Title of Invention

AN IMPROVED PROCESS FOR HIGH PURITY 1-METHYLINDAZOLE-3- CARBOXYLIC ACID

Abstract

The invention disclosed in this application relates to an improved process for the preparation of highly pure I-Methyl-indazole-3- carboxylic acid of the formula II useful for the preparation of pharmaceutical grade granisetron which comprises (a) methylating Indazole -3-carboxylic acid of the formula (I) using dimethylsulfate in the presence of a base to produce a mixture of I-Methyl-indazole-3-carboxylic Acid of the formula (II) and 2-Methyl-indazole-3-carboxylic acid of the formula (III), (b) preferential esterification of l-methyl-indazole-3-carboxylic acid over 2-methyl isomer (c) separating the esterified I-Methyl-indazole-3-carboxylic acid from the unesterified 2-Methyl-indazole-3- carboxylic acid (d) hydrolysing the ester of the acid of the formula (II)

Full Text

Introduction. The invention relates to an improved process for the preparation of l-Methylindazole-3-carboxylic acid useful for the preparation of pharmaceutical^ active compound granisetron. 1-Methylindazole-3-carboxylic acid (II) and granisetron have the following formulae. Background of invention: The literature method for the preparation of l-Methylindazole-3-carboxylic acid [Ref; (i) Chem. Ber. 1919, 52, 1340 (ii) J. Am. Chem. Soc. 1950,72,3047] involves methylation of the indazole derivative of the formula IV. Which gives a roughly equal mixture of two products of the formulae (V) and (VI) containing the methyl group at either 1- or 2- position. The mixture of the products, then, has to be separated by chromatographic methods and then the required 1-Methyl isomer hydrolyzed to give the compound of the formula (II) resulting in low yield. This process is shown in scheme-I. Another process is disclosed in (EP 323105, 1988, Beecham group) which claims a high yielding one-stage process avoiding the need for separation of the isomers. This method involves methylation of indazole-3-carboxylic acid of the formula (I) employing methylating agents like dimethyl sulfate or methyl iodide in a polar solvent in the presence of a alkali metal alkoxide like sodium isopropoxide. The product l-Methylindazole-3-carboxylic acid is claimed in 85-90% yield. The isomeric purity of the compound of the formula-II is not mentioned in this patent. This process is shown in scheme-2. On repetition of the above method (scheme-2) disclosed in EP 0323105, we observed the following short-comings: 1) The yield of l-methyl-indazole-3-carboxylic acid of the formula (II) obtained is only about 37% as against the 85-90% claimed. 2) The method, in fact, produces a mixture of the isomeric compounds of the formulae (II) and (III) and other impurities, which has to be purified by solvent extraction employing ethyl acetate and 4-Methyl-2-pentanone, 3) The purity of the compound of the formula (II) generated after purification is only about 93%. The remaining 7% constitute the impurity isomeric 2-Methyl-indazole-carboxylic acid of the formula (III) and other impurities which still stays along with the final product as contaminant. 4) The resulting product of the formula (II) produced by this process is thus unsuitable for the preparation of pharmaceutical grade granisetron as the isomeric impurity of the formula (III) also participates in further steps and almost impossible to separate afterwards. For the preparation of pharmaceutical grade granisetron it is required to synthesize the intermediate of the formula (II) in high isomeric purity (>99.8%). As explained above the existing prior art processes including the one disclosed in EP 0323105 are far from satisfactory. Therefore we continued our relentless investigations in developing an industrially feasible, dependable process for the preparation of high purity (>99.8%).l-Methyl-indazole-3-carboxylic acid of the formula (II) consistently. Therefore the main objective of the present invention is to provide an improved process for the preparation of high purity (>99.8%) l-Methyl-indazole-3-carboxylic acid of the formula (II) consistently, which is useful for the preparation of pharmaceutical grade granisetron Summary of the invention: While carrying out the investigations towards developing the improved process for the preparation of high purity (>99.8%) l-Methyl-indazole-3-carboxylic acid of the formula (II) we observed surprisingly that Indazole-3-carboxylic acid can be converted to l-methyl-indazole-3-carboxylic and by adopting the simple procedure as shown in scheme-3 Accordingly, the present invention provides an improved process for the preparation of highly pure l-Methyl-indazole-3- carboxylic acid of the formula (II) Useful for the preparation of pharmaceutical grade granisetron which comprises (a) methylating Indazole -3-carboxylic acid of the formula (I) using dimethylsulfate in the presence of a base to produce a mixture of l-Methyl-indazole-3-carboxylic Acid of the formula (II) and 2-Methyl-indazole-3 -carboxylic acid of the formula (III) (ID on) (b) Preferential esterification of the compound of formula (II) over the compound of formula (III) in methanol medium containing 1 to 10% Cone. Sulfuric acid at a temperature in the range of 35°C to reflux temperature of methanol for a period of 1 to 6 hrs. (c) Isolating the esterified l-Methyl-indazole-3-carboxylic acid from the unesterified 2-Methyl-indazole-3-carboxylic acid by crystallisation of the ester or by purification technique such as washing with a base and. (d) Hydrolysing the ester of the acid of the formula (II) by conventional methods. The l-Methyl-indazole-3-carboxylic acid of the formula (II) thus isolated in more than 99.8% purity (by HPLC) and is suitable for conversion to pharmaceutical grade granisetron. In a preferred embodiment of the present invention the base used in step (a) is selected from sodium hydroxide, potassium hydroxide and the carbonates like Sodium or potassium carbonate and the like. The solvent used is selected from alcohols like Methanol, Ethanol, isopropanol, n-butanol, t-butanol and the like, preferably isopropanol or n-butanol. In the preferential esterification step (b) the temperature used is preferably 50°C to reflux temperature of methanol more preferably reflux temperature of methanol. The required reaction time is preferably 4 to 6 hrs and the amount of catalyst used is preferably 1 to 2% sulfuric acid. The solvent used in the crystallization step (c) is selected from non-polar solvents such as Hexane, Heptane, Petroleum ether, Toluene, Ethers like Diethyl ether, Isopropyl ether and the like. The base used in the washing step (c) is selected from inorganic bases such as Sodium or Potassium hydoxide, carbonates, bicarbonates and the like, preferably sodium or potassium hydroxide or organic bases such as Ammonia, Triethylamine, Pyridine and the like preferably ammonia. Acids used in the hydrolysis step (d) is selected from 2-20% HC1, 2-40% sulfuric acid, polyphorphoric acid, sulfonic acids such as methanesulfonic acid, Toluene sulfonic acid and the like. Preferably 2-40% sulfuric acid, more preferably 10-15% sulfuric acid The base used in the hydrolysis step (d) is selected from sodium or potassium hydroxide or carbonate, preferably sodium or potassium hydroxide. The medium of reaction is water or aqueous alcohols like methanol, ethanol, isopropanol, and preferably water. The details of the invention are given in the Examples provided below which are given to illustrate the invention only and therefore should not be construed to limit the scope of the invention. Example-1 Preparation of 1-Methyl-indazole-3- carboxylic acid Indazole-3-carboxolic acid : 25 g Potassium hydroxide flakes : 26 g Dimethyl sulfate : 29.6 g Isopropanol : 250 ml Methanol : 250 ml Cone, sulfuric acid : 2.5 ml Methylene chloride : 15 0 ml Aq. Sodium hydroxide (4%) : 100 ml Into a 1 It 4-necked round bottom flask provided with a mechanical stirrer, a reflux condenser and a dropping funnel were charged potassium hydroxide flakes (26g) followed by isopropanol (200ml) and indazole-3- carboxalic acid (25g). The mixture was heated under stirring and a solution of dimethyl sulfate (29.6 g) in isopropanol (50 ml) was slowly added at reflux temperature during 3hours. The reflux was continued for another 3 hours and the solvent was distilled off under vacuum. Water (200 ml) was added to the residue the solution was treated with activated carbon and the filtrate was acidified to pH 2.0-2.5 employing cone, hydrochloric acid. The precipitated product is filtered washed with water (25 ml) and dried (24.5 g) The dried intermediate (24.0) obtained as described above was suspended in methanol (250 ml) and cone, sulfuric acid (2.5 ml) was added. The mixture was refluxed for 5 hours and the solvent distilled off completely under vacuum and the residue partitioned between water (100 ml) and methylene chloride (150 ml). Aqueous sodium hydroxide was added to the mixture to adjust the pH of the aqueous layer to 8.0-8.5. The mixture was stirred for 10 min and the layers were allowed to separate. The alkaline aqueous layer was acidified to get the isomeric 2-Methyl-indazole-3—carboxolic acid (7.8 g) The organic layer was stripped of methylene chloride and the residue was heated with an aqueous solution of sodium hydroxide (4%, 100 ml) at 70-75°C for 1 14 hour. The reaction mass was treated with activated carbon and the filtrate was acidified with cone. HC1 to pHl.5-2.0, and the product slurry was filtered. The product was washed with water dried at 70-75°C under vacuum. Yield of l-Methyl-3-indazole carboxolic acid : 12.2 g Melting point : 216°C HPLC purity : 99.85% Example-2 Preparation of l-Methyl-indazole-3- carboxylic acid Indazole-3-carboxolic acid : 25 g Sodium hydroxide flakes : 18.5 g Dimethyl sulfate : 29.6 g n-Butanol : 250 ml Methanol : 250 ml Cone, sulfuric acid : 2.5 ml Methylene chloride : 150 ml Aq. Sodium hydroxide (4%) : 100 ml Into a 1 It 4-necked round bottom flask provided with a mechanical stirrer a reflux condenser and a dropping funnel were charged sodium hydroxide flakes (18.5g) followed by n-butanol (200ml) and indazole-3- carboxalic acid (25g). The mixture was heated under stirring and a solution of dimethyl sulfate (29.6 g) in n-butanol (50 ml) was slowly added at reflux temperature during 3 hours. The temperature was maintained at reflux for another 3 hours and the solvent is distilled off under vacuum. Water (200 ml) was added to the residue and decolorized with activated carbon. The clarified filtrate was acidified to pH 2.0-2.5 employing cone, hydrochloric acid the precipitate product was filter washed and dried (24.0 g) The dried intermediate (methylated-indazole-3-carboxylic acid mixture) obtained as described above (23.5) was suspended in methanol (250 ml) and cone, sulfuric acid (2.5 ml) was added. The mixture was refluxed for 5 hours and the solvent distilled off completely under vacuum and the residue partitioned between water (100 ml) and methylene chloride (150 ml). Aqueous sodium hydroxide was added to the mixture to adjust the pH of the aqueous layer to 8.0-8.5. The mixture was stirred for 10 min and the layers were separated. The alkaline aqueous layer was acidified to get the isomeric 2-Methyl-indazole-3--carboxolic acid (7.0 g). The organic layer was stripped of methylene chloride and the residue was heated with an aqueous solution of sodium hydroxide (4%, 100 ml) at 70-75°C for 2 hours. The reaction mixture was treated with activated carbon a filtered. The filter was acidified with cone. HC1 to pH: 1.5-2.0. The product was filtered, washed with water dried at 70-75 °C under vacuum. Yield of l-Methyl-3-indazole carboxolic acid : 13.60 g Melting point : 217°C HPLC purity : 99.9% Advantages of the present method: 1. The intermediate of the formula (II) required in the manufacture of high purity pharmaceutical grade granisetron (for ex. as specified in pharma Europa 2003) is produced in more than 99.8% purity 2. The method also provides a means of isolating 2-Methyl-indazole-3-carboxylic acid in high purity 99.5% useful as a synthetic intermediate 3. The method does not require hazardous handling of sodium metal. 4. The method does not require preparation of anhydrous sodium isopropoxide as base used in the alkylation of Indazole-3-carboxylic acid as given in EP 0323105 5. The method at no stage involves laborious chromatographic separation of isomeric mixtures. 6. The method poses no problem in upscaling and is industrially viable as a manufacturing process. We claim: 1. An improved process for the preparation of highly pure l-Methyl-indazole-3- carboxylic acid of the formula (II) Useful for the preparation of pharmaceutical grade granisetron which comprises (a) methylating Indazole -3-carboxylic acid of the formula (I) using dimethylsulfate in the presence of a base to produce a mixture of l-Methyl-indazole-3-carboxylic Acid of the formula (II) and 2-Methyl-indazole-3-carboxylic acid of the formula (III) (ii) on) (b) Preferential esterification of the compound of formula (II) over the compound of formula (III) in methanol medium containing 1 to 10% Cone. Sulfuric acid at a temperature in the range of 35°C to reflux temperature of methanol for a period in the range of 1 to 6 hrs. (c) Isolating the esterified l-Methyl-indazole-3-carboxylic acid from the unesterified 2-Methyl- indazole-3-carboxylic acid by crystallisation of the ester or by purification technique such as washing with a base and (d) hydrolysing the ester of the acid of the formula (II) by conventional methods 2. An improved process as claimed in claim 1 wherein the base used in step (a) is selected from sodium hydroxide, potassium hydroxide and the carbonates like sodium or potassium carbonate and the like. 3. An improved process as claimed in claims 1 & 2 wherein the solvent used in step (a) is selected from alcohols like methanol, ethanol, isopropanol, n-butanol, t-butanol and the like, preferably isopropanol or n-butanol. 4. An improved process as claimed in claims 1 to 3 wherein the temperature used in step (b) is in the range of 50 °C to reflux temperature of methanol more preferably reflux temperature of methanol. 5. An improved process as claimed in claims 1 to 4 wherein the preferential esterification step (b) the required reaction time is preferably 4 to 6 hrs. 6. An improved process as claimed in claims 1 to 5 wherein the amount of catalyst used is preferably 1 to 2% sulfuric acid. 7. An improved process as claimed in claims 1 to 6 wherein the isolation of 1-Methyl-indazole-3- carboxylic acid from the unesterified 2-Methyl-indazole-3-carboxylic acid by crystallization step (c) the solvent used is selected from non-polar solvents such as Hexane, Heptane, Petroleum ether, Toluene, Ethers like Diethyl ether, Isopropyl ether and the like. 8. An improved process as claimed in claims 1 to 5 wherein the isolation of 1-Methyl-indazole-3- carboxylic acid from the unesterified 2-Methyl-indazole-3-carboxylic acid by purification technique such as washing with a base step (c) the base used is selected from inorganic bases such as Sodium or Potassium hydoxide, carbonates, bicarbonates and the like, preferably sodium or potassium hydroxide. 9. An improved process as claimed in claims 1 to 7 wherein the isolation of 1-Methyl-indazole-3- carboxylic acid from the unesterified 2-Methyl-indazole-3-carboxylic acid by purification technique such as washing with a base step (c) the organic base used is selected from Ammonia, Triethylamine, Pyridine and the like, preferably ammonia. 10. An improved process as claimed in claims 1 to 9 wherein the acid used in the hydrolysis of the ester of the formula (II) in step (d) is selected from 2-20% Hydrochloric acid, 2-40% sulfuric acid, polyphosphoric acid, sulfonic acids such as methanesulfonic acid, Toluene sulfonic acid and the like. Preferably 2-40% sulfuric acid, more preferably 10-15% sulfuric acid. 11. An improved process as claimed in claims 1 to 9 wherein the base used in the hydrolysis of the ester of the formula (II) in step (d) is selected from sodium or potassium hydroxide or carbonate, preferably sodium or potassium hydroxide. 12. An improved process as claimed in claims 11 wherein the solvent used in the base hydrolysis of the ester of the formula (II) in step (d) is selected from water or aqueous alcohols like methanol, ethanol, isopropanol, preferably water. 13. An improved process for the preparation of highly pure l-Methyl-indazole-3- carboxylic acid of the formula (II) useful for the preparation of pharmaceutical grade granisetron substantially as herein described with reference to the examples.

Documents:

636-che-2004-abstract.pdf

636-che-2004-claims duplicate.pdf

636-che-2004-claims original.pdf

636-che-2004-correspondnece-others.pdf

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636-che-2004-description(complete) duplicate.pdf

636-che-2004-description(complete) original.pdf

636-che-2004-form 1.pdf

636-che-2004-form 19.pdf

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