A new method for the synthesis of flurbiprofen

Abstract

The application discloses a new method for synthesizing flurbiprofen, which comprises the following steps: coupling reaction of a compound of formula IV with malononitrile or coupling reaction of a compound of formula V with a compound of formula VI to obtain a compound of formula III; methylating the compound of formula III to prepare a compound of formula II; and hydrolytic decarboxylation of the compound of formula II to prepare a compound of formula I. The method is suitable for industrial production, raw materials are cheap and easy to obtain, reaction steps are short, and the yield is high. 1 selected from Cl, Br and I; R 2 selected from borate and boronic acid.

Description

Technical Field

[0001] This invention belongs to the field of drug synthesis technology, specifically relating to the preparation method of flurbiprofen and its intermediates. Background Technology

[0002] Flurbiprofen is a nonsteroidal, potent phenylpropionic acid antipyretic, anti-inflammatory, and analgesic drug. It exerts its analgesic, anti-inflammatory, and antipyretic effects by inhibiting the production of cyclooxygenase from prostaglandins. Its chemical name is 2-(2-fluorobiphenyl-4-yl)propionic acid, and its structure is shown below:

[0003]

[0004] The following are the routes for preparing flurbiprofen via intermediate cyanide:

[0005] Chinese patent CN110872237A discloses the preparation of arylpropionic acid from phenylacetonitrile and its derivatives by dimethyl carbonate methylation, decarboxylation and hydrolysis, with a conversion rate of 95%.

[0006]

[0007] The methylation process requires temperature and pressure control, which places very strict requirements on the equipment for subsequent scale-up reactions. In addition, the hydrolysis of monocyano compounds requires high temperatures, making it unsuitable for industrial production.

[0008] Chinese patent CN107137387A discloses a method for obtaining arylpropionic acid nonsteroidal anti-inflammatory drugs by using aryl acetonitrile compounds as substrates, amine borane complexes, and N,N-dimethylformamide as solvents, under alkaline conditions, followed by methylation and hydrolysis under strongly alkaline conditions. The reaction is as follows:

[0009]

[0010] The methylation process uses amine borane complexes, mainly including pyridine borane, dimethylamine borane, or aminoborane. These reagents are highly harmful, especially pyridine borane, which has a strong irritating odor and requires special gas cylinders for storage, making it difficult to use.

[0011] Chinese patent CN102452867A discloses a decarboxylation coupling reaction between decarboxylation coupling reagent IX and electrophilic substrate X under conditions of palladium catalyst, phosphine ligand, and organic solvent, as follows:

[0012]

[0013] The post-processing of decarboxylation coupling is relatively complex, with high reaction temperatures and long reaction times. Most of the product purification requires column chromatography. In addition, when choosing solvents, the yield can only reach more than 70% when diethylene glycol dimethyl ether and mesitylene are used.

[0014] The literature J. Org. chem. 2020, 85, 6, 4560-4564 reports the coupling of malononitrile with aryl halides to give dinitrile compounds in the presence of sodium hydride and palladium catalysts, as follows:

[0015]

[0016] The coupling process uses the highly hazardous reagent NaH, which is not conducive to large-scale production. Summary of the Invention

[0017] In view of the problems existing in the prior art, the present invention provides a new method for preparing 2-(2-fluorobiphenyl-4-yl)propionic acid, which is easy to operate, facilitates methylation reaction, and avoids the need for high-temperature hydrolysis decarboxylation. At the same time, the reaction yield is high, the cost is low, and it is easy to industrially produce.

[0018] A first aspect of the present invention provides a method for preparing a compound of formula I, comprising the following steps:

[0019]

[0020] Compound II is hydrolyzed and decarboxylated under acidic or alkaline conditions to form compound I.

[0021] The acidic conditions can be carried out in the presence of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid and p-toluenesulfonic acid, as long as the hydrolysis reaction can be carried out effectively.

[0022] The alkaline conditions can be carried out under alkaline conditions where one or more of the following substances are present: triethylamine, potassium tert-butoxide, sodium tert-butoxide, lithium carbonate, potassium carbonate, sodium carbonate, sodium hydroxide, lithium hydroxide, and potassium hydroxide; preferably, the alkaline conditions in the presence of sodium carbonate, potassium carbonate, lithium hydroxide, sodium hydroxide, or potassium hydroxide are present, with sodium hydroxide being the most preferred.

[0023] And / or, the molar ratio of the compound of formula II to the basic substance is 1:6 to 15, preferably 1:8 to 13.

[0024] In the hydrolysis and decarboxylation reactions, the reaction solvent is one or any combination of an organic solvent and water; the organic solvent is selected from one or more of alcohol solvents, aromatic hydrocarbon solvents, amide solvents, halogenated hydrocarbon solvents, ether solvents, sulfone solvents, and ester solvents; the alcohol solvent is, for example, methanol, ethanol, ethylene glycol, and / or n-butanol; the aromatic hydrocarbon solvent is, for example, toluene; the amide solvent is, for example, N,N-dimethylformamide; the halogenated hydrocarbon solvent is, for example, dichloromethane; the ether solvent is, for example, tetrahydrofuran and / or 1,2-dioxane; the sulfone solvent is, for example, dimethyl sulfoxide; the ester solvent is, for example, ethyl acetate; the reaction solvent preferably includes n-butanol, dimethyl sulfoxide, or toluene, with n-butanol being the most preferred;

[0025] And / or, in the hydrolysis and decarboxylation reaction, the mass ratio of the compound of formula II to the volume ratio of the reaction solvent is 1:1 to 10 g / mL, preferably 1:2 to 5 g / mL, and most preferably 1:3 to 5 g / mL;

[0026] The hydrolysis and decarboxylation reaction steps are performed at a temperature of 20–140°C, preferably 110–135°C, and most preferably 120–130°C.

[0027] The hydrolysis and decarboxylation reaction steps take 0.5 to 36 hours, preferably 10 to 30 hours, and most preferably 18 to 24 hours.

[0028] And / or, after the hydrolysis and decarboxylation reaction is completed, the reaction further includes a post-processing step: cooling, filtration, adding water and acidifying the reaction solution to pH 1-2, followed by extraction, filtration and drying to obtain flurbiprofen.

[0029] A second aspect of the present invention provides a method for preparing a compound of formula II, comprising the following steps:

[0030]

[0031] Compound of Formula III is methylated with a methylating agent to form compound of Formula II.

[0032] The methylating agent is selected from dimethyl sulfate, dimethyl carbonate, or iodomethane, with iodomethane being preferred.

[0033] In the methylation reaction, the reaction solvent is an organic solvent, including N,N-dimethylformamide, dimethyl sulfoxide, or acetonitrile, preferably dimethyl sulfoxide.

[0034] And / or, the mass ratio of the compound of Formula III to the volume ratio of the reaction solvent is 1:1 to 1:15 g / mL, preferably 1:6 to 1:13 g / mL, and most preferably 1:9 to 1:12 g / mL;

[0035] And / or, the methylation reaction further includes a base, wherein the base includes potassium carbonate, potassium hydroxide or triethylamine, preferably potassium carbonate;

[0036] And / or, the molar ratio of the compound of formula III, the methylating agent and the base is 1:1.0 to 1.6:1.0 to 1.9, preferably 1:1.0 to 1.4:1.3 to 1.7, more preferably 1:1.2:1.5.

[0037] The reaction temperature for the methylation reaction is 10-50℃, preferably 20-30℃;

[0038] The reaction time for the methylation reaction is 1 to 12 hours, preferably 2 to 3 hours.

[0039] And / or, after the methylation reaction is completed, a post-processing step is further included: cooling, extraction with an organic solvent (e.g., ethyl acetate), adjusting the pH to 6-7, washing the organic phase, drying with anhydrous sodium sulfate, filtering, concentrating, and drying to obtain compound of formula II.

[0040] A third aspect of the present invention provides a method for preparing a compound of formula III, comprising the following steps:

[0041] Method 1:

[0042]

[0043] In formula IV, X is selected from Cl, Br, and I;

[0044] Compound IV was coupled with malononitrile to give compound III.

[0045] Method 2:

[0046]

[0047] In formula V, R 1 Selected from Cl, Br, I; R 2 Selected from borate esters or borate groups;

[0048] The compound of formula V is coupled with the compound of formula VI to obtain the compound of formula III.

[0049] In the technical solution of method one provided by the present invention:

[0050] In the coupling reaction described in the method, the reaction solvent is an organic solvent, which includes N,N-dimethylformamide, toluene, or xylene, or any combination thereof, with xylene being preferred.

[0051] And / or, the mass ratio of the compound of formula IV to the volume ratio of the reaction solvent is 1:1 to 15 g / mL, preferably 1:6 to 13 g / mL, and most preferably 1:9 to 12 g / mL;

[0052] And / or, the coupling reaction of the method further includes a base, wherein the base includes potassium carbonate, diisopropylethylamine or potassium tert-butoxide, preferably potassium tert-butoxide.

[0053] And / or, the molar ratio of the compound of formula IV, malononitrile, and base is 1:1 to 1.8: 2.5 to 3.5, preferably 1:1 to 1.6: 2.7 to 3.3, and more preferably 1:1.5: 3.0;

[0054] The reaction temperature of the coupling reaction in Method 1 is 100-150℃, preferably 120-130℃;

[0055] And / or, the coupling reaction uses a palladium catalyst, which is selected from one or more of Pd(PPh3)4, Pd(PPh3)2Cl2, PdCl2(dppf), PdCl2(dtbpf), PdCl2(Amphos)2, and Pd(Pt-Bu3)2, with Pd(PPh3)2Cl2 being preferred.

[0056] And / or, the molar amount of the palladium catalyst is 0.001 to 0.5 times the molar amount of the compound of formula V, for example preferably 0.01 to 0.5, 0.02 to 0.5, 0.03 to 0.5, 0.04 to 0.5, 0.05 to 0.1, 0.05 to 0.2, 0.05 to 0.3, 0.05 to 0.4 or 0.05 to 0.5.

[0057] And / or, the reaction time of the coupling reaction is 1 to 5 hours, preferably 2 to 3 hours.

[0058] And / or, after the coupling reaction is completed, the method further includes a post-processing step: cooling, adding ethyl acetate, adjusting the pH to 6-7, filtering, washing the organic phase, separating and concentrating, and drying to obtain compound III.

[0059] In the second method provided by this invention:

[0060] In method two, R 2 When selected from borate ester groups, compounds of formula VI are pinacol phenylboronic acid, dimethyl phenylboronic acid, and diisopropyl phenylboronic acid; R 2 When the group is selected from borate, the compound of formula VI is phenylboronic acid;

[0061] And / or, R 2 Boric acid groups are preferred, and phenylboronic acid is preferred for compounds of formula VI;

[0062] In the second method, the reaction solvent in the coupling reaction is one or any combination of N,N-dimethylformamide, 1,4-dioxane, toluene, diethyl ether, tetrahydrofuran, cyclopentyl methyl ether, ethylene glycol dimethyl ether, methyl tert-butyl ether, n-butyl ether, and xylene, preferably 1,4-dioxane.

[0063] And / or, the molar mass ratio of the compound of formula V to the compound of formula VI is 1:1 to 3, preferably 1:1.2 to 1.5;

[0064] And / or, the mass ratio of the compound of formula V to the volume ratio of the reaction solvent is 1:1 to 15 g / mL, preferably 1:6 to 13 g / mL, and most preferably 1:9 to 11 g / mL;

[0065] And / or, the coupling reaction uses a palladium catalyst, which is one or a combination of several of Pd(PPh3)4, PdCl2(dppf), PdCl2(dtbpf), PdCl2(Amphos)2, and Pd(Pt-Bu3)2, preferably PdCl2(dppf).

[0066] And / or, the coupling reaction further includes a base, wherein the base includes potassium carbonate, potassium acetate, sodium carbonate, triethylamine or potassium hydroxide, preferably potassium acetate;

[0067] The reaction temperature for the coupling reaction is 60-120℃, preferably 80-120℃;

[0068] Typical but non-limiting temperatures for the reaction can be, for example, 80°C, 82°C, 84°C, 86°C, 88°C, 90°C, 92°C, 94°C, 96°C, 98°C, 100°C, 102°C, 104°C, 106°C, 108°C, 110°C, 112°C, 114°C, 116°C, 118°C, or 120°C.

[0069] And / or, the reaction time of the coupling reaction is 1 to 5 hours, preferably 2 to 3 hours.

[0070] And / or, after the coupling reaction is completed, further operations include post-processing steps: cooling, extraction with an organic solvent (e.g., ethyl acetate), adjusting the pH to 6-7, separating the liquid, washing the organic phase, drying with anhydrous sodium sulfate, filtering, concentrating, and drying to obtain compound V.

[0071] In a fourth aspect, the present invention provides novel intermediate compounds III and II, having the following structural formulas:

[0072]

[0073] A fifth aspect of the present invention is a method for preparing flurbiprofen, comprising the method of preparing compound II according to the second aspect of the present invention and the method of preparing compound III according to the third aspect of the present invention, and comprising an intermediate compound III or compound II according to the fourth aspect.

[0074] Compared with the prior art, the advantages of this invention are:

[0075] a) A novel method for preparing 2-(2-fluorobiphenyl-4-yl)propionic acid is provided, using novel intermediate compounds II and III;

[0076] b) This method uses readily available starting materials, has a short reaction time, and is low in cost;

[0077] c) This method has a high yield, with a total yield of over 50%, making it suitable for large-scale industrial production.

[0078] d) Good product quality. Detailed Implementation

[0079] The present invention is further illustrated below with reference to specific embodiments. For illustrative purposes only, the preparation method of compound III 2-(2-fluorobiphenyl-4-yl)-2-methylmalononitrile is used as an example to illustrate the method of the present invention. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the present invention. Experimental methods in the following embodiments without specific conditions are generally performed under conventional conditions or as recommended by the manufacturer.

[0080] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as are familiar to those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to the methods of this invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0081] Example 1: Preparation of Compound III

[0082] 4-Bromo-2-fluorobiphenyl (10.00 g, 0.04 mol) was added to a 250 mL round-bottom flask, followed by xylene (100 mL) and stirring. Then, sodium tert-butoxide (11.48 g, 0.12 mol), malononitrile (3.95 g, 0.06 mol), and palladium dichloride bis(triphenylphosphine) (1.82 g, 2.59 mmol) were added sequentially at 20–30 °C. The mixture was evacuated three times, and nitrogen gas was introduced through a nitrogen balloon for protection. The reaction was carried out at 120–130 °C for 2–3 h. The reaction was monitored by thin-layer chromatography (TLC), and the reaction was considered complete after 3 h. The reaction solution was cooled to 10–30 °C, 100 mL of ethyl acetate was added, and the pH of the solution was adjusted to 6–7 by adding 3 M hydrochloric acid. The solution was then filtered, and the filtrate was separated into layers. The organic phase was washed once with water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a brownish-yellow liquid. 120 mL of petroleum ether was added dropwise to the liquid, and the mixture was stirred at 20–30 °C for 0.5 h. A solid precipitated out, which was then filtered, dried, and 7.79 g of compound III was obtained, with a yield of 82.5%.

[0083] 1 H NMR (400MHz, CDCl3) δ7.61-7.24 (m, 8H), 5.11 (s, 1H).

[0084] Example 2 Preparation of Compound III

[0085] 2-(3-fluoro-4-iodophenyl)malononitrile (11.44 g, 0.04 mol) was added to a 250 mL round-bottom flask, followed by 1,4-dioxane (115 mL). The mixture was stirred, and then potassium acetate (7.85 g, 0.08 mol), phenylboronic acid (7.32 g, 0.06 mol), and bis(triphenylphosphine)palladium dichloride and 1,1-bis(diphenylphosphine)ferrocene palladium dichloride (1.4 g) were added sequentially at 20–30 °C. The mixture was evacuated three times, and nitrogen gas was introduced through a nitrogen balloon for protection. The reaction was then carried out at 80–120 °C for 2–3 h. The reaction was monitored by thin-layer chromatography (TLC), and the reaction was considered complete after 3 h. The reaction solution was cooled to 10–20 °C, 100 mL of ethyl acetate was added, and the pH of the solution was adjusted to 6–7 by adding 3 M hydrochloric acid. The solution was then filtered, and the filtrate was separated into layers. The organic phase was washed once with water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a brownish-yellow liquid. 120 mL of petroleum ether was added dropwise to the liquid, and the mixture was stirred at 20–30 °C for 0.5 h. A solid precipitated out, which was then filtered, dried, and 9.46 g of compound III was obtained, with a yield of 90.0%.

[0086] 1 H NMR (400MHz, CDCl3) δ7.61-7.24 (m, 8H), 5.11 (s, 1H).

[0087] Example 3 Preparation of Compound II

[0088] Compound III (7.20 g, 0.03 mol) was added to a 100 mL round-bottom flask, followed by dimethyl sulfoxide (72 mL) and potassium carbonate (6.22 g, 0.045 mol). The mixture was stirred for 10 min, and the flask was evacuated three times. Nitrogen gas was then introduced through a nitrogen balloon for protection. Iodomethane (5.20 g, 0.036 mol) was then added dropwise at 20–30 °C. After the addition was complete, the mixture was allowed to react at 20–30 °C for 2–3 h. The reaction was monitored by thin-layer chromatography (TLC), and the reaction was considered complete after 3 h. The reaction solution was cooled to 10–20 °C, 200 mL of ethyl acetate was added, and the pH of the solution was adjusted to 6–7 by adding 1 M hydrochloric acid. The filtrate separated into layers, the organic phase was washed once with water, separated, and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to obtain a brownish-red liquid. 40 mL of petroleum ether was added dropwise, and the mixture was stirred at 20–30 °C for 1 h. A solid precipitated out, which was then filtered, dried, and 6.4 g of compound II was obtained, with a yield of 84.4%.

[0089] 1 H NMR (400MHz, CDCl3) δ7.61-7.38 (m, 8H), 2.17 (s, 3H).

[0090] Example 4: Preparation of Compound I

[0091] Compound II (5.00 g, 19.9 mmol) was added to a 50 mL round-bottom flask, followed by 6.5 mL of water, 6.35 g of sodium hydroxide (0.16 mol), and 15 mL of n-butanol. The mixture was then reacted at 120–130 °C for 18–24 h, monitored by thin-layer chromatography (TLC) until completion. The reaction mixture was cooled to 20–30 °C and stirred for 1 h. After filtration, 50 mL of water was added to the filter cake and stirred. 10 mL of 12 M hydrochloric acid was added dropwise, and the mixture was heated to 70–80 °C and stirred for 1 h. Subsequently, the mixture was cooled to 20–30 °C and stirred for 1 h, precipitating a solid. The solid was filtered, dried, and 3.5 g of compound I was obtained, with a yield of 71.7%.

[0092] 1 H NMR (400MHz, CDCl3) δ7.57-7.50(m,2H),7.48-7.33(m,4H),7.21-7.12(m,2H),3.79 (q,J=7.2Hz,1H),1.57(d,J=7.2Hz,3H).

Claims

1. A method for preparing a compound of formula I, characterized in that, Includes the following steps: (1) Preparation of compound III: Compound IV is coupled with malononitrile in the presence of sodium tert-butoxide to obtain compound III; In formula IV, X is selected from Cl, Br, and I; (2) Methylation reaction: The compound of formula III is reacted with iodomethane to form the compound of formula II; (3) Hydrolysis and decarboxylation reaction: Compound II is hydrolyzed and decarboxylated under alkaline conditions to form compound I; The alkaline condition described in step (3) is the presence of an alkaline substance, which is selected from one or more of triethylamine, potassium tert-butoxide, sodium tert-butoxide, lithium carbonate, potassium carbonate, sodium carbonate, sodium hydroxide, lithium hydroxide, and potassium hydroxide. The molar ratio of compound II to alkaline substance in step (3) is 1:6 to 15.

2. The method according to claim 1, characterized in that, In the coupling reaction of step (1), the reaction solvent is an organic solvent, which is selected from N,N-dimethylformamide, toluene or xylene or any combination thereof; And / or, the mass ratio of the compound of formula IV to the volume of the reaction solvent is 1:1 to 15 g / mL; And / or, the molar ratio of the compound of formula IV, malononitrile, and sodium tert-butoxide is 1:1 to 1.8:2.5 to 3.5; And / or, the coupling reaction further includes a palladium catalyst, which is selected from one or a combination of several of Pd(PPh3)4, Pd(PPh3)2Cl2, PdCl2(dppf), PdCl2(dtbpf), PdCl2(Amphos)2, and Pd(Pt-Bu3)2; And / or, the reaction temperature of the coupling reaction is 100-150°C; And / or, the reaction time of the coupling reaction is 1 to 5 hours.

3. The method according to claim 1 or 2, characterized in that, After the coupling reaction in step (1) is completed, the following post-processing steps are also included: cooling, adding ethyl acetate, adjusting the pH to 6-7, filtering, washing the organic phase, separating and concentrating, and drying to obtain compound III.

4. The method according to claim 1, characterized in that, The methylation reaction in step (2) is carried out in an organic solvent, including N,N-dimethylformamide, dimethyl sulfoxide or acetonitrile. And / or, the mass ratio of the compound of formula III to the volume of the reaction solvent is 1:1 to 1:15 g / mL; And / or, the methylation reaction further includes a base, wherein the base includes potassium carbonate, potassium hydroxide or triethylamine; And / or, the molar ratio of the compound of formula III, the methylating agent, and the base is 1:1.0 to 1.6:1.0 to 1.9; And / or, the reaction temperature of the methylation reaction is 10-50°C; And / or, the reaction time for the methylation reaction is 1 to 12 hours.

5. The method according to claim 1 or 4, characterized in that, After the methylation reaction is completed, the following post-processing steps are also included: cooling, extraction with ethyl acetate, adjusting the pH to 6-7, washing the organic phase, drying with anhydrous sodium sulfate, filtering, concentrating, and drying to obtain compound II.

6. The method according to claim 1, characterized in that, The alkaline substance mentioned in step (3) is sodium hydroxide; And / or, the molar ratio of the compound of formula II in step (3) to the basic substance is 1:8 to 13.

7. The method according to claim 1, characterized in that, In the hydrolysis and decarboxylation reaction described in step (3), the reaction solvent is one or any combination of an organic solvent and water; the organic solvent is selected from one or more of alcohol solvents, aromatic hydrocarbon solvents, amide solvents, halogenated hydrocarbon solvents, ether solvents, sulfone solvents, and ester solvents; the alcohol solvent is selected from methanol, ethanol, ethylene glycol, and / or n-butanol; the aromatic hydrocarbon solvent is selected from toluene; the amide solvent is selected from N,N-dimethylformamide; the halogenated hydrocarbon solvent is selected from dichloromethane; the ether solvent is selected from tetrahydrofuran and / or 1,4-dioxane; the sulfone solvent is selected from dimethyl sulfoxide; and the ester solvent is selected from ethyl acetate. And / or, in the hydrolysis and decarboxylation reactions, the mass ratio of the compound of formula II to the volume of the reaction solvent is 1:1 to 10 g / mL; And / or, the reaction temperature of the hydrolysis and decarboxylation reaction steps is 20–140°C; And / or, the reaction time for the hydrolysis and decarboxylation steps is 0.5 to 36 hours.

8. The method according to claim 7, characterized in that, After the hydrolysis and decarboxylation reactions are completed, the process also includes post-processing steps: cooling, filtration, adding water and acidifying the reaction solution to pH 1-2, filtration, and drying to obtain flurbiprofen.

9. The method according to claim 7, characterized in that, The organic solvent is selected from n-butanol, dimethyl sulfoxide, or toluene.

10. The method according to claim 9, characterized in that, The organic solvent is n-butanol.

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