A kind of preparation method of flurbiprofen

Abstract

The invention relates to a method for preparing flurbiprofen. The whole reaction conditions are mild, the intermediate product obtained does not need to be treated and can be directly used for the next step reaction. The preparation method is simple, the yield of the product is high, reaching more than 90%, the purity is high, reaching more than 99%, the post-processing is simple, the cost is reduced, and the method is suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the field of drug synthesis, and particularly relates to a method for preparing flurbiprofen. Background Art

[0002] Flurbiprofen is chemically named (±)-2-(2-fluoro-4-biphenyl)-propionic acid, and its molecular formula is C 15 H 13 FO2 is a white or off-white crystalline powder. It is easily soluble in methanol, ethanol, acetone or ether, soluble in acetonitrile, and almost insoluble in water.

[0003] Flurbiprofen is a fluorine-containing non-steroidal anti-inflammatory drug developed by British Buzzard. The drug was launched in the UK in 1976 and can inhibit the synthesis of cyclooxygenase by prostaglandins to cause analgesia, anti-inflammatory and antipyretic effects. Flurbiprofen ester was jointly developed by Japan Research and Pharmaceutical Co., Ltd. and Green Cross Pharmaceutical Co., Ltd., launched in Japan in 1992 and in China in 2004. According to the chiral structure of flurbiprofen, separation and research have been carried out to develop the drug esflurbiprofen, i.e. (S)-flurbiprofen, which is further developed by them using flurbiprofen as raw material. At present, flurbiprofen-related preparations launched at home and abroad have dosage forms such as gel plasters, patches, tablets and injections, which are mainly applicable to rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, etc. clinically, and can also be used for the symptomatic treatment of soft tissue diseases (such as sprains and strains), mild to moderate pain (such as dysmenorrhea and postoperative pain, toothache, etc.) and various cancer pains, showing a broad market prospect. Flurbiprofen itself is a drug and is also the basis for some prodrugs and improvements. It plays a very important role. In order to ensure the safety and quality of flurbiprofen and related improved drugs, it is necessary to conduct rigorous and prudent research on its related impurities and control the impurities within safe and reasonable limits.

[0004] Chinese patent CN108558651A discloses a method for preparing flurbiprofen, wherein 4-bromo-2-fluorobiphenyl reacts with metallic magnesium to generate Grignard reagent (2-fluoro-[1,1'-biphenyl]-4-yl) magnesium bromide, which is then coupled with ethyl 2-bromopropionate under the catalysis of TiCl4. The prepared intermediate flurbiprofen ethyl ester is subjected to alkaline hydrolysis, acidification and recrystallization to obtain flurbiprofen. However, this method has the following defects: 1) TiCl4 is highly corrosive and has great corrosiveness to reaction equipment and feeding equipment; 2) TiCl4 is highly volatile and reacts violently when in contact with water. During use, when in contact with the atmosphere, it reacts with moisture in the air to produce highly irritating and corrosive HCl white smoke, and releases a large amount of heat, which requires high protection for production personnel, and a large amount of heat release increases safety hazards, requiring enhanced protection, thereby increasing production costs, which is not conducive to industrial production; 3) TiCl4 is highly volatile, the feeding amount is not accurately controlled, and the reaction is violent, the reaction is poorly controllable, resulting in a large number of by-products in the preparation of the product, increasing the difficulty of product purification and three waste treatment, extending the production cycle, and thereby increasing production costs, which is not conducive to large-scale industrial production.

[0005] Therefore, it is necessary to provide a method for preparing flurbiprofen which is simple to operate, safe and controllable, has high yield, high purity, is green and environmentally friendly, has low production cost, and is easy to industrialize. Summary of the invention

[0006] The purpose of the present invention is to provide a method for preparing flurbiprofen based on the prior art.

[0007] The technical solution of the present invention is as follows:

[0008] A method for preparing flurbiprofen comprises the following steps:

[0009] (1) Under the protection of N2, compound 1 and a solvent are uniformly mixed, and a mixed solution obtained by mixing CH3MgCl and a solvent is slowly added dropwise at -25 to 10°C to carry out a chemical reaction to prepare compound 3;

[0010] (2) Under the protection of N2, magnesium chips, solvent and CH3I are mixed evenly, and the mixed solution obtained by mixing compound 2 and solvent is slowly added dropwise at 10-40°C to carry out a chemical reaction to prepare compound 4;

[0011] (3) Under the condition of 0-20° C., the reaction solution obtained in step (1) is added to the reaction solution obtained in step (2) to carry out a chemical reaction to prepare the target product compound 5. The specific synthesis route is as follows:

[0012]

[0013] In step (1), when preparing the intermediate product compound 3 from compound 1 and CH3MgCl, the reaction temperature needs to be strictly controlled. If the reaction temperature is too low, the reaction will not be complete, which is not conducive to the smooth progress of the reaction and leads to a low yield of the intermediate product; if the reaction temperature is too high, side reactions are likely to occur, resulting in a decrease in the yield and purity of the intermediate product.

[0014] For the present invention, in step (1), the reaction temperature is strictly controlled to be -25 to 10°C, which can be but not limited to -25°C, -20°C, -15°C, -10°C, -5°C, 0°C, 5°C or 10°C, which can improve the yield and purity of the intermediate product compound 3, and does not need to be post-processed, and directly participates in the next step of the reaction. The preparation method is simple, which can improve the efficiency of the entire reaction, reduce the possibility of side reactions, and make the yield and purity of the target product flurbiprofen (compound 5) high, the yield reaches more than 90%, the purity reaches more than 99%, the post-processing is simple, the cost is reduced, and it is suitable for industrial production. In a preferred embodiment, the reaction temperature is -20 to 0°C, and further, the reaction temperature is -15 to -10°C.

[0015] In step (1), when preparing intermediate product compound 3 from compound 1 and CH3MgCl, the selection of reaction raw material CH3MgCl is particularly important. In the experimental process of exploring reaction raw materials, the present invention finds that using CH3MgCl as a reducing agent and strictly controlling the dosage of CH3MgCl can improve the efficiency of the reaction, reduce the possibility of side reactions, and the yield and purity of intermediate product compound 3 are high. It directly participates in the reaction of the next step, can improve the efficiency of the entire reaction, reduce the possibility of side reactions, and make the yield and purity of target product flurbiprofen high, the yield reaches more than 90%, and the purity reaches more than 99%. While using other similar reaction raw materials, for example, CH3CH2MgCl, (CH3)2CHMgCl, under the same reaction conditions, the yield and purity of the target product are low.

[0016] For the present invention, in step (1), the mass volume ratio of compound 1 and CH3MgCl is 1:2.5-5.0 g / mL, which may be but not limited to 1:2.5 g / mL, 1:2.8 g / mL, 1:3.0 g / mL, 1:3.1 g / mL, 1:3.2 g / mL, 1:3.3 g / mL, 1:3.4 g / mL, 1:3.5 g / mL, 1:3.8 g / mL, 1:4.0 g / mL, 1:4.3 g / mL, 1:4.5 g / mL or 1:5.0 g / mL. In order to obtain better effect, the mass volume ratio of compound 1 and CH3MgCl is 1:3.0-4.5 g / mL. More preferably, the mass volume ratio of compound 1 and CH3MgCl is 1:3.2-3.5 g / mL.

[0017] In the present invention, in step (1), the solvent is tetrahydrofuran, dichloromethane or ethanol; preferably tetrahydrofuran.

[0018] Compared with the prior art which generally uses compound 2, magnesium chips and iodine particles to prepare intermediate compound 4, the present invention selects compound 2, magnesium chips and CH3I as reaction raw materials to prepare intermediate compound 4 in step (2), which has lower reaction temperature requirements, reduces the possibility of side reactions, improves the yield and purity of intermediate compound 4, does not require post-treatment, and directly participates in the next step of reaction, which can improve the efficiency of the entire reaction, so that the yield and purity of the target product flurbiprofen are high, with a yield of more than 90% and a purity of more than 99%.

[0019] In the present invention, in step (2), the reaction temperature is 10-40°C, and may be but not limited to 10°C, 15°C, 20°C, 25°C, 30°C, 35°C or 40°C. In order to obtain better effects, the reaction temperature is 15-35°C, and more preferably 20-30°C.

[0020] In the present invention, in step (2), when compound 2, magnesium chips and CH3I are used as reaction raw materials to prepare intermediate compound 4, the molar ratio of compound 2 to magnesium chips is 1:1.0-2.0, which can be but not limited to 1:1.0, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.8, 1:2.0. In order to obtain better effect, the molar ratio of compound 2 to magnesium chips is 1:1.0-1.5.

[0021] In step (2), when compound 2, magnesium chips and CH3I are used as reaction raw materials to prepare the intermediate product compound 4, the dosage of CH3I needs to be strictly controlled. A high or low dosage is not conducive to the smooth progress of the reaction, resulting in a decrease in the yield and purity of the intermediate product compound 4. When it directly participates in the next step of the reaction, it leads to a decrease in the yield and purity of the target product. In the present invention, in step (2), the mass volume ratio of the compound to CH3I is 1:0.01-0.1 g / mL, and may be but is not limited to 1:0.01 g / mL, 1:0.02 g / mL, 1:0.03 g / mL, 1:0.04 g / mL, 1:0.05 g / mL, 1:0.06 g / mL, 1:0.07 g / mL, 1:0.08 g / mL, 1:0.09 g / mL or 1:0.1 g / mL. In order to obtain better effects, the mass volume ratio of the compound to CH3I is 1:0.03-0.05 g / mL.

[0022] For the present invention, the material ratio of compound 2 to compound 1 has a great influence on the yield and purity of the target product. Too high or too low a ratio will result in a significant decrease in the yield and purity of the target product. In step (2), the molar ratio of compound 2 to compound 1 is 1:1.0 to 2.0, and may be but is not limited to 1:1.0, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.8, 1:2.0. In order to obtain better results, the molar ratio of compound 2 to compound 1 is 1:1.0 to 1.5.

[0023] In the present invention, in step (2), the solvent is tetrahydrofuran, dichloromethane or ethanol; preferably tetrahydrofuran.

[0024] For the present invention, when the reaction solution obtained in step (1) is added to the reaction solution obtained in step (2) to carry out a chemical reaction to prepare the target product compound 5, the effect of the reaction temperature on the yield and purity of the target product cannot be ignored. If the reaction temperature is too low, the reaction is not thorough, which is not conducive to the smooth progress of the reaction, resulting in a low yield of the product; if the reaction temperature is too high, side reactions are prone to occur, resulting in a decrease in the yield and purity of the product. For the present invention, in step (3), the reaction temperature is 0 to 20°C, which can be but not limited to 0°C, 5°C, 10°C, 15°C or 20°C. In a preferred embodiment, the reaction temperature is 10 to 15°C, and further, the reaction temperature is 5 to 10°C.

[0025] Adopt the technical scheme of the present invention, the advantages are as follows:

[0026] The preparation method of flurbiprofen provided by the invention has mild reaction conditions, and the obtained intermediate product does not need to be treated and can be directly used for the next step reaction. The preparation method is simple, the yield of the product is high, reaching more than 90%, the purity is high, reaching more than 99%, the post-treatment is simple, the cost is reduced, and the method is suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 The product prepared in Example 1 1 H NMR and chemical shift magnification.

[0028] Figure 2 It is the HPLC spectrum of flurbiprofen prepared in Example 1. DETAILED DESCRIPTION

[0029] The preparation method of flurbiprofen of the present invention is further described by the following examples, but these examples do not constitute any limitation to the present invention.

[0030] Example 1 Synthesis of Flurbiprofen (Compound 5)

[0031]

[0032] (1) Under N2 protection, 59.66 g (0.39 mol) of compound 1 and 150 mL of THF were added to a 500 mL dry three-necked flask. After stirring, 200 mL of CH3MgCl was slowly added dropwise at a temperature of -15 to -10°C. The addition time was controlled to be 2 h. After TLC showed that the reaction was complete, a reaction solution containing the intermediate product compound 3 was obtained.

[0033] (2) Under N2 protection, 8.75 g (0.36 mol) of magnesium chips, 150 mL of THF and 3 mL of CH3I were added to a dry 1 L four-necked flask. After stirring, a mixed solution prepared by dissolving 75.33 g (0.3 mol) of compound 2 in 150 mL of THF was slowly added dropwise at a temperature of 20 to 30°C. The addition time was controlled to be 4 h. After TLC showed that compound 2 was completely reacted, a reaction solution containing the intermediate product compound 4 was obtained.

[0034] (3) under the condition of temperature of 5-10° C., the reaction solution containing intermediate product compound 3 obtained in step (1) is added to the reaction solution containing intermediate product compound 4 obtained in step (2), and the dripping time is controlled to be 10 min. After TLC shows that the reaction is completed, the pH value of the obtained reaction solution is adjusted to 1 with 2N hydrochloric acid, and ethyl acetate is added for extraction. The obtained organic phase is concentrated to dryness, and then 2N KOH aqueous solution is added for dissolution. The obtained aqueous phases are combined, and the pH value is adjusted to 1 with 6N hydrochloric acid to precipitate a large amount of white solid. The precipitated solid is filtered and dried to obtain white solid flurbiprofen with a yield of 96.5% and a purity of 99.95%.

[0035] Hydrogen spectrum analysis: 1H-NMR: (600MHz, DMSO-d6) δ: 1.40 (3H, m), 3.75 (1H, m),

[0036] 7.22-7.55(8H,m),12.49(1H,m);

[0037] The singlet at a chemical shift of 1.40 is the three Hs on CH3-; the doublet at a chemical shift of 3.75 is the H on CH-; the singlet at a chemical shift of 12.49 is the H on -COOH; and the multiplets at chemical shifts of 7.22-7.55 are the Hs on the 2-fluorobiphenyl group.

[0038] Example 2 Synthesis of Flurbiprofen (Compound 5)

[0039] (1) Under N2 protection, 59.66 g (0.39 mol) of compound 1 and 150 mL of THF were added to a 500 mL dry three-necked flask. After stirring, 250 mL of CH3MgCl was slowly added dropwise at a temperature of -15 to -10°C. The addition time was controlled to be 2 h. After TLC showed that the reaction was complete, a reaction solution containing the intermediate product compound 3 was obtained.

[0040] (2) Under N2 protection, 8.75 g (0.36 mol) of magnesium chips, 150 mL of THF and 3 mL of CH3I were added to a dry 1 L four-necked flask. After stirring, a mixed solution prepared by dissolving 75.33 g (0.3 mol) of compound 2 in 150 mL of THF was slowly added dropwise at a temperature of 20 to 30°C. The addition time was controlled to be 4 h. After TLC showed that compound 2 was completely reacted, a reaction solution containing the intermediate product compound 4 was obtained.

[0041] (3) under the condition of temperature of 5-10° C., the reaction solution containing intermediate product compound 3 obtained in step (1) is added to the reaction solution containing intermediate product compound 4 obtained in step (2), and the dripping time is controlled to be 10 min. After TLC shows that the reaction is completed, the pH value of the obtained reaction solution is adjusted to 1 with 2N hydrochloric acid, and ethyl acetate is added for extraction. The obtained organic phase is concentrated to dryness, and then 2N KOH aqueous solution is added for dissolution. The obtained aqueous phases are combined, and the pH value is adjusted to 1 with 6N hydrochloric acid to precipitate a large amount of white solid. The precipitated solid is filtered and dried to obtain white solid flurbiprofen with a yield of 91.8% and a purity of 99.1%.

[0042] Example 3 Synthesis of Flurbiprofen (Compound 5)

[0043] (1) Under N2 protection, 59.66 g (0.39 mol) of compound 1 and 150 mL of THF were added to a 500 mL dry three-necked flask. After stirring, 200 mL of CH3MgCl was slowly added dropwise at a temperature of -5 to 0°C. The addition time was controlled to be 2 h. After TLC showed that the reaction was complete, a reaction solution containing the intermediate product compound 3 was obtained.

[0044] (2) Under N2 protection, 8.75 g (0.36 mol) of magnesium chips, 150 mL of THF and 3 mL of CH3I were added to a dry 1 L four-necked flask. After stirring, a mixed solution prepared by dissolving 75.33 g (0.3 mol) of compound 2 in 150 mL of THF was slowly added dropwise at a temperature of 20 to 30°C. The addition time was controlled to be 4 h. After TLC showed that compound 2 was completely reacted, a reaction solution containing the intermediate product compound 4 was obtained.

[0045] (3) under the condition of temperature of 5-10° C., the reaction solution containing intermediate product compound 3 obtained in step (1) is added to the reaction solution containing intermediate product compound 4 obtained in step (2), and the dripping time is controlled to be 10 min. After TLC shows that the reaction is completed, the pH value of the obtained reaction solution is adjusted to 1 with 2N hydrochloric acid, and ethyl acetate is added for extraction. The obtained organic phase is concentrated to dryness, and then 2N KOH aqueous solution is added for dissolution. The obtained aqueous phases are combined, and the pH value is adjusted to 1 with 6N hydrochloric acid to precipitate a large amount of white solid. The precipitated solid is filtered and dried to obtain white solid flurbiprofen with a yield of 90.1% and a purity of 99.3%.

[0046] Comparative Example 1

[0047] (1) Under N2 protection, 59.66 g (0.39 mol) of compound 1 and 150 mL of THF were added to a 500 mL dry three-necked flask. After stirring, 200 mL of CH3MgCl was slowly added dropwise at a temperature of 15 to 20°C. The addition time was controlled to be 2 h. After TLC showed that the reaction was complete, a reaction solution containing the intermediate product compound 3 was obtained.

[0048] (2) Under N2 protection, 8.75 g (0.36 mol) of magnesium chips, 150 mL of THF and 3 mL of CH3I were added to a dry 1 L four-necked flask. After stirring, a mixed solution prepared by dissolving 75.33 g (0.3 mol) of compound 2 in 150 mL of THF was slowly added dropwise at a temperature of 20 to 30°C. The addition time was controlled to be 4 h. After TLC showed that compound 2 was completely reacted, a reaction solution containing the intermediate product compound 4 was obtained.

[0049] (3) under the condition of temperature of 5-10° C., the reaction solution containing intermediate product compound 3 obtained in step (1) was added to the reaction solution containing intermediate product compound 4 obtained in step (2), and the dripping time was controlled to be 10 min. After TLC showed that the reaction was completed, the pH value of the obtained reaction solution was adjusted to 1 with 2N hydrochloric acid, and ethyl acetate was added for extraction. The obtained organic phase was concentrated to dryness, and then 2N KOH aqueous solution was added for dissolution. The obtained aqueous phases were combined, and the pH value was adjusted to 1 with 6N hydrochloric acid to precipitate a large amount of white solid. The precipitated solid was filtered and dried to obtain white solid flurbiprofen with a yield of 78.6% and a purity of 94.3%.

[0050] Comparative Example 2

[0051] (1) Under N2 protection, 59.66 g (0.39 mol) of compound 1 and 150 mL of THF were added to a 500 mL dry three-necked flask. After stirring, 200 mL of CH3MgCl was slowly added dropwise at a temperature of -30 to -25°C. The addition time was controlled to be 2 h. After TLC showed that the reaction was complete, a reaction solution containing the intermediate product compound 3 was obtained.

[0052] (2) Under N2 protection, 8.75 g (0.36 mol) of magnesium chips, 150 mL of THF and 3 mL of CH3I were added to a dry 1 L four-necked flask. After stirring, a mixed solution prepared by dissolving 75.33 g (0.3 mol) of compound 2 in 150 mL of THF was slowly added dropwise at a temperature of 20 to 30°C. The addition time was controlled to be 4 h. After TLC showed that compound 2 was completely reacted, a reaction solution containing the intermediate product compound 4 was obtained.

[0053] (3) under the condition of temperature of 5-10° C., the reaction solution containing intermediate product compound 3 obtained in step (1) was added to the reaction solution containing intermediate product compound 4 obtained in step (2), and the dripping time was controlled to be 10 min. After TLC showed that the reaction was completed, the pH value of the obtained reaction solution was adjusted to 1 with 2N hydrochloric acid, and ethyl acetate was added for extraction. The obtained organic phase was concentrated to dryness, and then 2N KOH aqueous solution was added for dissolution. The obtained aqueous phases were combined, and the pH value was adjusted to 1 with 6N hydrochloric acid to precipitate a large amount of white solid. The precipitated solid was filtered and dried to obtain white solid flurbiprofen with a yield of 72.5% and a purity of 89.1%.

[0054] Comparative Example 3

[0055] (1) Under N2 protection, 59.66 g (0.39 mol) of compound 1 and 150 mL of THF were added to a 500 mL dry three-necked flask. After stirring, 100 mL of CH3MgCl was slowly added dropwise at a temperature of -15 to -10°C. The addition time was controlled to be 2 h. After TLC showed that the reaction was complete, a reaction solution containing the intermediate product compound 3 was obtained.

[0056] (2) Under N2 protection, 8.75 g (0.36 mol) of magnesium chips, 150 mL of THF and 3 mL of CH3I were added to a dry 1 L four-necked flask. After stirring, a mixed solution prepared by dissolving 75.33 g (0.3 mol) of compound 2 in 150 mL of THF was slowly added dropwise at a temperature of 20 to 30°C. The addition time was controlled to be 4 h. After TLC showed that compound 2 was completely reacted, a reaction solution containing the intermediate product compound 4 was obtained.

[0057] (3) Under the condition of a temperature of 5 to 10° C., the reaction solution containing the intermediate product compound 3 obtained in step (1) is added to the reaction solution containing the intermediate product compound 4 obtained in step (2), and the dripping time is controlled to be 10 min. After TLC shows that the reaction is completed, the pH value of the obtained reaction solution is adjusted to 1 with 2N hydrochloric acid, and ethyl acetate is added for extraction. The obtained organic phase is concentrated to dryness, and then a 2N KOH aqueous solution is added for dissolution. The obtained aqueous phases are combined, and the pH value is adjusted to 1 with 6N hydrochloric acid to precipitate a large amount of white solid. The precipitated solid is filtered and dried to obtain white solid flurbiprofen with a yield of 75.2% and a purity of 92.4%.

[0058] Comparative Example 4

[0059] (1) Under N2 protection, 100.96 g (0.66 mol) of compound 1 and 150 mL of THF were added to a 500 mL dry three-necked flask. After stirring, 200 mL of CH3MgCl was slowly added dropwise at a temperature of -15 to -10°C. The addition time was controlled to be 2 h. After TLC showed that the reaction was complete, a reaction solution containing the intermediate product compound 3 was obtained.

[0060] (2) Under N2 protection, 8.75 g (0.36 mol) of magnesium chips, 150 mL of THF and 3 mL of CH3I were added to a dry 1 L four-necked flask. After stirring, a mixed solution prepared by dissolving 75.33 g (0.3 mol) of compound 2 in 150 mL of THF was slowly added dropwise at a temperature of 20 to 30°C. The addition time was controlled to be 4 h. After TLC showed that compound 2 was completely reacted, a reaction solution containing the intermediate product compound 4 was obtained.

[0061] (3) Under the condition of a temperature of 5 to 10° C., the reaction solution containing the intermediate product compound 3 obtained in step (1) is added to the reaction solution containing the intermediate product compound 4 obtained in step (2), and the dripping time is controlled to be 10 min. After TLC shows that the reaction is completed, the pH value of the obtained reaction solution is adjusted to 1 with 2N hydrochloric acid, and ethyl acetate is added for extraction. The obtained organic phase is concentrated to dryness, and then a 2N KOH aqueous solution is added for dissolution. The obtained aqueous phases are combined, and the pH value is adjusted to 1 with 6N hydrochloric acid to precipitate a large amount of white solid. The precipitated solid is filtered and dried to obtain white solid flurbiprofen with a yield of 85.6% and a purity of 98.2%.

[0062] Comparative Example 5

[0063] (1) Under N2 protection, 59.66 g (0.39 mol) of compound 1 and 150 mL of THF were added to a 500 mL dry three-necked flask. After stirring, 200 mL of (CH3)2CHMgCl was slowly added dropwise at a temperature of -15 to -10°C. The addition time was controlled to be 2 h. After TLC showed that the reaction was complete, a reaction solution containing the intermediate product compound 3 was obtained.

[0064] (2) Under N2 protection, 8.75 g (0.36 mol) of magnesium chips, 150 mL of THF and 3 mL of CH3I were added to a dry 1 L four-necked flask. After stirring, a mixed solution prepared by dissolving 75.33 g (0.3 mol) of compound 2 in 150 mL of THF was slowly added dropwise at a temperature of 20 to 30°C. The addition time was controlled to be 4 h. After TLC showed that compound 2 was completely reacted, a reaction solution containing the intermediate product compound 4 was obtained.

[0065] (3) Under the condition of a temperature of 5 to 10° C., the reaction solution containing the intermediate product compound 3 obtained in step (1) is added to the reaction solution containing the intermediate product compound 4 obtained in step (2), and the dripping time is controlled to be 10 min. After TLC shows that the reaction is completed, the pH value of the obtained reaction solution is adjusted to 1 with 2N hydrochloric acid, and ethyl acetate is added for extraction. The obtained organic phase is concentrated to dryness, and then a 2N KOH aqueous solution is added for dissolution. The obtained aqueous phases are combined, and the pH value is adjusted to 1 with 6N hydrochloric acid to precipitate a large amount of white solid. The precipitated solid is filtered and dried to obtain white solid flurbiprofen with a yield of 83.5% and a purity of 95.3%.

[0066] Comparative Example 6

[0067] (1) Under N2 protection, 59.66 g (0.39 mol) of compound 1 and 150 mL of THF were added to a 500 mL dry three-necked flask. After stirring, 200 mL of CH3MgCl was slowly added dropwise at a temperature of -15 to -10°C. The addition time was controlled to be 2 h. After TLC showed that the reaction was complete, a reaction solution containing the intermediate product compound 3 was obtained.

[0068] (2) Under N2 protection, 8.75 g (0.36 mol) of magnesium chips, 150 mL of THF and 3 iodine grains were added to a dry 1 L four-necked flask. After stirring, a mixed solution prepared by dissolving 75.33 g (0.3 mol) of compound 2 in 150 mL of THF was slowly added dropwise at a temperature of 20 to 30°C. The addition time was controlled to be 4 h. After TLC showed that compound 2 was completely reacted, a reaction solution containing the intermediate product compound 4 was obtained.

[0069] (3) Under the condition of a temperature of 5 to 10° C., the reaction solution containing the intermediate product compound 3 obtained in step (1) is added to the reaction solution containing the intermediate product compound 4 obtained in step (2), and the dripping time is controlled to be 10 min. After TLC shows that the reaction is completed, the pH value of the obtained reaction solution is adjusted to 1 with 2N hydrochloric acid, and ethyl acetate is added for extraction. The obtained organic phase is concentrated to dryness, and then a 2N KOH aqueous solution is added for dissolution. The obtained aqueous phases are combined, and the pH value is adjusted to 1 with 6N hydrochloric acid to precipitate a large amount of white solid. The precipitated solid is filtered and dried to obtain white solid flurbiprofen with a yield of 58.1% and a purity of 81.8%.

[0070] Comparative Example 7

[0071] (1) Under N2 protection, 59.66 g (0.39 mol) of compound 1 and 150 mL of THF were added to a 500 mL dry three-necked flask. After stirring, 200 mL of CH3MgCl was slowly added dropwise at a temperature of -15 to -10°C. The addition time was controlled to be 2 h. After TLC showed that the reaction was complete, a reaction solution containing the intermediate product compound 3 was obtained.

[0072] (2) Under N2 protection, 8.75 g (0.36 mol) of magnesium chips, 150 mL of THF and 3 mL of CH3I were added to a dry 1 L four-necked flask. After stirring, a mixed solution prepared by dissolving 75.33 g (0.3 mol) of compound 2 in 150 mL of THF was slowly added dropwise at a temperature of 20 to 30°C. The addition time was controlled to be 4 h. After TLC showed that compound 2 was completely reacted, a reaction solution containing the intermediate product compound 4 was obtained.

[0073] (3) Under the condition of a temperature of 20-25° C., the reaction solution containing the intermediate product compound 3 obtained in step (1) is added to the reaction solution containing the intermediate product compound 4 obtained in step (2), and the dripping time is controlled to be 10 min. After TLC shows that the reaction is completed, the pH value of the obtained reaction solution is adjusted to 1 with 2N hydrochloric acid, and ethyl acetate is added for extraction. The obtained organic phase is concentrated to dryness, and then a 2N KOH aqueous solution is added for dissolution. The obtained aqueous phases are combined, and the pH value is adjusted to 1 with 6N hydrochloric acid to precipitate a large amount of white solid. The precipitated solid is filtered and dried to obtain white solid flurbiprofen with a yield of 79.5% and a purity of 92.4%.

[0074] The above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, a person skilled in the art should understand that it is still possible to modify the technical solutions described in the aforementioned embodiments, or to perform equivalent replacements on some of the technical features therein. However, these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for preparing flurbiprofen, characterized in that, It includes the following steps: (1) Under N2 protection, compound 1 and a solvent are uniformly mixed, and a mixed solution obtained by mixing CH3MgCl and the solvent is slowly added dropwise at -15 to -10°C to carry out a chemical reaction to prepare compound 3; wherein the mass volume ratio of compound 1 to CH3MgCl is 1:3.0 to 4.5 g / mL; (2) Under the protection of N2, magnesium chips, solvent and CH3I are uniformly mixed, and the mixed solution obtained by mixing compound 2 and solvent is slowly added dropwise at 20-30°C to carry out a chemical reaction to prepare compound 4; wherein the molar ratio of compound 2 to magnesium chips is 1:1.0-1.5; the mass volume ratio of compound 2 to CH3I is 1:0.03-0.05 g / mL; and the molar ratio of compound 2 to compound 1 is 1:1.0-1.5; (3) Under the condition of 5-10° C., the reaction solution obtained in step (1) is added to the reaction solution obtained in step (2) to carry out a chemical reaction to prepare the target product compound 5. The specific synthesis route is as follows:

2. The method for preparing flurbiprofen according to claim 1, wherein In step (1), the mass volume ratio of compound 1 and CH3MgCl is 1:3.2-3.5 g / mL.

3. The preparation method of flurbiprofen according to claim 1, characterized in that, In step (1), the solvent is tetrahydrofuran, dichloromethane or ethanol.

4. The method for preparing flurbiprofen according to claim 3, wherein In step (1), the solvent is tetrahydrofuran.

5. The method for preparing flurbiprofen according to claim 1, characterized in that, In step (2), the solvent is tetrahydrofuran, dichloromethane or ethanol.

6. The method for preparing flurbiprofen according to claim 5, characterized in that, In step (2), the solvent is tetrahydrofuran.

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