Title of Invention

AN IMPROVED PROCESS FOR THE PREPARATION OF ZOLEDRONIC ACID

Abstract

The invention disclosed in this application relates to an improved process for the preparation of zoledronic acid of formula (I) given below which comprises heating at a temperature in the range of 50-80 °C a solution of imidazol-1-ylacetic acid hydrochloride with ortho-phosphoric acid in a solvent medium where boiling point of the solvent used in lesser or close to that of phosphorous trichloride, adding phosphorous trichloride to the reaction mass slowly over a period of 2-3hr at a temperature in the range of 50-80 °C, keeping the resulting reaction mass at a temperature in the range of 50-80 °C for a period of 1-6hr, adding hydrochloric acid to the reaction mass and keeping the reaction mass at a temperature in the range of 60-120 °C, separating the organic solvent from the reaction mass while it is still hot, and diluting the aqueous layer containing zoledronic acid with water miscible solvent. Zoledronic acid is widely used as a bone resorption inhibitor.

Full Text

The above process has some disadvantages like no control on exothermic nature of reaction, no control on loss of phosphorus trichloride due to vigorous evolution of hydrogen chloride gas and poor yield. Loss of phosphorous trichloride will lead to shortage of required moles of this reagent in the reaction. Shortage of phosphorous trichloride will lead to formation of gummy impurities and poor yield. Also, the boiling point (131-132 °C) of chlorobenzene used in the process is higher than the boiling point (76 °C) of phosphorous trichloride. Controlling the reaction temperature (100 °C) is not possible using chlorobenzene as a solvent. Another disadvantage in the prior art is the reaction mass becomes very thick within no time and mixing of reagents is practically impossible using standard stirrers. Zolidronic acid has become a well-known bone resorption inhibition drug that has now been on the market and has shown great promise as a valuable bone resorption inhibitor with few side effects. Keeping in view of the difficulties in commercialization of above-mentioned process for the preparation of zoledronic acid we aimed to develop a simple and economical process for commercial production of zoledronic acid. We observed that a promising approach for such a process is to (a) control the rate of reaction by controlling the addition of one or more reagents (b) do the reaction at lowest possible temperature so that the loss of reagents such as phosphorous trichloride can be avoided and (c) improve the mixing capacity of reagents to the maximum possible time of reaction so that the yield can be consistent at any scale of reaction. Accordingly, the main objective of the present invention is to provide an improved process for the preparation of zoledronic acid. Another objective of the present invention is to provide an improved process for the preparation of zoledronic acid at much higher yield (ca. 80%) than the yield (41%) obtained in the prior art process. Yet another objective of the present invention is to provide an improved process for the preparation of zoledronic acid which is free from the problems experienced hitherto in the scaling up of the process for commercial purposes. Still another objective of the present invention is to provide an improved process for the preparation of zoledronic acid wherein the yield of zoledronic acid produced is consistent. Another objective of the present invention is to provide an improved process for the preparation of zoledronic acid which is commercially applicable. Another objective of the present invention is to provide an improved process for the preparation of zoledronic acid wherein the exothermic nature of the reaction mass is avoided by controlling the addition of phosphorous trichloride, thereby making the process safe. Another objective of the present invention is to provide an improved process for the preparation of zoledronic acid wherein the reaction is conducted at lowest possible temperature such as 50-80 °C for better control over stirring problem. Another objective of the present invention is to provide an improved process for the preparation of zoledronic which is simple and economical The present invention has been developed based on our finding that by controlling the rate of addition of phosphorus trichloride to the reaction mass exothermic nature of the reaction can be controlled. Further, the reaction takes place at temperatures as low as 50 °C. Therefore, heating of reaction mass to 100 °C as mentioned in the prior art is not essential to get optimum yield of zoledronic acid. Also, stirring of reaction mass by using standard stirrers became easy without any difficulty. (vi) diluting the aqueous layer containing zoledronic acid with water miscible solvents (vii) filtering the crude zoledronic acid and (viii) recrystallising zoledronic acid from water or aqueous alcohols In a preferred embodiment of the present invention temperature of the reaction mass during phosphorous trichloride addition in the step (i) may be preferably 60-70 °C. Initial maintenance of reaction mass for first two hours should be in the range of 50°C - 60 °C. Solvent used for the reaction should be hydrocarbon solvents such as heptane, cyclohexane, benzene, fluorobenzene, halogenated solvent such as chloroform, ethylene dichloride, carbon tetrachloride, preferably cyclohexane or ethylene dichloride. Solvents like toluene, xylene or chlorobenzene can also be used if one controls the rate of phosphorous trichloride addition and maintains the reaction temperature between 50-80°C. After implementing these process parameters yield of zoledronic acid was found to be more than 75%. Preferred reaction time in step (iii) is between 4-6hr. Temperature of reaction mass during the hydrolysis in step (iv) is preferably the boiling point of reaction mass containing water and the organic solvent used, preferably 80-100 °C. This simplification has led to the synthesis of zoledronic acid in a very simple and easy to adopt manner suitable for any commercial scale. Also, without any repeated recrystallization techniques, zoledronic acid could be prepared in very high purity (>99.8%). The invention is described in detail in the Examples given below which are provided only by way of illustration and therefore should not be construed to limit the scope of the invention further illustrated by the following example. (i) Preparation of Imidazol-1-ylacetic acid Into a 1-L, three-necked RB flask is charged lOOg of imidazole, 40ml of DMF, 400ml of toluene, 180g of potassium carbonate and lOg of potassium iodide. After stirring for lOmin, 240g of methyl chloroacetate was added slowly over a period of 1.5-2.0hr at 25-30°C. The reaction mass was kept under stirring at 25-30 °C for lhr and slowly heated to 60-65°C. After maintaining at the same temperature for 2-3hr reaction was found to be over by TLC. The reaction mass was cooled to 25-30°C and added 200ml of ethyl acetate. The reaction mass was stirred for 20-30min and decanted the top organic layer. The residue was once again extracted with ethyl acetate (200ml). Finally water (200ml) was added to the reaction mass and stirred for 30min. Inorganic salts were removed by filtration and the filtrate extracted with ethyl acetate (2 x 200ml). All ethyl acetate extractions were combined and distilled off under vaccum to get 220g of crude mass. The crude mass was suspended in 500ml of water and refluxed for 4-5hr. Reaction mass became a clear liquid. The reaction mass was treated with charcoal and distilled off water under vaccum keeping the temperature below 80°C. The residue was cooled to 25-30°C and added 250ml of methanol. The suspension was stirred for lhr and filtered the mass. The wet cake was washed with 50ml of methanol and dried at 50-60°C to get 150g of white crystalline solid of imidazol-1-ylacetic acid. Melting point is 268-269 °C. Purity by HPLC is 99.2%. Into a 500-ml5 three-necked RB flask is added 200ml of isopropanol and 60g of imidizol-1-ylacetic acid prepared by the process described in step (i). The contents were heated to 70°C and maintained for 20min. A solution of IPA-HC1 (150g, 14% solution) was added to the reaction mass at 60-70°C over a period of 60-90min. After maintaining a 60-70°C for 30min, reaction mass was cooled to 25-30°C and kept for 2hr before filtration. The wet cake was washed with 50ml of IPA and dried at 60-70°C to get 70g of white crystalline imidazol-lylacetic acid hydrochloride. (iii) Preparation of zoledronic acid Into a 2L5 three-necked RB flask was added 60g of imidazol-1 -ylacetic acid hydrochloride prepared by the process described in step (ii), 105g of o-phosphoric acid and 250ml of ethylene dichloride. The reaction mass was heated to 50-55°C and added 152g of phosphorous trichloride over a period of 2.0-2.5h keeping the temperature below 80°C. After maintaining at 70-80°C for 4 hr the reaction was quenched by adding 30ml of water and 165g of concentrated HC1. The reaction mass was heated to reflux temperature and maintained for 5-6 hr. The reaction mass was cooled to 25-30°C, separated ethylene dichloride layer, and treated the aqueous layer with carbon. Acetone (700ml) was added to the reaction mass and cooled to 5-10°C. After maintaining for 2-3 hr reaction mass was filtered and the wet cake washed with 100ml of acetone. The Zoledronic acid so produced was dried at 50-60°C to get 85g of white crystalline solid. Purity by HPLC is 98.5%. A small sample was dissolved in 20 times refluxing water and cooled to 25-30°C. Pure zoledronic acid was isolated by filtration. Purity by HPLC is 99.4%. Example 2 Preparation of zoledronic acid Into a 2L, three-necked RB flask was added 60g of imidazol-1-ylacetic acid hydrochloride prepared by the process described in step (i) of the Example 1, 105g of o-phosphoric acid and 250ml of cyclohexane. The reaction mass was heated to 50-55°C and added 152g of phosphorous trichloride over a period of 2.0-2.5hr keeping the temperature below 80°C. After maintaining at 80°C for 6hr, the reaction was quenched by adding 100 ml of water and 165g of concentrated HC1. The reaction mass was heated to reflux temperature and maintained for 5-6hr. The reaction mass was cooled to 25-30°C, separated cyclohexane layer, and treated the aqueous layer with carbon. Acetone (700ml) was added to the reaction mass and cooled to 5-10°C. After maintaining for 2-3hr reaction mass was filtered and the wet cake washed with 100ml of acetone. Crude zoledronic acid was dried at 50-60°C to get 80g as white crystalline solid. Purity by HPLC is 98.0%. The above crude zoledronic acid was taken into a 2L glass flask and added 1600ml of DM water. The reaction mass was heated to 90-95°C and maintained for 2-3hr to dissolve the solid. Carbon (lOg) was added to the reaction mass and filtered while hot. The filtrate was cooled to 25-30°C and maintained for 3-4hr before filtration. Wet cake was washed with water and dried at 50»60°C till the moisture content reached 6-10%. Yield of pure zoledronic acid, as monohydrate was 70g. Purity by HPLC is 99.3%. Example 3 Preparation of zoledronic acid Into a 200L glass flask containing 10.5kg of o-phosphoric acid and 25L of chlorobenzene was added 6.0 kg of imidazol-1-ylacetic acid hydrochloride prepared by the process described in step (i) of the Example 1. The reaction mass was heated to 50-55 °C and added 15.2 kg of phosphorous trichloride over a period of 2.0-2.5hr keeping the temperature below 80 °C. After maintaining at 60-80 °C for 5hr the reaction was quenched by adding 3.0 L of water and 16.5 kg of concentrated HC1. The reaction mass was heated to reflux temperature and maintained for 5-6hr. The reaction mass was cooled to 25-30 °C, separated chlorobenzene layer, and treated the aqueous layer with carbon. Acetone (70.0 L) was added to the reaction mass and cooled to 5-10 °C. After maintaining for 2-3hr reaction mass was filtered and the wet cake washed with 10.0 L of acetone. Crude zoledronic acid was dried at 50-60 °C to get 8.0 kg as white crystalline solid. Purity by HPLC is 99.0%. The above crude zoledronic acid was taken into a 250-L, glass lined reactor and added 160 L of DM water. The reaction mass was heated to 90-95 °C and maintained for 2-3hr to dissolve the solid. Carbon (1.0 kg) was added to the reaction mass and filtered while hot. The filtrate was cooled to 25-30 °C and maintained for 3-4hr before filtration. Wet cake was washed with water and dried at 50-60 °C till the moisture content reached 6-10%. Yield of pure zoledronic acid, as monohydrate was 7.0 Kg. Purity by HPLC is 99.8%. Advantages of present invention: 1. Zoledronic acid is produced at much higher yield (ca. 80%) than the yield (41%) as per the prior art process. 2. The process is free from the problems experienced hitherto in the scaling up of the process for commercial purposes. Hence the process is useful for commercial application. 3. The yield of zoledronic acid produced is consistent and in a purity of more than 99.8% 4. There is no exothermic reaction in the process and therefore the process is simple and safe. (viii) recrystallising zoledronic acid from water or aqueous alcohols. 2. The process as claimed in claim 1 wherein the solvent employed in the reaction in step (i) is selected from hydrocarbon solvents such as cyclohexane, hexane, heptane, benzene, fluorobenzene, halogenated solvents such as chloroform, ethylene dichloride, carbon tetrachloride, preferably, cyclohexane, ethylene dichloride, or heptane. 3. The process as claimed in claims 1 and 2 wherein the hydrochloric acid in step (v) is 2- 4 times the weight of imidazoM-ylacetic acid hydrochloride in the process. 4. The process as claimed in claims 1-3 wherein the amount of miscible solvent in step (vii) is 10-20 times, preferably 10-15 times to the weight of imidazol-1-ylacetic acid hydrochloride in the process. 5. The process as claimed in claims 1-4 wherein the miscible solvent in step (vii) is selected from acetone, methanol, isopropanol, acetonitrile, THF, preferably methanol or acetone. 6. The process as claimed in claims 1-5 wherein the amount of water in recrystallization of crude zoledronic acid is 20-30 times the weight of imidazol-l-ylacetic acid hydrochloride in the process. 7. A process for the preparation of zoledronic acid of the formula-I as herein described with reference to Examples. The above process has some disadvantages like no control on exothermic nature of reaction, no control on loss of phosphorus trichloride due to vigorous evolution of hydrogen chloride gas and poor yield. Loss of phosphorous trichloride will lead to shortage of required moles of this reagent in the reaction. Shortage of phosphorous trichloride will lead to formation of gummy impurities and poor yield. Also, the boiling point (131-132 °C) of chlorobenzene used in the process is higher than the boiling point (76 °C) of phosphorous trichloride. Controlling the reaction temperature (100 °C) is not possible using chlorobenzene as a solvent. Another disadvantage in the prior art is the reaction mass becomes very thick within no time and mixing of reagents is practically impossible using standard stirrers. Zolidronic acid has become a well-known bone resorption inhibition drug that has now been on the market and has shown great promise as a valuable bone resorption inhibitor with few side effects. Keeping in view of the difficulties in commercialization of above-mentioned process for the preparation of zoledronic acid we aimed to develop a simple and economical process for commercial production of zoledronic acid. We observed that a promising approach for such a process is to (a) control the rate of reaction by controlling the addition of one or more reagents (b) do the reaction at lowest possible temperature so that the loss of reagents such as phosphorous trichloride can be avoided and (c) improve the mixing capacity of reagents to the maximum possible time of reaction so that the yield can be consistent at any scale of reaction. Accordingly, the main objective of the present invention is to provide an improved process for the preparation of zoledronic acid. Another objective of the present invention is to provide an improved process for the preparation of zoledronic acid at much higher yield (ca. 80%) than the yield (41%) obtained in the prior art process. Yet another objective of the present invention is to provide an improved process for the preparation of zoledronic acid which is free from the problems experienced hitherto in the scaling up of the process for commercial purposes. Still another objective of the present invention is to provide an improved process for the preparation of zoledronic acid wherein the yield of zoledronic acid produced is consistent. Another objective of the present invention is to provide an improved process for the preparation of zoledronic acid which is commercially applicable. Another objective of the present invention is to provide an improved process for the preparation of zoledronic acid wherein the exothermic nature of the reaction mass is avoided by controlling the addition of phosphorous trichloride, thereby making the process safe. Another objective of the present invention is to provide an improved process for the preparation of zoledronic acid wherein the reaction is conducted at lowest possible temperature such as 50-80 °C for better control over stirring problem. Another objective of the present invention is to provide an improved process for the preparation of zoledronic which is simple and economical The present invention has been developed based on our finding that by controlling the rate of addition of phosphorus trichloride to the reaction mass exothermic nature of the reaction can be controlled. Further, the reaction takes place at temperatures as low as 50 °C. Therefore, heating of reaction mass to 100 °C as mentioned in the prior art is not essential to get optimum yield of zoledronic acid. Also, stirring of reaction mass by using standard stirrers became easy without any difficulty. (vi) diluting the aqueous layer containing zoledronic acid with water miscible solvents (vii) filtering the crude zoledronic acid and (viii) recrystallising zoledronic acid from water or aqueous alcohols In a preferred embodiment of the present invention temperature of the reaction mass during phosphorous trichloride addition in the step (i) may be preferably 60-70 °C. Initial maintenance of reaction mass for first two hours should be in the range of 50°C - 60 °C. Solvent used for the reaction should be hydrocarbon solvents such as heptane, cyclohexane, benzene, fluorobenzene, halogenated solvent such as chloroform, ethylene dichloride, carbon tetrachloride, preferably cyclohexane or ethylene dichloride. Solvents like toluene, xylene or chlorobenzene can also be used if one controls the rate of phosphorous trichloride addition and maintains the reaction temperature between 50-80°C. After implementing these process parameters yield of zoledronic acid was found to be more than 75%. Preferred reaction time in step (iii) is between 4-6hr. Temperature of reaction mass during the hydrolysis in step (iv) is preferably the boiling point of reaction mass containing water and the organic solvent used, preferably 80-100 °C. This simplification has led to the synthesis of zoledronic acid in a very simple and easy to adopt manner suitable for any commercial scale. Also, without any repeated recrystallization techniques, zoledronic acid could be prepared in very high purity (>99.8%). The invention is described in detail in the Examples given below which are provided only by way of illustration and therefore should not be construed to limit the scope of the invention further illustrated by the following example. (i) Preparation of Imidazol-1-ylacetic acid Into a 1-L, three-necked RB flask is charged lOOg of imidazole, 40ml of DMF, 400ml of toluene, 180g of potassium carbonate and lOg of potassium iodide. After stirring for lOmin, 240g of methyl chloroacetate was added slowly over a period of 1.5-2.0hr at 25-30°C. The reaction mass was kept under stirring at 25-30 °C for lhr and slowly heated to 60-65°C. After maintaining at the same temperature for 2-3hr reaction was found to be over by TLC. The reaction mass was cooled to 25-30°C and added 200ml of ethyl acetate. The reaction mass was stirred for 20-30min and decanted the top organic layer. The residue was once again extracted with ethyl acetate (200ml). Finally water (200ml) was added to the reaction mass and stirred for 30min. Inorganic salts were removed by filtration and the filtrate extracted with ethyl acetate (2 x 200ml). All ethyl acetate extractions were combined and distilled off under vaccum to get 220g of crude mass. The crude mass was suspended in 500ml of water and refluxed for 4-5hr. Reaction mass became a clear liquid. The reaction mass was treated with charcoal and distilled off water under vaccum keeping the temperature below 80°C. The residue was cooled to 25-30°C and added 250ml of methanol. The suspension was stirred for lhr and filtered the mass. The wet cake was washed with 50ml of methanol and dried at 50-60°C to get 150g of white crystalline solid of imidazol-1-ylacetic acid. Melting point is 268-269 °C. Purity by HPLC is 99.2%. Into a 500-ml5 three-necked RB flask is added 200ml of isopropanol and 60g of imidizol-1-ylacetic acid prepared by the process described in step (i). The contents were heated to 70°C and maintained for 20min. A solution of IPA-HC1 (150g, 14% solution) was added to the reaction mass at 60-70°C over a period of 60-90min. After maintaining a 60-70°C for 30min, reaction mass was cooled to 25-30°C and kept for 2hr before filtration. The wet cake was washed with 50ml of IPA and dried at 60-70°C to get 70g of white crystalline imidazol-lylacetic acid hydrochloride. (iii) Preparation of zoledronic acid Into a 2L5 three-necked RB flask was added 60g of imidazol-1 -ylacetic acid hydrochloride prepared by the process described in step (ii), 105g of o-phosphoric acid and 250ml of ethylene dichloride. The reaction mass was heated to 50-55°C and added 152g of phosphorous trichloride over a period of 2.0-2.5h keeping the temperature below 80°C. After maintaining at 70-80°C for 4 hr the reaction was quenched by adding 30ml of water and 165g of concentrated HC1. The reaction mass was heated to reflux temperature and maintained for 5-6 hr. The reaction mass was cooled to 25-30°C, separated ethylene dichloride layer, and treated the aqueous layer with carbon. Acetone (700ml) was added to the reaction mass and cooled to 5-10°C. After maintaining for 2-3 hr reaction mass was filtered and the wet cake washed with 100ml of acetone. The Zoledronic acid so produced was dried at 50-60°C to get 85g of white crystalline solid. Purity by HPLC is 98.5%. A small sample was dissolved in 20 times refluxing water and cooled to 25-30°C. Pure zoledronic acid was isolated by filtration. Purity by HPLC is 99.4%. Example 2 Preparation of zoledronic acid Into a 2L, three-necked RB flask was added 60g of imidazol-1-ylacetic acid hydrochloride prepared by the process described in step (i) of the Example 1, 105g of o-phosphoric acid and 250ml of cyclohexane. The reaction mass was heated to 50-55°C and added 152g of phosphorous trichloride over a period of 2.0-2.5hr keeping the temperature below 80°C. After maintaining at 80°C for 6hr, the reaction was quenched by adding 100 ml of water and 165g of concentrated HC1. The reaction mass was heated to reflux temperature and maintained for 5-6hr. The reaction mass was cooled to 25-30°C, separated cyclohexane layer, and treated the aqueous layer with carbon. Acetone (700ml) was added to the reaction mass and cooled to 5-10°C. After maintaining for 2-3hr reaction mass was filtered and the wet cake washed with 100ml of acetone. Crude zoledronic acid was dried at 50-60°C to get 80g as white crystalline solid. Purity by HPLC is 98.0%. The above crude zoledronic acid was taken into a 2L glass flask and added 1600ml of DM water. The reaction mass was heated to 90-95°C and maintained for 2-3hr to dissolve the solid. Carbon (lOg) was added to the reaction mass and filtered while hot. The filtrate was cooled to 25-30°C and maintained for 3-4hr before filtration. Wet cake was washed with water and dried at 50»60°C till the moisture content reached 6-10%. Yield of pure zoledronic acid, as monohydrate was 70g. Purity by HPLC is 99.3%. Example 3 Preparation of zoledronic acid Into a 200L glass flask containing 10.5kg of o-phosphoric acid and 25L of chlorobenzene was added 6.0 kg of imidazol-1-ylacetic acid hydrochloride prepared by the process described in step (i) of the Example 1. The reaction mass was heated to 50-55 °C and added 15.2 kg of phosphorous trichloride over a period of 2.0-2.5hr keeping the temperature below 80 °C. After maintaining at 60-80 °C for 5hr the reaction was quenched by adding 3.0 L of water and 16.5 kg of concentrated HC1. The reaction mass was heated to reflux temperature and maintained for 5-6hr. The reaction mass was cooled to 25-30 °C, separated chlorobenzene layer, and treated the aqueous layer with carbon. Acetone (70.0 L) was added to the reaction mass and cooled to 5-10 °C. After maintaining for 2-3hr reaction mass was filtered and the wet cake washed with 10.0 L of acetone. Crude zoledronic acid was dried at 50-60 °C to get 8.0 kg as white crystalline solid. Purity by HPLC is 99.0%. The above crude zoledronic acid was taken into a 250-L, glass lined reactor and added 160 L of DM water. The reaction mass was heated to 90-95 °C and maintained for 2-3hr to dissolve the solid. Carbon (1.0 kg) was added to the reaction mass and filtered while hot. The filtrate was cooled to 25-30 °C and maintained for 3-4hr before filtration. Wet cake was washed with water and dried at 50-60 °C till the moisture content reached 6-10%. Yield of pure zoledronic acid, as monohydrate was 7.0 Kg. Purity by HPLC is 99.8%. Advantages of present invention: 1. Zoledronic acid is produced at much higher yield (ca. 80%) than the yield (41%) as per the prior art process. 2. The process is free from the problems experienced hitherto in the scaling up of the process for commercial purposes. Hence the process is useful for commercial application. 3. The yield of zoledronic acid produced is consistent and in a purity of more than 99.8% 4. There is no exothermic reaction in the process and therefore the process is simple and safe. (viii) recrystallising zoledronic acid from water or aqueous alcohols. 2. The process as claimed in claim 1 wherein the solvent employed in the reaction in step (i) is selected from hydrocarbon solvents such as cyclohexane, hexane, heptane, benzene, fluorobenzene, halogenated solvents such as chloroform, ethylene dichloride, carbon tetrachloride, preferably, cyclohexane, ethylene dichloride, or heptane. 3. The process as claimed in claims 1 and 2 wherein the hydrochloric acid in step (v) is 2- 4 times the weight of imidazoM-ylacetic acid hydrochloride in the process. 4. The process as claimed in claims 1-3 wherein the amount of miscible solvent in step (vii) is 10-20 times, preferably 10-15 times to the weight of imidazol-1-ylacetic acid hydrochloride in the process. 5. The process as claimed in claims 1-4 wherein the miscible solvent in step (vii) is selected from acetone, methanol, isopropanol, acetonitrile, THF, preferably methanol or acetone. 6. The process as claimed in claims 1-5 wherein the amount of water in recrystallization of crude zoledronic acid is 20-30 times the weight of imidazol-l-ylacetic acid hydrochloride in the process. 7. A process for the preparation of zoledronic acid of the formula-I as herein described with reference to Examples.

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