Title of Invention

A NOVEL ONE-POT PROCESS FOR PREPARATION OF PANTOPRAZOLE SODIUM

Abstract

ABSTRACT A novel one-pot process for the pfeparation of pantoprazole sodium by reacting 2-chloro methyl 3, 4 -dimethoxy pyridine hydrochloride with 2-mercapto-5-difluoromethoxy benzknidazole in an organic solvent system in presence of a phase transfer catalyst and further treating with aqueous sodium hypohalite solution comprising sodium hydroxide to obtain pantoprazole sodium in high yield and purity. The process for conversion of pantoprazole sodium to pantoprazole sesquihydrate and also pantoprazole sodium mono hydrate are also disclosed herein.

Full Text

FORM 2 THE PATENTS ACT, 1970 (39 of 1970) COMPLETE SPECIFICATION [See section 10; rule 13] "A novel one-pot process for preparation of pantoprazole sodium" (a) CIPLA LTD. (b) 289, Bellasis Road, Mumbai Central, Mumbai - 400 008, Maharashtra, India (c) Indian Company incorporated under the Companies Act 1956 The following specification describes the nature of this invention and the manner in which it is to be performed: Granted 17-7-2006 17 JUL 2006 Technical Field of the Invention The present invention relates to a novel one-pot process for the preparation of pantoprazole sodium in high yields and purity. The present invention further relates to process for conversion of pantoprazole sodium to pantoprazole sodium sesquihydrate and also to pantoprazole sodium monohydrate in good yields. Background and Prior art Pantoprazole an international non-proprietary name of a substituted benzimidazole (5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole) is a compound that inhibits gastric acid secretion. Pantoprazole sodium is a proton pump inhibitor (PPI) used to treat ulcers, gastroesophageal reflux disorder (GERD), erosive esophagitis and Zollinger-Ellison syndrome. It works by blocking acid production in the stomach. It may be used in combination with antibiotics (e.g., amoxicillin, clarithromycin) to treat certain types of ulcers. Pantoprazole was disclosed for the first time in European patent application EPO166287. The complete pharmacological and therapeutic effect for Pantoprazole can be achieved in the acid secreting parietal cells. By means of a feed back mechanism, this effect is diminished at the same rate as acid secretion is inhibited. As with other proton pump inhibitors and H2 Receptor inhibitors, treatment with Pantoprazole causes reduced acidity in the stomach causing a reversible increase in gastrin in proportion to the reduction in acidity. Pantoprazole sodium can be represented by the following structural formula. In one of the processes, described in this patent application that the reaction of 2-Chloromethyl-3,4-dimethoxy pyridine with 2-mercapto-5-difluoromethoxy benzimidazole to prepare the precursor sulfide, which was isolated and oxidized by using metachloroperbenzoic acid to yield pantoprazole base in a yield of 102% by weight with respect to 2-Chloromethyl-3,4 dimethoxy pyridine. PCT Application WO 97/29103 discloses the preparation of Pantoprazole by coupling carbonyl fragments to form the sulfoxide precursor which was further cyclised to obtain pantoprazole base. PCT Application WO 02/28852 discloses synthesis of pantoprazole and the preparation of key intermediates useful in its synthesis. Pantoprazole base was prepared by oxidation of the chloro derivative of pantoprazole using ammonium per molybdate or ammonium per tungstate in the presence of hydrogen peroxide. Further the chloro group in the resulting product was replaced by methoxy group to obtain pantoprazole base, the yield being about 70 % by weight of the pyridine precursor. PCT Application WO 02/062786 discloses a process for preparation of pantoprazole base by oxidizing the precursor of pantoprazole (i.e. sulfide) using tertiary butyl hydroperoxide and oxone in yield of about 79% weight percent of the sulfide intermediate. WO 91/19710 discloses Pantoprazole sodium sesquihydrate and their typical characteristics. US Patent 04/0186139A1 describes the preparation of Crystalline Form-I of Pantoprazole sodium sesquihydrate from pantoprazole free base by precipitation using various solvents. It is evident from the teachings of the prior art that multiple steps are required for the synthesis of pantoprazole sodium, also the intermediates involved for the synthesis are needed to be isolated at various steps and further purification is required to get the desired purity of the final product Since these methods involve many steps which results in a lower yield of pantoprazole sodium. The prior art methods described above also involves the use of many hazardous reagents like hydrogen peroxide, metachloroperbenzoic acid, etc. thus the processes from the prior art are unable to provide an environmentally safe and industrially applicable process with "substantial yields. Solution of these problems associated with prior art, becomes the objects of the present invention. Hence, the pressent invention provides industrially viable and economically feasible process thereby eliminating the all the above-mentioned shortcomings. Object of the invention The object of the present invention is to provide a novel one pot process for the synthesis of Pantoprazole sodium without the isolation and purification of the intermediates involved in the process. Another object of the present invention is to provide a process, which involves the use of a phase transfer catalyst. Further object of the present invention is to provide a process, which avoids the use of hazardous reagents. Yet another object of the present invention is to provide a industrially viable process for synthesis of pantoprazole sodium in a high yield and good purity and overcoming all the shortcomings as described in the prior art. Another object of the present invention is to provide a process for conversion of pantoprazole sodium to pantoprazole sesquihydrate. Yet another object of the present invention is to provide a process for conversion of pantoprazole sodium to pantopprazole monohydrate. Summary of the Invention The present invention discloses a novel one-pot process for the synthesis of pantoprazole sodium by reacting 2-chloro methyl 3, 4 -dimethoxy pyridine hydrochloride with 2-mercapto-5-difiuoromethoxy benzimidazole in an organic solvent system in presence of a phase transfer catalyst and further treating with aqueous sodium hypohalite solution to obtain pantoprazole sodiam in high yield and purity. The present invention further discloses a process for conversion of pantoprazole sodium to pantoprazole sodium sesquihydrate and also the conversion to pantoprazole sodium monohydrate. Detailed Description of the Invention The present invention relates to a novel one pot process for the synthesis of Pantoprazole sodium of Formula (I). (I) The present invention provides a one pot process for the preparation of pantprazole sodium wherein 2-chloromethyl-3,4-dimethoxypyridine hydrochloride (III) was reacted with 2-mercapto-5-difluoromethoxy benzimidazole (IV) in an organic solvent system and water containing an inorganic base, in presence of a phase transfer catalyst at a temperature ranging from 0°15 to the reflux temperature of the solvent used, preferably at a temperature range of 25-306C. Compound of the formula (III) was used directly as starting material or optionally synthesized by reacting 2-hydroxymethyl 3,4-dimethoxy pyridine (II) with a chlorinating agent preferably thionyl chloride at a temperature ranging from -5°C to ambient temperature preferably 0 to 5 °C. Water was added to the reaction mass and this reaction mass was used as such without isolation of the compound of formula (III) for the one-pot reaction. In another aspect, the present invention provides the use of phase transfer catalyst, which is advantageous as it helps in the progress of the reaction, which involves biphasic medium. The phase transfer catalyst was selected from a group consisting of tetrabutyl ammonium bromide, tetrabutyl ammonium chloride, benzyltriethyl ammonium chloride, methyltrioctyl ammonium chloride, hexadecyltrimethyl ammonium chloride and crown ethers preferably tetrabutyl ammonium bromide. The solvent system used in the process of present invention comprises water immiscible organic solvent and water containing an inorganic base. The water immiscible organic solvent is an aliphatic chlorinated hydrocarbon, selected from the group consisting of methylene dichloride, carbon tetrachloride, cyclohexane, chloroform and dichloroethane. The preferable solvent is methylene dichloride. The inorganic base employed in the present invention being alkaline metal hydroxides or carbonates more preferably sodium hydroxide. The process of the present invention was carried out in one pot without the isolation of any intermediates as illustrated in Scheme below. The intermediates (V) pantoprazole sulfide and pantoprazole base as shown in the scheme were not isolated during the process of the present invention were neither subjected to any purification. Further, the pantoprazole sulfide obtained in situ was oxidized using aqueous sodium hypohalite solution preferably aqueous solution of sodium hypochlorite with a strength in range of 2- 14 %, and having sodium hydroxide content 0.5 to 10 % preferably 1.0 to 3.0 % more preferably 2.0 to 2.3 %, at a temperature ranging from 0°C to ambient temperature, more preferably 5-8°C. The resulting reaction mass was cooled to afford pantoprazole sodium. Pharmaceutical preparations comprising pantoparazole sodium synthesized by above said method are prepared by conventional methods. Pantoprazole sodium as obtained by the process of the present invention was optionally further converted to pantoprazole sodium sesquihydrate by dissolving it in acetone and replacing the solvent by ethyl acetate followed by co-distilling with ethyl acetate and isolating the sesquihydrate from ethyl acetate - water mixture, this mixture contains water in a quantity sufficient enough to form the sesquihydrate Pantoprazole sodium as obtained by the process of the present invention was optionally converted to pantoprazole sodium monohydrate by stirring in ethyl acetate. Pantoprazole sodium obtained by the process of the present invention has a very high level of purity and the known impurities like sulfone, sulfone N- oxide, and sulfide were below 0.15% and individual unknown impurities were less than 0.1%. The following specific examples presented to illustrate the best mode of carrying out the process of the present invention. The examples are not limited to the particular embodiments illustrated herein but include the permutations, which are obvious set forth in the description. Examples Example-1 Preparation, of 5-(difluoromethoxy)-2[[(3?4-dimethoxy-2-pyridinyl) methyl]sulfinyl}-lH benzimidazole sodium 2-Chloromethyl-3,4-dimethoxy pyridine hydrochloride (50 gms), 2-mercapto-5-difiuoromethoxy benzimidazole (50 gms) and Tetra butyl ammonium bromide (2 gms) was added under stirring to dichloromethane (300 m ) followed by solution of sodium hydroxide ( 37.5 gms ) in 120 ml water. The contents were then stirred at 25 - 30° C for about 12 hours. After reaction completion, dichloromethane layer was separated; the aqueous layer was extracted with dichloromethanV(6( ml) twice. The organic layer was pooled together distilled to about 250ml and cooled to 0°C. 3.5% aqueous sodium hypochlorite solution (464 g) having a sodhun hydroxide content of 2.2% was added to the reaction mass, which was maintained at 5 - 8°C for about 6 hours. After completion of the reaction; the reaction mass was further cooled to 0 to 5°C. The resulting solid was then filtered and washed with cold acetone (about 100ml) and dried under vacuum at 35-40°C to give pantoprazole sodium (75 gms) Example-2 Preparation of 5-(difluoromethoxy)-2[[(3,4-dimethoxjr-2-pyridinyl) methyl]sulfmyl]-lH benzimidazole sodium 2-hydroxymethyl-3,4-dimethoxy pyridine hydrochbride (45.8 g) was taken in dichloromethane (300 ml). Thionyl chloride (30.3 gms.) was added at about 0 to 5°C and reaction mass was further stirred at 10 - 15°C for ; hour. After reaction completion, purified water (100 ml) was added maintaining the reaction temperature between 15 - 20° C. To this reaction mass, 2-mefcapto 5-difluoromethoxy benzimidazole (50 gms) and tetra butyl ammonium bromide (2 gms) were added. Fhe contents were cooled to 10° C and pH of the reaction mass was adjusted to 10 - 11 using aqueous sodium hydroxide solution (30% solution) and the contents were stirred at 25 - 30° C for 12 hours After completion of reaction, dichloromethane layer was separated and the aqueous layer was extracted with dichloromethane (60 ml) twice. The combined organic layer was washed with purified water (150 ml) twice. The dichloromethane layer was then cooled to 0° C, 3.5% aqueous sodium hypochlorite solution (464 g ) having sodium hydroxide content of 2.1% was added to the reaction mass, and maintained at 5 - 8° C for about 6 hours. After the completion of reaction, the reaction mass was cooled to 0 to 5° C and the resulting solid was filtered and washed with cold acetone (about 100ml) and dried under vacuum at 35-40°C to give pantoprazole sodium (72 gms) Example-3 Preparation of pantoprazole sesquihydrate Pantoprazole sodium (75 gms) as prepared according to Example-1 or Example-2 was dissolved in 375 ml of acetone at about 50 - 55° C, charcoal (5 gms) was added and reaction mass was stir ed for 15 minutes and clarified hot. The resulting clear filtrate was concentrated to approx. volume of 150 ml, ethyl acetate (400 ml) was added and distillation was continued till precipitation was observed in the reaction mass. The reaction mass was cooled to room temperature and water (4.2 ml) was added, the suspension was stirred for 1 hr. and later chilled and stirred at 0-5°C for 1 hr. The product was the isolated by filtration and was dried at 40 - 45° C under vacuum to give pantoprazole sodium sesquihydrate (68 gms.) having moisture content 6.5 %. Example-4 Preparation of pantoprazole monohydrate Pantoprazole sodium (75 gms) as prepared according to Example-1 or Example-2 was dissolved in 375 ml of acetone at about 50 - 55°C, charcoal (5 gms) was added and reaction mass was stirred for 15 minutes and filtered hot. The resulting clear filtrate was concentrated to approx. volume of 150 ml and ethyl acetate (400 ml) was added, distillation was continued till precipitation was observed in the reaction mass. The reaction mass was cooled to room temperature and the suspension was stirred for 1 hr. and later chilled and stirred at 0-5°C for 1 hr. The product was isolated by filtration and dried at 40 - 45° C under vacuum to give pantoprazole sodium monohydrate (64 gms.) having moisture content 4.5%. Example- 5 Preparation of pantoprazole sesquihydrate Pantoprazole sodium (75 gms) as prepared according to Example-1 or Example-2 was dissolved in 375 ml of acetone at about 50 - 55° C, and reaction mass was stirred for 15 minutes and filtered hot. The resulting clear filtrate was cooled to about 25-30°C and 375ml of diisopropyl ether was added under stirring the resulting product was filtered and dried at 35-40°C to give pantoprazole sodium (72 gms ). The dried product was stirred in mixture of 216ml ethylacetate and 3.6ml purified water fori hr., further the slurry was chilled and stirred at 0-5°C for about 1 hr. The product was filtered and dried at 40 - 45° C under vacuum to give pantoprazole sodium sesquihydrate (68 gms.) having moisture content 6.5 %. Example- 6 Preparation of pantoprazole monohydrate Pantoprazole sodium (75 gms) as prepared according to Example-1 or Example-2 was dissolved in 375 ml of acetone at about 50 - 55° C, and reaction mass was stirred for 15 minutes and filtered hot. The resulting clear filtrate was cooled to about 25-30°C and 375ml of diisopropyl ether was added the resulting solid was filtered and dried under vacuum at 35-40°C to give pantoprazole sodium (72 gms ). The dried product was stirred in 216ml ethylacetate fori hr. and further chilled and stirred at 0-5°C for 1 hr. The product was isolated by filtration and dried at 40 - 45° C under vacuum to give pantoprazole sodium monohydrate (68 gms.) having moisture content 4.5 %. We claim, 1. A novel one-pot process for preparation of pantoprazole sodium, wherein said process comprises the steps of a) reacting 2-chloromethyl 3, 4 dimethoxy pyridine hydrochloride with 2-mercapto-5-difluoromethoxy benzimidazole in a water immiscible organic solvent and aqueous sodium hydroxide solution in presence of a phase transfer catalyst to obtain pantoprazole sulphide; and b) treating the said pantoprazole sulphide in the organic phase with an aqueous sodium hypohalite solution containing sodium hydroxide to yield pantoprazole sodium. 2. The process as claimed in claims 1, wherein said organic solvent is aliphatic chlorinated hydrocarbon. 3. The process as claimed in claims 1 or 2, wherein said water immiscible organic solvent is selected from the group consisting of methylene dichloride, carbon tetrachloride, cyclohexane, chloroform, dichloroethane. 4. The process as claimed in any of the preceding claims wherein said phase transfer catalyst used is selected from a group consisting of tetrabutylammonium bromide, tetrabutylammonium chloride, benzyltriethylammonium chloride, methyltrioctylammonium chloride, hexadecyltrimethylammonium chloride and crown ethers. 5. The process as claimed in any of the preceding claims wherein the concentration of said aqueous sodium hyophalite is used in strength of 2 to 14%. 6. The process as claimed in any of the preceding claims, wherein the content of said sodium hydroxide in aqueous solution of sodium hypochlorite is at least 2.0 %. 7. A process for converting pantoprazole sodium to pantoprazole sodium sesquihydrate, wherein said process comprises the steps of; a) dissolving pantoprazole sodium in acetone; b) co-distilling with ethyl acetate till precipitation occurs; c) cooling the suspension to room temp; d) adding water in a quantity sufficient enough to form the sesquihydrate; e) stirring at room temp; f) chilling the reaction mixture; and g) isolating pantoprazole sodium sesquihydrate by filtration and drying. 8. A process for converting pantoprazole sodium to pantoprazole sodium monohydrate which comprises the steps of; a) dissolving pantoprazole sodium in acetone; b) co-distilling with ethyl acetate till precipitation occurs; c) cooling the suspension to room temp; d) chilling the reaction mass; and e) isolating pantoprazole sodium monohydrate by filtration and drying. 9. A process for preparation pantoprazole sodium, patoprazole sodium sesquihydrate and pantoprazole sodium monohydrate as substantially described herein with reference to the foregoing examples 1 to 6. Dated this 17 day of July 2006

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1350-mum-2004-abstract(17-07-2006).doc

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1350-mum-2004-cancelled pages(17-07-2006).pdf

1350-mum-2004-claims(granted)-(17-07-2006).doc

1350-mum-2004-claims(granted)-(17-07-2006).pdf

1350-mum-2004-correspondence(17-07-2006).pdf

1350-mum-2004-correspondence(ipo)-(09-01-2006).pdf

1350-mum-2004-form 1(16-12-2004).pdf

1350-mum-2004-form 1(17-07-2006).pdf

1350-mum-2004-form 18(26-08-2005).pdf

1350-mum-2004-form 2(granted)-(17-07-2006).doc

1350-mum-2004-form 2(granted)-(17-07-2006).pdf

1350-mum-2004-form 26(05-04-2003).pdf

1350-mum-2004-form 3(16-12-2004).pdf

1350-mum-2004-form 3(17-07-2006).pdf

1350-mum-2004-form 9(16-05-2005).pdf