Preparation method of ketoprofen

Abstract

The invention relates to a preparation method of ketoprofen, and belongs to the technical field of medicine synthesis. In order to solve the problems of large steric hindrance and low yield in the prior art, the preparation method of ketoprofen comprises the following steps: under the action of a reducing agent, carrying out carbonyl reduction reaction on a compound in a formula I to obtain an intermediate; under the action of an acid catalyst, reacting with 3, 4-dihydro-2H-pyran to obtain an intermediate of a compound shown as a formula III; under the action of iodine, carrying out Grignard reaction on the intermediate and magnesium in an ether solvent to obtain Grignard reaction liquid; under the action of a cobalt catalyst and a ligand, carrying out a cross-coupling reaction with ethyl 2-bromopropionate to obtain a compound as shown in a formula IV; under an acidic condition, carrying out hydrolysis and deprotection reaction on the compound in the formula IV to obtain a compound in a formula V; and carrying out oxidation reaction on hydroxyl in the compound shown in the formula V under the action of TEMPO and an oxidizing agent to obtain ketoprofen.

Description

TECHNICAL FIELD

[0001] The present application relates to a preparation method of ketoprofen, and belongs to the technical field of drug synthesis. BACKGROUND

[0002] Ketoprofen (KP) is also known as ketoprofen, ketoprofen, ketoprofen, ketoprofen, ketoprofen or profenid. It is a good 2-arylpropionic acid non-steroidal anti-inflammatory analgesic drug developed by French Rhone-Poulenc Company chemists Farge, Messer and Moutounier in 1967. Its chemical name is 2-(3-benzoylphenyl) propionic acid, and its molecular formula is C 16 H 14 O3, which is a white or white crystalline powder. Clinical studies have shown that ketoprofen, as an important non-steroidal anti-inflammatory drug, has the advantages of small dose, high efficacy, good tolerance and slight side effects compared with similar drugs, and has become an ideal drug for treating rheumatoid arthritis, rheumatoid arthritis, osteoarthritis, ankylosing spondylitis and gout. It is widely used in the treatment of dysmenorrhea, toothache, neuralgia, migraine, postoperative pain, cancer pain and neuritis, lupus erythematosus, pharyngeal and bronchial inflammation and other diseases, and has better effect on the treatment of soft tissue injury.

[0003] At present, ketoprofen has a wide range of uses in the medical field. At present, the general synthesis route mainly includes the following synthesis routes, for example, patent application (publication number: EP0209905A1) discloses that m-methylbenzoic acid is used as a starting material, acyl chloride is prepared, and then Friedel-Crafts acylation reaction occurs, followed by methyl bromination, cyano substitution, methylation and cyano hydrolysis to obtain the target compound. The synthesis route is as follows:

[0004]

[0005] In the first step of the synthesis route, a large amount of thionyl chloride is used to prepare the acyl chloride intermediate, which has environmental problems and does not meet the requirements of green chemistry. Similarly, the use of bromine in the third step also has the problem of difficult operation in actual production, and the reaction also has 10-30% of dibromide by-product, which causes waste of raw materials and difficulty in purification of the product. In step four, the highly toxic reagent potassium cyanide is used, which has a certain safety risk. In step five, the two hydrogens on the ortho position C of the intermediate cyano group may be replaced by methyl groups.

[0006] For example, the following document (Bashkirskii Khimicheskii Zhurnal (2006), 13(1), 74-77) discloses a six-step reaction using benzoic acid as a raw material, which is bromination, acyl chloride preparation, Friedel-Crafts reaction, ethylene glycol protection, cross-coupling and deprotection hydrolysis, to finally prepare ketoprofen.

[0007]

[0008] The method has the following disadvantages: in the fourth step, the protection of the carbonyl group by ethylene glycol, since the molecular structure of the diaryl ketone is a planar structure, the steric hindrance of the ketone carbonyl group is large, the reaction has the disadvantages of high temperature, long reaction time, large amount of remaining raw material and low reaction yield. At the same time, a large amount of ethylene glycol is used as a solvent in the reaction, which not only increases the cost, but also makes the post-treatment more troublesome. SUMMARY

[0009] The present application aims at the problems existing in the prior art, and provides a preparation method of ketoprofen, which solves the problem of how to effectively avoid steric hindrance and improve the yield and quality of the product.

[0010] The object of the present application is achieved by the following technical scheme, a preparation method of ketoprofen, characterized in that the method comprises the following steps:

[0011] A. Under the action of a reducing agent, a carbonyl reduction reaction is carried out on the compound of formula I to obtain a compound of formula II;

[0012]

[0013] B. Under the action of an acidic catalyst, a protection reaction is carried out on the compound of formula II with 3,4-dihydro-2H-pyran to obtain a compound of formula III;

[0014]

[0015] C. Under the catalysis of a catalytic amount of iodine, a Grignard reaction is carried out on the compound of formula III with magnesium in an ether solvent to obtain a Grignard reaction liquid containing a compound of formula III-1; then under the action of a catalytic amount of cobalt catalyst and a catalyst ligand, a cross-coupling reaction is carried out on the compound of formula III-1 in the Grignard reaction liquid with 2-bromopropionic acid ethyl ester to obtain a compound of formula IV;

[0016]

[0017] D. Under acidic conditions, a hydrolysis and deprotection reaction is carried out on the compound of formula IV to obtain a compound of formula V; then an oxidation reaction is carried out on the hydroxyl group in the compound of formula V under the action of TEMPO and an oxidizing agent to obtain a compound of formula VI;

[0018]

[0019] By reducing the carbonyl group in the starting material m-bromobenzophenone to form a hydroxyl group, the hydroxyl group is not in the same plane as the two phenyl groups, which can effectively avoid the influence of steric hindrance at the reaction site, facilitate the reaction of 3,4-dihydro-2H-pyran (DHP) with the hydroxyl group, and has the advantages of high yield of intermediate product, the yield is more than 90%, and the method is simple to operate, and the method can also effectively overcome the defects of large steric hindrance, difficulty in reaction and low yield of intermediate product existing in the reaction of ethylene glycol directly with the carbonyl group. Then through Grignard reaction with magnesium to form Grignard reagent, under the synergistic effect of cobalt catalyst and ligand, the Grignard reagent can be coupled with ethyl bromopropionate, and by using this new catalytic system, the yield of the coupling cross-reaction is greatly improved, and the yield of the intermediate product of the coupling cross-reaction is more than 85%, and the reaction cost is reduced; then by hydrolysis to remove the protecting group, and under the action of TEMPO (2,2,6,6-tetramethylpiperidine-1-oxyl) and oxidant, the hydroxyl group is oxidized to carbonyl group to obtain the desired product, the overall synthesis route has the advantages of simple operation and easy control, and the overall yield of the product is high and the purity quality is high, and potassium cyanide and other cyanides are not needed in the subsequent reaction, which improves the safety of operation and is more conducive to industrialized production.

[0020] In the above preparation method of ketoprofen, as a preferred, the cobalt catalyst in step C is selected from one or more of CoCl2, Co(acac)3, CoCl2(PPh3)2, CoCl2(dppe) and CoO; the catalyst ligand is selected from one or more of TEMDA, TMPDA, dppp, dpph and PPh3. By using the above-mentioned metal cobalt catalyst and ligand, a catalytic amount is used, that is, the introduction of ethyl α-propionate group on the benzene ring can be realized very efficiently by one-step method, which has the advantages of high reaction efficiency and selectivity, and the yield of the intermediate product is more than 90%, compared with the traditional equivalent zinc reagent to promote the reaction, which has the advantages of low cost and environmental friendliness. For cobalt catalyst and catalyst ligand, only a catalytic amount is used to promote the reaction, which is less, and is more conducive to reducing production cost, as a further preferred, the molar ratio of the compound of formula III: ethyl 2-bromopropionate: cobalt catalyst: catalyst ligand is 1:1.2-2.0:0.04-0.08:0.04-0.08.

[0021] In the above ketoprofen preparation method, the reaction is carried out in an ether solvent, which is advantageous for the high-efficiency completion of the Grignard reaction, can better form a solution of the Grignard intermediate product, can be directly used in the next cross-coupling reaction, and is more advantageous for operation and simplifies the production operation. As a preferred, the ether solvent in step C is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, 2-methylcyclopentyl ether and isopropyl ether. The amount of the ether solvent can be according to the general solvent amount in chemical synthesis, and preferably the amount of the added ether solvent is 2-6 times the mass of the compound of formula III, so that the reaction can be carried out more gently. Further, preferably the molar ratio of the compound of formula III to magnesium chips is 1:1.1-1.5, and the Grignard reaction time can be controlled within 1-3 hours, and the intermediate III compound can be confirmed to be completely reacted by sampling and analysis as needed, and after the reaction is completed, the Grignard reaction solution does not need to be treated, and can be directly used in the next cross-coupling reaction, which is more advantageous for operation, avoids loss in the treatment process, is more advantageous for ensuring the yield of the intermediate product, can better improve the utilization rate of raw materials, reduces waste, and improves the purity and quality of the product. The amount of iodine can initiate the reaction, and preferably the molar ratio of one mole of the compound of formula III to iodine is 1:0.003-0.005.

[0022] In the above ketoprofen preparation method, as a preferred, the temperature of the Grignard reaction in step C is 60-80°C, and the temperature of the cross-coupling reaction is -40- -10°C. This can effectively carry out the reaction, better improve the reaction efficiency, and ensure the quality and yield of the intermediate product, avoid unnecessary impurities, and better improve the purity and quality of the product. As a further preferred, the temperature of the Grignard reaction is preferably 65-75°C, and the temperature of the cross-coupling reaction is -30- -20°C. The cross-coupling reaction time is preferably controlled within 1-3 hours.

[0023] In the above ketoprofen preparation method, as a preferred, the acid catalyst in step B is selected from one or more of p-toluenesulfonic acid, hydrochloric acid, phosphoric acid, sulfuric acid, lithium tetrafluoroborate, pyridine p-toluenesulfonate, aluminum trichloride, iron trichloride, boron trifluoride etherate, trimethylchlorosilane and boron tribromide. Since the carbonyl group is first reduced to a hydroxyl group in the present application, the influence of the steric hindrance of the two benzene groups of the biphenyl is effectively avoided when the DHP group is introduced, and under the action of the acid catalyst, the reaction can be more selectively promoted, and has the advantages of high yield of the intermediate product and better purity and quality. As a further preferred, the acid catalyst is selected from one or more of p-toluenesulfonic acid, hydrochloric acid, aluminum trichloride and pyridine p-toluenesulfonate.

[0024] In the above preparation method of ketoprofen, as a preferred, the molar ratio of the acid catalyst to the compound of formula II in step B: 3,4-dihydro-2H-pyran: 1:1.1~2.0:0.05~0.2; the temperature of the protection reaction is 10~50°C. It can promote the reaction more effectively. For the above protection reaction is preferably carried out in an organic solvent. The amount of solvent can be added as needed, preferably the amount of organic solvent I here is 2~5 times the mass of the compound of formula II. Further, preferably the temperature of the protection reaction is 20~30°C, the above organic solvent I is selected from one or more of ether solvents, halogenated alkanes, nitrile solvents, ester solvents and alcohol solvents; such as ether solvents such as tetrahydrofuran, halogenated alkanes such as dichloromethane, chloroform, etc.; nitrile solvents such as acetonitrile, propionitrile, etc.; ester solvents such as ethyl acetate, propyl acetate, etc.; alcohol solvents such as methanol, ethanol, propanol, isopropanol, etc. The time of the above protection reaction is preferably controlled in 12h~15h.

[0025] In the above preparation method of ketoprofen, as a preferred, the reducing agent in step A is selected from one or more of isopropyl aluminum, sodium borohydride, sodium cyanoborohydride, sodium borohydride acetate and lithium aluminum hydride. It can effectively reduce the carbonyl group to hydroxyl group, with the effect of high conversion rate. The amount of raw material can be added with a catalytic amount of reducing agent to make the reaction proceed effectively, preferably the molar ratio of the compound of formula I to the reducing agent is 1:0.3~1.2.

[0026] In the above preparation method of ketoprofen, as a preferred, the temperature of the carbonyl reduction reaction in step A is 20~85°C. It can make the reaction more effectively, and is beneficial to operation. In order to better improve the efficiency of the reaction, when the reducing agent is selected from isopropyl aluminum, the temperature of the reaction is controlled at 70~85°C, when sodium borohydride, sodium cyanoborohydride, sodium borohydride acetate or lithium aluminum hydride is used, the temperature of the reaction is controlled at 20~40°C, which can make the reaction more fully, and is beneficial to improve the yield and purity of the product. The above reduction reaction can be carried out in organic solvent II. In order to better improve the efficiency of the reaction and the cost of solvent use. As a preferred, the reduction reaction is preferably carried out in alcohol solvent or halogenated alkane solvent. The alcohol solvent can be methanol, ethanol, propanol, isopropanol, etc.; halogenated alkanes can be selected from dichloromethane, chloroalkane, etc. The amount of organic solvent II is preferably 2~6 times the mass of the compound of formula I. Further, preferably after the reduction reaction is completed, it also includes post-treatment, the post-treatment is specifically: adding water and non-water-soluble organic solvent to the reaction liquid, stirring, standing and separating, collecting the organic phase, drying with sodium sulfate, filtering, distilling the filtrate to remove the solvent, and obtaining the corresponding intermediate product. The above non-water-soluble solvent is an ester solvent such as ethyl acetate, propyl acetate, etc.

[0027] In the above preparation method of Ketoprofen, as a preferred, the oxidizing agent in step D is selected from one or more of sodium hypochlorite, pyridinium chlorochromate, pyridinium dichromate, sodium periodate, hydrogen peroxide, tert-butyl hydroperoxide and perchloric acid; the molar ratio of the compound of formula V: TEMPO: oxidizing agent is 1:0.1-0.2:2.0-5.0. Under the action of TEMPO and the above-mentioned oxidizing agent, the hydroxyl group in it can be more effectively converted into carbonyl group, and the reaction is more mild, which can better improve the purity, quality and yield of the product. Preferably, the molar ratio of the compound of formula V: TEMPO: oxidizing agent is 1:0.1-0.15:2.5-4.0. As a further preferred, the oxidizing agent is selected from sodium hypochlorite and / or tert-butyl hydroperoxide.

[0028] In the above-mentioned oxidation reaction process, the oxidation reaction is preferably carried out in a solvent, which can be water or an organic solvent. The reaction can be carried out more mildly. The organic solvent can be selected from one or more of alcohol solvents, nitrile solvents, ether solvents and halogenated alkanes. The above-mentioned alcohol solvents can be one or more of methanol, ethanol, propanol and isopropanol; the nitrile solvents can be selected from acetonitrile, propionitrile, etc.; the ether solvents can be selected from tetrahydrofuran, 2-methyltetrahydrofuran, etc.; and the halogenated alkanes can be selected from dichloromethane, chloroform, etc. The amount of solvent can be adjusted according to actual needs, and the amount used in the chemical synthesis field can be used, preferably the amount of the solvent is 3-5 times the amount of the intermediate compound of formula IV. The above-mentioned organic solvent one, organic solvent two and organic solvent three are described for more clear expression, and do not necessarily limit the nature of the organic solvent, which refers to the organic solvent in the chemical field.

[0029] In the above preparation method of Ketoprofen, as a preferred, the temperature of the oxidation reaction in step D is 10-30°C, and the reaction can be carried out more mildly, which is conducive to better ensuring the purity of the product. Further preferred, the time of the oxidation reaction is preferably controlled to be 6-12h.

[0030] In the above ketoprofen preparation method, as preferred, the acid used in the acidic condition in step D is selected from inorganic acid or organic acid. Since the hydroxyl group is first protected by DHP, the reaction can better realize the deprotection and hydrolysis of the ester group, and is more conducive to operation and easier to react. The above inorganic acid can be selected from one or more of sulfuric acid, hydrochloric acid and phosphoric acid; the organic acid can be selected from one or more of trifluoroacetic acid, acetic acid and formic acid. Preferably, the amount of the above acid is 1-3 times the mass of the compound of formula V. Further preferably, the hydrolysis reaction is preferably carried out in a solvent, and the solvent can be selected from one or more of water, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, isopropanol, acetone, etc. The amount of solvent is not limited, and general solvent usage can be used, preferably the amount of solvent is 2-4 times the mass of the intermediate compound of formula VI.

[0031] The temperature of the deprotection and hydrolysis reaction in the above step D is preferably controlled at 40-100°C. The reaction is more efficient, and further preferably, the temperature of the deprotection and hydrolysis reaction is controlled at 55-80°C.

[0032] The above ketoprofen preparation method can be represented by the following reaction equation:

[0033]

[0034] In summary, compared with the prior art, the present application has the following advantages:

[0035] 1. The present application can be used for industrial production by reducing the carbonyl group of the starting material m-bromobenzophenone, then protecting and deprotecting, and then oxidizing to a carbonyl group. The reaction has the advantages of simple operation, high yield and low reagent cost, etc. and can be used for industrial production. By reducing to a hydroxyl group and then reacting with DHP, the influence of the reaction site on the steric hindrance can be effectively avoided, which is conducive to efficient reaction and high product yield, and greatly overcomes the defects of difficult direct protection of the carbonyl group by ethylene glycol and troublesome post-treatment.

[0036] 2. The intermediate product of formula III after DHP protection can better react with 2-bromopropionic acid ethyl ester in a new catalytic system. Under the synergistic action of cobalt metal catalyst and ligand, the α-propionic acid ethyl ester group can be introduced into the benzene ring in one step. The present application uses a new catalytic system of cobalt metal catalyst, which has lower reagent cost and greatly improves the environmental friendliness compared with the traditional method using equivalent zinc reagent to promote the reaction, and has higher yield, with a yield of more than 85%. DETAILED DESCRIPTION

[0037] The technical solutions of the present application are further specifically described below through specific examples, but the present application is not limited to these examples.

[0038] Example 1

[0039] Synthesis of compound of formula II

[0040]

[0041] The compound of formula I, m-bromobenzophenone 52.2 g (0.20 mol), aluminum isopropoxide 12.3 g (0.06 mol) and isopropyl alcohol 160 g were added into a reaction flask, replaced by nitrogen for three times, warmed to 80 °C for reflux stirring for 10 h, TLC detection showed that the reaction was complete, cooled to room temperature, isopropyl alcohol was removed by distillation under reduced pressure, 150 g of toluene and 60 g of 2M hydrochloric acid solution were added to the system, the temperature was controlled at 50 °C and stirred for 1 h, the layers were separated after standing, the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the collected filtrate was concentrated and distilled to remove the solvent, to obtain the intermediate product, compound of formula II, colorless liquid 50.7 g, purity 96.7%, yield 96.3%.

[0042] The obtained product was analyzed as follows:

[0043] MS: 264.1 (M+H) + .

[0044] 1 H-NMR (400 MHz, CDCI3) δ 7.57 (s, 1H), 7.42-7.35 (m, 5H), 7.33-7.27 (m, 2H), 7.20 (t, 1H), 5.78 (s, 1H).

[0045] Example 2

[0046] Synthesis of compound of formula III

[0047]

[0048] Into a clean reaction flask, 39.5 g (0.15 mol) of compound II, 16.8 g (0.2 mol) of 3,4-dihydro-2H-pyran, 1.7 g (0.01 mol) of p-toluene sulfonic acid and 120 g of THF were weighed and stirred at 20-25 °C for 10 h. TLC was used to monitor the reaction. The reaction was cooled to room temperature and 150 g of ethyl acetate and 100 g of saturated sodium bicarbonate solution were added. After stirring for 30 min, the mixture was allowed to stand and separate into two layers. The aqueous layer was extracted with 50 g of ethyl acetate. The organic layers were combined and concentrated under reduced pressure to remove the solvent. The residue was purified by flash column chromatography to obtain 47.1 g of compound III as a colorless liquid. The purity of the product was 99.1% by HPLC and the yield was 90.4%.

[0049] MS: 370.2 (M+Na) + .

[0050] Example 3

[0051] Synthesis of intermediate compound IV

[0052]

[0053] Into a clean reaction flask, 39.5 g (0.15 mol) of compound II, 16.8 g (0.2 mol) of 3,4-dihydro-2H-pyran, 1.7 g (0.01 mol) of p-toluene sulfonic acid and 120 g of THF were weighed and stirred at 20-25 °C for 10 h. TLC was used to monitor the reaction. The reaction was cooled to room temperature and 150 g of ethyl acetate and 100 g of saturated sodium bicarbonate solution were added. After stirring for 30 min, the mixture was allowed to stand and separate into two layers. The aqueous layer was extracted with 50 g of ethyl acetate. The organic layers were combined and concentrated under reduced pressure to remove the solvent. The residue was purified by flash column chromatography to obtain 47.1 g of compound III as a colorless liquid. The purity of the product was 99.1% by HPLC and the yield was 90.4%.

[0054] Into another clean reaction flask, was added CoCl2 0.33 g (0.0025 mol), tetramethylethylenediamine 0.29 g (0.0025 mol), 2-bromoethyl acrylate 13.6 g (0.075 mol) and tetrahydrofuran 30 g under nitrogen protection, and the temperature was lowered to -30 to -20 °C. The above obtained Grignard reaction solution was added dropwise into the reaction solution slowly, and the internal temperature was controlled at -30 to -20 °C. After the dropwise addition was completed, the internal temperature was continuously controlled at -30 to -20 °C for stirring reaction for 1 h. After the reaction was completed, the temperature was raised to room temperature, HPLC detection showed that the reaction was complete. Water 30 g and ethyl acetate 80 g were added into the reaction, and filtration was performed. The solid was washed with ethyl acetate 10 g, and the water layer was separated after standing. The water layer was extracted with ethyl acetate 30 g again, and the collected organic phase was dried over anhydrous sodium sulfate. Filtration was performed, and the collected filtrate was concentrated under reduced pressure to remove the solvent. Fast column chromatography was performed to obtain 15.7 g of the compound of formula IV in the form of colorless liquid, with HPLC purity of 97.6%, and yield of 85.2%.

[0055] MS: 369.5 (M+H) + .

[0056] Example 4

[0057] Synthesis of the compound of formula V

[0058]

[0059] Into a reaction flask was added the compound of formula IV 18.4 g (0.05 mol) and water 40 g, and then 37% concentrated hydrochloric acid 40 g and acetic acid 15 g were added into the reaction system. The temperature was raised to reflux, and stirring reaction was performed for 20 h. HPLC detection showed that the reaction was complete. Dichloromethane 80 g was added into the reaction, and stirring was performed. After standing, the water phase was separated. The organic phase was washed with water 20 g, and the organic phase was concentrated to remove the solvent to obtain a crude product. The crude product was dissolved in a mixed solvent of ethyl acetate 15 g and n-heptane 40 g at 40 °C, and then the temperature was lowered to 0 to 5 °C for stirring crystallization for 1 h. The solid wet product was collected by filtration, and was dried to obtain 11.7 g of the target product of formula V in the form of white solid, with HPLC purity of 98.9%, and yield of 91.2%.

[0060] MS: 257.3 (M+H) + .

[0061] Example 5

[0062] Synthesis of the target product of formula VI

[0063]

[0064] Into a clean reaction flask, add compound of formula V 10.3 g (0.04 mol), 2,2,6,6-tetramethylpiperidine-1-oxyl free radical 0.63 g (0.004 mol) and potassium bromide 0.48 g (0.004 mol), then add dichloromethane 50 g and water 1 g, dropwise add 90 g of 10% mass fraction sodium hypochlorite aqueous solution, control the temperature to be 10-15°C, continue to control the temperature and stir for 2 h, then raise the temperature to room temperature and stir for 8 h, detect the reaction completion by TLC, then add 50 g of dichloromethane to the reaction liquid, adjust the pH of the reaction to 2-3 with 2M HCl solution, stand and separate the layers, separate the water phase, and the collected organic phase is washed with 20 g of water, stand and separate the layers, then add 50 g of 2M NaOH solution to the organic phase, stir for 10 min, stand and separate the layers, collect the water phase, control the temperature to be 10-15°C, adjust the pH of the water phase to 2-3 with 2M HCl solution, then add 100 g of dichloromethane, stir, stand and separate the layers, collect the organic phase, dry the organic phase with anhydrous sodium sulfate, filter, collect the filtrate, and remove the solvent to dryness under reduced pressure, to obtain 9.5 g of compound of formula VI in white solid, with a HPLC purity of 99.1% and a yield of 93.4%.

[0065] Example 6

[0066] Synthesis of compound of formula II

[0067]

[0068] Into a reaction flask, add compound of formula I, 4-bromobenzophenone 52.2 g (0.20 mol), tetrahydrofuran 150 g and methanol 15 g, replace with nitrogen for three times, then add sodium borohydride 8.3 g (0.22 mol) to the reaction in batches, control the internal temperature to be no more than 30°C, after the addition is completed, then control the temperature to be 20-30°C and stir for 6 h, detect the reaction completion by TLC. The reaction temperature is lowered to 0-10°C, then add 50 g of water to the reaction liquid, stir for 20 min, then add 100 g of ethyl acetate to the system, stir, stand and separate the layers, separate the water phase, and the water phase is extracted with 30 g of ethyl acetate, combine the organic phases, dry with anhydrous sodium sulfate, filter, and collect the filtrate to remove the solvent to dryness, to obtain compound of formula II in colorless liquid 51.9 g, with a purity of 96.7% and a yield of 98.6%.

[0069] Example 7

[0070] Synthesis of compound of formula III

[0071] Into a clean reaction flask, 26.3 g (0.1 mol) of the compound of formula II, 10.1 g (0.12 mol) of 3,4-dihydro-2H-pyran and 60 g of tetrahydrofuran were added. 0.5 g of 37% hydrochloric acid was added to the reaction. The reaction was stirred at 20-25 °C for 10 h. The reaction was detected by TLC. The reaction was cooled to room temperature. 100 g of ethyl acetate and 50 g of saturated sodium bicarbonate solution were added to the reaction. After stirring for 30 min, the reaction was allowed to stand and separate into layers. The aqueous layer was separated. The aqueous layer was extracted with 20 g of ethyl acetate. The collected organic phases were combined. The organic phase was concentrated under reduced pressure to remove the solvent. The residue was subjected to flash column chromatography to obtain 31.7 g of the compound of formula III in the form of a colorless liquid. The purity of the compound was 98.4% as determined by HPLC. The yield was 91.2%.

[0072] Example 8

[0073] Synthesis of the intermediate compound of formula IV

[0074] Under the protection of nitrogen, 1.3 g (0.055 mol) of magnesium turnings, 30 g of tetrahydrofuran and 0.05 g (0.0002 mol) of iodine were added to a clean reaction flask. The temperature was raised to 50-60 °C. A solution of 17.4 g (0.05 mol) of the compound of formula III in 25 g of tetrahydrofuran was slowly added to the reaction flask while the internal temperature was controlled at 65-75 °C. After the addition was completed, the temperature was controlled at 65-75 °C and the reaction was stirred for 1.5 h. A small amount of magnesium turnings remained. The solution was a gray-black Grignard reaction. The reaction was cooled to room temperature and directly used in the next step.

[0075] Under the protection of nitrogen, 0.89 g (0.0025 mol) of Co(acac)3, 0.29 g (0.0025 mol) of tetramethylethylenediamine, 13.6 g (0.075 mol) of ethyl 2-bromopropenoate and 30 g of tetrahydrofuran were added to another clean reaction flask. The temperature was slowly lowered to -30 to -20 °C. The above obtained Grignard reaction solution was slowly added to the reaction flask while the internal temperature was controlled at -30 to -20 °C. After the addition was completed, the temperature was controlled at -30 to -20 °C and the reaction was stirred for 1 h. After the reaction was completed, the temperature was raised to room temperature. The reaction was detected by HPLC. 30 g of water and 80 g of ethyl acetate were added to the reaction. The solid was filtered and washed with 10 g of ethyl acetate. The reaction was allowed to stand and separate into layers. The aqueous layer was separated. The aqueous layer was extracted with 30 g of ethyl acetate. The collected organic phases were combined. The organic phase was dried over anhydrous sodium sulfate. The filtrate was collected and concentrated under reduced pressure to remove the solvent. The residue was subjected to flash column chromatography. Finally, 16.1 g of a colorless liquid was obtained. The purity of the compound was 97.6% as determined by HPLC. The yield was 87.4%.

[0076] Example 9

[0077] Synthesis of the compound of formula II

[0078]

[0079] Into a clean reaction flask, put 2-bromo-3-formylbenzoic acid 52.2 g (0.20 mol), 2-methyltetrahydrofuran 200 g and ethanol 20 g, replace with nitrogen for 3 times, then add sodium borohydride 46.6 g (0.22 mol) into the reaction flask in batches, control the internal temperature below 35 °C, after the addition, control the temperature at 35 °C to 40 °C, and stir for 5 h, then detect the reaction completion by TLC. Reduce the reaction temperature to 0 °C to 10 °C, then add water 50 g into the reaction solution, stir for 20 min, then add ethyl acetate 100 g into the system, stir and separate the layers, separate the water phase, then extract the water phase with ethyl acetate 30 g again, dry the combined organic phase with anhydrous sodium sulfate 15 g for 30 min, filter, and concentrate the collected filtrate to dryness to obtain the compound of formula II 51.1 g in colorless liquid, with a purity of 97.57% and a yield of 97%.

[0080] Example 10

[0081] Synthesis of the compound of formula III

[0082]

[0083] Into a clean reaction flask, put the compound of formula II 39.5 g (0.15 mol), 3,4-dihydro-2H-pyran 25.2 g (0.3 mol), aluminum chloride 4.0 g (0.03 mol) and THF 150 g, control the temperature at 25 °C to 30 °C, and stir for 8 h, then detect the reaction completion by TLC. Cool the reaction solution to room temperature, then add ethyl acetate 200 g and saturated sodium bicarbonate solution 100 g into the reaction solution, stir for 30 min, then separate the layers, separate the water phase, extract the water phase with ethyl acetate 60 g again, combine and collect the organic phase, concentrate the organic phase to dryness by vacuum distillation, and perform flash column chromatography to obtain 47.3 g of the compound of formula III in colorless liquid, with a HPLC purity of 99.2% and a yield of 90.8%.

[0084] Example 11

[0085] Synthesis of the intermediate compound of formula IV

[0086]

[0087] Into a clean reaction flask, under the protection of nitrogen, add magnesium turnings 1.44g (0.06mol), 2-methyltetrahydrofuran 50g and iodine 0.05g (0.0002mol), heat to 50-55°C, slowly add dropwise to the reaction flask a solution of the compound of formula III 17.4g (0.05mol) dissolved in 2-methyltetrahydrofuran 30g, and control the internal temperature at 65-70°C. After the dropwise addition is complete, continue to stir the reaction at 65-70°C for 2.0h, with a small amount of magnesium turnings remaining, the solution is a grayish black Grignard reaction, cool the reaction liquid to room temperature, and directly use in the next step reaction.

[0088] Into another clean reaction flask, under the protection of nitrogen, add CoCl2(PPh3)21.96g (0.003mol), dppp 1.24g (0.003mol), ethyl 2-bromopropenoate 17.9g (0.1mol) and tetrahydrofuran 30g, begin to slowly cool to -25-20°C, slowly add dropwise to the reaction flask the Grignard reaction solution obtained above, control the internal temperature at -25-20°C, after the dropwise addition is complete, continue to stir the reaction at -25-20°C for 2.0h, after the reaction is complete, heat to room temperature, detect by HPLC to confirm that the reaction is complete, add to the reaction water 50g and ethyl acetate 100g, filter and wash the solid with ethyl acetate 10g, stand to separate the layers, separate the aqueous layer, extract the aqueous layer with ethyl acetate 30g, combine the collected organic phases, dry with 20g of anhydrous sodium sulfate for 30min, filter, and concentrate the collected filtrate under reduced pressure to remove the solvent, fast column chromatography, and finally obtain 15.9g of a colorless liquid, HPLC purity 98.2%, yield 86.3%.

[0089] Example 12

[0090] Synthesis of the target product compound of formula VI

[0091]

[0092] Into a reaction flask, add the compound of formula IV 18.4g (0.05mol) and water 40g, then add concentrated hydrochloric acid 40g with a mass percentage of 37% and formic acid 18g to the reaction system, heat to reflux and stir the reaction for 18h, detect by HPLC to confirm that the reaction is complete; then add to the reaction liquid dichloromethane 100g, stir and stand, separate the aqueous phase, wash the organic phase with 20g of water, concentrate the organic phase to remove the solvent, obtain the crude product, then dissolve the crude product in a mixed solvent of ethyl acetate 15g and n-heptane 40g at 40°C, and cool to 0-5°C, stir for 1h to crystallize, filter to collect the solid wet product, and dry to obtain 11.8g of a white solid target product compound of formula V, HPLC purity 99.2%, yield 92.3%.

[0093] To another clean reaction flask, add the above obtained compound of formula V 10.3 g (0.04 mol), 2,2,6,6-tetramethylpiperidine-1-oxyl 0.63 g (0.004 mol) and potassium bromide 0.48 g (0.004 mol), then add dichloromethane 50 g and water 1 g, drop chloro-pyridine acid salt 30 g, control the temperature and the internal temperature at 10-15 °C, continue to control the temperature and stir for 2 h, then raise the temperature to room temperature and stir for 8 h, test the reaction completion by TLC, then add dichloromethane 50 g to the reaction liquid, adjust the pH of the reaction to 2-3 with 2M HCl solution, stand and separate the layers, collect the water phase, then wash the collected organic phase with 20 g of water, stand and separate the layers, then add 2M NaOH solution 50 g to the organic phase, stir for 10 min, stand and separate the layers, collect the water phase, control the temperature at 10-15 °C, adjust the pH of the water phase to 2-3 with 2M HCl solution, then add 100 g of dichloromethane, stir, stand and separate the layers, collect the organic phase, dry the organic phase with anhydrous sodium sulfate, filter, collect the filtrate, perform vacuum distillation to concentrate and remove the solvent to dryness, to obtain 9.2 g of white solid compound of formula VI, with HPLC purity of 99.3% and yield of 90.5%.

[0094] The specific embodiments described in the present application are only illustrative of the spirit of the present application. Those skilled in the art of the present application can make various modifications or supplements to the described specific embodiments or replace them with similar ways, but will not deviate from the spirit of the present application or exceed the scope defined by the appended claims.

[0095] Although detailed description has been made to the present application and some specific embodiments have been cited, it is obvious for those skilled in the art to make various changes or modifications without deviating from the spirit and scope of the present application.

Claims

1. A method for preparing ketoprofen, characterized in that, The method comprises the following steps: A. In the presence of a reducing agent, subjecting the compound of formula I to carbonyl reduction reaction to obtain the compound of formula II; B. Under the action of an acidic catalyst, the compound of formula II is subjected to a protection reaction with 3,4-dihydro-2H-pyran to obtain a compound of formula III; C. Under the catalytic action of a catalytic amount of iodine, the compound of formula III is subjected to a Grignard reaction with magnesium in an ether solvent to obtain a Grignard reaction solution containing the compound of formula III-1; and under the action of a cobalt catalyst and a catalyst ligand, the compound of formula III-1 in the Grignard reaction solution is subjected to a cross-coupling reaction with ethyl 2-bromopropionate to obtain a compound of formula IV; D. Under acidic conditions, subjecting the compound of formula IV to hydrolysis and deprotection reaction to obtain a compound of formula V; and then subjecting the hydroxyl group in the compound of formula V to oxidation reaction under the action of TEMPO and an oxidizing agent to obtain a compound of formula VI; 2. The preparation method of ketoprofen according to claim 1, wherein The cobalt catalyst in step C is selected from one or more of CoCl2, Co(acac)3, CoCl2(PPh3)2, CoCl2(dppe) and CoO; the catalyst ligand is selected from one or more of TEMDA, TMPDA, dppp, dpph and PPh3.

3. The preparation method of ketoprofen according to claim 2, wherein The molar ratio of the compound of formula III in step C: ethyl 2-bromopropionate: cobalt catalyst: catalyst ligand is 1: 1.2-2.0: 0.04-0.08: 0.04-0.

08.

4. The method for preparing ketoprofen according to claim 2, wherein The ether solvent in step C is one or more selected from tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, 2-methylcyclopentyl ether and isopropyl ether.

5. The method for preparing ketoprofen according to claim 2, 3 or 4, wherein: The temperature of the Grignard reaction in step C is 60°C to 80°C, and the temperature of the cross-coupling reaction is -40°C to -10°C.

6. The method for preparing ketoprofen according to claim 2, 3 or 4, wherein: The acidic catalyst in step B is selected from one or more of p-toluenesulfonic acid, hydrochloric acid, phosphoric acid, sulfuric acid, lithium tetrafluoroborate, pyridine p-toluenesulfonate, aluminum chloride, ferric chloride, boron trifluoride etherate, trimethylchlorosilane and boron tribromide.

7. The method for preparing ketoprofen according to claim 6, wherein In step B, the molar ratio of the compound of formula II: 3,4-dihydro-2H-pyran: acidic catalyst is 1:1.1-2.0:0.05-0.2; the temperature of the protection reaction is 10°C-50°C.

8. The method for preparing ketoprofen according to claim 2, 3 or 4, wherein: The reducing agent in step A is selected from one or more of aluminum isopropoxide, sodium borohydride, sodium cyanoborohydride, sodium acetate borohydride and lithium aluminum hydride.

9. The method for preparing ketoprofen according to claim 8, wherein The temperature of the carbonyl reduction reaction in step A is 20°C to 85°C.

10. The method for preparing ketoprofen according to claim 2, 3 or 4, characterized in that: The oxidant in step D is selected from one or more of sodium hypochlorite, pyridinium chlorochromate, pyridinium dichromate, sodium periodate, hydrogen peroxide, tert-butyl peroxide and perchloric acid; the molar ratio of the compound of formula V:TEMPO:oxidant is 1:0.1-0.2:2.0-5.0.

Images