WO2010148314A2

WO2010148314A2 - Preparation of esomeprazole and its pharmaceutically acceptable salts

Info

Publication number: WO2010148314A2
Application number: PCT/US2010/039187
Authority: WO
Inventors: Srinivasa Reddy Bhimavarapu; Sree Naga Venkata Lakshmi Vara Prasad Vakamudi; Ravi Ram Chandra Sekhar Elati; Vijaya Bhaskar Bolugoddu
Original assignee: Dr. Reddy's Laboratories Ltd.; Dr. Reddy's Laboratories, Inc.
Priority date: 2009-06-19
Filing date: 2010-06-18
Publication date: 2010-12-23
Also published as: WO2010148314A3

Abstract

Processes for the preparation of esomeprazole and its pharmaceutically acceptable salts.

Description

PREPARATION OF ESOMEPRAZOLE AND ITS PHARMACEUTICALLY

ACCEPTABLE SALTS

INTRODUCTION

The present application relates to processes for the preparation of esomeprazole and its pharmaceutically acceptable salts.

The drug compound having the adopted name "esomeprazole magnesium," in its anhydrous form, has a chemical name bis(5-methoxy-2-[(S)- [(4-methoxy-3,5-dimethyl-2-pyhdinyl)methyl]sulfinyl]-1 /-/-benzimidazole-1 -yl) magnesium, and has the structure of formula (Ia).

2

(Ia)

Esomeprazole magnesium is a proton pump inhibitor, developed as an oral treatment for peptic ulcer, gastroesophangeal reflux disease (GERD), duodenal ulcer, and esophagitis.

Esomeprazole magnesium thhydrate is the active ingredient in products sold by AstraZeneca Pharmaceuticals as NEXIUM™, in the form of delayed- release capsules for oral administration. Each delayed-release capsule contains 20 mg or 40 mg of esomeprazole (present as 22.3 mg or 44.5 mg of esomeprazole magnesium trihydrate) in enteric-coated pellets.

U.S. Patent No. 5,948,789 discloses a process for enantioselective synthesis of 2-(2-pyridinylmethylsulphinyl)-1 H-benzimidazoles or an alkaline salt thereof, in the form of a single enantiomer or in an enantiomerically enriched form, by oxidizing a pro-chiral sulfide with an oxidizing agent in the presence of a chiral titanium complex and a base in an organic solvent.

International Application Publication No. WO 2005/054228 A1 discloses a process for making 2-(2-pyhdinylmethylsulphinyl)-1 H-benzimidazoles, either as a single enantiomer or in an enantiomerically enriched form by asymmetric oxidation of the corresponding prochiral 4-chloro or 4-nitro analog of 2-(2-pyridinylmethyl- sulphanyl)-1 H-benzimidazole with an oxidizing agent and a chiral titanium complex in an organic solvent, followed by reaction of the 4-chloro or 4-nitro analog of 2-(2-pyridinylmethylsulphanyl)-1 H-benzimidazole with an alkali metal or alkaline earth metal alkoxide. International Application Publication No. WO 2005/080374 A1 discloses a process for preparation of 2-[[(4-X-3,5-dimethylpyridin-2-yl)methyl]thio]-5- methoxy-1 H-benzimidazole or 2-[[(4-X-3,5-dimethyl-1 -oxidopyridin-2- yl)methyl]thio]-5-methoxy-1 H-benzimidazole, either as a single enantiomer or in an enantiomehcally enriched form, wherein X is a leaving group such as a halogen (F, Cl, Br, or I), NO₂, N₂ ⁺, or OSO₂R (where R is CH₃, CF₃, p-toluene, m- chlorobenzene, or p-chlorobenzene), by asymmetric oxidation of the corresponding prochiral sulfide with an oxidizing agent and a chiral titanium complex in an organic solvent. The obtained 2-[[(4-X-3,5-dimethylpyridin-2- yl)methyl]thio]-5-methoxy-1 H-benzimidazole or 2-[[(4-X-3,5-dimethyl-1 - oxidopyridin-2-yl)methyl]thio]-5-methoxy-1 H-benzimidazole, either as a single enantiomer or in an enantiomerically enriched form, is further converted to esomeprazole.

These processes suffer from one or more drawbacks such as low enantiomeric purity, low yield, and high levels of sulfide and sulfone impurities. Hence, there is a need to provide simple, economical and robust processes for the preparation of esomeprazole and its pharmaceutically acceptable salts.

SUMMARY

In an aspect, the present invention relates to processes for the preparation of esomeprazole of formula I, or pharmaceutically acceptable salts thereof, embodiments including one or more of the following steps: (a) reacting the pro-chiral sulfide of formula (II),

(H) with an oxidizing agent, in the presence of a chiral auxiliary, to provide a compound of formula (III) or a salt thereof, in the form of a single enantiomer or in an enantiomerically enriched form;

(b) converting a compound of formula (III) or a salt thereof, in the form of a single enantiomer or in an enantiomerically enriched form, to esomeprazole free base of formula (I),

(I) or a pharmaceutically acceptable salt thereof; and

(c) optionally, when a salt is formed in (b), converting the salt of esomeprazole into a second salt of esomeprazole.

The present invention also includes a piperidine salt of 5-methoxy-2-[(S)- [(4-nitro-3,5-dimethylpyridin-2-yl)methyl] sulfinyl]-1 H-benzimidazole having formula (IV).

BRIEF DESCRIPTION OF THE DRAWING Fig. 1 is an illustration of an X-ray powder diffraction (PXRD) pattern for a piperidine salt of 5-methoxy-2-[(S)-[(4-nitro-3,5-dimethylpyridin-2- yl)methyl]sulfinyl]-1 H-benzimidazole. DETAILED DESCRIPTION

Percentages herein are expressed on a weight basis, unless the context indicates otherwise.

In an aspect, the present invention relates to processes for the preparation of esomeprazole of formula (I), or a pharmaceutically acceptable salt thereof, embodiments including one or more of the following steps: (a) reacting the pro-chiral sulfide of formula (II),

(ill) (b) converting a compound of formula (III) or a salt thereof, in the form of a single enantiomer or in an enantiomerically enriched form, to esomeprazole free base of formula (I),

(I) or a pharmaceutically acceptable salt thereof; and

Step (a) involves reacting the pro-chiral sulfide of formula (II) with an oxidizing agent. The pro-chiral sulphide compound can have a significant moisture content, as synthesized or received from a supplier. For example, the pro-chiral sulphide compound can be a hydrate, having an amount of water that can be about 5% by weight, or higher. In embodiments, the pro-chiral sulphide of formula (II) can first be subjected to a water removal procedure, using methods such as azeotropic distillation, fractional distillation, or any other techniques, to reduce its water content before reacting with an oxidizing agent.

For example, the pro-chiral sulphide of formula (II) may be combined with an organic solvent, such as, but not limited to, a solvent that forms an azeotrope with water, then heated to reflux temperature, removing the water from the mixture by techniques such as azeotropic distillation, simple distillation, and the like, at atmospheric pressure or under reduced pressure, until water is substantially completely removed from the mixture.

In embodiments, a substantially anhydrous pro-chiral sulphide of formula (II) having less than about 1 % by weight, such as about 0.01 to 1 %, or about 0.1 to 1 %, of water is used for the reaction of step (a). The pro-chiral sulfide of formula (II) is subjected to enantioselective oxidation with an oxidizing agent in the presence of a chiral auxiliary to provide a compound of formula (III), in the form of a single enantiomer or in an enantiomerically enriched form.

Suitable oxidizing agents that may be used in step (a) include, but are not limited to: hydroperoxide reagents such as t-butylhydroperoxide, cumene hydroperoxide, hydrogen peroxide and the like; peracids such as peracetic acid, m-chloroperbenzoic acid, perphthalic acid, ε-phthalimidoperhexanoic acid and the like; sodium perborate and the like; and any other suitable oxidizing agents.

The quantities of oxidizing agent that may be used may range from about 0.8 to about 2 molar equivalents, or about 1 molar equivalent, of the oxidizing agent, per mole of the pro-chiral sulfide of formula (II).

Suitable chiral auxiliaries that may be used in step (a) for enantioselective oxidation of a pro-chiral sulfide of formula (II) include, but are not limited to, chiral transition metal complexes such as chiral titanium complexes, chiral zirconium complexes, chiral vanadium complexes, chiral hafnium complexes, and the like, and any other suitable chiral metal complexes.

A chiral auxiliary that may be used in step (a) may be prepared in the presence or absence of a pro-chiral sulfide of formula (II). Chiral transition metal complexes may be prepared from transition metal compounds and chiral ligands.

The transition metal compounds that can be used for the preparation of the chiral transition metal complexes include, but are not limited to: titanium(IV) isopropoxide, titanium(IV) propoxide, titanium(IV) ethoxide, and titanium(IV) methoxide; zirconium(IV) acetylacetonate, zirconium(IV) butoxide, zirconium(IV) t- butoxide, zirconium(IV) ethoxide, zirconium(IV) n-propoxide, and zirconium(IV) isopropoxide; vanadium oxythpropoxide, vanadium oxyisopropoxide, and vanadyl acetylacetonate; hafnium(IV) acetylacetonate, hafnium(IV) butoxide, hafnium(IV) n-propoxide, hafnium(IV) isopropoxide, hafnium(IV) ethoxide, and hafnium(IV) t- butoxide; iron based compounds; and any other suitable metal compounds.

The amounts of transition metal compound that may be used in step (a) range from about 0.4 to about 2 molar equivalents, or about 0.6 molar equivalent, of transition metal compound, per mole of a pro-chiral sulfide of formula (II). The chiral ligands that may be used for the preparation of chiral transition metal complexes include, but are not limited to: chiral alcohols, such as binaphthol; mandelic acid; hydrobenzoin; esters of tartaric acid such as (+)-dialkyl- L-tartrates or (-)-dialkyl-D-tartrates, including (+)-dimethyl-L-tartrate, (-)-dimethyl- D-tartrate, (+)-diethyl-L-tartrate, (-)-diethyl-D-tartrate, (+)-diisopropyl-L-tartrate, (-)- diisopropyl-D-tartrate, (+)-dibutyl-L-tartrate, (-)-dibutyl-D-tartrate, (÷)-di-t-butyl-L- tartrate, and (-)-di-t-butyl-D-tartrate; and any other suitable chiral ligands.

The amounts of chiral ligand that may be used range from about 1 .5 to about 3 molar equivalents, or about 2 molar equivalents, of chiral ligand, per mole of transition metal compound. Step (a) may be optionally carried out in the presence of water, in order to improve the enantioselectivity of the reaction to provide a compound of formula (III) with greater enantiomeric purity. For this, either water may be used in the preparation of a chiral transition metal complex, which may be in turn used for the reaction in step (a), or water may be added to the reaction mixture comprising a chiral transition metal complex and a pro-chiral sulfide of formula (II). The amount of water that may be used in step (a) ranges from about 0.4 to about 0.8 molar equivalents, or about 0.6 molar equivalent, of water, per mole of transition metal compound. Step (a) may be optionally carried out in the presence of a base. Suitable bases that may be used in step (a) include, but are not limited to: organic bases such as triethylamine, tributylamine, N,N-diisopropylethylamine, N- methylpyrrolidine, pyridine, 4-(N,N-dimethylamino)pyridine, N-methylmorpholine, morpholine, imidazole, 2-methylimidazole, 4-methyl imidazole and the like; inorganic bases including alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, and cesium hydroxide, alkaline hydroxides such as aluminum hydroxide, magnesium hydroxide, calcium hydroxide and the like, alkali metal carbonates such as sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate and the like, alkaline earth metal carbonates such as magnesium carbonate, calcium carbonate and the like, alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate and the like; ion exchange resins including resins bound to ions such as sodium, potassium, lithium, calcium, magnesium, substituted or unsubstituted ammonium, and the like; and any other suitable bases.

The quantities of base that may be used for enantioselective oxidation of a pro-chiral sulfide of formula (II) in step (a) range from about 0.4 to about 2 molar equivalents, or about 1 molar equivalent, of base, per mole of transition metal compound. The molar ratios of different reagents used in step (a) as described above promote formation of a homogeneous reaction mixture, which is desired for improved results. If the reaction mixture is heterogeneous, it results in one or more problems like incomplete reaction, low yield, poor quality, poor enantioselectivity, or longer reaction times. Step (a) may be optionally carried out in a suitable solvent. Suitable solvents that may be used in step (a) include, but are not limited to: ketones such as acetone, butanone, 2-pentanone, 3-pentanone, methyl butyl ketone, methyl isobutyl ketone, and the like; esters such as ethyl formate, methyl acetate, ethyl acetate, propyl acetate, t-butyl acetate, isobutyl acetate, methyl propanoate, ethyl proponoate, methyl butanoate, ethyl butanoate, and the like; ethers such as diethyl ether, diisopropyl ether, t-butyl methyl ether, dibutyl ether, tetrahydrofuran, 1 ,2-dimethoxyethane, 1 ,4-dioxane, anisole, and the like; unsubstituted or substituted aliphatic or alicyclic hydrocarbons such as hexanes, n-heptane, n- pentane, cyclohexane, methylcyclohexane, nitromethane, and the like; halogenated hydrocarbons such as dichloromethane, chloroform, 1 ,1 ,2- trichloroethane, 1 ,2-dichloroethane, and the like; aromatic hydrocarbons such as toluene, xylenes, chlorobenzene, tetraline, and the like; nitriles such as acetonitrile, propionitrile, and the like; polar aprotic solvents such as N, N- dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, pyridine, dimethylsulphoxide, sulpholane, formamide, acetamide, propanamide, and the like; and any mixtures thereof.

Enantioselective oxidation of a pro-chiral sulfide of formula (II) in step (a) may be carried out at temperatures less than about 100⁰C, or less than about 50⁰C, or less than about 30°C, or less than about 10⁰C, or less than about 5°C, or less than about 0°C, or less than about -5°C, or less than about -10⁰C, or less than about -20°C, or less than about -40⁰C, or less than about -80°C or any other suitable temperatures. Suitable temperatures that may be used for the preparation of a chiral transition metal complex may be less than about 100°C, or less than about 80⁰C, or less than about 60°C, or less than about 40°C, or any other suitable temperatures.

Optionally, the compound of formula (III) obtained in step (a) may be reacted with a suitable base to obtain a salt of a compound of formula (III).

Suitable bases that may be used for preparation of a salt of a compound of formula (III) include, but are not limited to, lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, calcium carbonate, magnesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium methoxide, potassium methoxide, sodium t-butoxide, potassium t- butoxide, magnesium sulfate, pipehdine, amines having the formula NR1R2R3, wherein Ri, R₂, and R3 independently are the same or different groups such as hydrogen, linear, branched, or cyclic C_M2 alkyl, which may be substituted or unsubstituted, C_3-6 aryl, C_3-6 arylalkyl, and the like.

The conversion may be optionally carried out in a suitable solvent. Suitable solvents that may be used for conversion include, but are not limited to: alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1 -butanol, 2-butanol, t-butyl alcohol, 1 -pentanol, 2-pentanol, neopentyl alcohol, amyl alcohol, 2- methoxyethanol, 2-ethoxyethanol, ethylene glycol, glycerol, and the like; ketones such as acetone, butanone, 2-pentanone, 3-pentanone, methyl butyl ketone, methyl ethyl ketone, methyl isobutyl ketone, and the like; esters such as ethyl formate, methyl acetate, ethyl acetate, propyl acetate, t-butyl acetate, isobutyl acetate, methyl propanoate, ethyl proponoate, methyl butanoate, ethyl butanoate, and the like; ethers such as diethyl ether, diisopropyl ether, t-butyl methyl ether, dibutyl ether, tetrahydrofuran, 1 ,2-dimethoxyethane, 1 ,4-dioxane, 2- methoxyethanol, 2-ethoxyethanol, anisole, and the like; unsubstituted or substituted aliphatic or alicyclic hydrocarbons such as hexanes, n-heptane, n- pentane, cyclohexane, methylcyclohexane, nitromethane, and the like; halogenated hydrocarbons such as dichloromethane, chloroform, 1 ,1 ,2- trichloroethane, 1 ,2-dichloroethane, and the like; aromatic hydrocarbons such as toluene, xylenes, chlorobenzene, tetraline, and the like; nitriles such as acetonitrile, propionitrile and the like; polar aprotic solvents such as N₁N- dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, pyridine, dimethylsulphoxide, sulpholane, formamide, acetamide, propanamide, and the like; water; and any mixtures thereof.

The compound of formula (III) or its salt may be isolated by any techniques known in the art. For example, useful techniques include but are not limited to: decantation, centhfugation, gravity filtration, suction filtration, concentrating, cooling, stirring, shaking, evaporation, flash evaporation, simple evaporation, rotational drying, spray drying, thin-film drying, freeze-drying, and the like.

The resulting solid may be optionally washed with a suitable solvent to remove occluded mother liquor in order to reduce the amount of impurities trapped in the wet cake. The wet cake may be optionally dried using conventional drying techniques such as a tray dryer, cone vacuum dryer, fludized bed dryer, thin film dryer, and the like, at atmospheric pressure or under reduced pressure. The compound of formula (III) obtained in step (a) may be crystalline, or amorphous, or a mixture thereof.

Step (b) involves reacting a compound of formula (III) in the form of a single enantiomer or in an enantiomehcally enriched form with an alkali metal methoxide or alkaline earth metal methoxide, to provide esomeprazole free base of formula (I) or a pharmaceutically acceptable salt thereof.

Suitable alkali metal methoxides that may be used in step (b) include, but are not limited to, sodium methoxide, potassium methoxide and the like. Suitable alkaline earth metal methoxides that may be used in step (b) include, but are not limited to, magnesium methoxide, calcium methoxide, and the like. Optionally, the alkali metal methoxides or alkaline earth metal methoxides may be used in the form of a solution in a suitable solvent such as alcohol, water and the like. Step (b) may be optionally carried out in a suitable solvent. Suitable solvents that may be used in step (b) include, but are not limited to: alcohols such as methanol, ethanol, 1 -propanol, 2-propanol, 1 -butanol, 2-butanol, t-butyl alcohol, 1 -pentanol, 2-pentanol, neopentyl alcohol, amyl alcohol, 2-methoxyethanol, 2- ethoxyethanol, ethylene glycol, glycerol, and the like; ketones such as acetone, butanone, 2-pentanone, 3-pentanone, methyl butyl ketone, methyl iso-butyl ketone, and the like; esters such as ethyl formate, methyl acetate, ethyl acetate, propyl acetate, t-butyl acetate, isobutyl acetate, methyl propanoate, ethyl proponoate, methyl butanoate, ethyl butanoate, and the like; ethers such as diethyl ether, diisopropyl ether, t-butyl methyl ether, dibutyl ether, tetrahydrofuran, 1 ,2-dimethoxyethane, 1 ,4-dioxane, anisole, and the like; unsubstituted or substituted aliphatic or alicyclic hydrocarbons such as hexanes, n-heptane, n- pentane, cyclohexane, methylcyclohexane, nitromethane, and the like; halogenated hydrocarbons such as dichloromethane, chloroform, 1 ,1 ,2- trichloroethane, 1 ,2-dichloroethane, and the like; aromatic hydrocarbons such as toluene, xylenes, chlorobenzene, tetraline, and the like; nitriles such as acetonitrile, propionitrile, and the like; polar aprotic solvents such as N₁N- dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, pyridine, dimethylsulphoxide, sulpholane, formamide, acetamide, propanamide, and the like; and any mixtures thereof.

Step (b) may be carried out at temperatures less than about 100⁰C, or less than about 80⁰C, or less than about 60°C, or less than about 40⁰C, or any other suitable temperatures.

Suitable times for completing step (b) depend on temperature and other conditions and may be generally less than about 15 hours, or less than about 10 hours, or less than about 5 hours, less than about 2 hours, or less than about 30 minutes, or any other suitable times.

The product of step (b) may be isolated in the form of a salt of esomeprazole of formula (I), directly from the reaction mixture itself after the reaction is complete in step (b), or after conventional work up with techniques such as filtration, quenching with a suitable reagent, extraction and the like. The salt of esomeprazole may be in crystalline or amorphous forms, or mixtures thereof.

Suitable solvents that may be used for isolation include, but are not limited to: alcohols such as methanol, ethanol, 1 -propanol, 2-propanol, 1 -butanol, 2- butanol, t-butyl alcohol, 1 -pentanol, 2-pentanol, neopentyl alcohol, amyl alcohol, 2-methoxyethanol, 2-ethoxyethanol, ethylene glycol, glycerol, and the like; ketones such as acetone, butanone, 2-pentanone, 3-pentanone, methyl butyl ketone, methyl ethyl ketone, methyl iso-butyl ketone, and the like; esters such as ethyl formate, methyl acetate, ethyl acetate, propyl acetate, t-butyl acetate, isobutyl acetate, methyl propanoate, ethyl proponoate, methyl butanoate, ethyl butanoate, and the like; ethers such as diethyl ether, diisopropyl ether, t-butyl methyl ether, dibutyl ether, tetrahydrofuran, 1 ,2-dimethoxyethane, 1 ,4-dioxane, 2- methoxyethanol, 2-ethoxyethanol, anisole, and the like; unsubstituted or substituted aliphatic or alicyclic hydrocarbons such as hexanes, n-heptane, n- pentane, cyclohexane, methylcyclohexane, nitromethane, and the like; halogenated hydrocarbons such as dichloromethane, chloroform, 1 ,1 ,2- trichloroethane, 1 ,2-dichloroethane, and the like; aromatic hydrocarbons such as toluene, xylenes, chlorobenzene, tetraline, and the like; nitriles such as acetonitrile, propionitrile, and the like; polar aprotic solvents such as N₁N- dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, pyridine, dimethylsulphoxide, sulpholane, formamide, acetamide, propanamide, and the like; water; and any mixtures thereof.

The isolation in step (b) may involve methods including removal of solvent, cooling, concentrating the reaction mass, adding seed crystals to induce crystallization, combining with an anti-solvent, extraction with a solvent, and the like. Stirring or other alternate methods such as shaking, agitation and the like, may also be employed for the said isolation.

The isolated salt of esomeprazole of formula (I) may be recovered as a solid using conventional methods, including decantation, centrifugation, gravity filtration, suction filtration, or other techniques known in the art for the recovery of solids. The salt of esomeprazole may be in crystalline or amorphous forms, or mixtures thereof.

The resulting solid may optionally be dried. Drying may be suitably carried out using a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, and the like, at atmospheric pressure or under reduced pressure. Drying may be carried out at temperatures less than about 100⁰C, or less than about 60⁰C, or less than about 40°C, or any other suitable temperatures, at atmospheric pressure or under reduced pressure, and in the presence or absence of an inert atmosphere such as nitrogen, argon, neon, or helium. The drying may be carried out for any time periods to achieve the desired quality of the product, such as, for example, about 1 to about 15 hours, or longer.

The obtained salt of esomeprazole of formula (I) may be optionally further purified by recrystallization or by slurrying in a suitable solvent. Suitable solvents that may be used for purification of esomeprazole include, but are not limited to: alcohols such as methanol, ethanol, 1 -propanol, 2- propanol, 1 -butanol, 2-butanol, t-butyl alcohol, 1 -pentanol, 2-pentanol, neopentyl alcohol, amyl alcohol, 2-methoxyethanol, 2-ethoxyethanol, ethylene glycol, glycerol, and the like; ketones such as acetone, butanone, 2-pentanone, 3- pentanone, methyl butyl ketone, methyl ethyl ketone, methyl iso-butyl ketone, and the like; esters such as ethyl formate, methyl acetate, ethyl acetate, propyl acetate, t-butyl acetate, isobutyl acetate, methyl propanoate, ethyl proponoate, methyl butanoate, ethyl butanoate, and the like; ethers such as diethyl ether, diisopropyl ether, t-butyl methyl ether, dibutyl ether, tetrahydrofuran, 1 ,2- dimethoxyethane, 1 ,4-dioxane, 2-methoxyethanol, 2-ethoxyethanol, anisole, and the like; unsubstituted or substituted aliphatic or alicyclic hydrocarbons such as hexanes, n-heptane, n-pentane, cyclohexane, methylcyclohexane, nitromethane, and the like; halogenated hydrocarbons such as dichloromethane, chloroform, 1 ,1 ,2-thchloroethane, 1 ,2-dichloroethane, and the like; aromatic hydrocarbons such as toluene, xylenes, chlorobenzene, tetraline, and the like; nitriles such as acetonitrile, propionitrile, and the like; polar aprotic solvents such as N₁N- dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, pyridine, dimethylsulphoxide, sulpholane, formamide, acetamide, propanamide, and the like; water; and any mixtures thereof. The resulting salt of esomeprazole of formula (I) may be recovered as a solid using conventional methods, including decantation, centrifugation, gravity filtration, suction filtration, or other techniques known in the art for the recovery of solids. The salt of esomeprazole may be in crystalline or amorphous form, or mixtures thereof. The resulting solid may optionally be dried. Drying may be suitably carried out using a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, and the like, at atmospheric pressure or under reduced pressure. Drying may be carried out at temperatures less than about 100⁰C, or less than about 60⁰C, or less than about 40°C, or any other suitable temperatures, at atmospheric pressure or under reduced pressure, and in the presence or absence of an inert atmosphere such as nitrogen, argon, neon, or helium. The drying may be carried out for any time periods to achieve the desired quality of the product, such as, for example, about 1 to about 15 hours, or longer. Optionally, if the product of step (b) is isolated as esomeprazole free base of formula (I), the esomeprazole free base of formula (I) may be further reacted with a suitable base to obtain a salt of esomeprazole.

Suitable bases that may be used for preparation of a salt of esomeprazole include, but are not limited to, lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, calcium carbonate, magnesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium methoxide, potassium methoxide, sodium t-butoxide, potassium t-butoxide, and the like. Suitable solvents that may be used for the conversion include, but are not limited to: alcohols such as methanol, ethanol, 1 -propanol, 2-propanol, 1 -butanol, 2-butanol, t-butyl alcohol, 1 -pentanol, 2-pentanol, neopentyl alcohol, amyl alcohol, 2-methoxyethanol, 2-ethoxyethanol, ethylene glycol, glycerol, and the like; ketones such as acetone, butanone, 2-pentanone, 3-pentanone, methyl butyl ketone, methyl ethyl ketone, methyl iso-butyl ketone, and the like; esters such as ethyl formate, methyl acetate, ethyl acetate, propyl acetate, t-butyl acetate, isobutyl acetate, methyl propanoate, ethyl proponoate, methyl butanoate, ethyl butanoate, and the like; ethers such as diethyl ether, diisopropyl ether, t-butyl methyl ether, dibutyl ether, tetrahydrofuran, 1 ,2-dimethoxyethane, 1 ,4-dioxane, 2- methoxyethanol, 2-ethoxyethanol, anisole, and the like; unsubstituted or substituted aliphatic or alicyclic hydrocarbons such as hexanes, n-heptane, n- pentane, cyclohexane, methylcyclohexane, nitromethane, and the like; halogenated hydrocarbons such as dichloromethane, chloroform, 1 ,1 ,2- trichloroethane, 1 ,2-dichloroethane, and the like; aromatic hydrocarbons such as toluene, xylenes, chlorobenzene, tetraline, and the like; nitriles such as acetonitrile, propionitrile, and the like; polar aprotic solvents such as N₁N- dimethylfornnannide, N,N-dimethylacetamide, N-methylpyrrolidone, pyridine, dimethylsulphoxide, sulpholane, formamide, acetamide, propanamide, and the like; water; and any mixtures thereof.

The isolation, optional purification of the obtained salt of esomeprazole of formula (I), an further drying and other conditions may follow the procedures given hereinabove for isolation and purification of a salt of esomeprazole of formula (I) in step (b). Step (c) involves optionally converting a first salt of esomeprazole into a second salt of esomeprazole.

Step (c) may be carried out using any processes known in the art. For example, step (c) may be carried out by treating a first salt of esomeprazole obtained from step (b) with a suitable base in a suitable solvent, to obtain the second salt of esomeprazole. The said second salt of esomeprazole may be isolated in any polymorphic form.

For example, step (c) may be carried out by the conversion of a salt of esomeprazole to esomeprazole magnesium trihydrate, and its subsequent conversion to esomeprazole magnesium dihydrate as disclosed in International Application Publication No. WO 2009/099933. In embodiments, step (c) may be carried out by the conversion of a salt of esomeprazole into amorphous esomeprazole magnesium, comprising:

(i) reacting a salt of esomeprazole with a source of magnesium ions, in water, at temperatures about 20⁰C or lower; (ii) isolating amorphous esomeprazole magnesium; and

(iii) optionally, drying the amorphous esomeprazole magnesium, the process being described in International Application No. PCT/US2010/030855, filed on April 13, 2010. These patent applications are incorporated herein by this reference, in their entireties. The present invention also includes a piperidine salt of 5-methoxy-2-[(S)-

[(4-nitro-3,5-dimethylpyhdin-2-yl)methyl]sulfinyl]-1 H-benzimidazole having formula (IV).

The piperidine salt of 5-methoxy-2-[(S)-[(4-nitro-3,5-dimethylpyridin-2- yl)methyl] sulfinyl]-1 H-benzimidazole may be characterized by a PXRD pattern comprising peaks located substantially at about 10, 10.2, 13, 16, 16.5, 19.0, 20.1 , 21 .18, 24.3, and 29.0, ±0.2 degrees 2-theta.

An illustration of a PXRD pattern for a piperidine salt of 5-methoxy-2-[(S)- [(4-nitro-3,5-dimethylpyhdin-2-yl)methyl] sulfinyl]-1 H-benzimidazole is shown in Fig. 1 .

For all analytical data discussed in this application, it should be kept in mind that the exact values obtained can depend on many factors, e.g., the specific instrument, sample preparation, and analyst technique. PXRD peak intensities are particularly influenced by sample preparation and handling techniques. The relative peak locations will permit identification of a given crystalline form by those skilled in the art. PXRD data reported herein were obtained using copper Ka radiation, and were obtained using a Bruker AXS D8 Advance powder X-ray diffractometer.

The present invention also provides substantially pure esomeprazole free base of formula (I), or a pharmaceutically acceptable salt thereof, obtained from a process of the present application. Substantially pure esomeprazole free base of formula (I), or a salt of esomeprazole of formula (I), has a purity greater than about 99%, or greater than about 99.2%, or greater than about 99.5%, or greater than about 99.7%, or greater than about 99.9%, as determined using high performance liquid chromatography (HPLC). The substantially pure esomeprazole free base of formula (I), or salt of esomeprazole of formula (I), obtained in step (b) may contain one or more of the following drug-related impurities, and any other drug-related impurities, each in amounts less than about 0.5%, or less than about 0.3%, or less than about 0.2%, or less than about 0.1 %, as determined using HPLC.

Nitrosulfone R-Nitroomeprazole

Sulphone R-Omeprazole

Sulphide

Certain specific aspects and embodiments of the present invention are described in further detail by the examples below, which are provided only for the purpose of illustration and are not intended to limit the scope of the invention in any manner.

EXAMPLE 1 : Preparation of 5-methoxy-2-[(S)-[(4-nitro-3,5-dimethylpyhdin-2- yl)methyl]sulfinyl]-1 H-benzimidazole sodium.

A solution of substantially anhydrous 5-methoxy-2-[[(4-nitro-3,5- dimethylpyridin-2-yl)methyl]thio]-1 H-benzimidazole (20 g, 58 mmol) in toluene is charged into a round bottom flask. (-)-Diethyl tartrate (22.7 g, 110 mmol) and titanium isopropoxide (15.69 g, 55 mmol) are added at 25°C. Water (60 μl_, 33 mmol) is added and the mixture is stirred for 10 minutes at 25°C. The mass is heated to 50⁰C and stirred for 60 minutes. The mass is cooled to 27.5±2.5°C. N,N-Diisopropylethylamine (7.13 g, 55 mmol) is added and stirred for 30 minutes. The mass is cooled to 4±1 °C and stirred for 65 minutes. Cumene hydroperoxide (79.5%, 11.50 g, 75 mmol) is added drop-wise over 70 minutes and stirred for 2 hours, 15 minutes. A solution of triethylamine (100 ml_) and water (150 ml_) is added and stirred for 30 minutes. The organic and aqueous layers are separated. A solution of triethylamine (100 ml_) and water (150 ml_) is added to the organic layer and stirred for 30 minutes. The organic and aqueous layers are separated. A solution of thethylamine (100 ml_) and water (150 ml_) is added to the organic layer and stirred for 20 minutes. All of the aqueous layers are combined and filtered. To the filtrate, ethyl acetate (200 ml_) is added and pH is adjusted to 7.5 to 8 using acetic acid (5 ml_). The organic and aqueous layers are separated. Ethyl acetate (100 ml_) is added to the aqueous layer. The organic and aqueous layers are separated. The ethyl acetate layers are combined and solvent is evaporated at 45°C under reduced pressure, to obtain 18.0 g of 5-methoxy-2-[(S)-[(4-nitro-3,5- dimethylpyridin-2-yl)methyl]sulfinyl]-1 /-/-benzimidazole. Chemical purity by HPLC: 99.7%; chiral purity by HPLC: 96.42% e.e.

1 g of the above residue is charged into a round bottom flask. Methanol (3 mL) and sodium hydroxide (0.1 g) are added at 26°C and stirred for 10 minutes, lsopropyl alcohol (6 mL) is added and stirred for 20 minutes. The solid is filtered and washed with isopropyl alcohol (3 mL). The wet solid is dried at 45°C under reduced pressure for 5 hours, to afford 0.7 g of the title compound. Chemical purity by HPLC: 99.57%.

EXAMPLE 2: Preparation of a pipehdine salt of 5-methoxy-2-[(S)-[(4-nitro-3,5- dimethylpyridin-2-yl)methyl]sulfinyl]-1 /-/-benzimidazole. 5-Methoxy-2-[[(4-nitro-3,5-dimethylpyridin-2-yl)methyl]thio]-1 /-/- benzimidazole monohydrate (50.0 g, 138 mmol) and toluene (1500 mL) are charged into a round bottom flask and heated to 1 10⁰C to remove water azotropically. Titanium isopropoxide (23.5 g, 82.9 mmol) and (-)-diethyl tartrate (34.1 g, 166 mmol) are added at 50⁰C. Water (900 μl_, 50 mmol) is added and stirred for 60 minutes at 50°C. The mass is cooled to 35°C and N₁N- diisopropylethylamine (10.7 g, 82.9 mmol) is added. The mass is cooled to - 4±4°C. Cumene hydroperoxide (73%, 28.8 g, 138 mmol) and toluene (150 mL) are added drop-wise over 60 minutes and further stirred for 3 hours, 15 minutes. A solution of piperidine (30 mL) and water (270 mL) is added at 1 °C and stirred for 15 minutes. The mass is allowed to reach 26±1 °C and is stirred for 90 minutes. The precipitated solid is filtered and washed with toluene (50 mL). The wet solid is dried at 55°C for 3 hours, to afford 55.0 g of the title compound. Chemical purity by HPLC: 98.12%. Chiral purity by HPLC: 95.8% e.e. [α]^D: 138°.

Piperidine content by GC: 24.6% by wt.

1 H NMR (CDCI₃, 400 MHz) : 58.39 (s,1 H), 57.58 (d, 1 H), 57.2 (br,1 H), 57.0 (d, 1 H), 54.8 (d, 1 H), 54.69 (d, 1 H), 53.8 (s,3H), 52.2-2.3 (6H), 52.9 (s, 4H), 51.5 (br, 6H), 52.8 (br, 4H).

PXRD pattern in accordance with Fig. 1.

EXAMPLE 3: Preparation of 5-methoxy-2-[(S)-[(4-nitro-3,5-dimethylpyridin-2- yl)methyl]sulfinyl]-1 H-benzimidazole.

5-Methoxy-2-[[(4-nitro-3,5-dimethylpyridin-2-yl)methyl]thio]-1 /-/- benzimidazole monohydrate (4.75 g, 13.8 mmol) and toluene (125 mL) are charged into a round bottom flask at 26°C and stirred for 10 minutes. The mass is heated to 110⁰C to remove water azotropically. The mass is further heated at 110⁰C for 30 minutes to partially remove toluene azotropically. The mass is cooled to 30⁰C, followed by addition of (-)-diethyl tartrate (5.7 g, 27.6 mmol) and titanium isopropoxide (3.92 g, 13.8 mmol). Water (150 μL, 8.3 mmol) is added and stirred for 10 minutes at 30°C. The mass is heated to 50⁰C and stirred for 45 minutes. N,N-Diisopropylethylamine (1.78 g, 13.8 mmol) is added and the mass is cooled to 4±1 °C. Cumene hydroperoxide (73%, 2.88 g, 13.8 mmol) and toluene (10 mL) are added drop-wise over 30 minutes and stirred for 60 minutes. A solution of triethylamine (25 mL) and water (25 mL) is added and stirred for 10 minutes. The mass is allowed to reach 26±1 °C and is stirred for 1814 hours. The formed solid is filtered and washed with water (20 mL). The wet solid is dried at 50⁰C for 6 hours, to afford 2.6 g of the title compound.

Chemical purity by HPLC: 98.31 %. Chiral purity by HPLC: 97.24% e.e.

EXAMPLE 4: Preparation of esomeprazole sodium. 5-Methoxy-2-[(S)-[(4-nitro-3,5-dimethylpyridin-2-yl)methyl]sulfinyl]-1 H- benzimidazole sodium (3 g) and methanol (30 mL) are charged into a round bottom flask and stirred at 25°C for 20 minutes. The solution is heated to 60°C and stirred for 30 minutes. Sodium methoxide in methanol solution (30%, 6 mL) is added at 65±5°C and stirred for 4 hours. Methanol (100 ml_) is added and stirred for 15 minutes. Sodium methoxide in methanol solution (30%, 3.9 ml_) is added at 70⁰C and stirred for 4 hours. Chilled water (30 ml_) is added, followed by addition of toluene (15 ml_) and stirring at 26±1 °C for 10 minutes. The organic and aqueous layers are separated. The aqueous layer is washed with toluene (15 ml_). pH of the aqueous layer is adjusted to about 7.5 using acetic acid (~4 ml_) and it is extracted with dichloromethane (30 ml_). The combined organic layer is dried over sodium sulphate (1 g). The solvent is evaporated from the organic layer at 50⁰C under reduced pressure. Methanol (15 ml_) is added to the residue at 26±1 °C and stirred for 10 minutes. Sodium hydroxide pellets (0.47 g) are added and stirred for 13 hours. The solvent is evaporated at 42.5±2.5°C under reduced pressure. Ethyl acetate (15 ml_) is added to the residue at 26°C and stirred for 20 minutes. The solvent is evaporated at 45±5°C under reduced pressure. Ethyl acetate (15 ml_) is added to the obtained residue. The solvent is evaporated at 50⁰C under reduced pressure. Ethyl acetate (30 ml_) is added to the obtained residue at 30⁰C and stirred for 30 minutes. The solid is filtered and washed with ethyl acetate (15 ml_). The wet solid is dried at 40°C for 5 hours to afford 2.4 g of the title compound.

EXAMPLE 5: Preparation of esomeprazole sodium. Methanol (6 ml_) and toluene (6 ml_) are charged into a round bottom flask, followed by addition of 5-methoxy-2-[(S)-[(4-nitro-3,5-dimethylpyridin-2- yl)methyl]sulfinyl]-1 H-benzimidazole sodium (3 g), and the mixture is stirred at 26±1 °C for 20 minutes. The solution is heated to 60⁰C and stirred for 30 minutes. Sodium methoxide in methanol solution (30%, 4.3 ml_) is added at 60°C and stirred for 4 hours. Methanol (100 ml_) is added and stirred for 15 minutes. Sodium methoxide in methanol solution (30%, 3.9 ml_) is added drop-wise at 60⁰C over 15 minutes. The temperature of the mass is raised to 70°C and the mass is stirred for AVz hours. The mass is cooled to 26±1 °C. Chilled water (30 ml_) is added, followed by addition of toluene (12 ml_) and stirring at 26±1 °C for 25 minutes. The organic and aqueous layers are separated. The aqueous layer is washed with toluene (15 ml_). pH of the aqueous layer is adjusted to about 7.5 using acetic acid (~4 ml_) and it is extracted with dichloromethane (30 ml_). The combined organic layer is dried over sodium sulphate (1 g). The solvent is evaporated from the organic layer at 42°C under reduced pressure. Methanol (15 ml_) is added to the residue at 26°C and stirred for 10 minutes. Sodium hydroxide pellets (0.47 g) and methanol (15 ml_) are added and stirred for 2Vz hours. The solvent is evaporated at 45°C under reduced pressure. Ethyl acetate (15 ml_) is added to the obtained residue. The solvent is evaporated at 50⁰C under reduced pressure. Ethyl acetate (15 ml_) is added to the obtained residue. The solvent is evaporated at 50⁰C under reduced pressure. Ethyl acetate (30 ml_) is added to the obtained residue at 29±1 °C and stirred for 2 hours. The solid is filtered and washed with ethyl acetate (6 ml_). The wet solid is dried at 50⁰C for 3 hours to afford 2.1 g of the title compound. Chemical purity by HPLC: 97.73%.

EXAMPLE 6: Preparation of esomeprazole sodium.

Methanol (6 mL) and toluene (6 mL) are added to a piperidine salt of 5- methoxy-2-[(S)-[(4-nitro-3,5-dimethylpyridin-2-yl)methyl]sulfinyl]-1 H-benzimidazole (3 g) in a round bottom flask and the mixture is stirred at 25°C for 20 minutes. Sodium methoxide solution (30%, 6.06 mL) is added. The mixture is heated to 50°C and stirred for 5 hours. The mass is allowed to cool to 26±1 °C, followed by addition of chilled water (30 mL). The organic and aqueous layers are separated. Dichloromethane (40 mL) is added to the aqueous layer and stirred for 20 minutes. pH of the aqueous layer is adjusted to about 7.5 using acetic acid (5 mL) at about 1 O⁰C. The organic layer is separated and the solvent is evaporated at 40⁰C under reduced pressure. Methanol (15 mL) is added to the residue at 25°C and stirred for 30 minutes. Sodium hydroxide (0.269 g) is added and stirred for 17 hours. The solvent is evaporated at 25°C under reduced pressure. Ethyl acetate (50 mL) is added to the obtained residue and stirred for 40 minutes. The solvent is evaporated at 40⁰C under reduced pressure. Ethyl acetate (50 mL) is added to the obtained residue at 25°C and stirred for 20 minutes. The solvent is evaporated at 40⁰C under reduced pressure. Ethyl acetate (50 mL) is added to the obtained residue at 25°C and stirred for 100 minutes. The solid is filtered and washed with ethyl acetate (20 mL). The wet solid is dried under reduced pressure at 40°C for 6 hours to afford 2 g of the title compound. EXAMPLE 7: Preparation of amorphous esomeprazole magnesium.

Esomeprazole sodium (6 g) and water (138 ml_) are charged into a round bottom flask at 25°C and stirred for 20 minutes. The resulting solution is stirred and cooled to 1⁰C over 40 minutes. A solution of MgSO₄ ^»7H₂O (2.21 g) in water (12 ml_) is added drop-wise at 1 °C and the mixture is stirred for 2^ΛA hours at 7°C. The solid is filtered, washed with water (30 ml_), and dried at 40⁰C for 3 hours to obtain 5.2 g of amorphous esomeprazole magnesium.

EXAMPLE 8: Preparation of a pipehdine salt of 5-methoxy-2-[(S)-[(4-nitro-3,5- dimethylpyridin-2-yl)methyl]sulfinyl]-1 H-benzimidazole.

5-Methoxy-2-[[(4-nitro-3,5-dimethylpyridin-2-yl)methyl]thio]-1 /-/- benzimidazole monohydrate (8 kg) and toluene (240 L) are charged into a rector and heated to 110⁰C to remove water azotropically. Titanium isopropoxide (3.76 kg) and (-)-diethyl tartrate (5.45 kg) are added at 50°C. Water (0.144 L) is added and stirred for 2 hours at 50⁰C. The mass is cooled to 35°C and N₁N- diisopropylethylamine (1.712 kg) is added. The mass is cooled to 0±2°C. Cumene hydroperoxide (73%, 4.6 kg) and toluene (24 L) are added drop-wise over 3 hours, 40 minutes and further stirred for 4 hours, 20 minutes. pH of the mass is adjusted to 13.3 using 6% aqueous potassium hydroxide solution (100 L) and the mass is filtered. The filtrate aqueous layer is separated and washed with toluene (24 L). A solution of piperidine (7.2 L) and water (67.2 L) is added to the aqueous layer at 10⁰C and stirred for 2 hours. pH of the mass is adjusted to 11.9 using aqueous acetic acid (4 L).The mass is cooled to 2°C and stirred for 8 hours. The precipitated solid is filtered and washed with water (16 L). The wet solid is dried at 55°C for 6 hours, to afford 8.74 kg of the title compound.

Chemical purity by HPLC: 95.88%; nitrosulphone 3.39%; R- nitroomeprazole 0.86%.

EXAMPLE 9: Purification of piperidine salt of 5-methoxy-2-[(S)-[(4-nitro-3,5- dimethylpyridin-2-yl)methyl]sulfinyl]-1 H-benzimidazole.

A piperidine salt of 5-methoxy-2-[(S)-[(4-nitro-3,5-dimethylpyridin-2- yl)methyl]sulfinyl]-1 H-benzimidazole (6 g; chemical purity by HPLC 97.4%, nitrosulphone 1.16%, nitrosulphide 0.19%) and isopropanol (36 mL) are charged into a round bottom flask. The mixture is heated to 60⁰C to obtain a clear solution and it is stirred at 60⁰C for 15 minutes, lsopropanol (84 ml_) is added at 25°C and stirred at 28°C for 21 hours. The mixture is filtered. Solvent is evaporated from the filtrate at 50⁰C under reduced pressure to afford 5.1. g of the title compound. Chemical purity by HPLC: 98.17%, nitrosulphone 0.15%, nitrosulphide 0.34%.

EXAMPLE 10: Purification of a piperidine salt of 5-methoxy-2-[(S)-[(4-nitro-3,5- dimethylpyridin-2-yl)methyl]sulfinyl]-1 /-/-benzimidazole.

Methanol (40 mL) and toluene (40 mL) are charged into a round bottom flask, followed by addition of a piperidine salt of 5-methoxy-2-[(S)-[(4-nitro-3,5- dimethylpyridin-2-yl)methyl]sulfinyl]-1 H-benzimidazole (10 g; chemical purity by HPLC 97.63%, nitrosulphone 0.91 %, nitrosulphide 0.22%) and the mixture is stirred at 27°C for 15 minutes. Sodium methoxide in methanol solution (30%, 20 g) is added at 26°C and stirred for 2 hours, 20 minutes at 26°C. The formed solid is filtered and washed with a mixture of methanol (5 mL) and toluene (5 mL). The wet solid is dried under reduced pressure at 45°C for 4 hours to afford 7.8 g of the title compound.

Chemical purity by HPLC: 99.64%, nitrosulphone 0.28%, nitrosulphide 0.03%.

EXAMPLE 11 : Preparation of esomeprazole sodium.

Methanol (100 mL) and toluene (100 mL) are charged into a round bottom flask, followed by addition of a piperidine salt of 5-methoxy-2-[(S)-[(4-nitro-3,5- dimethylpyridin-2-yl)methyl]sulfinyl]-1 H-benzimidazole (25 g), and the mixture is stirred at 26°C for 40 minutes. The mass is filtered through a Hyflow (flux-calcined diatomaceous earth) bed and the bed is washed with mixture of methanol (25 mL) and toluene (25 mL). The filtrate is charged into a round bottom flask. Sodium methoxide in methanol solution (30%, 70.8 g) is added and the mixture is heated to 68°C and stirred for 10 hours. The mass is cooled to 4°C and stirred at 4°C for 40 minutes. The mass is filtered and the solid is washed with a mixture of methanol (25 mL) and toluene (25 mL). The solvent is evaporated from the filtrate at 48°C under reduced pressure. Methanol (87.5 mL) is added to the residue at 28°C, the temperature is raised to 45°C, and the mixture is stirred for 10 minutes. The mixture is cooled to 32°C and stirred for 1 hour, then further cooled to 3°C and stirred for 70 minutes. The formed solid is filtered and washed with toluene (25 ml_) and cyclohexane (100 ml_). The wet solid and ethyl acetate (100 ml_) are charged into a round bottom flask and the solvent is evaporated at 45°C under reduced pressure. Ethyl acetate (100 ml_) is added to the residue at 45°C and the solvent is evaporated at 45°C under reduced pressure. Ethyl acetate (200 ml_) is added to the residue. The mass is cooled to 2°C and stirred for 60 minutes. The solid is filtered and washed with ethyl acetate (50 ml_). The wet solid is dried under reduced pressure at 50⁰C for 4 hours, to afford 17.0 g of the title compound. Chemical purity by HPLC: 99.60%, nitrosulphone 0.01 %, R-omeprazole

0.02%, sulphone 0.01 %, sulphide 0.01 %.

EXAMPLE 12: Preparation of esomeprazole sodium.

Methanol (400 mL) and toluene (400 mL) are charged into a round bottom flask, followed by addition of a piperidine salt of 5-methoxy-2-[(S)-[(4-nitro-3,5- dimethylpyridin-2-yl)methyl]sulfinyl]-1 H-benzimidazole (100 g), and the mixture is stirred at 26°C for 30 minutes. The mass is filtered through a Hyflow bed and the bed is washed with mixture of methanol (100 mL) and toluene (100 mL). The filtrate is charged into a round bottom flask and sodium methoxide in methanol solution (30%, 284.5 g) is added. The mixture is heated to 68°C and stirred for 10 hours. The mass is cooled to 5°C, stirred at 5°C for 60 minutes, is filtered, and the solid is washed with a mixture of methanol (50 mL) and toluene (50 mL). The solvent is evaporated from the filtrate at 45°C under reduced pressure. Methanol (350 mL) is added to the residue at 30⁰C and the mixture is cooled to 5°C and stirred for 80 minutes. The solid is filtered and washed with toluene (100 mL) and cyclohexane (400 mL). The wet solid and ethyl acetate (400 mL) are charged into a round bottom flask. The solvent is evaporated at 45°C under reduced pressure. Ethyl acetate (400 mL) is added to the residue at 45°C and the solvent is evaporated at 45°C under reduced pressure. Ethyl acetate (800 mL) is added to the residue. The resultant mixture is cooled to 2°C and stirred for 60 minutes. The solid is filtered and washed with ethyl acetate (200 mL). The wet solid and ethyl acetate (600 mL) are charged into a round bottom flask. The mixture is heated to 45°C and stirred at 45°C for 30 minutes. The mixture is cooled to 5°C and stirred at 5°C for 50 minutes. The solid is filtered and washed with ethyl acetate (200 ml_). The wet solid is dried under reduced pressure at 50⁰C for 15 hours to afford 71.0 g of the title compound.

Chemical purity by HPLC: 99.88%, nitrosulphone 0.02%, R-omeprazole 0.06%, sulphone 0.01 %, sulphide not detected.

EXAMPLE 13: Preparation of esomeprazole sodium.

Methanol (200 mL) and toluene (200 mL) are charged into a round bottom flask, followed by addition of a piperidine salt of 5-methoxy-2-[(S)-[(4-nitro-3,5- dimethylpyridin-2-yl)methyl]sulfinyl]-1 H-benzimidazole (50 g), and the mixture is stirred at 31⁰C for 10 minutes. The mass is filtered through a Hyflow bed and the bed is washed twice with a mixture of methanol (50 mL) and toluene (50 mL). The filtrate is charged into a round bottom flask. Sodium methoxide in methanol solution (30%, 141.6 g) is added and the mixture is heated to 70⁰C and stirred for 12 hours. The mass is cooled to 5°C and stirred at 5°C for 10 minutes. The mass was filtered and the solid is washed twice with a mixture of methanol (25 mL) and toluene (25 mL). The solvent is evaporated from the filtrate at 40⁰C under reduced pressure. Methanol (150 mL) is added to the residue at 35°C. The mixture is cooled to 5°C and stirred for 5 minutes. The solid is filtered and washed with toluene (2*50 mL). The wet solid and ethyl acetate (200 mL) are charged into a round bottom flask. The solvent is evaporated at 40⁰C under reduced pressure. Ethyl acetate (400 mL) is added to the residue and the mixture is heated to 45°C and stirred at 45°C for 30 minutes. The mixture is cooled to 3°C and stirred for 60 minutes. The solid is filtered and washed with ethyl acetate (3x100 mL). The wet solid is dried under reduced pressure at 50⁰C for 19 hours to afford 35.6 g of the title compound.

Chemical purity by HPLC: 99.43%, nitrosulphone 0.02%, R-omeprazole 0.06%, sulphone 0.12%, sulphide 0.01 %.

EXAMPLE 14: Preparation of amorphous esomeprazole magnesium. Esomeprazole sodium (7 kg) and water (140 L) are charged into a reactor at 30⁰C and stirred for 20 minutes. The resulting solution is stirred and cooled to 5°C over 20 minutes. A solution of MgSO₄ ^»7H₂O (2.933 kg) in water (35 L) is added drop-wise to the reaction mass at 5°C over 2 hours. The mass is stirred for 2 hours at 5°C. The solid is filtered and washed with water (21 L). The wet solid and methanol (140 L) are charged into a reactor at 30⁰C and stirred for 20 minutes. Basic carbon (pH 7-8.5, 0.525 kg) is added and the mass is filtered. The solid is washed with methanol (28 L). The filtrate is subjected to thin film drying using a vacuum not less than 680 mm Hg and a water inlet temperature of 45°C. The solid is dried under reduced pressure to yield 3.3 kg (66.29%) of the title compound in an amorphous form.

Chemical purity by HPLC: 99.86%, R-omeprazole not detected, sulphone 0.06%, sulphide not detected.

EXAMPLE 15: Preparation of amorphous esomeprazole magnesium.

Esomeprazole sodium (25 g) and water (625 mL) are charged into a round bottom flask at 28°C and stirred for 10 minutes. The resulting solution is stirred and cooled to 2°C over 20 minutes. A solution of MgSO₄ ^»7H₂O (1 1 .43 g) in water (125 mL) is added drop-wise at 2°C over 40 minutes. The mass is stirred for 2^ΛA hours at 4°C. The solid is filtered and washed with water (375 mL). The wet solid and methanol (550 mL) are charged into a round bottom flask and stirred for 4 hours at -1 1 °C. The resultant solution is subjected to spray drying. The obtained solid is dried under reduced pressure at 40⁰C for 10 hours, to yield 8.7 g of the title compound in an amorphous form. Magnesium content: 3.44% by weight (anhydrous basis).

Claims

CLAIMS:

1. A process for the preparation of esomeprazole of formula (I), or pharmaceutically acceptable salts thereof,

(I) comprising:

(a) reacting a pro-chiral sulfide of formula (II),

(II) with an oxidizing agent, in the presence of a chiral auxiliary, to provide a compound of formula (III) or a salt thereof, in the form of a single enantiomer or in an enantiomerically enriched form;

(b) converting a compound of formula (III) or a salt thereof, in the form of a single enantiomer or in an enantiomerically enriched form, to esomeprazole free base of formula (I), or a pharmaceutically acceptable salt thereof; and

(I) (c) optionally, if a salt is formed in (b), converting the salt of esomeprazole into a second salt of esomeprazole.

2. The process of claim 1 , wherein the water content of a pro-chiral sulfide of formula (II), or a hydrate thereof, is reduced, prior to reacting with an oxidizing agent.

3. The process of claim 1 , wherein the pro-chiral sulfide of formula (II) has a water content less than about 1 percent by weight.

4. The process of claim 1 , wherein the oxidizing agent in (a) comprises t-butylhydroperoxide, cumene hydroperoxide, hydrogen peroxide, peracetic acid, m-chloroperbenzoic acid, or perphthalic acid.

5. The process of claim 1 , wherein the oxidizing agent comprises cumene hydroperoxide.

6. The process of claim 1 , wherein a chiral auxiliary comprises a chiral titanium complex, chiral zirconium complex, chiral vanadium complex, or chiral hafnium complex.

7. The process of claim 1 , wherein a chiral auxiliary is a chiral titanium complex or chiral vanadium complex.

8. The process of claim 1 , wherein a salt of a compound of formula (III) is produced in (a).

9. The process of claim 1 , wherein a pipehdine salt of a compound of formula (III) is produced in (a).

10. The process of claim 1 , wherein converting comprises reacting with sodium methoxide, potassium methoxide, magnesium methoxide, or calcium methoxide.

11. The process of claim 1 , wherein converting comprises reacting with sodium methoxide or potassium methoxide.

12. The process of claim 1 , wherein a sodium salt of esomeprazole is produced in (b).

13. The process of claim 10, wherein a magnesium salt of esomeprazole is produced in (c).

14. A pipehdine salt of 5-methoxy-2-[(S)-[(4-nitro-3,5-dimethylpyhdin-2- yl)methyl]sulfinyl]-1 H-benzimidazole having formula (IV).

15. The piperidine salt of 5-methoxy-2-[(S)-[(4-nitro-3,5-dinnethylpyridin- 2-yl)methyl]sulfinyl]-1 H-benzimidazole of claim 14, having an X-ray powder diffraction pattern with peaks at about 10, 10.2, 13, 16, 16.5, 19.0, 20.1 , 21.18, 24.3, and 29.0, ±0.2 degrees 2-theta.

16. The piperidine salt of 5-methoxy-2-[(S)-[(4-nitro-3,5-dimethylpyhdin- 2-yl)methyl]sulfinyl]-1 H-benzimidazole of claim 14, having an X-ray powder diffraction pattern substantially as depicted in Fig. 1.