A process for the synthesis of dexketoprofen

Abstract

The application provides a method for synthesizing dextroketoprofen. The method comprises the following steps: S1: taking ketoprofen amide as a raw material, performing a hydrolysis reaction in a reaction medium, a cosolvent, a phase transfer catalyst and an amidase system, and performing separation and purification to obtain dextroketoprofen and levo-ketoprofen amide; S2: performing a chemical racemization reaction on the levo-ketoprofen amide in the presence of a solvent and a base to obtain ketoprofen amide; and repeating step S1 by taking the ketoprofen amide as a raw material. The method has high substrate concentration, low enzyme substrate ratio, high selectivity, high conversion rate and high product purity, higher efficiency, low solvent consumption, lower cost, fully utilized raw materials, less solid waste discharge, can meet the requirements of industrialized production of enzyme catalysis, and has good industrial application potential.

Description

Technical Field

[0001] This invention relates to the field of enzyme hydrolysis synthesis technology, and in particular to a method for synthesizing dextro-ketoprofen. Background Technology

[0002] Dextro-ketoprofen, also known as (S)-(+)-ketoprofen, (S)-ketoibuprofen, or (S)-(+)-2-(3-benzoylphenyl)propionic acid, is a 2-arylpropionic acid class of nonsteroidal anti-inflammatory drugs (NSAIDs). Its commercial form is dextro-ketoprofen tromethamine. Ketoprofen has one chiral center and two enantiomers, only of which dextro-ketoprofen possesses anti-inflammatory, antirheumatic, and analgesic effects. Levo-ketoprofen has almost no pharmacological activity and toxic side effects. Dextro-ketoprofen was developed by the Italian company Menarini in 1996 and first marketed in Spain. Its anti-inflammatory and analgesic effects are twice that of the racemic mixture, indicating that levo-ketoprofen is ineffective. Therefore, the synthesis and production of the single isomer dextro-ketoprofen has significant application value.

[0003] Currently, the main synthetic methods for dextro-ketoprofen include chemical asymmetric synthesis, chemical resolution, and enzymatic resolution (including esterases, lipases, nitrile hydrolases, nitrile hydratases, and amidases).

[0004] Chemical asymmetric synthesis methods require heavy metal chiral catalysts and high temperature and pressure conditions. Most catalysts are highly toxic and cause environmental pollution, and chiral catalysts are also expensive. Chemical resolution involves recrystallization, which is time-consuming, increases costs, and reduces yield. In addition, the resolving agent is used in large quantities, resulting in high costs and a lot of wastewater and waste solvent. Lipase or esterase catalytic resolution has disadvantages such as low raw material concentration, large enzyme dosage, environmentally unfriendly reaction medium, low ee% value of product, and difficulty in separating product mixtures. Nitrile hydrolase hydrolysis resolution yields products with very low ee% values. The two-step enzymatic hydrolysis resolution of ketoprofen nitrile to synthesize dextro-ketoprofen using nitrile hydratase and amidase mostly results in low concentration and low yield. The two-step enzymatic method increases costs, and the post-processing steps are cumbersome.

[0005] There are numerous reports on the hydrolysis and resolution of ketoprofen amide by amidases to synthesize dextro-ketoprofen. For example, Appl. Microbiol. Biotechnol., 1994, 42:1-7 reported that amidase derived from Agrobacterium tumefaciens strain d3 achieved a conversion rate of 5% and an ee% value of 97%. BIOTECHNOLOGY LETTERS, 1995, 17(2):187-192 introduced microbial amidases, showing that Rhodococcus sp. C3II cells converted 2 mM feedstock achieved a conversion rate of 53% after 20.5 h, with a dextro-ketoprofen ee% value of 97%; Rhodococcus erythropolis MP 50 cells converted 0.2 mM feedstock achieved a conversion rate of 49%, with a dextro-ketoprofen ee% value of 99%. Protein & Peptide Letters, 2008, 15, 617-623, reports the amidase reaction of Sulfolobus solfataricus: 1.5 g ketoprofen amide was dissolved in 100 mL of methanol, 500 mL of Tris-HCl buffer was added, 12 mg of purified enzyme was added, and the reaction was carried out at 70 °C for 24 h, with an optical purity of 99.6% ee. CN111363736 reports the preparation of dextro-ketoprofen using Klebsiella amidase: 0.8 g of enzyme powder was resuspended in 100 mL of sodium phosphate buffer, 4 g of ketoprofen amide was dissolved in 10 mL of toluene and added to the reaction flask, and the reaction was incubated for 10 h, with a product ee% of 100% and a conversion rate of 50.85%. CN111378637 describes the preparation of dextro-ketoprofen using Agrobacterium amidase, as in Example 6. 1g of enzyme powder was resuspended in 100mL of sodium phosphate buffer, and 4g of ketoprofen dissolved in 10mL of toluene was added dropwise to the reaction flask. The reaction was incubated for 10 hours, yielding a product ee% of 99.8% and a conversion rate of 50.75%. CN114134132 describes the mutation of Rhodococcus erythropolis MP50 amidase. The highest activity mutant was used in Example 9, as in Example 9. 0.37g of AMD03-38 enzyme powder was added dropwise to 100mL of sodium phosphate buffer, and 6g of ketoprofen dissolved in 10mL of ethyl acetate was added dropwise to the reaction flask. The reaction was incubated for 24 hours, yielding a conversion rate of 49% and a product ee% of 99.5%.

[0006] Based on the aforementioned synthetic methods for dextro-ketoprofen, chemical asymmetric synthesis and chemical resolution methods are environmentally unfriendly, cumbersome, and require large amounts of solvent. Other enzymatic resolution methods suffer from low enzyme activity, low reactant concentrations, high enzyme-to-base ratios, high costs, and low ee% of the product. A relatively ideal method is the amidase hydrolysis resolution of ketoprofen amides, but several issues limit its industrial application, specifically including:

[0007] (1) The reaction feed concentration is generally low, the enzyme-to-bottom ratio is high, the space-time yield is not high, and it cannot meet the requirements of large-scale industrial production.

[0008] (2) Since the raw materials are almost insoluble in water, a lot of cosolvents need to be added. Using a lot of water-soluble solvents such as methanol will affect the enzyme activity. Using water-insoluble solvents such as toluene and ethyl acetate will cause enzyme interface inactivation, insufficient contact of raw materials, emulsification of reaction solution and large amount of solvent.

[0009] (3) The ineffective L-ketoprofenamide was not recycled, resulting in increased material costs and the generation of solid waste;

[0010] (4) The reaction medium is not environmentally friendly. Adding a large amount of phosphorus-containing buffer solution will generate phosphorus-containing wastewater, which is not conducive to scale-up production.

[0011] Therefore, it is necessary to develop more efficient, environmentally friendly, and high-yield amidase hydrolysis and resolution methods to meet the requirements of industrial production. Summary of the Invention

[0012] To address the shortcomings of existing technologies, this invention provides a method for synthesizing dextro-ketoprofen, which solves the problems of low concentration of reaction raw materials, high enzyme-to-solvent ratio, large amount of co-solvent used, environmentally unfriendly reaction medium, and non-recovery of ineffective components in existing technologies.

[0013] This invention provides a method for synthesizing dextro-ketoprofen, comprising the following steps:

[0014] S1: Using ketoprofen amide as raw material, hydrolysis reaction was carried out in a reaction medium, co-solvent, phase transfer catalyst, and amidase system, followed by separation and purification to obtain dextro-ketoprofen and levo-ketoprofen amide;

[0015] S2: Levoketoprofenamide is subjected to a chemical racemization reaction in the presence of a solvent and a base to obtain ketoprofenamide; step S1 is repeated using ketoprofenamide as a starting material, and the reaction process is shown below:

[0016]

[0017] Further, in step S1, the reaction medium is one of Tris-HCl buffer, water, and triethanolamine-HCl, preferably water;

[0018] The phase transfer catalyst is one of benzyltrimethylammonium chloride, benzyltriethylammonium chloride, benzyltributylammonium chloride, tetramethylammonium chloride, tetraethylammonium chloride, tetrabutylammonium chloride, tetrabutylammonium fluoride, and tetrabutylammonium bromide, preferably tetramethylammonium chloride;

[0019] The co-solvent is one of dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), methanol, ethanol, acetone, acetonitrile, ethyl acetate, and toluene, preferably dimethyl sulfoxide.

[0020] Because the hydrolysis product of amide is an ammonium carboxylate, the pH change during the process is minimal, eliminating the need for excess buffer solution, especially phosphate, as the reaction medium. DMSO is a highly polar, inert solvent with good water solubility, high solubility of the raw materials, and limited effect of low concentrations on the enzyme. Adding a small amount of phase transfer catalyst facilitates the dispersion of the raw materials and contact with the enzyme, thereby increasing the reaction rate.

[0021] Furthermore, in step S1, the amidase has selective ketoprofen amide hydrolysis activity.

[0022] Preferably, it is an amidase derived from Rhodococcus erythropolis CCM2595, the amino acid sequence of which is shown in SEQ ID NO.1.

[0023] Furthermore, in step S1, the amidease exists in one of the following forms: enzyme solution, enzyme powder, bacterial cells, or immobilized enzyme.

[0024] Furthermore, in step S1, the hydrolysis reaction is carried out at a temperature of 40°C and a pH value of 8.0.

[0025] Further, in step S1, the concentration of ketoprofenamide in the reaction medium is 100 g / L; the mass ratio of amidase to ketoprofenamide is 1 / 20.

[0026] Furthermore, the volume concentration of the co-solvent in the reaction medium is 1-50%, preferably 5%; and the mass concentration of the phase transfer catalyst in the reaction medium is 0.1-10%, preferably 0.5%.

[0027] Further, in step S2, the alkali is one of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, and potassium carbonate, preferably potassium hydroxide.

[0028] Further, in step S2, the solvent is one of methanol, ethanol, n-propanol, and isopropanol, preferably ethanol.

[0029] Furthermore, in step S2, the temperature of the racemization reaction is 20-80℃, preferably 40℃.

[0030] The term "mass concentration" refers to the mass of a component in a unit volume of a mixture, denoted by the symbol ρ, and measured in g / ml.

[0031] The term "volume concentration" refers to the concentration of substance B at the same temperature and pressure, expressed as a percentage of its volume V. B The ratio of substance B to the volume V of the solution is called the volume fraction of substance B, also known as the volume percentage, denoted by φB, and expressed as φB = (V / V). B (÷V)×100%, V / V or ml / ml.

[0032] Compared with the prior art, the present invention has the following beneficial effects:

[0033] (1) The novel method for preparing dextro-ketoprofen by amidase catalysis of the present invention has a high substrate concentration and a low enzyme-to-substrate ratio. The substrate concentration is as high as 100 g / L and the enzyme-to-substrate ratio is as low as 1 / 20. It has high selectivity, high conversion rate and high product purity, with a conversion rate of >46%, product optical purity of >99.5% and product purity of >99.5%. It can meet the requirements of enzyme catalysis industrial production and has great potential for industrial application.

[0034] (2) The present invention utilizes a reaction system of reaction medium, low concentration co-solvent, small amount of phase transfer catalyst, and amidase to hydrolyze ketoprofen amide to prepare dextro-ketoprofen. The amidase is preferably derived from Rhodococcus erythropolis CCM2595. The reaction medium (preferably water) is safer and more environmentally friendly during the reaction process, the co-solvent concentration (5% by volume) is lower, the amount of phase transfer catalyst used is less (0.5% by mass), and the cost is lower.

[0035] (3) In the process of preparing dextro-ketoprofen using amidase, only 50% is generally converted to dextro-ketoprofen. The lack of recovery of levo-ketoprofen amide leads to excessively high production costs and is detrimental to the industrial production of enzyme-catalyzed products. This invention separates the ineffective levo-ketoprofen amide from the reaction solution and performs chemical racemization on it. The racemic ineffective amide is then recycled as a reaction raw material. This method achieves a recovery rate of over 95% for the ineffective amide, ensuring full utilization of the raw materials, improving raw material utilization, and reducing costs and solid waste emissions. Attached Figure Description

[0036] Figure 1 This is a reversed-phase high-performance liquid chromatogram of the raw material conversion rate in Example 7 of the present invention.

[0037] Figure 2 This is a high-performance liquid chromatogram of the optical purity of the product in Example 7 of the present invention. Detailed Implementation

[0038] The technical solutions of the present invention are further illustrated below with reference to the embodiments. Different amidases are prepared according to conventional enzyme preparation methods (see Enzyme Engineering, 4th Edition, Science Press, by Guo Yong; Genetic Engineering, 2nd Edition, Science Press, by Guo Jiangfeng and Yu Wei), that is, by constructing genetically engineered Escherichia coli that produces enzymes, then inducing culture and expression, and then preparing the required enzyme preparation. The amino acid sequence of Rhodococcus erythropolis CCM2595 amidase is shown in SEQ ID NO.1, Rhodococcus eythropolis MP50 amidase is from BIOTECHNOLOGY LETTERS, 1995, 17(2):187-192, and Sulfolobus solfataricus amidase is from Protein & Peptide Letters, 2008, 15, 617-623.

[0039] Example 1: Different amidase test reactions

[0040] In a 500ml reaction flask, 100mL of 0.1M Tris-HCl buffer (pH 8.0) was added. 10g of ketoprofen amide was dissolved in 20mL of DMSO and added to the reaction flask. Different prepared amidases were then added. The pH was adjusted to 8.0 with sodium hydroxide aqueous solution. The mixture was stirred at 40℃ for 24h. Samples were taken for analysis to determine the conversion rate and the ee% value of the product dextro-ketoprofen. The results are shown in Table 1.

[0041] Table 1. Conversion rates and product ee values ​​for different amidase reactions.

[0042]

[0043]

[0044] As shown in Table 1, the catalytic activity of the amidase of Rhodococcus erythropolis CCM2595 is significantly higher than that of the amidases of Rhodococcus eythropolis MP50 and Sulfolobus solfataricus.

[0045] Example 2: Amide enzyme resolution reaction in different media

[0046] In a 500ml reaction flask, add 100mL of pH 8.0 buffer or pure water. Dissolve 10g of ketoprofen amide in 20mL of DMSO and add it to the reaction flask. Then add 0.5g of Rhodococcus erythropolis CCM2595 amidase powder. Adjust the pH to 8.0 with sodium hydroxide solution. Stir the reaction at 40℃ for 24h. Take samples for analysis to determine the conversion rate and the ee% value of the product dextro-ketoprofen. The results are shown in Table 2.

[0047] Table 2. Conversion rate and ee value of amidase reaction in different media

[0048] reaction medium Conversion rate Product ee% value 0.1M Tris-HCl 43.10％ 99.72％ 0.1M triethanolamine-HCl 42.65％ 99.70％ pure water 42.74％ 99.74％

[0049] As shown in Table 2, pure water medium has a similar effect to both buffer reactions. Based on cost and environmental protection requirements, pure water is selected as the reaction medium.

[0050] Example 3: Resolution reaction of different cosolvent amidases

[0051] In a 50ml reaction flask, 10mL of pure water was added. 1g of the raw material ketoprofen amide was dissolved in 2mL of solvent and added to the reaction flask. Then, 50mg of Rhodococcus erythropolis CCM2595 amidase powder was added. The pH was adjusted to 8.0 with sodium hydroxide aqueous solution. The mixture was stirred at 40℃ for 24h. Samples were taken for analysis, and the conversion rate and the ee% value of the product dextro-ketoprofen were determined. The results are shown in Table 3.

[0052] Table 3. Conversion rate and ee value of amidase reaction under different cosolvents.

[0053]

[0054]

[0055] As shown in Table 3, DMSO is the best co-solvent for the reaction.

[0056] Example 4: Amide enzyme resolution reaction with different DMSO concentrations

[0057] In a 50ml reaction flask, 10mL of pure water, 1g of ketoprofen amide, and different amounts of DMSO were added. Finally, 50mg of Rhodococcus erythropolis CCM2595 amidase powder was added. The pH was adjusted to 8.0 with sodium hydroxide aqueous solution, and the reaction was stirred at 40℃ for 24h. Samples were taken for analysis, and the conversion rate and the ee% value of the product dextro-ketoprofen were determined. The results are shown in Table 4.

[0058] Table 4. Conversion rate and product ee value of amidase reaction at different DMSO concentrations

[0059] DMSO concentration Conversion rate Product ee% value 1％ 36.63％ 99.74％ 5％ 41.31％ 99.75％ 10％ 42.69％ 99.73％ 20％ 43.72％ 99.75％ 30％ 40.33％ 99.74％ 50％ 29.87％ 99.70％

[0060] As shown in Table 4, based on cost and reaction effect, the dosage of 5% DMSO was determined.

[0061] Example 5: Amidease Resolution Reaction with Different Phase Transfer Catalysts

[0062] In a 50ml reaction flask, add 10mL of pure water, 1g of ketoprofen amide, 0.5mL of DMSO, then add 1% phase transfer catalyst (100mg), and finally add 50mg of Rhodococcus erythropolis CCM2595 amidase powder. Adjust the pH to 8.0 with sodium hydroxide aqueous solution, stir at 40℃ for 24h, take samples for analysis, and determine the conversion rate and the ee% value of the product dextro-ketoprofen. The results are shown in Table 5.

[0063] Table 5. Conversion rate and ee value of amidase reaction under different phase transfer catalysts.

[0064]

[0065]

[0066] As shown in Table 5, the optimal phase transfer catalyst is tetramethylammonium chloride.

[0067] Example 6: Resolution reaction of tetramethylammonium chloride enzyme at different concentrations

[0068] In a 50ml reaction flask, 10mL of pure water, 1g of ketoprofen amide, and 0.5mL of DMSO were added. Then, varying amounts of tetramethylammonium chloride were added, followed by 50mg of Rhodococcus erythropolis CCM2595 amidase powder. The pH was adjusted to 8.0 with sodium hydroxide solution, and the reaction was carried out at 40℃ with stirring for 24h. Samples were taken for analysis to determine the conversion rate and the ee% value of the product dextro-ketoprofen. The results are shown in Table 6.

[0069] Table 6. Conversion rate and product ee value of amidase reaction with different concentrations of tetramethylammonium chloride.

[0070] Tetramethylammonium chloride concentration Conversion rate Product ee% value 0.1％ 43.27％ 99.75％ 0.5％ 46.39％ 99.73％ 1％ 46.04％ 99.71％ 2％ 44.38％ 99.72％ 5％ 40.19％ 99.73％ 10％ 35.67％ 99.75％

[0071] As shown in Table 6, the optimal concentration of the phase transfer catalyst, tetramethylammonium chloride, is 0.5%.

[0072] Example 7: Amide enzyme resolution of ketoprofen amide to synthesize dextro-ketoprofen.

[0073] In a 3L reaction flask, add 2L of pure water, 200g of ketoprofen amide, 100mL of DMSO, and 10g of tetramethylammonium chloride. Start stirring and maintain the temperature at 40℃. Once the set temperature is reached, add 10g of Rhodococcus erythropolis CCM2595 amidase powder. Adjust the pH to 8.0 with sodium hydroxide solution and maintain the reaction temperature. Monitor the reaction process by TLC and detect the conversion rate by HPLC. When the conversion rate is greater than 45%, stop the reaction and adjust the pH to 10.0. Extract the reaction solution three times with an equal volume of ethyl acetate. Centrifuge and separate the liquids. Combine the organic phases, distill under reduced pressure, and dry in an oven to obtain 100.73g of ineffective levo-ketoprofen amide, with an ee% value of 93.75% and an HPLC purity of 99.72%. After acidifying the aqueous phase, extract three times with an equal volume of ethyl acetate. Combine the ethyl acetate phases, distill under reduced pressure, and dry in an oven to obtain 86.32g of dextro-ketoprofen, with an ee% value of 99.75% and an HPLC purity of 99.91%. The reversed-phase high-performance liquid chromatogram of the sample taken at the end of the amidase reaction to analyze the conversion rate is shown below. Figure 1 As shown, the retention time of ketoprofen was 7.299 min, and the retention time of ketoprofenamide was 10.148 min. The normal-phase chiral high-performance liquid chromatogram of the product's optical purity, obtained by sampling and analysis at the end of the reaction, is shown below. Figure 2 As shown, the products involved are dextro-ketoprofen and levo-ketoprofen, and the raw materials are dextro-ketoprofenamide and levo-ketoprofenamide. The retention times of levo-ketoprofen are 8.148 min, dextro-ketoprofen is 10.297 min, dextro-ketoprofenamide is 11.377 min, and levo-ketoprofenamide is 13.798 min.

[0074] Example 8 Racemic reaction of levonorfenamide in different solvents

[0075] 2g of levonorfenamide, 10mL of solvent, and 0.04g of sodium hydroxide were added sequentially to a 50mL reaction flask. The mixture was stirred at 50℃ for 3h. After the reaction was completed, a sample was taken and the ee% value of the amide was determined. The results are shown in Table 7.

[0076] Table 7 Results of racemic reactions of levonorfenamide in different solvents

[0077] solvent racemic amide ee% value racemic amide ee% value methanol 93.75％ 0.61％ ethanol 93.75％ 0.27％ n-Propanol 93.75％ 1.53％ Isopropanol 93.75％ 2.98％

[0078] As shown in Table 7, the optimal solvent for racemic reactions is ethanol.

[0079] Example 9 Racemic reaction of levonorfenamide in different bases

[0080] 2g of levonorfenamide, 10mL of ethanol, and 0.04g of alkali were added sequentially to a 50mL reaction flask. The reaction was carried out at 50℃ for 3h. After the reaction was completed, a sample was taken and the ee% value of the amide was determined. The results are shown in Table 8.

[0081] Table 8 Results of racemic reactions of L-ketoprofenamide with different bases

[0082] alkali racemic amide ee% value racemic amide ee% value Sodium hydroxide 93.75％ 0.35％ potassium hydroxide 93.75％ 0.23％ Lithium hydroxide 93.75％ 3.50％ Sodium carbonate 93.75％ 37.53％ Potassium carbonate 93.75％ 1.24％

[0083] As shown in Table 8, the optimal base for the racemic reaction is potassium hydroxide.

[0084] Example 10 Racemic reaction of levonorfenamide at different temperatures

[0085] 2g of levonorfenamide, 10mL of ethanol, and 0.04g of potassium hydroxide were added sequentially to a 50mL reaction flask. The reaction was carried out at different temperatures, and samples were taken during the process to determine the ee% value of the amide. The results are shown in Table 9.

[0086] Table 9 Results of racemic reactions of levonorfenamide at different temperatures

[0087] temperature racemic amide ee% value racemic amide ee% value racemization time 20℃ 93.75％ 1.75％ 10h 40℃ 93.75％ 0.25％ 4h 60℃ 93.75％ 0.26％ 2h 80℃ 93.75％ 0.17％ 1h

[0088] As shown in Table 9, based on safety, energy consumption, and reaction efficiency, the optimal temperature for the racemic reaction is 40℃.

[0089] Finally, it should be noted that 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 preferred embodiments, those skilled in the art should understand that modifications or equivalent substitutions can be made to the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention, and all such modifications or substitutions should be covered within the scope of the claims of the present invention.

Claims

1. A method for synthesizing dextro-ketoprofen, characterized in that: Includes the following steps: S1: Using ketoprofen amide as a raw material, a hydrolysis reaction is carried out in a reaction medium, a co-solvent, a phase transfer catalyst, and an amidase system to obtain dextro-ketoprofen and levo-ketoprofen amide; wherein, the reaction medium is water or Tris-HCl buffer, the phase transfer catalyst is tetramethylammonium chloride, and the amidase is derived from Rhodococcus erythropolis CCM2595, whose amino acid sequence is shown in SEQ ID NO.1; S2: Levo-ketoprofen amide is subjected to a chemical racemization reaction in the presence of a solvent and a base to obtain ketoprofen amide; step S1 is repeated using ketoprofen amide as a raw material, and the reaction process is shown below: 。 2. The method for synthesizing dextro-ketoprofen as described in claim 1, characterized in that: In step S1, the amidase exists in one of the following forms: enzyme solution, enzyme powder, bacterial cells, or immobilized enzyme.

3. The method for synthesizing dextro-ketoprofen as described in claim 1, characterized in that: In step S1, the hydrolysis reaction is carried out at a temperature of 40°C and a pH value of 8.

0.

4. The method for synthesizing dextro-ketoprofen as described in claim 1, characterized in that: In step S1, the concentration of ketoprofenamide in the reaction medium is 100 g / L; the mass ratio of amidase to ketoprofenamide is 1 / 20.

5. The method for synthesizing dextro-ketoprofen as described in claim 1, characterized in that: In step S1, the volume concentration of the co-solvent in the reaction medium is 1-50%; the mass concentration of the phase transfer catalyst in the reaction medium is 0.1-10%.

6. The method for synthesizing dextro-ketoprofen as described in claim 5, characterized in that: The volume concentration of the co-solvent in the reaction medium is 5%; the mass concentration of the phase transfer catalyst in the reaction medium is 0.5%.

7. The method for synthesizing dextro-ketoprofen as described in claim 1, characterized in that: In step S2, the alkali is one of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, and potassium carbonate.

8. The method for synthesizing dextro-ketoprofen as described in claim 1, characterized in that: In step S2, the solvent is one of methanol, ethanol, n-propanol, and isopropanol.

9. The method for synthesizing dextro-ketoprofen as described in claim 1, characterized in that: In step S2, the temperature of the racemization reaction is 20-80℃.

10. The method for synthesizing dextro-ketoprofen as described in claim 9, characterized in that: The racemization reaction was carried out at a temperature of 40°C.

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