Title of Invention

NOVEL INTERMEDIATES AND AN IMPROVED PROCESS FOR THE PREPARATION OF OMEPRAZOLE EMPLOYING THE SAID INTERMEDIATES

Abstract

This invention relates to an improved process for the preparation of omeprazole of the formula 1 starting from 4-nitro-2.3.5-trimethylpyridine-N-oxide and through novel intermediates 2-hydroxymethy1-3.5-dimethy1-4-intro pyridine of the formula II and novel 2- chloromethy1-3,5-dimethy1-4-nitro pyridine of the formula III. This invention also relates to process for the preparation of the above said novel intermediates. Omeprazole is one of the world's widely used drugs for the treatment of ulcer diseases. This compound act by irreversible inhibition of the H+ K+ ATPase enzyme, which is part of the proton pump located in the parietal cell of the stomach wall.

Full Text

FIELD OF INVENTION: The present invention, relates to an improved process for the preparation of Omeprazole. This invention particularly relates to an improved process for the preparation of Omeprazole Omeprazole is one of the world's widely used drugs for the treatment of ulcer diseases. This compound act by irreversible inhibition of the H' K" ATPase enzyme, which is part of the proton pump located in the parietal cell of the stomach wall. The Spanish patent no 9002764/European Patent - 0484265 A1 discloses a process for the preparation of Omeprazole starting with 4-nitro-2, 3,5-trimethyl pyridine-N-Oxide of the formula IV, * and through intermediates 2-chloromethyl-3, 5-drmethyl-4-nitropyridine hydrochloride of the formula VI, According to the above mentioned patents (ES-9002764/EP-0484265 A1 the process for the preparation of the Omeprazole (schemes A & B) and the novel intermediates 2-hydroxymethyl-3, 5-dimethyl-4-nitropyridine hydrochloride (scheme C) shown below. is reacted with phosphorous trichloride to get 4-nitro-2,3,5-trimethylpyridine of formula -V, The compound of formula VIII Is reacted with sodium methoxide and benzyl triethyl ammonium chloride in methanol to get desoxyomeprazole of formula IX. The compound of formula VI is converted to Omeprazole of formula I as mentioned in scheme -A. Scheme - C 4-Nitro-2,3,5-trimethyl pyridine-N-Oxide of formula IV Is reacted with acetic anhydride in presence of 4-dimethylaminopyridine to get 2-acetyloxymethyl-3,5-dimethyl-4-nitro-pyridine of formula XI, which on acid hydrolysis gives 2-hydroxymethyl-3,5-dimethyl-4-nitropyridine hydrochloride of formula-XII. On our repeating the process disclosed in ES 9002764/EP0484265 A1 for obtaining omeprazole, we found that the Omeprazole obtained is contaminated with chlorine containing impurities at about 2% level. The cause for this impurity was traced to the instability of HCI salts of compounds of the formulae -VI and XII resulting in formation of 4-chloro derivatives by displacement of 4-nitro group by chloride ion. originates from 2-hydroxymethyl-3, 5-dimethyl-4-nitropyridine hydrochloride of formula -XII (as HCf salt). In our sustained efforts to produce omeprazole minimizing the formation of impurities of the formula -XIII and formula-XIV and in the later stage the impurity 5-methoxy-2-{({4-chloro-3,5- dimethylpyridinyl)methyl)thio)-1H--benzimidazoleofformula-XV, Formula-XV with limit less than 0.1%, we could develop a process based on our findings that the compound of formula-XI is hydrolyzed by base hydrolysis avoiding acid hydrolysis, and in the subsequent stage the compound 2-chloromethyl-3,5-dimethyl-4-nitropyridine of the formula III is isolated in base form by neutralising immediately after completion of the reaction with a base. Such a procedure avoids the formation of impurities 2-hydroxymethyl-3,5-dimethyl-4-chloropyridine of formula-XIV and 2 chloromethyl-3,5-dimethyl-4-chloropyridine of formula XIII and the impurity of formula -XV in later stage. 2,3,5-trimethyl-4-nitropyridine-N-Oxide, of formula-IV, can then be rearranged to 2-acetyloxymethyl-3,5-dimethyl-4-nitropyridine of the formula-XI which on base hydrolysis gives 2-hydroxymethyl-3,5-dimethyl-4-nitropyridine, of the formula -II. This intermediate of formula-II is purified by recrystalisation from different solvents. The compound of the formula -II is reacted at a temperature in the range 0-15° C with a chlorinating agent, such as thionyl chloride to get 2-chloromethyl-3,5-dimethyl-4-nitro-pyridine hydrochloride of the formula -VI which is neutralized immediately to obtain compound of formula -III in base form with the impurity 2-chloromethyl-4-chloro-3,5- -dimethylpyridine of formula- XIII less than 0.2%. The 2-chloromethyl-3,5-dimethyl-4-nitropyridine of formula -III is dissolved in a protic solvent and reacted with 2-mercapto-5-methoxy benzimidazole, of the formula-VII with a base to get 5-metlioxy-2-(({3,5-dimethyl-4-nitro-2-pyridinyl)methyl)thio)-1H-benzimidazole, of formula-VIII. After recrystallization from suitable solvents, pure compound-VIU is obtained with an impurity, 5-methoxy-2-(((3,5-dimethyl-4-chloro-2-pyridinyl) methyl)thio -1 H- benzimidazole of formula -XV less than 0.1%. t The compound of the formula -VIII is refluxed with methanolic sodium methoxide solution to obtain 5-methoxy-2-(((3,5-dimethyl-4-methoxy-2-pyridinyl)methyl)thio)-1H- -benzimidazole, of the formula -IX. The desoxyomeprazole of the formula -IX is reacted with hydrogen peroxide - urea complex and acid anhydride in the presence of a protic solvent at low temperature i.e. -5 to 0°C to get technical omeprazole, which is purified to get Pharmacopeal grade Omeprazole. The Omeprazole thus prepared contain impurities 5-methoxy-2-(((3,5-dimethyl-4-chloro-2- The present invention provides an improved process for the preparation of omeprazole using novel intermediates 2-hydroxymethyl-3,5-dimethyl-4-nitro pyridine of the formula II and 2-chloro methyl-3,5-dimethyl-4-nitro pyridine of the formula III. These two intermediates are very stable when compared to its hydrochloride salts. The 2-hydroxymethyl-3,5-dimethyl-4-nitro pyridine of the formula II and 2-chloro methyl-3,5-dimethyl-4-nitro pyridine of the formula III both in their base form prepared according to the process disclosed above have not been reported in the literature. These compounds are very stable when compared to their hitherto known hydrochloride salts, which are produced according to the process disclosed in the above said Spanish patent. The employment of these new intermediates results in the reduction of impurities in the preparation of omeprazole. The main objective of the present invention is, therefore to provide an improved process for the preparation of Omeprazole having impurities less than 0.1%. Another objective of the present invention is to provide an improved process for the preparation of Omeprazole starting from 2,3,5-trimethyl-4-nitro pyridine-N-oxide of formula IV and through novel intermediates 2-hydroxymethyl-3,5-dimethyl-4-nitro pyridine of the formula II and novel 2-chloromethyl-3,5-dimethy[-4-nitro pyridine of the formula III. Yet another objective of the present invention is to provide novel intermediates 2-hydroxymethyl-3,5-dimethyl-4-nitropyridine of the formula II and 2-chloromethyl-3,5-dimethyl-4-nitropyridine of the formula III and processes for their preparation. The Scheme of the Present Invention: This invention, particularly relates to an improved process for the preparation of Omeprazole of the formula I useful as anti-ulcer, drug through intermediate desoxyomeprazole of formula IX. Accordingly, the present invention provides an improved process for the preparation of Omeprazole of the formula I which comprises. (i) Rearranging 4-nitro-2,3,5-trimethy|pyridine-N-oxide of the formula -IV, by conventional methods to 2-acetyloxymethyl-3,5-dimethyl-4-nitropyridine of the formula XI. (ii) Hydrolyzing the compound of the formula -XI to novel 2-hydroxymethyl-3,5-dimethyl-4-nitropyridine of the formula II by employing a base. (iii) Chlorinating the compound of the formula -II with a chlorinating agent at a temperature in the range of 0-15 degree C to obtain novel 2-chloromethyl-3,5-dimethyl-4-nitropyrrdine of the formula III. (iv) Coupling of the compound of the formula -III with 5-methoxy-2-mercapto benzimidazole of the formula-VII in aqueous alkali to obtain 5-methoxy2- (v) Converting the compound of the formula -VIII to obtain 5-methoxy-2-(((3,5-dimethyl-4- methoxy-2-pyridinyl) methyl )thio)-1 H-benzimidazole of formula-IX by known methods and (vi) Oxidizing the compound of the formula IX with an oxidising agent to obtain omeprazole [5-methoxy-2-(((3,5-dimethyl-4-methoxy-2-pyridinyl)methyl) sulphiny!)-1 H-benzimidazole] of the formula -I given above. According to another feature of the present invention there is provided a process for the preparation of novel 2-hydroxymethyl-3,5-dimethyl-4-nitropyridine of the formula II which comprises. (i) Rearranging 4-nitro-2,3,5-trimethylpyridine-N-oxide of the formula IV by conventional methods to 2-acetyloxymethyl-3,5-dimethyl-4-nitropyridine of the formula-XI. (ii) Hydrolyzing the compound of the formula XI to novel 2-hydroxymethyl-3,5-dimethyl-4-nitropyridine of the formula 11 by employing a base. Accordingly yet another feature of the present invention there is provided a process for the preparation of novel 2-chloromethyl-3,5-dimethyl-4-nitropyridine of the formula III, which comprises (i) Rearranging 4-nitro-2,3,5-trimethylpyridine-N-oxide of he formula IV by conventional methods to 2-acetyloxymethyl-3,5-dimethyl-4-nitropyridine of the formula XI. (ii) Hydrolyzing the compound of the formula -XI to novel 2 hydroxymethyl-3,5-dimethyl-4-nitripyridine of the formula -II by employing a base. (iii) Chlorinating the compound of the formula II with a chlorinating agent at a temperature in the range of 0-15 degree C to obtain novel 2-chloromethyl-3,5-dimethyl-4-nitropyridine of the formula-III. The present invention also includes the novel intermediates 2-hydroxymethyl-3,5-dimethyl-4--nrtropyndine of the formula II and 2-chloromethyl-3,5-dimethyl-4-nitropyridine of the formula III. In a preferred embodiment of the present invention, the rearrangement in step (I) may be effected by employing acetic anhydride at a temperature in the range of 70 to 90 degree C. The base used in step (ii) may be selected from sodium hydroxide, potassium hydroxide etc. The chlorinating agent employed in step (Hi) may be selected from thtortyl chloride, phosphorous oxychloride, phosphorous pentachloride etc. The alkali used in step (iv) may be sodium hydroxide or potassium hydroxide etc. This reaction is conducted in the presence of a protic solvent such as methanol, ethanol etc. The step (v) of the process of the present invention may be carried out employing sodium methoxide in the presence of methanol. The oxidising agent in step (vi) may be selected from meta chloro perbenzoic acid, hydrogen peroxide in combination with a catalyst such as ammonium molybdate, vanadium pentoxide etc. Preferable oxidising agent is urea-hydrogen peroxide complex. This oxidising agent has not so far been employed in this step for the process of preparing omeprazole which accordingly adds further novelty to the invention. The invention is described in detail in the example given below which is provided by way of illustration only and therefore should not be construed to limit the scope of the present invention. Example -1: (a) Preparation of novel 2-hydroxymethyl-3,5-dimethyl-4-nitropyridine of formula II (base): 151.3 gms (1.4833 mole) of acetic anhydride was added at 45- 50° C to a mixture of 90.0 gm (0.4595 moles) of 4-nitro-2,3,5-trimethylpyridine-N-oxide of formula -IV and 45.0 gms of acetic acid and heated to 85° C and maintained the temperature at 85-90° C for 4 hrs. 75 ml of methanol was added to the reaction mixture at room temperature and distilled off acetic acid and methanol at temperature at 60 - 65" C under vacuum to get an oil. 40% Lye (240 grams) was added to the cooled oil at 0 - 5° C and stirred at 0 - 5° C for 4 hrs. The crude product was obtained by extraction of the reaction mass with methylene chloride and distillation of the solvent. Pure 2-hydroxymethyl-3,5-dimethyl-4-nitropyridine of formula -II was obtained by recrystallising the crude material in toluene. Yield-60.0 gms (60.0%) Purity -99.0% (by HPLC) MR - 65-68° C. (b) Preparation of novel 2-chlormethyl-3,5-dimethyl-4-nitropyridine of formula III (base) 8.0 ml (0.11 mole) of thionyl chloride in 20.0 ml of methylenechloride was added to a solution of 20.0 gms 2-hydroxymethyl-3,5-dimethyl-4-nitropyridine, of formula -II obtained in step (a) at temperature 10-15° C over a period of 1 hr. The reaction is maintained at 10 -15°C for further 30 min. Aqueous 10% solution of sodium carbonate was slowly added to the reaction mixture at 10-15°C and pH adjusted to 8.0 to 8.5. The organic base (compound) is extracted into methylenechloride. The combined methylenechloride extractions are dried over anhydrous sodium sulfate and solvent was removed under vacuum to obtain crude oil. (compound of formula -III in base form). Yield-22.0 gms (85%) Purity by GC - 85% (about 15% is compound of formula II) (c) Preparation of 5-methoxy-2-(((3,5-dimethyl-4-nitro-2-pyridinyl)methyl)thio)-1H- benzimidazole of formula -VIII. A solution of 10.0 gms (0.25 mole) of sodium hydroxide in 50 ml of water is slowly added to a suspension of 21.54 gms (0.1197 mole) of 2 mercapto-5-methoxy benzimidazole of formula-VII in 48.0 ml of methanol under N2 atmosphere at 10-15 °C. Then a solution of 28.2 gms (85%) pure) (0.1197 mole) of 2-chloromethyl-3-5-dimethyl-4-nitropyridine of formula III obtained in step-b in 84.0 ml of-the methanol is added at 10 -15° C. After stirring at 10 -15° C for 30 min 250 ml of water is added and the mixture is again stirred for 30 min. Solid product is filtered and washed with 5% sodium hydroxide solution to remove unreacted 5-methoxy-2-mercapto benzimidazole of formula -4. Recrystallised the crude product from dimethylformamide and acetonitrile resulted in pure 5-methoxy-2-(((3,5-dimethyl-4-nitro-2--pyridinyl)methyl)thio)-1H-benzimidazole of formula-VIII. Yield: 31.0 gms (75%) MR - 126-128° C HPLC Purity : 99.5%. (d) Preparation of 5-methoxy-2-(((3,5-dimethyt-4-methoxy-2-pyridinyl)methyl)thio)-1H-benzimidazole monohydrate of the formula - IX. The traces of water present in 83.0 gms (0.241 moles) of 5-methoxy-2-(({3,5-dimethyl-4-nitro-2-pyridinyl)methyl)thio)-1H-benzimidazole of formula -VIII obtained in step - c was separated byazeotrope distillation in 400 ml of benzene, and benzene was distilled off completely and the residual solid was dissolved in 100 ml of methanol. At reflux temperature 253.0 ml (1.204 moles) of sodium methoxide solution was added over a period of 2 hrs. Later 100 ml of methanol was distilled. The mass was maintained at reflux temperature for 6 hrs. Checked TLC for absence of starting material. The pH was adjusted to 8-8.5 with acetic acid and the inorganics were filtered. Distilled off methanol under vacuum, extracted the product into methylene chloride (500 ml) washed with 5% NaOH (100 ml) and then with water (100 ml). The methylene chloride layer was given activated carbon (5.0 gms) treatment, filtered and dried over anhydrous sodium sulphate. The solvent was removed by distillation and the residual gum was dissolved in 100 ml of methanol, treated with 200 ml of water and stirred at room temperature till solid formed. The solid was filtered and washed with DM water (50.0 ml) dried at 40 - 50°C under vacuum, to obtain the compound of formula IX as monohydrate HPLC Purity = 99.5% Yield : 68.0 gms (80%) (e)Preparation of 5-methoxy-2-(((3,5- 50.0 gms (0.144 moles) of 5-methoxy-2-(((3,5-dimethyl-4-methoxy-2-pyridyi)methyl)thio)--1H-benzimidazole monohydrate, of formula -IX obtain in step - d was dissolved in 400.0 ml of methanol, cooled to + 5° C. The pH of the solution was adjusted to 8.5 with sodium carbonate solution (25%), teated with urea-hydrogenperoxide complex. 33.0 gms (0.288 mol) and stirred to dissolve at 5-10° C, added acetic anhydride (18.0 gms - 0.1765 molss) slowly at 5-10° C and maintained the pH of the reaction mixture at 8 - 8.5 by simultaneous addition of 25% sodium carbonate solution. Then the reaction mass was maintained at 5-10° C for 30 min. Checked the TLC till starting material was absent. Added 700 ml of water and stirred for 30 min at 0-5" C. The compound was extracted with 4x200 ml of methylene chloride The combined methylenechloride layer again extracted with 200 ml of 3% sodium hydroxide solution, given activated carbon treatment (5.0 gms) for sodium hydroxide solution. Filtered, filtrate cooled to 0°C and neutralised with 1.5% acetic acid solution to pH 7.5 - 8.0 at 0 - 5° C. The precipitate was filtered and washed with acetone (50 ml). The product was dried at 40-45° C under vacuum to obtain technical grade Omeprazole. Dissolved the technical grade omeprazole in 160 ml of dimethyl formamide at 40 C and added 700 ml of methyl ethyl ketone. Cooled to 0° C and stirred for 2 hrs at 0 - 5° C. Filtered washed with 10 ml of chilled methyl ethyl ketone and dried under vacuum at 40 - 45° C. The dried product is dissotved in 200 ml of 3% sodium hydroxide solution. Filtered and cooled to 0° C. Neutralised and adjusted pH 7.5 to 8.0 by slowly adding 1.5% acetic acid solution at 0-5° C. Filtered, washed the precipitate with 30 ml of acetonitrile, dried in vacuum at 40 - 45° C to obtain pharmacopeal grade omeprazole. MR - 154-156° C Yield - 42.0 gms (85.00%) The omeprazole prepared conforms to pharmacopeal standards. We Claim: 1. A process for the preparation of 5-methoxy-2-{((3,5-dimethyl-4-methoxy-2-pyridinyl)methyi)sulphinyl)-lH -benzimidazole (Omeprazole) of the formula I, (ii) hydrolyzing the compound of the formula - XI to novel 2-hydroxymethyl-3, 5-dimethyl-4--nitropyridine of the formula-I! by employing a base; (v) converting the compound of the formula VIII by refluxing with sodium methoxide solution in presence of methanol to obtain 5-methoxy-2-(((3,5-dimethyl-4-methoxy-2-pyridinyl)methyl)thio)-lH-benzimidazole of formula-IX and (vi) oxidizing the compound of the formuIa-IX with an oxidising agent at a temperature in the range of 5- 10 "C to obtain 5-methoxy-2-(((3,5-dimethyl-4-methoxy-2-pyridinyl)methyl)sulphinyl)-lH -benzimidazole (Omeprazole) of the formula-I. 2. A process as claimed in claim 1 wherein the rearrangement in step (i) is effected by employing acetic anhydride at a temperature in the range of 70 to 90 degree C. 3. A process as claimed in claim 1 wherein the base used in step (ii) is selected from sodium hydroxide, potassium hydroxide. 4. A process as claimed in claim I wherein the chlorinating agent employed in step (Hi) is selected from thionyl chloride, phosphorous oxy chloride, and phosphorous penlachloride. 5. A process as claimed in claim 1 wherein the alkali used in step (iv) is selected from sodium hydroxide or potassium hydroxide and the reaction is conducted in the presence of a protic solvent such as methanol, ethanol. 6. A process as claimed in claim 1 wherein the step (v) is carried out employing sodium methoxide in the presence of methanol. 7. A process as claimed in claim 1 wherein the oxidising agent in step (vi) is selected from meta chloro perbenzoic acid, hydrogen peroxide in combination with a catalyst such as " ammonium molybdate, vanadium pentoxide. 8. A process as claimed in claim 1 wherein the oxidising agent used is urea-hydrogen peroxide complex. 9. Novel intermediate 2-hydroxymethyl-3-5-dimethyl-4-nitropyridine of the formula II useful for the preparation of 5-methoxy-2-(((3,5-dimethyl-4-methoxy-2- pyridinyl)methyl)sulphinyl)-lH -benzimidazole (Omeprazole) of the formula I 10. Novel intermediate 2-chloromethyl-3,5-dimethyl-4-nitropyridine of the formula-Ill useful for the preparation of 5-methoxy-2-(({3,5-dimethyl-4-methoxy-2- pyridinyl)methyl)sulphinyl)-lH -benzimidazole (Omeprazole) of the formula I. 11. An improved process for the preparation of 5-methoxy-2-(((3,5-dimethyl-4-methoxy- 2-pyridinyl)methyl)sulphinyl)-lH -benzimidazole (Omeprazole) of the formula I substantially as herein described with reference to the Example.

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