Preparation method of high-purity Efinprofen axetil

Abstract

The invention provides a preparation method of high-purity efiniprofen axetil, sodium bicarbonate and magnesium sulfate are adopted to pretreat a reaction material 1-bromoethyl acetate, then the product reacts with S-flurbiprofen to prepare the efiniprofen axetil, the obtained target product is very low in impurity content and high in yield and purity, the yield reaches 98% or above, and the purity reaches 99% or above. The single impurity can be controlled to be 0.1% or below, the total impurity can be controlled to be 0.5% or below, complex post-treatment processes such as molecular distillation and column chromatography are avoided, and the whole preparation method is simple and suitable for industrial large-scale production.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical chemistry technology, specifically relating to a method for preparing high-purity levonorfen ester. Background Technology

[0002] Alfluofen ester, chemical name 1-acetoxyethyl (2-ethylhexyl) S 2-(2-fluoro-4-biphenyl)-2-hydroxypropionate is a novel nonsteroidal anti-inflammatory analgesic with advantages such as low dosage, good selectivity, and long duration of action. Its structure is as follows:

[0003] However, during the preparation process, it is necessary to solve the problem of low product purity caused by the large number of impurities and the difficulty in purification. The sources of impurities are, on the one hand, the introduction of a large number of impurities from the starting material 1-bromoethyl acetate, and on the other hand, the impurities introduced by the side reactions during the reaction process.

[0004] Patent CN119735507A discloses a highly efficient method for suppressing racemization during a reaction process. This method can effectively suppress racemization and decomposition of the product, control the content of single isomer impurities to below 0.1%, and increase the product yield to over 90%. However, it cannot effectively control impurities in related substances of the product, resulting in a product purity of approximately 80%. The impurity content is very high, and complex post-processing such as molecular distillation and column chromatography are required to remove impurities and improve product purity, which is not conducive to large-scale industrial production. Summary of the Invention

[0005] The purpose of this invention is to provide a method for preparing high-purity levorprofen ester based on existing technology. The method involves pretreating the reactant 1-bromoethyl acetate with sodium bicarbonate and magnesium sulfate, followed by reaction with S-flurbiprofen to prepare levorprofen ester. The resulting target product has very low impurity content, high yield and purity (yield exceeding 98% and purity exceeding 99%), with individual impurities controlled below 0.1% and total impurities below 0.5%. This method avoids complex post-processing steps such as molecular distillation and column chromatography, and is simple and suitable for large-scale industrial production.

[0006] The technical solution of the present invention is as follows: A method for preparing high-purity levonorfen ester includes the following steps: (1) Mix 1-bromoethyl acetate, alkaline reagent and inorganic salt evenly, and stir the reaction at 10-40℃ to obtain pretreated 1-bromoethyl acetate; (2) The pretreated 1-bromoethyl acetate, S-flurbiprofen, N,N-diisopropylethylamine and dichloromethane were mixed evenly and stirred at 15-20℃. The resulting reaction solution was quenched with water, washed and dried to obtain crude aflurbiprofen ester. Organic solvent and adsorbent were added to the crude product, stirred evenly, filtered and concentrated to obtain aflurbiprofen ester.

[0007] For the purposes of this invention, in step (1), the alkaline reagent is sodium bicarbonate, sodium hypophosphite, sodium citrate, potassium bicarbonate, potassium carbonate, potassium phosphate, sodium bisulfite, N,N-diisopropylethylamine (DIPEA), diisopropylamine, 2,4,6-trimethylpyridine, DBU, triethylamine, sodium carbonate, tetrabutylammonium hydroxide, sodium acetate, or sodium silicate; preferably sodium bicarbonate.

[0008] In step (1), the mass ratio of 1-bromoethyl acetate to the alkaline reagent is 1:0.1-0.8, which may be, but is not limited to, 1:0.1, 1:0.15, 1:0.2, 1:0.25, 1:0.3, 1:0.35, 1:0.4, 1:0.45, 1:0.5, 1:0.6, 1:0.7 or 1:0.8. Preferably, the mass ratio of 1-bromoethyl acetate to the alkaline reagent is 1:0.2-0.4.

[0009] In this invention, in step (1), the inorganic salt is magnesium sulfate, sodium sulfate, aluminum silicate or potassium sulfate; preferably magnesium sulfate.

[0010] In step (1), the mass ratio of 1-bromoethyl acetate to inorganic salt is 1:0.1-0.8, which may be, but is not limited to, 1:0.1, 1:0.12, 1:0.13, 1:0.14, 1:0.15, 1:0.2, 1:0.25, 1:0.3, 1:0.35, 1:0.4, 1:0.45, 1:0.5, 1:0.6, 1:0.7 or 1:0.8. Preferably, the mass ratio of 1-bromoethyl acetate to inorganic salt is 1:0.14-0.4.

[0011] In this invention, in step (1), 1-bromoethyl acetate, an alkaline reagent, and an inorganic salt are mixed evenly and stirred at 10-40°C. The reaction temperature can be 10-40°C, 20-40°C, 30-40°C, 15-40°C, 15-35°C, 15-30°C, or 20-30°C. Preferably, the reaction temperature is 15-35°C, and more preferably, the reaction temperature is 20-30°C.

[0012] In step (1), the reaction time is 1-3 hours, preferably 0.5 hours.

[0013] In this invention, in step (2), the adsorbent is zinc oxide, benzenesulfonic acid silica gel, alumina, bentonite, molecular sieve or HP1050 resin; preferably zinc oxide.

[0014] In step (2), the mass ratio of 1-bromoethyl acetate to the adsorbent is 1:0.3-1.0, and can be, but is not limited to, 1:0.3, 1:0.4, 1:0.5, 1:0.55, 1:0.6, 1:0.65, 1:0.66, 1:0.67, 1:0.68, 1:0.7, 1:0.8, 1:0.9 or 1:1.0. Preferably, the mass ratio of 1-bromoethyl acetate to the adsorbent is 1:0.5-0.7; more preferably, the mass ratio of 1-bromoethyl acetate to the adsorbent is 1:0.67.

[0015] In this invention, in step (2), the organic solvent is n-heptane, isopropyl ether, petroleum ether, methyl tert-butyl ether, n-hexane or cyclohexane; preferably n-heptane.

[0016] In step (2), the mass ratio of 1-bromoethyl acetate to the organic solvent is 1:2.5-4.4, and may be, but is not limited to, 1:2.5, 1:2.8, 1:3.0, 1:3.2, 1:3.28, 1:3.3, 1:3.35, 1:3.38, 1:3.4, 1:3.5, 1:3.8, 1:4.0, 1:4.2 or 1:4.4. Preferably, the mass ratio of 1-bromoethyl acetate to the organic solvent is 1:3.2-3.4; more preferably, the mass ratio of 1-bromoethyl acetate to the organic solvent is 1:3.35.

[0017] The advantages of using the technical solution of this invention are as follows: This invention provides a method for preparing high-purity levonorfen ester. The method involves pretreating the reactant 1-bromoethyl acetate with sodium bicarbonate and magnesium sulfate, followed by reaction with S-flurbiprofen to prepare levonorfen ester. The resulting product has very low impurity content, high yield and purity (over 98% yield, over 99% purity), with individual impurities controlled below 0.1% and total impurities below 0.5%. This method avoids complex post-processing steps such as molecular distillation and column chromatography, making it simple and suitable for large-scale industrial production. Detailed Implementation

[0018] The present invention can be better understood from the following embodiments. However, those skilled in the art will readily understand that the descriptions in the embodiments are for illustrative purposes only and should not, and will not, limit the invention as detailed in the claims.

[0019] Example 1 A method for preparing high-purity levonorfen ester includes the following steps: (1) Under nitrogen protection, 1-bromoethyl acetate (compound 2, 6.70 g, 0.04 mol), 2 g of sodium bicarbonate and 1.4 g of magnesium sulfate were added to a 250 ml reaction flask. After stirring evenly, the mixture was stirred and reacted at 20-30 °C for 0.5 hours. The mixture was then filtered to obtain the pretreated 1-bromoethyl acetate. (2) Take another clean 250ml reaction flask, add S-flurbiprofen (compound 1, 9.80g, 0.04mol), the pretreated 1-bromoethyl acetate obtained in step (1), and 75ml of dichloromethane. After stirring evenly, the resulting mixed solution is cooled to 15-20℃ under nitrogen protection and N,N-diisopropylethylamine (DIPEA, 5.20g, 0.04mol) is added dropwise. After the addition is complete, the reaction is stirred at 15-20℃ for 10-12 hours. The resulting reaction solution is quenched with water. The resulting organic phase is washed 4 times with 5% sodium carbonate aqueous solution, washed with water, dried with anhydrous magnesium sulfate, and the resulting organic phase is concentrated. Then, 33.5g of n-heptane and 6.7g of zinc oxide are added and stirred for 1 hour. After filtration, the solution is concentrated to obtain levorbiprofen ester with a yield of 98.5%, a purity of 99.704%, a maximum single impurity of 0.095%, and a total impurity of 0.296%. Example 2

[0020] A method for preparing high-purity levonorfen ester includes the following steps: (1) Under nitrogen protection, 1-bromoethyl acetate (compound 2, 6.70 g, 0.04 mol), 4 g of sodium bicarbonate and 4 g of magnesium sulfate were added to a 250 ml reaction flask. After stirring evenly, the mixture was stirred and reacted at 20-30 °C for 0.5 hours. The mixture was then filtered to obtain the pretreated 1-bromoethyl acetate. (2) Take another clean 250ml reaction flask, add S-flurbiprofen (compound 1, 9.80g, 0.04mol), the pretreated 1-bromoethyl acetate obtained in step (1), and 75ml of dichloromethane. After stirring evenly, the resulting mixed solution is cooled to 15-20℃ under nitrogen protection and N,N-diisopropylethylamine (DIPEA, 5.20g, 0.04mol) is added dropwise. After the addition is complete, the reaction is stirred at 15-20℃ for 10-12 hours. The resulting reaction solution is quenched with water. The resulting organic phase is washed 4 times with 5% sodium carbonate aqueous solution, washed with water, dried with anhydrous magnesium sulfate, and the resulting organic phase is concentrated. Then, 33.5g of n-heptane and 6.7g of zinc oxide are added and stirred for 1 hour. After filtration, the solution is concentrated to obtain levorbiprofen ester with a yield of 96.2%, a purity of 99.404%, a maximum single impurity of 0.295%, and a total impurity of 0.399%. Example 3

[0021] A method for preparing high-purity levonorfen ester includes the following steps: (1) Under nitrogen protection, 1-bromoethyl acetate (compound 2, 6.70 g, 0.04 mol), 1 g of sodium bicarbonate and 1.4 g of magnesium sulfate were added to a 250 ml reaction flask. After stirring evenly, the mixture was stirred and reacted at 20-30 °C for 0.5 hours. The mixture was then filtered to obtain the pretreated 1-bromoethyl acetate. (2) Take another clean 250ml reaction flask, add S-flurbiprofen (compound 1, 9.80g, 0.04mol), the pretreated 1-bromoethyl acetate obtained in step (1), and 75ml of dichloromethane. After stirring evenly, the resulting mixed solution is cooled to 15-20℃ under nitrogen protection, and N,N-diisopropylethylamine (DIPEA, 5.20g, 0.04mol) is added dropwise. After the addition is complete, continue cooling at 15-20℃. The reaction was stirred at ℃ for 10-12 hours. The resulting reaction solution was quenched with water. The resulting organic phase was then washed four times with 5% sodium carbonate aqueous solution, washed with water, dried with anhydrous magnesium sulfate, and the resulting organic phase was concentrated. Then, 33.5 g of n-heptane and 6.7 g of partially neutralized sodium polyacrylate were added and stirred for 1 hour. After filtration and concentration, levonorfen ester was obtained with a yield of 98.8%, a purity of 99.814%, a maximum single impurity of 0.083%, and a total impurity of 0.186%.

[0022] Comparative Example 1 (Refer to Example 1 in CN119735507A) S-flurbiprofen (compound 1, 9.80 g, 0.04 mol), 1-bromoethyl acetate (compound 2, 6.70 g, 0.04 mol), and 75 ml of dichloromethane were added to a 250 ml reaction flask. After stirring until homogeneous, the resulting mixture was cooled to 15-20 °C under nitrogen protection, and N,N-diisopropylethylamine (DIPEA, 5.20 g, 0.04 mol) and trifluoroacetic acid (2.28 g, 0.02 mol) were added dropwise. After the addition was complete, the reaction was stirred at 15-20 °C for 10-12 hours. The resulting reaction solution was quenched with water, and the resulting organic phase was washed four times with 5% sodium carbonate aqueous solution, washed with water, dried over anhydrous magnesium sulfate, and then evaporated to dryness to obtain levonorfen ester with a yield of 96.1%, a purity of 84.426%, a maximum single impurity of 2.216%, and a total impurity of 15.574%.

[0023] Comparative Example 2 (without sodium bicarbonate) A method for preparing high-purity levonorfen ester includes the following steps: (1) Under nitrogen protection, 1-bromoethyl acetate (compound 2, 6.70 g, 0.04 mol) and 1.4 g of magnesium sulfate were added to a 250 ml reaction flask. After stirring evenly, the mixture was stirred and reacted at 20-30 °C for 0.5 hours. The mixture was then filtered to obtain the pretreated 1-bromoethyl acetate. (2) Take another clean 250ml reaction flask, add S-flurbiprofen (compound 1, 9.80g, 0.04mol), the pretreated 1-bromoethyl acetate obtained in step (1), and 75ml of dichloromethane. After stirring evenly, the resulting mixed solution is cooled to 15-20℃ under nitrogen protection and N,N-diisopropylethylamine (DIPEA, 5.20g, 0.04mol) is added dropwise. After the addition is complete, the reaction is stirred at 15-20℃ for 10-12 hours. The resulting reaction solution is quenched with water. The resulting organic phase is washed 4 times with 5% sodium carbonate aqueous solution, washed with water, dried with anhydrous magnesium sulfate, and the resulting organic phase is concentrated. Then, 33.5g of n-heptane and 6.7g of zinc oxide are added and stirred for 1 hour. After filtration, the solution is concentrated to obtain levorbiprofen ester with a yield of 95.8%, a purity of 92.886%, a maximum single impurity of 0.838%, and a total impurity of 7.114%.

[0024] Comparative Example 3 (excessive sodium bicarbonate dosage) A method for preparing high-purity levonorfen ester includes the following steps: (1) Under nitrogen protection, 1-bromoethyl acetate (compound 2, 6.70 g, 0.04 mol), 9 g of sodium bicarbonate and 1.4 g of magnesium sulfate were added to a 250 ml reaction flask. After stirring evenly, the mixture was stirred and reacted at 20-30 °C for 0.5 hours. The mixture was then filtered to obtain the pretreated 1-bromoethyl acetate. (2) Take another clean 250ml reaction flask, add S-flurbiprofen (compound 1, 9.80g, 0.04mol), the pretreated 1-bromoethyl acetate obtained in step (1), and 75ml of dichloromethane. After stirring evenly, the resulting mixed solution is cooled to 15-20℃ under nitrogen protection and N,N-diisopropylethylamine (DIPEA, 5.20g, 0.04mol) is added dropwise. After the addition is complete, the reaction is stirred at 15-20℃ for 10-12 hours. The resulting reaction solution is quenched with water. The resulting organic phase is washed 4 times with 5% sodium carbonate aqueous solution, washed with water, dried with anhydrous magnesium sulfate, and the resulting organic phase is concentrated. Then, 33.5g of n-heptane and 6.7g of zinc oxide are added and stirred for 1 hour. After filtration, the solution is concentrated to obtain levorbiprofen ester with a yield of 68.5%, a purity of 95.704%, a maximum single impurity of 1.120%, and a total impurity of 4.296%.

[0025] Comparative Example 4 (excessive magnesium sulfate dosage) A method for preparing high-purity levonorfen ester includes the following steps: (1) Under nitrogen protection, 1-bromoethyl acetate (compound 2, 6.70 g, 0.04 mol), 2 g of sodium bicarbonate and 9 g of magnesium sulfate were added to a 250 ml reaction flask. After stirring evenly, the mixture was stirred and reacted at 20-30 °C for 0.5 hours. The mixture was then filtered to obtain the pretreated 1-bromoethyl acetate. (2) Take another clean 250ml reaction flask, add S-flurbiprofen (compound 1, 9.80g, 0.04mol), the pretreated 1-bromoethyl acetate obtained in step (1), and 75ml of dichloromethane. After stirring evenly, the resulting mixed solution is cooled to 15-20℃ under nitrogen protection and N,N-diisopropylethylamine (DIPEA, 5.20g, 0.04mol) is added dropwise. After the addition is complete, the reaction is stirred at 15-20℃ for 10-12 hours. The resulting reaction solution is quenched with water. The resulting organic phase is washed 4 times with 5% sodium carbonate aqueous solution, washed with water, dried with anhydrous magnesium sulfate, and the resulting organic phase is concentrated. Then, 33.5g of n-heptane and 6.7g of zinc oxide are added and stirred for 1 hour. After filtration, the concentration yields 77.5% flurbiprofen ester, with a purity of 98.828%, a maximum single impurity of 0.215%, and a total impurity of 1.172%.

[0026] Comparative Example 5 (without magnesium sulfate) A method for preparing high-purity levonorfen ester includes the following steps: (1) Under nitrogen protection, 1-bromoethyl acetate (compound 2, 6.70 g, 0.04 mol) and 2 g of sodium bicarbonate were added to a 250 ml reaction flask. After stirring evenly, the mixture was stirred and reacted at 20-30 °C for 0.5 hours. The mixture was then filtered to obtain the pretreated 1-bromoethyl acetate. (2) Take another clean 250ml reaction flask, add S-flurbiprofen (compound 1, 9.80g, 0.04mol), the pretreated 1-bromoethyl acetate obtained in step (1), and 75ml of dichloromethane. After stirring evenly, the resulting mixed solution is cooled to 15-20℃ under nitrogen protection and N,N-diisopropylethylamine (DIPEA, 5.20g, 0.04mol) is added dropwise. After the addition is complete, the reaction is stirred at 15-20℃ for 10-12 hours. The resulting reaction solution is quenched with water. The resulting organic phase is washed 4 times with 5% sodium carbonate aqueous solution, washed with water, dried with anhydrous magnesium sulfate, and the resulting organic phase is concentrated. Then, 33.5g of n-heptane and 6.7g of zinc oxide are added and stirred for 1 hour. After filtration, the concentration yields 96.7% flurbiprofen ester, with a purity of 95.135%, a maximum single impurity of 0.832%, and a total impurity of 4.865%.

[0027] Comparative Example 6 (different alkaline reagents) A method for preparing high-purity levonorfen ester includes the following steps: (1) Under nitrogen protection, 1-bromoethyl acetate (compound 2, 6.70 g, 0.04 mol), 2 g sodium hypophosphite and 1.4 g magnesium sulfate were added to a 250 ml reaction flask. After stirring evenly, the mixture was stirred and reacted at 20-30 °C for 0.5 hours. The mixture was then filtered to obtain the pretreated 1-bromoethyl acetate. (2) Take another clean 250ml reaction flask, add S-flurbiprofen (compound 1, 9.80g, 0.04mol), the pretreated 1-bromoethyl acetate obtained in step (1), and 75ml of dichloromethane. After stirring evenly, the resulting mixed solution is cooled to 15-20℃ under nitrogen protection and N,N-diisopropylethylamine (DIPEA, 5.20g, 0.04mol) is added dropwise. After the addition is complete, the reaction is stirred at 15-20℃ for 10-12 hours. The resulting reaction solution is quenched with water. The resulting organic phase is washed 4 times with 5% sodium carbonate aqueous solution, washed with water, dried with anhydrous magnesium sulfate, and the resulting organic phase is concentrated. Then, 33.5g of n-heptane and 6.7g of zinc oxide are added and stirred for 1 hour. After filtration, the solution is concentrated to obtain levorbiprofen ester with a yield of 96.7%, a purity of 96.126%, a maximum single impurity of 1.632%, and a total impurity of 3.874%.

[0028] Comparative Example 7 (different inorganic salts) A method for preparing high-purity levonorfen ester includes the following steps: (1) Under nitrogen protection, 1-bromoethyl acetate (compound 2, 6.70 g, 0.04 mol), 2 g of sodium bicarbonate and 1.4 g of sodium sulfate were added to a 250 ml reaction flask. After stirring evenly, the mixture was stirred and reacted at 20-30 °C for 0.5 hours. The mixture was then filtered to obtain the pretreated 1-bromoethyl acetate. (2) Take another clean 250ml reaction flask, add S-flurbiprofen (compound 1, 9.80g, 0.04mol), the pretreated 1-bromoethyl acetate obtained in step (1), and 75ml of dichloromethane. After stirring evenly, the resulting mixed solution is cooled to 15-20℃ under nitrogen protection and N,N-diisopropylethylamine (DIPEA, 5.20g, 0.04mol) is added dropwise. After the addition is complete, the reaction is stirred at 15-20℃ for 10-12 hours. The resulting reaction solution is quenched with water. The resulting organic phase is washed 4 times with 5% sodium carbonate aqueous solution, washed with water, dried with anhydrous magnesium sulfate, and the resulting organic phase is concentrated. Then, 33.5g of n-heptane and 6.7g of zinc oxide are added and stirred for 1 hour. After filtration, the solution is concentrated to obtain levorbiprofen ester with a yield of 92.5%, a purity of 98.804%, a maximum single impurity of 0.135%, and a total impurity of 1.196%.

[0029] Comparative Example 8 (Temperature Too High) A method for preparing high-purity levonorfen ester includes the following steps: (1) Under nitrogen protection, 1-bromoethyl acetate (compound 2, 6.70 g, 0.04 mol), 2 g of sodium bicarbonate and 1.4 g of magnesium sulfate were added to a 250 ml reaction flask. After stirring evenly, the mixture was stirred and reacted at 50-60 °C for 0.5 hours. The mixture was then filtered to obtain the pretreated 1-bromoethyl acetate. (2) Take another clean 250ml reaction flask, add S-flurbiprofen (compound 1, 9.80g, 0.04mol), the pretreated 1-bromoethyl acetate obtained in step (1), and 75ml of dichloromethane. After stirring evenly, the resulting mixed solution is cooled to 15-20℃ under nitrogen protection and N,N-diisopropylethylamine (DIPEA, 5.20g, 0.04mol) is added dropwise. After the addition is complete, the reaction is stirred at 15-20℃ for 10-12 hours. The resulting reaction solution is quenched with water. The resulting organic phase is washed 4 times with 5% sodium carbonate aqueous solution, washed with water, dried with anhydrous magnesium sulfate, and the resulting organic phase is concentrated. Then, 33.5g of n-heptane and 6.7g of zinc oxide are added and stirred for 1 hour. After filtration, the concentration yields 88.5% flurbiprofen ester, with a purity of 95.608%, a maximum single impurity of 1.750%, and a total impurity of 4.392%.

[0030] Comparative Example 9 (lower temperature) A method for preparing high-purity levonorfen ester includes the following steps: (1) Under nitrogen protection, 1-bromoethyl acetate (compound 2, 6.70 g, 0.04 mol), 2 g of sodium bicarbonate and 1.4 g of magnesium sulfate were added to a 250 ml reaction flask. After stirring evenly, the mixture was stirred and reacted for 0.5 hours at 0-5 °C. The mixture was then filtered to obtain the pretreated 1-bromoethyl acetate. (2) Take another clean 250ml reaction flask, add S-flurbiprofen (compound 1, 9.80g, 0.04mol), the pretreated 1-bromoethyl acetate obtained in step (1), and 75ml of dichloromethane. After stirring evenly, the resulting mixed solution is cooled to 15-20℃ under nitrogen protection and N,N-diisopropylethylamine (DIPEA, 5.20g, 0.04mol) is added dropwise. After the addition is complete, the reaction is stirred at 15-20℃ for 10-12 hours. The resulting reaction solution is quenched with water. The resulting organic phase is washed 4 times with 5% sodium carbonate aqueous solution, washed with water, dried with anhydrous magnesium sulfate, and the resulting organic phase is concentrated. Then, 33.5g of n-heptane and 6.7g of zinc oxide are added and stirred for 1 hour. After filtration, the solution is concentrated to obtain levorbiprofen ester with a yield of 97.5%, a purity of 87.668%, a maximum single impurity of 2.75%, and a total impurity of 12.332%.

[0031] Comparative Example 10 (Adsorbent dosage was too low) A method for preparing high-purity levonorfen ester includes the following steps: (1) Under nitrogen protection, 1-bromoethyl acetate (compound 2, 6.70 g, 0.04 mol), 2 g of sodium bicarbonate and 1.4 g of magnesium sulfate were added to a 250 ml reaction flask. After stirring evenly, the mixture was stirred and reacted at 20-30 °C for 0.5 hours. The mixture was then filtered to obtain the pretreated 1-bromoethyl acetate. (2) Take another clean 250ml reaction flask, add S-flurbiprofen (compound 1, 9.80g, 0.04mol), the pretreated 1-bromoethyl acetate obtained in step (1), and 75ml of dichloromethane. After stirring evenly, the resulting mixed solution is cooled to 15-20℃ under nitrogen protection and N,N-diisopropylethylamine (DIPEA, 5.20g, 0.04mol) is added dropwise. After the addition is complete, the reaction is stirred at 15-20℃ for 10-12 hours. The resulting reaction solution is quenched with water. The resulting organic phase is washed 4 times with 5% sodium carbonate aqueous solution, washed with water, dried with anhydrous magnesium sulfate, and the resulting organic phase is concentrated. Then, 33.5g of n-heptane and 2.5g of zinc oxide are added and stirred for 1 hour. After filtration, the solution is concentrated to obtain levorbiprofen ester with a yield of 97.5%, a purity of 97.688%, a maximum single impurity of 0.185%, and a total impurity of 2.312%.

[0032] Comparative Example 11 (Adsorbent dosage was too high) A method for preparing high-purity levonorfen ester includes the following steps: (1) Under nitrogen protection, 1-bromoethyl acetate (compound 2, 6.70 g, 0.04 mol), 2 g of sodium bicarbonate and 1.4 g of magnesium sulfate were added to a 250 ml reaction flask. After stirring evenly, the mixture was stirred and reacted at 20-30 °C for 0.5 hours. The mixture was then filtered to obtain the pretreated 1-bromoethyl acetate. (2) Take another clean 250ml reaction flask, add S-flurbiprofen (compound 1, 9.80g, 0.04mol), the pretreated 1-bromoethyl acetate obtained in step (1), and 75ml of dichloromethane. After stirring evenly, the resulting mixed solution is cooled to 15-20℃ under nitrogen protection and N,N-diisopropylethylamine (DIPEA, 5.20g, 0.04mol) is added dropwise. After the addition is complete, the reaction is stirred at 15-20℃ for 10-12 hours. The resulting reaction solution is quenched with water. The resulting organic phase is washed 4 times with 5% sodium carbonate aqueous solution, washed with water, dried with anhydrous magnesium sulfate, and the resulting organic phase is concentrated. Then, 33.5g of n-heptane and 12g of zinc oxide are added and stirred for 1 hour. After filtration, the concentration yields 78.5% flurbiprofen ester, with a purity of 98.788%, a maximum single impurity of 0.135%, and a total impurity of 1.212%.

[0033] Comparative Example 12 (Adsorbent type replaced) A method for preparing high-purity levonorfen ester includes the following steps: (1) Under nitrogen protection, 1-bromoethyl acetate (compound 2, 6.70 g, 0.04 mol), 2 g of sodium bicarbonate and 1.4 g of magnesium sulfate were added to a 250 ml reaction flask. After stirring evenly, the mixture was stirred and reacted at 20-30 °C for 0.5 hours. The mixture was then filtered to obtain the pretreated 1-bromoethyl acetate. (2) Take another clean 250ml reaction flask, add S-flurbiprofen (compound 1, 9.80g, 0.04mol), the pretreated 1-bromoethyl acetate obtained in step (1), and 75ml of dichloromethane. After stirring evenly, the resulting mixed solution is cooled to 15-20℃ under nitrogen protection, and N,N-diisopropylethylamine (DIPEA, 5.20g, 0.04mol) is added dropwise. After the addition is complete, continue cooling at 15- The reaction was stirred at 20°C for 10-12 hours. The resulting reaction solution was quenched with water. The resulting organic phase was then washed four times with 5% sodium carbonate aqueous solution, washed with water, dried with anhydrous magnesium sulfate, and concentrated. 33.5 g of n-heptane and 6.7 g of benzenesulfonic acid silica gel were added and stirred for 1 hour. The mixture was filtered and concentrated to obtain levonorfen ester with a yield of 95.5%, a purity of 97.764%, a maximum single impurity of 0.235%, and a total impurity of 2.236%.

[0034] Comparative Example 13 (low amount of n-heptane) A method for preparing high-purity levonorfen ester includes the following steps: (1) Under nitrogen protection, 1-bromoethyl acetate (compound 2, 6.70 g, 0.04 mol), 2 g of sodium bicarbonate and 1.4 g of magnesium sulfate were added to a 250 ml reaction flask. After stirring evenly, the mixture was stirred and reacted at 20-30 °C for 0.5 hours. The mixture was then filtered to obtain the pretreated 1-bromoethyl acetate. (2) Take another clean 250ml reaction flask, add S-flurbiprofen (compound 1, 9.80g, 0.04mol), the pretreated 1-bromoethyl acetate obtained in step (1), and 75ml of dichloromethane. After stirring evenly, the resulting mixed solution is cooled to 15-20℃ under nitrogen protection and N,N-diisopropylethylamine (DIPEA, 5.20g, 0.04mol) is added dropwise. After the addition is complete, the reaction is stirred at 15-20℃ for 10-12 hours. The resulting reaction solution is quenched with water. The resulting organic phase is washed 4 times with 5% sodium carbonate aqueous solution, washed with water, dried with anhydrous magnesium sulfate, and the resulting organic phase is concentrated. Then, 20.5g of n-heptane and 6.7g of zinc oxide are added and stirred for 1 hour. After filtration, the solution is concentrated to obtain levorbiprofen ester with a yield of 78.5%, a purity of 99.114%, a maximum single impurity of 0.105%, and a total impurity of 0.886%.

[0035] Comparative Example 14 (High amount of n-heptane) A method for preparing high-purity levonorfen ester includes the following steps: (1) Under nitrogen protection, 1-bromoethyl acetate (compound 2, 6.70 g, 0.04 mol), 2 g of sodium bicarbonate and 1.4 g of magnesium sulfate were added to a 250 ml reaction flask. After stirring evenly, the mixture was stirred and reacted at 20-30 °C for 0.5 hours. The mixture was then filtered to obtain the pretreated 1-bromoethyl acetate. (2) Take another clean 250ml reaction flask, add S-flurbiprofen (compound 1, 9.80g, 0.04mol), the pretreated 1-bromoethyl acetate obtained in step (1), and 75ml of dichloromethane. After stirring evenly, the resulting mixed solution is cooled to 15-20℃ under nitrogen protection and N,N-diisopropylethylamine (DIPEA, 5.20g, 0.04mol) is added dropwise. After the addition is complete, the reaction is stirred at 15-20℃ for 10-12 hours. The resulting reaction solution is quenched with water. The resulting organic phase is washed 4 times with 5% sodium carbonate aqueous solution, washed with water, dried with anhydrous magnesium sulfate, and the resulting organic phase is concentrated. Then, 45.5g of n-heptane and 6.7g of zinc oxide are added and stirred for 1 hour. After filtration, the solution is concentrated to obtain levorbiprofen ester with a yield of 99.0%, a purity of 98.304%, a maximum single impurity of 0.165%, and a total impurity of 1.696%.

[0036] Comparative Example 15 (solvent replacement) A method for preparing high-purity levonorfen ester includes the following steps: (1) Under nitrogen protection, 1-bromoethyl acetate (compound 2, 6.70 g, 0.04 mol), 2 g of sodium bicarbonate and 1.4 g of magnesium sulfate were added to a 250 ml reaction flask. After stirring evenly, the mixture was stirred and reacted at 20-30 °C for 0.5 hours. The mixture was then filtered to obtain the pretreated 1-bromoethyl acetate. (2) Take another clean 250ml reaction flask, add S-flurbiprofen (compound 1, 9.80g, 0.04mol), the pretreated 1-bromoethyl acetate obtained in step (1), and 75ml of dichloromethane. After stirring evenly, the resulting mixed solution is cooled to 15-20℃ under nitrogen protection and N,N-diisopropylethylamine (DIPEA, 5.20g, 0.04mol) is added dropwise. After the addition is complete, the reaction is stirred at 15-20℃ for 10-12 hours. The resulting reaction solution is quenched with water. The resulting organic phase is washed 4 times with 5% sodium carbonate aqueous solution, washed with water, dried with anhydrous magnesium sulfate, and the resulting organic phase is concentrated. Then, 33.5g of isopropyl ether and 6.7g of zinc oxide are added and stirred for 1 hour. After filtration, the solution is concentrated to obtain levorbiprofen ester with a yield of 98.0%, a purity of 99.304%, a maximum single impurity of 0.386%, and a total impurity of 0.696%.

[0037] The above embodiments are only used to illustrate the technical solutions of the present invention, and are not intended to limit it. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications may still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions may be made to some of the technical features. Such modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for preparing high-purity levonorfen ester, characterized in that, Includes the following steps: (1) Mix 1-bromoethyl acetate, alkaline reagent and inorganic salt evenly, and stir the reaction at 10-40℃ to obtain pretreated 1-bromoethyl acetate; (2) The pretreated 1-bromoethyl acetate, S-flurbiprofen, N,N-diisopropylethylamine and dichloromethane were mixed evenly and stirred at 15-20℃. The resulting reaction solution was quenched with water, washed and dried to obtain crude aflurbiprofen ester. Organic solvent and adsorbent were added to the crude product, stirred evenly, filtered and concentrated to obtain aflurbiprofen ester.

2. The method for preparing high-purity levorprofen ester according to claim 1, characterized in that, In step (1), the alkaline reagent is sodium bicarbonate, sodium hypophosphite, sodium citrate, potassium bicarbonate, potassium carbonate, potassium phosphate, sodium bisulfite, N,N-diisopropylethylamine, diisopropylamine, 2,4,6-trimethylpyridine, DBU, triethylamine, sodium carbonate, tetrabutylammonium hydroxide, sodium acetate, or sodium silicate; preferably sodium bicarbonate.

3. The method for preparing high-purity levorprofen ester according to claim 2, characterized in that, In step (1), the mass ratio of 1-bromoethyl acetate to alkaline reagent is 1:0.1-0.8; preferably 1:0.2-0.

4.

4. The method for preparing high-purity levorprofen ester according to claim 1, characterized in that, In step (1), the inorganic salt is magnesium sulfate, sodium sulfate, aluminum silicate or potassium sulfate; preferably magnesium sulfate.

5. The method for preparing high-purity levorprofen ester according to claim 4, characterized in that, In step (1), the mass ratio of 1-bromoethyl acetate to inorganic salt is 1:0.1-0.8; preferably 1:0.14-0.

4.

6. The method for preparing high-purity levorprofen ester according to claim 1, characterized in that, In step (1), during the stirring reaction, the reaction temperature is 15-35℃, preferably 20-30℃; the reaction time is 1-3 hours, preferably 0.5 hours.

7. The method for preparing high-purity levorprofen ester according to claim 1, characterized in that, In step (2), the adsorbent is zinc oxide, benzenesulfonic acid silica gel, alumina, bentonite, molecular sieve or HP1050 resin; preferably zinc oxide.

8. The method for preparing high-purity levorprofen ester according to claim 7, characterized in that, In step (2), the mass ratio of 1-bromoethyl acetate to adsorbent is 1:0.3-1.0; preferably 1:0.5-0.7, more preferably 1:0.

67.

9. The method for preparing high-purity levorprofen ester according to claim 1, characterized in that, In step (2), the organic solvent is n-heptane, isopropyl ether, petroleum ether, methyl tert-butyl ether, n-hexane or cyclohexane; preferably n-heptane.

10. The method for preparing high-purity levorprofen ester according to claim 9, characterized in that, In step (2), the mass ratio of 1-bromoethyl acetate to organic solvent is 1:2.5-4.4; preferably 1:3.2-3.4, more preferably 1:3.35.

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