Process for the synthesis of flurbiprofen and intermediates thereof

Abstract

The application discloses a synthesis method of flurbiprofen and an intermediate thereof. The intermediate of the flurbiprofen is 3-fluoro-4-biphenyl boronic pinacol ester, and the synthesis method comprises the following steps: step A: 2-fluoro-4-bromobiphenyl is subjected to a coupling reaction with bispinacolyl diboron under the action of an alkali and a metal catalyst to obtain 3-fluoro-4-biphenyl boronic pinacol ester. The synthesis method of the flurbiprofen comprises the following steps: step C: 3-fluoro-4-biphenyl boronic pinacol ester is subjected to a coupling reaction with sodium 2-bromopropionate under the action of an alkali and a metal catalyst, and then the obtained reaction product is acidified to obtain flurbiprofen. According to the application, 2-fluoro-4-bromobiphenyl is prepared into 3-fluoro-4-biphenyl boronic pinacol ester, and then the 3-fluoro-4-biphenyl boronic pinacol ester is subjected to a Suzuki coupling reaction with sodium 2-bromopropionate to prepare flurbiprofen, the method has less side reactions, and the molar yield is high, which is obviously higher than the yield in the literature of preparing flurbiprofen by means of Grignard reaction.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of drug synthesis, and specifically relates to a synthesis method of flurbiprofen and intermediates thereof. BACKGROUND

[0002] Flurbiprofen, chemically named as 2-(2-fluoro-4-biphenyl)-propionic acid, is a non-steroidal anti-inflammatory drug developed by British Boots Company, and has analgesic, anti-inflammatory and antipyretic effects. The anti-inflammatory effect of flurbiprofen is 250 times that of aspirin, and the analgesic effect is 50 times that of aspirin. Flurbiprofen has low toxicity and good tolerance, and is mainly clinically used for rheumatoid arthritis, osteoarthritis, ankylosing spondylitis and the like, and can also be used for the symptomatic treatment of soft tissue diseases (such as sprains and strains) and mild to moderate pain (such as menstrual pain and postoperative pain, toothache and the like). The structural formula is as follows:

[0003]

[0004] There are many reports on the synthesis method of flurbiprofen at home and abroad. However, many reaction steps are complicated, raw materials are difficult to be commercially obtained, the yield is low, impurities are many, the cost is high, and industrial production is not easy.

[0005] The mainstream process route for synthesizing the compound at present is as follows: 2-fluoro-4-bromoaniline is subjected to diazotization reaction, then coupled with benzene under alkaline conditions to obtain 2-fluoro-4-bromobiphenyl, and then subjected to Grignard reaction with 2-bromopropionic acid sodium to obtain flurbiprofen, and the synthesis route is as follows:

[0006]

[0007] The problems of the synthesis route are as follows:

[0008] (1) The yield of Grignard reaction is low, and the yield in the literature is only about 50%, and the reaction conditions are harsh and difficult to control, and there is a great safety hazard.

[0009] (2) Regardless of how the Grignard reaction is controlled, about 30% of the double-substituted impurities will be formed, which can be removed through purification, but seriously affects the yield. The structural formula of the double-substituted impurities is as follows:

[0010] SUMMARY

[0011] Based on this, the present application provides a synthesis method of flurbiprofen and intermediates thereof, and the yield of the method is high, which is significantly higher than the yield of flurbiprofen prepared by Grignard reaction in the literature.

[0012] The present application comprises the following technical solutions.

[0013] A method for synthesizing a flurbiprofen intermediate, 3-fluoro-4-biphenyl boronic acid pinacol ester, comprising the following steps:

[0014] Step A: coupling reaction of 2-fluoro-4-bromobiphenyl with bis(pinacolato)diboron in the presence of a base and a metal catalyst to obtain 3-fluoro-4-biphenyl boronic acid pinacol ester;

[0015] The reaction formula is as follows:

[0016]

[0017] In some embodiments, the metal catalyst in step A is a combination of one or more of a hexahydrate chloride and a palladium metal catalyst; the hexahydrate chloride is hexahydrate nickel chloride and / or hexahydrate cobalt chloride; and the palladium metal catalyst is Pd(PPh3)4, PdCl2(dppf), PdCl2(dtbpf), PdCl2(Amphos)2, and / or PdCl2(Pt-Bu3)2.

[0018] In some embodiments, the metal catalyst in step A is a combination of a hexahydrate chloride and a palladium metal catalyst.

[0019] In some embodiments, the metal catalyst in step A is a combination of hexahydrate nickel chloride and PdCl2(dppf).

[0020] In some embodiments, the metal catalyst in step A is a combination of hexahydrate cobalt chloride and PdCl2(dppf).

[0021] In some embodiments, the metal catalyst in step A is a combination of hexahydrate cobalt chloride, hexahydrate nickel chloride, and PdCl2(dppf).

[0022] In some embodiments, the molar ratio of the hexahydrate chloride to the 2-fluoro-4-bromobiphenyl in step A is 0.02-0.3:1.

[0023] In some embodiments, the molar ratio of the hexahydrate chloride to the 2-fluoro-4-bromobiphenyl in step A is 0.05-0.25:1.

[0024] In some embodiments, the molar ratio of the hexahydrate chloride to the 2-fluoro-4-bromobiphenyl in step A is 0.08-0.2:1.

[0025] In some embodiments, the molar ratio of the hexahydrate chloride to the 2-fluoro-4-bromobiphenyl in step A is 0.08-0.15:1.

[0026] In some of the embodiments, the molar ratio of the hexahydrate chloride to the 2-fluoro-4-bromo-biphenyl in step A is 0.09-0.12: 1.

[0027] In some of the embodiments, the molar ratio of the hexahydrate chloride to the 2-fluoro-4-bromo-biphenyl in step A is 0.1: 1.

[0028] In some of the embodiments, the molar ratio of the palladium metal catalyst to 2-fluoro-4-bromo-biphenyl in step A is (0.00001-0.005): 1.

[0029] In some of the embodiments, the molar ratio of the palladium metal catalyst to 2-fluoro-4-bromo-biphenyl in step A is (0.00003-0.0001): 1.

[0030] In some of the embodiments, the molar ratio of the palladium metal catalyst to 2-fluoro-4-bromo-biphenyl in step A is (0.00004-0.00006): 1.

[0031] In some of the embodiments, the molar ratio of the 2-fluoro-4-bromo-biphenyl to the bis(pinacolato)diboron in step A is 1: 1-1.5.

[0032] In some of the embodiments, the molar ratio of the 2-fluoro-4-bromo-biphenyl to the bis(pinacolato)diboron in step A is 1: 1-1.3.

[0033] In some of the embodiments, the base in step A is a combination of one or more of sodium bicarbonate, potassium bicarbonate, potassium phosphate, potassium carbonate, potassium acetate, and sodium acetate.

[0034] In some of the embodiments, the solvent for the coupling reaction in step A is a combination of one or more of ethanol, toluene, tetrahydrofuran, dimethylformamide, dioxane, ethylene glycol dimethyl ether.

[0035] In some of the embodiments, the molar ratio of the 2-fluoro-4-bromo-biphenyl to the base in step A is 1: 0.8-3.

[0036] In some of the embodiments, the molar ratio of the 2-fluoro-4-bromo-biphenyl to the base in step A is 1: 0.9-2.

[0037] In some of the embodiments, the molar ratio of the 2-fluoro-4-bromo-biphenyl to the base in step A is 1: 0.9-1.1.

[0038] In some of the embodiments, the mass to volume ratio of the 2-fluoro-4-bromo-biphenyl to the solvent in step A is 1 g: (2-5) ml.

[0039] In some embodiments, the temperature of the coupling reaction in step A is 65-85°C.

[0040] In some embodiments, the temperature of the coupling reaction in step A is 70-80°C.

[0041] In some embodiments, the time of the coupling reaction in step A is 1-5h.

[0042] In some embodiments, the time of the coupling reaction in step A is 2-3h.

[0043] In some embodiments, the addition of the double pinacolylboron in step A is by slow addition in batches, and the addition time is 1-2h.

[0044] In some embodiments, the method for synthesizing the flurbiprofen intermediate comprises the following steps: adding the 2-fluoro-4-bromobiphenyl, metal catalyst, base and solvent into a reaction bottle, warming to 70-80°C, slowly adding the double pinacolylboron in batches, and the addition time is 1-2h, after the addition is completed, reacting at 70-80°C, to obtain the 3-fluoro-4-biphenylboronic acid pinacol ester.

[0045] In some embodiments, the method for synthesizing the flurbiprofen intermediate further comprises the following steps for preparing 2-fluoro-4-bromobiphenyl: subjecting 2-fluoro-4-bromoaniline to diazotization reaction, and then coupling with benzene to obtain 2-fluoro-4-bromobiphenyl.

[0046] In some embodiments, the method for synthesizing the flurbiprofen intermediate further comprises the following steps for preparing 2-fluoro-4-bromobiphenyl: adding sodium nitrite, water and isopropyl alcohol into a reaction bottle, adding concentrated hydrochloric acid dropwise at a temperature of 10-30°C, and reacting at the same temperature for 1-2h, separating the reaction liquid into layers, and taking the organic phase; adding the 2-fluoro-4-bromoaniline, catalyst and benzene into another reaction bottle, adding the organic phase dropwise at a temperature of 10-30°C, and reacting at the same temperature for 1-2h to obtain 2-fluoro-4-bromobiphenyl.

[0047] In some embodiments, the molar ratio of the 2-fluoro-4-bromoaniline and benzene in the step of preparing 2-fluoro-4-bromobiphenyl is 1:(5.0-10.0).

[0048] In some embodiments, the catalyst in the step of preparing 2-fluoro-4-bromobiphenyl is copper chloride.

[0049] In some embodiments, the molar ratio of the 2-fluoro-4-bromoaniline and copper chloride in the step of preparing 2-fluoro-4-bromobiphenyl is 1:0.05-0.15.

[0050] In some embodiments, the molar ratio of sodium nitrite and isopropanol is 1:1.8-2.2; the volume ratio of water and isopropanol is 1:1.5-2; the volume ratio of water and concentrated hydrochloric acid is 1:0.8-1.2.

[0051] In some embodiments, the mass concentration of the concentrated hydrochloric acid is 36%-38%.

[0052] The present application also provides a synthesis method of flurbiprofen, comprising the following steps:

[0053] Step C: 3-fluoro-4-biphenylboronic acid pinacol ester is coupled with sodium 2-bromopropionate in the presence of a base and a metal catalyst, and the obtained reaction product is acidified to obtain flurbiprofen;

[0054] The reaction formula is as follows:

[0055]

[0056] In some embodiments, the synthesis method of flurbiprofen further comprises the steps of synthesizing the intermediate of flurbiprofen according to the present application.

[0057] In some embodiments, the metal catalyst in step C is a combination of one or more of hexahydrate chloride and palladium metal catalysts; the hexahydrate chloride is hexahydrate nickel chloride and / or hexahydrate cobalt chloride; and the palladium metal catalyst is Pd(PPh3)4, PdCl2(dppf), PdCl2(dtbpf), PdCl2(Amphos)2, and / or PdCl2(Pt-Bu3)2.

[0058] In some embodiments, the metal catalyst in step C is a combination of hexahydrate chloride and palladium metal catalysts.

[0059] In some embodiments, the metal catalyst in step C is a combination of hexahydrate nickel chloride and PdCl2(dppf).

[0060] In some embodiments, the metal catalyst in step C is a combination of hexahydrate cobalt chloride and PdCl2(dppf).

[0061] In some embodiments, the metal catalyst in step C is a combination of hexahydrate cobalt chloride, hexahydrate nickel chloride, and PdCl2(dppf).

[0062] In some embodiments, the molar ratio of the hexahydrate chloride to the 3-fluoro-4-biphenylboronic acid pinacol ester in step C is 0.02-0.3:1.

[0063] In some of the embodiments, the molar ratio of the hexahydrate chloride to the 3-fluoro-4-biphenylboronic acid pinacol ester in step C is 0.05-0.25:1.

[0064] In some of the embodiments, the molar ratio of the hexahydrate chloride to the 3-fluoro-4-biphenylboronic acid pinacol ester in step C is 0.08-0.2:1.

[0065] In some of the embodiments, the molar ratio of the hexahydrate chloride to the 3-fluoro-4-biphenylboronic acid pinacol ester in step C is 0.08-0.15:1.

[0066] In some of the embodiments, the molar ratio of the hexahydrate chloride to the 3-fluoro-4-biphenylboronic acid pinacol ester in step C is 0.09-0.12:1.

[0067] In some of the embodiments, the molar ratio of the hexahydrate chloride to the 3-fluoro-4-biphenylboronic acid pinacol ester in step C is 0.1:1.

[0068] In some of the embodiments, the molar ratio of the palladium metal catalyst to the 3-fluoro-4-biphenylboronic acid pinacol ester in step C is (0.00001-0.005):1.

[0069] In some of the embodiments, the molar ratio of the palladium metal catalyst to the 3-fluoro-4-biphenylboronic acid pinacol ester in step C is (0.00003-0.0001):1.

[0070] In some of the embodiments, the molar ratio of the palladium metal catalyst to the 3-fluoro-4-biphenylboronic acid pinacol ester in step C is (0.00004-0.00006):1.

[0071] In some of the embodiments, the molar ratio of the 3-fluoro-4-biphenylboronic acid pinacol ester to the sodium 2-bromopropionate in step C is 1:1-1.5.

[0072] In some of the embodiments, the molar ratio of the 3-fluoro-4-biphenylboronic acid pinacol ester to the sodium 2-bromopropionate in step C is 1:1-1.3.

[0073] In some of the embodiments, the molar ratio of the 3-fluoro-4-biphenylboronic acid pinacol ester to the base in step C is 1:0.8-3.

[0074] In some of the embodiments, the molar ratio of the 3-fluoro-4-biphenylboronic acid pinacol ester to the base in step C is 1:0.9-2.

[0075] In some embodiments, the molar ratio of 3-fluoro-4-biphenylboronic acid pinacol ester to base in step C is 1:0.9-1.1.

[0076] In some embodiments, the base in step C is a combination of one or more of sodium bicarbonate, potassium bicarbonate, potassium phosphate, potassium carbonate, potassium acetate and sodium acetate.

[0077] In some embodiments, the solvent of the coupling reaction in step C is a combination of water and an organic solvent, wherein the organic solvent is a combination of one or more of ethanol, toluene, tetrahydrofuran, dimethylformamide, dioxane and ethylene glycol dimethyl ether.

[0078] In some embodiments, the mass ratio of sodium 2-bromopropionate to water in step C is 1:1.5-2.5.

[0079] In some embodiments, the mass-volume ratio of 3-fluoro-4-biphenylboronic acid pinacol ester to organic solvent in step C is 1g:(2-5)ml.

[0080] In some embodiments, the temperature of the coupling reaction in step C is 65℃-85℃.

[0081] In some embodiments, the temperature of the coupling reaction in step C is 70℃-80℃.

[0082] In some embodiments, the time of the coupling reaction in step C is 1h-5h.

[0083] In some embodiments, the time of the coupling reaction in step C is 2h-3h.

[0084] In some embodiments, the 3-fluoro-4-biphenylboronic acid pinacol ester in step C is added in a slow batch manner, and the addition time is 1-2h.

[0085] In some embodiments, the synthesis method of the flurbiprofen comprises the following steps: adding sodium 2-bromopropionate, water, a metal catalyst, a base and an organic solvent in a reaction bottle, heating to 70℃-80℃, slowly adding 3-fluoro-4-biphenylboronic acid pinacol ester in batches, the addition time is 1-2h, after the addition is completed, reacting at 70℃-80℃, and then obtaining flurbiprofen after acidification of the obtained reaction product.

[0086] The synthesis method of flurbiprofen and its intermediates of the present application has the following advantages:

[0087] 1. The present application prepares 3-fluoro-4-biphenyl boronic acid pinacol ester from 2-fluoro-4-bromobiphenyl, and then performs Suzuki coupling reaction with sodium 2-bromopropionate to prepare flurbiprofen, which has less side reactions, high molar yield, and is obviously higher than the yield of flurbiprofen prepared by Grignard reaction in the literature.

[0088] 2. Further, the addition of the double pinacolyl diboron and 3-fluoro-4-biphenyl boronic acid pinacol ester is in the form of batch slow addition, which avoids the occurrence of polysubstitution reaction, thereby further improving the reaction yield.

[0089] 3. The addition of nickel chloride hexahydrate and / or cobalt chloride hexahydrate in the Suzuki coupling reaction can reduce the amount of alkali, thereby avoiding the generation of self-coupling impurities, achieving the effect of further reducing impurities and improving yield.

[0090] 4. By adjusting the proportion of the reaction solvent, the use amount of metal catalyst can be effectively reduced, and the synthesis cost is saved.

[0091] 5. The raw materials are widely available and can be obtained commercially; the reaction conditions are mild and easy to control, which is conducive to industrial production. BRIEF DESCRIPTION OF DRAWINGS

[0092] Figure 1 The nuclear magnetic resonance hydrogen spectrum of flurbiprofen prepared in Example 3 of the present application.

[0093] Figure 2 The nuclear magnetic resonance carbon spectrum of flurbiprofen prepared in Example 3 of the present application.

[0094] Figure 3 The LCMS spectrum of flurbiprofen prepared in Example 3 of the present application.

[0095] The LCMS spectrum has a molecular weight of 244.10, which is consistent with the molecular weight of the target compound 244.27, and through the analysis of the nuclear magnetic resonance hydrogen spectrum and the nuclear magnetic resonance carbon spectrum, it is also proved that the compound obtained by the present application is flurbiprofen. DETAILED DESCRIPTION

[0096] The technical solutions of the present application will be further described below through specific examples. Those skilled in the art should understand that the examples are only to help understand the present application, and should not be regarded as a specific limitation of the present application.

[0097] Unless otherwise defined, all technical and scientific terms used in the present application have the same meaning as understood by those skilled in the art to which the present application belongs. The terms used in the specification of the present application are only for the purpose of describing the specific examples, and are not used to limit the present application.

[0098] The terms "comprising" and "having" and any variations thereof in the present invention are intended to cover a non-exclusive inclusion. For example, a process, method, article, or apparatus that comprises a list of steps or modules is not necessarily limited to those listed steps or modules, but can optionally include additional steps or modules not expressly listed or can optionally include steps or modules inherent to such process, method, article, or apparatus.

[0099] "Multiple" mentioned in the present invention refers to two or more. "And / or", which describes the association relationship of associated objects, means that there can be three relationships, for example, A and / or B can mean that A exists alone, A and B exist together, and B exists alone. The character " / " generally represents that the associated objects before and after it are in an "or" relationship.

[0100] The following is a specific example.

[0101] Example 1

[0102] (1) Synthesis of 2-fluoro-4-bromobiphenyl

[0103]

[0104] In a 500ml reaction bottle, 62.1g (0.9mol) of sodium nitrite, 80ml of water, and 138ml (1.8mol) of isopropyl alcohol were added. The temperature was controlled at 10-30°C, and 80ml of 37% hydrochloric acid was added dropwise. After the dropwise addition was completed, the reaction was carried out at the same temperature for 1.5 hours. The reaction solution was separated into layers, and the organic phase was taken for use.

[0105] In a 500ml reaction bottle, 40g (0.21mol) of 2-fluoro-4-bromoaniline, 2.72g (0.02mol) of copper chloride, and 120ml (1.35mol) of benzene were added. The temperature was controlled at 10-30°C, and the above-mentioned organic phase was added dropwise. After the dropwise addition was completed, the reaction was carried out at the same temperature for 1.5 hours. Filtration was performed, and the filtrate was washed with 400ml of water. The organic phase was concentrated to dryness, and then recrystallized with 120ml of methanol to obtain the target compound 2-fluoro-4-bromobiphenyl 48.2g, with a molar yield of 91.4%.

[0106] HNMR (DMSO-d6): δ 7.31-7.55 (8H, m).

[0107] (2) Synthesis of 3-fluoro-4-biphenylboronic acid pinacol ester

[0108]

[0109] Into a 1000ml reaction flask, was placed 40g (0.16mol) of 2-fluoro-4-bromobiphenyl, 31.2g (0.32mol) of potassium acetate, 120ml of dioxane, 0.0058g (0.008mmol) of [l,l'-bis(diphenylphosphino)ferrocene]dichloropalladium (PdCl2(dppf)). After warming to 80°C, 48.5g (0.19mol) of bis(pinacolato)diboron was added slowly in portions over a period of 1.5h. After the addition was completed, the reaction was allowed to proceed for 2.5h at the same temperature. The reaction was concentrated to dryness, and then 400ml of dichloromethane was added and stirred for 25min. The reaction was filtered, and the filtrate was concentrated to dryness. 200ml of n-heptane was added and stirred for 1h to obtain the target compound, 3-fluoro-4-biphenylboronic acid pinacol ester, 37.0g, in 77.5% molar yield.

[0110] HNMR (CDC13): δ 1.36 (s, 12H), 7.37 (m, IH), 7.42-7.47 (m, 3H), 7.56-7.59 (m, 3H), 7.63 (dd, J = 7.6, 1.0 Hz, IH).

[0111] (3) Synthesis of flurbiprofen

[0112]

[0113] Into a 1000ml three-necked flask, was placed 25.8g (0.15mol) of 2-bromopropionic acid sodium salt, 51.6g of water, 26.4g (0.27mol) of potassium acetate, 120ml of dioxane, 0.0049g (0.007mmol) of PdCl2(dppf). After warming to 70°C, 40g (0.134mol) of 3-fluoro-4-biphenylboronic acid pinacol ester was added slowly in portions over a period of 1.5h. After the addition was completed, the reaction was allowed to proceed for 2.5h at the same temperature. 2g of acetylcysteine was added and stirred for 1h at the same temperature. The reaction was filtered, and the filtrate was concentrated to dryness. 200ml of ethyl acetate, 4g of tributylphosphine, 200ml of water were added, and stirred for 1h. The aqueous layer was separated, and washed with 200ml of ethyl acetate once. 2g of activated carbon was added to the aqueous layer and stirred for 0.5h. The reaction was filtered, and the aqueous layer was separated. The pH of the aqueous layer was adjusted to 2-3 with concentrated hydrochloric acid, and stirred for 1h at 35°C, and then stirred for 1h at 5°C. The reaction was filtered, and the target compound, flurbiprofen, was obtained as a white solid. The solid was dissolved in 200ml of methyl tert-butyl ether and stirred for 25min. 200ml of water was added and stirred for 25min. The organic layer was separated, and concentrated to dryness. The target compound, flurbiprofen, was recrystallized from 200ml of cyclohexane. The yield of flurbiprofen was 26.1g in 79.7% molar yield, and the purity was 99.3%.

[0114] Example 2

[0115] (1) Synthesis of 2-fluoro-4-bromobiphenyl

[0116]

[0117] In a 500ml reaction flask, add 62.1g (0.9mol) sodium nitrite, 80ml water, 138ml (1.8mol) isopropyl alcohol. Control the temperature at 10-30°C, and drop 80ml 37% hydrochloric acid. After dropping, react at the same temperature for 1.5 hours. Separate the organic phase for later use.

[0118] In a 500ml reaction flask, add 40g (0.21mol) 2-fluoro-4-bromoaniline, 2.72g (0.02mol) copper chloride, 120ml (1.35mol) benzene. Control the temperature at 10-30°C, and drop the above organic phase. After dropping, react at the same temperature for 1.5 hours. Filter, and wash the filtrate with 400ml water. Concentrate the organic phase to dryness, then recrystallize with 120ml methanol to obtain the target compound 2-fluoro-4-bromobiphenyl 47.8g, with a molar yield of 90.5%.

[0119] (2) Synthesis of 3-fluoro-4-biphenylboronic acid pinacol ester

[0120]

[0121] Under nitrogen protection, in a 1000ml reaction flask, add 40g (0.16mol) 2-fluoro-4-bromobiphenyl, 2.35g (0.016mol) nickel chloride hexahydrate, 15.6g (0.16mol) potassium acetate, 120ml dioxane, 0.0058g (0.008mmol) PdCl2(dppf). After warming to 80°C, slowly add 48.5g (0.19mol) bispinacolyl diboron in batches, about 1.5h. After adding, react at the same temperature for 2.5h. Concentrate the reaction liquid to dryness, then add 400ml dichloromethane and stir for 25min. Filter, concentrate the filtrate to dryness, add 200ml n-heptane and beat for 1h to obtain the target compound 3-fluoro-4-biphenylboronic acid pinacol ester 45.1g, with a molar yield of 95.0%.

[0122] (3) Synthesis of flurbiprofen

[0123]

[0124] In a 1000ml flask, 25.8g (0.15mol) of 2-bromopropionic acid sodium salt, 51.6g of water, 1.98g (0.013mol) of nickel chloride hexahydrate, 13.2g (0.135mol) of potassium acetate, 120ml of dioxane, 0.0049g (0.007mmol) of PdCl2(dppf) were added under nitrogen protection. After the temperature was raised to 70°C, 40g (0.134mol) of 3-fluoro-4-biphenylboronic acid pinacol ester was added slowly in batches for about 1.5h. After the addition was completed, the reaction was continued at the same temperature for 2.5h. 2g of acetylcysteine was added and stirred at the same temperature for 1h. Filtration was performed and the filtrate was concentrated to no liquid outflow. 200ml of ethyl acetate, 4g of tributylphosphine, 200ml of water were added, and after stirring for 1h, the layers were separated, and the aqueous phase was taken and washed with 200ml of ethyl acetate once. 2g of activated carbon was added to the aqueous phase and stirred for 0.5h, then filtered and the aqueous phase was taken. The pH of the aqueous phase was adjusted to 2-3 with concentrated hydrochloric acid, stirred at 35°C for 1h, then stirred at 5°C for 1h, and suction filtration was performed to obtain a white solid. The solid was added with 200ml of methyl tert-butyl ether and stirred for 25min, then 200ml of water was added and stirred for 25min, and the layers were separated to obtain the organic phase. The organic phase was concentrated to dryness, and then recrystallized with 200ml of cyclohexane to obtain the target compound flurbiprofen 28.2g, with a molar yield of 86.0% and a purity of 99.3%.

[0125] Example 3

[0126] (1) Synthesis of 2-fluoro-4-bromobiphenyl

[0127]

[0128] In a 500ml reaction bottle, 62.1g (0.9mol) of sodium nitrite, 80ml of water, 138ml (1.8mol) of isopropyl alcohol were added. The temperature was controlled at 10-30°C, and 80ml of 37% hydrochloric acid was added dropwise. After the dropwise addition was completed, the reaction was continued at the same temperature for 1.5h. The reaction liquid was separated, and the organic phase was taken for use.

[0129] In a 500ml reaction bottle, 40g (0.21mol) of 2-fluoro-4-bromoaniline, 2.72g (0.02mol) of copper chloride, 120ml (1.35mol) of benzene were added. The temperature was controlled at 10-30°C, and the above-mentioned organic phase was added dropwise. After the dropwise addition was completed, the reaction was continued at the same temperature for 1.5h. Filtration was performed, and the filtrate was washed with 400ml of water. The organic phase was concentrated to dryness, and then recrystallized with 120ml of methanol to obtain the target compound 2-fluoro-4-bromobiphenyl 48.1g, with a molar yield of 91.0%.

[0130] (2) Synthesis of 3-fluoro-4-biphenylboronic acid pinacol ester

[0131]

[0132] In a 1000ml reaction flask, 40g (0.16mol) 2-fluoro-4-bromobiphenyl, 2.35g (0.016mol) cobalt chloride hexahydrate, 15.6g (0.16mol) potassium acetate, 120ml dioxane, 0.0058g (0.008mmol) PdCl2(dppf) were added under nitrogen protection. After warming to 80°C, 48.5g (0.19mol) bis(pinacolato)diboron was added slowly in batches for about 1.5h. After the addition was completed, the reaction was carried out at the same temperature for 2.5h. The reaction solution was concentrated to dryness, then 400ml dichloromethane was added and stirred for 25min. Filtration was performed, the filtrate was concentrated to dryness, 200ml n-heptane was added and stirred for 1h to obtain the target compound 3-fluoro-4-biphenylboronic acid pinacol ester 45.2g, with a molar yield of 95.2%.

[0133] (3) Synthesis of flurbiprofen

[0134]

[0135] In a 1000ml three-necked flask, 25.8g (0.15mol) 2-bromopropionic acid sodium, 51.6g water, 1.98g (0.013mol) cobalt chloride hexahydrate, 13.2g (0.135mol) potassium acetate, 120ml dioxane, 0.0049g (0.007mmol) PdCl2(dppf) were added under nitrogen protection. After warming to 70°C, 40g (0.134mol) 3-fluoro-4-biphenylboronic acid pinacol ester was added slowly in batches for about 1.5h. After the addition was completed, the reaction was carried out at the same temperature for 2.5h. 2g acetylcysteine was added and stirred at the same temperature for 1h. Filtration was performed, the filtrate was concentrated to dryness. 200ml ethyl acetate, 4g tributylphosphine, 200ml water were added, after stirring for 1h, the layers were separated, the aqueous phase was taken and washed with 200ml ethyl acetate once. 2g activated carbon was added to the aqueous phase and stirred for 0.5h, then filtration was performed and the aqueous phase was taken. The pH of the aqueous phase was adjusted to 2-3 with concentrated hydrochloric acid, stirred at 35°C for 1h, then stirred at 5°C for 1h, and then suction filtration was performed to obtain a white solid. The solid was added to 200ml methyl tert-butyl ether and stirred for 25min, 200ml water was added and stirred for 25min, then the layers were separated and the organic phase was taken. The organic phase was concentrated to dryness, then recrystallized with 200ml cyclohexane to obtain the target compound flurbiprofen 29.3g, with a molar yield of 89.6% and a purity of 99.5%.

[0136] Example 4

[0137] (1) Synthesis of 2-fluoro-4-bromobiphenyl

[0138]

[0139] In a 500ml reaction flask, add 62.1g (0.9mol) sodium nitrite, 80ml water, 138ml (1.8mol) isopropyl alcohol. Control the temperature at 10-30°C, and drop 80ml 37% hydrochloric acid. After dropping, react at the same temperature for 1.5 hours. Separate the reaction solution into organic phase and aqueous phase, and use the organic phase.

[0140] In a 500ml reaction flask, add 40g (0.21mol) 2-fluoro-4-bromoaniline, 2.72g (0.02mol) copper chloride, 120ml (1.35mol) benzene. Control the temperature at 10-30°C, and drop the above organic phase. After dropping, react at the same temperature for 1.5 hours. Filter, and wash the filtrate with 400ml water. Concentrate the organic phase to dryness, then recrystallize with 120ml methanol to obtain the target compound 2-fluoro-4-bromobiphenyl 48.4g, with a molar yield of 91.6%.

[0141] (2) Synthesis of 3-fluoro-4-biphenylboronic acid pinacol ester

[0142]

[0143] Under nitrogen protection, in a 1000ml reaction flask, add 40g (0.16mol) 2-fluoro-4-bromobiphenyl, 4.7g (0.032mol) cobalt chloride hexahydrate, 15.6g (0.16mol) potassium acetate, 120ml dioxane, 0.0058g (0.008mmol) PdCl2(dppf). After warming to 80°C, slowly add 48.5g (0.19mol) bis-pinacolylboron diol in batches, about 1.5h. After adding, react at the same temperature for 2.5h. Concentrate the reaction solution to dryness, then add 400ml dichloromethane and stir for 25min. Filter, concentrate the filtrate to dryness, add 200ml n-heptane and beat for 1h to obtain the target compound 3-fluoro-4-biphenylboronic acid pinacol ester 43.7g, with a molar yield of 92.1%.

[0144] (3) Synthesis of flurbiprofen

[0145]

[0146] In a 1000ml flask, 25.8g (0.15mol) of 2-bromopropionic acid sodium salt, 51.6g of water, 3.96g (0.026mol) of cobalt chloride hexahydrate, 13.2g (0.135mol) of potassium acetate, 120ml of dioxane, 0.0049g (0.007mmol) of PdCl2(dppf) were added under nitrogen protection. After the temperature was raised to 70°C, 40g (0.134mol) of 3-fluoro-4-biphenylboronic acid pinacol ester was added slowly in batches for about 1.5h. After the addition was completed, the reaction was continued at the same temperature for 2.5h. 2g of acetylcysteine was added and stirred at the same temperature for 1h. Filtration was performed and the filtrate was concentrated to no liquid outflow. 200ml of ethyl acetate, 4g of tributylphosphine, 200ml of water were added, and after stirring for 1h, the layers were separated, and the aqueous phase was taken and washed with 200ml of ethyl acetate once. 2g of activated carbon was added to the aqueous phase and stirred for 0.5h, then filtered and the aqueous phase was taken. The pH of the aqueous phase was adjusted to 2-3 with concentrated hydrochloric acid, stirred at 35°C for 1h, then stirred at 5°C for 1h, and suction filtration was performed to obtain a white solid. The solid was added with 200ml of methyl tert-butyl ether and stirred for 25min, then 200ml of water was added and stirred for 25min, and the layers were separated to obtain the organic phase. The organic phase was concentrated to dryness, and then recrystallized with 200ml of cyclohexane to obtain the target compound flurbiprofen 27.1g, with a molar yield of 83.0% and a purity of 99.4%.

[0147] Example 5

[0148] (1) Synthesis of 2-fluoro-4-bromobiphenyl

[0149]

[0150] In a 500ml reaction bottle, 62.1g (0.9mol) of sodium nitrite, 80ml of water, 138ml (1.8mol) of isopropyl alcohol were added. The temperature was controlled at 10-30°C, and 80ml of 37% hydrochloric acid was added dropwise. After the dropwise addition was completed, the reaction was continued at the same temperature for 1.5h. The reaction solution was separated into layers, and the organic phase was taken for use.

[0151] In a 500ml reaction bottle, 40g (0.21mol) of 2-fluoro-4-bromoaniline, 2.72g (0.02mol) of copper chloride, 120ml (1.35mol) of benzene were added. The temperature was controlled at 10-30°C, and the above-mentioned organic phase was added dropwise. After the dropwise addition was completed, the reaction was continued at the same temperature for 1.5h. Filtration was performed, and the filtrate was washed with 400ml of water. The organic phase was concentrated to dryness, and then recrystallized with 120ml of methanol to obtain the target compound 2-fluoro-4-bromobiphenyl 48.7g, with a molar yield of 92.2%.

[0152] (2) Synthesis of 3-fluoro-4-biphenylboronic acid pinacol ester

[0153]

[0154] Into a 1000ml reaction flask, 40g (0.16mol) 2-fluoro-4-bromobiphenyl, 7.05g (0.048mol) cobalt chloride hexahydrate, 15.6g (0.16mol) potassium acetate, 120ml dioxane, 0.0058g (0.008mmol) PdCl2(dppf) were added under nitrogen protection. After warming to 80°C, 48.5g (0.19mol) bis(pinacolato)diboron was added slowly in batches for about 1.5h. After the addition was completed, the reaction was carried out at the same temperature for 2.5h. The reaction solution was concentrated to dryness, then 400ml dichloromethane was added and stirred for 25min. Filtration was performed, the filtrate was concentrated to dryness, 200ml n-heptane was added and stirred for 1h to obtain the target compound 3-fluoro-4-biphenylboronic acid pinacol ester 38.3g, with a molar yield of 80.7%.

[0155] (3) Synthesis of flurbiprofen

[0156]

[0157] Into a 1000ml three-necked flask, 25.8g (0.15mol) 2-bromopropionic acid sodium, 51.6g water, 6.09g (0.040mol) cobalt chloride hexahydrate, 13.2g (0.135mol) potassium acetate, 120ml dioxane, 0.0049g (0.007mmol) PdCl2(dppf) were added under nitrogen protection. After warming to 70°C, 40g (0.134mol) 3-fluoro-4-biphenylboronic acid pinacol ester was added slowly in batches for about 1.5h. After the addition was completed, the reaction was carried out at the same temperature for 2.5h. 2g acetylcysteine was added and stirred at the same temperature for 1h. Filtration was performed, the filtrate was concentrated to dryness. 200ml ethyl acetate, 4g tributylphosphine, 200ml water were added, after stirring for 1h, the layers were separated, the aqueous phase was taken and washed with 200ml ethyl acetate once. 2g activated carbon was added to the aqueous phase and stirred for 0.5h, then filtration was performed and the aqueous phase was taken. The pH of the aqueous phase was adjusted to 2-3 with concentrated hydrochloric acid, stirred at 35°C for 1h, then stirred at 5°C for 1h, and then suction filtration was performed to obtain a white solid. The solid was added to 200ml methyl tert-butyl ether and stirred for 25min, 200ml water was added and stirred for 25min, then the layers were separated and the organic phase was taken. The organic phase was concentrated to dryness, then recrystallized with 200ml cyclohexane to obtain the target compound flurbiprofen 23.3g, with a molar yield of 71.4% and a purity of 99.1%.

[0158] Example 6

[0159] (1) Synthesis of 2-fluoro-4-bromobiphenyl

[0160]

[0161] In a 500ml reaction flask, add 62.1g (0.9mol) sodium nitrite, 80ml water, 138ml (1.8mol) isopropyl alcohol. Control the temperature at 10-30°C, and drop 80ml 37% hydrochloric acid. After dropping, react at the same temperature for 1.5 hours. Separate the reaction solution into organic phase and aqueous phase, and use the organic phase.

[0162] In a 500ml reaction flask, add 40g (0.21mol) 2-fluoro-4-bromoaniline, 2.72g (0.02mol) copper chloride, 120ml (1.35mol) benzene. Control the temperature at 10-30°C, and drop the above organic phase. After dropping, react at the same temperature for 1.5 hours. Filter, and wash the filtrate with 400ml water. Concentrate the organic phase to dryness, then recrystallize with 120ml methanol to obtain the target compound 2-fluoro-4-bromobiphenyl 48.1g, with a molar yield of 91.0%.

[0163] (2) Synthesis of 3-fluoro-4-biphenylboronic acid pinacol ester

[0164]

[0165] Under nitrogen protection, in a 1000ml reaction flask, add 40g (0.16mol) 2-fluoro-4-bromobiphenyl, 2.35g (0.016mol) cobalt chloride hexahydrate, 15.6g (0.16mol) potassium acetate, 120ml dioxane, 0.0058g (0.008mmol) PdCl2(dppf), and 48.5g (0.19mol) bispinacolyl diboron. Warm to 80°C and react for 4h. Concentrate the reaction solution to dryness, then add 400ml dichloromethane and stir for 25min. Filter, concentrate the filtrate to dryness, and add 200ml n-heptane to make a slurry for 1h to obtain the target compound 3-fluoro-4-biphenylboronic acid pinacol ester 24.4g, with a molar yield of 51.4%.

[0166] (3) Synthesis of flurbiprofen

[0167]

[0168] In a 1000ml flask, 25.8g (0.15mol) of 2-bromopropionic acid sodium, 51.6g of water, 1.98g (0.013mol) of cobalt chloride hexahydrate, 13.2g (0.135mol) of potassium acetate, 120ml of dioxane, 0.0049g (0.007mmol) of PdCl2(dppf) and 40g (0.134mol) of 3-fluoro-4-biphenyl boronic acid pinacol ester were added under nitrogen protection. The temperature was raised to 70°C for 4h. 2g of acetylcysteine was added and stirred at the same temperature for 1h. Filtration was performed and the filtrate was concentrated to no liquid outflow. 200ml of ethyl acetate, 4g of tributylphosphine, 200ml of water were added, stirred for 1h, and then separated into two layers. The aqueous phase was taken and washed with 200ml of ethyl acetate once. 2g of activated carbon was added to the aqueous phase and stirred for 0.5h. Filtration was performed and the aqueous phase was taken. The pH of the aqueous phase was adjusted to 2-3 with concentrated hydrochloric acid, stirred at 35°C for 1h, and then stirred at 5°C for 1h. Filtration was performed and the white solid was obtained. The solid was added with 200ml of methyl tert-butyl ether and stirred for 25min. 200ml of water was added and stirred for 25min, and then separated into two layers. The organic phase was taken. The organic phase was concentrated to dryness, and then recrystallized with 200ml of cyclohexane to obtain the target compound flurbiprofen 19.0g, with a molar yield of 58.2% and a purity of 97.6%.

[0169] The technical features of the above-described embodiments can be combined in any manner. For brevity, not all possible combinations of the technical features in the above-described embodiments are described, but it should be understood that any combination of the technical features is within the scope of the present disclosure as long as the combination does not result in a contradiction.

[0170] The above-described embodiments only express several implementation manners of the present application, and the description is relatively specific and detailed, but it should not be understood as a limitation on the scope of the patent. It should be noted that, for those skilled in the art, some modifications and improvements can be made without departing from the concept of the present application, and these are within the protection scope of the present application. Therefore, the protection scope of the present application should be subject to the appended claims.

Claims

1. A method of synthesizing flurbiprofen, characterized by, comprising the steps of: Step C: coupling reaction of 3-fluoro-4-biphenylboronic acid pinacol ester with sodium 2-bromopropionate in the presence of a base and a metal catalyst, followed by acidification of the resulting reaction product to obtain flurbiprofen; The reaction formula is as follows: ； The metal catalyst in step C is a combination of one or more of a hexahydrate chloride and a palladium metal catalyst; the hexahydrate chloride is hexahydrated nickel chloride and / or hexahydrated cobalt chloride; and the palladium metal catalyst is Pd(PPh3)4, PdCl2(dppf), PdCl2(dtbpf), PdCl2(Amphos)2, and / or PdCl2(Pt-Bu3)2.

2. The method of synthesis of flurbiprofen as claimed in claim 1 wherein, Further comprising: The 3-fluoro-4-biphenylboronic acid pinacol ester is synthesized by the following steps: Step A: coupling reaction of 2-fluoro-4-bromobiphenyl with bis(pinacolato)diboron in the presence of a base and a metal catalyst to obtain 3-fluoro-4-biphenylboronic acid pinacol ester; The reaction formula is as follows: 。 3. The method of synthesis of flurbiprofen as claimed in claim 2 wherein, The metal catalyst in step A is a combination of a hexahydrate chloride and a palladium metal catalyst.

4. The method of synthesis of flurbiprofen as claimed in claim 3 wherein, The metal catalyst in step A is a combination of a hexahydrate chloride and a palladium metal catalyst.

5. The method of synthesis of flurbiprofen as claimed in claim 4 wherein, The molar ratio of the hexahydrate chloride to the 2-fluoro-4-bromobiphenyl in step A is 0.02-0.3:

1.

6. The method of synthesis of flurbiprofen as claimed in claim 5 wherein, The molar ratio of the hexahydrate chloride to the 2-fluoro-4-bromobiphenyl in step A is 0.08-0.2:

1.

7. The method of synthesis of flurbiprofen as claimed in claim 6 wherein, The molar ratio of the hexahydrate chloride to the 2-fluoro-4-bromobiphenyl in step A is 0.09-0.12:

1.

8. The method of synthesis of flurbiprofen as claimed in claim 4 wherein, The molar ratio of the palladium metal catalyst to the 2-fluoro-4-bromobiphenyl in step A is (0.00001-0.005):

1.

9. The method of synthesis of flurbiprofen as claimed in claim 8 wherein, The molar ratio of the palladium metal catalyst to the 2-fluoro-4-bromobiphenyl in step A is (0.00003-0.0001):

1.

10. The method of synthesis of flurbiprofen as claimed in claim 9 wherein, The molar ratio of the palladium metal catalyst to the 2-fluoro-4-bromobiphenyl in step A is (0.00004-0.00006):

1.

11. The method for synthesizing flurbiprofen according to any one of claims 2-10, wherein, The base in step A is a combination of one or more of sodium bicarbonate, potassium bicarbonate, potassium phosphate, potassium carbonate, potassium acetate, and sodium acetate; and / or, The solvent for the coupling reaction in step A is a combination of one or more of ethanol, toluene, tetrahydrofuran, dimethylformamide, dioxane, and ethylene glycol dimethyl ether; and / or, The molar ratio of the 2-fluoro-4-bromobiphenyl to the base in step A is 1:0.8-3; and / or, The mass-volume ratio of the 2-fluoro-4-bromobiphenyl to the solvent in step A is 1 g:(2-5) ml; and / or, The molar ratio of the 2-fluoro-4-bromobiphenyl to the bis(pinacolato)diboron in step A is 1:1-1.5; and / or, The temperature of the coupling reaction in step A is 65-85℃; and / or, The time of the coupling reaction in step A is 1-5h; and / or, The adding mode of the bispinacolyl diboron in step A is slow batch adding, and the adding time is 1-2h.

12. The method of synthesis of flurbiprofen according to any one of claims 2-10, characterized in that, The synthesis of the 3-fluoro-4-biphenyl boronic acid pinacol ester comprises the following steps: adding the 2-fluoro-4-bromobiphenyl, metal catalyst, base and solvent in a reaction bottle, heating to 70-80℃, slowly adding the bispinacolyl diboron in batches, and the adding time is 1-2h, and after adding, reacting at 70-80℃, to obtain the 3-fluoro-4-biphenyl boronic acid pinacol ester.

13. The method of synthesis of flurbiprofen according to any one of claims 2-10, characterized in that, It also comprises the following steps for preparing 2-fluoro-4-bromobiphenyl: 2-fluoro-4-bromoaniline is subjected to diazotization reaction, and then subjected to coupling reaction with benzene to obtain 2-fluoro-4-bromobiphenyl.

14. The method of synthesizing flurbiprofen according to claim 13, wherein, The synthesis method also comprises the following steps for preparing 2-fluoro-4-bromobiphenyl: adding sodium nitrite, water and isopropanol in a reaction bottle, adding concentrated hydrochloric acid dropwise at 10-30℃, and reacting at the same temperature for 1-2h, separating the reaction solution into layers, and taking the organic phase; adding the 2-fluoro-4-bromoaniline, catalyst and benzene in another reaction bottle, adding the organic phase dropwise at 10-30℃, and reacting at the same temperature for 1-2h to obtain 2-fluoro-4-bromobiphenyl.

15. The method of synthesis of flurbiprofen as claimed in claim 14 wherein, The molar ratio of the 2-fluoro-4-bromoaniline and benzene is 1: (5.0-10.0).

16. The method of synthesizing flurbiprofen as claimed in claim 14 wherein, The catalyst in the step of preparing 2-fluoro-4-bromobiphenyl is copper chloride.

17. The method of synthesizing flurbiprofen according to claim 16, wherein, The molar ratio of the 2-fluoro-4-bromoaniline and copper chloride is 1:0.05-0.

15.

18. The method of synthesis of flurbiprofen as claimed in claim 14 wherein, The molar ratio of the sodium nitrite and isopropanol is 1:1.8-2.2; the volume ratio of the water and isopropanol is 1:1.5-2; and the volume ratio of the water and concentrated hydrochloric acid is 1:0.8-1.

2.

19. The method of synthesis of flurbiprofen according to any one of claims 1-10, wherein, The metal catalyst in step C is a combination of hexahydrate chloride and palladium metal catalyst.

20. The method of synthesizing flurbiprofen according to claim 19, wherein, The molar ratio of the hexahydrate chloride and the 3-fluoro-4-biphenyl boronic acid pinacol ester in step C is 0.02-0.3:

1.

21. The method of synthesizing flurbiprofen according to claim 20, wherein, The molar ratio of the hexahydrate chloride and the 3-fluoro-4-biphenyl boronic acid pinacol ester in step C is 0.08-0.2:

1.

22. The method of synthesizing flurbiprofen according to claim 21, wherein, The molar ratio of the hexahydrate chloride and the 3-fluoro-4-biphenyl boronic acid pinacol ester in step C is 0.09-0.12:

1.

23. The method of synthesizing flurbiprofen according to claim 19, wherein, The molar ratio of the palladium metal catalyst and the 3-fluoro-4-biphenyl boronic acid pinacol ester in step C is (0.00001-0.005):

1.

24. The method of synthesizing flurbiprofen according to claim 23, wherein, The molar ratio of the palladium metal catalyst and the 3-fluoro-4-biphenyl boronic acid pinacol ester in step C is (0.00003-0.0001):

1.

25. The method of synthesizing flurbiprofen according to claim 24, wherein, The molar ratio of the palladium metal catalyst and the 3-fluoro-4-biphenyl boronic acid pinacol ester in step C is (0.00004-0.00006):

1.

26. The synthesis method of flurbiprofen according to any one of claims 1-10, wherein, The base in step C is a combination of one or more of sodium bicarbonate, potassium bicarbonate, potassium phosphate, potassium carbonate, potassium acetate and sodium acetate; and / or, The solvent of the coupling reaction in Step C is a combination of water and an organic solvent, wherein the organic solvent is a combination of one or more of ethanol, toluene, tetrahydrofuran, dimethylformamide, dioxane and ethylene glycol dimethyl ether; and / or, The molar ratio of 3-fluoro-4-biphenyl boronic acid pinacol ester to sodium 2-bromopropionate in Step C is 1:1-1.5; and / or, the molar ratio of 3-fluoro-4-biphenyl boronic acid pinacol ester to base in Step C is 1:0.8-3; and / or, The temperature of the coupling reaction in Step C is 65-85°C; and / or, The time of the coupling reaction in Step C is 1-5h; and / or, The 3-fluoro-4-biphenyl boronic acid pinacol ester in Step C is added in a slow batch mode, and the addition time is 1-2h.

27. The method of synthesizing flurbiprofen as claimed in claim 26 wherein, The mass ratio of sodium 2-bromopropionate to water in Step C is 1:1.5-2.

5.

28. The method of synthesizing flurbiprofen as claimed in claim 26 wherein, The mass-volume ratio of 3-fluoro-4-biphenyl boronic acid pinacol ester to organic solvent in Step C is 1g:(2-5)ml. The mass-volume ratio of 3-fluoro-4-biphenyl boronic acid pinacol ester to organic solvent in Step C is 1g:(2-5)ml.

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