A process for the preparation of ketoprofen

Abstract

The application belongs to the field of medicine and chemical industry, and particularly relates to a preparation method of ketoprofen. 3-bromobenzoic acid is used as a starting material, and a chlorination reaction is carried out with thionyl chloride. Then, a Friedel-Crafts reaction is carried out with benzene under the catalysis of aluminum chloride. The reaction product is subjected to a Friedel-Crafts reaction with ethylene, an addition reaction with hydrobromic acid, a reaction with a cyanating agent, and then hydrolysis under the action of an acid, so as to obtain ketoprofen. The application provides a reasonable reaction route, realizes the preparation of ketoprofen by using cheap and readily available and green and environmentally-friendly reagents, avoids the use of highly corrosive, highly toxic, flammable and expensive reagents, has low requirements on equipment, reduces the operation difficulty and the burden of post-reaction treatment, and reduces the cost. The application is a simple, green and economic process route for preparing ketoprofen, the obtained product has high yield and good purity, and is suitable for industrial mass production of ketoprofen.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical chemical industry, and specifically relates to a method for preparing ketoprofen. Background Technology

[0002] Ketoprofen (KPF), also known as ketoprofen, phenylpropanoic acid, or Profenid, is chemically named α-methyl-3-benzoylphenylacetic acid [2-(3-Benzoylphenyl)propanoic acid [CAS:22071-15-4]]. It is a superior 2-arylpropionic acid nonsteroidal anti-inflammatory and analgesic drug developed in 1967 by chemists Farge, Messer, and Moutounier of the French company Rhone-Poulenc. Its mechanism of action primarily involves inhibiting the biological activity of cyclooxygenases (COXs) and lipoxygenases (LOXs) in the body, thereby inhibiting the synthesis of pro-inflammatory substances such as prostaglandins (PGs) and leukotrienes (LTs). It also counteracts bradykinin release, scavengees hydroxyl free radicals, and stabilizes lysosomal membrane activity, thus producing good antipyretic, analgesic, and anti-inflammatory effects, and enhancing its peripheral analgesic effect. Clinical studies have shown that ketoprofen, as an important nonsteroidal anti-inflammatory drug, has significant advantages over similar drugs, such as lower dosage, higher efficacy, better tolerability, and milder side effects. It has become an ideal drug for treating rheumatoid arthritis, rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, and gout. It is also widely used to treat dysmenorrhea, toothache, postoperative pain, cancer pain, neuritis, lupus erythematosus, pharyngitis, bronchitis, and other diseases. It is even more effective in treating soft tissue injuries.

[0003]

[0004] Many synthetic methods for ketoprofen have been reported, and the following routes are some of the more representative ones.

[0005] (1) The Chinese Journal of Medicinal Chemistry, 2000, 10, 127-128, reported a method for preparing ketoprofen using benzoic acid as a starting material. This method uses benzoic acid as a raw material, proceeding through bromination, Grignard reaction, and Darzens reaction to prepare ketoprofen. While the raw materials are inexpensive, this method has the following drawbacks: low yield, especially due to the lack of protection of the carbonyl group in the Grignard reaction, which affects the overall yield. Furthermore, the Darzens reaction, the final step in this synthetic route, also has a low yield, further impacting the overall yield. Additionally, the production process involves the use of large quantities of toxic, hazardous, flammable, and explosive materials such as bromine, phosphorus pentachloride, Grignard reagent, and metallic sodium, making industrial production difficult, dangerous, and posing significant challenges for hazardous waste disposal.

[0006] The combined approach of this method is as follows:

[0007]

[0008] (2) Using acetophenone as the starting material, the product is obtained through chloromethylation, Friedel-Crafts reaction, Darzens reaction, potassium permanganate oxidation, and finally purification, with an overall yield of about 40%. Although the raw materials are readily available, this method has the following disadvantages: the overall yield is low; the Darzens condensation reaction requires a large amount of metallic sodium, posing a significant fire hazard to safe production; moreover, the yield and selectivity of the potassium permanganate oxidation step are not high; during the oxidation process, ketoprofen undergoes further oxidation, producing impurities, and the product requires multiple purification processes to meet European and American pharmacopoeia standards, with reported overall yields of less than 40%.

[0009] The synthesis route of this method is as follows:

[0010]

[0011] (3) Starting with m-methylbenzoic acid, the product is obtained through esterification, halogenation, cyanation, methylation, hydrolysis, followed by acylation, Friedel-Crafts reaction, hydrolysis, and purification. This method has the following disadvantages: the reaction route has 6 steps, and highly toxic sodium cyanide is required during the reaction. Furthermore, dimethylated impurities are generated during methylation, leading to product defects.

[0012] The synthesis route of this method is as follows:

[0013]

[0014] (4) The "New Synthesis Process of Ketoprofen" (Patent No. 95109877) uses 2-amino-benzophenone or 4-amino-benzophenone or their amino-protected compounds as starting materials, and synthesizes ketoprofen through α-halopropionylation (or propionylation followed by halogenation), ketalization, rearrangement, hydrolysis, and diazo deamination. This method has the following disadvantages: this route involves five steps, and the amino and ketone groups are protected and transformed separately, resulting in a decrease in the utilization rate of the raw materials, an increase in cost, and poor atom economy.

[0015] The synthesis route of this method is as follows:

[0016]

[0017] (5) A new route for the preparation of ketoprofen, published by Chen Fen'er et al. in the journal Organic Process Research & Development (2023, 27(5), 922-927). This route uses cyclohexanone as the starting material, reacts with pyrrole to generate an intermediate, which then reacts with benzyl chloride to obtain intermediate 12. Intermediate 12 undergoes a cyclization reaction with ethyl pyruvate at -78℃ and under the action of titanium tetrachloride, followed by a two-step reaction at 230-250℃ to obtain deoxyketoprofen. It is then oxidized with potassium permanganate to obtain ketoprofen. The overall yield of this route is about 45%. This method has the following disadvantages: the route includes a one-step low-temperature reaction (-78℃) and a one-step high-temperature reaction (230-250℃), which makes industrialization difficult.

[0018] The synthesis route of this method is as follows:

[0019]

[0020] In summary, the main shortcomings of existing synthetic routes for ketoprofen are: 1. The use of highly corrosive materials such as bromine and phosphorus pentachloride, which places high demands on equipment; 2. The use of Grignard reagents, metallic sodium, and other materials, which makes production operations difficult and poses significant safety hazards; 3. The use of cyaniding reagents such as sodium cyanide, which are highly toxic and require very high production standards; 4. Most synthetic routes involve cumbersome processes, difficult-to-control reactions, and numerous impurities. Post-processing often involves column chromatography purification, which is difficult to operate and unsuitable for industrial production.

[0021] Therefore, finding a route that uses cheap and readily available raw materials, has mild reaction conditions, high yield, and low cost is an urgent need for the large-scale commercial production of ketoprofen. Summary of the Invention

[0022] In order to overcome the shortcomings of the prior art, the purpose of this invention is to provide a method for preparing ketoprofen that avoids the use of highly corrosive bromine, phosphorus pentachloride, and highly flammable Grignard reagents, metallic sodium, etc. At the same time, the process route is simple to operate, the reaction conditions are mild, the product yield is high, the purity is good, and it is easy to industrialize.

[0023] This invention provides a method for preparing ketoprofen, comprising the following steps:

[0024] (1) Using 3-bromobenzoic acid, a compound of formula 2, as the starting material, it undergoes a chlorination reaction with thionyl chloride, and then undergoes a Friedel-Crafts reaction with benzene under the catalysis of aluminum trichloride to obtain compound 3;

[0025] (2) Compound of Formula 3 reacts with ethylene in a Friedel-Crafts reaction to give compound of Formula 4;

[0026] (3) Compound of formula 4 undergoes an addition reaction with hydrobromic acid to produce compound of formula 5;

[0027] (4) The compound of formula 5 reacts with the cyaniding reagent to produce the compound of formula 6;

[0028] (5) The compound of formula 6 is hydrolyzed under the action of acid to obtain the compound of formula 1, which is ketoprofen.

[0029] The reaction equation is as follows:

[0030]

[0031] Preferably, the Friedel-Crafts reaction in step (2) uses copper bromide as a metal catalyst and lithium chloride as an additive.

[0032] Preferably, the mass ratio of copper bromide to lithium chloride is 2.23:10.0-10.6, and copper bromide accounts for 2.0-2.1 mol% of the compound of formula 3.

[0033] Preferably, after the Friedel-Crafts reaction in step (2) is complete, the reaction solution is cooled to room temperature and then added dropwise to water at 5–8°C. After the addition is complete, the mixture is stirred and filtered to obtain compound of formula 4. By adopting this process, the yield of compound of formula 4 is greatly improved.

[0034] Preferably, step (2) is as follows: Take compound of formula 3, add copper bromide, lithium chloride and DMAc (N,N-dimethylacetamide) and mix them. The ratio of the amount of compound of formula 3, copper bromide, lithium chloride and DMAc added is 130g:2.10g-2.23g:10.0g-10.6g:1300-1400mL. Introduce ethylene gas and keep the pressure below 0.1MPa. Stir at 88-90℃ for 15-16h. After the reaction is completed, cool to room temperature and add the reaction solution dropwise to water at 5-8℃. After the addition is completed, stir, filter and dry the filter cake to obtain compound of formula 4.

[0035] Existing Friedel-Crafts reactions often use palladium acetate as a catalyst, but palladium acetate is expensive, resulting in high costs. The inventors conducted extensive research on the synthesis of compound 4 in step (2). Through screening different catalysts and optimizing reaction conditions, they discovered that using copper bromide as a catalyst and adding lithium chloride as an additive, under the above conditions, the Friedel-Crafts reaction in step (2) could proceed smoothly, and the obtained compound 4 had high purity and yield, reaching over 94.0%. Copper bromide and lithium chloride are inexpensive, significantly reducing costs.

[0036] Preferably, step (3) is as follows: Take compound of formula 4, add TBAB (tetrabutylammonium bromide) and 48% aqueous solution of hydrogen bromide, the ratio of the amount of compound of formula 4, TBAB and 48% aqueous solution of hydrogen bromide is 78-80g:0.4g:240-250mL; heat to 88-90℃, keep warm for 2.5-3h, after the reaction is completed, cool to room temperature, add dichloromethane, separate the liquid and liquid phases, wash the organic phase once with NaHCO3 and purified water respectively, dry, concentrate, and obtain compound of formula 5.

[0037] Preferably, in step (4), the compound of formula 5 reacts with a cyaniding agent in the presence of a catalyst and under ultraviolet light to generate the compound of formula 6; wherein the catalyst in step (4) is copper bromide and the cyaniding agent is potassium ferricyanide.

[0038] Preferably, step (4) is as follows: Take compound of formula 5, add copper bromide, potassium ferricyanide and acetonitrile, the ratio of the amount of compound of formula 5, copper bromide, potassium ferricyanide and acetonitrile added is 70-71g:1.1g:80-82g:340-350ml, heat to 80±2℃ and stir for 15-16h under ultraviolet light irradiation, after the reaction is completed, cool to room temperature, add the reaction liquid dropwise to 1700-1750ml of water at a temperature below 10℃, solid precipitates out, after the addition is complete, stir, filter, dry the filter cake to obtain compound of formula 6.

[0039] This invention screened and optimized different catalysts and process conditions, discovering that using potassium ferricyanide as the cyanidation reagent and copper bromide as the catalyst, under ultraviolet light irradiation, can efficiently prepare the ketoprofen intermediate cyanoketoprofen, thus successfully preparing compound 6. Compound 6 then undergoes hydrolysis in the presence of acid to yield ketoprofen with high yield and purity, exceeding 93.0%. Potassium ferricyanide is environmentally friendly, avoiding the use of highly toxic cyanides and significantly reducing material toxicity and operational difficulty.

[0040] Preferably, step (5) is as follows: take compound of formula 6, add sulfuric acid solution, heat to 100±2℃, react, after the reaction is completed, cool to room temperature, add toluene to separate the phases, add sodium hydroxide solution to the toluene phase and stir, add hydrochloric acid to the separated aqueous phase, a white solid precipitates out, filter, and dry to obtain ketoprofen.

[0041] Preferably, step (1) is as follows: using compound 3-bromobenzoic acid of formula 2 as the starting material and ethyl acetate as the solvent, a chlorination reaction is carried out with thionyl chloride. The reaction system is heated to 50±2℃ and kept at the temperature for 5.5-6h. After the reaction is completed, it is cooled to room temperature. The temperature is lowered to below 10℃, and aluminum trichloride and benzene are added. After the addition is completed, the temperature is raised to 30-40℃ and kept at the temperature for 5.5-6h. After the reaction is completed, post-processing is performed to purify the compound of formula 3.

[0042] Compared with the prior art, the present invention has the following beneficial effects:

[0043] This invention provides a reasonable reaction route that enables the preparation of ketoprofen using inexpensive, readily available, and environmentally friendly reagents. It avoids the use of highly corrosive materials such as bromine and phosphorus pentachloride, as well as highly flammable reagents such as Grignard reagents, metallic sodium, and sodium cyanide, which are highly corrosive, highly toxic, flammable, and expensive. The invention also reduces equipment requirements, operational complexity, and the burden of post-reaction processing, thus lowering costs. It simplifies the synthetic process, reduces impurities, simplifies post-processing, and provides mild reaction conditions. This is a simple, green, and economical process for preparing ketoprofen, yielding a high-yield, high-purity product suitable for large-scale industrial production. Attached Figure Description

[0044] Figure 1 This is the HPLC spectrum of the compound of formula 3 prepared in the embodiments of the present invention;

[0045] Figure 2 This is the NMR spectrum of the compound of formula 3 prepared in the embodiments of the present invention;

[0046] Figure 3 This is the HPLC spectrum of the compound of formula 4 prepared in the embodiments of the present invention;

[0047] Figure 4 This is the HPLC spectrum of the compound of formula 5 prepared in the embodiments of the present invention;

[0048] Figure 5 This is the NMR spectrum of the compound of formula 5 prepared in the embodiments of the present invention;

[0049] Figure 6 This is the HPLC spectrum of the compound of formula 6 prepared in the embodiments of the present invention;

[0050] Figure 7 This is the NMR spectrum of the compound of formula 6 prepared in the embodiments of the present invention;

[0051] Figure 8 This is the HPLC chromatogram of ketoprofen prepared according to an embodiment of the present invention;

[0052] Figure 9 This is the mass spectrum of ketoprofen prepared according to an embodiment of the present invention;

[0053] Figure 10 This is the NMR spectrum of ketoprofen prepared according to an embodiment of the present invention. Detailed Implementation

[0054] The present invention will be further illustrated below with specific embodiments. These embodiments are merely illustrative and do not limit the scope of the invention.

[0055] Example 1

[0056] A method for preparing ketoprofen, comprising the following steps:

[0057] Example 1

[0058] (1) Preparation of compound 3: In a 2000 ml reaction flask, 200 g of 3-bromobenzoic acid (compound 2), 1000 ml of ethyl acetate, and 130 g of thionyl chloride were added. The reaction system was heated to 50 °C and kept at this temperature for 6 h. After the reaction was completed by TLC, it was cooled to room temperature. After cooling to below 10 °C, 75 g of aluminum trichloride and 100 g of benzene were added. After the addition was complete, the temperature was raised to 35 ± 5 °C and stirred for 6 h. After the reaction was completed by TLC, the mixture was post-processed and purified to obtain compound 3 with a yield of 93.1% and a liquid chromatography purity of 99.41%. The HPLC chromatogram of the prepared compound 3 is shown in [Figure number missing]. Figure 1 See the NMR spectrum. Figure 2 ; MP: 77~80℃, Rf(CH2Cl2 / pentane=50 / 50): 0.49; 1 H NMR (300MHz, CDCl3) δ7.94(t,1H,)7.80-7.78(m,2H),7.71-7.72(dd,2H),7.63-7.60(m,1H),7.52-7.49(m,2H),7.36(t,1H).

[0059] (2) Preparation of compound 4: In a 3000 ml autoclave, 130 g of compound 3 (molecular weight 261, 0.5 mol), 2.23 g of copper bromide (molecular weight 223, 0.01 mol), 10.6 g of lithium chloride (molecular weight 42, 0.25 mol), and 1300 ml of DMAc were added. Ethylene gas was introduced, and the pressure was maintained below 0.1 MPa. The mixture was stirred at 90 °C for 15 h. The reaction progress was monitored by TLC. After the reaction was completed, the mixture was cooled to room temperature, and the reaction solution was added dropwise to water at 5–8 °C. After the addition was complete, the mixture was stirred for 30 min, filtered, and the filter cake was vacuum-sealed to obtain compound 4. The yield was 94.3%, and the liquid phase purity was 99.46%. The HPLC chromatogram of the prepared compound 4 is shown in [Figure number missing]. Figure 3 MP: 37~41℃.

[0060] (3) Preparation of compound 5: In a 1000 ml flask, add 80 g of compound 4, 0.4 g of TBAB, and 240 ml of 48% hydrogen bromide aqueous solution. Heat to 90 °C and maintain the reaction temperature for 3 h. After the reaction is complete as detected by TLC, cool to room temperature and add 240 ml of dichloromethane. Separate the mixture, wash the organic phase once with 5% NaHCO3 and purified water, dry with anhydrous sodium sulfate, and concentrate to obtain compound 5 with a yield of 91.0%. The HPLC chromatogram of the prepared compound 5 is shown in [Figure number missing]. Figure 4 See the NMR spectrum. Figure 5 A yellow, oily substance with a liquid phase purity of 99.73%. 1 H NMR (500MHz, CDCl3): δ=7.87(t,1H),7.81–7.79(m,2H),7.71–7.67(m,2H),7.6 2–7.59(m,1H),7.51–7.45(m,3H),5.24(q,J=6.9Hz,1H),2.07(d,J=6.9Hz,3H).

[0061] (4) Preparation of compound 6: In a 1000 ml reaction flask, 70 g of compound 5 (molecular weight 285, 0.25 mol), 1.1 g of copper bromide (molecular weight 223, 0.005 mol), 82 g of potassium ferricyanide (molecular weight 329, 0.25 mol), and 350 ml of acetonitrile were added. The mixture was irradiated with ultraviolet light and stirred at 80 °C for 16 h. The reaction progress was monitored by TLC. After the reaction was completed, the mixture was cooled to room temperature. In another 3000 ml reaction flask, 1750 ml of water was added and the temperature was lowered to below 10 °C. The reaction solution was added dropwise to the water, and a solid precipitated. After the addition was complete, the mixture was stirred for 1 h, filtered, and the filter cake was dried under vacuum to obtain compound 6 with a yield of 93.1% and a liquid phase purity of 99.77%. The HPLC chromatogram of the prepared compound 6 is shown in [Figure number missing]. Figure 6 See the NMR spectrum. Figure 7 . 1H NMR (500MHz, CDCl3): δ = 7.80 (t, 1H), 7.79 (m, 2H), 7.75-7.73 (m, 1H), 7.64-7.61 (m, 2H), 7.54-7.49 (m, 3H), 4.00 (q, 1H), 1.69 (d, 3H).

[0062] (5) Preparation of ketoprofen (compound of formula 1): 60 g of compound of formula 6 was added to a 1000 ml reaction flask, followed by 300 ml of 50% sulfuric acid solution. The mixture was heated to 100 °C and reacted for 2 h. After the reaction was complete as detected by TLC, the mixture was cooled to room temperature. Toluene was added and the mixture was separated. 10% sodium hydroxide solution was added to the toluene phase and stirred for 10 minutes. Hydrochloric acid was added dropwise to the aqueous phase, resulting in the precipitation of a white solid. The solid was filtered and dried under vacuum to obtain ketoprofen with a yield of 95.0% and a liquid chromatography purity of 99.93%. The HPLC chromatogram of the prepared ketoprofen is shown below. Figure 8 Mass spectrum (see) Figure 9 See the NMR spectrum. Figure 10 Ketoprofen molecular weight M: 254.28 g / mol, [M+H] + 255.1, [MH] - :253.0; 1H NMR (500MHz, CDCl3): δ=7.80(t,1H),7.79(m,2H),7.70-7.68(m,1H),7.60-7.56(m,2H),7.49-7.44(m,3H),3.83(q,1H),1.55(d,3H).

[0063] Comparative Example 1

[0064] Preparation of compound 4 in step (2):

[0065] The procedure was essentially the same as step (2) in Example 1, except that the catalyst copper bromide (2 mol% of the compound of formula 3) was replaced with an equimolar amount of catalyst Pd(OAc)2 (2 mol% of the compound of formula 3); and lithium chloride was not added. The yield of the compound of formula 4 after preparation was 12.3%.

[0066] Comparative Example 2

[0067] Preparation of compound 4 in step (2):

[0068] The procedure was essentially the same as step (2) in Example 1, with the only difference being that copper bromide was replaced with an equimolar amount of Pd(OAc)₂ catalyst, and lithium chloride was replaced with an equimolar amount of triphenylphosphine. The yield of compound 4 after preparation was 82.5%.

[0069] Comparative Example 3

[0070] Preparation of compound 4 in step (2):

[0071] The procedure is essentially the same as step (2) in Example 1, except that copper bromide catalyst is replaced with an equimolar amount of FeCl2 catalyst, and lithium chloride is replaced with an equimolar amount of NMP. Compound of Formula 4 could not be prepared.

[0072] Comparative Example 4

[0073] Preparation of compound 4 in step (2):

[0074] The procedure is essentially the same as step (2) in Example 1, except that lithium chloride is not added. The yield of compound 4 after preparation was 15.4%.

[0075] We experimented with different catalysts to synthesize the compound of formula 4, as shown in the table below:

[0076]

[0077] Comparative Example 5

[0078] Preparation of compound 4 in step (2):

[0079] The reaction was basically the same as in Example 1, except that after the reaction was completed, the mixture was cooled to room temperature and the reaction solution was added dropwise to water at 40°C. After the addition was complete, the mixture was stirred for 30 minutes, filtered, and the filter cake was vacuum-sealed to obtain compound 4 with a yield of 85.1%.

[0080] Through screening different catalysts and optimizing reaction conditions, we found that using copper bromide as a catalyst and adding lithium chloride as an additive, under the conditions of this invention, the Friedel-Crafts reaction in step (2) can proceed smoothly, and the resulting compound of formula 4 has high purity and yield, with a yield of over 94.0%. Copper bromide and lithium chloride are inexpensive, greatly reducing costs.

[0081] Comparative Example 6

[0082] Preparation of compound 6 in step (4):

[0083] The procedure was essentially the same as step (4) in Example 1, with the only difference being that, referring to relevant literature, highly toxic potassium cyanide was used instead of an equimolar amount of potassium ferricyanide as the cyaniding agent, copper bromide was not added, and no ultraviolet light was applied. The yield of compound 6 after preparation was 92.0%.

[0084] Comparative Example 7

[0085] Preparation of compound 6 in step (4):

[0086] The procedure was essentially the same as step (4) in Example 1, with the only difference being that, referring to relevant literature, cuprous cyanide was used instead of an equimolar amount of potassium ferricyanide as the cyaniding agent, copper bromide was not added, and no ultraviolet light was applied. The yield of compound 6 after preparation was 86.2%.

[0087] Comparative Example 8

[0088] Preparation of compound 6 in step (4):

[0089] The procedure was essentially the same as step (4) in Example 1, except that no ultraviolet light was used. The yield of compound 6 after preparation was 66.0%.

[0090] Comparative Example 9

[0091] Preparation of compound 6 in step (4):

[0092] The procedure is essentially the same as step (4) in Example 1, except that copper bromide catalyst is not added. The yield of compound 6 after preparation was 3.5%.

[0093] We experimented with different reaction conditions to synthesize the compound of formula 6, as shown in the table below:

[0094]

[0095] This invention screened and optimized different catalysts and process conditions, discovering that using potassium ferricyanide as the cyanidation reagent and copper bromide as the catalyst, under ultraviolet light irradiation, a highly efficient preparation of the ketoprofen intermediate cyanoketoprofen was achieved. This allowed for the successful preparation of compound 6 with high yield and purity, exceeding 93.0%. Potassium ferricyanide is environmentally friendly, avoiding the use of highly toxic cyanides and significantly reducing material toxicity and operational difficulty.

Claims

1. A method for preparing ketoprofen, characterized in that: Includes the following steps: (1) Using compound 3-bromobenzoic acid of formula 2 as the starting material, it is chlorinated with thionyl chloride, and then reacted with benzene under the catalysis of aluminum trichloride to obtain compound 3; (2) Compound of Formula 3 undergoes a Friedel-Crafts reaction with ethylene to give compound of Formula 4; (3) Compound of formula 4 undergoes an addition reaction with hydrobromic acid to produce compound of formula 5; (4) The compound of formula 5 reacts with the cyaniding reagent to produce the compound of formula 6; (5) The compound of formula 6 is hydrolyzed under the action of acid to obtain the compound of formula 1, which is ketoprofen; The reaction equation is as follows: The Friedel-Crafts reaction in step (2) uses copper bromide as a metal catalyst and lithium chloride as an additive. In step (4), compound 5 reacts with a cyaniding agent in the presence of a catalyst and under ultraviolet light to generate compound 6; wherein the catalyst in step (4) is copper bromide and the cyaniding agent is potassium ferricyanide.

2. The method for preparing ketoprofen according to claim 1, characterized in that: The mass ratio of copper bromide to lithium chloride is 2.23:10.0-10.6, and copper bromide accounts for 2.0-2.1 mol of the compound of formula 3.

3. The method for preparing ketoprofen according to claim 2, characterized in that: After the Friedel-Crafts reaction in step (2) is complete, the reaction solution is cooled to room temperature and then added dropwise to water at 5-8°C. After the addition is complete, the mixture is stirred and filtered to obtain compound 4.

4. The method for preparing ketoprofen according to any one of claims 1-3, characterized in that: Step (2) is as follows: Take compound of formula 3, add copper bromide, lithium chloride and DMAc and mix them. The ratio of the amount of compound of formula 3, copper bromide, lithium chloride and DMAc added is 130g: 2.23g: 10.0-10.6g: 1300-1400mL; introduce ethylene gas, keep the pressure below 0.1MPa, stir at 88-90℃ for 15-16h. After the reaction is completed, cool to room temperature, add the reaction solution dropwise to water at 5~8℃. After the addition is completed, stir, filter, dry the filter cake to obtain compound of formula 4.

5. The method for preparing ketoprofen according to claim 1, characterized in that: Step (3) is as follows: Take compound of formula 4, add TBAB and 48% hydrogen bromide aqueous solution, the ratio of compound of formula 4, TBAB and 48% hydrogen bromide aqueous solution is 78-80g:0.4g:240-250mL; heat to 88-90℃, keep warm for 2.5-3h, after the reaction is completed, cool to room temperature, add dichloromethane, separate the liquid and liquid, wash the organic phase once with NaHCO3 and purified water respectively, dry, concentrate, and obtain compound of formula 5.

6. The method for preparing ketoprofen according to claim 1, characterized in that: Step (4) is as follows: Take compound of formula 5, add copper bromide, potassium ferricyanide and acetonitrile. The ratio of the amount of compound of formula 5, copper bromide, potassium ferricyanide and acetonitrile added is 70-71g: 1.1g: 80-82g: 340-350ml. Under ultraviolet light irradiation, heat to 80±2℃ and stir for 15-16h. After the reaction is completed, cool to room temperature and add the reaction liquid dropwise to 1700-1750ml of water at a temperature below 10℃. Solid precipitates out. After the addition is complete, stir, filter, dry the filter cake, and obtain compound of formula 6.

7. The method for preparing ketoprofen according to claim 1, characterized in that: Step (5) is as follows: Take compound of formula 6, add sulfuric acid solution, heat to 100±2℃, react, after the reaction is complete, cool to room temperature, add toluene to separate the phases, add sodium hydroxide solution to the toluene phase and stir, add hydrochloric acid to the separated aqueous phase, a white solid precipitates out, filter, and dry to obtain ketoprofen.

8. The method for preparing ketoprofen according to claim 1, characterized in that: Step (1) is as follows: using compound 3-bromobenzoic acid of formula 2 as the starting material and ethyl acetate as the solvent, thionyl chloride is reacted with chlorination. The reaction system is heated to 50±2℃ and kept at the temperature for 5.5-6h. After the reaction is completed, it is cooled to room temperature. The temperature is lowered to below 10℃, aluminum trichloride and benzene are added. After the addition is completed, the temperature is raised to 30~40℃ and kept at the temperature for 5.5-6h. After the reaction is completed, post-processing is performed to purify the compound of formula 3.

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