FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10 and rule13)
1. TITLE OF THE INVENTION:
"Process For Optically Active Sulfoxide Compounds"
2. APPLICANT (S):
(a) NAME: IPCA LABORATORIES LIMITED
(b) NATIONALITY: Indian Company incorporated under the Indian
Companies ACT, 1956
(c) ADDRESS: 48 Kandivli Industrial Estate, Mumbai - 400 067,
Maharashtra, India
3. PREAMBLE TO THE DESCRIPTION:
The following specification describes the invention .

Field of the invention
The present invention relates to novel processes for preparing optically active sulphoxide compounds. More specifically, the invention relates to enantioselective oxidation processes for optically active proton pump Inhibitors (PPI) or their optically active precursor (intermediate) compounds (Formula I) that can be converted into pharmaceutically useful PPIs, and in particular, to process to control the formation of sulfone and purification methods thereof.
Background of the invention.
Sulphoxide compounds, particularly, Pyridinylmefhylsulphinyl benzimidazoles
compounds of the following structure are known to have H+/K+-ATPase-inhibitory
action and therefore have considerable importance in the therapy of diseases associated
with an increased secretion of gastric acid or used as anti-ulcerative agent. Many
sulphoxide compounds of closely related structure are known, for example, from
EP0005129, EP166287, EP174726 and EP268956.

wherein Rl, R2 and R3 are the same or different and selected from hydrogen, halogen, nitro, alkyl, alkylthio, alkoxy optionally substituted by fluorine, alkoxyalkoxy, dialkylamino, piperidino, morpholino, halogen, phenylalkyl and phenylalkoxy; R4 and
R5 are the same or different and selected from hydrogen, alkyl and aralkyl; R6' is hydrogen, halogen, trifluoromethyl, alkyl or alkoxy; R6 -R9 are the same or different and selected from hydrogen, alkyl, alkoxy, halogen, halo-alkoxy, alkylcarbonyl, alkoxycarbonyl, oxazolyl, trifluoroalkyl, or adjacent groups R6 -R9 form ring structures which may be further substituted; RIO is hydrogen or forms an alkylene chain together with R3 and Rl 1 and R12 are the same or different and selected from hydrogen, halogen and alkyl; R13 is hydrogen or a protective group such as benzyl, trityl etc.
In the above definitions alkyl groups, alkoxy residues may be branched or straight C1 -C9 -chains or comprise cyclic alkyl groups, for example cycloalkylalkyl.
Examples of pharmaceutically active PPIs falls with in the compounds of Formula I, are 5-methoxy-2- [ (4-methoxy-3, 5-dimethyl-2-pyridinyl) methylsulphinyl]-lH-benzimidazole (also named as omeprazole), (S)-5-methoxy-2- [ (4-methoxy-3, 5-dimethyl-2- pyridinyl) methylsulphinyl]-lH-benzimidazole (common name: esomeprazole), 5-difluoromethoxy-2- [ (3, 4-dim- ethoxy-2-pyridinyl) methylsulphinyl]-lH-benzimidazole (Common name: pantoprazole), 2- [3-methyl-4- (2, 2,2-trifluoroethoxy)-2-pyridinyl) methylsulphinyl]-lH-benzimidazole (Common name: lansoprazole), 2- { [4- (3- methoxypropoxy)-3-methylpyridin-2-yl] methylsulphinyl}-lH-benzimidazole (rabeprazole) and 5-methoxy-2- ( (4-methoxy-3, 5-dimethyl-2-pyridylmethyl) sulphinyl)-l H-imidazo (4,5-b) pyridine (tenatoprazole).
The above mentioned sulphoxide compounds are also referred to as proton pump inhibitors or abbreviated as PPI owing to their mechanism of action. These compounds are chiral because of generation of chirality at sulphur atom when a prochiral sulphide is oxidized to sulphoxide, and therefore exists in two enantiomeric forms, namely the dextrorotatory isomer and Levorotatory isomer, which is also symbolized as R-isomer and the S-isomer. The process conventionally used for preparing the sulphoxide is the oxidation of the corresponding prochiral sulphides leading to a racemic mixture comprising about the same proportions of the two enantiomers, i. e. the (+) -and (-) -form or the (R) -and (S) -form of the sulphoxide compound.

Optical isomers of above sulphoxide compounds are known to have better efficacy or advantages in administration or helpful in reducing the dose regimen and therefore, of interest to a pharmaceutical chemist.
The preparation of optically active sulphoxide compounds are known from W091/12221, which describes a process for separating enantiomers using a cellulase enzyme. One of the active compounds illustrated in this process includes omeprazole.
A chemical process by classical racemate resolution was reported in W092/08716 that describes the separation of pyridin-2-ylmethylsulphinyl-l H-benzimidazole compounds into their optical isomers by formation of chiral diasteromeric derivatives. Compounds so prepared includes (+)-and (-)-5-difluoromethoxy-2- [ (3, 4-dimethoxy-2-pyridinyl) methylsulphinyl]-l H-benzimi- dazole [ (+) -and (-)-pantoprazole] and (R) or (S)-omeprazole. A similar resolution process is disclosed in W094/27988 for the separation of racemic omeprazole into the enantiomers, using chiral auxiliaries and isolation of various pharmaceutical salts.
These methods suffer from various drawbacks, as they lead to loss of more than 50% of product as the unwanted isomer in the resolution process itself. The increased number of processing steps further escalates the cost and also the acid labile nature of tartget sulfoxides reduces the applicability for large scale application and therefore, such processes are not suitable for industrial production of pure optically active sulphoxide compounds.
Interestingly, US 5948789 patent describes a process for the enantioselective synthesis of PPI using chiral titanium complexes, which is referred to as an improvement over the well known asymmetric oxidation processes of prochiral sulphides developed by Kagan et al.. Kagan et al (please refer to J. Am. Chem. Soc. 106 (1984), 8188, or its improved version in Euro. J. Biochem. 166 (1987) 453) described a process for asymmetric oxidation of prochiral sulphides in presence of a chiral titanium complex (made of titanium derivative and a chiral ligand such as diethyl tartarate) in an organic solvent.

But according to the description of US5948789, even the Kagan's improved version of asymmetric oxidation of sulphides comprising a system of Ti(0-iPr)4 /diethyl tartrate/water (1:2:1) in methylene chloride was reported to give very poor enantioselectivity/ no selectivity for PPI's like Esomeprazole .
Therefore, in US5948789 patent, the enantioselectivity of oxidation of prochiral sulfides, especially for PPIs, was improved by conducting the oxidation using the same reactants/reagents in presence of a base in an organic solvent.
Similar processes are disclosed in WO l999/025711, US20050187256 & WO2005054228 for sulphoxide compounds or its intermediate including esomeprazole. The enantioselective sulphoxidation for preparing esomperazole on a large scale using a chiral titanium complex is also described in Tetrahedron, Asymmetry, (2000), 11,3819-3825. The enantioselective sulphoxidation of prochiral sulphides is extended to other chiral metal ligands like chiral Zirconium or vanadium complexes in J. Org. Chem., (1999), 64 (4), 1327 & WO2004/052882
A further process is disclosed in WO2006040685, by conducting the oxidation of sulphides in the presence of a chiral titanium complex & base in the absence of solvent.
Apart from achieving the enantioselectivity, however, the most common problem with the above processes are the simultaneous formation of relative amounts of sulphone of formula III during reaction. This is due to the oxidation of the product sulfoxides (Formula I) during the reaction and no control method is available.
The formation of sulfones of formula(III) due to over-oxidation is almost impossible to avoid and this impurity is formed in very significant amounts, especially in the case of enantioselective oxidation processes, rather than conventional oxidation leading to a racemic product. There are some alternative solutions, such as performing the oxidation reaction at a very low temperature or lowering the amount of oxidizing agent were proposed to reduce the sulfone formation.. But these alternatives are also reducing the efficacy of the oxidation reaction, and usually the amount of oxidizing agent or the

reaction temperature are parameters affecting maximum conversion of starting material, maximum formation of sulfoxides of formula(I), overall enantioselectivity and overall product yield; and therefore one cannot compromise on these parameters..
It is being observed that the enantioselective oxidation processes described above, invariably leads to the formation of about 2 to 8 % of the corresponding sulfone derivative (please refer to exemplary procedures of US5948789 or the comparative examples presented with this application), an over oxidized product. There is various purification processes described in the art, but the very similar physico-chemical characteristics of the product sulfoxide (Formula I) and sulfone impurity (Formula III) renders it difficult to purify and obtain high quality. To meet the pharmacopeial quality requirement of being the impurity below 0.1% in the PPIs can only be achieved by several repeated purification, which affects the overall economy of the process/product.
Therefore, there is a need for an alternative solution for controlling the formation of sulphone impurity to an acceptably low level during the process for oxidation of prochiral sulphide compounds, especially the PPIs, owing to the importance of said compounds. This becomes the subject of the present invention.
Summary of the invention.
Accordingly, the present invention provides new processes for preparation of optically active sulfoxide compounds of Formula I,

wherein R2, R2 and R3 are the same or different and selected from hydrogen, halogen, nitro, alkyl, alkylthio, alkoxy optionally substituted by fluorine, alkoxyalkoxy, dialkylamino, piperidino, morpholino, halogen, phenylalkyl and phenylalkoxy; R4 and R5 are the same or different and selected from hydrogen, alkyl and aralkyl; R6' is hydrogen, halogen, trifluoromethyl, alkyl or alkoxy; R6 -R9 are the same or different and selected from hydrogen, alkyl, alkoxy, halogen, halo-alkoxy, alkylcarbonyl, alkoxycarbonyl, oxazolyl, trifluoroalkyl, or adjacent groups R6 -R9 form ring structures which may be further substituted; RIO is hydrogen or forms an alkylene chain together with R3 and Rl 1 and R12 are the same or different and selected from hydrogen, halogen and alkyl; and R13 is hydrogen or a protective substituent like benzyl, trityl etc.; in the above definitions alkyl groups, alkoxy residues may be branched or straight C1 -C9 -chains or comprise cyclic alkyl groups, for example cycloalkylalkyl, comprising asymmetric oxidation of prochiral sulphide compounds of Formula II,

wherein the groups are as defined above, in the presence of a chiral transition metal complex and tritylhydroperoxide. The characteristic of the invention lies in the enantio-selective oxidation that is carried out in the presence of triphenylmethyl hydroperoxide (Also termed as tritylhydroperoxide), which reduces the formation sulphone impurity of Formula III to an acceptably low level. One or more of the phenyl rings may be appropriately substituted with an inert group, which may further increase the bulkiness of the oxidizing agent to reduce the sulfone impurity.
The enantioselective oxidation according to the present invention may be performed in the presence of a base substance or a catalyst which improves the enantioselctivity for a specific enantiomer. The reaction may be performed in the presence or absence of a solvent such as of aqueous or organic solvents.
Optically active Sulfoxide compounds of Formula I, wherein R2 is a leaving group such as halo, nitro results in chiral sulphoxide compounds which are useful as penultimate intermediates for PPIs. On substitution with appropriate alkoxide according to any known procedure the above proton pump inhibitors of pharmaceutical interest can be obtained.
The transition metal may be selected from the group comprising titanium, zirconium, hafnium and vanadium. The most preferred transition metal is titanium. The transition metal complex may be prepared from a transition metal derivative and a chiral ligand. Thus, the chiral transition metal complex is prepared by the reaction of transition metal derivative and the complexing chiral ligand, either separately or in the presence of the prochiral sulphide substrate of Formula II at suitable conditions. The preparation of the complex is effected at a temperature above 0 degrees, preferably above ambient temperature, more preferably at a temperature above 50 degrees. The complex preparation may be carried out for a prolonged period of time, either separately or in presence of prochiral sulfide of formula II A suitable reagents and solvent, if required may be used to achieve the complexation of transition metal with the ligand.

The details of one or more embodiments of the inventions are set forth in the description below. Other features, objects and advantages of the inventions will be apparent from the appended examples and claims.
Detailed Description of the invention.
Unless specified otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art, to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are described. To describe the invention, certain terms are defined herein specifically as follows.
Unless stated to the contrary, any of the words 'including', 'includes', 'comprising' and 'comprises' mean 'including without limitation' and shall not be construed to limit any general statement that it follows to the specific or similar items or matters immediately following it. Embodiments of the invention are not mutually exclusive, but may be implemented in various combinations. The described embodiments of the invention and the disclosed examples are given for the purpose of illustration rather than limitation of the invention as set forth the appended claims.
The expressions "pro-chiral sulphide(s)" are used for the sulphides of the corresponding sulphoxides suitable for being prepared by the novel process according to the present invention. If the corresponding sulphide already contains a stereogenic centre in the molecule, such a sulphide is not a pro-chiral compound, but a chiral compound. Since the sulphur atom of such sulphides does not have asymmetry such a compound is referred to as a pro-chiral sulphide in the present specification and appending claims.
The term "omeprazole", as used herein unless specified otherwise, refers to a racemic mixture of 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridyl)methylsulfinyl]-lH-benzimidazole and 6-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridyl)methylsulfinyl]-lH-benzimidazole in the solid state.

As used herein, "omeprazole" is also represented as 5(6)-methoxy-2-[(4-methoxy-3,5-
dimethyl-2-pyridyl)methylsulfinyl]-lH-benzimidazole.
The term "S-omeprazole" or "esomeprazole", as used herein unless specified otherwise,
refers to the S stereoisomer of omeprazole and including its known salts..
The term "R-omeprazole", as used herein unless specified otherwise, refers to the R
stereoisomer of omeprazole.
The terms "S" and "R", as used herein unless specified otherwise, refer to stereoisomers
resulting from the spacial arrangement of groups at a chiral centre, and in the present
context, the person of ordinary skill will appreciate that the groups attached with the
sulfoxide represents the plane for purposes of determining the configuration.
The term 'tritylhydroperoxide' refers to triphenylmethylhydroperoxide and may be used
interchangeably throughout this specification.
The term "alkyl" refers to a straight or branched alkyl group having from 1 to 6 carbon
atoms. Exemplary alkyl groups include but are not limited to methyl, ethyl, n-propyl, iso-
propyl, n-butyl, and iso-butyl.
The term "aryl" refers to an aromatic, optionally fused, carbocycles having from 6 to 20
carbon atoms. Examples of C6-12-aryl include but are not limited to phenyl and napthyl.
The term "alkylaryl" or 'aralkyl' refers to an alkyl substituted with one or more aromatic
residues, optionally with substituents. Examples of alkylaryl include but are not limited to
biphenylmethyl or triphenyl methyl.
The term 'Enantioselective' as used herein, refers to the preferential formation of one of
the enantiomer to obtain an optically pure compound or optically enriched enantiomeric
mixtures in which the ratio of the enantiomers differs.
The term 'enantiomeric excess' as used herein, refers generally to the concentration of
one stereoisomer that exceeds the concentration of another stereoisomer. Typically, the
term is used to characterize the optical purity of an optically active compound that exists
in the bulk as two or more stereoisomers. In the present context, the term also refers to
the excess of either S- or R-omeprazole over the other that are present in a given
enantiomeric enriched mixture of the present invention.

This invention is directed to processes for preparation of sulphoxide compounds that, by virtue of the processes of this invention, are substantially optically pure or optically enriched mixtures of enantiomers and are substantially free of sulfone impurity. Accordingly, the present invention provides processes for controlling the sulfone impurity to minimum level during the preparation of optically active substituted pyridinylmethyl sulfinyl-benzimidazoles of the compound of Formula I,

wherein R2, R2 and R3 are the same or different and selected from hydrogen, halogen, nitro, alkyl, alkylthio, alkoxy optionally substituted by fluorine, alkoxyalkoxy, dialkylamino, piperidino, morpholino, halogen, phenylalkyl and phenylalkoxy; R4 and R5 are the same or different and selected from hydrogen, alkyl and aralkyl; R6' is hydrogen, halogen, trifluoromethyl, alkyl or alkoxy; R6 -R9 are the same or different and selected from hydrogen, alkyl, alkoxy, halogen, halo-alkoxy, alkylcarbonyl, alkoxycarbonyl, oxazolyl, trifluoroalkyl, or adjacent groups R6 -R9 form ring structures which may be further substituted; RIO is hydrogen or forms an alkylene chain together with R3 and Rl 1 and R12 are the same or different and selected from hydrogen, halogen and alkyl; and R13 is hydrogen or a protective substituent like benzyl, trityl etc.; in the above definitions alkyl groups, alkoxy residues may be branched or straight C1 -C9 -chains or comprise cyclic alkyl groups, for example cycloalkylalkyl. R2 may be a groups

suitable for PPIs or a leaving group such as nitro or halo, that can be substituted with the alkoxy analogs to obtain any of the PPIs listed above.
The process, according to the present invention, comprises enantioselective oxidation of a substituted pyridinylmethyl prochiral sulfide derivative of compound of Formula II,

wherein Rl to R6 are as defined above, in the presence of an oxidizing agent selected from triphenylmethyl hydroperoxide. The prochiral sulphides may be employed as its stable alkali metal salts during the oxidation. It should be understood that compounds wherein R2 is a leaving group such as halo, nitro are useful as penultimate intermediates for PPIs listed above. On substitution with appropriate alkoxide according to any known procedure, the above proton pump inhibitors of pharmaceutical interest can be obtained. The products obtained may thereafter be converted to pharmaceutically acceptable salts thereof by conventional processes either for facilitating purification/isolation or pharmaceutical application.
Substituted optically active sulphoxides prepared by the enantioselective catalytic oxidation process of the present invention may be obtained either in optically active enantiomer or enantiomerically enriched forms, preferably as an optically enriched substituted pyridinylmethyl-sulfinyl-benzimidazole according to the formula I.
Preferably, the process of the present invention provides an enantioselective process for the preparation of optically active or enantiomerically enriched sulfoxides , especially omeprazole, pantoprazole, rabeprazole, tenatoprazole and lansoprazole, in free forms or their alkali and/or alkaline earth metal salts , which are proton pump inhibitors useful in the treatment of ulcers.

Thus the present invention provides processes for the preparation of alkali and/or alkaline earth metal salts of an optically active enantiomer or an enantiomerically enriched form of substituted pyridinylmethyl-sulfinyl-benzimidazole, which are of pharmaceutical interest or useful as intermediates for formation/purification of said optically active compounds of Formula I.
The process of the invention is characterized by the enantioselective oxidation of the corresponding prochiral sulphide of Formula II being carried out in the presence of a chiral transition metal complex and triphenyl methyl hydroperoxide as oxidizing agent.
In one embodiment of the present invention, a process for controlling the sulfone formation during the enantioselective oxidation of the corresponding prochiral sulphide of Formula II being carried out in the presence of a chiral transition metal complex and triphenyl methyl hydroperoxide in the presence of a base substance or an catalyst.
In another embodiment of the present invention, a process for controlling the sulfone formation during the enantioselective oxidation of the corresponding prochiral sulphide of Formula II being carried out in the presence of a chiral transition metal complex and triphenyl methyl hydroperoxide in the presence of a base substance and/or an catalyst in a solvent either aqueous or organic.
In yet another embodiment of the present invention, a process for controlling the sulfone formation during the enantioselective oxidation of the corresponding prochiral sulphide of Formula II being carried out in the presence of a chiral transition metal complex and triphenyl methyl hydroperoxide in the presence water. The oxidation is carried out advantageously in the absence of any organic solvent.
In yet another embodiment of the present invention, a process for controlling the sulfone formation during the enantioselective oxidation of the corresponding prochiral sulphide of Formula II is provided which being carried out in the presence of a chiral transition metal complex and triphenyl methyl hydroperoxide wherein the titanium complex is

prepared at above ambient temperature either separately or in the presence of prochiral sulfide substrate. The reaction may be performed in the presence or absence of a solvent.
In a preferred embodiment of the present invention, a process for preparing the sulfoxides of Formula I being controlling the sulfone to substantially minimum comprises enantioselective oxidation of the corresponding prochiral sulphide of Formula II in the presence of a chiral transition metal complex and triphenyl methyl hydroperoxide in the presence of a base substance in an organic solvent.
The phenyl group in the oxidizing agent trityl hydroxides may be optionally substituted with inert groups. It may help in improving the control of over oxidation. Biarylmethyl hydroperoxide also found to give reasonably good control over the formation of sulfone impurity, which also falls within the scope of the oxidizing agent covered in this application. The use of triphenylmethyl hydroperoxide as the oxidizing agent found to reduce the amount of sulfone impurity, at least by 30%, more preferably at least 50%, and still more preferably at least 70% in the enantioseletive oxidation. It should be understood that the results achieved by the use of trityl hydroperoxide is applicable with any process alternatives discussed above or any process of similar nature, for enantioseletive oxidation of the above PPIs. In general, 0.50 to molar excess oxidation equivalents, preferably 0.99-1. 3 equivalents, of the oxidizing agent are used.
The transition metal may be selected from the group comprising titanium, zirconium, hafnium and vanadium. The most preferred transition metal is titanium. The transition metal complex may be prepared from a transition metal derivative and a chiral ligand. Suitable transition metal derivative are transition metal (IV) halides or transition metal (IV) alkoxides, or transition metal (IV)acetylacetonates. Examples of halide is chloride, alkoxides are butoxide, tert-butoxide, ethoxide and, in particular, n-propoxide, isopropoxide. The most preferred transition metal derivative is titanium tetrachloride or titanium isopropoxide.

The chiral ligand may be a monodentate, bidentate or polydentate ligand, but preferably a chiral branched or unbranched alkyl diol or an aromatic diol or an aminoalcohol. The preferred chiral diol may be a chiral ester or amide of tartaric acid. Suitable optically pure tartaric acid derivatives are, for example, (+) -L-tartaric acid amides, such as (+)-L-tartaric acid bis-(N, N-diallylamide), (+)-L-tartaric acid bis-(N, N-dibenzylamide), (+)-L-tartaric acid bis- (N, N-diisopropylamide), (+)-L-tartaric acid bis- (N, N-dimethylamide), (+)-L-tartaric acid bis- (N- pyrrolidinamide, (+) -L-tartaric acid bis- (N-piperidinamide), (+) -L-tartaric acid bis- (N-morpholinamide), (+) -L-tartaric acid bis- (N-cycloheptylamide) or (+) -L-tartaric acid bis- (N-4-methyl-N-piperazinamide), or dialkyl (+) -L-tartrate esters such as dibutyl (+)-L-tartrate, di-tert-butyl (+) -L-tartrate, diisopropyl (+) -L-tartrate, dimethyl (+) -L-tartrate and diethyl (+) -L-tartrate, or (-) -D-tartaric acid amides, such as (-) -D-tartaric acid bis-(N, N-diallylamide), (-)-D-tartaric acid bis-(N, N-dibenzylamide), (-)-D-tartaric acid bis-(N, N- diisopropylamide), (-) -D-tartaric acid bis- (N, N-dimethylamide), (-) -D-tartaric acid bis- (N- pyrrolidinamide), (-) -D-tartaric acid bis- (N-piperidinamide), (-) -D-tartaric acid bis- (N-morpholinamide), (-) -D-tartaric acid bis- (N-cycloheptylamide) or (-) -D-tartaric acid bis- (N-4-methyl-N-piperazinamide), or dialkyl (-) -D-tartrate esters such as dibutyl (-) -D-tartrate, di-tert-butyl (-) -D-tartrate, diisopropyl (-) -D-tartrate, dimethyl (-) -D-tartrate and diethyl (-)-D-tartrate or the like.
The chiral transition metal complex can be prepared by the reaction of transition metal derivative and the complexing chiral ligand, either separately or in the presence of the prochiral sulphide substrate of Formula II. A suitable reagents and solvent, if required may be used to achieve the complexation of transition metal with the ligand. For example the titanium isoproxide is reacted with diethyltartarate directly before addition of the substrate or may be prepared in the presence of the prochiral sulphide of formula II.
The especially preferred titanium complex used advantageously in the present invention is prepared from a chiral diethyltartarate and a titanium (IV) compound, preferably titanium(IV)alkoxide in the presence or absence of water. An especially preferred titanium(IV)alkoxide is titanium(IV)isopropoxide or n-propoxide. When the titanium

complex is prepared by reacting titanium tetra chloride with a chiral ligand, a base is advantageously used in the process.
The base used in the enantioselective oxidation may be an inorganic or an organic base; examples of organic base include trimethylamine, triethylamine, tributylamine, triisopropylamine, diisopropylethylamine, pyridine, morpholine, DBU (1,8-diazabicyclo-[5.4.0]-undec-7-ene), DBN (l,5-diazabicyclo-[4.3.0]- non-5-ene), 4-dimethylamino pyridine and mixtures thereof. Examples of inorganic bases include alkali metal carbonate, bicarbonate, hydroxide and mixtures thereof. Examples of alkali metal carbonates include lithium carbonate, sodium carbonate and potassium carbonate. Examples of alkali metal bicarbonates include sodium bicarbonate and potassium bicarbonate. Examples of alkali metal hydroxides include sodium hydroxide and potassium hydroxide. Organic bases are preferred for this application and especially suitable bases are amines, preferably triethylamine or N,N-diisopropylethylamine. The amount of base added to the reaction mixture is not very critical but should be adjusted with respect to the respective substrates or can be established by trial.
The catalyst, according to the invention, may be selected from sulphoxides compounds. Especially preferred sulfoxide is dimethylsulphoxide. The quantity of the catalyst is not critical for success of oxidation, rather its presence, and it can be in catalytic amounts to molar amounts.
The oxidation process is advantageously carried out in an organic solvent, such as those customarily used, for example, chlorinated hydrocarbons, ethyl acetate, toluene, diethylether, tetrahydrofuran, dioxane, or methyl isobutyl ketone etc. The reaction may be done in presence of water.
The metal complex may be added to the reaction mixture containing prochiral sulfide. Alternately, the reaction mixture containing prochiral sulfide may be added to the metal complex. The amount of the chiral titanium complex is not critical to the success. Even in catalytic quantities of chiral titanium complexes are sufficient to give excellent

steroselective oxidation of the sulphide and an optimum amount may be worked out by trial in a particular substrate..
The oxidation is carried out at a temperature, for example between 20 - 70 degrees, preferably carried at room temperature or just above room temperature. Lower temperature results in longer reaction times and a suitable temperature range is chosen depending on the stability /decomposition of the compounds.
In the process of the present invention, the preparation of the chiral titanium complex is performed at a temperature between 20-70 degrees and optionally in presence of the prochiral sulfide substrate. The transition metal complex preparation time is approximately from 0-2.5 hours. Then the oxidizing agent is introduced in the reaction. The enantioselective oxidation time varies depending on the reaction temperature and of the pro-chiral sulphide, and usually completes within 10 minutes to 3.5 hours. In some cases prololnged reaction is not advisable, as the product/starting sulfide degrades during reaction.
If the process is carried out in a suitable manner, the optically pure sulphinyl compound of formula I is obtained in an optical purity of >70%, preferably greater than 80%, and more preferably greater than 95%. In the process of the present invention, the sulfone content in the reaction is below 1.5%, preferably below 1% and more preferably less than 0.5%. By further steps, such as, for example, pH-controlled reprecipitation and/or recrystallization in a suitable solvent, it is possible to further increase the optical purity to even greater than 99.5% as well as control the sulfone to below 0.1%. Reprecipitation is carried out via intermediate preparation of suitable salts, such as, for example, potassium or sodium salt or magnesium salt.
The obtained crude product may be extracted in an organic solvent. It may also be crystallized in an organic or aqueous solvent resulting in an optically pure product. A special mention can be made to isolation solvents useful for further removing the sulfone impurity which include alcohol, for example, methanol; keones, for example acetone;

nitriles, for example acetonitrile; ethers such as for example tetrahydrofuran; or any of their cross combinations. A suitable metal salt of the compound of Formula I may be obtained by treating the crude product with a base such as NaOH followed by crystallization of the formed salt in a solvent which may result in a product with an improved optical purity.
Thus process of the present invention is applicable for the preparation of an optically active alkali and/or alkaline earth metal salt of substituted sulphinyl- benzimidazole by treating the optically active substituted sulphinylbenzimidazole compound of Formula I, obtained by enantioselective catalytic oxidation with an alkali and/or alkaline earth metal source. The alkali or alkaline earth metal source may be selected from Na+, Li+, Mg+2, Ca+2 and Ba+2 salts such as bicarbonates, carbonates, hydrides, hydroxides, halides, sulphates, alkoxides and oxides. In particular, sodium hydroxide, sodium methoxide, sodium ethoxide, potassium hydroxide, potassium tertiarybutoxide, barium hydroxide, lithium hydroxide, magnesium hydroxide, magnesium chloride, calcium chloride may be used.
The process of the present invention further includes the optional steps of isolating the alkali or alkaline earth metal salts of the optically active substituted pyridinylmethyl-sulfinyl-benzimidazole compound of Formula 1 by solvent evaporation with or without vacuum, followed by addition of the and organic solvent and/or an antisolvent and filtering the product, and drying, as required. It may be again purified by similar or any known procedures to either increase the optical purity or to reduce the sulphone content, for examples, esomeprazole potassium is purified from alcohol such as methanol to reduce the sulphone impurity.
The products described above can be further processed if desired. Alkali or alkaline earth metal salts of benzimidazole compounds may be exchanged with another alkali or alkaline earth metal salts to prepare a desired PPI for pharmaceutical application. For example, esomeprazole sodium or potassium can be converted into esomeprazole magnesium.

The PPIs obtained by the process of the present invention, for example, esomeprazole
magnesium, may be formulated into a dosage form, e.g., tablet, capsule, etc., by
combining with one or more pharmaceutically acceptable excipients using known
techniques. The resulting dosage form may include a suitable amount of the active
ingredient. For example, the resulting dosage form may contain between 5 and 50 mg of
esomeprazole magnesium. Further, the dosage form may be immediate release or
extended release. The dosage forms may be administered to a mammal in need, as proton
pump inhibitors useful for treating ulcers.
Trityl hydroperoxide used in the present invention can be of from any commercial source
or prepared according to the method given in the examples or by any other conventional
methods.
The following examples are presented to further explain the invention with experimental
conditions, which are purely illustrative and are not intended to limit the scope of the claimed
invention.
Examples 1.
Preparation of tritylhydroperoxide.
In a 1 L flask, 50 gm trityl chloride and toluene (250 ml) were taken and stirred for 30
minutes at room temperature. After cooling, 17.92 gm sodium bicarbonate and 81.4 gm
H2O2 (45%) was added and the pH of the solution adjusted to 4 -5. After stirring for 30
minutes, 50 ml water was added, layer separated and aqueous layer extracted with 100 ml
toluene. The organic layer was dried using anhydrous sodium sulphate, filtered to get 290
ml of titylhydroperoxide in toluene solution. HPLC purity 85-90%, and yield = 98%.
Example 2.
In a 1 L flask under nitrogen atmosphere, 50 gm 5-methoxy[(2-(4-methoxy)-3,5-dimethyl-2-pyridinyl] methylsulfenyl]-lH-benzimidazole (also termed as pyremetazole or PMT) was mixed with 160 ml toluene and heated to 65-70 degrees. To this mixture 18.8 gm diethyl (-)-D-tartrate and 45 ml toluene, 5.9 gm diisopropyl ethyl amine, 12.9 gm titanium(IV) isopropoxide were added and continue to stir at 60-65 degree for 1 hour. To this mixture after cooling, trityl hydroperoxide solution in toluene (279 ml having 47

gm tritylhydroperoxide) was added room temperature. The mixture was maintained under
stirring for 3 hours at room temperature. The reaction mixture was analyzed for
sulphoxide and sulfone. The sulfone content was less than 1%.
To the reaction mixture 30 ml methanol, 0.1 gm KI, and 2.74 gm potassium methoxide
was added and stirred. The mixture cooled to 20 degree and filtered, washed with 150 ml
Toluene-methanol mixture, followed by 50 ml Methanol. Yield =83%. The HPLC
analysis of product shows:
Esomeprazole (as potassium salt) 99.21% (99% ee) and sulfone content 0.59%.
Purification of esomeprazole potassium.
In a 1 Litre flask, 100 gm crude esomeprazole potassium in 500 ml methanol were taken and heated to reflux. After 1 hour reflux, the mass was cooled to 0-5 degree, filtered, washed with chilled methanol, and dried to obtain 90 gm of esomeprazole potassium. HPLC analysis shows: Esomperazole ee 99.5% and sulfone 0.05%.
Example 3.
The example 2 was repeated by varying the molar amounts of trityl hydroperoxide and
the results are summarized below:
Reaction mass:

Serial No. Stage of HPLC analysis Molar amount of THP Reaction time Esomeprazole content Sulfone content
A Reaction mass
1 0.85 6 hours 79.5 0.55
2 0.95 3 hours 88.8 1.06
3 1.25 3 hours 92.07 2.36
B Crude product
1 0.85 97.78 0.32
2 0.95 99.21 0.59
3 1.25 98.50 1.23
C Purification

1 0.85 99.70 0.03
2 0.95 99.60 0.05
3 1.25 99.60 0.30
Example 4.
Purification in THF was carried out in place of methanol and the results are as follows:

Serial No. Stage of HPLC analysis Esomeprazole content Sulfone content
A Crude 99.10 0.67
Pure 99.70 0.08
B Crude 99.23 0.25
Pure 92.80 0.015
Example 4. Preparation of esomeprazole magnesium.
In a 250 ml flask, 20 gm esomeprazole potassium (pure) and 120 ml water were taken and stirred until a clear solution was formed. To this 20 ml Toluene was added and separated the organic layer. To the aqueous layer containing esomeprazole potassium salt, 40 ml methanol and 7.7 gm Magnesium sulphate in 20 ml water was added. The suspension is stirred for 1 hour and filtered, washed with 100 ml waster, and dried to obtain 14.5gm of esomeprazole magnesium. HPLC analysis shows: Esomperazole e.e. 99.93% and sulfone <0.05%.
Example 5.
In a 1 L flask under nitrogen atmosphere, 50 gm pyremetazole was mixed with 160 ml toluene and heated to 65-70 degrees. To this mixture 18.8 gm diethyl (+)-L-tartrate and 45 ml toluene, 12.9 gm titanium (IV) isopropoxide were added and continue to stir at 60-65 degree for 1 hour. To this mixture after cooling, 1.5 gm DMSO and trityl hydroperoxide solution in toluene (279 ml having 27% tritylhydroperoxide content) was added room temperature. The mixture was maintained under stirring for 3 hours at room

temperature. The reaction mixture was analyzed for sulphoxide and sulfone. The sulfone
content was less than 1.0%.
To the reaction mixture 30 ml methanol, 0.1 gm KI, and 2.74 gm potassium methoxide
was added and stirred. The mixture cooled to 20 degree and filtered, washed with 150 ml
Toluene-methanol mixture, followed by 50 ml Methanol. Yield 80%. The HPLC
analysis of product shows:
Esomeprazole (as potassium salt) 99.3%, e.e. 99% and sulfone content 0.90%.
Comparative example 1.
With the application of Cumene hydroperoxide & tertiary butyl hydroperoxide in the place of tritylhydroperoxide as the oxidizing agent in example 2.
The reaction mass analysis results are as follows:
1. Results of Cumene hydroperoxide as oxidizing agent.

SerialNo. No. of moles of oxidizing agent w.r.t. PMT Reaction mass Crude isolated
Esomeprazole content Sulfone content Esomeprazole content Sulfone content
A
1 0.97 82.0% 2.05 97.80 1.48
2 1.15 93.0 3.07 97.70 2.60
3 1.25 95.05 3.90 97.90 2.96

2. Results of Tritylhydroperoxide as oxidizing agent

SerialNo. No. of moles of oxidizing agent w.r.t. PMT Reaction mass Crude isolated
Esomeprazole content Sulfone content Esomeprazole content Sulfone content
A
1 0.85 79.5 0.55 97.78 0.32
2 0.95 88.8 1.06 99.21 0.59
3 1.25 92.07 2.36 98.50 1.23