A synthetic method of flunixin meglumine applicable to industrial production

Abstract

The present invention discloses a method for synthesizing flunixin meglumine suitable for industrial production, which solves the problems in the current synthesis route of flunixin meglumine, such as the excessively high production cost of the flunixin intermediate, for example, using expensive p-toluenesulfonic acid as a catalyst, excessive dosage of 2-methyl-3-(trifluoromethyl)aniline, reaction time up to 24 h, reaction temperature up to 150 °C, and low yield. The present invention uses inexpensive boric acid as a catalyst, only requires 1.05 equivalents of 2-methyl-3-(trifluoromethyl)aniline, reacts at 90 °C for 8-10 h, with a yield as high as 95% and a purity as high as 99.9%. Subsequently, flunixin and meglumine are refluxed in an isopropanol solvent for 1 h to obtain flunixin meglumine, with a yield as high as 96% and a purity as high as 99.9%. In summary, the total yield of the two steps is as high as 91.2% and the purity is as high as 99.9%, making it more suitable for industrialization.

Description

Technical Field

[0001] The present invention belongs to the technical field of chemical synthesis, and particularly relates to a method for synthesizing flunixin meglumine salt from 2-methyl-3-(trifluoromethyl)aniline, 2-chloronicotinic acid and meglumine. Background Art

[0002] The chemical formula of flunixin meglumine: C 21 H 28 F 3 N 3 O 7 , and its English name is Flunixin meglumine. The structural formula is as follows:

[0003]

[0004] Flunixin meglumine is a veterinary antipyretic, anti-inflammatory and analgesic drug, which has antipyretic, anti-inflammatory and analgesic effects. Using it alone or in combination with antibiotics can significantly improve clinical symptoms and enhance the activity of antibiotics. In the 1990s, Schering-Plough Corporation of the United States first developed the synthesis process of flunixin meglumine (trade name Banamine), which has been widely used in many countries. According to statistics, about 95% of veterinarians use flunixin meglumine alone or in combination with other antibiotics clinically. At present, the Ministry of Agriculture of China has approved some veterinary drug factories to produce flunixin meglumine.

[0005] According to literature research, the synthesis process of flunixin meglumine mainly includes two steps. The first step is the synthesis of flunixin, and the second step is the salt formation of flunixin and meglumine to obtain flunixin meglumine. Among them, the synthesis of flunixin is the key of the reaction.

[0006] At present, according to the different starting materials for the synthesis of flunixin, it is mainly divided into two categories:

[0007] The first category uses 2-chloronicotinic acid and 2-methyl-3-trifluoromethylaniline as starting materials. In US5484931, water is used as the solvent and p-toluenesulfonic acid is used as the catalyst, and the reaction is carried out at 100 °C for 24 h, and flunixin can be obtained with a yield of 83%. However, this reaction requires 2.1 equivalents of 2-methyl-3-trifluoromethylaniline, and there are problems such as too long reaction time, cumbersome post-treatment operation and low yield. In order to further improve the reaction yield, in CN103694167A, by adding CuO to the reaction system, the catalytic efficiency can be greatly increased, so that the reaction time can be shortened to 4 h and the yield can be increased to 91%. However, such reactions still require 2 equivalents of 2-methyl-3-trifluoromethylaniline and the reaction temperature is too high (100 °C).

[0008]

[0009] The second category uses ethyl 2-chloronicotinate and 2-methyl-3-(trifluoromethyl)aniline as starting materials. In US5248781, heating to 200 °C in the absence of solvent or refluxing in xylene can obtain ethyl flunixin, and after hydrolysis, flunixin can be obtained, with an overall yield of 43.2 - 58.5%. In Heterocycles (1994, 38, 2243.), using ethylene glycol as a solvent and reacting at 165 °C for 6 h can generate ethyl flunixin, which is then hydrolyzed in methanol to form flunixin, with an overall two-step yield of 77.4%. However, when using ethyl 2-chloronicotinate as a substrate as above, an additional hydrolysis step is required. At the same time, such two-step strategies all have problems such as too high reaction temperature, too low conversion rate, and cumbersome post-treatment operations.

[0010]

[0011] Through the comparison of the above routes and the availability of raw materials, we finally chose 2-chloronicotinic acid and 2-methyl-3-(trifluoromethyl)aniline as the raw materials for synthesizing flunixin.

[0012] Currently, for the method of synthesizing flunixin from 2-chloronicotinic acid and 2-methyl-3-(trifluoromethyl)aniline, the main difference lies in the types of catalysts: (1) p-toluenesulfonic acid (CN1803773A); (2) copper oxide and p-toluenesulfonic acid (CN103694167A); (3) benzyltriethylammonium chloride (TEBAC) (CN104193674B); (4) pyridine and p-toluenesulfonic acid (Cryst. Growth Des. 2018, 18, 7006.), etc. Among them, most of the literature uses p-toluenesulfonic acid as a catalyst, but its price and dosage are not suitable for industrial production. However, inorganic acid catalysis is rarely used in the existing flunixin technology.

[0013] Based on the above discussion, such reactions have problems such as too long reaction time, expensive catalyst, too high reaction temperature, too large dosage of 2-methyl-3-(trifluoromethyl)aniline, and relatively high three wastes, thus not being suitable for industrial production.

[0014] In CN201410428267.0, although a two-phase catalytic system was developed, which also solved the problems of too large dosage of 2-methyl-3-(trifluoromethyl)aniline in the production process and the high difficulty in its recovery, purification, and utilization, but in actual repetition, the reproducibility of this process is poor and fails to achieve the expected goal. Therefore, this patent improved the common catalysts for synthesizing flunixin and chose boric acid, which is more suitable for industrial production, as the catalyst. Summary of the Invention

[0015] To solve the above technical problems, the present invention provides a method for synthesizing flunixin, which uses inexpensive boric acid as a Lewis catalyst and has the characteristics of simple operation, short reaction time, high yield, and low consumption of 2-methyl-3-(trifluoromethyl)aniline. At the same time, the synthesized flunixin can be directly reacted with meglumine to obtain flunixin meglumine, and the finished product meets the requirements of the pharmacopoeia.

[0016] The present invention is achieved by the following technical solutions:

[0017] (1) Synthesis of flunixin: Aromatic amination reaction is carried out on boric acid catalyst, 2-chloronicotinic acid and 2-methyl-3-(trifluoromethyl)aniline to generate flunixin;

[0018] (2) Synthesis of flunixin meglumine: Flunixin and meglumine are subjected to a salt-forming reaction in an isopropanol solvent to obtain flunixin meglumine.

[0019] The reaction formula is:

[0020]

[0021] In the above method for synthesizing flunixin, the reaction solvent is water, and the amount of water used is 3 times the mass of 2-chloronicotinic acid.

[0022] In the above method for synthesizing flunixin, the molar ratio of 2-chloronicotinic acid to 2-methyl-3-(trifluoromethyl)aniline is 1:1.05.

[0023] In the above method for synthesizing flunixin, the amount of the boric acid catalyst used is 0.1-0.3 times the molar amount of 2-chloronicotinic acid; further preferably, the amount of the boric acid catalyst used is 0.2 times the molar amount of 2-chloronicotinic acid.

[0024] In the above method for synthesizing flunixin, the reaction temperature is 85-90 °C.

[0025] In the above method for synthesizing flunixin, the reaction time is 8-10 h.

[0026] In the above method for synthesizing flunixin, the reaction further includes a post-treatment step, and the post-treatment step is to adjust the pH of the reaction solution to 12, extract with dichloromethane, adjust the pH of the reaction solution to about 3-5 with sulfuric acid, and filter. The filter cake is dried to obtain flunixin.

[0027] More preferably, 2-chloronicotinic acid, 2-methyl-3-(trifluoromethyl)aniline, water and boric acid are added to the reaction kettle, the reaction temperature is 90 °C, the reaction time is 10 h. After the reaction is completed, add NaOH solution to adjust the pH to about 12, extract twice with DCM, let it stand for stratification, dropwise add sulfuric acid to the aqueous phase to adjust the pH to 3-5, stir at room temperature for 1 h, filter the solid, and dry it to obtain flunixin.

[0028] In the above synthetic method of flunixin meglumine, the molar ratio of flunixin to meglumine is 1:1.03 to 1:1.05.

[0029] In the above synthetic method of flunixin meglumine, the reaction time is 1 - 2 h.

[0030] In the above synthetic method of flunixin meglumine, the reaction temperature is 80 - 90 °C.

[0031] In the above synthetic method of flunixin meglumine, the reaction solvent is isopropanol, and the solvent dosage is 7 times the mass of flunixin.

[0032] In the above synthetic method of flunixin meglumine, the reaction also includes a post-treatment step, which is to cool down, crystallize, filter, and obtain flunixin after drying the filter cake.

[0033] Furthermore, flunixin and meglumine are added to the reaction kettle, the reaction temperature is 90 °C, and the reaction time is 1 - 2 h. After the reaction is completed, it is cooled to 10 °C and kept warm for 1 - 2 h, then filtered by suction, and flunixin meglumine is obtained after drying.

[0034] Beneficial effects:

[0035] Compared with the prior art, the present invention has the following advantages: (1) In the synthetic method of flunixin, the dosage of 2-methyl-3-(trifluoromethyl)aniline is only 1.05 equivalents (up to 2 equivalents are used in the literature, and the market price is as high as 1000 yuan / kg), which is more suitable for industrial production; (2) In the synthetic method of flunixin, boric acid is selected as the catalyst (the market price is more than 10 times lower than that of p-toluenesulfonic acid), which is more suitable for industrial production; (3) In the synthetic method of flunixin, the conversion rate is as high as 99.9%, the yield is as high as 90%, and the purity is as high as 99.9%. Specific embodiments

[0036] The following is a further description of the present invention in combination with specific embodiments, so that those skilled in the art can better understand the present invention, but it does not limit the invention accordingly.

[0037] Example 1 Catalytic experiments with different catalysts

[0038] 31.4 g (200 mmol) of 2-chloronicotinic acid, 36.8 g (210 mmol) of 2-methyl-3-(trifluoromethyl)aniline, 90 g of water, and different catalysts were respectively added to a 500 mL reaction kettle. The temperature was 90 °C, and the reaction was carried out for 8 - 14 h. The types of catalysts and the conversion results are shown in Table 1.

[0039] The molar ratio of the catalyst refers to the ratio of the molar dosage of the catalyst to 2-chloronicotinic acid.

[0040] Table 1

[0041]

[0042]

[0043] Example 2

[0044] In a 50 L reactor, 3.14 kg (20 mol) of 2-chloronicotinic acid, 3.68 kg (21 mol) of 2-methyl-3-(trifluoromethyl)aniline, 9 kg of water, and 0.24 kg (4 mol) of boric acid were added respectively. The temperature was 90 °C, and the reaction was carried out for 8 h with a conversion rate of 99.6%. After the reaction was completed, NaOH solution was added to adjust the pH to about 12, and DCM (15 kg) was added for extraction, followed by standing and separating the layers. Sulfuric acid was added dropwise to the aqueous phase to adjust the pH to 3 - 5, and the mixture was stirred at room temperature for 1 h. The solid was filtered by suction, and after drying the filter cake, 5.58 kg of flunixin was obtained with a yield of 94.1% and a purity of 99.3%.

[0045] Example 3

[0046] In a 50 L reactor, 3.14 kg (20 mol) of 2-chloronicotinic acid, 3.68 kg (21 mol) of 2-methyl-3-(trifluoromethyl)aniline, 9 kg of water, and 0.24 kg (4 mol) of boric acid were added respectively. The temperature was 90 °C, and the reaction was carried out for 10 h with a conversion rate of 99.9%. After the reaction was completed, NaOH solution was added to adjust the pH to about 12, and DCM (15 kg) was added for extraction, followed by standing and separating the layers. Sulfuric acid was added dropwise to the aqueous phase to adjust the pH to 3 - 5, and the mixture was stirred at room temperature for 1 h. The solid was filtered by suction, and after drying the filter cake, 5.63 kg of flunixin was obtained with a yield of 95.1% and a purity of 99.9%.

[0047] Example 4

[0048] In a 50 L reactor, 3.14 kg (20 mol) of 2-chloronicotinic acid, 3.68 kg (21 mol) of 2-methyl-3-(trifluoromethyl)aniline, 9 kg of water, and 0.24 kg (4 mol) of boric acid were added respectively. The temperature was 90 °C, and the reaction was carried out for 10 h with a conversion rate of 99.7%. After the reaction was completed, NaOH solution was added to adjust the pH to about 12, and DCM (15 kg) was added for extraction, followed by standing and separating the layers. Sulfuric acid was added dropwise to the aqueous phase to adjust the pH to 3 - 5, and the mixture was stirred at room temperature for 1 h. The solid was filtered by suction, and after drying the filter cake, 5.61 kg of flunixin was obtained with a yield of 94.7% and a purity of 99.8%.

[0049] Example 5

[0050] In a 50L reactor, add 4.44 kg (15 mol) of flunixin, 3.07 kg (15.75 mol) of meglumine and 31 kg of isopropanol. Heat up to 90 °C and reflux for 1 h. Cool the reaction solution to 10 °C and stir while maintaining the temperature for 1 h. Filter the solid by suction. After drying the filter cake, 6.99 kg of flunixin meglumine is obtained, with a yield of 94.8% and a purity of 99.8%.

[0051] Example 6

[0052] In a 50L reactor, add 4.44 kg (15 mol) of flunixin, 3.07 kg (15.75 mol) of meglumine and 31 kg of isopropanol. Heat up to 90 °C and reflux for 2 h. Cool the reaction solution to 10 °C and stir while maintaining the temperature for 1 h. Filter the solid by suction. After drying the filter cake, 7.02 kg of flunixin meglumine is obtained, with a yield of 95.2% and a purity of 99.9%.

[0053] Example 7

[0054] In a 50L reactor, add 4.44 kg (15 mol) of flunixin, 3.07 kg (15.75 mol) of meglumine and 31 kg of isopropanol. Heat up to 90 °C and reflux for 2 h. Cool the reaction solution to 10 °C and stir while maintaining the temperature for 1 h. Filter the solid by suction. After drying the filter cake, 7.00 kg of flunixin meglumine is obtained, with a yield of 95.0% and a purity of 99.9%.

Claims

1. A synthetic method of flunixin, characterized in that, 2-chloronicotinic acid and 2-methyl-3-trifluoromethylaniline react under the catalysis of boric acid to form flunixin; the molar ratio of 2-chloronicotinic acid to 2-methyl-3-trifluoromethylaniline is 1:1.05, and the dosage of the boric acid catalyst is 0.1-0.3 times the molar dosage of 2-chloronicotinic acid; the reaction solvent is water, and the water dosage is 3 times the mass of 2-chloronicotinic acid, the reaction temperature is 85-90 °C, and the reaction time is 8-10 h.

2. The synthetic method of flunixin according to claim 1, characterized in that, the reaction further comprises a post-treatment step, and the post-treatment step is to adjust the pH of the reaction solution to 12, extract with dichloromethane, adjust the pH of the reaction solution to 3-5 with sulfuric acid, filter, wash with water, and dry the filter cake to obtain flunixin.

3. The synthetic method of flunixin according to claim 1, characterized in that, Add 2-chloronicotinic acid, 2-methyl-3-trifluoromethylaniline, water and boric acid to the reaction kettle, the reaction temperature is 90 °C, and the reaction time is 10 h. After the reaction is completed, add NaOH solution to adjust the pH to about 12, extract twice with DCM, let it stand for stratification, dropwise add sulfuric acid to the aqueous phase to adjust the pH to 3-5, stir at room temperature for 1 h, filter the solid, and dry it to obtain flunixin.

4. A synthetic method of flunixin meglumine, comprising the following steps: 1) 2-chloronicotinic acid and 2-methyl-3-trifluoromethylaniline react under the catalysis of boric acid to form flunixin; 2) Flunixin and meglumine react under reflux in an organic solvent to form flunixin meglumine; In step 1), the molar ratio of 2-chloronicotinic acid to 2-methyl-3-trifluoromethylaniline is 1:1.05, and the dosage of the boric acid catalyst is 0.1-0.3 times the molar dosage of 2-chloronicotinic acid; the reaction solvent is water, and the water dosage is 3 times the mass of 2-chloronicotinic acid, the reaction temperature is 85-90 °C, and the reaction time is 8-10 h; In step 2), the molar ratio of flunixin to meglumine is 1:1.03~1:1.05; In step 2), the reaction time is 1-2 h, and the reaction temperature is 80-90 °C; In step 2), the organic solvent is isopropanol.

5. The synthetic method of flunixin meglumine according to claim 4, in step 2), the reaction further comprises a post-treatment step, and the post-treatment step is to cool down to 10 °C for crystallization, keep warm for 1-2 h, then filter, and dry to obtain flunixin meglumine.

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