Title of Invention

PROCESS FOR THE SYNTHESIS OF SULPHINYL DERIVATIVES FROM CORRESPONDING CO-DERIVATIVES

Abstract

An improved process for synthesis of substituted 2-(2-pyridylmethyl) sulphinyl-1-H- benzimidazoles compounds of formula (I) Wherein R1 R2, R3 and R4 represent e)R1= CH3, R2= OCH3, R3= CH3, R4= OCH3) or f)R1= CH3 R2= OCH2CF3, R3= H, R4= H) or g)R1= OCH3, R2= OCH3, R3= H, R4= OCHF2) or h)R1= CH3, R2= OCH2CH2CH2OCH2, R3= H, R4= H). and pharmaceutically acceptable salts thereof, comprising the steps of oxidizing the sulphide compound of Formula II. wherein R1, R2, R3 and R4 represent e)R1= CH3, R2= OCH3, R3= CH3, R4= OCH3) or f)R1= CH3, R2= OCH2CF3, R3= H, R4= H) or g)R1= OCH3, R2= OCH3, R3= H, R4= OCHF2) or h)R1= CH3, R2= OCH2CH2CH2OCH2, R3= H, R4= H) with hypochlorite in the presence of phase transfer catalyst in liquid diluent.

Full Text

COMPLETE AFTER PROVISIONAL 2 9 JUN 2005 FORM2 THE PATENTS ACT, 1970 (39 of 1970) & The Patents Rules, 2003 COMPLETE SPECIFICATION (See section 10; rule 13) Title of the invention. PROCESS FOR THE SYNTHESIS OF SULPHINYL DERIVATIVES FROM CORRESPONDING CO-DERIVATIVES 2. Applicant(s) (a) Dishman Pharmaceuticals & Chemicals Ltd, (b) Bhadr-Raj Chambers, Swastik Cross Roads, Navrangpura, Ahmedabad - 380 009, State of Gujarat, India, (c) an Indian Company 3. PREAMBLE TO THE DESCRIPTION The following specification particularly describes the invention and the manner in which it is to be performed: 2 9 JUN 2005 FIELD OF INVENTION The present invention relates to an improved process for the preparation of substituted 2-(2-pyridylmethyl) sulphinyl-1-H-benzimidazoles compounds of formula (I) and pharmaceutically acceptable salts thereof from the corresponding substituted 2-(2-pyridylmethylthio)-1-H-benzimidazole compounds of formula (II) in high purity. BACKGROUND OF THE INVENTION Several proton-pump inhibitors, which are useful in the treatment of duodenal ulcers, of formula (I) are known. These include omeprazole (R1= CH3, R2= OCH3, R3= CH3, R4=OCH3) which is described in EP0005129, lansoprazole (Ri= CH3, R2= OCH2CF3, R3= H, R4= H) which is described in EP174,726, pantoprazole (Ri= OCH3, R2= OCH3, R3= H, R4= OCHF2) which is described in EP166.287 and rabeprazole (R1= CH3, R2= OCH2CH2CH2OCH2, R3= H, R4= H) which is described in US 5,045,552. Many methods for preparing such compounds by the oxidation of the corresponding substituted 2-(2-pyridylmethylthio)-1-H-benzimidazole have been described in patent specifications. Examples of the oxidizing agents used are 3-chloroperoxybenzoic acid, MCPBA (WO 91/18895, EP 533752, US 5,386,032, ES 043816 and EP 484265), magnesium monoperoxyphthalate-MMPP (EP 533264 and US 5,391,752), ammonium molybdate (EP 484,265), iodosobenzene (ES539793), methyl iodosobenzene (ES 540147) sodium periodate (ES 550070) and vanadium oxide (EP 302720) US4758579 discloses use of sodium hypochlorite in dioxane as an oxidizing agent, which affords poor yield. As per the current ICH guidelines dioxane is classified as class- II solvent and maximum possible limit in API is 380 ppm, which cannot be obtained, in temperature sensitive drugs like pantoprazole and rabeprazole at commercial scale. The prior art methods suffer from the following shortcomings: • Most of these oxidizing agents are hazardous, explosive and cannot be operated at large scale. • One of the major disadvantages in using the aforesaid oxidizing agents is side product formation (eg: Sulphone, N-oxide, Sulphone, N-oxide) especially with reagents like Hydrogen peroxide, MCPBA, and MMPP. One of the major impurities, commonly formed by the use of the stated oxidizing agents, is the sulphone impurity, which cannot be easily separated from the end product. • Difficult purification techniques for isolating the end product, which are difficult to carry out at commercial scale particularly for removing sulphone impurity. • Very low temperature requirements (with agent like MCPBA) below- 50°C are very difficult to achieve at commercial scale. • Lower yields in processes using MMPP and Hydrogen peroxide. • Non-reproducibility in terms of yield and purity. • Lower stability due to residual impurity of the reagent (MMPP, NCS and MCPBA) • In most of the processes product remains as base which is very sensitive towards mild acidic condition. There thus remains a need for a cheap and efficient process for oxidizing 2-(2-pyriylmethylthio)-1H-benzimiazoles that is reliable, produces waste streams which are easily disposed of without causing harm to the environment and produces a stable final product of high yield and purity. OBJECTS OF THE INVENTION An object of the invention is to provide an improved process for synthesis of substituted 2-(2-pyridylmethyl) sulphinyl-1-H-benzimidazoles compounds of formula (I) and pharmaceutically acceptable salts thereof from the corresponding substituted 2-(2-pyridylmethylthio)-1-H-benzimidazole compounds of formula (II) in high purity, with negligible sulphone impurity. Another object of the invention is to provide an improved process for synthesis of substituted 2-(2-pyridylmethyl) sulphinyl-1-H-benzimidazoles compounds of formula (f) and pharmaceuticaffy acceptable safts thereof by oxidizing the corresponding substituted 2-(2-pyridylmethylthio)-1-H-benzimidazole compounds of formula (II) using the non-hazardous hypochlorites in presence of phase transfer catalyst thus overcoming the shortcomings of prior art methods. Yet another object of the invention is to provide an improved process for synthesis of substituted 2-(2-pyridylmethyl) sulphinyl-1-H-benzimidazoles compounds of formula (I) and pharmaceutically acceptable salts thereof, using environmentally friendly diluents and cheap yet effective raw materials giving compound (I) of high purity and thereby making the process cost-effective and eco-friendly and easily adapted to commercial scale. Yet another object of the invention is to provide an improved process for synthesis of substituted 2-(2-pyridylmethyl) sulphinyl-1-H-benzimidazoles compounds of formula (I) and pharmaceutically acceptable salts thereof which have high stability and are obtained in high yields. Yet another object of the invention is to provide an improved process for synthesis of substituted 2-(2-pyridylmethyl) sulphinyl-1-H-benzimidazoles compounds of formula (I) and pharmaceutically acceptable salts thereof by oxidizing the corresponding substituted 2-(2-pyridylmethylthio)-1-H-benzimidazole compounds of formula (II) wherein isolated or commercially available compounds of formula (II) may be obtained or compounds of formula (II) may be formed and concurrently oxidized without isolation. SUMMARY OF INVENTION Thus according to an aspect of the present invention there is provided a process for the preparation of a compound of formula I, wherein R1, R2, R3 and R4 represent a) (R1= CH3, R2= OCH3, R3= CH3, R4= OCH3) or b) (R1= CH3> R2= OCH2CF3, R3= H, R4= H) or c) (R1 OCH3, R2= OCH3, R3= H, R4= OCHF2) or d) (R1= CH3, R2= OCH2CH2CH2OCH2, R3= H, R4= H) and pharmaceutically acceptable salts thereof, comprising the steps of reacting a compound of formula II (ID wherein R1 R2> R3 and R4 represent a) (R1= CH3, R2= OCH3, R3= CH3, R4= OCH3) or b) (R1= CH3, R2= OCH2CF3, R3= H, R4= H) or c) (R1= OCH3, R2= OCH3, R3= H, R4= OCHF2) or d) (R1= CH3, R2= OCH2CH2CH2OCH2, R3= H, R4= H) with hypochlorite in presence of a phase transfer catalyst in a liquid diluent. in which R4 is as previously defined; with a compound of formula IV, or a salt thereof In another aspect of the present invention, there is provided a single-step process for the preparation of a compound of formula I, comprising steps of: -reacting a compound of formula III, or a salt thereof in which R1,R2, and R3 are as previously defined, in a second liquid diluent at a pH in the range of 10 to 13 at a temperature in the range of 0°C to the boiling point of the second liquid diluent employed, to give compound of formula II; further oxidizing the compound of formula II, with a hypochlorite in presence of phase transfer catalyst, to give compound of formula I or pharmaceutically acceptable salts thereof. The compound of formula II is prepared as a part of the process of the present invention and is concurrently used for oxidation without isolation. DETAILED DESCRIPTION: The present inventors have surprisingly found that substituted 2-(2-pyridylmethyl) sulphinyl-1-H-benzimidazoles compounds of formula (I) and pharmaceutically acceptable salts thereof can be synthesized by oxidizing the corresponding substituted 2-(2-pyridylmethylthio)-1-H-benzimidazole compounds of formula (II) using the non-hazardous hypochlorites in presence of phase transfer catalyst in a liquid diluent at a pH in the range 9.5 to 13 and temperature in the range of 0°C to boiling point of the liquid diluent employed. A phase transfer catalyst, when used with sodium hypochlorite forms a complex, which is then transported into organic phase from aqueous phase. In this process, oxidant and oxidizing molecule are in the same phase, which accelerates the oxidation reaction, and making the reaction neat and clean. In the presence of phase transfer catalyst minimum sodium hypochlorite is used which helps to reduce the pollution load in environment, reaction time and impurity profile in the APIs, thereby producing a stable final product in high yield and purity. The compound of formula II may be obtained from commercial sources. Hypochlorites: The hypochlorite is in aqueous basic media. Suitably the hypochlorite is a metallic hypochlorite preferably potassium or sodium hypochlorite. More preferably the hypochlorite is sodium hypochlorite. Suitably the amount of hypochlorite employed in the process is in the range of 0.8 to 2.0 moles per mole, preferably in the range 0.95-1.5 moles per mole, of the compound of formula II employed in the process. More preferably the amount of hypochlorite employed is in the range 0.95-1.1 moles of the compound of formula II. Most preferably the amount of sodium hypochlorite employed is in the range 0.95-0.98 moles per mole of the compound of formula II employed in the process. Phase transfer catalyst (PTC): PTC plays a crucial role in the present invention. The present inventors have surprisingly found that when the oxidation of compounds of formula (I) is carried out in presence of a phase transfer catalyst in the set conditions, it leads to the formation of high purity, high yield and highly stable sulfoxide with purity greater than 99% as opposed to prior art sulfoxide compounds of formula (I) having purity 97% and yield 54%. The present process thus offers a viable process for synthesis of compounds of formula (I) by eliminating the possibility of the highly undesirable sulphone impurity. Employing PTC is thus advantageous as to control the impurity stream & thereby enhancing the purity & yield. PTC acts as a media to transfer the hypochlorite to the organic phase from aqueous phase in controlled fashion which prompts spontaneous reaction and thereby controls the impurity stream. The use of PTC leads to a biphasic reaction medium. The sulfoxide once formed is carried/transported from the organic to the aqueous phase where it is quite stable and as sulfide cant form sodium salt under these condition it can be eliminated easily by extracting the aq.phase with Methylene dichloride thereby we can eliminate the purification step to remove the sulfide. PTC advantages: - 1. Solvent like Methylene dichloride, which is non hazardous and inexpensive can be employed which is advantageous at the plant scale operation. 2. Even though such a mild oxidizing agent like Sodium hypochlorite is employed the reaction is clean and complete which is possible only due to PTC. 3. Since the sulfoxide is completely going into the aqueous layer, sulphide impurity can be easily removed by separating out the aqueous layer there by purification process can be avoided which is very advantageous at the plant scale as solvent used for the crystallization can be saved and the loss of the compound can be avoided. Mostly quaternary ammonium salts like Tetra alkyl (C2-C8) ammonium halide salts and benzyl trialkyl (C2-C8) ammonium halide salts may act as phase transfer catalyst. For the purpose of the invention PTC is 1.0 to 5.0%. Liquid Diluents: The purpose of the liquid diluent is to allow contact between the compound of formula II and the hypochlorite at the required temperature. Any liquid diluent, which is inert to the reactants in which this purpose is achieved, is suitable for the purpose of the invention. Environmentally friendly liquid diluents may also be used for the purpose of the present invention. Preferably the liquid diluent is selected from water, C1-4 alcohols, acetonitrile, methylene dichloride, C2-6 diols and mixtures thereof. More preferably the liquid diluent is a water/ methylene dichloride mixture or a water/ acetonitrile mixture in the ratio of about 1:1.5.The liquid diluent is added from 5 to 10 volumes of sulfide. Preferably the process is carried out a pH in the range of 8.5 to 13 more preferably in the range of 10 to 13, most preferably in the range of 10 to 12. Suitably the pH of the process is controlled by the addition of a base for example an alkali metal hydroxide an alkali metal carbonate, an alkali metal bicarbonate or an amine e.g. ammonia or an organic amine or mixtures thereof. Preferably the base is sodium hydroxide. It will be appreciated by those skilled in the art that when the reaction is carried out at high pH a salt of the desired product may be obtained. Lowering the pH of the reaction mixture, for example by addition of an acid or preferably of a less basic base, allows the isolation of the compound of formula I as the free heterocycle. Preferably the process is carried out at a temperature in the range of 0 to 40°C and more preferably in the range of 0 to 25°C. Most preferably the process is carried out at a temperature in the range of 10°C to 25°C, particularly at a temperature in the range of 10°C to 20°C. The process of the present invention can be carried out as a two-step reaction comprising formation of compound of formula II in first step, isolating the said compound of formula II and oxidation of the compound of formula II to give compound of formula I in the second step. Alternatively, the process of the present invention can be carried out as a one-step reaction, comprising formation of compound of formula II and oxidation of the compound of formula II to give compound of formula I in the same step. Preferably, the compound of formula I is prepared by a single-step process comprising steps of: in which R4 is as previously defined; with a compound of formula IV, or a salt thereof -reacting a compound of formula III, or a salt thereof in which R1,R2, and R3 are as previously defined, in a second liquid diluent at a pH in the range of 10 to 13 at a temperature in the range of 0°C to the boiling point of the second liquid diluent employed, to give compound of formula II; further oxidizing the compound of formula II, with a hypochlorite in presence of phase transfer catalyst, to give compound of formula I or pharmaceutically acceptable salts thereof. The compound of formula II is prepared as a part of the process of the present invention and is concurrently used for oxidation without isolation. The purpose of the second liquid diluent is to allow contact between the compound of formula III and the compound of formula IV. The reaction is carried out at temperature in the range of 10°C -50°C, preferably at a temperature in the range of 15°C - 25°C and more preferably at a temperature in the range of 20°C - 30 °C. Preferably the second liquid diluent is selected from water, methylene dichloride, acetone, ethyl acetate or mixtures thereof. More preferably the second liquid diluent is a water/ acetonitrile mixture, a water/ methylene dichloride. Especially preferred second liquid diluent is methylene dichloride. This avoids further mixing of the solvent for the extraction of the compound. The desired compound of formula (I) can be isolated from the reaction mixture by solvent extraction and direct crystallization can be achieved in aqueous media by using acid such as glacial acetic acid along with acetone or ethyl acetate. Alternatively the compound of formula I is isolated as the free solid in aqueous by using acid such as glacial acetic acid along with acetone or ethyl acetate. In the process of the present invention impurity formation is minimized and no further purification is required as direct crystallization leads to higher yield and purity. Purification if required, can be carried out by conventional means e.g. extraction and recrystallisation or filtration followed optionally by recrystallisation. The purification solvent used can be selected from hydrocarbon or ether (mainly acetone and ethyl acetate). II (a) (R,= CH3, R2= OCH3, R3= CH3, R4= OCH3) The process can be employed for the synthesis of proton-pump inhibitors of formula (I), which are useful in the treatment of duodenal ulcers, including omeprazole, lansoprazole, pantoprazole, rabeprazole and similar molecules. In a preferred process of the present invention a compound of formula (IIa) is reacted with sodium hypochlorite in a mixture of water and methanol at a pH in the range of 10 - 12 at temperature in the range of 10°C -20°C to give a compound of formula (la) I (a ) (R1= CH3, R2= OCH3, R3= CH3, R4= OCH3) (Omeprazole). ADVANTAGES: The process of the present invention has several advantages over previously described oxidation processes. Some of the advantages are listed below: • The reagents employed are cheap, non-hazardous and environmentally friendly, for example sodium hypochlorite is used in domestic bleaching powder, has considerable good storage stability and is not shock sensitive. • The process gives good yields with reproducibility and provides a product of high purity which is chemically more stable than the products of other oxidation processes especially those carried out in acidic conditions (e.g. processes utilizing 3-chloroperoxybenzoic acid- MCPBA -WO 91/18895, EP 533752, US 5,386,032, ES 043816 and EP 484265, where oxidizing reagent itself is acidic. • Environmentally friendly liquid diluents may be used. • The process is a commercially viable and cost effective process. • Generated effluent can be safely and easily disposed. • Process gives the highest reproducible results. • Lowest temperature requirement is 10-15°C, which is possible in all commercial plants. • The final product remains as sodium salt during the entire process, which makes product stable even for couple of days. • Oxidizing agents like 3-chloroperoxybenzoic acid are not reactive in crude form of reaction mass and require isolated compounds of formula II before oxidation. On the other hand, in the process of the present invention, the oxidation step may concurrently follow the process steps of formation of compounds of formula II and thus avoid the requirement of isolation of the compound of formula II prior to oxidation. This leads to cost reduction in the process through improved processing times. • Sodium hypochlorite gives negligible, almost below 0.1% by area, impurities arising from over-oxidation, for example impurities like sulphone, or an N-oxide, or a sulphone N-oxide, than previously know oxidants, for example 3-chloroperoxybenzoic acid. • The desired product can be isolated from the reaction mixture and purified by conventional means e.g. extraction and recrystallisation or filtration followed optionally by recrystallisation, thus removing the problems associated with purification of the product obtained by the prior art processes. The details of the invention, its objects and advantages are explained hereunder in greater details in relation to non-limiting exemplary illustrations: The examples are merely illustrative and do not limit the teaching of this invention and it would be obvious that various modifications or changes in the procedural steps by those skilled in the art without departing from the scope of the invention and shall be consequently encompassed within the ambit and spirit of this approach and scope thereof. The final product of each of these examples was characterized by one or more of the following procedures; high performance liquid chromatograph; elemental analysis, nuclear magnetic resonance spectroscopy, infrared spectroscopy and high-resolution mass spectroscopy. The compounds of formula II, III and IV used in the Examples were either commercially available or were prepared by the methods given in EP0005129, EP174726 or EP166287. EXAMPLES PART 1: Synthesis of 2-f(4-(3-Methoxv propoxv) - 3- methyl pvridine-2-yl } - methvlthiol -1H-benzimidazole (Rabeprazole) SODIUM HYPOCHLORITE SOLUTION ROUTE Example: -1 100 gm of Rabeprazole sulfide dissolved in 500 ml of methylene dichloride at RT and added 2.0 gm of tertiary butyl ammonium bromide under stirring at RT. Cool the reaction mass to 10-15°C temperature and charge sodium hypochlorite solution slowly for 45 min. and stir for one hour. Warm the RM to 20-25°C temperature and stir for 1-2 hrs. Adjust the pH to 7.5 to 8.0 with 50% acetic acid. Separate the Methylene di chloride layer and extract the aqueous layer with 300 ml of methylene di chloride. Evaporate the solvent under vacuum at 35°C and add 300 ml of acetonitrile at room temperature. Heat the resultant mass to 50-55°C to dissolve the residue completely. Cool to 0-5°C temperature and maintain for 1.0 hour and filter the compound. Wash with 2 x 25 ml of acetonitrile. Dry the compd. at 40 - 45°C under vacuum for 2-3 hrs. Dry Wt: 70-75 gm (70%). Purity by HPLC 98.5-99 %. Example:-02 100 gm of Rabeprazole sulfide is dissolved in 500 ml of Methylene di chloride at room temperature and charged with 700 ml of water. To this reaction mass, add 2.0 gm of tertiary butyl ammonium bromide under stirring at room temperature. Cool the reaction mass to 10-15°C and charge sodium hypochlorite solution slowly for 45 minutes at the same temperature. Warm the reaction mass to 20-25°C and stir for 2-3 hrs. Separate methylene dichloride layer and collect aqueous layer and add 200 ml of methylene dichloride. Separate the aqueous layer and adjust the pH to 7.5 to 8.0 with 50% acetic acid at 10-15°C. Stir the content for 3 hr at 10-15°C. Filter the product and wash with 4 X 25 ml D M Water. Dry Wt: 70-75 gm (70%) Purity by HPLC: 99%. Example:-03 100 gm of Rabeprazole sulfide is dissolved in 500 ml of Methylene dichloride at room temperature and charged with 700 ml of water. To this reaction mass add 2.0 gm of tertiary butyl ammonium bromide under stirring at RT. Cool the RM to 10-15°C and charge sodium hypochlorite solution slowly for 45 min. at the same temp. Warm the RM to 20-25 temperature and stir for 2-3 hrs. Separate MDC layer and collect aqueous layer and add 200 ml of Methylene dichloride. Separate the aqueous layer and adjust the pH to 7.5 to 8.0 with 50% acetic acid at 10-15°C. Stir the content for 3 hr at 10-15°C. Filter the product and wash with 4 X 25 ml DM Water. Dry Wt: 70-75 gm (70 %) Purity by HPLC: 99%. PART II: Synthesis of 2-r(3.4-Dimethoxv) - pyridine-2-vl } - methylsulfinvl] -5- difluoromethoxv-1H-benzimidazole-(Pantoprazole) SODIUM HYPOCHLORITE SOLUTION ROUTE Example: -4 The mixture of 100 gm of pantoprazole sulfide, acetonitrile (200 ml), D.M water (150 ml) is cooled to 5- 10°C to which TBAB (2 gm) is added at the same temperature. This is then charged with 5 % sodium hypochlorite solution (430 ml) slowly for 45 min. and stirred for 1.0 to 2.0 hr. The excess of hypochlorite is decomposed using 5% sodium thiosulphate solution (100 ml). pH is adjusted to 7.5 to 8.0 with 50% acetic acid at 10 -15°C. The mass is then extracted with Methylene di chloride 3 X 300 ml. The solvent is evaporated under vacuum at 35°C and 300 ml of Ethyl acetate is added at RT. This is then heated to 50-55°C to dissolve the residue completely. Further it is cooled to D-5°C temperature and maintained at this temperature for 1.0 hr and the compound is then filtered. It is washed with 2x 25 ml of acetonitrile. The compound is dried at 40 - 45 temperature under vacuum for 2-3 hrs. Dry Wt: 65-70 gm (66%) Purity by HPLC: 98..5 % to 99% Example: -5 The mixture of 100 gm of pantoprazole sulfide, MDC (600 ml), D.M water (400 ml) is cooled to 0- 5°C and added TBAB (2 gm) at the same temperature. Then charged 5 % sodium hypochlorite solution (430 ml) slowly for 45 min. and stir for 1.0 to 2.0 hr. Decomposed the excess of hypochlorite using 5% sodium thiosulphate solution (100 ml). Separate the MDC layer and extract with 200 ml of MDC. Then adjusted the pH of aqueous layer 7.5 to 8.0 with 50% acetic acid at 10 -15°C. Extracted the gummy compound with methylene di chloride 3 X 300 ml. Evaporate the solvent under vacuum at 35 temperature and Add 300 ml of Ethyl acetate at RT. Then heat it to 50-55°C temperature to dissolve the residue completely. Cool to 0-5°C temperature and maintain for 1.0 hr and filter the compd. Wash with 2x 25 ml of acetonitrile. Dry the compd. at 40 - 45 temp, u N for 2-3 hrs. Dry Wt: 75-80 gm (75 %). Purity by HPLC: 98.5 % to 99%. Example: -6 The mixture of 100 gm of pantoprazole sulfide, MDC (600 ml), D.M water (400 ml) is cooled to 0- 5 °C and added TBAB (2 gm) at the same temperature. Then charged 5 % sodium hypochlorite solution (430 ml) slowly for 45 min. and stir for 1.0 to 2.0 hr. Decomposed the excess of hypochlorite using 5% sodium thiosulphate solution (100 ml). Separate the MDC layer and extract with 200 ml of MDC. Then adjusted the pH of aqueous layer 7.5 to 8.0 with 50% acetic acid at 10 -15°C. Added 80 ml of Acetone and stirred for 2-3 hr at 10 - 15°C.Then filtered the white crystalline compound and washed with 50 ml of Hexane. Dry the compound under vacuum at 40-45 °C for 6 hr. Dry Wt: 75-80 gm (75%) Purity by HPLC: 98.5-99%. Example: -7 The mixture of 100 gm of pantoprazole sulfide, MDC (600 ml), D.M water (400 ml) is cooled to 0- 5 °C and added TBAB (2 gm) at the same temperature. Then charged 5 % sodium hypochlorite solution (430 ml) slowly for 45 min. and stir for 1.0 to 2.0 hr. Decomposed the excess of hypochlorite using 5% sodium thiosulphate solution (100 ml). Separated the MDC layer and extracted with 200 ml of MDC. Then adjusted the pH of aqueous layer 7.5 to 8.0 with 50% acetic acid at 10 -15 °C. Added 80 ml of ethyl acetate and stirred for 2-3 hr at 10 - 15°C.Then filtered the white crystalline compound and washed with 50 ml of Hexane. Dry the compound under vacuum at 40-45 °C for 6 hr. Dry Wt: 75-80 gm (75%) Purity by HPLC: 98.5% to 99%. Example: "8 Synthesis of 2-r(3.4-Dimethoxv) - pvridine-2-vl) - methvlsulfinyll -5- difluoromethoxv-1H-benzimidazole without isolation of sulphide To a solution of NaOH (46.59 gm in 500 ml D.M.water), add 5-difluoro methoxy benzimadazole and stir for 15 min for complete dissolution. Then add 200 ml of methanol cool to 15 °C. Add 2-chloro methyl -3,4 dimethoxy pyridine hydrochloride slowly at 10 to 15 °C. Warm the reaction mass upto 20 -30 °C and stir for 6-8 hr. Then add 600 ml MDC and cool RM to 0 - 5 °C. Add TBAB (2 gm). Then add 5 % sodium hypochlorite solution (602 ml) slowly for 45 min. Then raise the temperature to 10 - 15 °C stir the reaction mass for 2-3 hr. Add 5 % sodium thiosulphate solution (100 ml) stir for 30 min. Separate MDC layer And Extract the aq.layer 2 X 200 ml MDC. Charcoalise the aqueous layer with 5% carbon. Filter the charcoal and cool the aq.layer. Then adjust the PH with 50 % acetic acid to 8.5. Extract the gummy compound with methylene di chloride 3 X 300 ml. Evaporate the solvent under vacuum at 35°C temperature and add 300 ml of Ethyl acetate at RT. Then heat it to 50-55°C temperature to dissolve the residue completely. Cool to 0-5°C temperature and maintain for 1.0 hr and filter the compd. Wash with 2x 25 ml of acetonitrile. Dry the compd. at 40 - 45 temp, u /v for 2-3 hrs. Dry Wt: 85-90 gm (65%) Purity by HPLC: 98.5% to 99% Also, further experiments were carried out for the comparative assessment of the results obtained without use of PTC and with use of PTC. PROCEDURE I: Preparation of Pantoprazole without phase transfer Catalyst: S. NO. RAW MATERIAL QTY. 1. 5-difluoromethoxy-2- [(3,4-dimethoxy-2-pylidinyl) methylthio]-1H-benzimidazole 100 gm. 2 Methylene dichloride 600 ml 3 D.M Water 600 ml 4 Sodium hypochlorite solution (3.1%w/w) 602 gm. 5 50% Dilute Acetic acid solution 50 ml 6. 5 % Sodium thiosulphate solution 100 ml 7. Carbon 5gm. 8. Sodium hydroxide flakes 25 gm 9 Acetone 100 ml PROCEDURE: Charge 600ml of D.M.Water at 20-30°C.Charge sodium hydroxide flakes slowly at 20-30°C & stir for 15 min to dissolve sodium hydroxide flakes. Charge 600 ml of Methylene dichloride. Cool the RM to 0-5°C. Charge 100 gm. Of 5-dif!uoromethoxy-2-[(3,4-dimethoxy-2-pylidinyl) methylthio]-1H-benzimidazole at 0-5°C.Add slowly solution of Sodium hypochlorite ( 3.1% w/w) at 0 to 5°C temperature in 1.0 to 2.0 hrs. Maintain at 0 to 5 °C temperature for 30 min. Heat to 10 to 15 °C temperature & Maintain for 1.0 to 2.0Hr. Add 400 ml of D M Water at 10 to 15 °C. Add sodium thiosulphate solution at 10 to 15°C temperature. Stir for 30 min. conduct the starch iodide test for the absence of Sodium Hypochlorite. Separate the MDC layer. Wash the aqueous layer with 2 X 150 ml Methylene dichloride. Wash the combined MDC layer with 200 ml water. Collect aqueous layer and add 5.0 gm of Carbon & Stir for 30 min. Filter the aqueous layer through hyflow bed. Wash hyflow bed with 2 X 20ml D.M Water. Collect the aqueous layer. Add 50% dilute acetic acid solution slowly to the aqueous layer to get the pH 7.5-8.0 at 10 to 15°C temperature. Add 100 ml of Acetone at 10 to 15°C temperature. Raise the temperature to 15 to 20°C & Stir the mass for 3-4 Hrs. at 15 to 20°C.Filter the product & Wash with 2 X 50 ml DM Water. Unload the compound. Wet Weight: 100-125 gm. Dry the compound at 40-45°C under Vacuum. Dry Weight: 55 gm. (52.7%). Send the sample for complete analysis toQC. Description: Cream color to Off White powder. HPLC purity: NLT 97.00 (% area) Single maximum impurity: 2.0 % TABLE-I Experimental data of Prazoles without PTC Sr. No. Batch No. Input Sodium hypochlorite (gm) Yield % HPLC Purity % Single maximum impurity % 1. RD/PPZ-04/01/05 5-difluoromethoxy-2- [(3,4-dimethoxy-2-pylidinyl) methylthio]-1H-benzimidazole 100.0 gm 602.0 53 96.52 2.20 2. RD/PPZ-04/02/05 5-difluoromethoxy-2- [(3,4-dimethoxy-2-pylidinyl) methylthio]-1H-benzimidazole 100.0 gm 602.0 51 96.90 1.89 3. RD/PPZ-04/03/05 5-difluoromethoxy-2- [(3,4- dimethoxy-2-pylidinyl) methylthioMH- 602.0 48 96.70 2.00 benzimidazole 100.0 gm 4. RD/RPZ-04/01/05 2[[[4-(3-methoxypropoxy)-3-methyi-2-pylidinyi] methyl] thio]-1 H-benzimidazole 100.0 gm 571.0 43 95.67 2.07 5. RD/RPZ-04/02/05 2[[[4-(3-methoxypropoxy)-3-methyl-2-pylidinyl] methyl] thioj-1 H-benzimidazole 100.0 gm 571.0 47 96.10 1.85 6. RD/RPZ-04/03/05 2[[[4-(3-methoxypropoxy)-3-methyl-2-pylidinyl] methyl] thio]-1 H-benzimidazole 100.0 gm 571.0 45 96.50 1.76 7. RD/LPZ-04/01/05 2[[[4-(2,2,2-trifluoroethoxy)-3-methyl-2-pylidinyl] methyl] thio]-1 H-benzimidazole 100.0 gm 388.0 43 95.00 2,20 8. RD/LPZ-04/02/05 2[[[4-(2,2,2-trifluoroethoxy)-3-methyl-2-pylidinyl] methyl] thio]-1 H-benzimidazole 100.0 gm 388.0 47 95.50 2.18 9. RD/LPZ-04/03/05 2[[[4-(2,2,2-trifluoroethoxy)-3-methyl-2-pylidinyl] methyl] thio]-1 H-benzimidazole 100.0 gm 388.0 45 95.70 2.08 10. RD/OMZ-04/01/05 5-methoxy-2- [[(4-methoxy-3, 5-dimethyl-2-pylidinyl) methyl] thio]-1H-benzimidazole 100.0 gm 672.0 44 95.80 2.17 11. RD/OMZ-04/02/05 5-methoxy-2- [[(4-methoxy-3, 5-dimethyl-2-pylidinyl) methyl] thio]-1H-benzimidazole 100.0 gm 672.0 45 96.70 2.23 12. RD/OMZ-04/03/05 5-methoxy-2- [[(4-methoxy-3, 5-dimethyl-2-pylidinyl) methyl] thio]-1H-benzimidazole 100.0 gm 672.0 47 96.83 2.36 PROCEDURE II: Preparation of Pantoprazole with Phase transfer catalyst RAW MATERIALS: s. NO. RAW MATERIAL QTY. 1. 5-difluoromethoxy-2-[(3,4-dimethoxy-2-pylidinyl) methylthio]-1 H-benzimidazole 100 gm. 2 Methylene dichloride (MDC) 600 ml 3 D.M Water 600 ml 4 Tetrabutyl ammonium bromide (catalyst-PTC) 2gm. 5 Sodium hypochlorite solution (3.1%w/w) 602 gm. 6. 50% Dilute Acetic acid solution 50 ml 7. 5 % Sodium thiosulphate solution 100 ml 8. Carbon 5gm. 9 Sodium hydroxide flakes 25 gm 10 Acetone 100 ml PROCEDURE: Charge 600ml of D.M. Water at 20-30°C.Charge Sodium hydroxide flakes slowly at 20-30°C & stir for 15 min to dissolve Sodium hydroxide. Charge 600 ml of Methylene dichloride. Cool the RM to 0-5°C.Charge 100 gm of 5-difluoromethoxy-2- [(3,4-dimethoxy-2-pylidinyl) methylthio]- 1 H-benzimidazole at 0-5°C.Charge 2.0 gm. Of Tetrabutyl ammonium bromide (Catalyst-PTC) at 0 to 5 °C temperature. Add slowly solution of Sodium hypochlorite (3.1% w/w) at 0 to 5°C temperature in 1.0 to 2.0 hrs. Maintain at 0 to 5 °C temperature for 30 min. Heat to 10 to 15 °C temperature & maintain for 1.0 to 2.0Hr.Add 400 ml of D M Water at 10 to 15 °C Add sodium thiosulphate solution at 10 to 15°C temperature. Stir for 30 min. Conduct starch iodide test for the absence of Sodium hypochlorite. Separate the Methylene dichloride layer. Wash the aq. Layer with 2 X 150 ml Methylene dichloride. Wash the combined MDC layer with 200 ml water. Collect aqueous Layer and add 5.0 gm of Carbon & Stir for 30 min. Filter the aqueous Layer through hyflow bed. Wash hyflow bed with 2 X 20ml D.M Water. Collect the aqueous layer Add 50% dilute acetic acid solution slowly to the aqueous layer to get the pH 7.5-8.0 at 10 to 15°C temperature. Add 100 ml of Acetone at 10 to 15°C temperature. Raise the temperature to 15 to 20°C & Stir the mass for 3-4 Hrs. at 15 to 20°C. Filter the product & Wash with 2 X 50 ml DM Water Unload the compound. Wet Weight: 100-125 gm. Dry the compound at 40-45°C under vacuum. Dry Weight: 90 gm. (87%). Send the sample for complete analysis to QC. Description: Cream color to Off White powder. HPLC purity: NLT 99.50 (% area) S Single max. Impurity: NMT 0.1% TABLE-II Experimental data of Prazoles with Phase transfer catalyst Sr. No. Batch No. Input Sodium hypochlorite Yield % HPLC Purity % Single maximum impurity % 1. RD/PPZ-04/01/05 5-difluoromethoxy-2-[(3,4-dimethoxy-2-pylidinyl) methylthio]-1H-benzimidazole 100.0 gm 602.0 89 99.52 0.03 2. RD/PPZ-04/02/05 5-difluoromethoxy-2-[(3,4-dimethoxy-2-pylidinyl) methylthio]-1H-benzimidazole 100.0 gm 602.0 87 99.65 0.04 3. RD/PPZ-04/03/05 5-difluoromethoxy-2-[(3,4-dimethoxy-2-pylidinyl) methylthioJ-1H-benzimidazole 100.0 gm 602.0 87 99.50 0.03 4. RD/RPZ-04/01/05 2[[[4-(3-methoxypropoxy)-3-methyl-2-pylidinyl] methyl] thio]-1 H-benzimidazole 100.0 gm 571.0 82 99.55 0.04 5. RD/RPZ-04/02/05 2[[[4-(3-methoxypropoxy)-3-methyl-2-pylidinyl] methyl] thio]-1 H-benzimidazole 100.0 gm 571.0 83 99.57 0.08 6. RD/RPZ-04/03/05 2[[[4-(3-methoxypropoxy)-3-methyl-2-pylidinyl] methyl] thio]-1 H-benzimidazole 100.0 gm 571.0 82 99.52 0.07 7. RD/LPZ-04/01/05 2[[[4-(2,2,2-trifluoroethoxy)-3-methyl-2-pylidinyl] methyl] thio]-1 H-benzimidazole 388.0 64 99.53 0.08 100.0 gm 8. RD/LPZ-04/02/05 2[[[4-(2,2,2-trifluoroethoxy)-3-methyl-2-pylidinyl] methyl] thio]-1 H-benzimidazole 100.0 gm 388.0 65. 99.54 0.06 9. RD/LPZ-04/03/05 2[[[4-(2,2,2-trifluoroethoxy)-3-methyl-2-pylidinyl] methyl] thio]-1 H-benzimidazole 100.0 gm 388.0 67 99.56 0.08 10. RD/OMZ-04/01/05 5-methoxy-2-[[(4-methoxy-3, 5-dimethyl-2-pylidinyl) methyl] thio]-1H-benzimidazole 100.0 gm 672.0 61 99.58 0.06 11. RD/OMZ-04/02/05 5-methoxy-2- [[(4-methoxy-3, 5-dimethyl-2-pylidinyl) methyl] thio]-1H-benzimidazole 100.0 gm 672.0 60 99.57 0.08 12. RD/OMZ-04/03/05 5-methoxy-2- [[(4-methoxy-3, 5-dimethyl-2-pylidinyl) methyl] thio]-1H-benzimidazole 672.0 60 99.54 0.08 Aforesaid results clearly establish the synergy existing in the combination of the phase transfer catalysts and the oxidizing agents as used in the invention. We claim: 1. An improved process for synthesis of substituted 2-(2-pyridylmethyl) sulphinyl-1-H- benzimidazoles compounds of formula (I) Wherein R1 R2, R3 and R4 represent e) (R1= CH3, R2= OCH3, R3= CH3, R4= OCH3) or f) (R1= CH3 R2= OCH2CF3, R3= H, R4= H) or g) (R1= OCH3, R2= OCH3, R3= H, R4= OCHF2) or h) (R1= CH3, R2= OCH2CH2CH2OCH2, R3= H, R4= H). and pharmaceutically acceptable salts thereof, comprising the steps of oxidizing the sulphide compound of Formula II. wherein R1, R2, R3 and R4 represent e) (R1= CH3, R2= OCH3, R3= CH3, R4= OCH3) or f) (R1= CH3, R2= OCH2CF3, R3= H, R4= H) or g) (R1= OCH3, R2= OCH3, R3= H, R4= OCHF2) or h) (R1= CH3, R2= OCH2CH2CH2OCH2, R3= H, R4= H) with hypochlorite in the presence of phase transfer catalyst in liquid diluent. 2. The process as claimed in claim 1, wherein the said oxidizing agent is selected from sodium hypochlorite and potassium hypochlorite. 3. The process as claimed in claim 2, where in the said oxidizing agent is sodium hypochlorite. 4. The process as claimed in claim 2 the concentration of hypochlorite is 3.1% & the mole ratio is 0.92 to 0.95 5. The process as claimed in claim 1, where in the said hypochlorite is employed in an amount of 0.8 to 2 mole per mole of the compound of Formula II. 6. The process as claimed in claim 1, where in the said hypochlorite is added at a temperature range of 0-5 ° C. 7. The process as claimed in claim 1, where in the said hypochlorite is added slowly and continuously in period of 1 to 2 Hrs. 8. The process as claimed in claim 1, where in the said phase transfer catalyst is selected from the class consisting of quartemary ammonium salts like Tetra alkyl (C2-C8) ammonium halide salts and Benzyl trialkyl (C2-C8) ammonium halide salts. 9. The process as claimed in claim 7, where in the said phase transfer catalyst is Tetrabutyl ammonium bromide. 10. The process as claimed in claim 1 or 7, where in the said phase transfer catalyst has a concentration in the range of 1.0 to 5.0% of compound Formula II. 11. The process as claimed in claim 1, wherein the said liquid diluent is selected from water, C1-4 alcohols, acetonitrile, methylene dichloride, C2-6 diols and mixtures thereof. 12. The process as claimed in claim 10, wherein the said liquid diluent is a mixture of water and methylene dichloride in the ratio of about 1:1.0. 13. The process as claimed in claim 10, wherein the said liquid diluent is a mixture of water and acetonitrile in the ratio of about 1:1.5. 14. The process as claimed in claim 1, where during the crystallization the pH is maintained between 7.5 to 8. 15.The process as claimed in claim 1, wherein the said process is carried out at a temperature in the range of 0 °C to 55 ° C. 16. The improved process for the synthesis of substituted 2-(2-pyridylmethyl) sulphinyl-1-H-benzimidazoles compounds of formula (I) and pharmaceutically acceptable salts thereof from the corresponding substituted 2-(2-pyridylmethylthio)-1-H-benzimidazole compounds of formula (II) substantially as herein before described with reference to the preferred aspects, embodiments and features of the invention and illustrated with reference to the examples.. Dated this 24th day of June 2005 Dr. Sanchita Ganguli Of S. Majumdar & Co. Applicant's Agent

Documents:

1200-mum-2004-abstract(29-6-2005).pdf

1200-mum-2004-claims(08-11-2004).doc

1200-mum-2004-claims(08-11-2004).pdf

1200-mum-2004-claims(29-6-2005).pdf

1200-MUM-2004-CLAIMS(AMENDED)-(19-7-2012).pdf

1200-MUM-2004-CLAIMS(AMENDED)-(20-2-2012).pdf

1200-MUM-2004-CLAIMS(MARKED COPY)-(19-7-2012).pdf

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1200-MUM-2004-CORRESPONDENCE(1-10-2012).pdf

1200-MUM-2004-CORRESPONDENCE(13-5-2009).pdf

1200-MUM-2004-CORRESPONDENCE(15-10-2012).pdf

1200-MUM-2004-CORRESPONDENCE(23-4-2010).pdf

1200-mum-2004-correspondence(29-06-2005).pdf

1200-MUM-2004-CORRESPONDENCE(29-4-2010).pdf

1200-MUM-2004-CORRESPONDENCE(30-9-2009).pdf

1200-mum-2004-correspondence(4-11-2008).pdf

1200-MUM-2004-CORRESPONDENCE(5-6-2012).pdf

1200-MUM-2004-CORRESPONDENCE(6-11-2008).pdf

1200-mum-2004-description(complete)-(29-6-2005).pdf

1200-mum-2004-description(provisional)-(8-11-2004).pdf

1200-MUM-2004-EP DOCUMENT(19-7-2012).pdf

1200-mum-2004-form 1(08-11-2004).pdf

1200-mum-2004-form 1(25-1-2005).pdf

1200-MUM-2004-FORM 18(6-11-2008).pdf

1200-mum-2004-form 2(complete)-(08-11-2004).doc

1200-mum-2004-form 2(complete)-(08-11-2004).pdf

1200-mum-2004-form 2(complete)-(29-6-2005).pdf

1200-mum-2004-form 2(provisional)-(8-11-2004).pdf

1200-mum-2004-form 2(title page)-(complete)-(29-6-2005).pdf

1200-mum-2004-form 2(title page)-(provisional)-(8-11-2004).pdf

1200-mum-2004-form 3(08-11-2004).pdf

1200-mum-2004-form 5(29-06-2005).pdf

1200-MUM-2004-OTHER DOCUMENT(15-10-2012).pdf

1200-MUM-2004-OTHER DOCUMENT(19-7-2012).pdf

1200-mum-2004-power of attorney(05-01-2005).pdf

1200-MUM-2004-POWER OF ATTORNEY(19-7-2012).pdf

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1200-MUM-2004-REPLY TO EXAMINATION REPORT(20-2-2012).pdf

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