Claims:
1. A process for preparing compounds of general formula (I) and their pharmaceutically acceptable salts

(I)

Wherein
R1, R2 and R3 are the same or different and selected from hydrogen, alkyl, alkylthio, alkoxy optionally substituted by fluorine, alkoxy, dialkylamino and halogen; R4-R7 are the same and selected from hydrogen, alkyl, alkoxy, halogen, halo-alkoxy, alkylcarbonyl, alkoxycarbonyl and trifluoroalkyl
wherein said process comprises the steps of reacting compound of general formula (V):

(V)
wherein,
R4-R7 are the same and selected from hydrogen, alkyl, alkoxy, halogen, halo-alkoxy, alkylcarbonyl, alkoxycarbonyl and trifluoroalkyl,
with alcohol R-OH wherein R is Cycloakyl optionally substituted by one or more C1-C4 alkyl groups or C7-C20 alkylaryl, preferably the alcohol is a C1-C4 alkyl, C3-C12 cycloalkyl optionally substituted by one or more C1-C4 alkyl groups or C7-C20 alkylaryl alcohol, more preferably the alcohol is methanol, ethanol, n-propanol, /- propanol, (-)-menthol, (+)-menthol, (-)-fenchol, (+)-fenchol, (-)-8- phenylmenthol or (+)-8-phenylmenthol in presence of oxidizing agent such as lead acetate, potassium permanganate, hydrogen peroxide, sodium perborate etc., more preferably lead acetate in chlorinated solvents such as dichloromethane, chloroform etc., more preferably chloroform preferably the alcohol is, (-)-menthol, (+)-menthol to give compound of formula II

II
wherein R4-R7 are the same and selected from hydrogen, alkyl, alkoxy, halogen, halo-alkoxy, alkylcarbonyl, alkoxycarbonyl and trifluoroalkyl,
and R is menthyl, which is further purified by column chromatography to get desired diastereomers.

wherein the desired diastereomers is reacted with compound of formula IV

IV

wherein:
R1, R2, R3 Wherein R1, R2 and R3 are the same or different and selected from hydrogen, alkyl, alkylthio, alkoxy optionally substituted by fluorine, alkoxy, dialkylamino and halogen M’ is an alkali or alkaline earth metal cation, a Mg-halogen cation or Zn-halogen cation.

2. A compound of formula V

(V)
wherein,
R4-R7 are the same and selected from hydrogen, alkyl, alkoxy, halogen, halo-alkoxy, alkylcarbonyl, alkoxycarbonyl and trifluoroalkyl.

3. A process for preparing compounds of general formula (V)

(V)

comprises,
reacting a thiol compound of formula (VI)

(VI)
with sodium perborate in presence of alcohol at the temperature 25-30°C.

4. A process according to claim 1, wherein the optical purity of the enantiomer of sulfoxide compound of formula (I) is at least 99.99%.

5. A process according to claim 1, wherein the compound of formula V is an intermediate for preparation of compound of formula (I).

6. The process according to claim 4, the starting material is 5-methoxy-1H-benzo[d]imidazole-2-thiol.

7. The process according to claim 2, wherein compound of formula V is 1, 2-bis (5-methoxy-1H-benzo[d]imidazol-2-yl) disulfane.

8. The process according to claim 1, wherein compound of formula IV is (4-methoxy-3, 5-dimethylpyridin-2-yl)methyl)magnesium chloride.

9. The process according to claim 1, wherein the product is magnesium salt of Esomeprazole.
, Description:Field of the invention
The present invention relates to a process for preparation of optically pure or optically enriched enantiomers of sulfoxide compounds, such as omeprazole and structurally related compounds, as well as their salts and hydrates.
Background of the invention
Substituted 2-(2-pyridinylmethylsulphinyl)-1-H-benzimidazole of formula (I) are useful as gastric acid secretion.

(I)
Wherein R1, R2 and R3 are the same or different and selected from hydrogen, alkyl, alkylthio, alkoxy optionally substituted by fluorine, alkoxy, dialkylamino and halogen; R4-R7 are the same and selected from hydrogen, alkyl, alkoxy, halogen, halo-alkoxy, alkylcarbonyl, alkoxycarbonyl and trifluoroalkyl.
For example, the compounds with generic name omeprazole, lansoprazole, rabeprazole, and pantoprazole are used in treatment of peptic ulcer. These compounds have a chiral center at the sulphur atom and thus exist as two optical isomers, i.e. enantiomers.
It has been well recognized in several pharmacologically active compounds that one of the enantiomer has superior biological property compared to the racemate and the other isomer.
For example, omeprazole (CAS Registry No. 73590-58-6), chemically known as 5- methoxy-2-{[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulphinyl}-IH­benzimidazole, is a highly potent inhibitor of gastric acid secretion. It has a chiral center at the sulphur atom and exists as two enantiomers (S)-(-)-omeprazole and (R)-{+)­ omeprazole. It has been shown that the (S)-enantiomer of omeprazole; has better pharmacokinetic and metabolic properties compared to omeprazole. The (S)-enatiomer of omeprazole having generic name esomeprazole is marketed by AstraZeneca in the form of magnesium salt under the brand name NEXIUM®. Therefore, there is a demand and need for an industrial scale process for manufacturing esomeprazole.
The methods of synthesis of racemic sulfoxide compounds of formula (I) are very successful for large-scale industrial manufacture. However, the production of optically pure sulfoxide compounds of formula (I) is not easy.
The prior art methodologies for the preparation of single enantiomers of sulfoxides of formula (I) are based on enantioselective or chiral synthesis, optical resolution of the racemate, separation by converting the racemate to diastereomers, or by chromatography.
For example, some of the earliest prior art on enantioselective synthesis of the single enantiomers of sulfoxide of formula (I) described in Euro. J. Biochem. 166, (1987), 453, employed asymmetric sulphide oxidation process developed and reported by Kagan and co-workers in J. Am. Chem. Soc. 106 (1984), 8188. The process disclosed therein provides sulfoxide products in an enantiomeric excess of only about 30%, which upon several recrystallization steps yielded optically pure sulfoxide upto an e.e. of 95%. The oxidation was performed by using tert-butyl hydroperoxide as oxidizing agent in the presence of one equivalent of a chiral complex obtained from Ti(OiPr)4/(+) or (-)-diethyl tartrate/water in the molar ratio of 1:2:1. A minimum of 0.5 equivalent of titanium reagent was found to be a must for obtaining very high enantioselectively.
An improvement in the above oxidation process to obtain higher enantioselctivity was reported by Kagan and co-workers in Tetrahedron (1987), 43, 5135; wherein tert-butyl hydroperoxide was replaced by cumene hydroperoxide. In their further study reported in Synlett (1990), 643; Kagan and co-workers, found t]; J.at high enantioselectivity can be obtained if the temperature is maintained: between -20°C to -40 °C, and methylene chloride is used as a solvent.
In contrary to Kagan's observation of requirement of low temperature and chlorinated solvent like methylene chloride for high enantioselectivity of the chiral oxidation.Larsson et al in U.S Patent No. 5,948,789 (equivalent to PCT publication WO 96/02535) have described an enantioselective process for the synthesis of the single enantiomers of compound of formula (I) by the chiral oxidation of the pro-chiral sulphide of formula (Ia) utilizing a.chiral titanium (IV) isopropoxide complex in solvent systems such as toluene, ethyl acetate at 20-40 °C, and most importantly a base like amine such as triethyl amine or diisopropyl amine.
Although the formation of% e.e. of the desired isomer is satisfactory, the method suffers from the disadvantage (a) of low chemical conversion; (b) formation of undesired sulphide and sulfone impurities in substantial amounts, necessitating further purification by one or more tedious crystallization.
It is obvious from the above that such conversions which result in low chemical conversion and require costly metal complex and protracted purification, surely, is not desirable process for making a product such as optically active prazole in an industrial scale.
WO 96/17076 teaches a method of enantioselective bio oxidation of the • sulphide compound (Ia), which is effected by the action of Penicillium frequentans, Breviba terium parafflnolyticum or Mycobacterium sp.
WO 96/1707 teaches the bioreduction of the racemic omeprazole to an enantiomer or enantiomerically enriched sulphide of formula (Ia), which is effected by the action of Proteus vulgaris, Proteus mirabilis, Escherichia• coli, Rhodobacter capsulatus or a DMSO reductase isolated from R. capsulatus.
The separation of enantiomers of omeprazole in analytical scale is described in Marle et.al. J Chromatography, 532, (1990), 305-19. WO 03/051867 describes a method forpreparation of an enantiomerically pure or optically enriched enantiomer •of eitheromeprazole, pantoprazole, lansoprazole, or raberpazole from a mixture containing the same using means for simulated moving bed chromatography with a chiral stationary phase such as amylose tris (S)-methylbenzycarbanmate. However, chromatographic methods are not suitable for large-scale manufacture of these prazoles.
The optical resolution methods taught in the art for separating the enantiomers of certain 2-(2-pyridinylmethylsulphinyl)-lH-benzimidazoles of formula (I) utilizes the iastereomer method, the crystallization method or the enzyme method.
The resolution process disclosed in DE 4035455 and WO 94/27988 involve converting the racemate 2-(2-pyridinylmethylsulphinyl)-1 H-benzimidazoles to a diastereomeric mixture using a chiral acyl group, such as mandeloyl, and the diastereomers are separated and the separated diastereomer IS converted to the optically pure sulphoxide compound by hydrolysis.

This method suffers from following disadvantages:

1. the resolution process involves additional steps of separation of diastereomeric mixture, and hydrolysis of the N-substituent in separated diastereomer;
2. the conversion of the racemate to diastereomeric acyl derivative 1s low yielding ( 40%);
3. the diastereomer from the unwanted (R)-enantiomer 1s separated and discarded.

WO 2004/002982 teaches a method for preparation of optically pure or optically enriched isomers of omeprazole by reacting the mixture of optical isomers with a chelating agent (D)-diethyl tartrate and transition metal complex titanium (IV) isopropoxide to form a titanium metal complex in an organic solvent such as acetone in presence of a base such as triethyl amine, which is then converted tö salt of L-mandelic acid. The mandelic acid salt ofthe titanium complex of optical isomer derived from (S)-enantiomer of omeprazole gets precipitated, which is separated and purified to obtain chiral purity of about 99.8%.

Optically active 1,1'-bi-2-naphthol (BINOL) and its derivatives are useful as chiral ligands in catalysts for asymmetric reactions to hosts for molecular recognition and enantiomer separation, and often intermediates for the synthesis of chiral molecules.

BINOL is known to form crystalline complexes with a variety of organic molecules through hydrogen bonding. The (S) .and/or (R) BINOL was found tobe useful as a chiral host for enantioselective complexation. The app k:don of BINOL in resolution of omeprazole is disclosed Deng et al in CN 1223262. The Chinese patent application CN 1223262 (Deng et al) teaches the utility of chiral host compounds such as dinaphthalenephenols (BINOL), diphenathrenols or tartaric acid derivatives in the resolution of prazoles. The method consists of formation of 1:1 solid complex between the chiral host and one of the enantiomer of the prazole, the guest molecule. The other enantiomer remains in the solution. The racemic prazole is treated with the chiral host in a mixture of solvent comprising of aromatic hydrocarbon solvents such as benzene, alkyl substituted benzene or acetonitrile and hexane. The solid complex is separated from the solution, and dissolved again in afresh solvent system by heating to 60-130°C and then keeping at -20-10°C for 6-36hrs to obtain higher e.e value of the solid complex. The process is repeated many times to obtain high e.e values for the solid complex. The host and the guest in the solid complex are separated by column chromatography. The final separated single enantiomer of the prazole is then recrystallized from the mixture of methylene chloride or chloroform or ether. The solid complex is separated from the solution and dissolved again in afresh solvent system by heating to 60-130°C and then keeping at -20-10°C for 6-36 hrs to obtain higher e.e value for the solid complex. The process is repeated many times to obtain high e.e values for the solid complex. The host and guest in the solid complex are separated by column chromatography .The final separated single enantiomer of the prazole is then recrystallized from a mixture of methylene chloride, chloroform and ether.

In a later publication in Tetrahedron Asymmetry 11 (2:000), 1729-1732 the inventors of the above mentioned Chinese patent application reported the resolution of omeprazole using (S)-BINOL. An inclusion complex of (S)-BINOL and (S)-omeprazole was obtained as a complex with 90.3% e.e by mixing racemate omeprazole and (S)-(-) BINOL in the mole ratio 1:1.5, n a solvent mixture of benzene:hexane (v/v = 4:1) at 110°C. The inclusion complex obtained was further purified by recrystallization in benzene: hexane (v/v, 1:1) and separated on a silica gel column to yield (S)-(-) ¬ omeprazole with 98.9% e.e. and 84.1% overall yield. The (S)-(-)-omeprazole so obtained was recrystallized in water to obtain.as a white powder with 99.2% e.e.

In this publication, the authors have reported their observation of criticality of the benzene: hexane solvent ratio in obtaining the inclusion complex and enantioselectivity. The authors reportedly have obtained the best enantioselectivity of 90.3% e.e when the solvent ratio of benzene: hexane is 4: 1 and mole ratio of racemate omeprazole and (S)-BINOL is 1:1.5.

The method described in the above-mentioned Chinese patent application suffers in that, due to very low e.e. value for the solid complex obtained for the first time, the complexation process has to be repeated till the desired e.e. value is obtained, to separate the host and the guest, one has to take recourse to tedious chromatographic methods,
1. overall the resolution involves several operations of complex formation, separation, purification by chromatography and recrystallization,
2. For the purpose of chromatography the amount silica and the solvent required is exorbitant
3. with more operation steps, there is considerable material loss leading to lowering of the overall yield, which is not satisfactory for a commercial scale production,
4. the use of hexane with low flash point is not recommended for industrial processes,
5. volumes of the solvents to be handled having low flash point are quite large, necessitating special design of plant and machinery for safety;
6. benzene is carcinogenic and is listed as a class 1 solvent in ICH guideline.

Taking these considerations, the process disclosed in the CN 1223262 (Deng et al) does not give cost effective and eco-friendly method of manufacture.

WO200910645 describes the process for preparation of prazole using menthyl derivative, however the method described in above mentioned patent application has certain drawbacks
1. It involves multiple steps;
2. Low yielding, hence cannot be used on large scale ;
3. Due to more operation steps there is considerable material loss.

WO2008142006 describes the process for preparation of prazole using menthyl derivative, however the method described in above mentioned patent application has certain drawbacks
1. It involves multiple steps;
2. Involves use of analytical columns for separation of diastereomers;
3. Because of the above mentioned reason it is not cost efficient;
4. It does not mention anything about e.e of the final product;
5. This process cannot be used for large scale.

It is evident from the above that there is a need for synthesizing optically pure sulfoxide compounds of formula (I), their salts, and their hydrates' by a process that is (a) cost effective (b) simple (c) easy to operate (d) eco-friendly ; (e) consistently give good yields and purity with minimum variables (e) highly reproducible.

OBJECT OF THE INVENTION
The object of the invention is to provide a novel method for the manufacture of single enantiomer of sulfoxide compounds of formula (I) and their pharmaceutically acceptable salts and hydrates, thereby resulting in significant economic and technological improvement over the prior art methods.
More specifically, the object of the invention is to manufacture single enantiomers of Omeprazole, Rabeprazole, Lansoprazole or Pantoprazole covered by formula (I), and pharmaceutically acceptable salts and hydrates.
Another object of the invention is process for preparation of novel intermediate in easily obtainable manner.
Yet another object of the invention is the use of the novel intermediate compound in the preparation of compound of formula (I) and its pharmaceutically acceptable salts thereof.

SUMMARY OF INVENTION
Thus, according to one aspect of present invention there is provided a novel process for preparation of an optically pure or optically enriched enantiomer of sulfoxide compound of formula (I) with good yield and high purity.

DETAILED DESCRIPTION OF THE INVENTION

The invention is directed to a process for preparation of an optically pure or optically enriched enantiomer of a sulfoxide compound of formula (I). Intermediates in the processes of this invention are also part of this invention, as are their salts and hydrates.
The sulfoxide compounds suitable as substrates for the process of this aspect of the invention include, for example, omeprazole, lansoprazole, pantoprazole, rabeprazole and active isomers thereof.
In a more preferred embodiment, the invention provides a specific process for preparing a substantially optically pure or optically enriched form of omeprazole and its pharmaceutically acceptable salts.

The process is depicted in Scheme 1.

Preparation of 2-(2-pyridylmethyl) sulphinyl-1H-benzimidazoles, compounds of general formula – (I).
An object of the invention is a process for preparing the compound of general formula (I) and their pharmaceutically acceptable salts

Wherein
R1, R2 and R3 are the same or different and selected from hydrogen, alkyl, alkylthio, alkoxy optionally substituted by fluorine, alkoxy, dialkylamino and halogen;
R4-R7 are the same and selected from hydrogen, alkyl, alkoxy, halogen, halo-alkoxy, alkyl carbonyl, alkoxycarbonyl and trifluoroalkyl. Characterized in that it comprises the reaction of a compound of general formula (II)

(II)
Wherein:
R4-R7 are the same and selected from hydrogen, alkyl, alkoxy, halogen, halo-alkoxy, alkylcarbonyl, alkoxycarbonyl and trifluoroalkyl.
R is Cycloakyl optionally substituted by one or more C1-C4 alkyl groups or C7-C20 alkylaryl
With a metalated derivative of compound of formula (III)

III
Wherein:
R1, R2 and R3 are the same or different and selected from hydrogen, alkyl, alkylthio, alkoxy
optionally substituted by fluorine, alkoxy, dialkylamino and halogen.

Preferably the compound of general formula (I) is omeprazole, pantoprazole, lansoprazole or rabeprazole, their pharmaceutically acceptable salts.
The starting material is a compound of general formula (II) as mentioned above. Preferable the compounds have the general formula II, wherein R4-R7 are the same and selected from hydrogen, alkyl, alkoxy, halogen, halo-alkoxy, alkylcarbonyl, alkoxycarbonyl and trifluoroalkyl and R is methyl, ethyl, isopropyl,(-)menthyl, (+) menthyl, (-)fenchyl, (+) fenchyl etc.

The metalated derivatives of the compound of formula (III) are obtained from substituted 2-methylpyridines, which are described in methods known in prior art.

Preferably, the metalated derivative of compound (III) is compound of formula IV

(IV)

Wherein:
R1, R2, R3 are as defined above
M’ is an alkali or alkaline earth metal cation, an Mg-halogen cation or Zn-halogen cation.

The reaction between compound of general formula (II) and metalated derivative of compound of formula (III) is carried out in inert solvent such as anhydrous tetrahydrofuran or anhydrous ether, preferably, anhydrous ether is used.

Generally, the metalated derivative of compound of formula (III) is not isolated and is added slowly to solution of compound of formula II in an inert solvent such as tetrahydrofuran, ether or anhydrous toluene, cooled to temperature normally below 10°C. After addition the reaction mixture is gradually brought to room temperature and compound of general formula (I) is isolated by conventional method.

Surprisingly, it has been observed that by using the process of present invention, 2-(2-pyridylmethyl)sulphinyl-1H-benimidazoles can be prepared with high yield and high enantiomeric purity.

Accordingly, one of the advantages of the process of the invention consists in the fact that each enantiomer of 2-(2- pyridylmethyl)sulphinyl-1 H-benzimidazole may be prepared if the R group of the compound of general formula (II) is -OR wherein R is a chiral alcohol radical such as (-)-menthol, (+)-menthol, (-)-fenchol, (+)-fenchol. Thereafter, the optical isomers of the compound of general formula (II) are separated by conventional methods.

When the compound of general formula (I) contains a chiral alcohol radical in the R group, a mixture of optical isomers, which are diastereoisomers, is obtained, i.e. optical isomers that are not enantiomers. Enantiomers are those optical isomers, which are mirror images of the other.

This is due to the fact that although the sulphur atom of the compound of general formula (I) may exhibit two possible configurations, the chiral alcohol exhibits only one of them.

The methods that can be used in the separation of mixtures formed by diastereoisomers are well known by a person skilled in the art. Unlike the enantiomers, the diastereoisomers normally show sufficiently different physical properties to be separated. For example, different solubilities in a same solvent.

One of the methods that can be used for separating the optical isomers of the compound of general formula (II) consists of the use of a column chromatography which is cheap and feasible on large scale easily.

Chiral alcohols, which may be used in the process of the invention, may be selected, for example, from the groups consisting of (-)- menthol, (+)-menthol, (-)-fenchol, (+)-fenchol, (-)-Preferably, (-)-menthol or (-)-fenchol are used.

On carrying out the reaction between the compound of formula (IV) and one of the optical isomers of the compound of general formula (II), one of the optical isomers of the compound of general formula (I) can be obtained in a stereospecifc form. Consequently, S-omeprazole, R-omeprazole, S- pantoprazole, R-pantoprazole, S-lansoprazole, R-lansoprazole S-rabeprazole, and R-rabeprazole, and their pharmaceutically acceptable salts, may be obtained by means of the process of the invention.

Preparation of compound of formula (II)
It is an object of invention a process for preparation of compounds of general formula (II)

II

Wherein:
R4-R7 are the same and selected from hydrogen, alkyl, alkoxy, halogen, halo-alkoxy, alkylcarbonyl, alkoxycarbonyl and trifluoroalkyl.
R is Cycloalkyl optionally substituted by one or more C1-C4 alkyl groups or C7-C20 alkylaryl
Characterized in that it comprises reacting the compound of formula V

V

Wherein:
R4-R7 are the same and selected from hydrogen, alkyl, alkoxy, halogen, halo-alkoxy, alkylcarbonyl, alkoxycarbonyl and trifluoroalkyl with alcohol R-OH wherein R is cycloakyl optionally substituted by one or more C1-C4 alkyl groups or C7-C20 alkylaryl in presence of oxidizing agent such as lead acetate, potassium permanganate, hydrogen peroxide, sodium perborate etc., more preferably lead acetate in chlorinated solvents such as dichloromethane, chloroform etc., more preferably chloroform..

Preferably the alcohol is a C1-C4 alkyl, C3-C12 cycloalkyl optionally substituted by one or more C1-C4 alkyl groups or C7-C20 alkylaryl alcohol, more preferably the alcohol is methanol, ethanol, n-propanol, /- propanol, (-)-menthol, (+)-menthol, (-)-fenchol, (+)-fenchol, (-)-8- phenylmenthol or (+)-8-phenylmenthol.
As discussed above the use of a chiral alcohol, such as (-)- menthol, (+)-menthol, (-)-fenchol, (+)-fenchol, shows some advantages, since it makes easier the separation of the optical isomers of the compound of general formula (I) and, consequently, the preparation of optically active 2-(2-pyridylmethyl)sulfinyl-1 H-benzimidazole isomers (enantiomers), such as S-omeprazole.

The reaction with alcohol and oxidizing agent may be carried out at room temperature then heated to reflux temperature, after completion of the reaction the reaction mass is cooled to room temperature subsequently treated with water followed by separation of phases.

The compound of formula (V) is obtained by evaporation of organic phase purified by means of column chromatography.

Preparation of compounds of general formula V

In a preferred embodiment, the compound of general formula (V)

V
Wherein: R4-R7 are the same and selected from hydrogen, alkyl, alkoxy, halogen, halo-alkoxy, alkylcarbonyl, alkoxycarbonyl and trifluoroalkyl, is obtained by a process which comprises reacting a compound of formula (VI)

VI
Wherein: R4-R7 are the same and selected from hydrogen, alkyl, alkoxy, halogen, halo-alkoxy, alkylcarbonyl, alkoxycarbonyl and trifluoroalkyl with oxidizing agents such as perborates, hydrogen peroxide, sodium permanganate, potassium permanganate etc preferably sodium perborate in presence of alcohol, water as solvent . This reaction method is simple can be easily carried out at room temperature , after completion of reaction any organic solvent immiscible in water is added,the orange layer is separated to get sufficiently pure disulphide intermediate of formula (V) which can be used to prepare compound of formula (I). Consequently, S-omeprazole, R-omeprazole, S- pantoprazole, R-pantoprazole, S-lansoprazole, R-lansoprazole S-rabeprazole, and R-rabeprazole, and their pharmaceutically acceptable salts, may be obtained by means of the process of the present novel intermediate of formula (V); wherein the intermediate of formula (V) is isolated in solid form or non-solid form such as prepared in-situ.

The invention is illustrated by following examples which should not be interpreted as the limiting the invention. The best mode to carry out the invention is according to one of the examples giving S-omeprazole Magnesium.

Scheme 2 depicts the preparation of Esomeprazole Magnesium.

Alternatively, if (R) enantiomer of omeprazole is desired, S-menthol derivative can be isolated can be used for further conversion into R-omeprazole.

Following are the examples illustrate the practice of the invention without limiting anyway.

Example 1:
Preparation of 1, 2-bis (5-methoxy-1H-benzo[d]imidazol-2-yl) disulfane.

5-methoxy-2-mercaptobenzimidazole (25gm) and sodium perborate (20mmol) was added to a mixture of methanol (60ml) and water (40ml) in a round bottom flask kept at 25-30°C .The reaction mixture was allowed to stir at RT for about 16hrs . After completion of reaction, ethyl acetate (100ml) was added to reaction mixture and stirred for 10 minutes. Organic layer was washed with water (50ml), dried on sodium sulphate and concentrated under vacuum on rotavapour to get oil.
Yield (27.5g, 55%).

Example 2:
Preparation of (-menthyl) 5-methoxy-2-benzimidazolylsulfinate

1, 2-bis (5-methoxy-1H-benzo[d]imidazol-2-yl) disulfane (25gm), menthol (28.97gm) was added to chloroform (125ml) in a round bottom flask. A solution of lead tetracetate (82.02gm) in chloroform (950ml) is added to reaction mixture under reflux temperature with temperature during 1hr and the reaction mixture is heated to reflux. After completion of reaction i.e. (till disulphide disappears), the reaction mixture is cooled to RT and added water (50ml), this reaction masss is filtered through celite, the organic layer washed with excess of water and the organic layer is concentrated under vacuum to get oil.

The desired product is isolated by column chromatography using cyclohexane and ethyl acetate to get pure isomer of (-) menthyl 5-methoxy-2-benzimidazolylsulfinate.
Yield (9.5gm, 39%).
NMR in CDCl3: d 0.80-0.95(m, 10H), 1.10-1.16(m, 1H), 1.25-1.32(m, 3H), 1.61-164(m, 2H), 1.9-2.27(m,2H), 3.78-3.83(s,3H), 4.31-4.35(m,1H),6.82-6.89(ddd,1H), 7.23-7.27(d,1H),7.37-7.51(dd,1H).
MP: 149-151°C.

Example 3
Preparation of Esomeprazole Magnesium
Preparation of Esomeprazole involves 2 steps first preparation of Grignard reagent and second addition of Grignard to (-) menthyl 5-methoxy-2-benzimidazolylsulfinate.

A Grignard solution of 2-chloromethyl-3,5-dimethyl-4-methoxy pyridine prepared from 2-chloromethyl-3,5-dimethyl 4-methoxy pyridine (5.7g), Magnesium (0.89gm), catalytic iodine and ether (30ml).

Grignard solution slowly added to solution of (-) menthyl 5-methoxy-2-benzimidazolylsulfinate (9gm) in anhydrous toluene between 0-10°C. After the addition, the mixture is stirred at room temperature for 2hrs and then hydrolyzed with saturated solution of ammonium chloride (200ml).Aq.layer extracted with ether (100ml).Then organic layer is washed with brine(100ml) and water(100ml). Organic layer concentrated under vacuum to get oil (4.8 gm). Charge methanol (24ml) and add KOH (0.87gm) and stirred at RT for 1hr and then filtered potassium salt of esomeprazole under vacuum. Charge methanol (15ml), magnesium sulfate heptahydrate (1.17gm) and stirred for 3 hrs at room temperature. Filter the inorganic salt and concentrate the mother liquor under vacuum till 1volume mass is left behind in flask and added water (4.8ml): acetone (19.2ml) and stirred for 5hrs at room temperature. Filtered the solid and dried under reduced pressure to get Esomeprazole Magnesium.
Yield= (3.36gm)
H1 NMR (DMSO-d6): 2.16-2.22(s, 6H), 3.59-3.68(s, 6H), 4.64-4.57(bd, 2H), 6.46-6.60(dd, 1H), 7.03-7.08(d, 1H), 7.31-7.39(d, 1H), 8.24-8.28(s, 1H)
HPLC Chiral purity: 99.99%