Preparation method of ketoprofen

Abstract

The invention belongs to the field of pharmaceutical chemicals, and particularly relates to a preparation method of ketoprofen. The preparation method comprises the following steps: carrying out chlorination on 3-bromobenzoic acid serving as an initial raw material and thionyl chloride, carrying out Friedel-Crafts reaction with benzene under the catalysis of aluminum trichloride, carrying out Friedel-Crafts reaction on the reaction product and ethylene, carrying out addition reaction with hydrobromic acid, reacting with a cyanation reagent, and hydrolyzing under the action of acid to obtain ketoprofen. The invention provides a reasonable reaction route, the ketoprofen is prepared from cheap, easily available, green and environment-friendly reagents, the use of high-corrosivity, high-toxicity, inflammable and expensive reagents is avoided, the requirement on equipment is low, the operation difficulty and the reaction post-treatment burden are reduced, and the cost is reduced; the method is a simple, green and economical process route for preparing ketoprofen, the obtained product is high in yield and good in purity, and the method is suitable for industrial mass production of ketoprofen.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical chemical industry, and specifically relates to a preparation method of ketoprofen. Background Art

[0002] Ketoprofen (KPF), also known as ketoprofen, ketoprofen, oxadifen, euprofen, euprofen or Profenid, has a chemical name of α-methyl-3-benzoylphenylacetic acid [2-(3-Benzoylphenyl)propanoic acid [CAS: 22071-15-4]]. It is an excellent 2-arylpropionic acid non-steroidal anti-inflammatory analgesic drug developed by chemists Farge, Messer and Moutounier of the French Rhone-Poulenc Company in 1967. Its mechanism of action is mainly to inhibit the biological activity of cyclooxygenase (COXs) and lipoxygenase (LOXs) in the body, thereby inhibiting the synthesis of inflammatory substances prostaglandins (PGs) and leukotrienes (LTs), and has the effects of counteracting bradykinin release, scavenging hydroxyl free radicals, and stabilizing lysosomal membrane activity, thereby producing good antipyretic, analgesic and anti-inflammatory effects, and enhancing its peripheral analgesic effect. Clinical studies have shown that ketoprofen, as an important non-steroidal anti-inflammatory drug, has significant advantages over similar drugs, such as small dosage, high efficacy, good tolerance and mild toxic side effects. It has become an ideal drug for the treatment of rheumatoid arthritis, rheumatic arthritis, osteoarthritis, ankylosing spondylitis and gout. It is widely used in the treatment of dysmenorrhea, toothache, postoperative pain, cancer pain, neuritis, lupus erythematosus, pharyngitis and bronchitis, and has better therapeutic effects on soft tissue injuries.

[0003]

[0004] There are many reported methods for the synthesis of ketoprofen, and the more representative ones are the following routes.

[0005] (1) Chinese Journal of Medicinal Chemistry, 2000, 10, 127-128, reported a method for preparing ketoprofen using benzoic acid as the starting material. The method uses benzoic acid as the raw material and prepares ketoprofen through bromination, Grignard reaction, and Darzens reaction. The raw material price of this method is cheap, but the method has the following disadvantages: the yield is low, especially the carbonyl group in the structure of the Grignard reaction is not protected, so the yield of the reaction is not high, affecting the total yield. At the same time, the yield of the last step of the Darzens reaction in the synthetic process route is not high, which also affects the total yield. At the same time, in the production process, a large amount of toxic, harmful, flammable and explosive materials such as bromine, phosphorus pentachloride, Grignard reagent, sodium metal, etc. will be used, so industrial production is difficult, dangerous, and hazardous waste treatment is difficult.

[0006] The method route 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 refined, with a total yield of about 40%. Although the raw materials are readily available, this method has the following disadvantages: low total yield, Darzens condensation reaction requires the use of a large amount of metallic sodium, which poses a great fire hazard to production safety; and the yield and selectivity of potassium permanganate oxidation are not high; during the oxidation process, ketoprofen will undergo further oxidation to produce impurities, and the product needs to be refined multiple times to meet the European and American pharmacopoeia standards. Literature reports that the total yield is less than 40%.

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

[0010]

[0011] (3) Using m-toluic acid as the starting material, the product is obtained through esterification, halogenation, cyanation, methylation, hydrolysis, chlorination, Friedel-Crafts reaction, hydrolysis, and purification. This method has the following disadvantages: the route has 6 reaction steps, and highly toxic sodium cyanide needs to be used during the reaction process, and dimethylated impurities are generated during the methylation process, resulting in unqualified products.

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

[0013]

[0014] (4) "New Synthesis Process of Ketoprofen" (Patent No. 95109877), using 2-amino-dibenzophenone or 4-amino-dibenzophenone or their amino protected compounds as starting materials, ketoprofen is synthesized through α-halopropionylation (or propionylation followed by halogenation), ketalization, rearrangement, hydrolysis, and diazo deamination. This method has the following disadvantages: this route has five steps of reaction, and the amino group and keto group are protected and converted separately, resulting in a decrease in the utilization rate of raw materials, an increase in costs, and poor atom economy of this route.

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

[0016]

[0017] (5) A new preparation route for ketoprofen published by Chen Fener 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 is then reacted with benzyl chloride to obtain intermediate 12. Intermediate 12 undergoes a ring-closing reaction with ethyl pyruvate at -78°C and under the action of titanium tetrachloride, and then undergoes a two-step reaction at a high temperature of 230-250°C to obtain deoxyketoprofen, which is then oxidized with potassium permanganate to obtain ketoprofen. The total yield of this route is about 45%. This method has the following disadvantages: This route includes a one-step low-temperature reaction (-78°C) and a one-step high-temperature reaction (230-250°C), which makes industrialization difficult.

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

[0019]

[0020] In summary, the existing synthetic routes of ketoprofen have the following main deficiencies: 1. The use of highly corrosive materials such as bromine and phosphorus pentachloride places high demands on equipment; 2. The use of materials such as Grignard reagents and metallic sodium makes production and operation difficult, posing great safety hazards; 3. The use of cyanation reagents such as sodium cyanide is very toxic and places high demands on production; 4. Most synthetic routes have complicated processes, difficult reactions to control, and many impurities. Post-processing mostly uses column chromatography for purification, which is difficult to operate and is not suitable for industrial production.

[0021] Therefore, it is an urgent need for large-scale commercial production of ketoprofen to find a route with cheap and readily available raw materials, mild reaction conditions, high yield and low cost. Summary of the invention

[0022] In order to overcome the deficiencies of the above-mentioned prior art, the object of the present invention is to provide a method for preparing ketoprofen, which avoids the use of highly corrosive bromine, phosphorus pentachloride, and highly flammable materials such as Grignard reagent and metallic sodium, and 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 production.

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

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

[0025] (2) the compound of formula 3 is subjected to Friedel-Crafts reaction with ethylene to obtain a compound of formula 4;

[0026] (3) the compound of formula 4 is subjected to addition reaction with hydrobromic acid to generate the compound of formula 5;

[0027] (4) reacting the compound of formula 5 with a cyanation reagent to generate a compound of formula 6;

[0028] (5) The compound of formula 6 is hydrolyzed under the action of an acid to obtain the compound of formula 1, namely 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 completed, 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 the compound of formula 4. By adopting this treatment process, the yield of the compound of formula 4 is greatly improved.

[0034] Preferably, step (2) is: take the compound of formula 3, add copper bromide, lithium chloride and DMAc (N, N-dimethylacetamide) to mix, the addition ratio of the compound of formula 3, copper bromide, lithium chloride and DMAc is 130g: 2.10g-2.23g: 10.0g-10.6g: 1300-1400mL; introduce ethylene gas, maintain the pressure below 0.1MPa, stir at 88-90°C for 15-16h, after the reaction is completed, cool to room temperature, add the reaction solution dropwise into water at 5-8°C, after the addition is complete, stir, filter, and dry the filter cake to obtain the compound of formula 4.

[0035] The existing Friedel-Crafts reaction often uses palladium acetate as a catalyst, but palladium acetate is expensive and has high cost. The inventor has conducted a lot of research on the synthesis of the compound of formula 4 in step (2). Through the screening of different catalysts and the optimization of reaction conditions, it is found that the use of metal catalyst copper bromide as a catalyst and the addition of lithium chloride as an additive under the above conditions can make the Friedel-Crafts reaction in step (2) proceed smoothly, and the obtained compound of formula 4 has a high purity and yield, and the yield reaches more than 94.0%. Copper bromide and lithium chloride are cheap, which greatly reduces the cost.

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

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

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

[0039] The present invention screens and optimizes different catalysts and process conditions, and finds that potassium ferrocyanide is used as a cyanation reagent, copper bromide is used as a catalyst, and under ultraviolet light, ketoprofen intermediate cyanoketoprofen can be efficiently prepared, thereby formula 6 compound can be smoothly prepared, and formula 6 compound is hydrolyzed in the presence of an acid to obtain ketoprofen, and has a high yield and purity, with a yield of more than 93.0%. Potassium ferrocyanide is green and environmentally friendly, avoids the use of highly toxic cyanide, and greatly reduces material toxicity and operation difficulty.

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

[0041] Preferably, step (1) is: using 3-bromobenzoic acid of the compound of formula 2 as the starting material, ethyl acetate as the solvent, and chlorination reaction with thionyl chloride, heating the reaction system to 50±2°C, keeping the temperature for reaction for 5.5-6h, and cooling to room temperature after the reaction is completed; cooling to below 10°C, adding aluminum chloride and benzene, and after the addition is completed, heating to 30-40°C, keeping the temperature for stirring for 5.5-6h, and after the reaction is completed, post-treating and refining to obtain the compound of formula 3.

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

[0043] The invention provides a reasonable reaction route, realizes the preparation of ketoprofen by using cheap, easily available and green environmentally friendly reagents, avoids the use of highly corrosive materials such as bromine and phosphorus pentachloride, and avoids the use of highly corrosive, highly toxic, flammable and expensive reagents such as highly flammable Grignard reagent, metallic sodium, sodium cyanide, etc., has low requirements on equipment, reduces the difficulty of operation and the burden of post-reaction treatment, and reduces the cost; simplifies the synthetic process route, reduces impurities, has a simple post-treatment process, and has mild reaction conditions. The invention is a simple, green and economical process route for preparing ketoprofen, has a high yield and high purity of the obtained product, and is suitable for industrial mass production of ketoprofen. BRIEF DESCRIPTION OF THE DRAWINGS

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

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

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

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

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

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

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

[0051] Figure 8 is the HPLC spectrum of ketoprofen prepared in the embodiment of the present invention;

[0052] Fig. 9 is a mass spectrum of ketoprofen prepared in an embodiment of the present invention;

[0053] Fig.10 It is the nuclear magnetic spectrum of ketoprofen prepared in the embodiment of the present invention. DETAILED DESCRIPTION

[0054] The present invention is further described below by means of specific examples. The examples described in the present invention are only used to illustrate the present invention and do not limit the scope of the present invention.

[0055] Example 1

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

[0057] Example 1

[0058] (1) Preparation of Formula 3 compound: In a 2000ml reaction bottle, add 200g of 3-bromobenzoic acid (Formula 2 compound), 1000ml of ethyl acetate, and 130g of thionyl chloride, heat the reaction system to 50°C, keep the temperature for 6h, and after TLC detection, cool to room temperature; cool to below 10°C, add 75g of aluminum chloride and 100g of benzene, and after the addition is complete, heat to 35±5°C, keep the temperature and stir for 6h, after TLC detection, post-treat and purify to obtain Formula 3 compound, with a yield of 93.1% and a liquid phase purity of 99.41%. The HPLC spectrum of the prepared Formula 3 compound is shown in Figure 1 , NMR spectrum see 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 Formula 4 Compound: In a 3000ml autoclave, add 130g of Formula 3 Compound (molecular weight 261, 0.5mol), 2.23g of copper bromide (molecular weight 223, 0.01mol), 10.6g of lithium chloride (molecular weight 42, 0.25mol), 1300ml of DMAc, introduce ethylene gas, maintain the pressure below 0.1MPa, stir at 90°C for 15h, monitor the reaction progress by TLC, after the reaction is completed, cool to room temperature, add the reaction solution dropwise to water at 5-8°C, stir for 30min after the addition is complete, filter, and vacuum the filter cake to obtain Formula 4 Compound, yield 94.3%, liquid phase purity 99.46%. The HPLC spectrum of the prepared Formula 4 compound is shown in Figure 3 ;MP:37~41℃.

[0060] (3) Preparation of Formula 5 Compound: In a 1000 ml flask, add 80 g of Formula 4 compound, 0.4 g of TBAB, and 240 ml of 48% aqueous hydrogen bromide solution, heat to 90°C, keep warm for 3 hours, and after TLC detection, cool to room temperature, add 240 ml of dichloromethane, separate the liquids, wash the organic phase with 5% NaHCO3 and purified water once, dry with anhydrous sodium sulfate, and concentrate to obtain Formula 5 compound with a yield of 91.0%. The HPLC spectrum of the prepared Formula 5 compound is shown in Figure 4 , NMR spectrum see Figure 5 ; Yellow oil, liquid purity 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 Formula 6 Compound: In a 1000ml reaction bottle, add 70g of Formula 5 Compound (molecular weight 285, 0.25mol), 1.1g of copper bromide (molecular weight 223, 0.005mol), 82g of potassium ferrocyanide (molecular weight 329, 0.25mol), 350ml of acetonitrile, irradiate with ultraviolet light, stir at 80°C for 16h, and monitor the progress of the reaction by TLC. After the reaction is completed, cool to room temperature, add 1750ml of water to another 3000ml reaction bottle, cool to below 10°C, and drop the reaction solution into the water. Solid precipitates. After the dropwise addition is completed, stir for 1h, filter, and vacuum dry the filter cake to obtain Formula 6 Compound, with a yield of 93.1% and a liquid phase purity of 99.77%. The HPLC spectrum of the prepared Formula 6 compound is shown in Figure 6 , NMR spectrum see 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): In a 1000 ml reaction bottle, add 60 g of Compound of Formula 6, add 300 ml of 50% sulfuric acid solution, heat to 100° C., react for 2 h, and after TLC detection, cool to room temperature, add toluene for separation, add 10% sodium hydroxide solution to the toluene phase and stir for 10 minutes, then add hydrochloric acid dropwise to the aqueous phase separated, white solid precipitates, filter, and vacuum dry to obtain Ketoprofen, with a yield of 95.0% and a liquid phase purity of 99.93%. The HPLC spectrum of the prepared Ketoprofen is shown in Figure 8 , mass spectrum see Fig. 9 , NMR spectrum see Fig.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] Step (2) Preparation of the compound of formula 4:

[0065] The method is basically the same as step (2) of Example 1, except that the catalyst copper bromide (accounting for 2 mol% of the compound of formula 3) is replaced by an equimolar equivalent of the catalyst Pd(OAc)2 (accounting for 2 mol% of the compound of formula 3); and lithium chloride is not added. After the preparation, the yield of the compound of formula 4 is 12.3%.

[0066] Comparative Example 2

[0067] Step (2) Preparation of the compound of formula 4:

[0068] The process is basically the same as step (2) of Example 1, except that the catalyst copper bromide is replaced by an equimolar amount of catalyst Pd(OAc)2; and the lithium chloride is replaced by an equimolar amount of triphenylphosphine. The yield of the compound of formula 4 after preparation is 82.5%.

[0069] Comparative Example 3

[0070] Step (2) Preparation of the compound of formula 4:

[0071] The process is basically the same as step (2) of Example 1, except that the catalyst copper bromide is replaced by an equimolar equivalent of catalyst FeCl2; and the lithium chloride is replaced by an equimolar equivalent of NMP. The compound of formula 4 cannot be prepared.

[0072] Comparative Example 4

[0073] Step (2) Preparation of the compound of formula 4:

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

[0075] We have tried different catalysts for the synthesis of the compound of formula 4, as shown in the following table:

[0076]

[0077] Comparative Example 5

[0078] Step (2) Preparation of the compound of formula 4:

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

[0080] Through screening of different catalysts and optimization of reaction conditions, we found that the use of metal catalyst copper bromide as a catalyst and the addition of lithium chloride as an additive, under the conditions of the present invention, the Friedel-Crafts reaction in step (2) can proceed smoothly, and the obtained compound of formula 4 has a high purity and yield, the yield is more than 94.0%. Copper bromide and lithium chloride are cheap, which greatly reduces the cost.

[0081] Comparative Example 6

[0082] Step (4) Preparation of the compound of formula 6:

[0083] The process is basically the same as step (4) of Example 1, except that: referring to relevant literature, highly toxic potassium cyanide is used to replace an equimolar amount of potassium ferrocyanide as the cyaniding agent, copper bromide is not added, and there is no ultraviolet light. After the preparation, the yield of the compound of formula 6 is 92.0%.

[0084] Comparative Example 7

[0085] Step (4) Preparation of the compound of formula 6:

[0086] The process is basically the same as step (4) of Example 1, except that: referring to relevant literature, cuprous cyanide is used to replace an equimolar amount of potassium ferrocyanide as the cyaniding agent, copper bromide is not added, and there is no ultraviolet light. After the preparation, the yield of the compound of formula 6 is 86.2%.

[0087] Comparative Example 8

[0088] Step (4) Preparation of the compound of formula 6:

[0089] The process is basically the same as step (4) of Example 1, except that no ultraviolet light is used. The yield of the compound of formula 6 after preparation is 66.0%.

[0090] Comparative Example 9

[0091] Step (4) Preparation of the compound of formula 6:

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

[0093] We have tried different reaction conditions for the synthesis of the compound of formula 6, as shown in the following table:

[0094]

[0095] The present invention screens and optimizes different catalysts and process conditions, and finds that potassium ferrocyanide is used as a cyanation reagent, copper bromide is used as a catalyst, and under ultraviolet light illumination, the ketoprofen intermediate cyanoketoprofen is efficiently prepared, so that the compound of formula 6 can be smoothly prepared with a high yield and purity, and the yield reaches more than 93.0%. Potassium ferrocyanide is green and environmentally friendly, avoids the use of highly toxic cyanide, and greatly reduces the toxicity of materials and the difficulty of operation.

Claims

1. A method for preparing ketoprofen, characterized in that: The following steps are involved: (1) using 3-bromobenzoic acid, a compound of formula 2, as a starting material, to undergo a chlorination reaction with thionyl chloride, and then to undergo a Friedel-Crafts reaction with benzene under the catalysis of aluminum chloride to obtain a compound of formula 3; (2) the compound of formula 3 is subjected to Friedel-Crafts reaction with ethylene to obtain a compound of formula 4; (3) the compound of formula 4 is subjected to addition reaction with hydrobromic acid to generate the compound of formula 5; (4) reacting the compound of formula 5 with a cyanation reagent to generate a compound of formula 6; (5) The compound of formula 6 is hydrolyzed under the action of an acid to obtain a compound of formula 1, namely ketoprofen; The reaction equation is as follows:

2. The method for preparing ketoprofen according to claim 1, wherein: The Friedel-Crafts reaction in step (2) uses copper bromide as a metal catalyst and lithium chloride as an additive.

3. The method for preparing ketoprofen according to claim 2, wherein: 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.

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

5. The method for preparing the ketoprofen according to any one of claims 1 to 4, characterized in that: Step (2) is: take the compound of formula 3, add copper bromide, lithium chloride and DMAc to mix, the added amount ratio of the compound of formula 3, copper bromide, lithium chloride and DMAc is 130g:2.10g-2.23g:10.0g-10.6g:1300-1400mL; introduce ethylene gas, maintain the pressure below 0.1MPa, stir at 88-90°C for 15-16h, after the reaction is completed, cool to room temperature, add the reaction solution dropwise into water at 5-8°C, after the addition is complete, stir, filter, and dry the filter cake to obtain the compound of formula 4.

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

7. The method for preparing ketoprofen according to claim 1, characterized in that: In step (4), the compound of formula 5 reacts with a cyanation reagent in the presence of a catalyst and under ultraviolet light to generate a compound of formula 6; wherein the catalyst in step (4) is copper bromide and the cyanation reagent is potassium ferrocyanide.

8. The method for preparing ketoprofen according to claim 7, characterized in that: Step (4) is: take a compound of formula 5, add copper bromide, potassium ferrocyanide and acetonitrile, the added amount ratio of the compound of formula 5, copper bromide, potassium ferrocyanide and acetonitrile is 70-71g:1.1g:80-82g:340-350ml, heat to 80±2°C under ultraviolet light and stir for 15-16h, after the reaction is completed, cool to room temperature, add the reaction solution dropwise to 1700-1750ml of water at a temperature below 10°C, solid precipitates, stir after the addition is complete, filter, and dry the filter cake to obtain a compound of formula 6.

9. The method for preparing ketoprofen according to claim 1, characterized in that: Step (5) is: take the compound of formula 6, add sulfuric acid solution, heat to 100±2°C, react, cool to room temperature after the reaction is completed, add toluene to separate the liquid, add sodium hydroxide solution to the toluene phase and stir, add hydrochloric acid dropwise to the separated aqueous phase, a white solid precipitates, filter and dry to obtain ketoprofen.

10. The method for preparing ketoprofen according to claim 1, characterized in that: Step (1) is: using 3-bromobenzoic acid, a compound of formula 2, as a starting material, ethyl acetate as a solvent, and thionyl chloride for chlorination reaction, heating the reaction system to 50±2° C., keeping the temperature for reaction for 5.5-6 hours, and cooling to room temperature after the reaction is completed; cooling to below 10° C., adding aluminum chloride and benzene, and after the addition is completed, heating to 30-40° C., keeping the temperature for stirring for 5.5-6 hours, and after the reaction is completed, post-treating and refining to obtain a compound of formula 3.

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