeprazole magnesium, wherein the alkali or alkaline earth metal source may be selected from Na+, Li+, K+, Mg+2, Ca+2 and Ba+2 salts such as bicarbonates, carbonates, hydrides, hydroxides, halides, sulphates, oxides and the like, preferably sodium hydroxide, potassium hydroxide, barium hydroxide, lithium hydroxide, magnesium hydroxide, calcium halide, magnesium halide and barium halide may be used.
The present improvement invention provides an improved process for producing magnesium salt of S-omeprazole.
According to the present invention the resultant S-omeprazole magnesium in amorphous form having moisture content between 7 to 11% by weight as measured by the karl fischer method is easy to prepare and convenient to operate on commercial scale.
The process for the preparation of S-omeprazole magnesium in amorphous form according to the present invention comprises of providing alkali or alkaline earth metal salt of S-omeprazole in water, adjusting pH of the reaction mixture to alkaline, contacting the resulting alkali or alkaline earth metal salt solution of S-omeprazole with an organic solvent selected from alkyl alcohol, adding a source of magnesium and isolating the precipitated solid.
The alkali or alkaline earth metal salt of S-omeprazole is prepared by treating neutral form of S-omeprazole with alkali and/or alkaline earth metal source. The alkali or alkaline earth metal source may be selected from Na+, K+, Li+, Mg+2, Ca+2 and Ba+2 salts such as bicarbonates, carbonates, hydrides, hydroxides, halides, sulphates, and oxides, preferably sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, magnesium hydroxide, magnesium halide, calcium halide, barium halide and the like.
The pH of the resulting mixture containing alkali or alkaline earth metal salt of S-omeprazole is adjusted between 10-11 using organic acid or weak base. The organic acid is selected from formic acid, acetic acid, propionic acid, butanoic acid and the like. The weak base is selected from ammonium salt such as ammonium chloride, ammonium acetate and the like.
According to the present invention, the organic solvent used during the process of the invention is selected from alkyl alcohol preferably selected from C1-C4 alkyl alcohol including but are not limited to straight or branched chain alcohols. Most preferably the

solvent is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol and the like.
The magnesium source used herein is selected from organic magnesium salt such as magnesium acetate, magnesium methoxide, and the like and mixture thereof. Preferably the magnesium source is magnesium acetate and/or magnesium methoxide. The molar ratio of the magnesium source to the alkali or alkaline earth metal salt of S-omeprazole ordinarily ranges from about 0.3 to about 0.8 and preferably from about 0.4 to 0.6.
The process is not temperature sensitive and is carried out at ambient temperature. Suitable temperatures for preparing the magnesium salt of S-omeprazole in the amorphous form range from about 20-40°C preferably of about 20-30°C.
The resulting solid is separated from the mother liquor (filtrate) by conventional methods such as by filtration or centrifugation. Other suitable procedure may be used to separate the product. The amorphous product is washed with water, and dried under vacuum at a temperature of about 40°C-60°C, preferably of about 40°C to 50°C to a constant weight.
The S-omeprazole magnesium in amorphous form obtained as per the above process is stable and is well suited for pharmaceutical applications. The process of the present invention is simple, non-hazardous and well suited for commercial production. The process provides better yield, better purity and avoids the byproduct generation and multiple steps purification.
The main advantage of the use of magnesium acetate as a source of magnesium in comparison to magnesium halides, is that during the conversion of S-omeprazole potassium to S-omeprazole magnesium, inorganic salts like potassium halide is generated as a by product. Removal of the said by product for example potassium halide from the final product require multiple purification steps as compared to the potassium acetate. This is due to reason that potassium halide has low solubility in water as compared to the potassium acetate. This enhanced the purity and yield of the final product.
The examples that follow are not intended to limit the scope of the invention as defined herein above or as claimed below.

Example 1
Preparation of 5-methoxv-2-[|"(4-methoxv-3.5-dimethvl-2-pvridinvlVmethvl1 sulfinvl]-lH-benzimidazole potassium salt
Titanium isopropoxide (60.4.g) and D- (-) diethyl tartarate (87.6 g) was taken and stirred at room temperature under an inert atmosphere. Temperature was increased up to 55-60°C and 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]thio]-lH-benzimidazole (100 g) was added at the above temperature. The resulting mixture was stirred for 30 minutes at the same temperature. Water (1.4 ml) was added and was stirred for another one hour. The resulting reaction mass was cooled to 5-10°C and cumene hydroperoxide (78 g) was added. The resulting mixture was stirred for 3-4 hours at 5-10°C. After completion of the reaction, toluene, triethylamine and water was added to the resulting reaction mixture. The organic layer was separated and washed with water. The organic layer was then cooled to 10-15°C and methanolic potassium hydroxide (17.9 g dissolved in 145 ml methanol) was added. The resulting mixture was stirred for 30 minutes, seeded with pure potassium S-omeprazole and further stirred for 3-4 hours at room temperature. The resulting solid was filtered off, washed with toluene and methanol and dried under vacuum for 2-3 hours at 45-50°C. The resulting solid was dissolved in water (350 ml) at room temperature. The pH was adjusted to 7.5-8.0 with acetic acid and dichloromethane (500 ml) was added. The organic layer was seperated, washed with brine and distilled off. The resulting oily mass was dissolved in methyl ethyl ketone (350 ml) at room temperature under stirring. The resulting reaction mass was then cooled to 10-15°C and methanolic potassium hydroxide (7.2 g potassium hydroxide in 36 ml methanol) was added. The resuting mixture was stirred for 4-5 hours at room temperature, first and then cooled to 10-15°C under stirring. Solid was filtered off, washed with methyl ethyl ketone and dried under vacuum at 40-45°C for 6-8 hours.
Yield: = 45-50 g
Sulfone =0.15%
HPLC Purity = 99.7%
Chiral purity =99.9%
Example 2
Preparation of amorphous form of S-omeprazole magnesium
S-Omeprazole potassium (100 g) was taken in water (800 ml) and was stirred at room temperature for 10-15 minutes. The pH of the resulting solution was adjusted between 10 to

11 with acetic acid. Methanol (200 ml) was added. Aqueous solution of magnesium acetate
tetrahydrate (25.7 g) was then added to the above mixture at room temperature under stirring.
The mixture was stirred for 30 minutes at room temperature. The precipitated solid was
filtered and washed with water. The resulting solid was dried under reduced pressure at 40-
45°C for 12-15 hours to isolate S-omeprazole magnesium as amorphous solid.
Yield: 76-77 g
Sulfone: Not detected
Chiral purity: 99.9%
HPLC Purity: 99.9%.
Moisture Content: 8.9%.
Example 3
Preparation of amorphous form of S-omeprazole magnesium
S-Omeprazole potassium (100 g) was taken in water (800 ml) and was stirred at room
temperature for 10-15 minutes. The pH of the resulting solution was adjusted between 10 to
11 with acetic acid. Isopropyl alcohol (200 ml) was added. Aqueous solution of magnesium
acetate tetrahydrate (25.7 g) was then added to the above mixture at room temperature under
stirring. The mixture was stirred for 30 minutes at room temperature. The precipitated solid
was filtered and washed with water. The resulting solid was dried under reduced pressure at
40-45°C for 12-15 hours to isolate S-Omeprazole Magnesium as amorphous solid.
Yield: 84-85 g
Sulfone: Not detected
Chiral purity: 99.9%
HPLC Purity: 99.9%.
Moisture Content: 9.2%
While this invention has been described in detail with reference to certain preferred embodiments, it should be appreciated that the present invention is not limited to those precise embodiments. Rather, in view of the present disclosure, which describes the current best mode for practicing the invention, many modification and variations would present themselves to those skilled in the art without departing from the scope and sprit of this invention.

We Claim:
1. An improved process for the preparation of S-omeprazole magnesium in
amorphous form, the process comprising:
providing alkali or alkaline earth metal salt of S-omeprazole in water; adjusting pH of the reaction mixture to alkaline;
contacting the resulting alkali or alkaline earth metal salt solution of S-omeprazole with an organic solvent;
adding an organic source of magnesium; and isolating the precipitated S-omeprazole magnesium.
2. The process according to claim 1, wherein the alkali or alkaline earth metal salt is prepared by treating neutral form of S-omeprazole with alkali and/or alkaline earth metal source.
3. The process according to claim 2, wherein alkali or alkaline earth metal source is selected from Na+, K+, Li+, Mg+2, Ca+2 and Ba+2 salts.
4. The process according to claim 1, wherein the pH of the resulting mixture containing salt of S-omeprazole is adjusted between 10 to 11 using an organic acid or a weak
base.
5. The process according to claim 4, wherein the organic acid is selected from formic acid, acetic acid, propionic acid, or butanoic acid.
6. The process according to claim 4, wherein the weak base is selected from an ammonium salt.
7. The process according to claim 6, wherein the ammonium salt is selected from ammonium chloride or ammonium acetate.
8. The process according to claim 1, wherein the organic solvent is selected from alkyl alcohol.

9. The process according to claim 8, wherein the alkyl alcohol is selected from C1-C4 alkyl alcohol.
10. The process according to claim 9, wherein the said C1-C4 alkyl alcohol is selected from straight or branched chain isomers.
11. The process according to claim 8, wherein the C1-C4 alkyl alcohol is preferably selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol or a mixture thereof.
12. The process according to claim 1, wherein the source of magnesium is preferably selected from magnesium acetate or magnesium methoxide.

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Patent Number

278588

Indian Patent Application Number

1317/DEL/2008

PG Journal Number

54/2016

Publication Date

30-Dec-2016

Grant Date

26-Dec-2016

Date of Filing

30-May-2008

Name of Patentee

JUBILANT ORGANOSYS LIMITED

Applicant Address

PLOT 1A, SECTOR 16 A, NOIDA-201 301, UP,INDIA.

Inventors:

#	Inventor's Name	Inventor's Address
1	SINGH, ANAND	JUBILANT ORGANOSYS LIMITED, C-26, SECTOR-59, NOIDA-201301, U.P.,INDIA.
2	SINGH, KHUSHWANT	JUBILANT ORGANOSYS LIMITED, C-26, SECTOR-59, NOIDA-201301, U.P.,INDIA.
3	DUBEY, SUSHIL KUMAR	JUBILANT ORGANOSYS LIMITED, C-26, SECTOR-59, NOIDA-201301, U.P.INDIA.

PCT International Classification Number

A61K31/4439 ; A61P1/04 ; C07D401/12

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA