Preparation method of 4-trifluoromethyl nicotinic acid

Abstract

The invention discloses a preparation method of 4-trifluoromethyl nicotinic acid. According to the method, a novel intermediate compound shown as a formula II is used for preparing a compound shown as a formula I, and the compound shown as the formula I is used for preparing 4-trifluoromethyl nicotinic acid. Compared with the prior art, the adopted raw materials are cheap and easy to obtain, the reaction intermediate is stable and easy to store, separation and purification are easy, operation is simple, the yield is high, and the method has the potential of industrial production. Wherein the structures of the compounds in the formula I and the formula II are as follows: # imgabs0 #, and R1 is C1-C10 alkyl.

Description

Technical Field

[0001] The present invention relates to the technical field of pesticide intermediate synthesis, and in particular to a method for preparing 4-trifluoromethylnicotinic acid. The method uses a new intermediate compound of formula II to prepare a compound of formula I, and the compound of formula I to prepare 4-trifluoromethylnicotinic acid. Background Art

[0002] Flunic acid amide is a new type of low-toxic pyridinamide insecticide, which obtained the temporary registration certificate for pesticide products in my country in 2007. Its structural formula is shown below. Flunic acid amide can effectively control piercing-sucking pests on cash crops and food crops, especially aphids, and is environmentally friendly. It has a different mechanism of action from existing insecticides and has a lower risk of cross-resistance, so it has broad market application prospects.

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

[0004]

[0005] In the preparation methods of 4-trifluoromethylnicotinic acid reported at home and abroad, the raw materials are mostly trifluoromethyl-containing compound building blocks. According to the different starting materials, they are mainly divided into three categories:

[0006] The first type uses ethyl trifluoroacetoacetate and cyanoacetamide as raw materials, and is prepared through steps such as cyclization, chlorination, catalytic hydrogenolysis, and cyanide hydrolysis. The reaction routes for the first two steps are relatively mature, but the latter two steps mostly require the use of expensive palladium catalysts. In addition, this type of reaction also faces problems such as large amounts of three wastes, and does not have prospects for industrial application.

[0007] The second type is obtained by using trifluoroacetic acid or trifluoroacetic anhydride as raw materials, acylation with vinyl ethyl ether, and then undergoing aminolysis, alkaline condensation, ring closure, and alkaline hydrolysis. This type of reaction mostly uses 3-methoxy methyl acrylate or 3,3-dimethoxy methyl propionate as raw materials, which are expensive and difficult to obtain. Patent CN 107298653 reported the preparation of 4-trifluoromethyl nicotinic acid using 2-methoxymethylenemalonate as raw material, with a total reaction yield of 49% and no need to separate and purify any intermediate products, but sodium hydride is required during the reaction, so the safety needs to be further improved. Patent CN 109467532 A reported that 4-ethoxy-1,1,1-trifluoro-3-ene-2-one and 3-aminoacrylonitrile were used as raw materials, and 4-trifluoromethyl nicotinic acid was obtained by ring closure and alkaline hydrolysis under the action of sodium ethoxide. The method is simple, but the raw material of 3-aminoacrylonitrile is not easy to obtain.

[0008] The third type is prepared from trifluoropyridine series compounds as raw materials, such as patents US5360806 and EP0580374. This method is generally prepared by reacting trifluoromethylpyridine derivatives with a strong base at low temperature, then reacting with carbon dioxide, acidifying, and palladium-catalyzed dehalogenation. Since organic metal reagents are required in the reaction and a low temperature is required, the industrialization prospect is low.

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

[0010]

[0011] It can be seen that although there are certain reports on the synthesis methods of 4-trifluoromethylnicotinic acid, they all have certain defects to a greater or lesser extent. Summary of the invention

[0012] In view of the various defects existing in the prior art, the present invention provides a method for preparing 4-trifluoromethylnicotinic acid. The present invention uses a stable and easily prepared compound 4-amino-1,1,1-trichloro-3-butene-2-one (Compound III) as a raw material, and prepares 4-trichloromethylnicotinic acid and its derivatives (Compound I) through condensation, ring closure, and alkaline hydrolysis, and then fluorination and acidification to prepare 4-trifluoromethylnicotinic acid. The raw materials used in the method of the present invention are cheap and easy to obtain, the reaction intermediates are stable and easy to store, the separation and purification are easy, the operation is simple, the yield is high, and it has the potential for industrial production.

[0013] To achieve the purpose of the present invention, the technical solution adopted by the present invention is as follows:

[0014] The present invention provides a method for preparing 4-trifluoromethylnicotinic acid, which comprises the following steps: a compound shown in formula I is subjected to fluorination and acidification to obtain 4-trifluoromethylnicotinic acid.

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

[0016] , wherein R of the compound of formula I 1C1~C 10 alkyl.

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

[0018] In the presence of an acid, the compound represented by formula III is subjected to a condensation reaction to obtain a compound represented by formula II;

[0019]

[0020] Wherein, the acid is selected from an organic acid or an inorganic acid, wherein 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 the compound of formula I, which comprises the following steps:

[0022] In the presence of a base, the compound of formula II undergoes a ring-closing reaction and an alcoholysis reaction to prepare a compound of formula I;

[0023]

[0024] in,

[0025] R 1 C1~C 10 alkyl.

[0026] Beneficial Effects of the Invention

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

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

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

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

[0031] The specific implementation methods of the present invention are further described in detail below in conjunction with the examples. In order to make the purpose, 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 part of the embodiments of the present invention, rather than all of the embodiments. Based on the embodiments in the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention. Unless otherwise expressly stated, throughout the specification and claims, the term "including" or its variations such as "comprising" or "including" will be understood to include the stated components and steps, without excluding the presence of other material components or steps.

[0032] In addition, in order to better illustrate the present invention, numerous specific details are given in the following detailed description.

[0033] Those skilled in the art will appreciate that the present invention can be implemented without certain specific details. In some embodiments, raw materials, methods, means, etc. that are well known to those skilled in the art are not described in detail in order to highlight the main purpose of the present invention.

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

[0035] In the present invention, unless otherwise specified, room temperature refers to about "20°C-25°C".

[0036] As used herein, the following terms used in the specification and claims have the following meanings when specific definitions are not otherwise provided.

[0037] In the present invention, C1-C 10 Alkyl means a group having 1 to 10 carbon atoms. 10 Examples of the alkyl group include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, 1-methylpropyl (sec-butyl), 2-methylpropyl (isobutyl), 1,1-dimethylethyl (tert-butyl), and the like.

[0038] The present invention provides a method for preparing 4-trifluoromethylnicotinic acid, which comprises preparing 4-trifluoromethylnicotinic acid by fluorination and acidification of a compound represented by formula I. The synthetic route is as follows:

[0039]

[0040] Wherein, the fluorination reaction is to add the compound shown in formula I and a fluorination agent into an organic solvent for fluorination reaction; the fluorination agent is one of anhydrous HF, SbF3, KF and NaF, and the amount of the fluorination agent added is 3 to 50 times the weight of the compound shown in formula I, preferably 4-10 times; the fluorination reaction temperature is between 100 and 250°C; the fluorination reaction pressure is 1 to 15MPa, preferably 1-5MPa; the organic solvent is selected from one or more of DMSO, DMF, DMA, and cyclopentane sulfone; the acidification reaction is to add the fluorination product to a sodium hydroxide solution for alkaline hydrolysis and then add hydrochloric acid for acidification.

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

[0042] In the presence of an acid, the compound represented by formula III is subjected to a condensation reaction to obtain a compound represented by formula II;

[0043]

[0044] Wherein, the acid is selected from one or more of organic acids or inorganic acids; wherein 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, preferably, the acid is selected from one or more of 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, and the organic solvent is 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 -15°C to 40°C, preferably 0°C to 25°C; the molar ratio of the compound represented by 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 the compound of formula I, which comprises the following steps:

[0047] In the presence of a base, the compound of formula II undergoes a ring-closing reaction and an alcoholysis reaction to prepare a compound of formula I;

[0048]

[0049] in,

[0050] R 1 C1~C 10 alkyl;

[0051] The base 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, N,N-dimethylaniline, preferably one or more of sodium methoxide, sodium ethoxide, triethylamine, sodium carbonate, potassium carbonate;

[0052] The ring-closing reaction and alcoholysis reaction are carried out 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, preferably one or more of tetrahydrofuran, dichloromethane, and 1,2-dichloroethane.

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

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

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

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

[0057] R 1 C1~C 10 alkyl.

[0058] The compounds of formula I and formula II disclosed in the present invention are used to prepare 4-trifluoromethylnicotinic acid, the process route is greatly optimized, the production cost is reduced, and the process route is simpler and easier to operate. The intermediate of the present invention can be prepared according to the above preparation method.

[0059] Unless otherwise specified, the experimental methods used in the following examples are all conventional methods; the reagents, materials, etc. used in the following examples, unless otherwise specified, can be obtained from commercial channels.

[0060] Example 1: Preparation of Compound II

[0061]

[0062] In a 500mL four-necked flask equipped with a mechanical stirrer, a thermometer, and a condenser, add 56.4g (0.3mol) of compound III and 200g of 1,2-dichloroethane, and add 16.7mL (0.6mol) of 35% hydrochloric acid at 0°C. After the addition is complete, warm to room temperature and continue stirring for 12h. Solids precipitate during the reaction. After the reaction is completed, remove the solvent to obtain 107g of brown solid. The purity is 98%, and the yield is 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 is 50% sulfuric acid, and the other molar ratios remain unchanged, to obtain 95 g 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 is glacial acetic acid, and the other molar ratios remain unchanged, to obtain 75 g 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 500ml four-necked flask equipped with a mechanical stirrer, a thermometer, and a condenser, add 35.7g (0.1mol) of compound II and 100g of 1,2-dichloroethane, stir at room temperature for 10min, then add 18g (0.13mol) of potassium carbonate. Continue stirring for 10min, then dropwise add 3.8g (0.12mol) of anhydrous methanol. After the dropwise addition is complete, stir at room temperature for 1h. After the reaction is complete, add 50g of water, extract the aqueous phase with 50g of 1,2-dichloroethane, combine the organic phases, evaporate the solvent 1,2-dichloroethane, add 20g of methanol to the residue, heat to 50-60℃ for recrystallization, and obtain 24.8g of off-white solid. The purity is 98%, and the yield is 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, and the other molar ratios remain unchanged, to obtain 18 g 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, and the other molar ratios remain unchanged, to obtain 15 g 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, and the other molar ratios remain unchanged, to obtain 21 g 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 500ml four-necked flask equipped with a mechanical stirrer, a thermometer, and a condenser, add 35.7g (0.1mol) of compound IV and 100g of 1,2-dichloroethane, stir at room temperature for 10min, then add 18g (0.13mol) of potassium carbonate. Continue stirring for 10min, then drop 5.63g (0.12mol) of anhydrous ethanol. After the addition is complete, stir at room temperature for 1h. After the reaction is complete, add 50g of water, extract the aqueous phase with 50g of 1,2-dichloroethane, combine the organic phases, evaporate the solvent 1,2-dichloroethane, add 20g of ethanol to the residue, heat to 50-60℃ for recrystallization, and obtain 25.9g of off-white solid. The purity is 98%, and the yield is 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 5.3g (0.1mol) of compound I-12 and 70g of DMSO to the autoclave, cover the autoclave, fill with nitrogen, and after confirming that the autoclave is leak-proof, vent the pressure in the autoclave and place the autoclave in an ice-salt bath to cool; when the temperature in the autoclave drops below -5°C, fill the autoclave with 12g (0.6mol) of anhydrous hydrogen fluoride, heat the reaction system to 150°C under stirring, and react for 10 hours. After the reaction is completed, cool to 30°C, replace with nitrogen in the autoclave for half an hour, press the reaction liquid into 100mL of ice water, and neutralize with 20% sodium hydroxide solution to about pH = 10. Then extract the reaction mixture with 100mL of dichloroethane three times, combine the extracts, and wash with water until neutral; remove dichloroethane at normal pressure. The residue was added with 50 mL of 30% sodium hydroxide solution and heated to 40-50° C. for alkaline hydrolysis for 2 hours. After the reaction was completed, concentrated hydrochloric acid was added dropwise to adjust the pH to 2-3, filtered, and dried to obtain 16.1 g of a yellow solid with a purity of 95% and a yield of 80%.

[0082] The preferred embodiments of the present invention are described in detail above, but the present invention is not limited thereto. Within the technical concept of the present invention, the technical solution of the present invention can be subjected to a variety of simple modifications, including the combination of various technical features in any other suitable manner, and these simple modifications and combinations should also be regarded as the contents disclosed by the present invention and belong to the protection scope of the present invention.

Claims

1. A method for preparing 4-trifluoromethylnicotinic acid, characterized in that: The method comprises the following steps: the compound shown in formula I is subjected to fluorination reaction and acidification reaction to prepare 4-trifluoromethylnicotinic acid, and the synthesis route thereof is as follows: Among them, R 1 C1~C 10 alkyl.

2. The preparation method according to claim 1, characterized in that: The fluorination reaction is to add the compound shown in formula I and a fluorination agent into an organic solvent for fluorination reaction; the fluorination agent is selected from anhydrous HF, SbF3, KF and NaF; the acidification reaction includes the steps of adding the fluorination product into sodium hydroxide solution for alkaline hydrolysis and then adding hydrochloric acid for acidification.

3. The preparation method according to claim 1 or 2, characterized in that: The compound of formula I is prepared by subjecting the compound of formula II to a ring-closing reaction in the presence of a base, followed by an alcoholysis reaction; wherein the compound of formula II has the following structure: The base 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; And / or, the ring-closing reaction and the alcoholysis reaction are carried out 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, preferably one or more of tetrahydrofuran, dichloromethane, and 1,2-dichloroethane; and / or, the reaction temperature of the ring-closing reaction and the alcoholysis reaction is -15°C to 40°C, preferably 0°C to 25°C; And / or, the alcohol in the alcoholysis reaction is selected from R 1 -OH,R 1 C1~C 10 alkyl; And / or the molar ratio of the compound of formula II, the base and the alcohol is 1:1.0-1.5:1.0-1.5, preferably 1:1.0-1.3:1.0-1.

3.

4. The preparation method according to claim 3, characterized in that: The formula II is prepared by condensation reaction of the compound of formula III in the presence of an acid, wherein the structure of formula III is as follows:

5. The preparation method according to claim 4, characterized in that: The acid in the condensation reaction is selected from one or more 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, and is particularly preferably one or more of formic acid, acetic acid, trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, and sulfuric acid; And / or, the condensation reaction is carried out in an organic solvent, the organic solvent is selected from one or more of organic alcohols, toluene, tetrahydrofuran, dichloromethane, 1,2-dichloroethane, 1,4-dioxane, preferably one or more of methanol, ethanol, dichloromethane, 1,2-dichloroethane; and / or, the reaction temperature of the condensation reaction is -15°C to 40°C, 0°C to 25°C; And / or the molar ratio of the compound of formula III to the acid is 1:0.5-2.0, preferably 1:0.8-1.

2.

6. A compound of formula I, R 1 C1~C 10 alkyl.

7. A compound of formula II,

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