FORM 2
THE PATENTS ACT, 1970 (39 OF 1970)
COMPLETE SPECIFICATION
(See section 10)
PROCESS FOR PREPARATION OF ALKALI METAL OR ALKALINE EARTH METAL SALTS OF AN OPTICALLY ACTIVE SUBSTITUTED PYRIDTNYLMETHYL-SULPHINYL-BENZIMIDAZOLE
SUN PHARMACEUTICAL INDUSTRIES LTD A company incorporated under the laws of India having their office at ACME PLAZA, ANDHERI-KURLA ROAD, ANDHERI (E), MUMBAI-400059. MAHARASHTRA,
INDIA


1 9 MAY 2003
The following specification particularly describes and ascertains the nature of this invention and the manner in which it is to be performed.

The present invention relates to a process for the preparation of alkali metal or alkaline earth metal salts of an optically active enantiomer or an enantiomerically enriched form of substituted pyridinylmethyl-sulphinyl-benzimidazole, compound of formula 1 wherein R1 to R4 may be selected from H, linear or branched (1-4C) alkyl, linear or branched (1-4 C) alkoxy, aryl, aryloxy and their halo or alkoxy substituted analogs, by enantioselective catalytic oxidation of a substituted pyridinylmethyl prochiral sulphide derivative of benzimidazole, compound of formula 2.

H Formula 1
Formula 2

Optically active substituted pyridinylmethyl-sulphinyl-benzimidazole enantiomers and their pharmaceutically acceptable salts are proton pump inhibitors, which are useful in the treatment of ulcers.
More specifically the present invention relates to a process for the preparation of the magnesium salt of 5-methoxy-2-[(S)-(4-methoxy-3,5-dimethyl-2-pyridinyl methyl) sulphinyl]-lH-benzimidazole [esomeprazole or S-omeprazole], a compound of Formula 3.

Formula 3

OCH3

This application has been divided out from Patent Application No. 299/Mum/2002

PRIOR ART
PCT publication WO 9427988 claims optically pure compounds characterized in that the compounds are Na+, Mg2+, Li+, K+, Ca2+ and N+(R)4 salts of (+) and (-) 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-li/-benzimidazole, wherein R is an alkyl with 1-4 carbon atoms. This invention also claims the process for the preparation of these compounds characterized in that a diastereomeric ester with a chiral acyl group such as mandeloyl, having either R or S configuration, is separated and each of the separated diasteromers is dissolved in an alkaline solution where the acyloxymethyl group is hydrolyzed to give the optically pure compound. This is a laborious process as it involves oxidation, resolution, separation and hydrolysis of the ester to yield the optically active omeprazole and there is large wastage of the unwanted isomer. It does not yield the optically active omeprazole directly on oxidation.
United States Patent No. 5948789 provides a process for enantioselective synthesis of a sulphoxide compound or an alkaline salt thereof in the form of a single enantiomer or in an enantiomerically enriched form comprising oxidizing a prochiral sulfide with an oxidizing agent and in presence of a chiral titanium complex and a base, and optionally converting the obtained sulfoxide into a pharmaceutically acceptable salt by a conventional process. The examples in the patent use only the chiral bidentate ligand of diethyl tartrate and the use of a catalyst with a chiral monodentate ligand is not disclosed.
PCT publication WO 9617076 claims the stereoselective bio-oxidation of the prochiral sulfide to the corresponding single enantiomer or in an enantiomeric enriched form of sulphinyl derivative. This invention does not disclose chemical oxidation using oxidizing agents such as cumene hydroperoxide.
PCT publication WO 9617077 claims the enantioselective preparation of pharmaceutically active sulphoxides by bioreduction. This invention does not disclose chemical oxidation using oxidizing agents such as cumene hydroperoxide.
PCT publication WO 9702261 claims a process for the optical purification of enantiomerically enriched preparation of esomeprazole and other similar compounds by

solvents. Resolution techniques can be employed for compounds possessing acidic, basic or hydroxyl groups by salt formation or derivatisation with appropriate chiral reagents. However chiral compounds like sulfoxides, hydrocarbons, nitro compounds, nitriles and several other neutral molecules do not possess the necessary features essential for a classical resolution technique to be applied for. Thus these compounds have to be synthesised as pure isomers during the bond formation process itself, using chiral reagent as an auxiliary or a catalyst. Moreover methods to resolve optically pure sulfoxides are limited due to neutral nature of the sulfoxide functionality, thus it is difficult to make derivative and resolve the racemic sulfoxides. Also many of the Sulfoxides are liquids hence enrichment of the enantiomeric purity by way of crystallisation is also of limited use.
Methods that are currently adopted to make chiral sulphoxides involve the usage of bidentate chiral ligands such as Sharpless's Ti(0'Pr)4/ Diethyltartrate catalyst conditions or Uemura's Ti(0'Pr)4 / Binol catalyst process. Although these oxidant systems offer many advantages, however in cases where the enantioselectivity is low, the above mentioned oxidant systems offer no options to improve the selectivity, since there is not much scope to make diverse Tartrates or Binols as asymmetric reagents. Hence there is a need to develop a system wherein one can choose appropriate chiral reagent from a pool of reagents to optimise the chiral purity or enantiomeric excess.
The method of asymmetric oxidation disclosed herein provides diverse pool of reagents to achieve the optical purity and provides enantiomeric excess of 10% to more than 90% Use of tertiary amine bases like diisopropylethylamine enhances chiral induction leading to the formation of chiral sulphoxides.
The object of the present invention is to provide a facile and an inexpensive process for the preparation of an alkali or alkaline earth metal salt of an optically active substituted pyridinylmethyl-sulphinyl-benzimidazole enantiomer, compound of formula 1.

treating with a solvent, precipitating the racemate, filtering off the racemate and solvent evaporation to yield the single enantiomer. This invention does not disclose catalytic oxidation of prochiral sulphides to the corresponding sulphinyl derivatives.
PCT publication WO 9828294 claims the S-omeprazole in a neutral form in a solid state. This invention does not disclose the catalytic oxidation of prochiral sulphides to the corresponding sulphinyl derivatives in the presence of a catalyst with a chiral monodentate ligand.
PCT publication WO 9854171 claims the process of preparing the magnesium salt of S-omeprazole by treating the potassium salt of S-omeprazole with a magnesium source in water. This invention does not disclose catalytic oxidation of prochiral sulphides to the corresponding sulphinyl derivatives in the presence of a catalyst with a chiral monodentate ligand.
PCT publication WO 0044744 claims the potassium salt of S-omeprazole form B, characterized in being a hydrate form. This invention does not disclose catalytic oxidation of prochiral sulphides to the corresponding sulphinyl derivatives in the presence of a catalyst with a chiral monodentate ligand.
German Patent No. 4035455 claims enantiomerically pure
(pyridylmethylsulphinyl)benzimidazoles by derivatizing their racemates (or racemate salts) at the benzimidazole N with an enantiomerically pure chiral compound, separating the resulting diastereomeric derivatives, and solvolyzing the separated derivative isomers in a strongly acidic medium. This invention does not disclose catalytic oxidation of prochiral sulphides to the corresponding sulphinyl derivatives.
OBJECT OF THE INVENTION:
Pharmaceutically active moieties possessing chirality need to be resolved to check the potency and untoward side-effects of the antipodes. Standard method of separating the unwanted isomer from a racemic mixture is by resolution using resolving agents and

It is a more specific object to provide a facile and inexpensive process for the preparation of an alkali or alkaline earth metal salt of an optically active 5-methoxy-2-[(S)-(4-methoxy-3,5-dimethyl-2-pyridinylmethyl)sulphinyl]-1 H-benzimidazole (esomeprazole).
It is yet another more specific object of the present invention to provide a method to prepare the magnesium salt of 5-methoxy-2-[(S)-(4-methoxy-3,5-dimethyl-2-pyridinylmethyl)sulphinyl]-lH-benzimidazole.
SUMMARY OF INVENTION :
Thus the present invention relates to process for the preparation of alkali metal or alkaline earth metal salts of an optically active enantiomer or an enantiomerically enriched form of substituted pyridinylmethyl-sulphinyl-benzimidazole, compound of formula 1

wherein R1 to R4 are selected from H, linear or branched (1-4C) alkyl, linear or branched (1-4 C) alkoxy, aryl, aryloxy and their halo or alkoxy substituted analogs, said process comprising enantioselective catalytic oxidation of a substituted pyridinylmethyl prochiral sulphide derivative of benzimidazole, compound of formula 2

Formula 2
wherein R1 to R4 are as defined above, with an oxidizing agent in an organic solvent in the presence of a base and a catalyst comprising titanium or vanadium complexed with a chiral monodentate ligand to obtain the compound of formula l,thereafter treating the compound of formula 1 with an alkali or alkaline earth metal source.

DETAILED DESCRIPTION OF THE INVENTION:
Compounds prepared by the process of the present invention are alkali metal or alkaline earth metal salts of optically active enantiomer or enantiomerically enriched forms of substituted pyridinylmethyl-sulphinyl-benzimidazole, compound of formula 1.
More specifically the process of the present invention provides a process for the preparation of alkali metal or alkaline earth metal salts of optically active or enantiomerically enriched sulfoxides of omeprazole, pantoprazole, rabeprazole and lansoprazole which are proton pump inhibitors useful in the treatment of ulcers.
The process of the present invention comprises enantioselective catalytic oxidation of prochiral sulphides with an oxidizing agent in an organic solvent in the presence of a base and a catalyst comprising titanium or vanadium complexed with a chiral monodentate ligand.
According to the preferred embodiment of the process of the present invention the oxidizing agent may be selected from hydrogen peroxide, alkyl hydroperoxides and arylalkyl hydroperoxide, preferably alkyl hydroperoxides and/or arylalkyl hydroperoxide. More preferably, the oxidising agent is an arylalkyl hydroperoxide, the most preferred being cumene hydroperoxide. The mole ratio of the oxidizing agent to the prochiral sulphide that may be used range from 0.8:1 to 1.5:1, most preferably 1:1 to 1.2:1.
The catalyst comprising titanium or vanadium complexed with a chiral monodentate ligand that can be used may be prepared by reacting a titanium or vanadium reagent with a chiral monodentate ligand. The titanium or vanadium reagent may be selected from titanium alkoxides or vanadium acetate. Preferably the reagent is a titanium reagent selected from alkoxides of Ti(IV), more preferably isopropoxide of Ti(IV). The mole ratio of the titanium or vanadium reagent to the prochiral sulphide that may be used range from 0.05:1 to 0.5:1, the most preferred being 0.25:1 to 0.35:1.

The chiral monodentate ligand may be selected from a pool of chiral alcohol moieties like diaryl alcohol, dialky alcohols, alkyl aryl alcohols, alkyl or aralkyl a-hydroxy acids (alkyl residues may be linear, branched , cyclic, etc with 1C to 20C carbon chain) or aryl, substituted aryl or heteroaryl a-hydroxy acetic acids and their derivatives such as esters, amides, hydrazides, hydroxamic acids etc. The more preferred being the aryl or substituted aryl a-hydroxy acetic acid esters, preferably lower alkyl esters of R or S mandelic acid, the most preferred being R(-) or S(+) Methyl mandelate, as the case may be. The mole ratio of the chiral monodentate ligand to the prochiral sulphide that may be used range from 1.2:1 to 3:1, most preferably 2:1 to 2.5:1.
According to the process of the present invention the enantioselective catalytic oxidation process is carried out in the presence of a base. The base may be an organic amine base selected from a group of primary, secondary or tertiary amines, preferably the hindered, alkyl, cyclic alkyl, aralkyl primary, secondary or tertiary amines, more preferably the hindered alkyl tertiary amines, the most preferred being N,N-diisopropylethylamine. The mole ratio of the base to the prochiral sulphide that may be used range from 0.05:1 to 1:1, most preferably 0.05:1 to 0.2:1.
According to the process of the present invention the organic solvent that may be used is selected from halo substituted or unsubstituted alkyl and aryl hydrocarbons such as hexane, toluene, xylenes, C-IX, methylene chloride, chlorobenzene and the like, alkyl or aryl ketones like acetone, methylisobutyl ketone, methylethyl ketone and the like, alky or aryl nitriles like benzonitrile, acetonitrile and the like.
According to the process of the present invention the preparation of the catalyst is carried out in the presence of the prochiral sulphide or before the addition of the prochiral sulphide, preferably before the addition of the prochiral sulphide.
The temperature during the preparation of the catalyst, by treating titanium or vanadium reagent with a chiral monodentate ligand, may be about 30-70 °C, most preferably about

40-50uC.
The time for preparation of the catalyst may range from 1-24 hours, the most preferred being 17-22 hrs.
According to the process of the present invention the enantioselective catalytic oxidation reaction may be carried out at a temperature between 20-40 °C, most preferably at 25-30°C for a period of 1-8 hrs, most preferably about 2-6 hrs.
The optically active substituted pyridinylmethyl-sulphinyl- benzimidazole is separated by treating the oxidized reaction mixture with an aqueous basic solution like aqueous ammonia solution followed by extraction with the same or different solvent.
The alkali or alkaline earth metal source may be selected from Na+, K+, Li+, Mg+2, Ca2+ salts like bicarbonates, carbonates, hydrides, hydroxides and oxides. Preferably sodium hydroxide, potassium hydroxide , lithium hydroxide and magnesium hydroxide, the most preferred being sodium hydroxide.
The process of the present invention further comprises the steps of isolation of the alkali or alkaline earth metal salts of the optically active substituted pyridinylmethyl-sulphinyl-benzimidazole, a compound of formula 1, by solvent evaporation with or without vacuum, addition of the same or different solvent and filtering the product, drying followed by crystallization, if required.
According to yet another embodiment, the process of the present invention may further comprise the preparation of the alkaline earth metal salts of the optically active substituted pyridinylmethyl-sulphinyl- benzimidazole by treating the alkali metal salt of optically active substituted pyridinylmethyl-sulphinyl-benzimidazole with an alkaline earth metal source, preferably an alkaline earth metal halide selected from calcium, magnesium and barium halide, the most preferred being magnesium chloride.

The alkaline earth metal salt of optically active substituted pyridinylmethyl-sulphinyl-benzimidazole may be isolated by filtration, drying followed by crystallization, if required.
The invention is illustrated but not restricted by the description in the following examples.
EXAMPLES
Example 1 :
(a) Preparation of sodium salt of 5-methoxy-2-[(S)(4-methoxy-3.5-dimethyl-2-pyridinylmethyl)sulphinyl]-lH-benzimidazole (esomprazole sodium)
Mix, S-(+)-Methyl mandelate 60.6 g, Toluene 250 ml and Titanium isopropoxide 15 ml, into a 500 ml R.B.Flask assembly and stir to make a clear solution under Nitrogen atmosphere. Heat the reaction mixture to 40°C and maintain for 17 hr. Cool to 25-30°C and charge Omeprazole sulfide 50 g and Diisopropylethylamine 1.35 ml to it and stir for 10-15 minutes. Add Cumene hydroperoxide (~ 80 % solution in cumene) 28 ml slowly through addition funnel to the reaction mixture at 25-30°C. Stir the reaction mixture at 25-30°C for 2.0 hr. Filter the solid and wash with Toluene 50 ml. Collect the filtrate and charge 12.5 % ammonia solution 300 ml, to the filtrate and stir the mixture for 15 minutes. Back extract the Toluene layer with 12.5% Ammonia solution ; 200 ml and add Methyl isobutyl ketone 250 ml, to the combined aqueous layer. Adjust the pH of the solution to 7.3-7.6 by adding Glacial Acetic acid at 25- 30 °C. Stir the content for 30 min. Separate the organic layer and extract the aq. layer with Methyl isobutyl ketone ; 50 ml. Charge sodium hydroxide solution (50% w/v) 11 ml to combined organic layer and stir the mixture for 15 minutes. Distil off solvent completely under vacuum at 55-60 °C. Add Acetonitrile; 300 ml, to the residue and stir the content at 25-30°C. Filter the product under nitrogen atmosphere and wash the cake with Acetonitrile 50 ml. Dry the product in vacuum at 50-55 C. Yield of Esomeprazole sodium = 22.4 g.

(b) Preparation of 5-methoxy-2-r(S)-(4-methoxy-3.5-dimethyl-2-pvridinylmethvnsulphinyl]-lH-benzimidazole magnesium (esomprazole magnesium)
Mix, esomeprazole sodium prepared in Example 1, 20 g and Distilled water, 200 ml, into a 500 ml R.B.flask Add a solution Magnesium chloride, 11 g in Distilled water, 50 ml slowly through addition funnel in 30 minutes at 25-30°C. Stir the reaction mixture for 1.0 hr. Filter the product and wash the cake with Distilled Water, 60 ml. Dry the product in vacuum at 50-55°C. Yield of Esomeprazole magnesium = 15 g with an enantiomeric excess >98%.

We claim:
1. A process for the preparation of alkali metal or alkaline earth metal salts of an optically active enantiomer or an enantiomerically enriched form of substituted pyridinylmethyl-sulphinyl-benzimidazole, compound of formula 1

Formula 1
wherein R1 to R4 are selected from H, linear or branched (1-4C) alkyl, linear or branched (1-4 C) alkoxy, aryl, aryloxy and their halo or alkoxy substituted analogs, said process comprising enantioselective catalytic oxidation of a substituted pyridinylmethyl prochiral sulphide derivative of benzimidazole, compound of formula 2

Formula 2
wherein R1 to R4 are as defined above, with an oxidizing agent in an organic solvent in the presence of a base and a catalyst comprising titanium or vanadium complexed with a chiral monodentate ligand to obtain the compound of formula l,thereafter treating the compound of formula 1 with an alkali or alkaline earth metal source.
2. A process as claimed in claim 1 wherein the optically active alkali metal salt of the compound of formula 1 is treated with an alkaline earth metal source to yield the alkaline earth metal salt of the optically active compound of formula 1.
3. A process as claimed in claim 1 wherein the oxidising agent is selected from hydrogen peroxide, alkyl hydroperoxides and alkylaryl hydroperoxide.

4. A process as claimed in claim 3 wherein the oxidising agent is cumene hydroperoxide.
5. A process as claimed in claim 4 wherein the mole ratio of the oxidising agent to the prochiral sulphide is 0.8:1 to 1:1.
6. A process as claimed in claim 1 wherein the base is an organic amine base.
7. A process as claimed in claim 6 wherein the organic amine base is N,N-diisopropylethylamine.
8. A process as claimed in claim 1 wherein the mole ratio of the base to the prochiral sulphide is in the range 0.05:1 to 1:1.
9. A process as claimed in claim 1 wherein the catalyst is prepared by reacting titanium or vanadium reagent with a chiral monodentate ligand.
10. A process as claimed in claim 9 wherein the titanium reagent is selected from alkoxides of Ti (IV).
11. A process as claimed in claim 10 wherein the titanium reagent is isopropoxide of Ti (IV).
12. A process as claimed in claim 1 wherein the chiral monodentate ligand is selected from S(+) methyl mandelate or R(-) methyl mandelate.
13. A process as claimed in claim 9 wherein the catalyst is prepared before the
addition of the prochiral sulphide.
14. A process as claimed in claim 9 further comprising preparation of the catalyst at
higher temperature or longer preparation time or both.

15. A process as claimed in claiml4 wherein preparation of the catalyst is at higher temperature of about 30-70°C.
16. A process as claimed in claim 15 wherein preparation of the catalyst is at higher temperature of about 40 - 50°C
17. A process as claimed in claim 14 wherein preparation of the catalyst at longer preparation time is about 17-22 hrs.
18. A process as claimed in claim 11 wherein the mole ratio of Ti (IV) reagent to the prochiral sulphide is 0.05:1 to 0.5:1.
19. A process as claimed in claim 1 wherein the mole ratio of the chiral monodentate ligand to the prochiral sulphide is 1.2:1 to 3:1.
20. A process as claimed in claim 1 wherein the organic solvent is selected from the group of toluene, methylisobutyl ketone and acetonitrile.
21. A process as claimed in claim 1 wherein the enantioselective catalytic oxidation is carried out at a temperature between 20 - 40°C.
22. A process as claimed in claim 1 wherein the enantioselective catalytic oxidation
is carried out for a period of 1 - 8 hrs.
23. A process as claimed in claim 1 wherein the process further comprises the step of treating the reaction mass after enantiomeric catalytic oxidation with an aqueous ammonia solution.
24. A process as claimed in claim 1 wherein the alkali or alkaline earth metal source is selected from Na+, K+, Li+, Mg+2, Ca2+ salts like bicarbonates, carbonates, hydrides, hydroxides and oxides.

25. A process as claimed in claim 2 wherein the optically active alkali metal salt is treated with alkaline earth metal source selected from barium halides, magnesium halides and calcium halides.
26. A process as claimed in claim 1 wherein the optically active substituted pyridinylmethyl-sulphinyl-benzimidazole enantiomer is 5-methoxy-2-[(S)-(4-methoxy-3,5-dimethyl-2-pyridinylmethyl)sulphinyl]-lH-benzimidazole.
27. A process as claimed in claims 1 to 26 substantially as herein described and
illustrated by example 1 (a) and (b)

,th
Dated this 13th day of May, 2003.

Dr. Sanchita Ganguli
OF S. MAJUMDAR & CO
(Applicant's Agent)