The following specification describes the invention and manner in which it is performed

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-pyridinyl)methyl]sulfinyl]-1H-benzimidazole-1-yl) magnesium  and has the structure of formula (Ia).

(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 trihydrate 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)-1H-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-pyridinylmethylsulphinyl)-1H-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)-1H-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)-1H-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-1H-benzimidazole or 2-[[(4-X-3 5-dimethyl-1-oxidopyridin-2-yl)methyl]thio]-5-methoxy-1H-benzimidazole  either as a single enantiomer or in an enantiomerically 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-1H-benzimidazole or 2-[[(4-X-3 5-dimethyl-1-oxidopyridin-2-yl)methyl]thio]-5-methoxy-1H-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) 

(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;

(III)
(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]-1H-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]-1H-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) 

(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;

(III)
(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.
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  -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 oxytripropoxide  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-methylimidazole 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 100°C  or less than about 50°C  or less than about 30°C  or less than about 10°C  or less than about 5°C  or less than about 0°C  or less than about -5°C  or less than about -10°C  or less than about -20°C  or less than about -40°C  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 80°C  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  piperidine  amines having the formula NR1R2R3  wherein R1  R2  and R3 independently are the same or different groups such as hydrogen  linear  branched  or cyclic C1-12 alkyl  which may be substituted or unsubstituted  C3-6 aryl  C3-6 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 N N-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  centrifugation  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 enantiomerically 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 N N-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 100°C  or less than about 80°C  or less than about 60°C  or less than about 40°C  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 N N-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 100°C  or less than about 60°C  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-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; 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 100°C  or less than about 60°C  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 N N-dimethylformamide  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 20°C 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-dimethylpyridin-2-yl)methyl]sulfinyl]-1H-benzimidazole having formula (IV).

The piperidine salt of 5-methoxy-2-[(S)-[(4-nitro-3 5-dimethylpyridin-2-yl)methyl] sulfinyl]-1H-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-dimethylpyridin-2-yl)methyl] sulfinyl]-1H-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 K 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-dimethylpyridin-2-yl)methyl]sulfinyl]-1H-benzimidazole sodium.
A solution of substantially anhydrous 5-methoxy-2-[[(4-nitro-3 5-dimethylpyridin-2-yl)methyl]thio]-1H-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 L  33 mmol) is added and the mixture is stirred for 10 minutes at 25°C. The mass is heated to 50°C 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 triethylamine (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]-1H-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. Isopropyl 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 piperidine salt of 5-methoxy-2-[(S)-[(4-nitro-3 5-dimethylpyridin-2-yl)methyl]sulfinyl]-1H-benzimidazole.
5-Methoxy-2-[[(4-nitro-3 5-dimethylpyridin-2-yl)methyl]thio]-1H-benzimidazole monohydrate (50.0 g  138 mmol) and toluene (1500 mL) are charged into a round bottom flask and heated to 110°C to remove water azotropically. Titanium isopropoxide (23.5 g  82.9 mmol) and (-)-diethyl tartrate (34.1 g  166 mmol) are added at 50°C. Water (900 L  50 mmol) is added and stirred for 60 minutes at 50°C. The mass is cooled to 35°C and N N-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.
[]D: 138°.
Piperidine content by GC: 24.6% by wt.
1H NMR (CDCl3  400 MHz) : 8.39 (s 1H)  7.58 (d  1H)  7.2 (br 1H)  7.0 (d  1H)  4.8 (d  1H)  4.69 (d  1H)  3.8 (s 3H)  2.2-2.3 (6H)  2.9 (s  4H)  1.5 (br  6H)  2.8 (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]-1H-benzimidazole.
5-Methoxy-2-[[(4-nitro-3 5-dimethylpyridin-2-yl)methyl]thio]-1H-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 110°C to remove water azotropically. The mass is further heated at 110°C for 30 minutes to partially remove toluene azotropically. The mass is cooled to 30°C  followed by addition of (-)-diethyl tartrate (5.7 g  27.6 mmol) and titanium isopropoxide (3.92 g  13.8 mmol). Water (150 L  8.3 mmol) is added and stirred for 10 minutes at 30°C. The mass is heated to 50°C 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 18½ hours. The formed solid is filtered and washed with water (20 mL). The wet solid is dried at 50°C 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]-1H-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 70°C 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 50°C 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 50°C under reduced pressure. Ethyl acetate (30 mL) is added to the obtained residue at 30°C 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]-1H-benzimidazole sodium (3 g)  and the mixture is stirred at 26±1°C for 20 minutes. The solution is heated to 60°C 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 60°C over 15 minutes. The temperature of the mass is raised to 70°C and the mass is stirred for 4½ 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 2½ 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 50°C under reduced pressure. Ethyl acetate (15 mL) is added to the obtained residue. The solvent is evaporated at 50°C 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 50°C 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]-1H-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 10oC. The organic layer is separated and the solvent is evaporated at 40°C 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 40°C 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 40°C 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 1°C 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 2½ hours at 7°C. The solid is filtered  washed with water (30 mL)  and dried at 40°C for 3 hours to obtain 5.2 g of amorphous esomeprazole magnesium.

EXAMPLE 8: Preparation of a piperidine salt of 5-methoxy-2-[(S)-[(4-nitro-3 5-dimethylpyridin-2-yl)methyl]sulfinyl]-1H-benzimidazole.
5-Methoxy-2-[[(4-nitro-3 5-dimethylpyridin-2-yl)methyl]thio]-1H-benzimidazole monohydrate (8 kg) and toluene (240 L) are charged into a rector and heated to 110°C 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 50°C. The mass is cooled to 35°C and N N-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 10°C 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]-1H-benzimidazole.
A piperidine salt of 5-methoxy-2-[(S)-[(4-nitro-3 5-dimethylpyridin-2-yl)methyl]sulfinyl]-1H-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 60°C to obtain a clear solution and it is stirred at 60°C for 15 minutes. Isopropanol (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 50°C 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]-1H-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]-1H-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]-1H-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 50°C 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]-1H-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 30°C 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 50°C 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]-1H-benzimidazole (50 g)  and the mixture is stirred at 31°C 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 70°C 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 40°C 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 40°C 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 (3×100 mL). The wet solid is dried under reduced pressure at 50°C 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 30°C 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 30°C 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 (11.43 g) in water (125 mL) is added drop-wise at 2°C over 40 minutes. The mass is stirred for 2½ 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 -11°C. The resultant solution is subjected to spray drying. The obtained solid is dried under reduced pressure at 40°C for 10 hours  to yield 8.7 g of the title compound in an amorphous form.
Magnesium content: 3.44% by weight (anhydrous basis).

WE CLAIM:
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;

(III)
(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 piperidine 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 piperidine salt of 5-methoxy-2-[(S)-[(4-nitro-3 5-dimethylpyridin-2-yl)methyl]sulfinyl]-1H-benzimidazole having formula (IV).

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