WO2009066317A2

WO2009066317A2 - Process for the preparation of pantoprazole sodium

Info

Publication number: WO2009066317A2
Application number: PCT/IN2008/000521
Authority: WO
Inventors: Rajendra Murlidhar Agarwal; Shekhar Bhaskar Bhirud; Bijukumar Gopinathan Pillai; Gopal Dnyandev Khude; Vallu Venkateswara Rao
Original assignee: MACLEODS PHARMACEUTICALS Ltd
Current assignee: MACLEODS PHARMACEUTICALS Ltd
Priority date: 2007-08-20
Filing date: 2008-08-21
Publication date: 2009-05-28
Anticipated expiration: 2010-02-20
Also published as: WO2009066317A3

Abstract

Disclosed herein the improved and industrially viable process for the preparation of pantoprazole sodium in high yields and purity.

Description

PROCESS FOR THE PREPARATION OF PANTOPRAZOLE SODIUM

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-(difiouromethoxy)-2[[(3, 4- dimethopyridinyl) methyl] sulphinyl]-lH-benzimidazole sodium (I) is an irreversible proton pump inhibitor.

(D

Pantoprazole sodium was disclosed for the first time in European patent application EPO 166287. The process described in the said patent comprises the condensation of 2-chloromethyl-3, 4-dimethoxypyridinium hydrochloride with 5-difiuoromethoxy-2- mercaptobenzimidazole to get the sulfide intermediate which is oxidized with m- chloroperoxybenzoic acid in dichloromethane yielding pantoprazole. The main disadvantage of this process is the formation of sulphone impurity which is difficult to remove; rø-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 oxidants such as tert-buty\ 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 førr-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-buty\ hydroperoxide catalysed by rhenium or a vanadium are not commercially feasible. WO 2006/040778 discloses the oxidation using hydrogen peroxide, tert-bvΛyl 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.

Chinese patent publication no CN 1,381,443 describes a process for preparing thioether compounds, such as 5-methoxy-2-(3,5-dimethyl-4-methoxy-2- pyridylmethylthio)- 1 H-benzimidazole, 2- [3 -methyl-4~2-pyridylmethylthio] - 1 H- benzimidazole,5-difluoromethoxy-2-(3 ,4-dimethoxy-2-pyridylmethylthio)- 1 H- benzimidazole, 2- [4-(3 -methoxypropoxy)-3 -methyl-2-pyridylmethylthio] - 1 H- benzimidazole, or (diphenylmethyl) thioacetamide, by oxidizing sulfur group to sulfoxide by using oxidizing reagent (such as tertiary-butyl hydroperoxide, tertiary- butyl hypochlorite, sodium hypochlorite, hydrogen peroxide, perbenzoic acid, or 3- chloroperbenzoic acid) in nonprotic solvent ( such as dichloromethane, chloroform, carbon tetrachloride, acetone, ethyl acetate, etc) in the presence of catalyst (such as titanium tetraisopropoxide, bis(pentane-2,4-dionato)vanadium oxide, bis(pentane-2,4- dionato)copper(II), bis(pentane-2,4-dionato)cobalt(II), tris(pentane-2,4- dionato)iron(III), bis(pentane-2,4-dionato)manganese(II), or tris(pentane-2,4- dionato)chromium(III)).

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 and involves the use of expensive catalyst. Summary of the Invention '

The present invention discloses the process for the preparation of 5-Difluoromethoxy- 2-[(3, 4-dimethoxy-2-pyridinyl)-methyl sulfmyl]-lH-benzimidzole (Pantoprazole) having formula (I),

(I)

The compound of formula I is prepared by subjecting respective 2-(2- pyridylmethylthio) benzimidazole compound to oxidation with ter/-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%w/w.) 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.

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 sulfϊnyl] - 1 H- benzimidzole (pantoprazole) having general formula (I);

(I)

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

Formula-II

The oxidation of compound of formula II with tert-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, tert-butyl hypochlorite is added at low temperature. The addition of oxidizing agent is performed at about - 2O⁰C to 20°C. The reaction mixture is stirred till the oxidation is completed. The reaction time is between about 30 minutes to 5 hours. 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%w/w.). 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%w/w.) and having no single impurity more than 0.1%w/w. thus meeting the highest quality ICH norms.

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 gm; 0.462 moles) in methanol(350.0 ml) at 10-15⁰C. 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 10-15⁰C. The reaction mass was maintained at 10-15°C for 30 minutes. The temperature of the reaction mass was slowly raised to 2O⁰C. The reaction mass was maintained at 20-25° C for 2 hours. Further the temperature was raised to 40⁰C and maintained at 40⁰C. 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 ml) was added to the residue and the reaction mass was extracted with methylene chloride (600 ml, 300 ml x 2). 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 0-5⁰C and maintained at 0-5°C for 30 minutes. The reaction mass was filtered at 0-5°C and washed with chilled hexane (100 ml). The solids were dried under vacuum at 4O⁰C; Dry wt-162 gm (Yield=95.3%); HPLC Purity=99.21% w/w.; Melting range=l 15-117⁰C (Lit.⁷mp-H5-1 18°C); MS (ESI); 368.0(M+H) ⁺. Example 2:

5-(diflouromethoxy)-2[[(3, 4-dimethopyridinyl) methyl] suIphynyI]-lH- benzimidazole sodium

Pantoprazole sodium

Charge 5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-ρyridinyl) methyl] Mo]-IH- benzimidazole (36.7 gm; 0.1 moles) and methylene chloride (367 ml) in a flask. Cool the reaction mass to 0-5⁰C. Add a clear solution of sodium hydroxide (6.0 gm 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 5-1O⁰C. Stir the reaction mass for 15 minutes and separate the organic layer. Extract the aqueous layer with methylene chloride (100 ml x 2). Distill out the organic layer completely under vacuum below 3O⁰C to get a residue. To the residue acetone (100 ml x 2) 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- 35⁰C and filtered through hyflow bed. The hyflow bed was washed with 50 ml acetone. The clear filtrate was cooled to 2O⁰C and sodium hydroxide solution (2.14 gm in 10.2 ml water) was added at 20-25⁰C. The reaction mass was maintained at 20- 25°C for 4.00 hours and cooled to 0⁰C and further maintained at 0-5⁰C for 3 hours. Filtered the solids separated and washed the solids with chilled acetone (50 ml.) The solids were dried under vacuum at 40-45⁰C for 6 hours, to get 18.0 gm of Pantoprazole sodium (Yield=95.0%); HPLC purity= 99.65 % w/w.; 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.

Claims

WE CLAIM:

1. A process for preparation of a pantoprazole sodium compound having formula I,

Formula -I

by oxidizing a compound having formula II

Formula-II

with tert-butylhypochlorite oxidizing agent in the absence of a catalyst.

2. The process as claimed in claim 1, wherein tert-butylhypochlorite oxidizing agent is used 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 the catalyst is selected from the group consisting of titanium tetraisopropoxide, bis(pentane-2,4-dionato)vanadium oxide, bis(pentane-2,4-dionato)copper(II), bis(pentane-2,4-dionato)cobalt(II), tris(pentane- 2,4-dionato)iron(III), bis(pentane-2,4-dionato)manganese(II), or tris(pentane-2,4- dionato)chromium(III)) .

5. The process as claimed in claim 1, wherein oxidation step is carried out in an aqueous organic solvent.

6. The process as claimed in claim 5, wherein organic solvent is selected from the group comprising of dichloromethane, dichloroethane, chloroform or carbon tetrachloride.

7. The process as claimed in claim 1 , wherein oxidation step is carried out at -2O⁰C to 2O⁰C for 30 minutes to 5 hours.

8. The process as claimed in claim 1, wherein pantoprazole sodium is isolated by filtering the reaction slurry obtained by stirring at 20⁰C and washing the wet solid with ethyl acetate.

9. The process as claimed in claim 1, wherein pantoprazole sodium obtained having no single impurity more than 0.1% w/w.

10. The process as claimed in claim 1, wherein pantoprazole sodium obtained having purity is 99.2% w/w to 99.8% w/w.