Preparation process of dexibuprofen

Abstract

The invention provides a dexibuprofen preparation process. The dexibuprofen preparation process comprises the following steps: (1) splitting: adding ibuprofen and meglumine into a solvent, dissolving, heating to form salt, cooling to crystallize, filtering and drying to obtain dexibuprofen meglumine salt; (2) dissociation: adding the dexibuprofen meglumine salt into a solvent, dissociating under an alkaline condition, filtering to remove meglumine, crystallizing the solution, and filtering to obtain a dexibuprofen crude product; and (3) crystallizing dexibuprofen: adding a solvent, heating and dissolving, cooling, separating out a solid, filtering, crushing or granulating, and drying to obtain dexibuprofen with different particle sizes. The dexibuprofen preparation process provided by the invention is high in production efficiency and conversion efficiency, and the prepared product is high in purity and few in impurities. The dexibuprofen product with the crystal form consistent with that of an original product can be stably prepared, the granularity is uniform, and the requirement of the dexibuprofen preparation on the granularity can be met after the dexibuprofen product is crushed.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, and in particular to a preparation process of dexibuprofen. Background Art

[0002] Dexibuprofen, as the dextrorotatory form of ibuprofen, has higher pharmacological activity and efficacy. Compared with the same dose of racemic ibuprofen, dexibuprofen can achieve therapeutic effects at a smaller dose and is superior in safety and pharmacokinetic properties.

[0003] Dexibuprofen is the dextrorotatory form of ibuprofen. Studies have found that the pharmacological activity of ibuprofen mainly comes from the dextrorotatory form, which has a higher efficacy than the racemic form of ibuprofen at the same dose, and a smaller dose can achieve a therapeutic effect. Dexibuprofen has the same effects and uses as ibuprofen, but the former's doses of 150 mg and 300 mg are equivalent to the latter's 200 mg and 400 mg in terms of efficacy, and is superior to ibuprofen in terms of safety and pharmacokinetic properties.

[0004] The preparation route is as follows:

[0005] Patent CN110615735A discloses a method for preparing dexibuprofen, comprising: (1) adding toluene to a reactor, then adding ibuprofen and glucamine, heating to 76-80°C and keeping the temperature to react for more than 0.5h, transferring the material to an amine salt crystallization kettle, adding purified water and cooling to crystallize, and after the temperature drops to 18-22°C, centrifugation and washing are performed, and dexibuprofen glucamine salt is obtained after drying; the feeding ratio of ibuprofen: glucamine: toluene: purified water is 1: 0.65-0.75: 7.5-8: 0.01-0.02; (2) hydrolysis reaction precipitates glucamine; (3) acidification reaction precipitates dexibuprofen. The applicant finally determined that the ratio of the volume of purified water added to the weight of ibuprofen during the preparation of the amine salt is 0.01-0.02L: 1kg, which ultimately makes the molar yield of dexibuprofen high while the melting point of the dextrorotatory amine salt reaches the qualified standard of 135-140°C. The patent uses water as a solvent in the hydrolysis reaction to precipitate octyl glucamine under potassium hydroxide conditions, but octyl glucamine is a white flaky solid, which is very difficult to filter in actual production, seriously affecting production efficiency. In addition, the patent describes the use of acetic acid crystallization in the example part. In the actual production process, the drying efficiency of the product is very low and the equipment is severely corroded.

[0006] Patent CN112500283B discloses a crystallization process of dextrobuprofen, including the following steps: step 1, dissolving the crude dextrobuprofen in acetone to obtain an acetone solution, filtering, and concentrating the acetone to dryness under reduced pressure to obtain a solid; step 2, adding acetone to the solid, heating to dissolve, cooling, stirring and slowly precipitating crystals; step 3, after observing the precipitation of crystals, keeping the temperature and speed unchanged, and steaming out the acetone with a slight negative pressure; step 4, after all the materials are converted into white crystals, turning on the vacuum to continue to evaporate the acetone, and then transferring the solid to a vacuum oven for drying to obtain the finished product. Patent CN102617327A introduces a method for adjusting the pH of dextrobuprofen in water using sodium alcoholate, concentrating and crystallizing to obtain fine dextrobuprofen. Patent CN1490297A introduces a method for dissolving, concentrating, crystallizing, separating, washing and drying dextrobuprofen in ethanol at 60°C to obtain fine dextrobuprofen. The above crystallization methods require complex operations such as dissolution and concentration, which seriously affect production efficiency, and the use of organic solvents is prone to environmental pollution. Dexibuprofen is an organic acid, and the use of alcohols as auxiliary reagents or solvents in the latter two inventions may lead to the production of dexibuprofen lipid impurities, which may affect the quality of the drug.

[0007] Patent CN104744236A The present invention discloses that crude dextrorotatory ibuprofen is dissolved in an organic solvent 1, sodium hydroxide solution is added dropwise to adjust the pH to 9-10, and then the temperature is lowered and crystallized to obtain dextrorotatory ibuprofen sodium salt; then the dextrorotatory ibuprofen sodium salt is dissolved in pure water, an organic solvent 2 is added, and hydrochloric acid is added dropwise under stirring to adjust the pH to 1-2; liquid separation is performed, and the organic phase is taken for vacuum distillation to obtain a solid, which is a pure dextrorotatory ibuprofen product. This process completely eliminates ibuprofen ester impurities, but it is difficult to avoid the influence of the auxiliary material sodium hydroxide and the sodium chloride produced by hydrochloric acid on the quality of the raw material dextrorotatory ibuprofen product.

[0008] In addition, different preparations of dexibuprofen have different requirements for the particle size of the product, and there are no clear patents or literature reports on the control of particle size in the production process of dexibuprofen raw materials.

[0009] Based on this, the present invention provides a process for preparing a dexibuprofen raw material with high purity, low impurities, high production efficiency, environmentally friendly equipment, and applicable to various dexibuprofen preparation requirements. Summary of the invention

[0010] The invention aims to provide a preparation process of dexibuprofen, which has high conversion efficiency and can produce a product with high purity and few impurities.

[0011] The present invention provides a process for preparing dexibuprofen, the steps comprising: (1) separation: adding ibuprofen and glucamine to a solvent, dissolving them, heating them to form salts, cooling them to crystallize, filtering them, and drying them to obtain dexibuprofen glucamine salt; (2) Freeing: Adding dexibuprofen glucamine salt to a solvent under alkaline conditions to free it, filtering to remove glucamine, and crystallizing the solution and filtering to obtain crude dexibuprofen; (3) Crystallization of dexibuprofen: After adding a solvent, the temperature is raised to dissolve, and after cooling, a solid is precipitated, which is then filtered, crushed or granulated, and dried to obtain dexibuprofen of different particle sizes; In the step (2), the solvent under alkaline conditions is a mixed solvent of one or more of methanol, ethanol, isopropanol, acetonitrile, acetone and water; in the step (3), the solvent includes a mixed solvent of one or more of DMF, acetonitrile, acetone and water.

[0012] Furthermore, the solvent in step (1) includes one or more mixed solvents of methanol, ethanol, isopropanol, acetonitrile, toluene, acetone or a mixed solvent with water.

[0013] Furthermore, in the step (2), the solvent under alkaline conditions is methanol.

[0014] Furthermore, the dissolving temperature in step (3) is 60-70°C, and the temperature after cooling is 10-20°C.

[0015] Furthermore, the solvent in step (3) is water.

[0016] Furthermore, the cooling rate in step (3) is 5-20°C / min.

[0017] Furthermore, the stirring speed in step (3) is 20-100 r / min.

[0018] The beneficial effects of the present invention are: In the free step of the present invention, if only water is used as a solvent when removing octylglucamine, octylglucamine is a white flaky solid, which is difficult to filter, and a large amount of foam is easily generated during the filtering process, which increases the difficulty of operation. By adding organic solvents such as methanol, ethanol, isopropanol and acetonitrile, the appearance of octylglucamine can be changed, converted into a white powder, and the filtering effect is improved. During the research process, it was surprisingly found that this method also avoids the generation of foam. Simple filtration can be used in the form of ordinary centrifugation, filter press, etc., and the filtration time is reduced from 12 to 24 hours to 30 to 60 minutes, which greatly improves production efficiency.

[0019] In the crystallization process of dexibuprofen, the use of organic solvents such as cyclohexane, n-hexane, and n-heptane will result in extremely low crystallization yields. These solvents are not only flammable and explosive, volatile, but also have low flash points, significant safety risks, and large solvent losses during use. Crystallization using alcohol solvents easily leads to the production of dexibuprofen esters. In contrast, the crystallization of dexibuprofen using water or a water-based mixed solvent not only has a high yield, but also has higher safety in actual production, a simple solvent recovery process, is environmentally friendly, and has a relatively low preparation cost. And under certain cooling rates and stirring speed conditions, the particle size of dexibuprofen API can be effectively controlled by co-crushing. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] In order to more clearly illustrate the technical solutions of the embodiments of the present application, the drawings required for use in the embodiments will be briefly introduced below. It should be understood that the following drawings only show certain embodiments of the present application and therefore should not be regarded as limiting the scope. For ordinary technicians in this field, other related drawings can be obtained based on these drawings without paying creative work.

[0021] Figure 1 is the optical purity spectrum of the dexibuprofen salt prepared in Example 1; Figure 2 is the liquid phase purity spectrum of dexibuprofen prepared in Example 1; Figure 3 is the optical purity spectrum of dexibuprofen prepared in Example 1; Figure 4 is a particle size distribution diagram of dexibuprofen prepared in Example 1; Figure 5 This is the XRD pattern of dexibuprofen prepared in Example 1.

[0022] Figure 6 It is a SEM image of dexibuprofen prepared in Example 1.

[0023] Figure 7 It is the PLM diagram of dexibuprofen prepared in Example 1. DETAILED DESCRIPTION

[0024] The technical scheme of the present invention is described clearly and completely below. Obviously, the described embodiments are part of the embodiments of the present invention, rather than all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in the field without creative work are within the scope of protection of the present invention. It should be noted that the raw materials can be obtained commercially.

[0025] The present invention provides a process for preparing dexibuprofen, the steps comprising: (1) Separation: Add ibuprofen and glucamine to a solvent and dissolve them, heat them up to form salts, cool them down to crystallize, filter them, and dry them to obtain dexibuprofen glucamine salt; (2) Free: Add dexibuprofen glucamine salt to a solvent under alkaline conditions to free it, filter out the glucamine, crystallize the solution, and filter it to obtain crude dexibuprofen; (3) Crystallization of dexibuprofen: Add a solvent and heat them up to dissolve them, cool them down to precipitate solids, filter them, crush or granulate them, and dry them to obtain dexibuprofen of different particle sizes.

[0026] Wherein, the solvent in step (1) comprises one or more mixed solvents of methanol, ethanol, isopropanol, acetonitrile, toluene, acetone or water; the temperature is maintained at 0-35°C when filtering out octyl glucamine in step (2); the solvent under alkaline conditions in step (2) is a mixed solvent of one or more of methanol, ethanol, isopropanol, acetonitrile, acetone or acetonitrile and water, wherein the mass ratio of the solvent is 2%-80%; the solvent under alkaline conditions in step (2) is methanol; the dissolution temperature in step (3) is 60-70°C, and the temperature after cooling is 10-20°C; the solvent in step (3) comprises one or more mixed solvents of ethanol, methanol, isopropanol, acetonitrile, acetone, acetic acid or water; the solvent in step (3) is water, the cooling rate in step (3) is 5-20°C / min, and the stirring speed in step (3) is 20-100r / min; The present invention will be further explained below with examples: The preparation of the dexibuprofen salt of the present invention, i.e. the separation step, is described by the following examples.

[0027] Example 1

[0028] (1) Resolution: 500 g of ibuprofen and 355 g of the resolution agent octylglucamine were added to a 5000 ml reaction bottle, and 3500 ml of methanol was added. The temperature was raised to 65°C, and the reaction was carried out for 1 hour. The temperature was slowly lowered to 10°C, and the mixture was stirred at this temperature for 1.5 hours. The mixture was filtered and dried to obtain 484.5 g of dextro-ibuprofen salt, and the content of levobprofen was about 0.4%.

[0029] (2) Free: Add a batch of dexibuprofen salt, 50 g of sodium hydroxide, 2500 g of water and 250 ml of methanol into a 5000 ml reaction bottle, heat to above 60°C, react for 1 hour, slowly cool to 10°C, filter (filtration time 30 min), adjust the acidity of the filtrate and filter to obtain crude dexibuprofen with a purity of 99.9%.

[0030] (3) Crystallization of dexibuprofen: Add one batch of crude dexibuprofen into a 2000 ml reaction bottle, add 1000 g of water, raise the temperature to 65°C, slowly cool to 10°C at a cooling rate of 5°C / min, rotate at 50 r / min, filter, grind and dry to obtain 199 g of dexibuprofen granules with a purity of 99.9%.

[0031] Dexibuprofen was crushed by a particle shaker to obtain products with D (0.9) of 943 um and D (0.5) of 666 um.

[0032] Example 2

[0033] (1) Resolution: In a 5000 ml reaction bottle, add 500 g of ibuprofen, 390 g of the resolution agent octylglucamine, 3500 g of methanol and 70 g of water, heat to 65°C, react for 1 h, slowly cool to 10°C, keep warm and stir for 1.5 h, filter and dry to obtain 469 g of right ibuprofen salt, with a left ibuprofen content of about 0.5%.

[0034] (2) Free: Add a batch of dexibuprofen salt, 60 g of sodium hydroxide, 2500 g of water and 250 g of ethanol into a 5000 ml reaction bottle, heat to above 60°C, react for 1 hour, slowly cool to 10°C, filter (filtration time 30 min), adjust the acidity of the filtrate and filter to obtain crude dexibuprofen with a purity of 99.9%.

[0035] (3) Crystallization of dexibuprofen: Add crude dexibuprofen into a 1000 ml reaction bottle, add 500 g of water and 200 g of DMF, raise the temperature to 65°C, slowly cool to 10°C at a cooling rate of 10°C / min, rotate at 80 r / min, filter, crush and dry to obtain 195 g of dexibuprofen granules with a purity of 99.9%.

[0036] Dexibuprofen was granulated by vacuum granulator to obtain products with D (0.9) 1542um and D (0.5) 879um.

[0037] Example 3

[0038] (1) Resolution: 500 g of ibuprofen, 355 g of resolution agent octylglucamine and 4000 ml of toluene were added to a 5000 ml reaction bottle, reacted at 80°C for 1 h, cooled to 10°C, filtered and dried to obtain 86 g of right ibuprofen salt with a left ibuprofen content of 0.9%.

[0039] (2) Free: Add dexibuprofen salt, 50 g of sodium hydroxide, 2500 g of water and 300 g of acetonitrile into a 5000 ml reaction bottle, heat to above 60°C, react for 1 hour, slowly cool to 10°C, filter (filtration time 20 min), adjust the acidity of the filtrate and filter to obtain crude dexibuprofen. Purity 99.9%.

[0040] (3) Crystallization of dextroprofen: crude dextroprofen was added to a 1000 ml reaction bottle, followed by 200 g of water and 100 g of acetone. The temperature was raised to 65°C, and the temperature was slowly lowered to 10°C at a rate of 15°C / min and a rotation speed of 80 r / min. The mixture was filtered, crushed and dried to obtain 198 g of dextroprofen granules with a purity of 99.9% and a yield of 99%.

[0041] Dexibuprofen was air flow crushed to obtain products with D (0.9) 23 um and D (0.5) 11 um.

[0042] Example 4

[0043] (1) Resolution: 500 g of ibuprofen, 355 g of the resolution agent octylglucamine, and 1000 ml of anhydrous ethanol were added to a 5000 ml reaction bottle, reacted at 80°C for 1 h, cooled to 10°C, filtered, and dried to obtain 83 g of dextro-ibuprofen salt with a levobuprofen content of 0.4%.

[0044] (2) Free: Add dexibuprofen salt, 50 g of sodium hydroxide, 2000 g of water and 200 g of acetonitrile into a 5000 ml reaction bottle, heat to above 60°C, react for 1 hour, slowly cool to 10°C, filter (filtration time 45 min), adjust the acidity of the filtrate, filter and dry to obtain crude dexibuprofen with a purity of 99.9%.

[0045] (3) Crystallization of dexibuprofen: Add crude dexibuprofen into a 1000 ml reaction bottle, add 200 g of water and 100 g of acetic acid, raise the temperature to 65°C, slowly cool to 10°C at a cooling rate of 15°C / min, rotate at 80 r / min, filter, crush and dry to obtain 198 g of dexibuprofen granules with a purity of 99.9%.

[0046] Dexibuprofen was dry granulated to obtain products with D (0.9) 1241 um and D (0.5) 869 um.

[0047] Example 5

[0048] (1) Resolution: In a 5000 ml reaction bottle, add 100 g of ibuprofen, 71 g of the resolution agent octylglucamine, 700 ml of anhydrous ethanol, and 35 ml of water. React at 80°C for 1 h, cool to 10°C, filter, and dry to obtain 90 g of dexibuprofen salt with a yield of 37.2% and a levoibuprofen content of 0.7%.

[0049] (2) Free: Add 500 g of dexibuprofen salt, 50 g of sodium hydroxide, 2000 g of water and 200 g of acetone into a 5000 ml reaction bottle, heat to above 60°C, react for 1 hour, slowly cool to 10°C, filter, adjust the acidity of the filtrate and filter to obtain crude dexibuprofen with a purity of 99.9%.

[0050] (3) Crystallization of dexibuprofen: In a 1000 ml reaction bottle, add 200 g of dexibuprofen, 200 g of water, and 100 g of acetonitrile, raise the temperature to 65°C, slowly cool to 10°C at a cooling rate of 12°C / min, rotate at 80 r / min, filter, crush, and dry to obtain 197 g of dexibuprofen granules with a purity of 99.9%.

[0051] Dexibuprofen was crushed by a WF-180 crusher to obtain products with D (0.9) 137 um and D (0.5) 69 um.

[0052] Example 6

[0053] (1) Resolution: In a 5000 ml reaction bottle, add 500 g of ibuprofen, 355 g of the resolution agent octylglucamine, 3500 ml of anhydrous ethanol, and 100 ml of water. React at 80°C for 1 h, cool to 10°C, filter, and dry to obtain 90 g of dexibuprofen salt with a levoibuprofen content of 0.7%.

[0054] (2) Free: Add dexibuprofen salt, 50 g of sodium hydroxide and 2500 g of water into a 5000 ml reaction bottle, heat to above 60°C, react for 1 hour, slowly cool to 10°C, filter (filtration time 6 hours), adjust the acidity of the filtrate and filter to obtain crude dexibuprofen with a purity of 99.8%.

[0055] (3) Crystallization of dextroprofen: 200 g of dextroprofen and 100 g of ethanol were added to a 1000 ml reaction bottle, the temperature was controlled to 25 °C, and the temperature was slowly lowered to 0 °C at a rate of 10 °C / min and a rotation speed of 150 r / min. The dextroprofen powder was filtered and dried to obtain 180 g of dextroprofen powder with a purity of 99.7%. Ethyl ibuprofen was significantly produced with a content of 0.2%.

[0056] The powdered dexibuprofen product cannot produce a product with larger and uniform particles that meets the requirements of some formulations, and can only produce a powdered product with smaller particle size. The product prepared in the present invention has different dexibuprofen particle sizes according to different crushing or granulation methods, as shown in the following table:

[0057] Comparative Example 1 (1) Resolution: In a 5000 ml reaction bottle, add 500 g of ibuprofen, 355 g of the resolution agent octylglucamine, and 3500 ml of methanol. Heat to 65°C, react for 1 h, slowly cool to 10°C, keep warm and stir for 1.5 h, filter, and dry to obtain dexibuprofen salt.

[0058] (2) Free: Add a batch of dexibuprofen salt, 50 g of sodium hydroxide, 2500 g of water and 250 ml of methanol into a 5000 ml reaction bottle, heat to above 60°C, react for 1 hour, slowly cool to 10°C, filter (filtration time 30 min), adjust the acidity of the filtrate and filter to obtain crude dexibuprofen with a purity of 99.9%.

[0059] (3) Crystallization of dexibuprofen: Add one batch of crude dexibuprofen into a 2000 ml reaction bottle, add 1000 g of water, raise the temperature to 65°C, slowly cool to 10°C at a cooling rate of 5°C / min, rotate at 120 r / min, filter, crush and dry to obtain 200 g of dexibuprofen granules with a purity of 99.7%.

[0060] In Comparative Example 1, too fast a rotation speed during crystallization would result in a decrease in the purity of the product.

[0061] Comparative Example 2 (1) Resolution: In a 5000 ml reaction bottle, add 500 g of ibuprofen, 355 g of the resolution agent octylglucamine, and 3500 ml of methanol. Heat to 65°C, react for 1 h, slowly cool to 10°C, keep warm and stir for 1.5 h, filter, and dry to obtain dexibuprofen salt.

[0062] (2) Free: Add a batch of dexibuprofen salt, 50 g of sodium hydroxide, 2500 g of water and 250 ml of methanol into a 5000 ml reaction bottle, heat to above 60°C, react for 1 hour, slowly cool to 10°C, filter (filtration time 30 min), adjust the acidity of the filtrate and filter to obtain crude dexibuprofen with a purity of 99.9%.

[0063] (3) Crystallization of dextroprofen: Add one batch of crude dextroprofen into a 2000 ml reaction bottle, add 1000 g of water, raise the temperature to 65°C, slowly cool to 20°C at a cooling rate of 5°C / min, rotate at 50 r / min, filter, grind and dry to obtain 195 g of dextroprofen granules with a purity of 99.9%.

[0064] The temperature after cooling in Comparative Example 2 is higher than that in Example 1, resulting in a decrease in the total amount of dexibuprofen particles obtained.

[0065] Comparative Example 3 (1) Resolution: In a 5000 ml reaction bottle, add 500 g of ibuprofen, 355 g of the resolution agent octylglucamine, and 3500 ml of methanol. Heat to 65°C, react for 1 h, slowly cool to 10°C, keep warm and stir for 1.5 h, filter, and dry to obtain dexibuprofen salt.

[0066] (2) Free: Add a batch of dexibuprofen salt, 50 g of sodium hydroxide, 2500 g of water and 250 ml of methanol into a 5000 ml reaction bottle, heat to above 60°C, react for 1 hour, slowly cool to 10°C, filter (filtration time 30 min), adjust the acidity of the filtrate and filter to obtain crude dexibuprofen with a purity of 99.9%.

[0067] (3) Crystallization of dextroprofen: Add one batch of crude dextroprofen into a 2000 ml reaction bottle, add 1000 g of water, raise the temperature to 65°C, slowly cool to 10°C at a cooling rate of 10°C / min, rotate at 50 r / min, filter, grind and dry to obtain 192 g of dextroprofen granules with a purity of 99.6%.

[0068] The cooling rate in Comparative Example 3 is faster than that in Example 1, resulting in a decrease in the total amount of dexibuprofen particles obtained and a decrease in purity.

[0069] In order to explore the effect of the temperature and time of the splitting step on the total amount of the prepared dexibuprofen salt, comparative examples 4-9 were designed as follows: Comparative Example 4 Splitting: In a 5000 ml reaction bottle, add 500 g of ibuprofen, 355 g of the splitting agent octylglucamine, and 3500 ml of methanol. Heat to 55°C, react for 1 hour, slowly cool to 10°C, keep warm and stir for 1.5 hours, filter and dry to obtain 465.3 g of right ibuprofen salt.

[0070] Comparative Example 5 Splitting: In a 5000 ml reaction bottle, add 500 g of ibuprofen, 355 g of the splitting agent octylglucamine, and 3500 ml of methanol. Heat to 75°C, react for 1 hour, slowly cool to 10°C, keep warm and stir for 1.5 hours, filter and dry to obtain 482.4 g of right ibuprofen salt.

[0071] Comparative Example 6 Splitting: In a 5000 ml reaction bottle, add 500 g of ibuprofen, 355 g of the splitting agent octylglucamine, and 3500 ml of methanol. Heat to 65°C, react for 50 min, slowly cool to 10°C, keep warm and stir for 1.5 h, filter and dry to obtain 455.7 g of right ibuprofen salt.

[0072] Comparative Example 7 Splitting: In a 5000 ml reaction bottle, add 500 g of ibuprofen, 355 g of the splitting agent octylglucamine, and 3500 ml of methanol. Heat to 65°C, react for 80 min, slowly cool to 10°C, keep warm and stir for 1.5 h, filter and dry to obtain 466.2 g of right ibuprofen salt.

[0073] Comparative Example 8 Splitting: In a 5000 ml reaction bottle, add 500 g of ibuprofen, 355 g of the splitting agent octylglucamine, and 3500 ml of methanol. Heat to 65°C, react for 1 hour, slowly cool to 10°C, keep warm and stir for 1 hour, filter and dry to obtain 476.4 g of right ibuprofen salt.

[0074] Comparative Example 9 Splitting: In a 5000 ml reaction bottle, add 500 g of ibuprofen, 355 g of the splitting agent octylglucamine, and 3500 ml of methanol. Heat to 65°C, react for 1 hour, slowly cool to 10°C, keep warm and stir for 2 hours, filter and dry to obtain 479.2 g of right ibuprofen salt.

[0075] In Comparative Examples 4 and 5, the reaction temperature was adjusted to 55°C and 75°C respectively based on Example 1; the reaction time was adjusted to 50min and 80min respectively in Comparative Examples 6 and 7; and the heat preservation and stirring time was adjusted to 1h and 2h in Comparative Examples 8 and 9. The results show that the temperature and time adjusted in the splitting step in Example 1 of the present invention are optimal, and the content of the dexibuprofen salt obtained is the highest.

[0076] The applicant declares that the present invention illustrates the product and detailed preparation method of the present invention through the above-mentioned embodiments, but the present invention is not limited to the above-mentioned product and detailed preparation method, that is, it does not mean that the present invention must rely on the above-mentioned product and detailed preparation method to be implemented. Those skilled in the art should understand that any improvement of the present invention, equivalent replacement of various raw materials of the product of the present invention and addition of auxiliary materials, selection of specific methods, etc., all fall within the protection scope and disclosure scope of the present invention.

[0077] The preferred embodiments of the present invention are described in detail above, but the present invention is not limited to the specific details in the above embodiments, and the technical solution of the present invention can be subjected to a variety of simple modifications within the technical concept of the present invention. These simple modifications all belong to the protection scope of the present invention.

[0078] It should also be noted that the various specific technical features described in the above specific embodiments can be combined in any suitable manner without contradiction. In order to avoid unnecessary repetition, the present invention will not further describe various possible combinations.

[0079] In addition, various embodiments of the present invention may be arbitrarily combined, and as long as they do not violate the concept of the present invention, they should also be regarded as the contents disclosed by the present invention.

Claims

1. A process for preparing dexibuprofen, characterized in that the steps include: (1) separation: ibuprofen and glucamine are added to a solvent, dissolved, heated to form a salt, cooled to crystallize, filtered, and dried to obtain dexibuprofen glucamine salt; (2) Freeing: Adding dexibuprofen glucamine salt to a solvent under alkaline conditions to free it, filtering to remove glucamine, and crystallizing the solution and filtering to obtain crude dexibuprofen; (3) Crystallization of dexibuprofen: After adding a solvent, the temperature is raised to dissolve the dexibuprofen. After cooling, the solid is precipitated. The dexibuprofen of different particle sizes is obtained by filtering, crushing or granulating, and drying.

2. A process for preparing dexibuprofen according to claim 1, characterized in that, The solvent in step (1) includes one or more mixed solvents of methanol, ethanol, isopropanol, acetonitrile, toluene, acetone or a mixed solvent with water.

3. A process for preparing dexibuprofen according to claim 1, characterized in that, In the step (2), the solvent under alkaline conditions is a mixed solvent of one or more of methanol, ethanol, isopropanol, acetonitrile, acetone and water.

4. A process for preparing dexibuprofen according to claim 3, characterized in that, In the step (2), the solvent under alkaline conditions is methanol.

5. A process for preparing dexibuprofen according to claim 1, characterized in that, The dissolving temperature in the step (3) is 60-70°C, and the temperature after cooling is 10-20°C.

6. A process for preparing dexibuprofen according to claim 1, characterized in that, The solvent in step (3) includes one or more mixed solvents of DMF, acetonitrile, acetone and water.

7. A process for preparing dexibuprofen according to claim 1, characterized in that, The solvent in step (3) is water.

8. A process for preparing dexibuprofen according to claim 1, characterized in that: The cooling rate of step (3) is 5-20°C / min.

9. A process for preparing dexibuprofen according to claim 1, characterized in that: The stirring speed in step (3) is 20-100 r / min.

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