A process for the preparation of 4-trifluoromethylnicotinic acid

Abstract

This invention discloses a method for preparing 4-trifluoromethylnicotinic acid. The method involves preparing compound I from a novel intermediate compound of formula II, and then preparing 4-trifluoromethylnicotinic acid from compound I. Compared with existing methods, the raw materials used are inexpensive and readily available, the reaction intermediates are stable and easy to store, separation and purification are easy, the operation is simple, the yield is high, and it has the potential for industrial production. The structures of compounds of formula I and formula II are as follows: Wherein, R... 1 C1~C 10 alkyl.

Description

Technical Field

[0001] This invention relates to the field of pesticide intermediate synthesis technology, specifically to a method for preparing 4-trifluoromethylnicotinic acid. This method involves preparing a compound of formula I from a novel intermediate compound of formula II, and then preparing 4-trifluoromethylnicotinic acid from compound I. Background Technology

[0002] Flupyradifurone is a novel, low-toxicity pyridine amide insecticide that received a temporary pesticide registration certificate in my country in 2007. Its structural formula is shown below. Flupyradifurone is effective in controlling piercing-sucking pests on cash and grain crops, especially aphids, and is environmentally friendly. Its mechanism of action differs from existing insecticides, resulting in a lower risk of cross-resistance, thus giving it broad market application prospects.

[0003] Flupyradifurone is usually prepared from the intermediate 4-trifluoromethylnicotinic acid.

[0004]

[0005] Currently, most reported methods for preparing 4-trifluoromethylnicotinic acid both domestically and internationally use trifluoromethyl compound building blocks as raw materials. Based on the different starting materials, they can be mainly divided into three categories:

[0006] The first type is prepared from ethyl trifluoroacetoacetate and cyanoacetamide through cyclization, chlorination, catalytic hydrogenolysis and cyano hydrolysis. The first two reaction routes are relatively mature, but the latter two steps mostly require expensive palladium catalysts. In addition, this type of reaction also faces problems such as large amounts of waste, and does not have the prospect of industrial application.

[0007] The second type involves using trifluoroacetic acid or trifluoroacetic anhydride as raw materials, followed by acylation with vinyl ethyl ether, and then ammonolysis, basic condensation, cyclization, and alkaline hydrolysis to obtain 4-trifluoromethylnicotinic acid. This type of reaction often uses methyl 3-methoxyacrylate or methyl 3,3-dimethoxypropionate as raw materials, which are expensive and difficult to obtain. Patent CN 107298653 reports the preparation of 4-trifluoromethylnicotinic acid from dimethyl 2-methoxymethylene malonate, achieving a total yield of 49% without the need for separation and purification of any intermediate products. However, the reaction requires the use of sodium hydride, thus its safety needs further improvement. Patent CN 109467532 A reports the cyclization and alkaline hydrolysis of 4-ethoxy-1,1,1-trifluoro-3-en-2-one and 3-aminoacrylonitrile as raw materials in the presence of sodium ethoxide to obtain 4-trifluoromethylnicotinic acid. This method has a simple route, but 3-aminoacrylonitrile is difficult to obtain.

[0008] The third type uses trifluoropyridine series compounds as raw materials, such as patents US5360806 and EP0580374. This method generally involves reacting a trifluoromethylpyridine derivative with a strong base at low temperature, followed by reaction with carbon dioxide, acidification, and palladium-catalyzed dehalogenation. Because the reaction requires organometallic reagents and relatively low temperatures, its industrialization prospects are limited.

[0009] The raw materials for the above three methods are all compounds containing trifluoromethyl groups. The direct fluorination of trichloromethylpyridine compounds to prepare trifluoromethylpyridine compounds provides a new approach for the preparation of 4-trifluoromethylnicotinic acid. For example, Edward G. Seovell et al. (EP0063872B1) synthesized 2-fluoro-3-chloro-5-trifluoromethylpyridine by reacting 2,3-dichloro-5-trichloromethylpyridine with KF as a fluorinating agent in a polar solvent. Zhang Wei et al. (CN1202082C) prepared 2-chloro-5-trifluoromethylpyridine using 2-chloro-5-trichloromethylpyridine and anhydrous HF as raw materials at a reaction temperature of 195℃. There are relatively few research reports on this type of synthetic method.

[0010]

[0011] It is evident that although there are some reported methods for synthesizing 4-trifluoromethylnicotinic acid, they all have certain shortcomings. Summary of the Invention

[0012] To address the various shortcomings of existing technologies, this invention provides a method for preparing 4-trifluoromethylnicotinic acid. Using the stable and readily available compound 4-amino-1,1,1-trichloro-3-buten-2-one (compound III) as a raw material, this invention prepares 4-trichloromethylnicotinic acid and its derivative (compound I) through condensation, cyclization, and alkaline hydrolysis. Further fluorination and acidification yield 4-trifluoromethylnicotinic acid. The method of this invention utilizes inexpensive and readily available raw materials, the reaction intermediates are stable and easy to store, separation and purification are easy, the operation is simple, and the yield is high, possessing the potential for industrial-scale production.

[0013] To achieve the objectives of this invention, the technical solution adopted is as follows:

[0014] This invention provides a method for preparing 4-trifluoromethylnicotinic acid, which includes the following steps: 4-trifluoromethylnicotinic acid is prepared by fluorination and acidification of the compound shown in Formula I.

[0015] This invention also discloses compounds of formula II and formula I, wherein the structures of compounds of formula II and formula I are as follows:

[0016] In which, R of compound I 1C1~C 10 alkyl.

[0017] The present invention also provides a method for preparing a compound of formula II, the method comprising the following steps:

[0018] In the presence of an acid, the compound shown in Formula III undergoes a condensation reaction to obtain the compound shown in Formula II;

[0019]

[0020] The acid is selected from organic acids or inorganic acids. The organic acid is selected from one or more of formic acid, acetic acid, trifluoroacetic acid, trichloroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, and p-toluenesulfonic acid. The inorganic acid is selected from one or more of hydrochloric acid, sulfuric acid, phosphoric acid, and nitric acid.

[0021] The present invention also provides a method for preparing a compound of formula I, comprising the following steps:

[0022] In the presence of a base, the compound of formula II undergoes a cyclization reaction and an alcoholysis reaction to prepare the compound shown in formula I;

[0023]

[0024] in,

[0025] R 1 C1~C 10 alkyl.

[0026] Beneficial effects of the present invention

[0027] The method of the present invention can effectively improve the yield of compounds, and the method uses inexpensive raw materials, is simpler to operate, safer and more environmentally friendly.

[0028] Furthermore, through the above technical solution, the present invention has at least the following advantages:

[0029] (1) Compared with trifluoroacetic acid, a commonly used raw material for the preparation of 4-trifluoromethylnicotinic acid, the starting material 4-amino-1,1,1-trichloro-3-buten-2-one used in this invention is stable and can be prepared from inexpensive trichloroacetyl chloride by acylation and amination. The other raw materials are also conventional reagents, and the reaction intermediates are stable and easy to separate and purify.

[0030] (2) The entire process of the present invention is simple, safe and low in cost, convenient in post-processing, and has a high yield, making it suitable for industrial production. Detailed Implementation

[0031] The specific embodiments of the present invention will be further described in detail below with reference to examples. To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention. Unless otherwise expressly stated, throughout the specification and claims, the term "comprising" or its variations such as "including" or "comprising of," etc., will be understood to include the stated components and steps, without excluding the presence of other substances or steps.

[0032] Furthermore, to better illustrate the present invention, numerous specific details are provided in the following detailed embodiments.

[0033] Those skilled in the art will understand that the present invention can be practiced even without certain specific details. In some embodiments, materials, methods, and means well known to those skilled in the art are not described in detail in order to highlight the spirit of the invention.

[0034] Embodiments of the invention are described in detail below. However, these embodiments are exemplary, and the invention is not limited thereto; rather, the invention is defined by the scope of the claims.

[0035] In this invention, unless otherwise specified, room temperature refers to approximately 20°C-25°C.

[0036] As used herein, unless otherwise specifically defined, the following terms used in the specification and claims have the following meanings.

[0037] In this invention, C1-C 10 Alkyl groups indicate the presence of 1-10 carbon atoms. (C1-C) 10 Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, 1-methylpropyl (sec-butyl), 2-methylpropyl (isobutyl), 1,1-dimethylethyl (tert-butyl), etc., but are not limited to these.

[0038] This invention provides a method for preparing 4-trifluoromethylnicotinic acid, which includes fluorination and acidification of the compound shown in Formula I to obtain 4-trifluoromethylnicotinic acid. The synthetic route is as follows:

[0039]

[0040] The fluorination reaction involves adding the compound shown in Formula I and a fluorinating reagent to an organic solvent to carry out the fluorination reaction; the fluorinating reagent is one of anhydrous HF, SbF3, KF, and NaF, and the amount of the fluorinating reagent added is 3 to 50 times the weight of the compound shown in Formula I, preferably 4 to 10 times; the fluorination reaction temperature is between 100 and 250°C; the fluorination reaction pressure is 1 to 15 MPa, preferably 1 to 5 MPa; the organic solvent is selected from one or more of DMSO, DMF, DMA, and sulfolane; the acidification reaction involves adding the fluorinated product to a sodium hydroxide solution for alkaline hydrolysis and then acidifying it with hydrochloric acid.

[0041] The present invention also provides a method for preparing a compound of formula II, comprising the following steps:

[0042] In the presence of an acid, the compound shown in Formula III undergoes a condensation reaction to obtain the compound shown in Formula II;

[0043]

[0044] The acid is selected from one or more organic acids or inorganic acids; the organic acid is selected from one or more formic acid, acetic acid, trifluoroacetic acid, trichloroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, and p-toluenesulfonic acid; the inorganic acid is selected from one or more hydrochloric acid, sulfuric acid, phosphoric acid, and nitric acid. Preferably, the acid is selected from one or more formic acid, acetic acid, trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, and sulfuric acid.

[0045] The condensation reaction is carried out in an organic solvent selected from one or more of organic alcohols, toluene, tetrahydrofuran, dichloromethane, 1,2-dichloroethane, and 1,4-dioxane, preferably one or more of methanol, ethanol, dichloromethane, and 1,2-dichloroethane; the reaction temperature of the condensation reaction is from -15°C to 40°C, preferably from 0°C to 25°C; the molar ratio of the compound shown in Formula III to the acid is 1:0.5 to 2.0, preferably 1:0.8 to 1.2.

[0046] The present invention also provides a method for preparing a compound of formula I, comprising the following steps:

[0047] In the presence of a base, the compound of formula II undergoes a cyclization reaction and an alcoholysis reaction to prepare the compound shown in formula I;

[0048]

[0049] in,

[0050] R 1 C1~C 10 alkyl;

[0051] The alkali is selected from one or more of sodium alkoxide, triethylamine, N,N-diisopropylethylamine, pyridine, sodium carbonate, sodium bicarbonate, potassium carbonate, sodium formate, sodium acetate, potassium acetate, and N,N-dimethylaniline, preferably one or more of sodium methoxide, sodium ethoxide, triethylamine, sodium carbonate, and potassium carbonate.

[0052] The cyclization reaction and alcoholysis reaction are carried out in the same organic solvent, which is selected from one or more of toluene, cyclohexane, tetrahydrofuran, dichloromethane, 1,2-dichloroethane, and 1,4-dioxane, preferably one or more of tetrahydrofuran, dichloromethane, and 1,2-dichloroethane.

[0053] The reaction temperature for the cyclization reaction and alcoholysis reaction is -15°C to 40°C, preferably 0°C to 25°C;

[0054] The alcohol used in the alcoholysis reaction is selected from R. 1 -OH,R 1 C1~C 10 Alkyl groups, preferably one of methanol and ethanol;

[0055] The molar ratio of the compound of formula II, the base, and the alcohol is 1:1.0 to 1.5:1.0 to 1.5, preferably 1:1.0 to 1.3:1.0 to 1.3.

[0056] The present invention also provides compounds of formula II and formula I.

[0057] R 1 C1~C 10 alkyl.

[0058] The compounds of formulas I and II disclosed in this invention are used to prepare 4-trifluoromethylnicotinic acid, resulting in a significantly optimized process route, reduced production costs, and a simpler and easier-to-operate process. The intermediates of this invention can be prepared according to the above-described preparation method.

[0059] Unless otherwise specified, the experimental methods used in the following examples are conventional methods; unless otherwise specified, the reagents and materials used in the following examples are commercially available.

[0060] Example 1: Preparation of Compound II

[0061]

[0062] In a 500 mL four-necked flask equipped with a mechanical stirrer, thermometer, and condenser, 56.4 g (0.3 mol) of compound III and 200 g of 1,2-dichloroethane were added. 16.7 mL (0.6 mol) of 35% hydrochloric acid was added dropwise at 0 °C. After the addition was complete, the mixture was brought to room temperature and stirred for 12 h. A solid precipitated during the reaction. After the reaction was complete, the solvent was removed to give 107 g of a brown solid. The purity was 98%, and the yield was 98%. 1 H NMR(500MHz,DMSO-d6)δ7.54(d,2H),5.82(d,2H).

[0063] Example 2: Preparation of Compound II

[0064] The difference from Example 1 is that the acid used is 50% sulfuric acid, while other molar ratios remain the same, yielding 95g of compound II with a purity of 98% and a yield of 87%.

[0065] Example 3: Preparation of Compound II

[0066] The difference from Example 1 is that the acid used is glacial acetic acid, while the other molar ratios remain the same, yielding 75g of compound II with a purity of 98% and a yield of 69%.

[0067] Example 4: Preparation of compound I-1

[0068]

[0069] In a 500 mL four-necked flask equipped with a mechanical stirrer, thermometer, and condenser, 35.7 g (0.1 mol) of compound II and 100 g of 1,2-dichloroethane were added. After stirring at room temperature for 10 min, 18 g (0.13 mol) of potassium carbonate was added. Stirring continued for another 10 min, followed by dropwise addition of 3.8 g (0.12 mol) of anhydrous methanol. After the addition was complete, the mixture was stirred at room temperature for 1 h. After the reaction was complete, 50 g of water was added, and the aqueous phase was extracted with 50 g of 1,2-dichloroethane. The organic phases were combined, and the solvent 1,2-dichloroethane was distilled off. The residue was then treated with 20 g of methanol and recrystallized at 50-60 °C to give 24.8 g of a grayish-white solid. The purity was 98%, and the yield was 96%. 1 H NMR (500MHz, CDCl3) δ8.45 (dd, J = 8.4Hz, 1.9Hz, 1H), 8.12 (d, J = 8.4Hz, 1H), 7.13 (d, J = 1.9Hz, 1H), 4.00 (s, 3H).

[0070] Example 5: Preparation of compound I-1

[0071] The difference from Example 4 is that the base is sodium methoxide, while the other molar ratios remain the same, yielding 18g of compound II with a purity of 98% and a yield of 70%.

[0072] Example 6: Preparation of compound I-1

[0073] The difference from Example 4 is that the base is triethylamine, while the other molar ratios remain the same, yielding 15g of compound II with a purity of 98% and a yield of 58%.

[0074] Example 7: Preparation of compound I-1

[0075] The difference from Example 4 is that the base is sodium carbonate, while the other molar ratios remain the same, yielding 21g of compound II with a purity of 98% and a yield of 81%.

[0076] Example 8: Preparation of compound I-2

[0077]

[0078] In a 500 mL four-necked flask equipped with a mechanical stirrer, thermometer, and condenser, 35.7 g (0.1 mol) of compound IV and 100 g of 1,2-dichloroethane were added. After stirring at room temperature for 10 min, 18 g (0.13 mol) of potassium carbonate was added. Stirring continued for another 10 min, followed by dropwise addition of 5.63 g (0.12 mol) of anhydrous ethanol. The mixture was stirred at room temperature for 1 h after the addition was complete. After the reaction was complete, 50 g of water was added, and the aqueous phase was extracted with 50 g of 1,2-dichloroethane. The organic phases were combined, and the solvent 1,2-dichloroethane was distilled off. The residue was then treated with 20 g of ethanol and recrystallized at 50-60 °C to give 25.9 g of a grayish-white solid. The purity was 98%, and the yield was 95%. 1 H NMR (500MHz, CDCl3) δ 8.44 (dd, J = 8.4Hz, 1.9Hz, 1H), 8.13 (d, J = 8.4Hz, 1H), 7.12 (d, J = 1.9Hz, 1H), 4.27 (q, J = 7.2Hz, 2H), 1.37 (t, J = 7.2Hz, 3H).

[0079] Example 9: Preparation of compound 4-trifluoromethylnicotinic acid

[0080]

[0081] Add 25.3 g (0.1 mol) of compound I-1 and 70 g of DMSO to a high-pressure reactor, cover the reactor, purge with nitrogen, and after confirming that the reactor is leak-proof, release the pressure inside the reactor and place it in an ice-salt bath to cool. When the temperature inside the reactor drops below -5°C, purge the reactor with 12 g (0.6 mol) of anhydrous hydrogen fluoride. Under stirring, heat the reaction system to 150°C and react for 10 hours. After the reaction is complete, cool to 30°C, purge the reactor with nitrogen for half an hour, and pressurize the reaction mixture into 100 mL of ice water. Neutralize with 20% sodium hydroxide solution to approximately pH 10. Then, extract the reaction mixture three times with 100 mL of dichloroethane, combine the extracts, wash with water until neutral, and remove the dichloroethane by evaporation under normal pressure. The residue was added to 50 mL of 30% sodium hydroxide solution, and the mixture was heated to 40–50 °C for 2 hours for alkaline hydrolysis. After the reaction was complete, concentrated hydrochloric acid was added dropwise to adjust the pH to 2–3. The mixture was then filtered, dried, and 16.1 g of yellow solid with a purity of 95% and a yield of 80% was obtained.

[0082] The preferred embodiments of the present invention have been described in detail above; however, the present invention is not limited thereto. Within the scope of the inventive concept, various simple modifications can be made to the technical solutions of the present invention, including combinations of various technical features in any other suitable manner. These simple modifications and combinations should also be considered as the content disclosed in the present invention and are all within the protection scope of the present invention.

Claims

1. A process for the preparation of 4-trifluoromethylnicotinic acid, characterized in that, The method comprises the following steps: preparing 4-trifluoromethyl nicotinic acid by fluorination and acidification of a compound shown in formula I, and a synthesis route is as follows: wherein R 1 is C1-C 10 alkyl; The fluorination is that the compound shown in formula I and a fluorination reagent are added into an organic solvent to perform the fluorination; the fluorination reagent is selected from one of anhydrous HF, SbF3, KF and NaF; and the acidification comprises the steps of adding the fluorination product into a sodium hydroxide solution to perform alkaline hydrolysis and then adding hydrochloric acid to perform acidification.

2. The production method according to claim 1, characterized by, The compound shown in formula I is prepared by ring-closing reaction of a compound shown in formula II in the presence of a base and then alcoholysis reaction; the compound shown in formula II is as follows: The base is selected from one or more of sodium methoxide, sodium ethoxide, triethylamine, N, N-diisopropyl ethylamine, pyridine, sodium carbonate, sodium bicarbonate, potassium carbonate, sodium formate, sodium acetate, potassium acetate and N, N-dimethyl aniline; The alcohol of the alcoholysis reaction is selected from R 1 -OH, R 1 C1-C4alkyl; and n is 1 or 2. 10 alkyl; The ring-closing reaction and the alcoholysis reaction are performed in the same organic solvent, and the organic solvent is selected from one or more of toluene, cyclohexane, tetrahydrofuran, dichloromethane, 1, 2-dichloroethane and 1, 4-dioxane; The reaction temperature of the ring-closing reaction and the alcoholysis reaction is-15℃ to 40℃; The molar ratio of the compound shown in formula II, the base and alcohol is 1: 1.0-1.5: 1.0-1.

5.

3. The preparation method according to claim 2, characterized in that, The base is selected from one or more of sodium methoxide, sodium ethoxide, triethylamine, sodium carbonate and potassium carbonate; the organic solvent is selected from one or more of tetrahydrofuran, dichloromethane and 1, 2-dichloroethane; the reaction temperature of the ring-closing reaction and the alcoholysis reaction is 0℃ to 25℃; and the molar ratio of the compound shown in formula II, the base and alcohol is 1: 1.0-1.3: 1.0-1.

3.

4. The preparation method according to claim 2, characterized in that, The compound shown in formula II is prepared by condensation reaction of a compound shown in formula III in the presence of an acid, and the structure of formula III is as follows: The acid in the condensation reaction is selected from one or more of organic acids or inorganic acids; the organic acid is selected from one or more of formic acid, acetic acid, trifluoroacetic acid, trichloroacetic acid, methyl sulfonic acid, trifluoromethanesulfonic acid and p-toluenesulfonic acid; and the inorganic acid is selected from one or more of hydrochloric acid, sulfuric acid, phosphoric acid and nitric acid; The condensation reaction is performed in an organic solvent, and the organic solvent is selected from one or more of organic alcohol, toluene, tetrahydrofuran, dichloromethane, 1, 2-dichloroethane and 1, 4-dioxane; The reaction temperature of the condensation reaction is-15℃ to 40℃; The molar ratio of the compound shown in formula III and the acid is 1: 0.5-2.

0.

5. The preparation method according to claim 3, characterized in that, The acid is selected from one or more of formic acid, acetic acid, trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid and sulfuric acid; the organic solvent is selected from one or more of methanol, ethanol, dichloromethane and 1, 2-dichloroethane; the reaction temperature of the condensation reaction is 0℃ to 25℃; and the molar ratio of the compound shown in formula III and the acid is 1: 0.8-1.

2.

6. A compound shown in formula I, R 1 For C1~C 10 alkyl.

7. A compound shown in formula II,

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