Preparation method of low-cost high-purity flurbiprofen

Abstract

The invention relates to a preparation method of flurbiprofen with low cost and high purity. The preparation method comprises the following steps: taking 4-bromine-2-fluorobiphenyl as a raw material, and carrying out Grignard reaction on the 4-bromine-2-fluorobiphenyl and magnesium powder to obtain 2-fluoro-4-biphenyl magnesium bromide; the preparation method comprises the following steps: in a solvent, enabling 2-fluoro-4-biphenyl magnesium bromide and N, N-dimethylacetamide to be subjected to a Bouveaut reaction, so as to obtain 2-fluoro-4-biphenyl ethyl ketone; the method comprises the following steps: under the action of a base catalyst, carrying out Wittig reaction on 2-fluoro-4-biphenyl ethanone and (methoxymethyl) triphenyl phosphonium chloride to obtain an alkene etherate, and carrying out acidolysis on the alkene etherate to obtain 2-(2-fluoro-4-biphenyl) propionaldehyde; and carrying out Pinnick oxidation on the 2-(2-fluoro-4-biphenyl) propionaldehyde, sodium chlorite and hydrogen peroxide to obtain racemic 2-(2-fluoro-4-biphenyl) propionic acid, namely, flurbiprofen. The process route totally comprises four steps of reactions, each step is a classical chemical reaction, the HPLC purity of the obtained flurbiprofen is greater than or equal to 99.5%, the materials are cheap and easy to obtain, the operation is simple, the post-treatment is convenient, and the method is suitable for industrial production.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical technology and specifically relates to a method for preparing flurbiprofen with low cost and high purity. Background Art

[0002] Non-steroidal anti-inflammatory drugs (NSAIDs) are a class of medications that do not contain a steroidal structure and exert their antipyretic, analgesic, and anti-inflammatory effects by inhibiting the activity of cyclooxygenase (COX). Since the introduction of the first NSAID, aspirin, in 1898, over a hundred NSAIDs have been marketed over the past century. They can be divided into seven major categories based on their structure: salicylates (such as aspirin, sodium salicylate, salsalate, and sulfasalazine), anilines (such as acetaminophen), indoles (such as indomethacin, sulindac, and etodolac), arylacetic acids (such as diclofenac), arylpropionic acids (such as ibuprofen, naproxen, flurbiprofen, ketoprofen, and fenoprofen), fenamates (such as mefenamic acid), enolic acids, and others (such as piroxicam, lornoxicam, tenoxicam, and nabumetone). NSAIDs generally have anti-inflammatory, antirheumatic, analgesic, antipyretic, and anticoagulant effects and are widely used clinically to relieve mild to moderate pain, reduce inflammation, fever, various osteoarthritis, and rheumatic autoimmune diseases. COX is divided into two isoenzymes, COX-1 and COX-2, which are the rate-limiting enzymes in the synthesis of prostaglandins (PGs). COX-1 is normally expressed in normal environments, and the PGs synthesized by COX-1 play an important role in the physiological functions of the gastrointestinal tract and kidneys, as well as regulating platelet aggregation. COX-2, on the other hand, is primarily induced in inflammatory cells and at sites of inflammation, and the synthesized PGs can induce inflammation. Traditional NSAIDs have no selectivity for inhibiting COX-1 and COX-2, and can cause varying degrees of gastrointestinal adverse reactions after use. In order to avoid adverse reactions in the digestive tract, kidneys, etc. caused by COX-1 inhibition, selective COX-2 inhibitors such as nimesulide and celecoxib have been developed and launched on the market. However, with the widespread use of these drugs, it has been found that COX-2 selective inhibitors increase patients' risk of developing serious cardiovascular diseases.

[0003] Flurbiprofen, an arylpropionic acid NSAID developed by Boots Pharmaceuticals in the UK and launched in the UK in 1977, is a non-selective COX inhibitor. Flurbiprofen contains a chiral carbon atom and has two optical isomers. The racemic form is currently marketed. These two optical isomers have distinct pharmacological activities. The S-isomer effectively inhibits COX and is the primary analgesic and anti-inflammatory component. The R-isomer has virtually no anti-inflammatory or analgesic effects and exhibits certain toxic side effects and physiological resistance. Recent studies have shown that the R-isomer can inhibit the expression of Aβ-42 protein and has a positive therapeutic effect on Alzheimer's disease. To further reduce adverse reactions and enhance pharmacological effects such as analgesia, Kaken, Mitsubishi Tanabe Pharma, and Fogangren Bio-Pharma jointly developed flurbiprofen into a prodrug, flurbiprofen axetil. The injectable formulation, flurbiprofen axetil injection, was launched by Kaken in 1992 in a 5 ml:50 mg dosage. It is clinically used for postoperative analgesia and for various cancers. Flurbiprofen axetil injection is a nonsteroidal targeted analgesic that effectively reduces surgical trauma-induced hyperalgesia by inhibiting COX in the spinal cord and peripherally, reducing progesterone synthesis. Lipomicrosphere formulations offer enhanced efficacy, a more rapid onset of action, a longer duration of action, and are less likely to cause adverse reactions such as gastric mucosal damage. They are primarily used for postoperative analgesia, with the advantage of having no central nervous system inhibitory effects and no impact on patient recovery from anesthesia. The structural formulas of flurbiprofen and flurbiprofen axetil are shown below:

[0004]

[0005] The following is a review and analysis of the reported flurbiprofen preparation process routes.

[0006] Adams et al. first reported the material and synthesis process patent of 2-(monofluoro- and difluoro-4-biphenyl) propionic acid (US3755427A, US3959364A, patent expired): ethyl 2-(2-fluoro-4-biphenyl) acetate (1) was used as the starting material and reacted with diethyl carbonate under strong alkaline conditions to obtain diethyl 2-(2-fluoro-4-biphenyl) malonate (2); compound 2 was methylated with methyl iodide to obtain diethyl 2-(2-fluoro-4-biphenyl)-2-methyl malonate (3); compound 3 was hydrolyzed to obtain 2-(2-fluoro-4-biphenyl)-2-methyl malonate (4); compound 4 was decarboxylated to obtain the target product flurbiprofen. This process route reported the preparation of a series of monofluoro and difluoro compounds. The starting material compound 1 is expensive and difficult to obtain. The process route of this synthesis method is as follows:

[0007]

[0008] Lu Fuyi et al. reported a method for synthesizing flurbiprofen and its intermediates (CN116715689A, substantive examination): using 4-bromo-2-fluorobiphenyl (5) as the starting material, compound 5 is coupled with bis-pinacol diboron in the presence of a base and a palladium metal catalyst to obtain 2-(2-fluoro-4-biphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (6); compound 6 is Suzuki coupled with racemic sodium 2-bromopropionate in the presence of a palladium metal catalyst, and the target product flurbiprofen is obtained after acidification. The product obtained by this process route has high purity, simple operation, and convenient post-processing, but it is prone to self-coupling, resulting in low yield, and the palladium metal catalyst and bis-pinacol diboron are expensive. The process route of this synthesis method is as follows:

[0009]

[0010] Yan Libo et al. reported a method for preparing flurbiprofen (CN101585760A, application withdrawn after publication): 4-bromo-2-fluorobiphenyl (5) was used as the starting material, and a Grignard reaction with magnesium powder was performed to obtain 2-fluoro-4-biphenyl magnesium bromide (7); compound 7 was subjected to a substitution reaction with racemic sodium 2-bromopropionate and then acidified to obtain the target product flurbiprofen. This process route has a short number of steps, but is prone to self-coupling, resulting in a low yield. In addition, the preparation of the Grignard reagent requires an anaerobic and anhydrous operation, which is relatively harsh. The process route of this preparation method is as follows:

[0011]

[0012] Yang Chunbo et al. reported a method for preparing flurbiprofen (CN112225657A, patent granted): 4-bromo-2-fluoro-nitrobenzene (8) is used as a starting material, and substituted with diethyl 2-methylmalonate to obtain 2-(3-fluoro-4-nitrophenyl)-2-methylmalonate (9); compound 9 is hydrolyzed and decarboxylated to obtain 2-(3-fluoro-4-nitrophenyl)propionic acid (10); compound 10 is reduced to obtain 2-(4-amino-3-fluorophenyl)propionic acid (11); compound 11 is diazotized and then subjected to Sandmeyer reaction to obtain 2-(4-bromo-3-fluorophenyl)propionic acid (12); in the presence of palladium catalyst, compound 12 is subjected to Suzuki coupling with phenylboronic acid to obtain the target product flurbiprofen. This process route is long, has a low yield, and is cumbersome to operate. The process route of this preparation method is as follows:

[0013]

[0014] Wang Zhiqiang et al. reported a method for preparing flurbiprofen (CN106496015, patent granted): 4-bromo-1-chloro-2-fluorobenzene (13) was used as the starting material and reacted with magnesium powder to prepare the Grignard reagent 4-chloro-3-fluorophenylmagnesium bromide (14); in the presence of a palladium catalyst, compound 14 was subjected to Kumada cross-coupling with racemic sodium 2-bromopropionate and then acidified to obtain 2-(4-chloro-3-fluorophenyl)propionic acid (15); compound 15 was subjected to Suzuki coupling with phenylboronic acid in the presence of a palladium catalyst to obtain the target product flurbiprofen. This process route is short, but the starting materials are not easy to obtain, the preparation of the Grignard reagent requires anhydrous and oxygen-free operation, and the reaction conditions are relatively harsh. The process route of this preparation method is as follows:

[0015]

[0016] Ma Bojun et al. reported a new method for the synthesis of flurbiprofen (CN115710177A, with changes in the description): 2-(4-bromo-3-fluorophenyl)malononitrile (16) was used as the starting material. In the presence of a palladium catalyst, it underwent Suzuki coupling with phenylboronic acid to obtain 2-(2-fluoro-4-biphenyl)malononitrile (17); compound 17 underwent methylation with iodomethane to obtain 2-(2-fluoro-4-biphenyl)-2-methylmalononitrile (18); and compound 18 was hydrolyzed and decarboxylated to obtain the target product, flurbiprofen. In this process, the starting material, compound 16, was expensive, and reagents such as iodomethane were highly toxic, resulting in a low yield. The process route of this synthesis method is shown below:

[0017]

[0018] Liu Na et al. reported a method for preparing 2-biphenylpropionic acid compounds (CN114195634A, substantive review): 2-fluoro-4-biphenyl magnesium bromide (7) is used as the starting material. In the presence of cobalt chloride catalyst, it undergoes a substitution reaction with racemic sodium 2-bromopropionate to obtain 2-fluoro-4-biphenyl propionate, which is then acidified to obtain the target product flurbiprofen. This process is short, but the starting material compound 7 is very active and easily reacts with water or air. It is not available on the market and needs to be customized. The cobalt salt is also expensive. The process route of this preparation method is as follows:

[0019]

[0020] Jin Shengfei et al. reported a method for preparing flurbiprofen (CN116102397A, patent granted): 4-bromo-2-fluoroaniline (19) was used as the starting material, and was coupled with benzene in the presence of trifluoroacetic acid and cuprous chloride to obtain 4-bromo-2-fluorobiphenyl (5); compound 5 was subjected to Kumada cross-coupling with racemic methyl 2-bromopropionate in the presence of a nickel catalyst to obtain methyl 2-(2-fluoro-4-biphenyl)propionate (20); compound 20 was hydrolyzed to obtain the target product flurbiprofen. In this process route, the starting material compound 19 is not easy to obtain, the coupling reaction yield is low, and the metal catalyst is expensive. The process route of this preparation method is as follows:

[0021]

[0022] Wang Yifeng et al. reported a method for synthesizing arylpropionic acid nonsteroidal anti-inflammatory drugs (CN107137387A, patent granted): 2-(2-fluoro-4-biphenyl)acetonitrile (21) was used as the starting material, and methyl iodide was reacted with the methylation reaction to obtain 2-(2-fluoro-4-biphenyl)acetonitrile (22); compound 22 was hydrolyzed to obtain the target product flurbiprofen. This process route is simple to operate and convenient for post-processing, but the starting material compound 21 is expensive, and the reagents such as methyl iodide are highly toxic. The process route of this synthesis method is as follows:

[0023]

[0024] Taniguchi et al. reported a synthesis process for flurbiprofen in the article "Carboxylation of Unsaturated Hydrocarbons with CO2 Catalyzed by Modified Supported Nickel Materials": 2-fluorophenylvinylene (24) was used as the starting material, and in the presence of a palladium catalyst and p-toluenesulfonamide, it reacted with carbon monoxide to directly synthesize the target product, flurbiprofen, in one step. This process is short, but the starting material, compound 24, is expensive and difficult to obtain, and requires high temperature and high pressure, making it unsuitable for industrial production. The process route of this synthesis method is as follows:

[0025]

[0026] Takeda et al. reported a method for preparing flurbiprofen (US4263457, patent expired): 1-(4-bromo-3-nitrophenyl)ethanone (24) was used as the starting material, and Ullmann coupling with benzene in the presence of cuprous iodide catalysis gave 1-(2-nitro-4-biphenyl)ethanone (25); compound 25 was reduced to give 1-(2-amino-4-biphenyl)ethanone (26); compound 26 was subjected to Balz-Schiemann diazotization and fluorination to give 1-( 2-fluoro-4-biphenyl) ethyl ketone (27); compound 27 undergoes Willgerodt-Kindle rearrangement to obtain ethyl 2-(2-fluoro-4-biphenyl) acetate (1), compound 1 reacts with diethyl carbonate under strong alkaline conditions to obtain ethyl 2-(2-fluoro-4-biphenyl) malonate (2); compound 2 undergoes methylation reaction with methyl iodide to obtain ethyl 2-(2-fluoro-4-biphenyl)-2-methyl malonate (3); compound 3 is hydrolyzed and decarboxylated to obtain the target product flurbiprofen. This process route has long steps, cumbersome operations, low yield, and is not suitable for industrial production. The process route of this preparation method is as follows:

[0027]

[0028] Stahly et al. reported a method for preparing flurbiprofen (US4370278, patent expired): 1-Fluoro-2-nitrobenzene (28) was used as the starting material, and a substitution reaction with 2-chloropropionitrile (chirality not indicated in the original text) was performed to obtain 2-(3-fluoro-4-nitrophenyl)propionitrile (29); compound 29 was reduced to obtain 2-(3-fluoro-4-aminophenyl)propionitrile (30); compound 30 underwent a Gomberg-Bachman coupling reaction with benzene to obtain 2-(2-fluoro-4-biphenyl)propionitrile (31); and compound 31 was hydrolyzed to obtain the target product flurbiprofen. The starting material compound 28 in this process route is not easy to obtain, the yield is low, and it is not suitable for industrial production. The process route of this preparation method is as follows:

[0029]

[0030] Wang Xiuhua et al. reported a method for preparing flurbiprofen (CN112778115A, patent granted): 4-bromo-2-fluorobiphenyl (5) is used as a starting material, and trimethylsilyl acetylene undergoes Sonogashira coupling under the catalysis of a palladium complex to obtain 4-trimethylsilylethynyl-2-fluorobiphenyl (32); compound 32 is detrimentally treated with trimethylsilyl in an alkaline solution to obtain 4-ethynyl-2-fluorobiphenyl (33); compound 33 is reacted with nickel acetylacetonate as a catalyst and formic acid as a carboxylation and hydrogenation reagent to obtain the target product flurbiprofen. Metal catalysts such as palladium or nickel in this process route are expensive. The process route of this preparation method is as follows:

[0031]

[0032] Wang Zunyuan and others " A new synthesis method of flurbiprofen ” This article reports a synthesis process for flurbiprofen: 2-fluoroaniline (34) is used as the starting material and reacted with NBS to obtain 4-bromo-2-fluoroaniline (35); compound 35 undergoes Gomberg-Bachman coupling with benzene to obtain 4-bromo-2-fluorobiphenyl (5); compound 5 reacts with magnesium powder to prepare the Grignard reagent 2-fluoro-4-biphenyl magnesium bromide (7); compound 7 undergoes a substitution reaction with racemic sodium 2-bromopropionate and then acidifies to obtain the target product flurbiprofen. This process route has a low yield, and the preparation of the Grignard reagent requires anaerobic and anhydrous operation, which is relatively harsh. The process route of this synthesis method is as follows:

[0033]

[0034] In the article "A New Synthesis Process for (2-Fluoro-4-Biphenyl)acetonitrile," Chen Hengchang et al. reported a method for preparing flurbiprofen: 4-methyl-2-fluorobiphenyl (36) was used as the starting material and reacted with NBS to obtain 4-bromomethyl-2-fluorobiphenyl (37); compound 37 was substituted with sodium cyanide to obtain 2-(2-fluoro-4-biphenyl)acetonitrile (38); compound 38 was reacted with dimethyl carbonate and iodomethane and then acidified to obtain the target product flurbiprofen. This process route uses highly toxic substances such as sodium cyanide, which is not conducive to labor protection. The process route of this synthesis method is as follows:

[0035]

[0036] Zheng Gengxiu et al. reported a synthesis method for flurbiprofen in the article "Synthesis of Flurbiprofen": 4-bromo-2-fluorobiphenyl (5) was used as the starting material, which reacted with magnesium powder to prepare the Grignard reagent 2-fluoro-4-biphenyl magnesium bromide (7); compound 7 underwent a substitution reaction with acetaldehyde to obtain 2-fluoro-4-biphenyl ethanol (39), and compound 39 reacted with sodium cyanide and hydrolyzed to obtain the target product flurbiprofen. In this process route, the starting material compound 5 is cheap and easy to obtain, but highly toxic substances such as sodium cyanide are used, which is not conducive to labor protection. In addition, the preparation of the Grignard reagent requires anhydrous and oxygen-free conditions, and the conditions are relatively harsh. The process route of this synthesis method is as follows:

[0037]

[0038] Duan Haotian et al. reported a method for preparing flurbiprofen (CN112778127A, substantive examination): 4-bromo-2-fluorobiphenyl (5) was used as the starting material, which reacted with magnesium powder to prepare the Grignard reagent 2-fluoro-4-biphenyl magnesium bromide (7); in the presence of a palladium catalyst, compound 7 was coupled with racemic ethyl 2-bromopropionate to obtain ethyl 2-(2-fluoro-4-biphenyl) propionate (40); and compound 40 was hydrolyzed to obtain the target product flurbiprofen. The starting material of this process route, compound 5, was cheap and readily available, but the palladium catalyst and other components were expensive, and the yield was low. The process route of this preparation method is as follows:

[0039]

[0040] Mohar et al. reported the synthesis route of flurbiprofen in the article "Synthesis of Flurbiprofen": 4-bromo-2-fluorobiphenyl (5) is used as the starting material, which reacts with magnesium powder to prepare the Grignard reagent 2-fluoro-4-biphenyl magnesium bromide (7); compound 7 reacts with ethyl pyruvate to obtain 2-(2-fluoro-4-biphenyl)-2-hydroxy-propionic acid ethyl ester (41); compound 41 is dehydrated under acidic conditions to obtain 2-(2-fluoro-4-biphenyl) ethyl acrylate (42); compound 42 is reduced to obtain 2-(2-fluoro-4-biphenyl) ethyl propionate (40); compound 40 is hydrolyzed under alkaline conditions to obtain flurbiprofen sodium, and flurbiprofen sodium is acidified to obtain the target product flurbiprofen. In this process route, the starting material compound 5 is cheap and easy to obtain, but the reaction step of the Grignard reagent and ethyl pyruvate produces many impurities and low yield, and requires anhydrous and oxygen-free operation and high pressure operation, which are relatively harsh conditions. The process route of this synthesis method is as follows:

[0041] Summary of the Invention

[0042] The purpose of the present invention is to provide a method for preparing flurbiprofen with low cost and high purity. The preparation method of the present invention comprises the following steps: using 4-bromo-2-fluorobiphenyl as a raw material, reacting the raw material with magnesium powder to undergo a Grignard reaction to obtain 2-fluoro-4-biphenyl magnesium bromide (7); then reacting 2-fluoro-4-biphenyl magnesium bromide with the inexpensive and readily available chemical reagent N,N-dimethylacetamide to undergo a Bouveault reaction to obtain 2-fluoro-4-biphenyl acetone (27); in the presence of a base catalyst, reacting 2-fluoro-4-biphenyl acetone with (methoxymethyl)triphenylphosphonium chloride to produce an etherified product, which is then acidified to obtain 2-(2-fluoro-4-biphenyl) propionaldehyde (41); and finally, reacting 2-(2-fluoro-4-biphenyl) propionaldehyde with sodium chlorite and hydrogen peroxide to undergo a Pinnick oxidation to obtain racemic 2-(2-fluoro-4-biphenyl) propionic acid, i.e., flurbiprofen. The preparation method of the present invention has a total of four reaction steps, each of which is a classic chemical reaction. The obtained flurbiprofen has an HPLC purity of ≥99.5%. The materials are cheap and easily available, the operation is simple, the post-processing is convenient, and the product is suitable for industrial production.

[0043] In order to achieve the purpose of the present invention, the technical solution of the present invention is as follows:

[0044] 4-Bromo-2-fluorobiphenyl is used as a raw material and reacts with magnesium powder to produce 2-fluoro-4-biphenyl magnesium bromide (7); 2-fluoro-4-biphenyl acetone (27) is subjected to substitution acidolysis with the inexpensive and readily available chemical reagent N,N-dimethylacetamide to remove ethylenediamine and undergo Bouveault reaction; 2-fluoro-4-biphenyl acetone and (methoxymethyl)triphenylphosphonium chloride undergo Wittig reaction in the presence of a base catalyst to produce an etherified product which is acidolyzed to produce 2-(2-fluoro-4-biphenyl) propionaldehyde (41); 2-(2-fluoro-4-biphenyl) propionaldehyde undergoes Pinnick oxidation reaction with sodium chlorite and hydrogen peroxide to produce racemic 2-(2-fluoro-4-biphenyl) propionic acid, i.e., flurbiprofen. The preparation method of the present invention has a total of four reaction steps, each of which is a classic chemical reaction. The obtained flurbiprofen has an HPLC purity of ≥99.5%. The materials are cheap and easily available, the operation is simple, the post-processing is convenient, and the product is suitable for industrial production.

[0045] The preparation process route involved in the present invention is as follows:

[0046]

[0047] The preparation process route involved in the present invention is described as follows: the first step in the route, in which 4-bromo-2-fluorobiphenyl (5) is used as a raw material and reacts with magnesium powder to undergo a Grignard reaction to prepare the Grignard reagent 2-fluoro-4-biphenyl magnesium bromide (7), has been reported in the literature (Chan LK, Gray GW, Lacey D., et al. Synthesis and liquid crystal behaviour offurther 4,4"-disubstituted 2'-fluoro-1,1',4', 1"-terphenyls[J]. Molecularcrystals and liquid crystals(1969-1991), 1988, vol. 158, p. 209-240). The relevant reports on the remaining steps and processes have not been retrieved from databases such as Reaxys, SciFind, and CNKI.

[0048] The gist of the present invention lies in a chemical synthesis preparation method, the principle of which is: 4-bromo-2-fluorobiphenyl (5) is used as a raw material, and undergoes a Grignard reaction with magnesium powder to prepare a Grignard reagent 2-fluoro-4-biphenyl magnesium bromide (7); the obtained Grignard reagent 2-fluoro-4-biphenyl magnesium bromide undergoes a Bouveault reaction with N,N-dimethylacetamide to obtain 2-fluoro-4-biphenyl acetone (27); under the action of an alkali catalyst, 2-fluoro-4-biphenyl acetone undergoes a Wittig reaction with (methoxymethyl)triphenylphosphonium chloride, and the obtained olefin ether is acidified to obtain 2-(2-fluoro-4-biphenyl) propionaldehyde (41); 2-(2-fluoro-4-biphenyl) propionaldehyde undergoes a Pinnick oxidation with sodium chlorite and hydrogen peroxide to obtain flurbiprofen.

[0049] Compared with the existing technology, the flurbiprofen preparation method of the present invention has the following advantages:

[0050] (1) Cheap and readily available materials: 4-bromo-2-fluorobiphenyl, N,N-dimethylacetamide, (methoxymethyl)triphenylphosphonium chloride and sodium chlorite are used as raw materials, without the use of highly toxic reagents and expensive metal catalysts (such as palladium, nickel, etc.);

[0051] (2) Each step of the process is a classic reaction: the process has four steps, the first step is the Grignard reaction, the second step is the Bouveault reaction, the third step is the Wittig reaction, and the fourth step is the Pinnick oxidation reaction. Each step is a classic reaction, and the reaction mechanism has been elucidated;

[0052] (3) The process is safe and easy to operate: No high-temperature and high-pressure equipment is used in the process. The process is safe and controllable, the operation is simple, the post-processing is convenient, and the obtained product has high purity, which is suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0053] Attachment Figure 1 This is the H NMR spectrum of flurbiprofen.

[0054] Attachment Figure 2 This is the C-NMR spectrum of flurbiprofen.

[0055] Attachment Figure 3 This is the LC-MS spectrum of flurbiprofen. DETAILED DESCRIPTION

[0056] The present invention is described in detail below with reference to specific embodiments. The following embodiments will help those skilled in the art to further understand the present invention, but do not limit the present invention in any form. It should be pointed out that, for those skilled in the art, several variations or improvements can be made without departing from the concept of the present invention, and these all fall within the scope of protection of the present invention.

[0057] Example 1

[0058] Step (1) Preparation of 2-fluoro-4-biphenyl magnesium bromide (7)

[0059] Under nitrogen, add magnesium turnings (4.8 g, 0.2 mol, 1.0 eq), two iodine pellets, and 100 ml of anhydrous tetrahydrofuran to a 1 L three-necked round-bottom flask equipped with a thermometer, dropping funnel, and reflux condenser. Heat with a blow torch to initiate the reaction. Add 500 ml of an anhydrous tetrahydrofuran solution containing 4-bromo-2-fluorobiphenyl (50 g, 0.2 mol, 1.0 eq) dropwise over approximately 2–3 hours. After the addition is complete, maintain the temperature at 60–65°C and continue stirring for 1–2 hours until the magnesium turnings have largely disappeared. The resulting solution of 2-fluoro-4-biphenyl magnesium bromide in tetrahydrofuran is cooled to 0–5°C and used for the next reaction without further treatment.

[0060] Step (2) Preparation of 2-fluoro-4-biphenyl acetone (21)

[0061] Under nitrogen protection, N,N-dimethylacetamide (34.8 g, 0.4 mol, 2.0 eq) and anhydrous tetrahydrofuran (400 ml) were added to a 2 L three-necked round-bottom flask equipped with a thermometer, a dropping funnel, and a magnetic stirrer. The temperature was lowered to -5~0°C, and a tetrahydrofuran solution of 2-fluoro-4-biphenyl magnesium bromide (0.2 mol, 1.0 eq) obtained in step (1) was added dropwise over 2~2.5 h. After the addition was complete, the temperature was slowly raised to room temperature and stirring was continued for 3~5 h. TLC (petroleum ether:ethyl acetate = 10:1) was used for monitoring, and the reaction endpoint was the disappearance of the starting material in the reaction solution. The temperature was lowered to -5~0°C, and a 5% hydrochloric acid solution (about 300 ml) was added to quench the reaction. The pH was adjusted to 3~5, and the tetrahydrofuran solvent was recovered by concentration under reduced pressure. The residue was extracted with ethyl acetate (500 ml), and the aqueous phase was re-extracted with ethyl acetate (500 ml). The organic phases were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a yellow solid, which was recrystallized from methyl tert-butyl ether and petroleum ether. After drying at 55°C for 6 h, 32.2 g of 2-fluoro-4-biphenyl acetone as a light yellow solid was obtained, with a yield of about 75.5% and an HPLC purity of about 99.1%.

[0062] ESI-MS m / z 215.26[M+H] + .

[0063] 1 H-NMR(400 MHz, CDCl3) δ: 7.80(dd, J=8.0, 1.7 Hz, 1H), 7.74(dd, J=11.2, 1.7 Hz, 1H), 7.61-7.52(m, 3H), 7.51-7.39(m, 3H), 2.63(s, 3H).

[0064] 13 C-NMR(100 MHz, CDCl3) δ: 196.67, 161.07, 137.99, 137.92, 134.81,134.02, 131.09, 129.16, 129.13, 128.76, 128.65, 124.50, 124.46, 26.80.

[0065] Step (3) Preparation of 2-(2-fluoro-4-biphenyl)propanal (41)

[0066] Under nitrogen, (methoxymethyl)triphenylphosphonium chloride (96 g, 0.28 mol, 2.0 eq) and anhydrous ether (300 ml) were added to a 1 L three-necked round-bottom flask equipped with a thermometer, dropping funnel, and magnetic stirring. The temperature was then cooled to -5–0°C. Potassium tert-butoxide (31.4 g, 0.28 mol, 2.0 eq) was added portionwise. Stirring was continued for 1 h after the addition was complete. A solution of 2-fluoro-4-biphenylethanone (30 g, 0.14 mol, 1.0 eq) in anhydrous ether (200 ml) was then added dropwise to the reaction mixture over a 0.5–1 h period. After the addition was complete, the temperature was slowly warmed to room temperature and stirring was continued for 5–8 h. The reaction was monitored by TLC (petroleum ether:ethyl acetate = 8:1). The reaction was terminated when the starting material disappeared from the reaction mixture. The ether solvent was recovered by concentration under reduced pressure. The residue was added with purified water (500 ml) and extracted with ethyl acetate (300 ml). The aqueous phase was re-extracted with ethyl acetate (300 ml). The organic phases were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a yellow oil. To the resulting yellow oil was added approximately 300 ml of ether and stirred until completely dissolved. Approximately 30 ml of perchloric acid was added dropwise. The mixture was stirred at room temperature for 0.5 h and then poured into 500 ml of water and extracted with ethyl acetate (300 ml). The aqueous phase was re-extracted with ethyl acetate (300 ml). The organic phases were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a yellow solid. This solid was recrystallized from ethanol and n-heptane and dried at 55°C for 6 h to obtain 26 g of 2-(2-fluoro-4-biphenyl)propanal as a white solid, with a yield of approximately 81.4% and an HPLC purity of approximately 98.8%.

[0067] ESI-MS m / z 229.15[M+H] + .

[0068] 1 H-NMR (400 MHz, CDCl3) δ: 9.10(s, 1H), 7.84(dd, J=10.0, 2.5 Hz, 1H), 7.78(dd, J=14.6, 3.4 Hz, 1H), 7.60-7.54(m, 2H), 7.48-7.34(m, 4H), 4.07(s,1H), 1.49-1.44(m, 1H).

[0069] 13C-NMR(100 MHz, CDCl3) δ: 201.07, 160.05, 140.15, 140.07, 135.91,135.07, 132.67, 130.05, 128.52, 127.72, 123.63, 123.60, 117.44, 61.05, 14.21.

[0070] Step (4) Preparation of Flurbiprofen

[0071] To a 1 L three-necked round-bottom flask equipped with a thermometer, dropping funnel, and magnetic stirring, add 2-(2-fluoro-4-biphenyl)propanal (25.5 g, 0.11 mol, 1.0 eq), Na₂HPO₄·12H₂O (19.7 g, 55 mmol, 0.5 eq), 30% H₂O₂ (12.5 g, 0.11 mol, 1.0 eq), 300 mL of acetonitrile, and 100 mL of purified water. The temperature was lowered to 0–5°C. Then, a 300 mL aqueous solution containing NaClO₂ (19.9 g, 0.22 mol, 2.0 eq) was added dropwise over approximately 0.5–1 h. Stirring was continued for 3–5 h after the addition was complete. Monitor by TLC (petroleum ether:ethyl acetate = 8:1). The reaction was terminated when the starting material disappeared from the reaction mixture. NaSO₃ was added to decompose excess HClO and H₂O₂. Sodium bicarbonate solution was added to adjust the pH to 9–10. The acetonitrile solvent was recovered by concentrating under reduced pressure. The residue was added with approximately 300 mL of ethyl acetate and stirred at room temperature for 0.5 h. The mixture was separated, and the organic phase was collected. The aqueous phase was extracted with 300 mL of ethyl acetate, which was discarded and the aqueous phase was collected. The aqueous phase was adjusted to a pH of 3–5 with hydrochloric acid and extracted with approximately 300 mL of ethyl acetate. The organic phase was collected and extracted with approximately 300 mL of ethyl acetate. The organic phases were combined, washed with approximately 300 mL of saturated brine, and dried over anhydrous magnesium sulfate. The filtrate was filtered, and approximately 0.5 g of activated carbon was added. The mixture was stirred at reflux for 0.5 h. Celite was added to aid filtration. The filtrate was concentrated under reduced pressure to yield 27 g of a colorless oil (wet weight). Approximately 27 mL of ethanol was added and stirred until completely dissolved. The temperature was lowered to 0–5°C, and 135 mL of purified water was added dropwise to precipitate a large amount of white solid. The filter cake was collected by filtration and dried at 65°C for 6 h to obtain 23.2 g of white flurbiprofen solid with a yield of about 85.1% and a HPLC purity of about 99.7%.

[0072] ESI-MS m / z 245.24[M+H] + .

[0073] 1H-NMR(400 MHz, CDCl3) δ: 11.66(s, 1H), 7.61-7.54(m, 2H), 7.52-7.33(m,4H), 7.25-7.11(m, 2H), 3.82(dd, J=13.9, 6.9 Hz, 1H), 1.58(d, J=6.5 Hz, 3H).

[0074] 13 C-NMR(100 MHz, CDCl3) δ: 180.74, 161.04, 158.57, 141.05, 140.98,135.51, 131.04, 129.10, 129.07, 128.59, 127.85, 123.85, 115.63, 115.40,45.00, 18.09.

[0075] Example 2

[0076] Step (1) Preparation of 2-fluoro-4-biphenyl magnesium bromide (7)

[0077] Under nitrogen, a 2 L three-necked round-bottom flask equipped with a thermometer, dropping funnel, and reflux condenser was charged with magnesium turnings (13.2 g, 0.55 mol, 1.1 eq), 3 iodine pellets, approximately 1 ml of the initiator 1,2-dibromoethane, and 150 ml of anhydrous tetrahydrofuran. Heat was initiated with a blow torch. A 900 ml solution of anhydrous tetrahydrofuran solution containing 4-bromo-2-fluorobiphenyl (125 g, 0.5 mol, 1.0 eq) was then added dropwise over approximately 2–3 hours. After the addition was complete, the temperature was maintained at 60–65°C and stirring was continued for 1–2 hours until the magnesium turnings were essentially eliminated. The resulting solution of 2-fluoro-4-biphenyl magnesium bromide in tetrahydrofuran was cooled to 0–5°C and used for the next reaction without further treatment.

[0078] Step (2) Preparation of 2-fluoro-4-biphenyl acetone (21)

[0079] Under nitrogen protection, N,N-dimethylacetamide (65.3 g, 0.75 mol, 1.5 eq) and anhydrous tetrahydrofuran (600 ml) were added to a 3 L three-necked round-bottom flask equipped with a thermometer, a dropping funnel, and a magnetic stirrer. The temperature was lowered to -5~0°C, and a tetrahydrofuran solution of 2-fluoro-4-biphenyl magnesium bromide (0.5 mol, 1.0 eq) obtained in step (1) was added dropwise. The addition time was controlled to be 2~2.5 h. After the addition was complete, the temperature was slowly raised to room temperature and stirring was continued for 3~5 h. TLC (petroleum ether:ethyl acetate = 10:1) was used for monitoring. The reaction endpoint was the disappearance of the starting material in the reaction solution. The temperature was lowered to -5~0°C, and a 5% hydrochloric acid solution (about 700 ml) was added to quench the reaction. The pH was adjusted to 3~5, and the tetrahydrofuran solvent was recovered by concentration under reduced pressure. The residue was extracted with ethyl acetate (800 ml), and the aqueous phase was re-extracted with ethyl acetate (800 ml). The organic phases were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a yellow solid, which was recrystallized from ether and petroleum ether. After drying at 55°C for 6 h, 82.8 g of 2-fluoro-4-biphenyl acetone as a light yellow solid was obtained, with a yield of about 77.4% and an HPLC purity of about 99.3%.

[0080] ESI-MS m / z 215.09[M+H] + .

[0081] 1 H-NMR(400 MHz, CDCl3) δ: 7.73(dd, J=12, 4.4 Hz, 1H), 7.67(dd, J=12.2,2.1 Hz, 1H), 7.53-7.45(m, 3H), 7.43-7.32(m, 3H), 2.56(s, 3H).

[0082] 13 C-NMR(100 MHz, CDCl3) δ: 196.71, 161.12, 138.04, 137.97, 134.89,134.42, 131.21, 129.36, 129.17, 128.56, 128.39, 124.66, 124.58, 26.72.

[0083] Step (3) Preparation of 2-(2-fluoro-4-biphenyl)propanal (41)

[0084] Under nitrogen, (methoxymethyl)triphenylphosphonium chloride (96 g, 0.61 mol, 1.6 eq) and anhydrous tetrahydrofuran (600 ml) were added to a 2 L three-necked round-bottom flask equipped with a thermometer, dropping funnel, and magnetic stirring. The temperature was then cooled to -5–0°C. Potassium tert-butoxide (31.4 g, 0.28 mol, 1.6 eq) was added portionwise. Stirring was continued for 1 h after the addition was complete. A solution of 2-fluoro-4-biphenylethanone (82 g, 0.38 mol, 1.0 eq) in anhydrous ether (200 ml) was then added dropwise to the reaction mixture over a 0.5–1 h period. After the addition was complete, the temperature was slowly warmed to room temperature and stirring was continued for 5–8 h. The reaction was monitored by TLC (petroleum ether:ethyl acetate = 8:1). The reaction was terminated when the starting material disappeared from the reaction mixture. The tetrahydrofuran solvent was recovered by concentration under reduced pressure. The residue was added with purified water (500 ml) and extracted with ethyl acetate (500 ml). The aqueous phase was re-extracted with ethyl acetate (500 ml). The organic phases were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a yellow oil. To the resulting yellow oil was added approximately 500 ml of ether and stirred until completely dissolved. Approximately 90 ml of hydrobromic acid was added dropwise. The mixture was stirred at room temperature for 0.5 h, then poured into 500 ml of water and extracted with ethyl acetate (500 ml). The aqueous phase was re-extracted with ethyl acetate (500 ml). The organic phases were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a yellow solid. This solid was recrystallized from ethanol and n-heptane and dried at 55°C for 6 h to obtain 68.4 g of 2-(2-fluoro-4-biphenyl)propanal as a white solid, with a yield of approximately 78.9% and an HPLC purity of approximately 98.7%.

[0085] ESI-MS m / z 229.10[M+H] + .

[0086] 1 H-NMR(400 MHz, CDCl3) δ: 8.95(s, 1H), 7.94(dd, J=11.2, 3.7 Hz, 1H), 7.71(dd, J=11.6, 4.4 Hz, 1H), 7.60-7.54(m, 2H), 7.48-7.34(m, 4H), 4.07(m,1H), 1.49-1.44(d, J=12.1 Hz, 1H).

[0087] 13C-NMR(100 MHz, CDCl3) δ: 200.17, 159.45, 141.11, 141.07, 136.81,136.77, 133.14, 131.02, 129.42, 128.43, 124.27, 124.16, 118.27, 63.27, 15.08.

[0088] Step (4) Preparation of Flurbiprofen

[0089] To a 2 L three-necked round-bottom flask equipped with a thermometer, dropping funnel, and magnetic stirring, add 2-(2-fluoro-4-biphenyl)propanal (67 g, 0.29 mol, 1.0 eq), Na₂HPO₄·12H₂O (51.9 g, 0.145 mol, 1.0 eq), 30% H₂O₂ (50 g, 0.44 mol, 1.5 eq), 900 mL of acetonitrile, and 300 mL of purified water. The temperature was lowered to 0–5°C. Then, 400 mL of an aqueous solution containing NaClO₂ (39.4 g, 0.435 mol, 1.5 eq) was added dropwise over approximately 0.5–1 h. Stirring was continued for 3–5 h after the addition was complete. Monitor by TLC (petroleum ether:ethyl acetate = 8:1). The reaction was terminated when the starting material disappeared from the reaction mixture. NaSO₃ was added to decompose excess HClO and H₂O₂. Sodium bicarbonate solution was added to adjust the pH to 9–10. The acetonitrile solvent was recovered by concentrating under reduced pressure. The residue was added with approximately 500 mL of ethyl acetate and stirred at room temperature for 0.5 h. The mixture was separated, and the organic phase was collected. The aqueous phase was extracted with 500 mL of ethyl acetate, which was discarded and the aqueous phase was collected. The pH of the aqueous phase was adjusted to 3–5 with hydrochloric acid and extracted with approximately 500 mL of ethyl acetate. The organic phase was collected and extracted with approximately 500 mL of ethyl acetate. The combined organic phases were washed with approximately 300 mL of saturated brine and dried over anhydrous magnesium sulfate. The filtrate was filtered, and approximately 1.5 g of activated carbon was added. The mixture was stirred at reflux for 0.5 h. Celite was added to aid filtration. The filtrate was concentrated under reduced pressure to yield 85 g of a colorless oil. Approximately 85 mL of ethanol was added and stirred until completely dissolved. The temperature was then lowered to 0–5°C. 340 mL of purified water was then added dropwise to precipitate a large amount of white solid. The filter cake was collected by filtration and dried at 65°C for 6 h to obtain 60.1 g of white flurbiprofen solid with a yield of about 84.9% and an HPLC purity of about 99.5%.

[0090] ESI-MS m / z 245.14[M+H] + .

[0091] 1H-NMR(400 MHz, CDCl3) δ: 11.76(s, 1H), 7.69-7.61(m, 2H), 7.50-7.42(m,4H), 7.29-7.10(m, 2H), 3.69(dd, J=15.7, 4.8 Hz, 1H), 1.55(d, J=7.2 Hz, 3H).

[0092] 13 C-NMR(100 MHz, CDCl3) δ: 180.64, 161.24, 158.22, 141.13, 141.01,135.37, 131.07, 129.13, 129.07, 128.23, 127.15, 124.36, 115.43, 115.26,45.12, 18.01.

Claims

1. A method for preparing low-cost and high-purity flurbiprofen, characterized in that: The flurbiprofen is prepared by the following steps: (1) 4-Bromo-2-fluorobiphenyl is used as the raw material, and a Grignard reaction occurs with magnesium powder in a solvent to obtain 2-fluoro-4-biphenyl magnesium bromide; (2) In a solvent, 2-fluoro-4-biphenyl magnesium bromide and N,N-dimethylacetamide undergo Bouveault reaction to obtain 2-fluoro-4-biphenyl acetone; (3) In the presence of a base catalyst, 2-fluoro-4-biphenyl acetone and (methoxymethyl)triphenylphosphonium chloride undergo Wittig reaction to obtain an etherified product, which is then acid-hydrolyzed to obtain 2-(2-fluoro-4-biphenyl)propionaldehyde; (4) 2-(2-Fluoro-4-biphenyl)propionaldehyde undergoes Pinnick oxidation with sodium chlorite and hydrogen peroxide to produce flurbiprofen.

2. A method for preparing low-cost, high-purity flurbiprofen according to claim 1, wherein: The solvent in step 1 or step 2 is one of anhydrous tetrahydrofuran, anhydrous ether or anhydrous 2-methyltetrahydrofuran.

3. A method for preparing low-cost, high-purity flurbiprofen according to claim 1, wherein: In step 1, the molar equivalent ratio of 4-bromo-2-fluorobiphenyl to magnesium powder is 1.0:1.0-1.1, and the preferred molar equivalent ratio is 1.0:1.

05.

4. A method for preparing low-cost, high-purity flurbiprofen according to claim 1, characterized in that: In step 2, the molar equivalent ratio of 2-fluoro-4-biphenyl magnesium bromide to N,N-dimethylacetamide is 1.0:1.0-2.0, and the preferred molar equivalent ratio is 1.0:1.

5.

5. A method for preparing low-cost, high-purity flurbiprofen according to claim 1, characterized in that: In step 3, the base catalyst is one of potassium tert-butoxide, sodium tert-butoxide, sodium ethoxide, potassium ethoxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, lithium hydroxide, sodium hydride, and potassium hydride, preferably potassium tert-butoxide.

6. A method for preparing low-cost, high-purity flurbiprofen according to claim 1, characterized in that: In step 3, the molar equivalent ratio of 2-fluoro-4-biphenyl acetone to (methoxymethyl)triphenylphosphonium chloride is 1.0:1.6-2.0, and the preferred molar equivalent ratio is 1.0:1.

6.

7. A method for preparing low-cost, high-purity flurbiprofen according to claim 1, characterized in that: The acid in step 3 is one of sulfuric acid, nitric acid, hydrochloric acid, perchloric acid, permanganic acid, hydroiodic acid, hydrobromic acid and acetic acid.

8. A method for preparing low-cost, high-purity flurbiprofen according to claim 1, characterized in that: The molar equivalent ratio of 2-(2-fluoro-4-biphenyl)propanal to sodium chlorite and hydrogen peroxide in step 4 is 1.0:1.5-2.0:1.0-1.5, and the preferred molar equivalent ratio is 1.0:2.0:1.2.

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