Preparation method for converting naproxen impurities into naproxen racemate
By carrying out a series of chemical reactions under a medium of hydrohalogenic acid and concentrated sulfuric acid, the residual impurities in the naproxen refining process are converted into naproxen racemates, which solves the problem of impurity removal and improves the utilization rate of raw materials and product quality.
Patent Information
- Application Number
- CN202411789249.5
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-12-06
- Publication Date
- 2025-03-14
AI Technical Summary
The prior art is difficult to effectively remove the residual impurity 2-(6-(6-(3 hydroxy-2,2-dimethyl)-propoxy-2-naphthyl)propionic acid during naproxen refining, resulting in solid waste pollution and low raw material utilization.
By removing the material containing the impurity in hydrogen halogen acid, converting it into an intermediate, then reacting with methanol under the catalysis of concentrated sulfuric acid, ester hydrolysis, and finally acidification reaction under acidic conditions, naproxen racemate is obtained.
The efficient conversion of impurities into naproxen racemates is achieved, which reduces solid waste pollution, and improves the utilization rate of raw materials and the yield and purity of products.
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Abstract
Description
Technical Field
[0001] The invention relates to a preparation method for converting naproxen impurities into a naproxen racemate, belonging to the technical field of drug synthesis. Background Art
[0002] The synthesis of D,L-naproxen is generally based on naphthyl propionyl methyl ether as raw material, and the crude D,L-naproxen is obtained through the processes of bromination, ketalization, rearrangement, hydrolysis, decolorization and acidification. After that, in order to remove impurities in the crude product, D,L-naproxen fine product is usually obtained through methanol recrystallization. However, in the process of recrystallization with methanol to remove impurities, the methanol mother liquor contains naproxen and the impurity 2-(6-(3-hydroxy-2,2-dimethyl)-propoxy-2-naphthyl) propionic acid, and the content of this impurity is relatively high. If the naproxen in the mother liquor is directly treated as waste after recovery, it is not conducive to environmental protection, and it is also not conducive to improving the utilization rate of raw materials and the yield quality of the product. Therefore, how to recover this impurity is of great significance to the industrial production of naproxen. The structural formula of the above-mentioned impurity 2-(6-(3-hydroxy-2,2-dimethyl)-propoxy-2-naphthyl) propionic acid is as follows:
[0003]
[0004] Since the impurity has a similar structure to naproxen, it is difficult to completely and effectively separate the two by using a general recrystallization method for refining, which is why the conventional base material after methanol refining still contains a large amount of naproxen. Therefore, the common recovery method for the alcohol mother liquor after naproxen refining is to recover methanol by distillation, add toluene and sulfuric acid to the alcohol mother liquor after naproxen refining, control the temperature at 70°C for extraction, collect the toluene organic phase by reflux treatment to dry the water in the toluene system, add methanol and sulfuric acid to the toluene solution for esterification, and after the esterification is completed and washed with water, distill and recover the toluene, continue to heat up to distill naproxen methyl ester out of the system at high temperature, then perform alkaline hydrolysis, adjust the acid, and obtain a crude naproxen product, which is then refined and dried to obtain a dry naproxen product. The refined methanol mother liquor contains about 30% of the impurity 2-(6-(3-hydroxy-2,2-dimethyl)-propoxy-2-naphthyl)propionic acid (Ⅰ). This method cannot effectively transform and recover the impurity, but directly treats it as solid waste. In addition, the recovered naproxen methyl ester undergoes high-temperature distillation with high safety risks and harsh conditions, resulting in a low yield. Summary of the invention
[0005] In view of the defects in the above prior art, the present invention provides a preparation method for converting naproxen impurities into naproxen racemate, and solves the problem of how to convert the impurities back into the naproxen racemate, reduce solid waste pollution and improve the yield.
[0006] The object of the present invention is achieved by the following technical scheme: a method for preparing naproxen impurities by converting them into a naproxen racemate, the method comprising the following steps:
[0007] A. putting the material containing naproxen impurity compound of formula I into hydrohalic acid for removal reaction to convert the naproxen impurity compound of formula I into compound of formula II;
[0008]
[0009] B. reacting the compound of formula II with methanol under the action of concentrated sulfuric acid, and after the reaction, adding an alkali metal hydroxide to carry out ester hydrolysis reaction to obtain a compound of formula III;
[0010]
[0011] C. The compound of formula III is subjected to an acidification reaction under acidic conditions to obtain the compound of formula IV, naproxen racemate;
[0012]
[0013] By allowing the impurity compound of formula I to react directly in a strong acid system of hydrohalic acid, the corresponding groups on the impurity compound I can be effectively removed to form hydroxyl groups; at the same time, since the hydrohalic acid medium system itself contains water, it can be directly used as a solvent, so there is no need to add other solvents during the reaction process, and after the reaction is completed, the intermediate product can be precipitated directly by cooling, which is more conducive to operation; this method can more thoroughly transform the impurity, and the intermediate product obtained has the advantages of high yield and high purity quality; then, under the catalytic action of concentrated sulfuric acid, methyl groups are introduced into the hydroxyl and carboxyl sites of the compound of formula II by reacting with methanol to form corresponding methoxy and carboxylate groups. The product is then hydrolyzed into a carboxylate, thereby effectively separating the product, and then acidifying to obtain the corresponding naproxen racemate; this is equivalent to solving the defect that the naproxen racemate cannot be separated by crystallization due to the similar structure of the impurity compound of formula I, thereby realizing a process of separating the naproxen racemate fraction without using high-temperature distillation, which is more conducive to operation and industrial production. The method of the present invention can efficiently convert the impurity compound of formula I into the naproxen racemate, and the reaction in step A can basically completely convert the impurity, thereby improving the final utilization rate of the raw materials, having the advantage of high product yield, and avoiding excessive solid waste generation to pollute the environment, having an environmentally friendly effect.
[0014] In the above-mentioned preparation method of converting naproxen impurities into naproxen racemate, preferably, the hydrohalic acid in step A is selected from hydrobromic acid, hydroiodic acid or hydrochloric acid. It has strong acidity and can make the reaction system contain water. Using water in the hydrohalic acid as a solvent in the system can also better reduce environmental pollution. As a further preference, the mass percentage of the hydrobromic acid is 40% to 48%; the mass percentage of the hydroiodic acid is 40% to 57%; and the hydrochloric acid is concentrated hydrochloric acid. It is best to use a mass percentage of 40% to 48% of hydrobromic acid; and a mass percentage of 40% to 57% of hydroiodic acid.
[0015] In the above-mentioned preparation method of converting naproxen impurities into naproxen racemate, the material containing naproxen impurity formula I compound in the above-mentioned step A can be directly using pure naproxen impurity formula I compound as the starting material. Since the naproxen impurity formula I compound itself is an impurity material, it is generally not produced in large quantities. Here, the material containing naproxen impurity formula I compound is preferably used as a naproxen refined base material as a raw material for reaction, which can be well recycled and improved. The overall yield can be improved, and further, the content of the impurity formula I compound in the targeted naproxen refined base material is greater than 5%. In order to better improve the productivity and cost operation, it is conducive to the recycling of naproxen refined base material, improve the utilization rate, and reduce the impact of solid waste on the environment. As a preference, the material containing naproxen impurity formula I compound in step A is a naproxen alcohol refined base material, and the content of naproxen racemate of formula IV compound in the naproxen alcohol refined base material is 45% to 60%; the content of the naproxen impurity formula I compound is 25% to 40%. In the reaction system of the present invention, the naproxen impurity compound of formula I can be effectively converted into the naproxen racemate, so that there is no need to separate the impurities in the refined master batch, and the impurities can be directly converted into the desired naproxen racemate by the method. In addition, the use of hydrohalic acid to catalyze the reaction of the substrate in the synthetic route can also remove the methyl group of the naproxen racemate in the naproxen alcohol refined base material and convert it into the intermediate compound of formula II, which can ensure the overall yield of the naproxen racemate, and will not cause the loss of the original naproxen in the naproxen alcohol refined base material or conversion into other impurity components, so that the total yield of the naproxen racemate can be increased to more than 70%, and the purity can also reach more than 99%.
[0016] In the above-mentioned preparation method of converting naproxen impurities into naproxen racemate, as a preference, the temperature of the removal reaction in step A is controlled at 60°C to reflux temperature; after the removal reaction in step A is completed, water is added to the reaction solution, and then the temperature is lowered to 15°C to 50°C for crystallization. By carrying out the removal reaction under the above-mentioned temperature conditions, the reaction can be better promoted; and after the reaction is completed, water is added to the reaction solution for the purpose of diluting the reaction solution to avoid the reaction solution being viscous and wrapping the impurities, which are not easy to remove. After dilution, the impurities soluble in water can be effectively taken away, thereby improving the purity and quality of the intermediate product. As a further preference, it is best to make the weight ratio of the material containing the naproxen impurity formula I compound: water be 1:6.0-15. It can play a dilution role, and can also more effectively remove impurities, avoiding the purity and quality of the intermediate product being affected by the viscosity of the reaction solution. Further, it is best to add water and then cool it to 15°C to 30°C for full crystallization for 0.5h to 1.5h.
[0017] In the above-mentioned preparation method for converting naproxen impurities into naproxen racemate, preferably, the reaction temperature in step B is 70°C to reflux temperature; the temperature of the ester hydrolysis reaction is 70°C to reflux temperature. By introducing methyl groups more effectively under the catalytic action of concentrated sulfuric acid and controlling the temperature within the above-mentioned temperature range, the hydroxyl group in the compound of formula II can be converted into a methoxy group, and the carboxylic acid group can be converted into the corresponding carboxylate group, which has the advantage of high reaction conversion rate, and the obtained intermediate is also easy to generate the corresponding compound of formula III through hydrolysis reaction. It is only necessary to add alkali to the reaction solution after the reaction is completed to allow the reaction to be hydrolyzed under alkaline conditions. It has good operability and is conducive to industrial production. As a further preference, the reaction temperature in step B is 80°C to 95°C; the temperature of the ester hydrolysis reaction is 85°C to 95°C.
[0018] In the above-mentioned preparation method of converting naproxen impurities into naproxen racemate, the amount of each raw material involved in the reaction in step B can generally be added according to the molar equivalent of the chemical reaction; in addition, since methanol can be used as both a solvent and a raw material involved in the reaction, the amount of methanol can be controlled to be added on the basis of being able to fully react with compound II. In order to better improve the utilization rate of raw materials and reduce waste, as a preference, the molar ratio of the compound of formula II: concentrated sulfuric acid in step B is 1:1.0-2.0; the mass ratio of the compound of formula II: methanol is 1:1.0-5.0. It can better make the reaction more effective and the intermediate product yield is high. As a further preference, the molar ratio of the compound of formula II: concentrated sulfuric acid in step B is 1:1.1-1.5; the mass ratio of the compound of formula II: methanol is 1:1.5-4.0.
[0019] In the above-mentioned preparation method of converting naproxen impurities into naproxen racemate, the ester hydrolysis reaction in step B can be carried out by hydrolysis under alkaline conditions commonly used in the art, and the amount of alkali metal hydroxide used can be any amount that can promote the hydrolysis of the carboxylate group of the intermediate product to form a carboxylate salt. For better explanation, as a preference, the alkali metal hydroxide in step B is selected from one or more of sodium hydroxide, potassium hydroxide and lithium hydroxide. The above-mentioned alkali metal hydroxide can be made of corresponding liquid alkali, that is, prepared into corresponding alkali metal hydroxide aqueous solution. For the amount of alkali used, it is best to make the molar ratio of the compound of formula II: alkali metal hydroxide be 1:1.0-2.0.
[0021] In the above-mentioned method for preparing naproxen impurities by converting them into naproxen racemate, preferably, the temperature of the acidification reaction in step C is 80°C to 95°C.
[0022] In the above-mentioned method for converting naproxen impurities into naproxen racemate, preferably, the acidic conditions in step C are specifically: adjusting the pH value of the system to an acidic condition of 1 to 6 by adding hydrochloric acid. The purpose is to remove excess alkali in the system and to convert the intermediate product carboxylate salt back into the carboxylic acid form by acidification, thereby obtaining the desired product. As a further preference, it is best to adjust the pH value of the system to an acidic condition of 1 to 4 by adding hydrochloric acid.
[0023] The chemical equation of the preparation method of converting naproxen impurities into naproxen racemate of the present invention is as follows:
[0024]
[0025] In summary, compared with the prior art, the present invention has the following advantages:
[0026] 1. The present invention can efficiently convert the impurity compound of formula I into the naproxen racemate, improve the utilization rate of raw materials, and has the advantage of high product yield; it can also avoid excessive solid waste generation and environmental pollution, is environmentally friendly, and does not require high-temperature distillation treatment, which is more conducive to operation and industrial production.
[0027] 2. The present invention can realize the process of converting the impurities in the refined naproxen masterbatch into the desired naproxen racemate directly without separating the impurities in the naproxen masterbatch, and the hydrohalic acid and the like used will not cause side reactions of the original naproxen in the masterbatch, thereby effectively improving the overall yield of naproxen. The total yield of the naproxen racemate can be increased to more than 70%, and the purity can also reach more than 99%. DETAILED DESCRIPTION
[0028] The technical solution of the present invention is further specifically described below through specific embodiments, but the present invention is not limited to these embodiments.
[0029] Example 1
[0030] The naproxen alcohol refined base material is used as the starting material for the reaction. The content of naproxen racemate in the naproxen alcohol refined base material is 57%, and the content of the impurity compound of formula I 2-(6-(3-hydroxy-2,2-dimethyl)-propoxy-2-naphthyl)propionic acid is 30%.
[0031] Weigh 15 g of naproxen alcohol refined base material and 110 mL of 48% hydrobromic acid solution by mass into a 500 mL three-necked flask, heat to 100° C. for reaction for 3 h, and after the reaction is completed, add 100 mL of water to the reaction solution, cool to 20° C. and keep warm for 1 h to fully precipitate the solid product, and filter to obtain a solid intermediate product of the intermediate formula II compound. Perform HPLC detection on the solid intermediate product to confirm that the impurity formula I compound 2-(6-(3-hydroxy-2,2-dimethyl)-propoxy-2-naphthyl)propionic acid content is <0.5%;
[0032] The solid of the intermediate compound of formula II was put into a 500mL four-necked flask, and then 15g of methanol was added, and then 10g of concentrated sulfuric acid was slowly added dropwise. After the addition was completed, the temperature was raised to 85°C-98°C for reaction for 6h. After the reaction was completed, the mixture was allowed to stand, separated into layers, and the upper layer of liquid was collected. The upper layer of liquid was then put into another 500mL three-necked flask, and 150mL of water and 13g of liquid alkali (35% by mass sodium hydroxide aqueous solution) were added. The temperature was raised to 90°C for hydrolysis and heat preservation for 2h, and then stirred for about 30min. The reaction was completed to obtain an aqueous solution containing the intermediate compound of formula III.
[0033] Slowly add hydrochloric acid dropwise to the aqueous solution containing the intermediate compound of formula III to adjust the pH value of the system to 3-4 to obtain a crude naproxen racemate. The crude naproxen racemate is added to 30 g of methanol solvent, heated to reflux to dissolve, and then slowly cooled to fully precipitate solids. The mixture is filtered and the filter cake is dried to obtain 9.75 g of a dry naproxen racemate with a yield of 74.71% and a purity of 99.6%. The yield here is calculated based on the sum of the weight of the naproxen racemate in the naproxen alcohol refined base material and the weight of the impurity compound of formula I 2-(6-(3-hydroxy-2,2-dimethyl)-propoxy-2-naphthyl)propionic acid (13.05 g).
[0034] Example 2
[0035] The naproxen alcohol refined base material is used as the starting material for the reaction. The content of naproxen racemate in the naproxen alcohol refined base material is 57%, and the content of the impurity compound of formula I 2-(6-(3-hydroxy-2,2-dimethyl)-propoxy-2-naphthyl)propionic acid is 30%.
[0036] Weigh 15 g of the above-mentioned naproxen alcohol refined base material and 130 ml of hydrobromic acid with a mass percentage of 40% and put them into a 500 ml three-necked flask, heat to 95° C. for reaction for 3.5 hours, then add 100 ml of water to the reaction solution, cool to 20° C. and keep warm for 1 hour to fully precipitate the solid product, filter to obtain a solid intermediate product of the intermediate formula II compound, perform HPLC detection on the solid intermediate product, and confirm that the impurity formula I compound 2-(6-(3-hydroxy-2,2-dimethyl)-propoxy-2-naphthyl)propionic acid content is <0.5%;
[0037] The solid of the intermediate compound of formula II was put into a 500ml four-necked flask, and then 20g of methanol was added. After the addition of 12g of concentrated sulfuric acid was completed, the temperature was raised to 90℃~95℃ to react for 5h. After the reaction was completed, the mixture was allowed to stand, separated into layers, and the upper layer of liquid was collected. The upper layer of liquid was then put into another 500ml three-necked flask, and 150ml of water and 13g of liquid alkali (35% by mass sodium hydroxide aqueous solution) were added. The temperature was raised to 90℃ for hydrolysis and heat preservation for 2h, and then stirred for about 30min. After the reaction was completed, an aqueous solution containing the intermediate compound of formula III was obtained.
[0038] Slowly add hydrochloric acid dropwise to the aqueous solution containing the intermediate compound of formula III, adjust the pH value of the system to 3-4, and obtain a crude naproxen racemate. The crude naproxen racemate is added to 30 g of methanol solvent, heated to reflux to dissolve, and then slowly cooled to fully precipitate solids, filtered, and the obtained filter cake is dried to obtain 9.5 g of a dry naproxen racemate with a yield of 72.8% and a purity of 99.5%. The yield here is calculated based on the sum of the weight of the naproxen racemate in the naproxen alcohol refined base material and the weight of the impurity compound of formula I 2-(6-(3-hydroxy-2,2-dimethyl)-propoxy-2-naphthyl)propionic acid (13.05 g).
[0039] Example 3
[0040] The naproxen alcohol refined base material is used as the starting material for the reaction. The content of naproxen racemate in the naproxen alcohol refined base material is 57%, and the content of the impurity compound of formula I 2-(6-(3-hydroxy-2,2-dimethyl)-propoxy-2-naphthyl)propionic acid is 30%.
[0041] Weigh 120 g of the above-mentioned naproxen alcohol refined base material and 1200 mL of hydrobromic acid with a mass percentage of 48% and put them into a 2000 mL three-necked flask. Heat to 100 ° C. and react for 3 hours. After the reaction is completed, 1000 ml of water is added to the reaction solution, and the temperature is slowly lowered to 20 ° C. and kept warm for 1 hour to fully precipitate the solid. The solid intermediate product of the intermediate formula II compound is filtered out, and the solid intermediate product is subjected to HPLC detection to confirm that the impurity formula I compound 2-(6-(3-hydroxy-2,2-dimethyl)-propoxy-2-naphthyl)propionic acid content is <0.5%.
[0042] The colored solid of the intermediate compound of formula II is put into a 2000mL four-necked flask, 160g of methanol is added, and 100g of concentrated sulfuric acid is slowly added dropwise. After the addition is completed, the temperature is raised to 85°C to 90°C for reaction for 6h. After the reaction is completed, the mixture is allowed to stand, separated into layers, and the upper layer of liquid is collected. The upper layer of liquid is then put into another 2000mL three-necked flask, 1300ml of water and 104g of liquid alkali (35% by mass sodium hydroxide aqueous solution) are added, the temperature is raised to 90°C for hydrolysis and heat preservation for 2h, and then stirred for about 30min. The reaction is completed to obtain an aqueous solution containing the intermediate compound of formula III.
[0043] Slowly add hydrochloric acid to the aqueous solution containing the intermediate compound of formula III, adjust the pH value of the system to 3-4, and obtain a crude naproxen racemate. Add the crude naproxen racemate to 300g of methanol solvent, heat to reflux to dissolve, and then slowly cool to fully precipitate solids, filter, and dry the obtained filter cake to obtain 75.84g of naproxen racemate dry product, with a yield of 72.64% and a content of 99.4%. The yield here is calculated based on the sum of the weight of the naproxen racemate in the naproxen alcohol refined base material and the weight of the impurity compound of formula I 2-(6-(3-hydroxy-2,2-dimethyl)-propoxy-2-naphthyl)propionic acid (104.4g) as the basis.
[0044] Example 4
[0045] The naproxen alcohol refined base material is used as the starting material for the reaction, the content of naproxen racemate in the naproxen alcohol refined base material is 60%, and the content of the impurity compound of formula I 2-(6-(3-hydroxy-2,2-dimethyl)-propoxy-2-naphthyl)propionic acid is 25%.
[0046] Weigh 15 g of the above-mentioned naproxen alcohol refined base material and 150 ml of 45% by mass hydroiodic acid into a 500 ml three-necked flask, heat to 95° C. for reaction for 4 h, then add 100 ml of water to the reaction solution, cool to 25° C. and keep warm for 1 h to fully precipitate the solid product, filter to obtain a solid intermediate product of the intermediate formula II compound, perform HPLC detection on the solid intermediate product, and confirm that the impurity formula I compound 2-(6-(3-hydroxy-2,2-dimethyl)-propoxy-2-naphthyl)propionic acid content is <0.5%;
[0047] The solid intermediate product of the intermediate compound of formula II is put into a 500ml four-necked flask, and then 25g of methanol is added, and 16g of concentrated sulfuric acid is slowly added dropwise. After the addition is completed, the temperature is raised to 70°C-80°C for reaction for 5h. After the reaction is completed, the mixture is allowed to stand, separated into layers, and the upper layer of liquid is collected. The upper layer of liquid is then put into another 500ml three-necked flask, and 150ml of water and 11g of liquid alkali (35% by mass sodium hydroxide aqueous solution) are added. The temperature is raised to 80°C for hydrolysis and heat preservation for 1.5h, and then stirred for about 30min. The reaction is completed to obtain an aqueous solution containing the intermediate compound of formula III.
[0048] Slowly add hydrochloric acid dropwise to the aqueous solution containing the intermediate compound of formula III, adjust the pH value of the system to 3-4, and obtain a crude naproxen racemate. The crude naproxen racemate is added to 40 g of methanol solvent, heated to reflux to dissolve, and then slowly cooled to fully precipitate solids, filtered, and the obtained filter cake is dried to obtain 9.84 g of a dry naproxen racemate with a yield of 77.2% and a purity of 99.4%. The yield here is calculated based on the sum of the weight of the naproxen racemate in the naproxen alcohol refined base material and the weight of the impurity compound of formula I 2-(6-(3-hydroxy-2,2-dimethyl)-propoxy-2-naphthyl)propionic acid (12.75 g).
[0049] Example 5
[0050] The naproxen alcohol refined base material is used as the starting material for the reaction, the content of naproxen racemate in the naproxen alcohol refined base material is 60%, and the content of the impurity compound of formula I 2-(6-(3-hydroxy-2,2-dimethyl)-propoxy-2-naphthyl)propionic acid is 25%.
[0051] Weigh 15 g of the above-mentioned naproxen alcohol refined base material and 130 ml of 57% hydroiodic acid by mass into a 500 ml three-necked flask, heat to reflux temperature for reflux reaction for 3 hours, then add 100 ml of water to the reaction solution, cool to 20° C. and keep warm for 1 hour to fully precipitate the solid product, filter to obtain a solid intermediate product of the intermediate formula II compound, perform HPLC detection on the solid intermediate product, and confirm that the impurity formula I compound 2-(6-(3-hydroxy-2,2-dimethyl)-propoxy-2-naphthyl)propionic acid content is <0.5%;
[0052] The solid intermediate product of the intermediate compound of formula II was put into a 500ml four-necked flask, and then 25g of methanol was added, and 16g of concentrated sulfuric acid was slowly added dropwise. After the addition was completed, the temperature was raised to 85°C-90°C for reaction for 4h. After the reaction was completed, the mixture was allowed to stand, separated into layers, and the upper layer of liquid was collected. The upper layer of liquid was then put into another 500ml three-necked flask, and 200ml of water and 11g of liquid alkali (35% by mass sodium hydroxide aqueous solution) were added. The temperature was raised to 85°C for hydrolysis and heat preservation for 1.5h, and then stirred for about 30min. The reaction was completed to obtain an aqueous solution containing the intermediate compound of formula III.
[0053] Slowly add hydrochloric acid dropwise to the aqueous solution containing the intermediate compound of formula III, adjust the pH value of the system to 1-3, and obtain a crude naproxen racemate. The crude naproxen racemate is added to 45 g of methanol solvent, heated to reflux to dissolve, and then slowly cooled to fully precipitate solids, filtered, and the obtained filter cake is dried to obtain 9.96 g of a dry naproxen racemate with a yield of 78.1% and a purity of 99.5%. The yield here is calculated based on the sum of the weight of the naproxen racemate in the naproxen alcohol refined base material and the weight of the impurity compound of formula I 2-(6-(3-hydroxy-2,2-dimethyl)-propoxy-2-naphthyl)propionic acid (12.75 g).
[0054] Example 6
[0055] The naproxen alcohol refined base material is used as the starting material for the reaction, the content of naproxen racemate in the naproxen alcohol refined base material is 45%, and the content of the impurity compound of formula I 2-(6-(3-hydroxy-2,2-dimethyl)-propoxy-2-naphthyl)propionic acid is 40%.
[0056] Weigh 16 g of naproxen alcohol refined base material and 150 mL of 40% by mass hydrobromic acid solution into a 500 mL three-necked flask, heat to 95° C. for reaction for 3 h, and after the reaction is completed, add 150 mL of water to the reaction solution, cool to 25° C. and keep warm for 1 h to fully precipitate the solid product, and filter to obtain a solid intermediate product mixed with the intermediate compound of formula II. The solid intermediate product is tested by HPLC to confirm that the impurity compound of formula I 2-(6-(3-hydroxy-2,2-dimethyl)-propoxy-2-naphthyl)propionic acid content is <0.5%;
[0057] The solid of the intermediate compound of formula II obtained was put into a 500mL four-necked flask, and then 20g of methanol was added, and then 11g of concentrated sulfuric acid was slowly added dropwise. After the addition was completed, the temperature was raised to 95°C-98°C for reaction for 5h. After the reaction was completed, the mixture was allowed to stand, separated into layers, and the upper layer of liquid was collected. The upper layer of liquid was then put into another 500mL three-necked flask, and 150mL of water and 13.5g of liquid alkali (35% by mass sodium hydroxide aqueous solution) were added. The temperature was raised to 90°C for hydrolysis and heat preservation for 2h, and then stirred for about 30min. The reaction was completed to obtain an aqueous solution containing the intermediate compound of formula III.
[0058] Slowly add hydrochloric acid dropwise to the aqueous solution containing the intermediate compound of formula III to adjust the pH value of the system to 3-4 to obtain a crude naproxen racemate. The crude naproxen racemate is added to 40 g of methanol solvent, heated to reflux to dissolve, and then slowly cooled to fully precipitate solids. The solid is filtered and the filter cake is dried to obtain 10.23 g of a dry naproxen racemate with a yield of 75.2% and a purity of 99.5%. The yield here is calculated based on the sum of the weight of the naproxen racemate in the naproxen alcohol refined base material and the weight of the impurity compound of formula I 2-(6-(3-hydroxy-2,2-dimethyl)-propoxy-2-naphthyl)propionic acid (13.6 g).
[0059] Comparative Example 1
[0060] The naproxen alcohol refined base material is used as the starting material for the reaction. The content of naproxen racemate in the naproxen alcohol refined base material is 57%, and the content of the impurity compound of formula I 2-(6-(3-hydroxy-2,2-dimethyl)-propoxy-2-naphthyl)propionic acid is 30%.
[0061] 100 g of naproxen alcohol refined base material and 150 g of toluene were put into a 500 ml clean three-necked flask, and then heated to reflux to dry the water in the toluene system, and then 40 g of methanol and 0.5 sulfuric acid were added, and the reflux temperature was raised to carry out reflux reaction for 4 hours. After the reaction was completed, 50 g of water was added to the reaction solution for washing, and the water was washed twice. The collected toluene organic phase was distilled at atmospheric pressure, heated to raise the temperature to 150 ° C, recovered toluene until it was completely evaporated, and then continued to heat to 180 ℃, naproxen methyl ester was distilled out of the system by high temperature, and distilled to 300 ℃, and the distillation was stopped. 46g of sodium hydroxide aqueous solution (35% by mass of sodium hydroxide aqueous solution) was added to the collected fraction for alkaline hydrolysis, and then hydrochloric acid was added to adjust the pH value of the system to 3-4 to obtain 71.68g of crude naproxen racemate. After refining with methanol, the obtained wet product was dried to obtain 31.45g of dry naproxen racemate, with a yield of 36.15% and a content of 99.4%.
[0062] The yield was calculated based on the sum of the weight of the naproxen racemate in the naproxen alcohol refined base material and the weight of the impurity compound of formula I 2-(6-(3-hydroxy-2,2-dimethyl)-propoxy-2-naphthyl)propionic acid (87 g).
[0063] The specific embodiments described in the present invention are merely examples of the spirit of the present invention. Those skilled in the art may make various modifications or additions to the specific embodiments described or replace them in similar ways, but they will not deviate from the spirit of the present invention or exceed the scope defined by the attached claims.
[0064] Although the present invention has been described in detail and some specific embodiments have been cited, it is obvious to those skilled in the art that various changes and modifications can be made without departing from the spirit and scope of the present invention.
Claims
1. A method for preparing naproxen impurities by converting them into naproxen racemates, characterized in that: The method comprises the following steps: A. putting the material containing naproxen impurity compound of formula I into hydrohalic acid for removal reaction to convert the naproxen impurity compound of formula I into compound of formula II; B. reacting the compound of formula II with methanol under the action of concentrated sulfuric acid, and after the reaction, adding an alkali metal hydroxide to carry out ester hydrolysis reaction to obtain a compound of formula III; C. The compound of formula III is subjected to an acidification reaction under acidic conditions to obtain the compound of formula IV, naproxen racemate; 2. The method for preparing naproxen impurities by converting them into naproxen racemate according to claim 1, characterized in that: The hydrohalic acid in step A is selected from hydrobromic acid, hydroiodic acid or hydrochloric acid.
3. The method for preparing naproxen impurities into naproxen racemate according to claim 2, characterized in that: The mass percentage of the hydrobromic acid is 40% to 48%; the mass percentage of the hydroiodic acid is 40% to 57%; and the hydrochloric acid is concentrated hydrochloric acid.
4. The method for preparing naproxen impurities into naproxen racemate according to claim 1, characterized in that: The material containing the naproxen impurity compound of formula I in step A is a naproxen alcohol refined base material, in which the content of the naproxen racemate of the compound of formula IV is 45% to 60%; the content of the naproxen impurity compound of formula I is 25% to 40%.
5. The method for preparing naproxen impurities by converting them into naproxen racemate according to any one of claims 1 to 4, characterized in that: The temperature of the removal reaction in step A is controlled at 60°C to reflux temperature; after the removal reaction is completed, water is added to the reaction solution, and then the temperature is lowered to 15°C to 50°C for crystallization treatment.
6. The method for preparing naproxen impurities by converting them into a naproxen racemate according to any one of claims 1 to 4, characterized in that: The reaction temperature in step B is 70°C to reflux temperature; the ester hydrolysis reaction temperature is 70°C to reflux temperature.
7. The method for preparing naproxen impurities by converting them into naproxen racemate according to claim 1, 2 or 3, characterized in that: In step B, the molar ratio of the compound of formula II: concentrated sulfuric acid is 1:1.0-2.0; the mass ratio of the compound of formula II: methanol is 1:1.0-5.
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8. The method for preparing naproxen impurities by converting them into naproxen racemate according to claim 7, characterized in that: The alkali metal hydroxide in step B is selected from one or more of sodium hydroxide, potassium hydroxide and lithium hydroxide.
9. The method for preparing naproxen impurities by converting them into naproxen racemate according to any one of claims 1 to 4, characterized in that: The temperature of the acidification reaction in step C is 80°C to 95°C.
10. The method for preparing naproxen impurities by converting them into naproxen racemate according to any one of claims 1 to 4, characterized in that: The acidic conditions in step C are specifically: adjusting the pH value of the system to 1-6 by adding hydrochloric acid.