Flurbiprofen amine butantriol salt as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of medicines, and particularly relates to flurbiprofen amine butantriol salt as well as a preparation method and application thereof. The flurbiprofen amine butantriol salt provided by the invention comprises one or more of raceme flurbiprofen amine butantriol salt, (R)-flurbiprofen amine butantriol salt and (S)-flurbiprofen amine butantriol salt. The flurbiprofen amine butantriol salt is obtained by mixing a flurbiprofen raw material, amine butantriol and an organic solvent and carrying out a salt forming reaction. Compared with flurbiprofen, the flurbiprofen amine butantriol salt provided by the invention has the advantages that the solubility in water is greatly increased, the flurbiprofen amine butantriol salt can be applied in a dosage form of an aqueous solution injection, the dosage form is simple, and the stability is high. Meanwhile, the (R)-flurbiprofen amine butantriol salt or the (S)-flurbiprofen amine butantriol salt has optical activity, the toxic and side effects are reduced, and the (R)-flurbiprofen amine butantriol salt has important significance. The preparation method provided by the invention has the characteristics of simple process flow method, convenience in industrial production and low cost.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceuticals, and particularly relates to a flurbiprofen tromethamine salt, a preparation method thereof, and an application thereof. Background Art

[0002] Flurbiprofen is a non-steroidal anti-inflammatory drug with anti-inflammatory and analgesic effects. The solubility of flurbiprofen in water is extremely low, and the currently widely used clinically in China is the prodrug of flurbiprofen - flurbiprofen axetil.

[0003] Flurbiprofen axetil is also poorly soluble in water. The currently clinically used flurbiprofen axetil injection is a preparation that encapsulates flurbiprofen axetil with fat emulsion as the drug carrier developed based on the concept of drug delivery system. It has little irritation during injection and a fast onset of analgesic effect.

[0004] The fat emulsion injection is a non-homogeneous liquid preparation and belongs to a thermodynamically unstable system. During the preparation process, phenomena such as demulsification and stratification may occur due to high-temperature sterilization. After demulsification, part of the main drug enters the water, resulting in a decrease in content; during long-term storage, phenomena such as an increase in particle size and aggregation of emulsion droplets are likely to occur; the sharp change in temperature during the transportation of the drug will also affect the stability of the fat emulsion injection. At the same time, flurbiprofen axetil is easily degraded to form flurbiprofen and 1-hydroxyethyl acetate, and 1-hydroxyethyl acetate is further degraded into acetic acid and formaldehyde. The higher the content of flurbiprofen formed by degradation, the higher the amount of acetic acid and formaldehyde formed by degradation, posing a safety hazard. Summary of the Invention

[0005] The purpose of the present invention is to provide a preparation method of flurbiprofen tromethamine salt. The flurbiprofen tromethamine salt prepared by the method provided by the present invention has good solubility in water, can be applied in the form of an aqueous solution injection, has a simple dosage form, high stability, and has a wide application in anti-inflammatory analgesia and reducing toxic and side effects.

[0006] In order to achieve the above purpose, the present invention provides the following technical solutions:

[0007] The present invention provides a flurbiprofen tromethamine salt, including one or more of a racemic flurbiprofen tromethamine salt, an (R)-flurbiprofen tromethamine salt, and an (S)-flurbiprofen tromethamine salt;

[0008] The chemical structural formula of the racemic flurbiprofen tromethamine salt is as shown in Formula 1:

[0009]

[0010] The chemical structural formula of the (R)-flurbiprofen tromethamine salt is as shown in Formula 2:

[0011]

[0012] The chemical structural formula of the (S)-flurbiprofen tromethamine salt is shown in Formula 3:

[0013]

[0014] The present invention provides a method for preparing the flurbiprofen tromethamine salt described in the above technical solution, comprising the following steps:

[0015] Mix the flurbiprofen raw material, tromethamine and an organic solvent to carry out a salt-forming reaction to obtain the flurbiprofen tromethamine salt; the flurbiprofen raw material includes racemic flurbiprofen, (R)-flurbiprofen or (S)-flurbiprofen; the chemical structural formula of the tromethamine is shown in Formula 4:

[0016]

[0017] Preferably, the method for preparing the racemic flurbiprofen comprises the following steps:

[0018] Mix magnesium metal, 4-bromo-2-fluorobiphenyl and an organic solvent to carry out a first reaction to obtain a Grignard reagent;

[0019] Mix the Grignard reagent, an alkali metal salt of 2-bromopropionic acid and an organic solvent to carry out a second reaction to obtain a reaction solution;

[0020] Carry out a first acidification on the reaction solution to obtain the racemic flurbiprofen.

[0021] Preferably, the method for preparing the (R)-flurbiprofen or (S)-flurbiprofen comprises the following steps:

[0022] Mix the racemic flurbiprofen, a chiral reagent and an organic solvent to carry out a chiral resolution reaction, the chiral reagent is (R)-phenylethylamine or (S)-phenylethylamine, to obtain the (R)-flurbiprofen phenylethylamine salt or the (S)-flurbiprofen phenylethylamine salt; the organic solvent used in the chiral resolution reaction is ethyl acetate and ethanol; the volume ratio of ethyl acetate to ethanol is 2-10:1;

[0023] Carry out a second acidification on the (R)-flurbiprofen phenylethylamine salt or the (S)-flurbiprofen phenylethylamine salt to obtain (R)-flurbiprofen or (S)-flurbiprofen.

[0024] Preferably, the molar ratio of the flurbiprofen raw material to the tromethamine is 1:1;

[0025] The organic solvent used in the salt-forming reaction includes one or more of water, acetone, methanol and ethanol.

[0026] Preferably, the molar ratio of the 4-bromo-2-fluorobiphenyl to the metallic magnesium is 1:1 to 1.2;

[0027] The temperature of the first reaction is ≤ 60°C.

[0028] Preferably, the temperature of the chiral resolution reaction is 30 to 75°C, and the time is 1 to 6 h.

[0029] Preferably, after the chiral resolution reaction, a crude product of (R)-flurbiprofen phenethylamine salt or a crude product of (S)-flurbiprofen phenethylamine salt is obtained; before the second acidification, the method further includes: recrystallizing the crude product of (R)-flurbiprofen phenethylamine salt or the crude product of (S)-flurbiprofen phenethylamine salt, and the solvent used for recrystallization is ethyl acetate and ethanol; the volume ratio of the ethyl acetate to the ethanol is 2 to 10:1.

[0030] Preferably, the alkali metal salt of 2-bromopropionic acid is sodium 2-bromopropionate;

[0031] The temperature of the second reaction is 50 to 65°C, and the time is 6 to 10 h;

[0032] The first acidification reagent used for the first acidification is a sulfuric acid solution,

[0033] After the first acidification, a first acidified solution is obtained; the method further includes:

[0034] Extracting the first acidified solution with an organic solvent to obtain an extracted organic phase;

[0035] After drying the extracted organic phase and removing the solvent, a crude product of racemic flurbiprofen is obtained;

[0036] Purifying the crude product of racemic flurbiprofen by silica gel column to obtain the racemic flurbiprofen; the elution solvent used for the silica gel column purification is petroleum ether and ethyl acetate.

[0037] The present invention provides an application of the flurbiprofen tromethamine salt described in the above technical solution or the flurbiprofen tromethamine salt prepared by the preparation method described in the above technical solution in the preparation of an anti-inflammatory and analgesic drug.

[0038] The present invention provides a flurbiprofen trometamol salt, including one or more of racemic flurbiprofen trometamol salt, (R)-flurbiprofen trometamol salt, and (S)-flurbiprofen trometamol salt. The solubility test results show that the solubility of the flurbiprofen trometamol salt provided by the present invention has been greatly improved compared with that of flurbiprofen, and it can meet the requirements of preclinical or clinical research. The present invention also provides the analgesic effect test and safety test of the flurbiprofen trometamol salt in an animal model. The results show that the analgesic effect of the flurbiprofen trometamol salt provided by the present invention is equivalent to that of flurbiprofen axetil widely used clinically at present. However, in terms of safety, such as reducing gastric ulcers, the (R)-flurbiprofen trometamol salt and (S)-flurbiprofen trometamol salt have been greatly improved compared with the racemic flurbiprofen trometamol salt. Therefore, the flurbiprofen trometamol salt provided by the present invention can be applied in the form of an aqueous injection. The dosage form is simple, and compared with the fat emulsion injection of flurbiprofen axetil, the dosage form has high stability, a simple preparation process, can effectively reduce the cost of flurbiprofen preparations, and has a wider clinical application value.

[0039] The present invention provides a preparation method of a flurbiprofen trometamol salt, including the following steps: mixing a flurbiprofen raw material, trometamol, and an organic solvent for a salt-forming reaction to obtain the flurbiprofen trometamol salt; the flurbiprofen raw material includes racemic flurbiprofen, (R)-flurbiprofen, or (S)-flurbiprofen; the chemical structural formula of the trometamol is as shown in Formula 4. The present invention provides a nuclear magnetic resonance control map after the salt-forming reaction of the flurbiprofen raw material and trometamol. It can be seen from the nuclear magnetic resonance control map that there are obvious differences in the characteristic chemical shifts of some characteristic peaks of the flurbiprofen raw material and trometamol compared with the flurbiprofen trometamol salt, indicating that the two have indeed formed a salt through the reaction to obtain the target product, flurbiprofen trometamol salt. The preparation method provided by the present invention has the characteristics of simple process flow, convenient for industrial production, and low cost. The flurbiprofen trometamol salt obtained by the present invention through the salt-forming reaction has greatly increased solubility in water compared with flurbiprofen, meeting the requirements of preparation and clinical use. In addition, more importantly, the chiral flurbiprofen trometamol salt ((R)-flurbiprofen trometamol salt or (S)-flurbiprofen trometamol salt) prepared by the present invention has been proved by in-vivo experiments on mice to have good analgesic and anti-inflammatory effects. The (R)-flurbiprofen trometamol salt and (S)-flurbiprofen trometamol salt have better safety compared with the racemic flurbiprofen trometamol salt. In addition, the action mechanisms of (R)-flurbiprofen and flurbiprofen are different, which is beneficial to further precise treatment and worthy of further research.

[0040] At the same time, the preparation method provided by the present invention has a simple process and low cost; the obtained product, flurbiprofen trometamol salt, is convenient to use, has good effects, and has small toxic and side effects, which has practical significance. Description of the Drawings

[0041] Figure 1 HPLC chiral analysis spectrum of the racemic flurbiprofen prepared in Example 1;

[0042] Figure 2 Nuclear magnetic resonance spectrum of the racemic flurbiprofen prepared in Example 1;

[0043] Figure 3 Nuclear magnetic resonance spectrum of tromethamine;

[0044] Figure 4 Nuclear magnetic resonance spectrum of the tromethamine salt of racemic flurbiprofen in Example 1;

[0045] Figure 5 Nuclear magnetic resonance overlay spectrum of racemic flurbiprofen and the tromethamine salt of racemic flurbiprofen in Example 1;

[0046] Figure 6 Nuclear magnetic resonance overlay spectrum of tromethamine and the tromethamine salt of racemic flurbiprofen in Example 1;

[0047] Figure 7 HPLC chiral analysis spectrum of (S)-flurbiprofen prepared in Example 2;

[0048] Figure 8 HPLC chiral analysis spectrum of (R)-flurbiprofen prepared in Example 3;

[0049] Figure 9 Absorbance-concentration working curve of the racemic flurbiprofen obtained in Example 4;

[0050] Figure 10 Flow chart for preparing the tromethamine salt of flurbiprofen in the examples of the present invention. Detailed Description of the Invention

[0051] The present invention provides a tromethamine salt of flurbiprofen, including one or more of racemic flurbiprofen tromethamine salt, (R)-flurbiprofen tromethamine salt, and (S)-flurbiprofen tromethamine salt;

[0052] The chemical structural formula of the racemic flurbiprofen tromethamine salt is as shown in Formula 1:

[0053]

[0054] The chemical structural formula of the (R)-flurbiprofen tromethamine salt is as shown in Formula 2:

[0055]

[0056] The chemical structural formula of the (S)-flurbiprofen tromethamine salt is shown in Formula 3:

[0057]

[0058] Compared with flurbiprofen, the solubility of the flurbiprofen tromethamine salt provided by the present invention in water is significantly improved.

[0059] The present invention provides a method for preparing a flurbiprofen tromethamine salt, comprising the following steps:

[0060] Mixing a flurbiprofen raw material, tromethamine and an organic solvent to carry out a salt formation reaction to obtain the flurbiprofen tromethamine salt; the flurbiprofen raw material includes racemic flurbiprofen, (R)-flurbiprofen or (S)-flurbiprofen; the chemical structural formula of the tromethamine is shown in Formula 4:

[0061]

[0062] In the present invention, unless otherwise specified, all preparation raw materials / components are commercially available products well-known to those skilled in the art.

[0063] In the present invention, the preparation method of the racemic flurbiprofen preferably comprises the following steps:

[0064] Mixing magnesium metal, 4-bromo-2-fluorobiphenyl and an organic solvent to carry out a first reaction to obtain a Grignard reagent;

[0065] Mixing the Grignard reagent, an alkali metal salt of 2-bromopropanoic acid and an organic solvent to carry out a second reaction to obtain a reaction solution;

[0066] Carrying out a first acidification on the reaction solution to obtain the racemic flurbiprofen.

[0067] The present invention mixes metallic magnesium, 4-bromo-2-fluorobiphenyl, and an organic solvent (hereinafter referred to as the first organic solvent) to conduct a first reaction to obtain a Grignard reagent. In the present invention, the first organic solvent used in the first reaction preferably includes tetrahydrofuran (THF) and / or diethyl ether, and may be THF in the examples. The molar ratio of the 4-bromo-2-fluorobiphenyl to the metallic magnesium is preferably 1:1 to 1.2, and may be 1:1.2 or 1:1 in the examples. The mass ratio of the first organic solvent used in the first reaction to the 4-bromo-2-fluorobiphenyl is preferably 6 to 10:1. The mixing of the metallic magnesium, 4-bromo-2-fluorobiphenyl, and the first organic solvent preferably includes the following steps: dissolving the 4-bromo-2-fluorobiphenyl in the first organic solvent to obtain a 4-bromo-2-fluorobiphenyl solution; mixing the 4-bromo-2-fluorobiphenyl solution and the metallic magnesium. The mixing of the 4-bromo-2-fluorobiphenyl solution and the metallic magnesium is specifically: dropping the 4-bromo-2-fluorobiphenyl solution onto the metallic magnesium. The temperature of the dropping is preferably 40°C. The first reaction is carried out in a protective gas atmosphere, and the protective gas is preferably nitrogen. The temperature of the first reaction is preferably ≤60°C. The time for continuing the first reaction after the dropping is preferably 3 to 4 h. The end point of the completion of the first reaction is the disappearance of the metallic magnesium. The raw materials of the first reaction preferably further include iodine. When the raw materials of the first reaction preferably further include iodine, the mixing of the 4-bromo-2-fluorobiphenyl solution and the metallic magnesium is replaced by mixing the 4-bromo-2-fluorobiphenyl solution, the metallic magnesium, and iodine, and the mixing of the 4-bromo-2-fluorobiphenyl solution, the metallic magnesium, and iodine is specifically dropping the 4-bromo-2-fluorobiphenyl solution onto the mixture of the metallic magnesium and iodine.

[0068] After obtaining the Grignard reagent, the present invention mixes the Grignard reagent, the alkali metal salt of 2-bromopropionic acid, and an organic solvent (hereinafter referred to as the second organic solvent) to carry out a second reaction to obtain a reaction solution. In the present invention, the alkali metal salt of 2-bromopropionic acid is preferably sodium 2-bromopropionate. The second organic solvent preferably includes tetrahydrofuran (THF) and / or diethyl ether, and may be THF in the examples. The molar ratio of the alkali metal salt of 2-bromopropionic acid to 4-bromo-2-fluorobiphenyl is preferably 1:1. The present invention has no special requirements for the dosage of the second organic solvent, as long as the alkali metal salt of 2-bromopropionic acid is completely dissolved. The mixing of the Grignard reagent, the alkali metal salt of 2-bromopropionic acid, and the second organic solvent preferably includes: dissolving the alkali metal salt of 2-bromopropionic acid in the second organic solvent to obtain a solution of the alkali metal salt of 2-bromopropionic acid; heating the solution of the alkali metal salt of 2-bromopropionic acid to reflux in a protective gas atmosphere, the protective gas is preferably nitrogen, and then dropping the Grignard reagent. The second reaction is carried out in a protective gas atmosphere, and the protective gas is preferably nitrogen. The temperature of the second reaction is preferably 50-65°C, more preferably 60°C; the time of the first reaction is preferably 6-10 h, more preferably 8 h. The present invention preferably uses TLC to detect the progress of the second reaction.

[0069] After obtaining the reaction solution, the present invention performs a first acidification on the reaction solution to obtain the racemic flurbiprofen. In the present invention, before the first acidification, the present invention preferably dilutes the reaction solution with water. The dilution is carried out at room temperature. The first acidification reagent used for the first acidification is preferably a sulfuric acid solution, and the mass content of the sulfuric acid solution is preferably 1-5%. The first acidification is carried out at room temperature, and the time of the first acidification is preferably 0.5-1 h. The first acidification is carried out under stirring conditions. In the present invention, a first acidification solution is obtained after the first acidification; the present invention preferably further includes: extracting the first acidification solution with an organic solvent to obtain an extraction organic phase, and the organic solvent used for the extraction is preferably dichloromethane. The number of extractions is preferably 2-3 times, and the present invention preferably combines the organic phases to obtain the extraction organic phase. After drying the extraction organic phase and removing the solvent, a crude product of the racemic flurbiprofen is obtained. The reagent used for drying is preferably anhydrous sodium sulfate. The crude product of the racemic flurbiprofen is purified by a silica gel column to obtain the racemic flurbiprofen. In the present invention, the elution solvent used for the silica gel column purification is preferably petroleum ether and ethyl acetate. The volume ratio of petroleum ether to ethyl acetate is preferably 10-15:1.

[0070] In the present invention, the preparation method of (R)-flurbiprofen or (S)-flurbiprofen preferably includes the following steps:

[0071] Mix the racemic flurbiprofen, chiral reagent and organic solvent for chiral resolution reaction. The chiral reagent is (R)-phenylethylamine or (S)-phenylethylamine to obtain (R)-flurbiprofen phenethylamine salt or (S)-flurbiprofen phenethylamine salt;

[0072] Perform second acidification on the (R)-flurbiprofen phenethylamine salt or (S)-flurbiprofen phenethylamine salt to obtain (R)-flurbiprofen or (S)-flurbiprofen.

[0073] The present invention mixes the racemic flurbiprofen, a chiral reagent, and an organic solvent (hereinafter referred to as the third organic solvent) to conduct a chiral resolution reaction. The chiral reagent is (R)-phenylethylamine or (S)-phenylethylamine, and (R)-flurbiprofen phenethylamine salt or (S)-flurbiprofen phenethylamine salt is obtained. In the present invention, the third organic solvent used in the chiral resolution reaction preferably includes one or more of methanol, ethanol, and ethyl acetate. From the perspectives of environmental protection and the health of operators, the third organic solvent preferably includes ethyl acetate, or a mixture of ethyl acetate and ethanol. The volume ratio of ethyl acetate to ethanol in the mixture of ethyl acetate and ethanol is preferably 1 to 10:1, and in the examples, it can be 10:1, 1:1, or 3:1. In the present invention, the mixing of the racemic flurbiprofen, the chiral reagent, and the third organic solvent preferably includes the following steps: dissolving the racemic flurbiprofen in a part of the third organic solvent to obtain a racemic flurbiprofen solution; dissolving the chiral agent in the remaining third organic solvent to obtain a chiral agent solution; and dropping the chiral agent solution into the racemic flurbiprofen solution. The temperature of the chiral resolution reaction is preferably 30 to 75°C, more preferably 65°C; the time of the chiral resolution reaction is 1 to 6 h, more preferably 2 h. After the chiral resolution reaction, a chiral resolution reaction solution is obtained; the present invention preferably further includes: cooling the chiral resolution reaction solution to room temperature and maintaining stirring at room temperature for 1 to 2 h; then continuing to cool to 0 to 5°C and maintaining stirring at 0 to 5°C for 1 to 2 h to obtain a cooled reaction material solution; the present invention preferably separates the solid and liquid of the cooled reaction material solution to obtain a solid-phase product. The solid-liquid separation is preferably suction filtration. The solid-phase product is washed with ethyl acetate to obtain the crude product of (R)-flurbiprofen phenethylamine salt or (S)-flurbiprofen phenethylamine salt. The number of times of washing with ethyl acetate is preferably 3 times. After obtaining the crude product of (R)-flurbiprofen phenethylamine salt or (S)-flurbiprofen phenethylamine salt; before the second acidification, the present invention preferably further includes: recrystallizing the crude product of (R)-flurbiprofen phenethylamine salt or (S)-flurbiprofen phenethylamine salt. The solvent used for recrystallization is preferably ethyl acetate and ethanol; the volume ratio of ethyl acetate to ethanol is preferably 2 to 10:1, and in the examples, it can be 10:1, 2:1, or 6:1. In the present invention, the recrystallization preferably includes the following steps: dissolving the crude product of (R)-flurbiprofen phenethylamine salt or (S)-flurbiprofen phenethylamine salt in the recrystallization solvent to obtain a crude product solution; placing the crude product solution at 2 to 4°C for cooling crystallization, and separating the solid and liquid to obtain the pure product of (R)-flurbiprofen phenethylamine salt or (S)-flurbiprofen phenethylamine salt. The heat preservation time of the cooling crystallization is preferably 1 to 2 h. The filtration separation is preferably suction filtration, and the recrystallization mother liquor obtained by the solid-liquid separation is preferably recycled after analyzing the contents of flurbiprofen and phenethylamine.

[0074] After obtaining (R)-flurbiprofen phenethylamine salt or (S)-flurbiprofen phenethylamine salt (or the pure product of (R)-flurbiprofen phenethylamine salt or (S)-flurbiprofen phenethylamine salt obtained by recrystallization), the present invention subjects the (R)-flurbiprofen phenethylamine salt or (S)-flurbiprofen phenethylamine salt to a second acidification to obtain (R)-flurbiprofen or (S)-flurbiprofen. The second acidification reagent used in the second acidification is preferably a hydrochloric acid solution, and the mass content of the hydrochloric acid solution is preferably 10-15%. The pH value of the second acidification is preferably 2-3. The second acidification is carried out at room temperature, and the time of the second acidification is preferably 0.5-1 h. The second acidification is carried out under stirring conditions. After the second acidification is completed, a second acidification feed liquid is obtained; the present invention preferably subjects the second acidification feed liquid to solid-liquid separation, water washing and drying in sequence to obtain the (R)-flurbiprofen or (S)-flurbiprofen. The solid-liquid separation is preferably suction filtration. The coefficient of the water washing is preferably 1-3 times.

[0075] In the present invention, the organic solvent used in the salt formation reaction preferably includes one or more of water, acetone, methanol and ethanol, specifically water and ethanol in the examples. The molar ratio of the flurbiprofen raw material to the tromethamine is preferably 1:1. The present invention has no special requirements on the amount of the organic solvent used in the salt formation reaction, as long as the salt formation reaction proceeds smoothly. The mixing of the flurbiprofen raw material, tromethamine and the organic solvent (hereinafter referred to as the fourth organic solvent) preferably includes the following steps: dissolving the flurbiprofen raw material in a part of the fourth organic solvent to obtain a flurbiprofen raw material solution; dissolving the tromethamine in the remaining fourth organic solvent to obtain a tromethamine solution; mixing the tromethamine solution with the flurbiprofen raw material solution. The part of the fourth organic solvent is preferably anhydrous ethanol, and the remaining fourth organic solvent is preferably a mixed solvent of ethanol and water, and the mass content of ethanol in the ethanol and water mixed solution is preferably 95%. The salt formation reaction is carried out at room temperature, the time of the salt formation reaction is preferably 1-2 h, and the salt formation reaction is carried out under stirring conditions. After the salt formation reaction is completed, a salt formation reaction liquid is obtained. The present invention preferably removes the solvent from the salt formation reaction liquid to obtain the flurbiprofen tromethamine salt, and the specific implementation manner of removing the solvent is preferably evaporation.

[0076] The flurbiprofen tromethamine salt prepared by the present invention has excellent solubility. At the same time, the (R)-flurbiprofen tromethamine salt or (S)-flurbiprofen tromethamine salt has optical activity and reduces the toxic and side effects, which is of great significance.

[0077] The present invention provides the application of the flurbiprofen tromethamine salt described in the above technical solution in the preparation of anti-inflammatory and analgesic drugs.

[0078] To further illustrate the present invention, the technical solutions provided by the present invention will be described in detail below in conjunction with embodiments, but they should not be construed as limiting the protection scope of the present invention.

[0079] The following examples are all carried out according to Figure 10 the flow chart for preparing flurbiprofen trometamol salt shown below.

[0080] Example 1

[0081] This example provides the synthesis of racemic flurbiprofen and the preparation of flurbiprofen trometamol salt:

[0082] Step 1: Prepare a Grignard reagent from 4-bromo-2-fluorobiphenyl:

[0083] Put magnesium strip (1.02 g, 0.042 mol) and iodine grains (0.12 g, 0.0040 mol) into a 250 mL three-necked flask, under nitrogen protection, at 40 °C, add dropwise an anhydrous tetrahydrofuran solution (30 mL) of 4-bromo-2-fluorobiphenyl (6.04 g, 0.040 mol). After the reaction is initiated, the brownish color fades, and the temperature is controlled not to exceed 60 °C. After the addition is complete, continue the reaction for 4 h until the magnesium strip basically disappears.

[0084] Step 2: Couple the Grignard reagent obtained in Step 1 with sodium 2-bromopropionate to prepare racemic flurbiprofen:

[0085] Put sodium 2-bromopropionate (7.98 g, 0.040 mol) and 45 mL of anhydrous THF into the reaction flask, under nitrogen protection, heat up to reflux, and add dropwise the Grignard reagent obtained in Step 1. After the addition is complete, keep the temperature at 60 °C and react for 8 h. TLC detection shows that the reaction is basically complete. At room temperature, add 50 mL of water in sequence, add dropwise 40 mL of 5 wt% dilute sulfuric acid, and stir for 1 h. Extract with 60 mL of dichloromethane three times, combine the organic phases, dry with anhydrous sodium sulfate, remove the solvent, and purify the crude product by silica gel column (volume ratio of petroleum ether: ethyl acetate = 15:1) to obtain 6.46 g of white solid. The yield is 66.14%. 1 H-NMR(400MHz,CD 3 OD)δ7.52(dt,J=8.1,1.5Hz,2H),7.46-7.39(m,3H),7.38-7.32(m,1H),7.23-7.12(m,2H),3.77(q,J=7.1Hz,1H),1.49(d,J=7.1Hz,3H).

[0086] The chiral HPLC analysis results of the white solid product obtained in Step 2 are as Figure 1 shown. From Figure 1It can be seen that the peak areas of (R)-flurbiprofen and (S)-flurbiprofen are similar, showing the characteristics of the white solid product obtained in Step 2 being a racemate, that is, the white solid product obtained in Step 2 is racemic flurbiprofen.

[0087] Step 3, Preparation of racemic flurbiprofen tromethamine salt:

[0088] Dissolve the racemic flurbiprofen (0.244 g, 1 mmol) obtained in Step 2 in 5 mL of absolute ethanol (denoted as Solution A); place tromethamine (0.121 g, 1 mmol) in a round-bottom flask, add 5 mL of 95 wt% ethanol, stir until completely dissolved, then add Solution A, stir at room temperature for 1 h, and rotary evaporate to remove the solvent to obtain a white solid, which is racemic flurbiprofen tromethamine salt. 1 H-NMR(400MHz,CD 3 OD)δ7.50(dt,J=8.1,1.5Hz,2H),7.44-7.34(m,3H),7.34-7.30(m,1H),7.26-7.16(m,2H),3.64(m,7H),1.45(d,J=7.2Hz,3H).

[0089] Figure 2 is the nuclear magnetic resonance spectrum of the racemic flurbiprofen prepared in Step 2, Figure 3 is the nuclear magnetic resonance spectrum of tromethamine, Figure 4 is the nuclear magnetic resonance spectrum of the racemic flurbiprofen tromethamine salt prepared in Step 3. From Figure 2 、 Figure 3 and Figure 4 it can be seen that after the racemic flurbiprofen prepared in Step 2 forms a salt, the chemical shifts of the chiral hydrogen of the racemic flurbiprofen and the methylene hydrogen of tromethamine change. The chemical shift of the hydrogen on the chiral carbon of the un-salted racemic flurbiprofen is 3.77, while in the racemic flurbiprofen tromethamine prepared in Step 3, the chemical shift is 3.64 (overlapping with the methylene part of tromethamine); the chemical shift of the methylene hydrogen of the un-salted tromethamine is 3.48, and it shifts to 3.64 after salting.

[0090] Figure 5 is the nuclear magnetic resonance overlay map of the racemic flurbiprofen prepared in Step 2 and the racemic flurbiprofen tromethamine salt prepared in Step 3. Figure 6 The nuclear magnetic resonance overlay map of tromethamine and the racemic flurbiprofen tromethamine salt prepared in Step 3. From Figure 5 and Figure 6 it can be clearly shown that the racemic flurbiprofen and tromethamine prepared in Step 2 have indeed reacted to form a salt.

[0091] Example 2

[0092] Example 2 provides the preparation of (S)-flurbiprofen and (S)-flurbiprofen tromethamine salt:

[0093] Step 1, prepare (S)-flurbiprofen phenethylamine salt:

[0094] Under room temperature conditions, place the racemic flurbiprofen (7.32 g, 0.030 mol) prepared in Example 1 in a 250 mL round-bottom flask, add a mixed solvent of 22.8 mL of ethyl acetate and 7.2 mL of ethanol, and dissolve it completely. Slowly add dropwise a solution of 7.2 mL of (S)-phenethylamine (1.80 g, 0.015 mmol) in ethyl acetate. After the addition is complete, heat at 65 °C for 1 h, cool to room temperature, and continue stirring for 2 h. Cool at 0 - 5 °C for 2 h, filter by suction, and wash with 48 mL of ethyl acetate three times to obtain a white crude solid. Recrystallize the crude product in a mixed solvent with a volume ratio of ethyl acetate / ethanol of 6:1, cool in a 4 °C refrigerator for 2 h, precipitate white crystals, and filter by suction to obtain 2.95 g of (S)-flurbiprofen phenethylamine salt, with a yield of 53.80%. After analyzing the contents of flurbiprofen and phenethylamine in the mother liquor, it is recycled.

[0095] Step 2, prepare (S)-flurbiprofen:

[0096] Under room temperature conditions, add the (S)-flurbiprofen phenethylamine salt (5.48 g, 0.015 mol) obtained in Step 1 to a 25 mL round-bottom flask, adjust the pH value to 2 - 3 with 7.5 mL of 15 wt% dilute hydrochloric acid, stir for 1 h, filter by suction, wash the filter cake with 2 mL of water three times, and dry to obtain 3.60 g of (S)-flurbiprofen, a white solid, with a yield of 98.35%. Figure 7 Figure 1 is the HPLC chiral analysis chromatogram of (S)-flurbiprofen prepared in Example 2. Table 1 is the analysis result of the optical purity (enantiomeric excess value) of (S)-flurbiprofen obtained in Example 2. Compared with Figure 1 the HPLC chiral chromatogram of the racemic flurbiprofen prepared in Example 1 in [reference], it can be seen that the peak area of the first peak near the retention time of 13.7 min in Table 1 is very small, at 1.71%; the peak area of the second peak near the retention time of 15.0 min is 98.29%. From this, the enantiomeric excess value of the obtained (S)-flurbiprofen is calculated to be 96.58%.

[0097] Table 1 Analysis result of the optical purity (enantiomeric excess value) of (S)-flurbiprofen obtained in Example 2

[0098] NO. Name RT Area %Area Height 1 R 13.751 52748 1.71 2380 2 S 15.062 3034665 98.29 149320

[0099] Step 3, prepare (S)-flurbiprofen tromethamine salt:

[0100] The method for preparing (S)-flurbiprofen tromethamine salt in Example 2 is basically the same as that in Step 3 of Example 1, except that: the racemic flurbiprofen in Step 3 of Example 1 is replaced with (S)-flurbiprofen prepared in Step 2 of Example 2 to obtain (S)-flurbiprofen tromethamine salt.

[0101] Example 3

[0102] Example 3 provides the preparation of (R)-flurbiprofen and (R)-flurbiprofen tromethamine salt:

[0103] Step 1, prepare (R)-flurbiprofen phenethylamine salt: At room temperature, place the racemic flurbiprofen (7.32 g, 0.030 mol) prepared in Example 1 in a 250 mL round-bottom flask, add a mixed solvent of 22.8 mL of ethyl acetate and 7.2 mL of ethanol, and dissolve it completely. Slowly add dropwise a solution of 7.2 mL of (R)-phenethylamine (1.80 g, 0.015 mol) in ethyl acetate. After the addition is complete, heat at 65 °C for 1 h, cool to room temperature, and continue stirring for 2 h. Cool at 0 - 5 °C for 2 h, filter by suction, and wash 3 times with 48 mL of ethyl acetate to obtain a white crude solid. Recrystallize the crude product in a mixed solvent with a volume ratio of ethyl acetate / ethanol of 6:1, cool in a 4 °C refrigerator for 2 h, precipitate white crystals, and filter by suction to obtain 2.91 g of (R)-flurbiprofen phenethylamine salt, yield: 53.79%.

[0104] Step 2, prepare (R)-flurbiprofen:

[0105] The method for preparing (R)-flurbiprofen in Example 3 is basically the same as that in Step 2 of Example 2, except that: the (S)-flurbiprofen phenethylamine salt in Step 2 of Example 2 is replaced with the (R)-flurbiprofen phenethylamine salt prepared in Step 1 of Example 3 to obtain 3.58 g of (R)-flurbiprofen, a white solid, yield: 98.1%. Figure 8 The HPLC chiral analysis chromatogram of (R)-flurbiprofen prepared for Example 3. Table 2 is the analysis result of the optical purity (enantiomeric excess value) of (R)-flurbiprofen obtained in Example 3. Compared with Figure 1 the HPLC chiral analysis chromatogram of the racemic flurbiprofen prepared in Example 1, it can be seen from Table 2 that the enantiomeric excess value of the obtained (R)-flurbiprofen calculated according to the peak area is 97.6%.

[0106] Table 2 Analysis result of the optical purity (enantiomeric excess value) of (R)-flurbiprofen obtained in Example 3

[0107]

[0108] Step 3, prepare (R)-flurbiprofen tromethamine salt:

[0109] Example 3 The method for preparing (R)-flurbiprofen tromethamine salt is substantially the same as that in Step 3 of Example 1, except that: the racemic flurbiprofen in Step 3 of Example 1 is replaced with (R)-flurbiprofen prepared in Step 2 of Example 3 to obtain (R)-flurbiprofen tromethamine salt.

[0110] Example 4

[0111] Solubility tests of the racemic flurbiprofen prepared in Example 1, the racemic flurbiprofen tromethamine salt prepared in Example 1, the (R)-flurbiprofen tromethamine salt prepared in Example 3, and the (S)-flurbiprofen tromethamine salt prepared in Example 2 in water.

[0112] 1) Determination of detection wavelength

[0113] Weigh about 10.00 mg of the racemic flurbiprofen prepared in Example 1, completely dissolve it with methanol and transfer it to a 100 mL volumetric flask, make up the volume, and shake well. A stock solution of racemic flurbiprofen with a concentration of 100.00 μg / mL is obtained. Precisely pipette 2.0 mL into a 25 mL volumetric flask, dilute and make up the volume with methanol to obtain a test solution of racemic flurbiprofen with a concentration of 8.0 μg / mL. Using methanol solvent as the blank control, perform UV scanning on the sample in the wavelength range of 200 - 400 nm to determine that the maximum absorption wavelength of racemic flurbiprofen is 245 nm.

[0114] 2) Establishment of UV standard curve

[0115] Precisely pipette an appropriate amount of the stock solution of racemic flurbiprofen with a concentration of 100.00 μg / mL into 25 mL volumetric flasks, and dilute with methanol to solutions with concentrations of 1.00, 2.00, 4.00, 6.00, 8.00, 10.00, 12.00, and 14.00 μg / mL respectively. Using methanol as the blank control, perform absorbance detection at the detection wavelength, and repeat the experiment three times in parallel. Plot a standard curve with the drug concentration as the abscissa and the sample absorbance as the ordinate, and perform linear fitting to obtain the absorbance-concentration working curve of racemic flurbiprofen as shown in Figure 9 Figure.

[0116] According to Figure 9 the concentration-absorbance standard curve of racemic flurbiprofen shown in Figure, the content (μg / mL) of racemic flurbiprofen in the test solution is calculated by formula 1:

[0117] x = (y - 0.1538) / 0.0842, R 2 = 0.9990 Formula 1;

[0118] In Formula 1: y is the absorbance value obtained from the test, and x is the content (μg / mL) of the racemic flurbiprofen in the test solution.

[0119] The concentration-absorbance standard curve of the racemic flurbiprofen tromethamine salt prepared in Example 1, the concentration-absorbance standard curve of the (R)-flurbiprofen tromethamine salt prepared in Example 3, and the concentration-absorbance standard curve of the (S)-flurbiprofen tromethamine salt prepared in Example 2 were established according to the method for establishing the concentration-absorbance standard curve of the racemic flurbiprofen prepared in Example 1 above. Thus, the standard curve equation of racemic flurbiprofen tromethamine salt was obtained: x = (y - 0.1457) / 0.0851, R 2 = 0.9990; the standard curve equation of (R)-flurbiprofen tromethamine salt: x = (y - 0.1426) / 0.0850, R 2 = 0.9998; the standard curve equation of (S)-flurbiprofen tromethamine salt: x = (y - 0.1406) / 0.0856, R 2 = 0.9990.

[0120] 3) Solubility determination

[0121] In a 25 mL round-bottom flask, add 5 mL of pure water and an appropriate amount of the racemic flurbiprofen prepared in Example 1, the racemic flurbiprofen tromethamine salt prepared in Example 1, the (R)-flurbiprofen tromethamine salt prepared in Example 3, or the (S)-flurbiprofen tromethamine salt prepared in Example 2, and keep the racemic flurbiprofen prepared in Example 1, the racemic flurbiprofen tromethamine salt prepared in Example 1, the (R)-flurbiprofen tromethamine salt prepared in Example 3, or the (S)-flurbiprofen tromethamine salt prepared in Example 2 in an excessive state, and stir at room temperature for 3 h. After centrifuging the solution, filter it through a 0.22 μm polyethersulfone membrane, accurately measure an appropriate amount of the filtrate, make up the volume to 25 mL in a volumetric flask, shake well, and measure the absorbance at 245 nM with pure water as a control. If the absorbance value is too large, dilute and make up the volume again according to the same method and then test.

[0122] Table 3 Solubility of flurbiprofen and flurbiprofen tromethamine salt in water *

[0123] Sample Name (±)Flurbiprofen (±)Flurbiprofen Trometamol (R)-Flurbiprofen Trometamol (S)-Flurbiprofen Trometamol Solubility 12.05 μg / mL 9.30 mg / mL 7.68 mg / mL 7.32 mg / mL

[0124] * The test temperature is 22 °C; the experiment was repeated three times.

[0125] As can be seen from the solubility test results in Table 3, the racemic flurbiprofen prepared in Example 1 has very low solubility in water and cannot meet the actual needs of research and clinical practice. Currently, it is derivatized into flurbiprofen axetil and then formulated into an emulsion with excipients such as refined soybean oil, refined lecithin, surfactants, and glycerol for use. Tromethamine is a non-sodium amino buffer base. Clinically, it is used to treat metabolic acidosis and respiratory acidosis with very low toxic and side effects. It should be noted that in the absence of excipients such as surfactants, the solubility of flurbiprofen axetil in water is even lower than that of flurbiprofen, and it is not detected in the aqueous phase. After salifying flurbiprofen with tromethamine in the present invention, the solubility is greatly improved, which can meet the actual needs of research and clinical practice.

[0126] Example 5

[0127] (±) / (R) / (S)-Flurbiprofen Tromethamine: Experimental Study on Its Effect on Pain Induced by Formaldehyde in Mice

[0128] 1. Experimental Animals

[0129] 25 - 34 g ICR mice, SPF grade, half male and half female, 110 in total.

[0130] 2. Grouping and Administration

[0131] Grouping: 110 ICR mice were screened according to body weight and gender and randomly divided into 11 groups, namely the model control group, positive control group (flurbiprofen axetil injection - 6 μM), (±)-flurbiprofen tromethamine low (3 μM), medium (6 μM), high (12 μM) dose groups, (R)-flurbiprofen tromethamine low (3 μM), medium (6 μM), high (12 μM) dose groups, (S)-flurbiprofen tromethamine low (3 μM), medium (6 μM), high (12 μM) dose groups, with 10 mice in each group, half male and half female. The day when the animals were included in the group was recorded as D0.

[0132] Administration: After grouping, the animals in each group were administered once a day by tail vein injection, with a dosing volume of 5 mL / kg. The model control group was given an equal volume of 0.9% sodium chloride injection.

[0133] 3. Detection Indexes

[0134] After administration, a 2.5% formaldehyde solution was subcutaneously injected into the right hind paw sole of each group of animals immediately, with an injection volume of 30 μL per mouse. After injection, the mice were placed in an inverted 1000 mL beaker and timed immediately. Then, the cumulative pain response time of the mice in two time phases of 0 - 10 min and 10 - 30 min after injection was recorded respectively, and the pain response time was recorded as the pain threshold.

[0135] 4. Experimental Results

[0136] Effect on the pain reaction time of mice after formaldehyde-induced pain.

[0137] Table 4 Effect on the pain reaction time of mice after formaldehyde-induced pain ( n = 10)

[0138]

[0139] Note: Compared with A: * indicates P < 0.05, ** indicates P < 0.01; compared with B: # indicates P < 0.05, ## indicates P < 0.01; compared with C: & indicates P < 0.05, && indicates P < 0.01; compared with D: △ indicates P < 0.05, △△ indicates P < 0.01; compared with E: ▲ indicates P < 0.05, ▲▲ indicates P < 0.01; compared with I: ◇ indicates P < 0.05, ◇◇ indicates P < 0.01; compared with J: ◆ indicates P < 0.05, ◆◆ indicates P < 0.01; compared with K: □ indicates P < 0.05, □□ indicates P < 0.01.

[0140] The results of the pain reaction time of mice after formaldehyde-induced pain in Table 4 show that: compared with the model control group, the positive control group (flurbiprofen axetil injection), the low, medium, and high dose groups of (±)-flurbiprofen tromethamine, the low, medium, and high dose groups of (R)-flurbiprofen tromethamine, and the low, medium, and high dose groups of (S)-flurbiprofen tromethamine all had significant inhibitory effects (P < 0.05 or P < 0.01). Compared with the positive control (flurbiprofen axetil injection), the (±)-flurbiprofen tromethamine, and the (S)-flurbiprofen tromethamine dose groups at equimolar doses, the (R)-flurbiprofen tromethamine significantly reduced the pain reaction time in the second phase (10 - 30 min) of formaldehyde-induced pain model mice (P < 0.05 or P < 0.01).

[0141] 5. Conclusion

[0142] In summary, the positive control (flurbiprofen axetil injection), the low, medium, and high dose groups of (±)-flurbiprofen tromethamine, the low, medium, and high dose groups of (R)-flurbiprofen tromethamine, and the low, medium, and high dose groups of (S)-flurbiprofen tromethamine all had significant inhibitory effects on the pain reaction time in the second phase of formaldehyde-induced pain model mice, and had no significant effect on the pain reaction time in the first phase, indicating that the pain inhibition effect of the three is not a central inhibitory effect. At equidose, the pain inhibition effect was (R)-flurbiprofen tromethamine > (±)-flurbiprofen tromethamine ≈ positive control group (flurbiprofen axetil injection) > (S)-flurbiprofen tromethamine.

[0143] Example 6

[0144] Experimental study on the effect of (±) / (R) / (S)-flurbiprofen tromethamine on toe tenderness after single-foot inflammation in rats

[0145] 1. Experimental animals

[0146] SD rats, weighing 173 - 259 g, SPF grade, with an equal number of males and females, 88 rats in total.

[0147] 2. Grouping, model establishment and drug administration

[0148] Grouping: A number of SD rats with qualified adaptive observation were selected, and the pain threshold of the plantar surface of the hind paws of both hind limbs was measured. Animals with a basic pain threshold outside 200 - 300 g were excluded. They were randomly and evenly divided into 11 groups according to the threshold: model control group, positive control group (flurbiprofen axetil injection - 4 μM), (±)-flurbiprofen tromethamine low (2 μM), medium (4 μM), high (8 μM) dose groups, (R)-flurbiprofen tromethamine low (2 μM), medium (4 μM), high (8 μM) dose groups, (S)-flurbiprofen tromethamine low (2 μM), medium (4 μM), high (8 μM) dose groups, with 8 rats in each group, and an equal number of males and females.

[0149] Model establishment: After grouping, 4% kaolin suspension was injected into the plantar surface of the right hind limb of each group of rats, 0.1 mL / rat, and massaged for 5 min after injection; 1 h later, 2% carrageenan was injected, 0.05 mL / rat, and massaged for 5 min after injection for model establishment.

[0150] Drug administration: Immediately after injecting carrageenan, single - dose administration was carried out once a day for each group. All groups were administered by intravenous injection, with a dosing volume of 5 mL / kg. The model control group was given an equal volume of 0.9% sodium chloride injection.

[0151] 3. Detection indexes

[0152] Measure the pain threshold of the plantar surface of the hind paws of both hind limbs of each group of rats at about 15 min, 0.5 h, 1 h, and 2 h after drug administration, and take the measured values of the left and right hind paws as the pain threshold at that time.

[0153] 4. Experimental results

[0154] Effect on the pain threshold of the inflamed hind paw of rats

[0155] Table 5 Effect on the pain threshold of the inflamed hind paw of rats ( n = 10)

[0156]

[0157]

[0158] Note: Compared with 0 h: & indicates P < 0.05, && indicates P < 0.01; compared with A: * indicates P < 0.05, ** indicates P < 0.01; compared with B: # indicates P < 0.05, ## indicates P < 0.01; compared with C: △ indicates P < 0.05, △△ indicates P < 0.01; compared with D: ▲ indicates P < 0.05, ▲▲ indicates P < 0.01; compared with E: ◇ indicates P < 0.05, ◇◇ indicates P < 0.01; compared with F: ◆ indicates P < 0.05, ◆◆ indicates P < 0.01; compared with G: □ indicates P < 0.05, □□ indicates P < 0.01; compared with H: ● indicates P < 0.05, ●● indicates P < 0.01.

[0159] The results of the effects on the pain threshold of the inflamed hind paw of rats in Table 5 showed that compared with 0 h, the pain threshold of the inflamed hind paw of rats in each group showed an upward trend at 15 min (except for the model control group), reached the peak at 0.5 h, and then turned to a downward trend within 1 - 2 h; compared with the model control group, the positive control group (flurbiprofen axetil injection), the low, medium, and high dose groups of (±)-flurbiprofen trometamol, the low, medium, and high dose groups of (R)-flurbiprofen trometamol, and the low, medium, and high dose groups of (S)-flurbiprofen trometamol all showed a significant upward trend in the pain threshold of the inflamed hind paw of rats within the time range of 0.15 - 2 h (P < 0.05 or P < 0.01). Among them, the pain threshold of the test substances in each group reached the peak at 0.5 h; compared with the positive control (flurbiprofen axetil injection) at an equimolar dose, the medium dose groups of (R)-flurbiprofen trometamol and (S)-flurbiprofen trometamol had an increase in the pain threshold of the inflamed hind paw of rats at 0.5 - 1 h (P < 0.01); compared with the low dose group of (±)-flurbiprofen trometamol, the low dose group of (R)-flurbiprofen trometamol had an increase in the pain threshold at 0.5 h (P < 0.05); compared with the medium dose group of (±)-flurbiprofen trometamol, the medium dose group of (R)-flurbiprofen trometamol had an increase in the pain threshold at 0.5 - 1 h (P < 0.05); compared with the high dose group of (±)-flurbiprofen trometamol, the high dose group of (R)-flurbiprofen trometamol had an increase in the pain threshold at 0.5 - 1 h (P < 0.05); compared with the medium dose group of (R)-flurbiprofen trometamol, the medium dose group of (S)-flurbiprofen trometamol had a decrease in the pain threshold at 0.5 - 1 h (P < 0.05), and compared with the high dose group of (R)-flurbiprofen trometamol, the high dose group of (S)-flurbiprofen trometamol had a decrease in the pain threshold at 0.5 h (P < 0.05).

[0160] 5. Conclusion

[0161] In summary, the positive control (flurbiprofen axetil injection), the low, medium, and high dose groups of (±)-flurbiprofen trometamol, the low, medium, and high dose groups of (R)-flurbiprofen trometamol, and the low, medium, and high dose groups of (S)-flurbiprofen trometamol all significantly reduced the toe pain threshold in rats after unilateral foot inflammation. At equal doses, the pain inhibition effect was (R)-flurbiprofen trometamol > (±)-flurbiprofen trometamol ≈ positive control group (flurbiprofen axetil injection) > (S)-flurbiprofen trometamol.

[0162] As can be seen from the above examples, in the present invention, flurbiprofen raw material, trometamol, and an organic solvent are mixed for a salt-forming reaction to obtain the flurbiprofen trometamol salt; the flurbiprofen raw material includes racemic flurbiprofen, (R)-flurbiprofen, or (S)-flurbiprofen. The preparation method provided by the present invention has the characteristics of simple process flow, convenient industrial production, and low cost. Compared with flurbiprofen, the flurbiprofen trometamol salt obtained by the salt-forming reaction in the present invention has greatly increased solubility in water, meeting the requirements of preparation and clinical use. The flurbiprofen trometamol salt provided by the present invention has excellent solubility. At the same time, the (R)-flurbiprofen trometamol salt or (S)-flurbiprofen trometamol salt has optical activity and reduces toxic and side effects, which is of great significance.

[0163] Although the above examples have described the present invention in detail, they are only a part of the embodiments of the present invention, not all of them. Other embodiments can be obtained based on these embodiments without creative efforts, and these embodiments all fall within the protection scope of the present invention.

Claims

1. A flurbiprofen amine triol salt, comprising one or more of a racemic flurbiprofen amine triol salt, a (R)-flurbiprofen amine triol salt and a (S)-flurbiprofen amine triol salt; The chemical structural formula of the racemic flurbiprofen amine triol salt is shown in Formula 1: The chemical structural formula of the (R)-flurbiprofen amine triol salt is shown in Formula 2: The chemical structural formula of the (S)-flurbiprofen amine triol salt is shown in Formula 3:

2. The method for preparing the flurbiprofen amine triol salt according to claim 1, characterized in that: The following steps are involved: The flurbiprofen raw material, tromethamine and an organic solvent are mixed to form a salt to obtain the flurbiprofen tromethamine salt; the flurbiprofen raw material includes racemic flurbiprofen, (R)-flurbiprofen or (S)-flurbiprofen; the chemical structure of the tromethamine is shown in Formula 4:

3. The preparation method according to claim 2, characterized in that: The preparation method of the racemic flurbiprofen comprises the following steps: Mixing magnesium metal, 4-bromo-2-fluorobiphenyl and an organic solvent for a first reaction to obtain a Grignard reagent; The Grignard reagent, 2-bromopropionic acid alkali metal salt and organic solvent are mixed to carry out a second reaction to obtain a reaction solution; The reaction solution is subjected to a first acidification to obtain the racemic flurbiprofen.

4. The preparation method according to claim 3, characterized in that: The preparation method of the (R)-flurbiprofen or (S)-flurbiprofen comprises the following steps: The racemic flurbiprofen, a chiral reagent and an organic solvent are mixed to perform a chiral resolution reaction, wherein the chiral reagent is (R)-phenethylamine or (S)-phenethylamine, to obtain (R)-flurbiprofen phenethylamine salt or (S)-flurbiprofen phenethylamine salt; the organic solvents used in the chiral resolution reaction are ethyl acetate and ethanol; the volume ratio of ethyl acetate to ethanol is 2 to 10:1; The (R)-flurbiprofen phenethylamine salt or (S)-flurbiprofen phenethylamine salt is subjected to a second acidification to obtain (R)-flurbiprofen or (S)-flurbiprofen.

5. The preparation method according to claim 2, characterized in that: The molar ratio of the flurbiprofen raw material to the tromethamine is 1:1; The organic solvent used in the salt-forming reaction includes water and one or more of acetone, methanol and ethanol.

6. The preparation method according to claim 3, characterized in that: The molar ratio of the 4-bromo-2-fluorobiphenyl to the metallic magnesium is 1:1 to 1.2; The temperature of the first reaction is ≤60°C.

7. The preparation method according to claim 4, characterized in that: The temperature of the chiral resolution reaction is 30-75° C. and the time is 1-6 hours.

8. The preparation method according to claim 4 or 7, characterized in that: After the chiral resolution reaction is completed, a crude product of (R)-flurbiprofen phenethylamine salt or a crude product of (S)-flurbiprofen phenethylamine salt is obtained; Before the second acidification, the method further includes: recrystallizing the crude (R)-flurbiprofen phenethylamine salt or the crude (S)-flurbiprofen phenethylamine salt, wherein the solvents used for the recrystallization are ethyl acetate and ethanol; and the volume ratio of ethyl acetate to ethanol is 2 to 10:

1.

9. The preparation method according to claim 3, characterized in that: The 2-bromopropionic acid alkali metal salt is sodium 2-bromopropionate; The temperature of the second reaction is 50-65°C and the time is 6-10h; The first acidification agent used in the first acidification is a sulfuric acid solution, The first acidification step obtains a first acidified solution; and further comprises: Extracting the first acidified solution with an organic solvent to obtain an extracted organic phase; The extracted organic phase is dried and then the solvent is removed to obtain the crude racemic flurbiprofen; The crude racemic flurbiprofen is purified by silica gel column to obtain the racemic flurbiprofen; the elution solvents used in the silica gel column purification are petroleum ether and ethyl acetate.

10. Use of the flurbiprofen amine triol salt according to claim 1 or the flurbiprofen amine triol salt prepared by the preparation method according to any one of claims 2 to 9 in the preparation of anti-inflammatory and analgesic drugs.

Images