阅读说明：本技术 一种氟比洛芬的制备方法 (Preparation method of flurbiprofen ) 是由 段浩田 范希丽 赵寅堡 甄志彬 邓声菊 徐艳君 王田园 于 2020-06-25 设计创作，主要内容包括：本发明涉及一种氟比洛芬的制备方法。该方法包括下述步骤：(1)2-氟-4-溴联苯和金属镁在40-65℃下反应,制得(2-氟-[1,1’-联苯]-4-基)溴化镁；(2)(2-氟-[1,1’-联苯]-4-基)溴化镁与2-溴丙酸乙酯在镍催化剂作用下反应,制得氟比洛芬乙酯；(3)氟比洛芬乙酯水解,制得氟比洛芬钠；(4)将氟比洛芬钠溶于水,加酸调pH,析出氟比洛芬。本发明制备方法避免使用高危试剂,所用化学试剂廉价易得；该制备方法具有操作简便、安全可控、重现性好、所得产品产率高、纯度高、安全环保、成本低、适合工业化生产等优点。(The invention relates to a preparation method of flurbiprofen. The method comprises the following steps: (1) reacting 2-fluoro-4-bromobiphenyl with metal magnesium at 40-65 ℃ to prepare (2-fluoro- [1,1' -biphenyl ] -4-yl) magnesium bromide; (2) reacting (2-fluoro- [1,1' -biphenyl ] -4-yl) magnesium bromide with ethyl 2-bromopropionate under the action of a nickel catalyst to prepare flurbiprofen ethyl ester; (3) hydrolyzing flurbiprofen ethyl ester to obtain flurbiprofen sodium; (4) dissolving flurbiprofen sodium in water, and adding acid to adjust pH to precipitate flurbiprofen. The preparation method avoids using high-risk reagents, and the used chemical reagents are cheap and easy to obtain; the preparation method has the advantages of simple operation, safety, controllability, good reproducibility, high yield of the obtained product, high purity, safety, environmental protection, low cost, suitability for industrial production and the like.)

1. A preparation method of flurbiprofen ethyl ester is characterized by comprising the following steps: reacting (2-fluoro- [1,1' -biphenyl ] -4-yl) magnesium bromide with ethyl 2-bromopropionate under the action of a nickel catalyst to prepare flurbiprofen ethyl ester, wherein the nickel catalyst carries any one of a complex or a ligand.

2. The method according to claim 1, wherein the nickel catalyst is selected from the group consisting of bis (triphenylphosphonium) bromide, ethylene glycol dimethyl ether nickel bromide, bromine [ (2, 6-pyridyldiyl) bis (3-methyl-1-imidazol-2-methylidene) ] nickel bromide, nickel bromide hexamine complex, bis (tributylphosphine) nickel dibromide, nickel bromide diethylene glycol dimethyl ether complex, 2, 3-bis (2, 6-diisopropylphenylimino) butane nickel dibromide, nickel dibromide dimethoxyethane, bis (triphenylphosphonium) chloride, 1, 2-bis (diphenylphosphino) ethane nickel chloride, 1, 3-bis (diphenylphosphinopropane) nickel dichloride, tetrakis (triphenylphosphine) nickel, (1,1' -bis (diphenylphosphino) ferrocene) nickel dichloride, bis (tricyclohexylphosphine) nickel dichloride, Nickel chloride ethylene glycol dimethyl ether complex, [1, 3-bis (2, 6-diisopropylphenyl) imidazole-2-methylidene ] triphenylphosphine nickel dichloride, bis [ (2-dimethylamino) phenyl ] amine nickel chloride, methallyl nickel chloride dimer, bis [ dicyclohexyl (phenyl) phosphine ] (o-tolyl) nickel chloride, bis (dicyclohexylphenylphosphino) nickel dichloride, [4,4 '-bis (1, 1-dimethylethyl) -2,2' -bipyridine ] nickel dichloride, bis (triethylphosphine) nickel chloride, nickel (cyclopentadienyl) triphenylphosphine nickel chloride, or a combination thereof.

3. The production method according to any one of claims 1 to 2, wherein the molar ratio of the (2-fluoro- [1,1' -biphenyl ] -4-yl) magnesium bromide: the molar ratio of the nickel catalyst is 1:0.01 to 1:0.50, preferably 1:0.02 to 1:0.30, more preferably 1:0.04 to 1: 0.15.

4. The process according to any one of claims 1 to 3, wherein the (2-fluoro- [1,1' -biphenyl ] -4-yl) magnesium bromide is prepared by reacting 2-fluoro-4-bromobiphenyl with magnesium metal at a temperature of 40 to 65 ℃, preferably at a temperature of 50 to 65 ℃.

5. A method for preparing flurbiprofen, comprising the steps of:

(1) reacting 2-fluoro-4-bromobiphenyl with metal magnesium at 40-65 ℃ to prepare (2-fluoro- [1,1' -biphenyl ] -4-yl) magnesium bromide;

(2) reacting (2-fluoro- [1,1' -biphenyl ] -4-yl) magnesium bromide with ethyl 2-bromopropionate under the action of a nickel catalyst to prepare flurbiprofen ethyl ester;

(3) hydrolyzing flurbiprofen ethyl ester to obtain flurbiprofen sodium;

(4) dissolving flurbiprofen sodium in water, and adding acid to adjust pH to precipitate flurbiprofen.

6. The method according to claim 5, wherein the hydrolysis reaction in step (3) is selected from any one of acid hydrolysis and base hydrolysis.

7. The process according to any one of claims 5 to 6, wherein the reaction solution obtained by the hydrolysis reaction in the step (3) is subjected to extraction, collection of an aqueous phase and crystallization to obtain flurbiprofen sodium.

8. The method according to any one of claims 5 to 7, wherein the extraction solvent in step (3) is a benzene-based reagent, preferably any one of benzene, xylene, toluene, or a combination thereof.

9. The process according to any one of claims 5 to 8, wherein the extraction temperature in step (3) is 60 to 100 ℃, preferably 70 to 100 ℃, more preferably 80 to 98 ℃.

10. The production method according to any one of claims 5 to 9, wherein the crystallization in the step (3) is temperature-reduced crystallization.

Technical Field

The invention belongs to the technical field of medicines, and particularly relates to a preparation method of flurbiprofen.

Background

Flurbiprofen is a nonsteroidal anti-inflammatory drug which is marketed in 1977, and is widely used for clinically treating collagen tissue diseases, soft tissue diseases, mild and moderate pain and the like, including rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, sprains and strains, dysmenorrhea, postoperative pain, toothache and the like. Flurbiprofen has a strong analgesic effect and small side effects, and is listed in the pharmacopoeias of many countries such as the united states, europe, japan, uk, india, korea, and china. Flurbiprofen ester is a prodrug of flurbiprofen, and is used for postoperative analgesia and various cancers.

CN108558651A discloses a preparation method of flurbiprofen, which comprises the following steps:

in the method, 4-bromo-2-fluorobiphenyl reacts with magnesium metal to generate Grignard reagent (2-fluoro- [1,1' -biphenyl)]After-4-yl) magnesium bromide, with 2-bromopropaneIn TiCl with ethyl acid ester₄Carrying out coupling reaction under the catalysis of the (1), and carrying out alkaline hydrolysis, acidification and recrystallization on the prepared intermediate flurbiprofen ethyl ester to obtain the flurbiprofen. However, this method has the following drawbacks: firstly, TiCl₄The material has strong corrosivity, and has large corrosivity on reaction equipment and feeding equipment; second, TiCl₄The volatility is high, the reaction is violent when the HCl white smoke is contacted with water, the HCl white smoke is reacted with water in the air when the HCl white smoke is contacted with the air in the using process, HCl white smoke with strong irritation and corrosivity is generated, a large amount of heat is emitted, the protection requirement on production personnel is high, the potential safety hazard is increased due to the large amount of heat emission, the protection needs to be strengthened, the production cost is further increased, and the industrial production is not facilitated; III is TiCl₄The volatility is high, the feeding amount is not accurately controlled, the reaction is violent, the controllability of the reaction is poor, a large number of byproducts are generated in the preparation of the product, the difficulty of product purification and three-waste treatment is increased, the production period is prolonged, the production cost is increased, and the industrial production is not facilitated.

Document 1 (zeihuxing et al, "synthesis of 2- (3-fluoro-4-phenyl) phenylpropionic acid", jiang xi chemical industry, 3 rd stage 2006, 83-86) discloses a method for preparing flurbiprofen, which comprises reacting 4-bromo-2-fluorobiphenyl with magnesium metal to generate Grignard reagent (2-fluoro- [1,1' -biphenyl ] -4-yl) magnesium bromide, then carrying out coupling reaction with ethyl 2-bromopropionate under the action of a catalyst to prepare intermediate flurbiprofen ethyl ester, and then carrying out acidification and hydrolysis to prepare flurbiprofen. However, this document does not disclose the catalyst and the purity of the product obtained.

Document 2 (Wangzunyuan et al, a new method for synthesizing flurbiprofen, Vol.24, No.11, 687-Buffersone 688, 2005) discloses a method for preparing flurbiprofen, which comprises reacting 4-bromo-2-fluorobiphenyl with magnesium metal to generate Grignard reagent (2-fluoro- [1,1' -biphenyl ] -4-yl) magnesium bromide, adding 2-bromosodium propionate, refluxing, performing coupling reaction, preparing intermediate flurbiprofen sodium, and acidifying to obtain flurbiprofen. This method has the following drawbacks: firstly, 2-bromosodium propionate is directly added, the coupling reaction is heterogeneous, the reaction yield is low, and a plurality of byproducts are generated; secondly, a large amount of salt is added in the reaction, so that the stirring is difficult, the reaction efficiency, the quality of the final product and the reaction yield are influenced, the manufacturing cost is high, and the method is not suitable for industrial production.

Therefore, the preparation method of flurbiprofen is simple and convenient to operate, safe and controllable, high in yield, high in purity, green and environment-friendly, low in production cost and easy for industrial production.

Disclosure of Invention

The invention aims to provide a preparation method of flurbiprofen ethyl ester, which comprises the following steps: reacting (2-fluoro- [1,1' -biphenyl ] -4-yl) magnesium bromide with ethyl 2-bromopropionate under the action of a nickel catalyst to obtain flurbiprofen ethyl ester.

In a preferred embodiment of the present invention, the nickel catalyst has either a complex or a ligand.

In a preferred embodiment of the present invention, the nickel catalyst is selected from the group consisting of bis (triphenyl) nickel bromide, ethylene glycol dimethyl ether nickel bromide, bromine [ (2, 6-pyridyldiyl) bis (3-methyl-1-imidazol-2-methylidene) ] nickel bromide, nickel bromide hexamine complex, bis (tributylphosphine) nickel dibromide, nickel bromide diethylene glycol dimethyl ether complex, 2, 3-bis (2, 6-diisopropylphenylimino) butane nickel dibromide, nickel dibromide dimethoxyethane, bis (triphenyl nickel chloride), 1, 2-bis (diphenylphosphino) ethane nickel chloride, 1, 3-bis (diphenylphosphinopropane) nickel dichloride, tetrakis (triphenylphosphine) nickel, (1,1' -bis (diphenylphosphino) ferrocene) nickel dichloride, bis (tricyclohexylphosphine) nickel dichloride, nickel chloride ethylene glycol dimethyl ether complex, Any one of [1, 3-bis (2, 6-diisopropylphenyl) imidazol-2-methylidene ] triphenylphosphine nickel dichloride, bis [ (2-dimethylamino) phenyl ] amine nickel chloride, methallyl nickel chloride dimer, bis [ dicyclohexyl (phenyl) phosphine ] (o-tolyl) nickel chloride, bis (dicyclohexylphenylphosphino) nickel dichloride, [4,4 '-bis (1, 1-dimethylethyl) -2,2' -bipyridine ] nickel dichloride, bis (triethylphosphine) nickel chloride, and (cyclopentadienyl) triphenylphosphine nickel chloride, or a combination thereof.

In a preferred embodiment of the present invention, the ratio of (2-fluoro- [1,1' -biphenyl ] -4-yl) magnesium bromide: the molar ratio of the nickel catalyst is 1:0.01 to 1:0.50, preferably 1:0.02 to 1:0.30, more preferably 1:0.04 to 1: 0.15.

In a preferred embodiment of the present invention, the ratio of (2-fluoro- [1,1' -biphenyl ] -4-yl) magnesium bromide: the molar ratio of ethyl 2-bromopropionate is 1:0.8 to 1:1.2, preferably 1:0.9 to 1: 1.1.

In the preferred technical scheme of the invention, the reaction temperature is 0-65 ℃, preferably 10-50 ℃, and more preferably 20-40 ℃.

In a preferred embodiment of the present invention, the reaction solvent is selected from any one or a combination of ethers, halogenated hydrocarbons, and benzenes.

In a preferred technical scheme of the invention, the ether is selected from one or a combination of tetrahydrofuran, methyl ethyl ether, diethyl ether, butyl ether and amyl ether.

In a preferred embodiment of the present invention, the halogenated hydrocarbon is selected from any one of dichloromethane and chloroform, or a combination thereof.

In a preferred embodiment of the present invention, the benzene is selected from any one of benzene, toluene, and xylene, or a combination thereof.

In the preferred technical scheme of the invention, the (2-fluoro- [1,1' -biphenyl ] -4-yl) magnesium bromide is prepared by reacting 2-fluoro-4-bromobiphenyl with metal magnesium at 40-65 ℃, and the preferred reaction temperature is 50-65 ℃.

Another object of the present invention is to provide a method for preparing flurbiprofen, which comprises the following steps:

(1) reacting 2-fluoro-4-bromobiphenyl with metal magnesium at 40-65 ℃ to prepare (2-fluoro- [1,1' -biphenyl ] -4-yl) magnesium bromide;

(2) reacting (2-fluoro- [1,1' -biphenyl ] -4-yl) magnesium bromide with ethyl 2-bromopropionate under the action of a nickel catalyst to prepare flurbiprofen ethyl ester;

(3) hydrolyzing flurbiprofen ethyl ester to obtain flurbiprofen sodium;

(4) dissolving flurbiprofen sodium in water, and adding acid to adjust pH to precipitate flurbiprofen.

In the preferred technical scheme of the invention, the reaction temperature in the step (1) is 50-65 ℃.

In a preferred embodiment of the present invention, the nickel catalyst in the step (2) has any one of a complex and a ligand.

In a preferred embodiment of the present invention, the nickel catalyst in step (2) is selected from the group consisting of bis (triphenyl) nickel bromide, ethylene glycol dimethyl ether nickel bromide, bromine [ (2, 6-pyridyldiyl) bis (3-methyl-1-imidazol-2-methylidene) ] nickel bromide, nickel bromide hexamine complex, bis (tributylphosphine) nickel dibromide, nickel bromide diethylene glycol dimethyl ether complex, 2, 3-bis (2, 6-diisopropylphenylimino) butane nickel dibromide, nickel dibromide dimethoxyethane, bis (triphenyl nickel chloride), 1, 2-bis (diphenylphosphino) ethane nickel chloride, 1, 3-bis (diphenylphosphinopropane) nickel dichloride, tetrakis (triphenylphosphine) nickel, (1,1' -bis (diphenylphosphino) ferrocene) nickel dichloride, bis (tricyclohexylphosphine) nickel dichloride, Nickel chloride ethylene glycol dimethyl ether complex, [1, 3-bis (2, 6-diisopropylphenyl) imidazole-2-methylidene ] triphenylphosphine nickel dichloride, bis [ (2-dimethylamino) phenyl ] amine nickel chloride, methallyl nickel chloride dimer, bis [ dicyclohexyl (phenyl) phosphine ] (o-tolyl) nickel chloride, bis (dicyclohexylphenylphosphino) nickel dichloride, [4,4 '-bis (1, 1-dimethylethyl) -2,2' -bipyridine ] nickel dichloride, bis (triethylphosphine) nickel chloride, nickel (cyclopentadienyl) triphenylphosphine nickel chloride, or a combination thereof.

In a preferred embodiment of the present invention, the (2-fluoro- [1,1' -biphenyl ] -4-yl) magnesium bromide in the step (2): the molar ratio of the nickel catalyst is 1:0.01 to 1:0.50, preferably 1:0.02 to 1:0.30, more preferably 1:0.04 to 1: 0.15.

In a preferred embodiment of the present invention, the (2-fluoro- [1,1' -biphenyl ] -4-yl) magnesium bromide in the step (2): the molar ratio of ethyl 2-bromopropionate is 1:0.8 to 1:1.2, preferably 1:0.9 to 1: 1.1.

In a preferred embodiment of the present invention, the temperature of the catalytic reaction in step (2) is 0 to 70 ℃, preferably 10 to 65 ℃, and more preferably 15 to 50 ℃.

In a preferred embodiment of the present invention, the reaction solvent in step (2) is selected from any one or a combination of ethers, halogenated hydrocarbons, and benzenes, preferably any one or a combination of tetrahydrofuran, methyl ethyl ether, butyl ether, amyl ether, dichloromethane, chloroform, benzene, toluene, and xylene.

In the preferred technical scheme of the invention, the reaction liquid prepared in the step (2) is directly used for the reaction in the step (3) after being filtered and/or extracted and then is subjected to concentration or non-concentration of the organic phase.

In a preferred embodiment of the present invention, the extraction solvent in step (2) is a benzene reagent, preferably any one or a combination of benzene, xylene and toluene.

In a preferred embodiment of the present invention, the concentration in step (2) is selected from any one or a combination of vacuum concentration, membrane concentration, atmospheric concentration, ultrafiltration concentration, and centrifugation concentration.

In a preferred embodiment of the present invention, the hydrolysis reaction in step (3) is selected from any one of acid hydrolysis and base hydrolysis.

In a preferred embodiment of the present invention, the hydrolysis reaction temperature in step (3) is 40 to 100 ℃, preferably 60 to 100 ℃, and more preferably 80 to 100 ℃.

In the preferable technical scheme of the invention, the reaction liquid obtained by hydrolysis reaction in the step (3) is extracted, the water phase is collected and crystallized to obtain the flurbiprofen sodium.

In a preferred embodiment of the present invention, the extraction solvent in step (3) is a benzene reagent, preferably any one or a combination of benzene, xylene and toluene.

In a preferred embodiment of the present invention, the extraction temperature in step (3) is 60 to 100 ℃, preferably 70 to 100 ℃, and more preferably 80 to 98 ℃.

In the preferred technical scheme of the invention, the crystallization in the step (3) is cooling crystallization.

In the preferred technical scheme of the invention, the crystallization temperature in the step (3) is 0-55 ℃, preferably 5-50 ℃, and more preferably 10-45 ℃.

In a preferred embodiment of the present invention, the flurbiprofen sodium aqueous solution in step (4) is heated to dissolve, preferably at a temperature of 70 to 100 ℃, more preferably 80 to 100 ℃, and still more preferably 85 to 95 ℃.

In a preferred embodiment of the present invention, the pH in step (4) is 1 to 5, preferably 1 to 4, more preferably 1 to 3, and still more preferably 1 to 2.

Unless otherwise indicated, when the present invention relates to percentages between liquids, said percentages are volume/volume percentages; the invention relates to the percentage between liquid and solid, said percentage being volume/weight percentage; the invention relates to the percentages between solid and liquid, said percentages being weight/volume percentages; the balance being weight/weight percent.

Compared with the prior art, the invention has the following beneficial technical effects:

first, the prior art uses TiCl as a catalyst₄The coupling reaction is carried out, the yield is very low, and the product is a high-risk and high-toxicity substance. The preparation method provided by the invention adopts the cheap and easily-obtained nickel catalyst, so that the reaction efficiency and the product yield are obviously improved, the purity of the prepared product is high, the generation of three wastes is reduced, the production period is shortened, the cost is further obviously reduced, and the preparation method has the advantages of high yield, environmental friendliness, suitability for industrial production and the like.

Secondly, column chromatography purification is avoided, hydrolysis recrystallization and acidification are adopted, and the prepared flurbiprofen is high in purity, meets the medicinal standard and guarantees the safety of medication.

Thirdly, the preparation method of the invention has stable process and good reproducibility, all the used reagents are industrial reagents, the price of the initial raw materials is low, the discharge of three wastes is reduced, and the preparation method is green and environment-friendly and is suitable for industrial production.

Detailed Description

The present invention is illustrated by the following examples, which should be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever. Other insubstantial modifications and adaptations of the present invention can be made without departing from the scope of the present invention.

Comparative examples 1 to 5Preparation method of flurbiprofen

Comparative examples 1-5 methods for the preparation of flurbiprofen (see table 1 for reaction conditions and results), comprising the following steps:

1) placing 15ml of tetrahydrofuran and 0.70g of magnesium chips in a reaction bottle, heating to reflux, dropping 2-fluoro-4-bromobiphenyl solution to initiate a Grignard reaction (6.25g of 2-fluoro-4-bromobiphenyl is dissolved in 15ml of tetrahydrofuran), and cooling to room temperature after the reaction is finished.

2) Adding 8.00g of ethyl 2-bromopropionate, a catalyst and 30ml of tetrahydrofuran into a reaction bottle, stirring, dropwise adding the Grignard reagent prepared in the step 1) at 20-30 ℃, and stirring overnight at 20-30 ℃ after dropwise adding. Filtering the reaction solution, leaching with tetrahydrofuran to remove solids, dripping purified water and dilute hydrochloric acid into the filtrate, separating an organic layer, extracting an aqueous layer with toluene, combining organic phases, washing with a saturated sodium chloride solution, drying with anhydrous sodium sulfate, and evaporating the solvent to dryness. Adding 1.5L of 3mol/L sodium hydroxide aqueous solution into the residue, heating and hydrolyzing at 80-100 ℃, carrying out thermal extraction on toluene at 30-90 ℃, taking the aqueous phase for crystallization at room temperature, filtering, and leaching the collected crystals. And adding water into the filter cake, heating to 80-100 ℃ for dissolving, decoloring by using activated carbon, carrying out heat filtration, adjusting the pH of the filtrate to 3 by using concentrated hydrochloric acid, precipitating a solid, filtering, washing with water, and drying to obtain the flurbiprofen.

TABLE 1

Comparative example	Kind of catalyst	Amount of catalyst used	The weight of flurbiprofen obtained	Yield of the reaction
					1	Anhydrous nickel chloride	0.18g	1.09g	18.0％
2	Titanium tetrachloride	0.26g	0.92g	15.1％
					3	Anhydrous ferric trichloride	0.22g	0.83g	13.7％
4	Cuprous iodide	0.26g	0.54g	9.1％
					5	Anhydrous zinc chloride	0.19g	0.86g	14.1％

Examples 1 to 8Preparation method of flurbiprofen

Example 1-8 Process for the preparation of flurbiprofen (see Table 2 for reaction conditions and results) comprising the following steps:

1) placing 20ml of tetrahydrofuran and 1.12g of magnesium chips in a reaction bottle, heating to reflux, dropping 2-fluoro-4-bromobiphenyl solution to initiate a Grignard reaction (10.0g of 2-fluoro-4-bromobiphenyl is dissolved in 20ml of tetrahydrofuran), and cooling to room temperature after the reaction is finished.

2) Adding 8.00g of ethyl 2-bromopropionate, a catalyst and 35ml of a reaction solvent into a reaction bottle, stirring, dropwise adding the Grignard reagent prepared in the step 1) at 15-65 ℃, and stirring overnight after dropwise adding. Filtering the reaction solution, leaching the leaching solvent, removing solids, dripping purified water and dilute hydrochloric acid into the filtrate, separating an organic layer, extracting an aqueous layer by using toluene, combining organic phases, washing the organic phases by using a saturated sodium chloride solution, drying the organic phases by using anhydrous sodium sulfate, and evaporating the solvent to dryness. Adding 1.5L of 3mol/L sodium hydroxide aqueous solution into the residue, heating and hydrolyzing at 80-100 ℃, extracting toluene at 30-95 ℃, collecting water phase, crystallizing at room temperature, filtering, leaching, and collecting crystals. Collecting crystal, adding water, heating to 80-100 deg.C for dissolving, decolorizing with activated carbon, heat filtering, adjusting pH of the filtrate to 1-5 with concentrated hydrochloric acid, precipitating solid, filtering, washing with water, and drying to obtain flurbiprofen.

TABLE 2

The above description of the specific embodiments of the present invention is not intended to limit the present invention, and those skilled in the art may make various changes and modifications according to the present invention without departing from the spirit of the present invention, which is defined in the appended claims.