Preparation method of flunixin

Abstract

The invention discloses a preparation method of 2-(2-methyl-3-(trifluoromethyl) anilino) nicotinic acid (flunixin). 2-methyl-3-chloroaniline is used as a raw material, a 2-methyl-3-trifluoromethylaniline intermediate is obtained through diazo iodination, trifluoromethylation and ammonolysis, and finally the 2-methyl-3-trifluoromethylaniline intermediate is coupled with 2-chloronicotinic acid to synthesize flunixin. The flunixin obtained in the process is an off-white solid, the purity is 98%, and the total yield of the whole process is 49.6%. The preparation method of flunixin is specifically limited, and on the premise of obtaining high yield, the whole steps are simple to operate, and the flunixin is easy to prepare.

Description

Technical Field

[0001] The present invention belongs to the field of production methods of non-steroidal anti-inflammatory drugs, and in particular relates to a method for preparing flunixin. Background Art

[0002] Nonsteroidal anti-inflammatory drugs (NSAIDs) are some of the most widely used therapeutic drugs, not only for treating inflammation but also as analgesics and antipyretics. They are widely used to treat a variety of human and animal conditions, including pain and inflammation. Flunixin, a representative example, is a non-narcotic, nonsteroidal anti-inflammatory drug used in veterinary medicine. It is widely used in horses and other livestock to treat muscle pain, joint disorders, and inflammatory diseases.

[0003] Flunixin meglumine is a novel nonsteroidal anti-inflammatory drug (NSAID) that combines with the solubilizer meglumine in a 1:1 ratio. Flunixin meglumine is a cyclooxygenase inhibitor and is used alone or in combination with antibiotics in veterinary medicine to treat visceral colic, bone pain, fever, and inflammation in cattle and pigs. It is also used to treat acute inflammatory conditions caused by infection in animals, such as mastitis, metritis, and agalactia in sows.

[0004] Currently, Chinese patent CN113372264A discloses a method for preparing flunixin. This method uses 3,4-dichlorotoluene, carbon tetrachloride, and aluminum trichloride as starting materials, and sequentially undergoes electrophilic substitution, halogen exchange, nitration, hydrogenation reduction, and carbon-nitrogen coupling to obtain flunixin. The preparation process has a high yield and good purity. However, this method uses hydrogen fluoride during the fluorine-chlorine exchange, which is toxic and corrosive. Long-term exposure may cause damage to human bones and teeth, and it can be absorbed through the skin, mucous membranes, respiratory tract, and digestive tract, making it a relatively unfriendly chemical reagent. In addition, the hydrogenation reduction uses a palladium-carbon catalyst, which is expensive and difficult to recover, and has many side reactions. In Chinese patent CN115073298A, o-methylbenzoic acid is used as the raw material, and the intermediate 2-methyl-3-trifluoromethylaniline is synthesized in a continuous flow microreactor through nitration, deoxyfluorination, and reduction reactions. Compared with the batch process using a traditional kettle reactor, this method has the characteristics of high yield, less post-treatment wastewater, low energy consumption and labor costs, low total project cost, and increased production capacity. However, there are problems such as relatively complex process and cumbersome reaction treatment. Summary of the Invention

[0005] Therefore, in order to solve the above problems, the present invention provides a method for preparing flunixin, which solves the defects of the prior art of flunixin such as high preparation cost, low yield and complicated preparation process.

[0006] To achieve the above object, the present invention adopts the following technical scheme: a method for preparing flunixin, which uses 2-methyl-3-chloroaniline as a raw material, obtains a 2-methyl-3-trifluoromethylaniline intermediate through diazo iodination, trifluoromethylation, and aminolysis, and finally couples with 2-chloronicotinic acid in a four-step reaction to synthesize flunixin.

[0007] Furthermore, the iodine diazotization reaction is specifically as follows: 2-methyl-3-chloroaniline and 30% sulfuric acid are added to a reactor and stirred, wherein the mass ratio of the volume of sulfuric acid to the mass ratio of 2-methyl-3-chloroaniline is 5.0-10.0 mL:1.0 g; the temperature is controlled to be approximately 0° C.; an aqueous solution of sodium nitrite is added under stirring, wherein the molar ratio of the sodium nitrite to the mass ratio of 2-methyl-3-chloroaniline is in the range of 1.0-1.2:1.0; after the addition is complete, the reaction is kept warm for 1 hour and the mixture is refrigerated for later use.

[0008] In another reaction flask, potassium iodide and water are added, with the molar ratio of potassium iodide to 2-methyl-3-chloroaniline being 1.0-1.2:1.0; the above-mentioned diazonium salt is added under stirring; during decomposition, the reaction temperature is controlled in the range of 20-50°C; after the addition is complete, stirring is continued and the reaction is kept warm for a period of time; dichloromethane is added for extraction, and the organic phase is washed with 10% sodium hydroxide solution and then with water until neutral, dried, and concentrated to obtain a dark brown liquid 2-chloro-6-iodotoluene.

[0009] Furthermore, the trifluoromethylation reaction is specifically as follows: 2-chloro-6-iodotoluene, potassium trifluoroacetate, cuprous oxide, and DMF are added to the reactor and stirred. The ratio of the amount of potassium trifluoroacetate to 2-chloro-6-iodotoluene is 3.5:1.0; the ratio of the amount of cuprous oxide to 2-chloro-6-iodotoluene is 0.4:1.0; the mass ratio of the solvent volume to 2-chloro-6-iodotoluene is 8.0 mL:1.0 g; the temperature is controlled at 160° C.; the reaction is kept warm for 8 hours, and GC tracking is performed. After the reaction is completed, the mixture is cooled to room temperature and filtered to obtain cuprous oxide; the reaction is diluted with dichloromethane, and an equal volume of ammonia and brine are added to wash until the organic phase is free of DMF, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a light yellow liquid 1-chloro-2-methyl-3-(trifluoromethyl)-benzene.

[0010] Furthermore, the aminolysis reaction is specifically as follows: 1-chloro-2-methyl-3-(trifluoromethyl)-benzene, cuprous chloride, oxalyl diamide, and aqueous ammonia are added to an autoclave, stirred, heated to 180° C., and kept warm for 10 hours; the mass ratio of cuprous chloride to 1-chloro-2-methyl-3-(trifluoromethyl)-benzene is 1.625:1.0; the mass ratio of oxalyl diamide to catalyst is 3.25:1.0; and the volume ratio of aqueous ammonia to the mass of 1-chloro-2-methyl-3-(trifluoromethyl)-benzene is 40 mL:1 g. After the reaction is completed, ethyl acetate is added to extract and separate the liquids, concentrated hydrochloric acid is added dropwise to the organic phase, the liquids are separated, the aqueous phase is adjusted to a pH greater than 10 with 10% sodium hydroxide solution, extracted with ethyl acetate, and the organic phase is separated and concentrated to obtain 2-methyl-3-trifluoromethylaniline as a brown solid.

[0011] Furthermore, the coupling reaction is specifically as follows: 2-chloronicotinic acid, 2-methyl-3-trifluoromethylaniline, boric acid, and water are added to a reactor, stirred, heated to 100° C., and monitored by HPLC; the molar ratio of 2-methyl-3-trifluoromethylaniline to 2-chloronicotinic acid is in the range of 1.00-1.05:1; the molar ratio of the catalyst to 2-methyl-3-trifluoromethylaniline is in the range of 0.1-0.4:1; after the reaction is completed, the temperature is lowered to room temperature, sodium hydroxide solution is added to adjust the pH to 12, dichloromethane is added for extraction, and after separation, the aqueous phase is adjusted to a pH of 3-4 with sulfuric acid, stirred at room temperature for 1 hour, filtered, and the solid is dried to obtain the target product.

[0012] By adopting the above technical solution, the beneficial effects of the present invention are as follows: the present invention specifically defines the preparation method of flunixin, and on the premise of obtaining a high yield, the overall steps are simple to operate, the cost is low, and it is easy to prepare. BRIEF DESCRIPTION OF THE DRAWINGS

[0013] Figure 1 The synthetic route of the present invention is shown in FIG. DETAILED DESCRIPTION

[0014] The present invention is further described below through specific embodiments.

[0015] A preparation method of flunixin, the synthesis route of which is shown in Figure 1 2-methyl-3-chloroaniline is used as the raw material. Iodination with diazo, trifluoromethylation, and aminolysis are performed to obtain the intermediate 2-methyl-3-trifluoromethylaniline. Finally, a four-step coupling reaction with 2-chloronicotinic acid is performed to synthesize flunixin. The specific steps are as follows:

[0016] Iodine addition reaction of diazonium: add 2-methyl-3-chloroaniline and 30% sulfuric acid by mass to a reactor, stir, and control the temperature at about 0-5°C; add an aqueous solution of sodium nitrite dropwise, and after addition, keep warm for 1 hour, and refrigerate for later use; add potassium iodide and water to another reactor, heat to 50°C and stir. After complete dissolution, begin to add the above diazonium salt dropwise; after addition, keep warm for 1 hour, add dichloromethane and stir to extract, wash the organic phase with alkali, wash with water, dry, and concentrate to obtain a dark brown liquid 2-chloro-6-iodotoluene.

[0017] Trifluoromethylation reaction: Add 2-chloro-6-iodotoluene, potassium trifluoroacetate, cuprous oxide, and DMF to a reactor, stir, and heat to 160°C. Track with GC. After the reaction of 2-chloro-6-iodotoluene is complete, cool to room temperature, filter, and recover the cuprous oxide. The filtrate is diluted with dichloromethane, and washed with equal volumes of ammonia and brine until the organic phase is free of DMF. Dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain 1-chloro-2-methyl-3-(trifluoromethyl)-benzene as a pale yellow liquid.

[0018] Ammonolysis reaction: 1-chloro-2-methyl-3-(trifluoromethyl)-benzene, cuprous chloride, oxalyl diamide, and aqueous ammonia were added to a high-pressure reactor, and the temperature was raised to 180°C and kept warm for 10 hours. After the reaction, the temperature was lowered to room temperature, the insoluble matter was removed by filtration, and the filtrate was extracted three times with ethyl acetate. The organic phases were combined, and concentrated hydrochloric acid was added dropwise to ethyl acetate. The layers were separated, and the pH of the aqueous phase was adjusted to greater than 10 with 10% sodium hydroxide solution, extracted with ethyl acetate, and the separated layers were concentrated to obtain 2-methyl-3-trifluoromethylaniline as a brown solid.

[0019] Coupling reaction: 2-chloronicotinic acid, 2-methyl-3-trifluoromethylaniline, boric acid, and water were added to a reaction kettle, stirred, and heated to 100°C for HPLC tracking. After the reaction was completed, the temperature was lowered to room temperature, sodium hydroxide solution was added to adjust the pH to 12, and dichloromethane was added for extraction. After standing and stratification, the separated aqueous phase was adjusted to a pH of 3-4 with sulfuric acid, stirred at room temperature for 1 hour, filtered, and dried to obtain flunixin as a white solid.

[0020] Example 1

[0021] Step 1: Iodine reaction on diazo

[0022] 2 g of 2-methyl-3-chloroaniline and 15 mL of 30% sulfuric acid were added to a reactor with stirring and the temperature controlled at approximately 0°C. A solution prepared by mixing 1.2 g of sodium nitrite with 2.2 g of water was added dropwise. After the addition was complete, the mixture was kept warm for 1 hour and refrigerated for later use. In another reactor, 2.7 g of potassium iodide and 10 mL of water were added and stirred at 50°C. After complete dissolution, the diazonium salt was added dropwise. After the addition was complete, the mixture was kept warm for 1 hour. Dichloromethane was added and extracted with stirring. The organic phase was washed with 10% sodium hydroxide, washed with water, dried, and concentrated to obtain 3.0 g of 2-chloro-6-iodotoluene with a yield of 84% and a purity of 99%.

[0023] Step 2: Trifluoromethylation

[0024] To the reactor were added 1 g of 2-chloro-6-iodotoluene, 2.1 g of potassium trifluoroacetate, 0.2 g of cuprous oxide, and 8 mL of DMF. The mixture was stirred and heated to 160° C. with GC tracking. After the reaction of 2-chloro-6-iodotoluene was complete, the mixture was cooled, filtered, and the cuprous oxide was recovered. The reaction mixture was diluted with dichloromethane and washed with equal volumes of aqueous ammonia and brine until the organic phase was free of DMF. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 0.64 g of 1-chloro-2-methyl-3-(trifluoromethyl)-benzene as a light yellow liquid with a yield of 83% and a purity of 99%.

[0025] Step 3: Ammonolysis reaction

[0026] To an autoclave were added 1 g of 1-chloro-2-methyl-3-(trifluoromethyl)-benzene, 1.625 g of cuprous chloride, 0.5 g of oxalyl diamide, and 40 mL of aqueous ammonia. The temperature was raised to 180° C. and maintained for 10 h. The mixture was cooled to room temperature, filtered to remove insoluble matter, and the filtrate was extracted three times with ethyl acetate. The organic phases were combined, and hydrochloric acid was added dropwise to ethyl acetate. The layers were separated, and the pH of the aqueous phase was adjusted to greater than 10 with 10% sodium hydroxide solution. The separated layers were concentrated to obtain 0.71 g of 2-methyl-3-trifluoromethylaniline with a yield of 79% and a purity of 98%.

[0027] Step 4, coupling reaction

[0028] To a reaction kettle were added 2 g of 2-chloronicotinic acid, 2.22 g of 2-methyl-3-trifluoromethylaniline, 0.16 g of boric acid, and 6 g of water. The mixture was stirred and heated to 100°C. HPLC monitoring was performed. After the reaction was completed, the temperature was lowered to room temperature, sodium hydroxide solution was added to adjust the pH to 12, and dichloromethane was added for extraction. After separation, the pH of the separated aqueous phase was adjusted to 3-4 with sulfuric acid. The mixture was stirred at room temperature for 1 h, filtered, and dried to obtain 3.76 g of flunixin with a yield of 90% and a purity of 98%.

[0029] Example 2

[0030] A preparation scheme of flunixin, the specific steps are as follows:

[0031] Step 1, iodination reaction:

[0032] 200g of 2-methyl-3-chloroaniline and 1500mL of 30% sulfuric acid were added to a reactor, stirred, and the temperature was controlled at about 0°C; a solution of 117.31g of sodium nitrite and 218g of water was added dropwise. After the addition was complete, the mixture was kept warm for 1 hour and refrigerated for later use; 270.5g of potassium iodide and 1000mL of water were added to another reactor, stirred at 50°C, and after complete dissolution, the diazonium salt was added dropwise; after the addition was completed, the mixture was kept warm for 1 hour, and dichloromethane was added and extracted with stirring. The organic phase was washed with 10% sodium hydroxide, washed with water, dried, and concentrated to give 295g of 2-chloro-6-iodotoluene with a yield of 83% and a purity of 98%.

[0033] Step 2: Trifluoromethylation

[0034] 198 g of 2-chloro-6-iodotoluene, 474 g of potassium trifluoroacetate, 45 g of cuprous oxide, and 1584 mL of DMF were added to the reactor, stirred, and heated to 160° C. for GC tracking. After the reaction of 2-chloro-6-iodotoluene was complete, the mixture was cooled, filtered, and the cuprous oxide was recovered. The reaction was diluted with dichloromethane, and an equal volume of ammonia water and brine were added to wash until the organic phase was free of DMF. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 127 g of 1-chloro-2-methyl-3-(trifluoromethyl)-benzene as a light yellow liquid with a yield of 83% and a purity of 98%.

[0035] Step 3: Ammonolysis reaction

[0036] 86 g of 1-chloro-2-methyl-3-(trifluoromethyl)-benzene, 139.75 g of cuprous chloride, 43 g of oxalyl diamide, and 3440 mL of aqueous ammonia were added to an autoclave, and the temperature was raised to 180° C. and kept warm for 20 h. The mixture was cooled to room temperature, filtered to remove insoluble matter, and the filtrate was extracted three times with ethyl acetate. The organic phases were combined, and hydrochloric acid was added dropwise to ethyl acetate. The layers were separated, and the pH of the aqueous phase was adjusted to greater than 10 with 10% sodium hydroxide solution. The separated layers were concentrated to give 55 g of 2-methyl-3-trifluoromethylaniline with a yield of 71% and a purity of 98%.

[0037] Step 4, coupling reaction

[0038] To a reactor, 90 g of 2-chloronicotinic acid, 100 g of 2-methyl-3-trifluoromethylaniline, 7.1 g of boric acid, and 270 g of water were added, stirred, and heated to 100° C. under HPLC monitoring. After completion of the reaction, the temperature was lowered to room temperature, sodium hydroxide solution was added to adjust the pH to 12, and dichloromethane was added for extraction. After separation, the separated aqueous phase was adjusted to a pH of 3-4 with sulfuric acid. The mixture was stirred at room temperature for 1 h, filtered, and dried to obtain 160 g of flunixin with a yield of 95% and a purity of 98%.

[0039] Although the present invention has been particularly shown and described in conjunction with preferred embodiments, it will be understood by those skilled in the art that various changes in form and details may be made to the present invention without departing from the spirit and scope of the invention as defined in the appended claims, and all such changes are within the scope of protection of the present invention.

Claims

1. A method for preparing flunixin, characterized in that: Using 2-methyl-3-chloroaniline as the raw material, 2-methyl-3-trifluoromethylaniline intermediate is obtained through diazo iodination, trifluoromethylation, and aminolysis. Finally, it is coupled with 2-chloronicotinic acid in four steps to synthesize flunixin. The specific synthetic route is as follows:

2. The method for preparing flunixin according to claim 1, wherein: During the iodine addition reaction of diazo, the diazotizing agent is selected from any one of hydrochloric acid, sulfuric acid, and sodium nitrite, or a mixture of two or more thereof in any ratio, and the reaction temperature is controlled within the range of 0-5°C.

3. The method for preparing flunixin as claimed in claim 2, wherein During the iodine-on-diazo reaction, 30% sulfuric acid and sodium nitrite are used as diazotization reagents; the ratio of the volume of the 30% sulfuric acid to the mass of 2-methyl-3-chloroaniline is in the range of 5.0-10.0 mL:1.0 g; the concentration of the sodium nitrite aqueous solution is in the range of 30-40%; and the ratio of the amount of sodium nitrite to the amount of 2-methyl-3-chloroaniline is in the range of 1.0-1.2:1.

0.

4. The method for preparing flunixin according to claim 1, wherein During the iodine decomposition reaction on the diazo, potassium iodide is selected as the iodine reagent, and the molar ratio of the potassium iodide to the 2-methyl-3-chloroaniline is in the range of 1.0-1.2:1.0; the reaction temperature is controlled in the range of 20-50° C., and 2-chloro-6-iodotoluene is obtained after the iodine decomposition reaction on the diazo.

5. The method for preparing flunixin as claimed in claim 4, wherein In the trifluoromethylation reaction, potassium trifluoroacetate is used as the trifluoromethylation reagent, and the molar ratio of the trifluoromethylation reagent to 2-chloro-6-iodotoluene is 3.5:1.

0.

6. The method for preparing flunixin according to claim 5, wherein In the trifluoromethylation reaction, cuprous oxide is used as a catalyst, and the molar ratio of the catalyst to 2-chloro-6-iodotoluene is 0.4:1.

0.

7. The method for preparing flunixin according to claim 6, wherein During the trifluoromethylation reaction, N,N-dimethylformamide (DMF) was used as a solvent, and the mass ratio of the solvent volume to 2-chloro-6-iodotoluene was 8.0 mL:1.0 g. The trifluoromethylation reaction temperature was controlled at 160° C., and 1-chloro-2-methyl-3-(trifluoromethyl)-benzene was obtained after the trifluoromethylation reaction.

8. The method for preparing flunixin according to claim 7, wherein During the ammonolysis reaction, cuprous chloride is used as a catalyst, and the mass ratio of the catalyst to 1-chloro-2-methyl-3-(trifluoromethyl)-benzene is 1.625:1.0; the reaction temperature is controlled in the range of 175-185°C.

9. The method for preparing flunixin as claimed in claim 8, wherein During the ammonolysis reaction, oxalyl diamide was selected as the ligand, the mass ratio of the catalyst to the ligand was 3.25:1.0, industrial ammonia water was used as the ammonolysis reagent, and the ratio of the volume of the ammonolysis reagent to the mass of 1-chloro-2-methyl-3-(trifluoromethyl)-benzene was 40 mL:1 g. After the ammonolysis reaction, 2-methyl-3-trifluoromethylaniline was obtained.

10. The method for preparing flunixin according to claim 9, wherein: The coupling reaction is specifically as follows: 2-chloronicotinic acid, the 2-methyl-3-trifluoromethylaniline, boric acid, and water are added to a reaction kettle, stirred, heated to 100° C., and monitored by HPLC; the molar ratio of the 2-methyl-3-trifluoromethylaniline to the 2-chloronicotinic acid is in the range of 1.00-1.05:1; the molar ratio of the catalyst to the 2-methyl-3-trifluoromethylaniline is in the range of 0.1-0.4:1; after the reaction is completed, the temperature is lowered to room temperature, sodium hydroxide solution is added to adjust the pH to 12, dichloromethane is added for extraction, and after separation, the aqueous phase is adjusted to a pH of 3-4 with sulfuric acid, stirred at room temperature for 1 hour, filtered, and the solid is dried to obtain the target product.

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