FORM 2
THE PATENTS ACT, 1970 (39 of 1970)
COMPLETE SPECIFICATION.
(See section 10]
1. Title of the invention: "Process for the preparation of Pantoprazole Sodium."
2. Macleods Pharmaceuticals Ltd., an Indian Company, having its Registered Office at 304 - Atlanta Arcade, Opp. Leela Hotel, Marol Church Road, Andheri (East), Mumbai - 400 059, Maharashta, India.
3. The following specification particularly describes and ascertains the nature of this invention and the manner in which it is to be performed.

Technical Field of the Invention
The present invention relates to an improved and industrially viable process for the preparation of pantoprazole sodium in high yields and purity.
Background and Prior art
Pantoprazole sodium, chemically known as 5-(diflouromethoxy)-2[[(3, 4-dimethopyridinyl) methyl] sulphinyl]-lH-benzimidazole sodium (I) is an irreversible proton pump inhibitor.

Pantoprazole sodium was disclosed for the first time in European patent application EPO166287. The process described in the said patent comprises the condensation of 2-chloromethyl-3, 4-dimethoxypyridinium hydrochloride with 5-difluoromethoxy-2-mercaptobenzimidazole to get the sulfide intermediate which is oxidized with m-chloroperoxybenzoic acid in dichlorometane yielding pantoprazole. The main disadvantage of this process is the formation of sulphone impurity which is difficult to remove; w-chloroperbenzoic acid is a costly reagent and also m-chloro benzoic acid is generated as a by product during the reaction thus affecting the purity of the product.
Use of several other oxidizing agents has been reported in different patent literatures for the preparation of pantoprazole from its corresponding intermediate by oxidation. The
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oxidants such as tert-butyl hydroperoxide or oxone (U.S. Publication No.2003036554), sodium percarbonate in presence of molybdenum salt as a catalyst (WO 2001/068594) , sodium perborate (EP 1071678) etc are reported and all these have either disadvantage of high cost or formation of impurities such as sulphone during the oxidation.
The article appeared in J.Med.Chem.35, 1049 (1992) reveals the preparation of pantoprazole and its derivatives. Sodium hypochlorite is used for the oxidation of sulfide to sulfoxide in ethyl acetate and aqueous alkali; however the use of alkali with ethyl acetate is associated with risk of degradation of ethyl acetate resulting in complex solvent system and difficulty in controlling the reaction and work-up pH.
WO 2007/026188 discloses the use of triethylbenzyl ammonium chloride, caustic lye and sodium hypochlorite solution for oxidation of sulfide to sulfoxide. WO 03/097606 discloses the use of m-chloroperbenzoic acid, oxone, magnesium salt of the monoperoxyphthalic acid and also hydrogen peroxide or tert-butyl hydroperoxide catalysed by rhenium or a vanadium compound. However, the use of m-chloroperbenzoic acid, oxone, magnesium salt of the monoperoxyphthalic acid, hydrogen peroxide or tert-butyl hydroperoxide catalysed by rhenium or a vanadium are not commercially feasible. WO 2006/040778 discloses the oxidation using hydrogen peroxide, tert-butyl hydroperoxide, cumene hydroperoxide. However the above reagents are not easy to handle on a bulk scale.
WO 2006/100243 discloses the use of oxidants such as per acetic acid and acetic acid in methylene chloride. However, the use of per acetic acid is not advisable on a bulk scale. WO 2007/068925 used 16.9% sodium hypochlorite solution (active chlorine assay) for oxidation, how ever the commercial availability of higher assay sodium hypochlorite is limited and this makes the process less attractive.
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It is evident from the teachings of the prior art that all the methods of synthesis of pantoprazole published to date, suffer from one or more shortcomings with regard to poor yields due to multiple crystallizations to get pure pantoprazole sodium.
Summary of the Invention
The present invention discloses the process for the preparation of 5-Difluoromethoxy-2-[(3, 4-dimethoxy-2-pyridinyl)-methyl sulfinyl]-lH-benzimidzole (Pantoprazole) having formula (I),

^N 0
y^ N
H3CO 0CH3 (i)
The compound of formula I is prepared by subjecting respective 2-(2-pyridylmethylthio) benzimidazole compound to oxidation with tert-butylhypochlorite solution in presence of an alkali in aqueous haloalkanes or ethyl acetate. The present invention has the advantage of simple reaction conditions, use of cheap and readily available reagents and solvents and efficient workup procedure that leads to isolation of high purity products (purity above 99%) The invention further provides an in-situ formation of sodium salt of pantoprazole. Final product of formula I isolated from the present invention is having almost negligible amount of sulfone impurity.

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Detailed Description of the Invention
The present invention relates to a process for the preparation of anti-ulcerative agent 5-Difluoromethoxy-2-[(3, 4-dimethoxy-2-pyridinyl)-methyl sulfinyl]-1 H-benzimidzole (pantoprazole) having general formula (I);

H3CO OCB3
(I)
The present invention provides a method for preparing compounds having formula I from 2-(2-pyridylmethylthio) benzimidazole compound of formula II;

H3CO Formula-II

OCH,

The oxidation of compound of formula II with ter/-butyl hypochlorite in aqueous alkaline condition yields to compound having formula I. This step involves making a suspension of cold mixture of compound having formula II in an aqueous organic solvent in basic medium. Suitable bases include, but not limited to sodium and potassium hydroxide. Suitable organic solvents include dichloromethane, dichloroethane, chloroform, carbon tetrachloride preferably dichloromethane, but are not limited to halo alkanes. To the resulting reaction mass, ter/-butyl hypochlorite is added at low temperature. The addition of oxidizing agent is performed at about -20°C to 20° C. The reaction mixture is stirred till the oxidation is completed. The reaction time is between about 30 minutes to 5 hours.
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After completion of the reaction, product is isolated by filtration of the reaction mass at lower temperatures.
The slow addition of tert-butyl hypochlorite at lower temperature gives a very clean reaction of sulfide oxidation with negligible formation of sulfone impurity. If peroxyacetic acid or m-chloroperoxybenzoic acid is used for oxidation the sulfone impurity formation is found to be 3 to 4% irrespective of temperature and other reaction conditions. To remove the sulfone impurity multiple crystallizations to be carried out, this results in the loss of yield of pantoprazole.
The present invention has the advantages of simple reaction conditions, use of cheap and readily available reagents and solvents and efficient work-up procedure that lead to isolation of high purity product (purity above 99.9%). The invention further provides a method for conversion of pantoprazole to pantoprazole sodium using a single solvent. The product is isolated by filtering the reaction slurry obtained by stirring at 20°C and washing the wet solid with ethyl acetate. The product obtained after dying is of high purity (about 99.9%) and having no single impurity more than 0.1% thus meeting the highest quality ICH norms.


N.
O

N PCH3
N^SH H3CON N
H

NaOH ^ MeOH F^F

V^
N=N
u
H3CO 0CH3

t-BuOCI, NaOH

N
O

N + Na

,N=>/
H3CO OCH3

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The following examples, which include preferred embodiments, will serve to illustrate the practice of this invention, it being understood that the particulars shown are by way of example and for purpose of illustrative discussion of preferred embodiments of the invention.
Examples
Example 1
5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]thio]]-lH-benzimidazole
10% NaOH solution (42.5 gm.in 425 ml.of water) is added drop wise to a solution of 5-(difluoromethoxy)-2-mercapto benzimidazole (100.0 g; 0.462 moles) in methanol(350.0 ml) at 10-15° C. To the above solution a clear solution of 2-chloro-3, 4-dimethoxy pyridine hydrochloride (105.5 gm.0.473 moles in 525 ml of methanol) was added at 10-15° C. The reaction mass was maintained at 10-15° C for 30 minutes. The temperature of the reaction mass was slowly raised to 20 C. The reaction mass was maintained at 20-25° C for 2 Hrs. Further the temperature was raised to 40° C and maintained at 40° C. Completion of the reaction is monitored by TLC. After completion of the reaction methanol is evaporated under reduced pressure to get a residue. Chilled water (600.0 ml) was added to the residue and the reaction mass was extracted with methylene chloride (600.0 ml, 300 ml X2). The organic layers were separated and evaporated under reduced pressure to obtain a residue. Isopropyl alcohol (50 ml) and hexane (600 ml) were added to the reaction mass. The reaction mass was cooled to 0-5° C and maintained at 0-5° C for 30 min. The reaction mass was filtered at 0-5° C and washed with chilled hexane (100 ml). The solids were dried under vacuum at 40 °C; Dry wt-162.0 gm (Yield=95.3%); HPLC Purity=99.21%; Melting range=115-117 °C (Lit.7mp-115-118°C); MS (ESI); 368.0(M+H)+.
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Example 2
5 -(diflouromethoxy)-2 [ [(3,4-dimethopyridinyl) methyl] sulphynyl] -1 H-benzimidazole sodium
Pantoprazole sodium.
Charge 5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl) methyl] thio]-lH-benzimidazole (36.7 g; 0.1 moles) and methylene chloride (367.0 ml) in a flask .Cool the reaction mass to 0-5°C. Add a clear solution of sodium hydroxide (6.0 g in 120.0 ml water) in the flask at 0-5°C. Add tert-butylhypochlorite solution in dichloromethane at 0-5°C. Maintain the reaction mass at 0-5°C for one hour. The completion of the reaction is monitored by TLC. After completion of the reaction, charge ammonium sulphate to the reaction mass at 5-10 °C. Stir the reaction mass for 15 minutes and separate the organic layer. Extract the aqueous layer with methylene chloride (100 mlX2).Distill out the organic layer completely under vacuum below 30°C to get a residue. To the residue acetone (100.0mlx2) was added and evaporated. Fresh acetone (150 ml) was added to the reaction mass and stirred the reaction mass to get a clear solution. Activated charcoal (1.0 gm) was added to the solution at 30-35°C and filtered through hyflow bed. The hyflow bed was washed with 50 ml acetone. The clear filtrate was cooled to 20 °C and sodium hydroxide solution (2.14 gm in 10.2 ml water) was added at 20-25°C. The reaction mass was maintained at 20-25 °C for 4.00 hrs and cooled to 0°C and further maintained at 0-5°Cfor 3 Hrs. Filtered the solids separated and washed the solids with chilled acetone(50 ml.) The solids were dried under vacuum at 40-45°C for 6 Hrs. to get 18.0 gm of Pantoprazole sodium (Yield=95.0%); HPLC purity= 99.65 %; Melting range- 142-145°C.
It will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative examples and that the present invention may be embodied in other specific forms without departing from the essential attributes thereof, and it is therefore desired that the present embodiments and examples be considered in all respects as illustrative and not restrictive, reference being made to the appended claims, rather than to the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.
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We claim,
1. A novel process for preparation of a compound having formula I,

H3CO OCH3
Formula -I by oxidizing a compound having formula II

H3CO OCBj
Formula-II with an oxidizing agent in an organic solvent or mixture of solvents.
2. The process as claimed in claim 1, wherein oxidizing agent is tert-butylhypochlorite in conjunction with an aqueous alkali.
3. The process as claimed in claim 2, wherein the alkali used is either sodium hydroxide or potassium hydroxide.
4. The process as claimed in claim 1, wherein oxidation step is carried out in an aqueous organic solvent.
5. The process as claimed in claim 3, wherein organic solvent is haloalkane preferably dichloromethane.
6. The process as claimed in claim 1, wherein pantoprazole sodium purity is 99.2% to 99.8%.
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Abstract

Disclosed herein the improved and industrially viable process for the preparation of pantoprazole sodium in high yields and purity.
Dated this 20th day of August, 2007


To
The Controller of Patents The patent Office, At Mumbai

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