Preparation method of 4-trifluoromethyl nicotinic acid
By combining the Bohlmann-Rahtz heterocyclization reaction with alkaline hydrolysis, a highly efficient, safe, and environmentally friendly method for preparing 4-trifluoromethylnicotinic acid was achieved. This method solves the problems of low yield and poor environmental compatibility in existing technologies and provides an efficient industrial production solution.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- QUZHOU KAIWO CHEM CO LTD
- Filing Date
- 2026-02-02
- Publication Date
- 2026-05-12
AI Technical Summary
Existing methods for preparing 4-trifluoromethylnicotinic acid suffer from low yield, poor environmental compatibility, use of highly toxic or corrosive reagents, and harsh reaction conditions, making it difficult to meet the needs of industrial production.
The Bohlmann-Rahtz heterocyclization reaction was adopted, using 4,4,4-trifluoro-2-butynaldehyde and β-enamine ester as raw materials. The alkynyl cyclization reaction was carried out in the presence of ZnBr2 catalyst to generate 4-trifluoromethylnicotinic acid ester intermediate, which was then obtained by alkaline hydrolysis. The entire process was carried out at room temperature and pressure.
The preparation of 4-trifluoromethylnicotinic acid with high yield (over 85%) and high purity (over 99%) has been achieved, avoiding highly toxic and corrosive reagents, meeting the requirements of green synthesis, and is suitable for industrial production.
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Figure CN122010831A_ABST
Abstract
Description
Technical Field
[0001] This invention belongs to the field of chemical synthesis technology, specifically relating to a method for preparing 4-trifluoromethylnicotinic acid. Background Technology
[0002] 4-Trifluoromethylnicotinic acid (4-TMCA) is a key intermediate in the synthesis of many important compounds and has irreplaceable application value in the fields of pesticides and pharmaceuticals. In pesticides, 4-TMCA is a core raw material for the synthesis of the highly effective insecticide flonicamid, which rapidly deters feeding by interfering with insect nerve conduction, showing significant control over piercing-sucking pests such as aphids. In pharmaceuticals, 4-TMCA, as a precursor for the synthesis of HCV NS5B polymerase inhibitors and CRAC channel modulators, shows potential application prospects in the development of antiviral and cardiovascular drugs.
[0003] Currently, the preparation methods of 4-trifluoromethylnicotinic acid are mainly divided into two categories: direct trifluoromethylation of the pyridine ring and trifluoromethyl building block method. Specifically, these include the ethyl trifluoroacetoacetate method, the trifluoroacetyl chloride / trifluoroacetic anhydride method, the direct cyanoation method, and the direct carbonylation method.
[0004] The ethyl trifluoroacetoacetate process uses ethyl trifluoroacetoacetate and cyanoacetamide as starting materials to synthesize the target product through four steps: cyclization, chlorination, hydrogenolysis, and hydrolysis. However, the critical chlorination step in this process requires the use of highly toxic phosphorus oxychloride, which not only generates phosphorus-containing wastewater and causes severe environmental pollution, but also results in a low overall yield of only 38.6%.
[0005] The trifluoroacetyl chloride / trifluoroacetic anhydride process uses highly corrosive trifluoroacetyl chloride or trifluoroacetic anhydride as raw materials. During the ammoniation process, byproducts such as methyl 3-methoxyacrylate are easily generated, reducing the purity and yield of the target product. For example, European patent application EP0744400A2 and Japanese patent application JP2007210923A both report the use of trifluoroacetyl chloride or trifluoroacetic anhydride as starting materials, followed by acylation, ammonolysis, condensation under alkaline conditions, and then ring-closure and hydrolysis reactions to obtain 4-trifluoromethylnicotinic acid. In the trifluoroacetyl chloride / trifluoroacetic anhydride process, the use of highly corrosive trifluoroacetyl chloride or trifluoroacetic anhydride as raw materials easily generates byproducts during the reaction, affecting product purity and yield, and the highly corrosive raw materials pose safety hazards.
[0006] While direct cyanidation avoids the use of highly toxic chlorinating agents, it uses toxic cyanide, and the cyano group is easily over-reduced during hydrogenolysis, resulting in up to 15% destruction of the pyridine ring structure, thereby reducing the yield of the target product.
[0007] The direct carbonylation method uses 4-trifluoromethylpyridine compounds as starting materials, reacting them with carbon dioxide in the presence of a strong base such as lithium diisopropylamino, followed by acidification to obtain the target product. However, the direct carbonylation method requires strictly anhydrous and low-temperature conditions for reaction with carbon dioxide, resulting in harsh reaction conditions, expensive raw materials, low yields, and difficulty in industrialization.
[0008] In summary, existing methods for preparing 4-trifluoromethylnicotinic acid generally suffer from low yields, failing to meet the efficiency requirements of industrial production; they also have poor environmental compatibility, either using highly toxic or corrosive reagents or generating large amounts of pollutants; furthermore, the harsh reaction conditions or insufficient operational safety lead to high production difficulty and costs. Summary of the Invention
[0009] To address the aforementioned technical problems, this invention provides a method for preparing 4-trifluoromethylnicotinic acid that offers excellent yield, is environmentally friendly, and involves a mild and controllable reaction. This method overcomes the technical limitations of existing synthesis methods, which often employ highly toxic or corrosive reagents, require stringent conditions, involve cumbersome steps, and result in low yields.
[0010] This invention is based on the Bohlmann-Rahtz heterocyclization reaction principle. 4,4,4-trifluoro-2-butynedal is used as a building block for the synthesis of trifluoromethyl, and it is cyclized with β-enamine ester to generate 4-trifluoromethyl nicotinic acid ester intermediate, which is then obtained by alkaline hydrolysis.
[0011] This invention provides a method for preparing 4-trifluoromethylnicotinic acid, comprising the following steps: Using 4,4,4-trifluoro-2-butynal and the β-enamine ester shown in Formula 1 as starting materials, the 4,4,4-trifluoro-2-butynal and the β-enamine ester shown in Formula 1 underwent an alkynyl cyclization reaction under the action of a catalyst, yielding a 4-trifluoromethylnicotinic acid ester intermediate. The catalyst was a Lewis acid. The 4-trifluoromethylnicotinic acid ester intermediate was then subjected to alkaline hydrolysis to yield 4-trifluoromethylnicotinic acid. The specific synthetic route is as follows: ; In the formula, R 1 It is an alkyl group of C1 to C4.
[0012] Preferred, R 1 It can be methyl, ethyl, isopropyl or tert-butyl.
[0013] Preferably, the specific preparation method of 4-trifluoromethylnicotinic acid is as follows: 4,4,4-trifluoro-2-butynaldehyde, β-enamine ester of Formula 1, catalyst and first solvent are mixed and subjected to alkynyl cyclization reaction under reflux to obtain 4-trifluoromethyl nicotinic acid ester intermediate; 4-trifluoromethyl nicotinic acid ester intermediate, second solvent and alkaline solution are mixed and subjected to alkaline hydrolysis reaction to obtain 4-trifluoromethyl nicotinic acid.
[0014] Preferably, the molar ratio of 4,4,4-trifluoro-2-butynal to the β-enamine ester shown in Formula 1 is 1:1 to 3; the molar amount of the catalyst is 10% to 20% of the molar amount of 4,4,4-trifluoro-2-butynal.
[0015] Preferably, the β-enamine ester represented by Formula 1 is at least one of ethyl 3-aminoacrylate, isopropyl 3-aminoacrylate, tert-butyl 3-aminoacrylate, and methyl 3-aminoacrylate.
[0016] Preferably, the catalyst is ZnBr2, ZnCl2 or ZnI2.
[0017] Preferably, the reflux temperature is 110℃~140℃; the alkynyl cyclization reaction time is 6h~10h.
[0018] Preferably, the alkaline hydrolysis reaction is carried out at a temperature of 50℃ to 80℃ for a time of 3h to 24h.
[0019] Preferably, the alkaline solution is an aqueous solution of sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide, sodium carbonate, or potassium carbonate.
[0020] Preferably, the mass concentration of the alkaline solution is 10wt% to 30wt%. If the concentration of the alkaline solution is too low, it will prolong the reaction time and reduce the yield. If the concentration of the alkaline solution is too high, it will not significantly improve the yield and will increase the amount of hydrochloric acid used in the post-treatment acidification.
[0021] Preferably, the molar ratio of the alkali to the 4-trifluoromethylnicotinic acid ester intermediate is 1 to 6:1.
[0022] Preferably, the first solvent is toluene, 1,4-dioxane, xylene, ethanol, N,N-dimethylformamide, or dimethyl sulfoxide; and the second solvent is an alcohol solvent.
[0023] Preferably, the alcohol solvent is one of methanol, ethanol or isopropanol.
[0024] Compared with the prior art, the present invention has the following technical effects: This invention uses 4,4,4-trifluoro-2-butynedal and β-enamine ester as raw materials, and carries out a cyclization reaction under the action of a catalyst to obtain a 4-trifluoromethylnicotinic acid ester intermediate; then, through hydrolysis, it yields 4-trifluoromethylnicotinic acid. This invention can construct the target product through only two steps; the cyclization reaction can be carried out in an air atmosphere without the need for inert gas protection, and the reaction temperature is a conventional reflux temperature; the hydrolysis reaction is under mild conditions, without the need for high temperature and high pressure. Furthermore, the raw materials and catalysts used are all commercially available or easily synthesized chemicals, avoiding the use of highly toxic or corrosive reagents, thus ensuring high production safety.
[0025] The catalyst used in this invention is highly efficient and inexpensive. ZnBr2, ZnCl2 or ZnI2 is used as the catalyst for the cyclization reaction. It has high catalytic activity and is used in amounts of 10% to 20% of the molar amount of 4,4,4-trifluoro-2-butynedal. Moreover, its cost is much lower than that of precious metal catalysts and it is easy to recycle.
[0026] The 4-trifluoromethylnicotinic acid synthesized by this invention has excellent yield, with a total yield of over 85% in the two-step reaction. The intermediates and target products have high purity, and the separation and purification are simple. After separation and purification, the purity of 4-trifluoromethylnicotinic acid can reach over 99%, which meets the application requirements of the pharmaceutical and pesticide fields. No large amount of by-products are generated during the reaction process, which conforms to the concept of green synthesis and is suitable for industrial-scale production. Attached Figure Description
[0027] Figure 1 The 1H NMR spectrum of 4-trifluoromethylnicotinic acid prepared in Example 1.
[0028] Figure 2 The liquid chromatography of the product 4-trifluoromethylnicotinic acid in Example 1. Detailed Implementation
[0029] As described in the background section, methods for preparing 4-trifluoromethylnicotinic acid include the ethyl trifluoroacetoacetate method, the trifluoroacetyl chloride / trifluoroacetic anhydride method, the direct cyanolation method, and the direct carbonylation method. The ethyl trifluoroacetoacetate method uses ethyl trifluoroacetoacetate and cyanoacetamide as starting materials, and synthesizes the target product through four steps: cyclization, chlorination, hydrogenolysis, and hydrolysis. The specific synthetic route is as follows:
[0030] ; The trifluoroacetyl chloride / trifluoroacetic anhydride method uses highly corrosive trifluoroacetyl chloride or trifluoroacetic anhydride as raw materials. For example, European patent application EP0744400A2 and Japanese patent application JP2007210923A both report the synthesis of 4-trifluoromethylnicotinic acid from trifluoroacetyl chloride or trifluoroacetic anhydride as starting materials, via acylation, ammonolysis, condensation under alkaline conditions, followed by ring closure and hydrolysis. The specific synthetic route is as follows:
[0031] .
[0032] The direct carbonylation method uses 4-trifluoromethylpyridine compounds as starting materials, reacting them with carbon dioxide in the presence of a strong base such as lithium diisopropylamino, followed by acidification to obtain the target product. The specific synthetic route is as follows:
[0033] .
[0034] In summary, existing methods for preparing 4-trifluoromethylnicotinic acid generally suffer from low yields, failing to meet the efficiency requirements of industrial production; they also have poor environmental compatibility, either using highly toxic or corrosive reagents or generating large amounts of pollutants; furthermore, the harsh reaction conditions or insufficient operational safety lead to high production difficulty and costs.
[0035] To enable those skilled in the art to better understand and implement the technical solutions of the present invention, the present invention will be further described below in conjunction with specific embodiments.
[0036] Unless otherwise specified, all reagents used in this invention are commercially available, and all methods used are conventional techniques in the art.
[0037] Example 1 A method for preparing 4-trifluoromethylnicotinic acid includes the following steps: Step 1, Preparation of the 4-trifluoromethylnicotinic acid intermediate: In a 20 mL round-bottom flask, 4,4,4-trifluoro-2-butynedal (2.0 mmol, 244.1 mg), ethyl 3-aminoacrylate (3.0 mmol, 345.4 mg), ZnBr2 (0.3 mmol, 68.6 mg), and toluene (12 mL) were added sequentially. After stirring thoroughly, the mixture was refluxed at 110 °C in an oil bath for 8 h. After the reaction was completed, the mixture was cooled to room temperature, diluted with 20 mL of ethyl acetate, washed three times with 5 mL of saturated brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to remove the solvent, yielding a yellowish-brown oily crude intermediate of ethyl 4-trifluoromethylnicotinate, with a yield of 341.9 mg and a yield of 78%.
[0038] Step 2, Preparation of 4-trifluoromethylnicotinic acid: In a 50 mL round-bottom flask, 1.0 mmol (219.2 mg) of ethyl 4-trifluoromethylnicotinic acid intermediate, 15 mL of ethanol, and 1.5 mL of sodium hydroxide aqueous solution (3.0 mmol) were added. After stirring, the mixture was reacted in an oil bath at 60 °C for 6 h. After the reaction was completed, the mixture was cooled to room temperature and acidified with 1 N hydrochloric acid to pH 2–3, precipitating a white solid. The solid was collected by filtration and recrystallized from ethanol to obtain a white powder of 4-trifluoromethylnicotinic acid, with a yield of 168.2 mg and a yield of 88%.
[0039] like Figure 1 As shown, the structure of the synthesized 4-trifluoromethylnicotinic acid product was verified.
[0040] like Figure 2 As shown in Table 1, the purity of the 4-trifluoromethylnicotinic acid product is 99.7%.
[0041] 4-Trifluoromethylnicotinic acid was tested by liquid chromatography with a detector wavelength of 254 nm.
[0042] Table 1. Chromatographic peak data of 4-trifluoromethylnicotinic acid Example 2 A method for preparing 4-trifluoromethylnicotinic acid is the same as that in Example 1, except that the catalyst and its amount are different. The catalyst and its amount are shown in Table 2.
[0043] Table 2. Preparation of 4-trifluoromethylnicotinic acid under different catalysts and dosages Note: "Amount of catalyst" indicates that the molar amount of catalyst is a percentage of the molar amount of 4,4,4-trifluoro-2-butynaldehyde.
[0044] Table 2 shows that ZnBr2 exhibits the best catalytic efficiency when used as the catalyst. Furthermore, high catalytic effects and high yields of 4-trifluoromethylnicotinic acid are achieved when the catalyst dosage is between 15% and 20%. Reducing the ZnBr2 dosage leads to a decrease in the yield of 4-trifluoromethylnicotinic acid. Replacing ZnBr2 with other Lewis acids (such as ZnCl2 or CuBr2) also reduces the yield. The reaction cannot occur without a catalyst.
[0045] Example 3 A method for preparing 4-trifluoromethylnicotinic acid is the same as that in Example 1, except that the temperature of the first solvent and the alkynyl cyclization reaction are different.
[0046] Table 3. Preparation of 4-trifluoromethylnicotinic acid under different solvent systems and reaction temperatures Table 3 shows that when toluene is used as the solvent, its polarity and boiling point ensure efficient reaction under reflux. Other solvents, due to excessively high or low polarity or mismatched boiling points, result in slightly lower yields. Furthermore, when toluene is used as the solvent, the lower the reaction temperature, the lower the yield; reflux is the optimal reaction temperature.
[0047] Example 4 A method for preparing 4-trifluoromethylnicotinic acid is the same as that in Example 1, except that the alkali and its concentration are different.
[0048] Table 4. Preparation of 4-trifluoromethylnicotinic acid by hydrolysis under different concentrations and types of alkaline systems. Table 4 shows that high hydrolysis rates and high yields of 4-trifluoromethylnicotinic acid can be obtained when the alkali is sodium hydroxide, potassium hydroxide, lithium hydroxide, or cesium hydroxide. Under the same reaction conditions, the hydrolysis efficiency reaches its highest when the alkali is NaOH, completing the reaction in 4 hours with a yield of over 85%. Too low an alkali concentration prolongs the reaction time and reduces the yield, while too high an alkali concentration does not significantly improve the yield and increases the amount of hydrochloric acid required for post-treatment acidification. Therefore, the alkali concentration is selected to be between 10 wt% and 30 wt%.
[0049] This invention achieves the efficient preparation of 4-trifluoromethylnicotinic acid through a two-step method combining cyclization and hydrolysis. The method uses 4,4,4-trifluoro-2-butynedal as the building block for trifluoromethyl synthesis, efficiently constructing a trifluoromethylpyridine skeleton via a ZnBr2-catalyzed Bohlmann-Rahtz heterocyclization reaction, followed by alkaline hydrolysis to obtain the target product. The entire synthetic route offers advantages such as readily available raw materials, mild reaction conditions, high yield, good purity, and environmental friendliness, making it suitable for industrial production and providing a new and efficient route for the synthesis of 4-trifluoromethylnicotinic acid.
[0050] It should be noted that when numerical ranges are involved in this invention, it should be understood that the two endpoints of each numerical range, as well as any value between the two endpoints, can be selected. Since the steps and methods used are the same as in the embodiments, preferred embodiments are described in this invention to avoid redundancy. Although preferred embodiments of this invention have been described, those skilled in the art, once they understand the basic inventive concept, can make other changes and modifications to these embodiments, and all such changes and modifications fall within the scope of this invention.
[0051] Obviously, those skilled in the art can make various modifications and variations to this invention without departing from its spirit and scope. If these modifications and variations fall within the scope of equivalents of this invention, then this invention also intends to include these modifications and variations.
Claims
1. A method for preparing 4-trifluoromethylnicotinic acid, characterized in that, Includes the following steps: Using 4,4,4-trifluoro-2-butynaldehyde and β-enamine ester of Formula 1 as raw materials, 4,4,4-trifluoro-2-butynaldehyde and β-enamine ester of Formula 1 undergo alkynyl cyclization reaction under the action of a catalyst to obtain 4-trifluoromethyl nicotinic acid ester intermediate. The catalyst is a Lewis acid. The intermediate 4-trifluoromethylnicotinic acid was obtained by alkaline hydrolysis; the specific synthetic route is as follows: ； In the formula, R 1 It is an alkyl group of C1 to C4.
2. The method for preparing 4-trifluoromethylnicotinic acid according to claim 1, characterized in that, R 1 It can be methyl, ethyl, isopropyl or tert-butyl.
3. The method for preparing 4-trifluoromethylnicotinic acid according to claim 1 or 2, characterized in that, The preparation method of 4-trifluoromethylnicotinic acid is as follows: 4,4,4-trifluoro-2-butynaldehyde, β-enamine ester of Formula 1, catalyst and first solvent are mixed and subjected to alkynyl cyclization reaction under reflux to give 4-trifluoromethyl nicotinic acid ester intermediate; The intermediate 4-trifluoromethyl nicotinic acid ester, a second solvent, and an alkaline solution are mixed and subjected to alkaline hydrolysis to obtain 4-trifluoromethyl nicotinic acid.
4. The method for preparing 4-trifluoromethylnicotinic acid according to claim 3, characterized in that, The molar ratio of 4,4,4-trifluoro-2-butynaldehyde to the β-enamine ester shown in Formula 1 is 1:1 to 3; The molar amount of the catalyst is 10% to 20% of the molar amount of 4,4,4-trifluoro-2-butynedal.
5. The method for preparing 4-trifluoromethylnicotinic acid according to claim 4, characterized in that, The β-enamine ester shown in Formula 1 is at least one of ethyl 3-aminoacrylate, isopropyl 3-aminoacrylate, tert-butyl 3-aminoacrylate, and methyl 3-aminoacrylate.
6. The method for preparing 4-trifluoromethylnicotinic acid according to claim 4, characterized in that, The catalyst is ZnBr2, ZnCl2 or ZnI2.
7. The method for preparing 4-trifluoromethylnicotinic acid according to claim 3, characterized in that, The alkaline solution is an aqueous solution of sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide, sodium carbonate, or potassium carbonate; the mass concentration of the alkaline solution is 10wt% to 30wt%.
8. The method for preparing 4-trifluoromethylnicotinic acid according to claim 3, characterized in that, The molar ratio of the base to the 4-trifluoromethylnicotinic acid ester intermediate is 1 to 6:
1.
9. The method for preparing 4-trifluoromethylnicotinic acid according to claim 3, characterized in that, The first solvent is toluene, 1,4-dioxane, xylene, ethanol, N,N-dimethylformamide, or dimethyl sulfoxide; the second solvent is an alcohol solvent.