A four-step method for preparing 4-trifluoromethylnicotinic acid from 2-chloroacrylonitrile.

Abstract

This invention discloses a four-step method for preparing 4-trifluoromethylnicotinic acid from 2-chloroacrylonitrile, belonging to the field of chemical pharmaceutical intermediate synthesis. Using 2-chloroacrylonitrile as a raw material, an amination reagent is added to prepare 3-amino-2-chloropropionitrile, which is then reacted with 4-ethoxy-1,1,1-trifluorobut-3-en-2-one to prepare 2-chloro-3-((4,4,4-trifluoro-3-oxobut-1-en-1-yl)amino)propionitrile. Finally, a two-step method involving cyclization and hydrolysis with the addition of an alkali yields the target product 4-trifluoromethylnicotinic acid. This method yields a product with high purity and high yield, low raw material cost, a short and efficient route, mild reaction conditions, and is environmentally friendly, making it more suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of organic compound synthesis technology, specifically relating to a four-step method for preparing 4-trifluoromethylnicotinic acid from 2-chloroacrylonitrile. Background Technology

[0002] Pyridine-containing heterocyclic intermediates are widely used in the synthesis of antibiotics, agricultural insecticides, fungicides, and herbicides. 4-Trifluoromethylnicotinic acid (TNA) is an aromatic compound containing a trifluoromethyl and pyridine ring and is a crucial intermediate in the highly effective insecticide flonicamid. Fluonicamid is a neonicotinoid insecticide discovered by Ishihara Sangyo Co., Ltd. of Japan and jointly developed with FMC Corporation. In addition to contact and stomach poison effects, it also exhibits excellent neurotoxicity and rapid antifeedant activity, primarily used to control aphids on grains, potatoes, fruit trees, cotton, and vegetable crops. When used at recommended dosages, it is safe for crops, humans, livestock, and the environment. The difficulty in developing the flonicamid process lies in the synthesis of its key intermediate, 4-trifluoromethylnicotinic acid. However, current synthetic processes for 4-trifluoromethylnicotinic acid and its derivatives still face numerous challenges, limiting their large-scale production and widespread application. Traditional synthetic methods often suffer from drawbacks such as lengthy routes, harsh reaction conditions, low yields, high costs, and environmental unfriendliness. Currently, the preparation methods for 4-trifluoromethylnicotinic acid both domestically and internationally can be mainly classified into the following categories: One method disclosed in Chinese patent CN109232407A involves using ethyl trifluoroacetoacetate and cyanoacetamide as starting materials, followed by cyclization, chlorination, cyano hydrolysis to amide, catalytic hydrogenolysis to dechlorinate, and finally hydrolysis to obtain 4-trifluoromethylnicotinic acid, as shown in the formula below. Although this method can avoid the reduction of cyano groups, the route is relatively long, the yield during chlorination is low, and the reaction process requires the use of expensive and difficult-to-recover palladium catalyst, which is not suitable for industrial production.

[0003]

[0004] The second method involves reacting vinyl ether with trifluoroacetyl chloride or trifluoroacetic anhydride, followed by reaction with ammonia or ammonia water, and then condensing with methyl 3-methoxyenoate or methyl 3,3-dimethoxypropionate. This is followed by cyclization, hydrolysis, and acidification steps to obtain 4-trifluoromethylnicotinic acid, as shown in the formula below. However, methyl 3-methoxyenoate is expensive and dependent on imports, and methyl 3,3-dimethoxypropionate is difficult to prepare and has poor stability. These factors significantly limit the application of this route in industrial production. Although some patents have improved this method by using methyl acrylate as a raw material to prepare methyl 3-oxopropionate, which is then reacted with 4-amino-1,1,1-trifluoro-3-buten-2-one to prepare the target product, the raw materials methyl 3-methoxyacrylate and methyl 3,3-dimethoxypropionate have poor stability and are expensive, making them unsuitable for industrial production.

[0005]

[0006] Thirdly, 4-trifluoromethylpyridine compounds are used as raw materials. They undergo a carbonylation reaction with carbon dioxide under the action of strong bases such as diisopropylaminolithium, and after acidification, 4-trifluoromethylnicotinic acid is obtained, as shown in the formula below. However, this reaction process has a regioselectivity problem, and the reaction conditions are harsh, requiring highly sophisticated reaction equipment and operation, making it difficult to achieve industrial production. Alternatively, 2-chloro-4-iodopyridine is used as a starting material to prepare 2-chloro-4-trifluoromethylpyridine, which is then reacted with carbon dioxide under the action of strong bases such as LDA. Finally, catalytic dechlorination with hydrogen is carried out to obtain 4-trifluoromethylnicotinic acid. This type of synthesis requires strong bases such as LDA and must be carried out under strictly anhydrous and low-temperature conditions. The reaction conditions are relatively harsh, and the raw materials are expensive and the yield is low, making it difficult to achieve industrial production.

[0007]

[0008] Fourth, methyl 3-oxopropionate is prepared by reacting methyl acrylates with a catalyst and an oxidant; then, it undergoes a condensation reaction with 4-amino-1,1,1-trifluoro-3-buten-2-one, followed by a ring-closing hydrolysis reaction under the action of a base to obtain the product 4-trifluoromethylnicotinic acid, as shown in the following formula. However, this reaction strategy requires the use of the noble metal palladium / copper, and the overall reaction yield is moderate.

[0009] Summary of the Invention

[0010] The purpose of this section is to outline some aspects of embodiments of the present invention and to briefly describe some preferred embodiments. Simplifications or omissions may be made in this section, as well as in the abstract and title of this application, to avoid obscuring the purpose of these documents; however, such simplifications or omissions should not be construed as limiting the scope of the invention.

[0011] In view of the problems existing in the above and / or prior art, the present invention is proposed.

[0012] One objective of this invention is to provide a four-step method for preparing 4-trifluoromethylnicotinic acid from 2-chloroacrylonitrile. The reaction is simple, the conditions are mild, the raw materials are inexpensive and readily available, and the equipment requirements are low, thus meeting the needs of large-scale industrial production.

[0013] To solve the above-mentioned technical problems, the present invention provides the following technical solution: a method for preparing 4-trifluoromethylnicotinic acid from 2-chloroacrylonitrile in four steps, comprising, 2-Chloroacrylonitrile of Formula I was reacted with an amination reagent to obtain 3-amino-2-chloropropionitrile of Formula II. ;

[0014] The 3-amino-2-chloropropionitrile shown in Formula II was reacted with the 4-ethoxy-1,1,1-trifluorobut-3-en-2-one shown in Formula III to give the compound shown in Formula IV. ; ; The compound shown in Formula IV was subjected to a cyclization hydrolysis reaction under the action of a base to obtain the target compound 4-trifluoromethylnicotinic acid shown in Formula V. (Form V).

[0015] As a preferred embodiment of the method for preparing 4-trifluoromethylnicotinic acid from 2-chloroacrylonitrile in four steps according to the present invention, wherein: the reaction is carried out in the presence of an amination reagent, and the reaction is carried out in solvent A, wherein solvent A is any one or two of chloroform, toluene, ethyl acetate, acetonitrile, tetrahydrofuran, dioxane, N,N-dimethylformamide, dimethyl sulfoxide, methanol, dichloromethane, isopropanol, acetic acid, water, dichloroethane, and chlorobenzene.

[0016] As a preferred embodiment of the method for preparing 4-trifluoromethylnicotinic acid from 2-chloroacrylonitrile in four steps according to the present invention, wherein: the amination reagent is any one or two of ammonia water, a methanol solution of ammonia, liquid ammonia, sodium amide, and an ethanol solution of ammonia; The molar ratio of 2-chloroacrylonitrile to the amination reagent shown in Formula I is 1:1~3; The reaction temperature is 0~40 ℃, and the reaction time is 6~24 h.

[0017] As a preferred embodiment of the method for preparing 4-trifluoromethylnicotinic acid from 2-chloroacrylonitrile in four steps according to the present invention, wherein: the reaction of 3-amino-2-chloropropionitrile (Formula II) with 4-ethoxy-1,1,1-trifluorobut-3-en-2-one (Formula III) is carried out in solvent B, wherein solvent B is any one or two of dichloromethane, chloroform, toluene, ethyl acetate, acetonitrile, tetrahydrofuran, dioxane, N,N-dimethylformamide, dimethyl sulfoxide, methanol, ethanol, water, or hexamethylphosphoric triamine.

[0018] As a preferred embodiment of the method for preparing 4-trifluoromethylnicotinic acid from 2-chloroacrylonitrile in four steps according to the present invention, wherein: in the reaction, the molar ratio of 4-ethoxy-1,1,1-trifluorobut-3-en-2-one shown in Formula III to 3-amino-2-chloropropionitrile shown in Formula II is 1~3:1; The reaction temperature is 0~40 ℃, and the reaction time is 30~60 min.

[0019] As a preferred embodiment of the method for preparing 4-trifluoromethylnicotinic acid from 2-chloroacrylonitrile in four steps according to the present invention, wherein: the ring-closing hydrolysis reaction occurs, the reaction is carried out in solvent C, and solvent C is any one of dichloromethane, chloroform, toluene, ethyl acetate, acetonitrile, tetrahydrofuran, dioxane, N,N-dimethylformamide, dimethyl sulfoxide, methanol, ethanol and water.

[0020] As a preferred embodiment of the method for preparing 4-trifluoromethylnicotinic acid from 2-chloroacrylonitrile in four steps according to the present invention, wherein: the base is a base for cyclization and a base for hydrolysis; The base used for cyclization includes any one or two of sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, or sodium hydride. The base used for hydrolysis includes any one or two of the following: triethylamine, N,N-diisopropylethylamine, N,N-dimethylaniline, pyridine, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, or sodium hydride. The molar ratio of the compound shown in Formula IV to the base used for cyclization is 1:1 to 3; The molar ratio of the compound shown in Formula IV to the base used for hydrolysis is 1:1 to 10; The reaction temperature is 25~100 ℃, and the reaction time is 12~24 h.

[0021] As a preferred embodiment of the method for preparing 4-trifluoromethylnicotinic acid from 2-chloroacrylonitrile in four steps according to the present invention, wherein: the compound shown in Formula IV undergoes a ring-closing hydrolysis reaction under the action of an alkali, the compound shown in Formula IV is first reacted with the alkali used for the cyclization reaction to undergo a ring-closing reaction, the reaction temperature is 60~100℃, and the reaction time is 2~5 h; Then, the alkali used for hydrolysis is added to carry out the hydrolysis reaction at a temperature of 80~120 ℃ for 15~20 h.

[0022] Compared with the prior art, the present invention has the following beneficial effects: The preparation method of this invention yields products with high purity and high yield, low raw material cost, a short and efficient route, mild reaction conditions, and environmental friendliness, making it more suitable for industrial production. Attached Figure Description

[0023] To more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings used in the description of the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort. Wherein: Figure 1 The NMR spectrum of the product of step (1) in Example 1 of this invention; Figure 2 The NMR spectrum of the product of step (2) in Example 1 of this invention; Figure 3 The NMR spectrum of the product of step (3) in Example 1 of this invention. Detailed Implementation

[0024] To make the above-mentioned objects, features and advantages of the present invention more apparent and understandable, the specific embodiments of the present invention will be described in detail below with reference to the examples in the specification.

[0025] Many specific details are set forth in the following description in order to provide a full understanding of the invention. However, the invention may also be practiced in other ways different from those described herein, and those skilled in the art can make similar extensions without departing from the spirit of the invention. Therefore, the invention is not limited to the specific embodiments disclosed below.

[0026] Secondly, the term "one embodiment" or "embodiment" as used herein refers to a specific feature, structure, or characteristic that may be included in at least one implementation of the present invention. The phrase "in one embodiment" appearing in different places in this specification does not necessarily refer to the same embodiment, nor is it a single or selective embodiment that is mutually exclusive with other embodiments.

[0027] Unless otherwise specified, all raw materials used in the examples are commercially available. Example 1

[0028] (1) Preparation of 3-amino-2-chloropropionitrile: Ammonia (21.92 g, 156 mmol) and DCM (60 ml) were added to a 500 ml four-necked reaction flask. Under nitrogen protection in an ice bath, 2-chloroacrylonitrile (9.12 g, 104 mmol) was slowly added dropwise using a constant pressure dropping funnel. The reaction was carried out for 6 h in an ice bath. Gas chromatography was used to monitor the completeness of the reaction. After standing and separating the layers, the aqueous phase was extracted with DCM. The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give a pale yellow oily product, 3-amino-2-chloropropionitrile (10.87 g, yield: 97%).

[0029]

[0030] like Figure 1 The NMR spectrum of the product is shown below: 1 H NMR (500 MHz, CDCl3) δ 4.41 (t, J = 5.7 Hz, 1H), 3.17 (dd, J = 5.7,1.7 Hz, 2H), 1.54 (s, 2H). (2) Preparation of 2-chloro-3-((4,4,4-trifluoro-3-oxobut-1-en-1-yl)amino)propionitrile: In a 200 ml four-necked reaction flask, 3-amino-2-chloropropionitrile (10.87 g, 101 mmol) was added and dissolved in 25 ml of DCM. Nitrogen gas was bubbled into the system for 10 min. Under ice bath conditions, 4-ethoxy-1,1,1-trifluorobut-3-en-2-one (18.66 g, 111 mmol) was dissolved in 45 ml of dichloromethane and slowly added dropwise to the reaction flask. The reaction was carried out for 1 h. TLC monitoring showed that the reaction was complete. The product was concentrated to give a pale yellow oily product 2-chloro-3-((4,4,4-trifluoro-3-oxobut-1-en-1-yl)amino)propionitrile (21.28 g, yield: 93%).

[0031]

[0032] like Figure 2 The NMR spectrum of the product is shown below: 1 H NMR (500 MHz, CDCl3) δ 10.48 – 10.23 (m, 1H), 7.21 (dd, J = 13.2, 7.4 Hz, 1H), 5.54 (d, J = 7.4 Hz, 1H), 4.71 (t, J = 6.3 Hz, 1H), 3.97 – 3.81(m, 2H). (3) Preparation of 4-trifluoromethylnicotinic acid: In a 500 ml four-necked reaction flask, sodium methoxide (7.61 g, 141 mmol) and 2-chloro-3-((4,4,4-trifluoro-3-oxobut-1-en-1-yl)amino)propionitrile (21.28 g, 94 mmol) were dissolved in 100 ml of methanol. The system was heated to 70 °C and refluxed for 3 hours. The reaction was monitored by TLC until complete. The mixture was then cooled to room temperature, the solvent was removed, and NaOH (2 mol / L, 380 ml) was added. The mixture was then refluxed at 100 °C for another 17 hours. The reaction was stopped when TLC monitoring showed that the reaction had ceased. The pH of the solution was adjusted to 2.3 with 1 M HCl. A large amount of solid precipitated from the system. The solid was filtered, and the filter cake was dried to obtain the white solid product 4-trifluoromethylnicotinic acid (16.17 g, yield: 90%).

[0033]

[0034] like Figure 3 The NMR spectrum of the product is shown below: 1 H NMR (500 MHz, DMSO- d 6) δ 9.08 (s, 1H), 8.99 (d, J = 5.1 Hz, 1H), 7.89 (d, J = 5.2 Hz, 1H). It can be seen that the raw materials of the present invention are inexpensive and readily available, the synthesis method is simple to operate, the reaction conditions are mild, the equipment requirements are low, it is technically feasible, economically reasonable, and has a high cost performance, making it suitable for industrial production. Example 2

[0035] Example 2 is based on Example 1, and the preparation conditions of 4-trifluoromethylnicotinic acid in step (3) are optimized and screened, as shown in Table 1.

[0036] Table 1

[0037] As shown in Table 1, this embodiment investigated the effects of sodium methoxide dosage, NaOH concentration and volume, sodium methoxide type, and substrate feed amount on the reaction yield. The results showed that the low-concentration NaOH (2 mol / L) system was significantly better than the high-concentration system; sodium methoxide was the preferred alcohol-base mixture, and its dosage needed to be moderate, as excess would reduce the yield; under optimized conditions, the yield could reach 90%, and the process stability was good. Example 3

[0038] Example 3: Based on Example 1, the solvents used in the preparation of 4-trifluoromethylnicotinic acid in step (3) were screened, as shown in Table 2 below:

[0039] Table 2

[0040] As can be seen from the data in Table 2, the reaction can only be carried out in an aqueous system. Pure organic solvents (methanol, ethanol) do not react at all. The methanol + water system has the highest yield (90%) and is the optimal solvent combination.

[0041] In addition, the reaction temperature is refluxed at the boiling point of the solvent. If the temperature is too low, the reaction effect will be poor and there will be residual raw materials. If the reaction time is shortened, the reaction will not be completed, while if the reaction time is extended, there will be no effect. Example 4

[0042] Example 4: Based on Example 1, the preparation conditions of 2-chloro-3-((4,4,4-trifluoro-3-oxobut-1-en-1-yl)amino)propionitrile in step (2) were optimized and screened, as shown in Table 3 below:

[0043] Table 3

[0044] As can be seen from the data in Table 3, the reaction in step (2) is relatively easy, and the yield is high under the screening conditions. Example 5

[0045] Example 5: Based on Example 1, the preparation conditions of 3-amino-2-chloropropionitrile in step (1) were optimized and screened, as shown in Table 4 below:

[0046] Table 4

[0047] As can be seen from the data in Table 4, this ammoniation reaction is more suitable for carrying out under low temperature conditions in an aqueous phase, and ammonia water is better than a methanol solution of ammonia as an ammoniation reagent; increasing the reaction temperature or increasing the amount of ammoniation reagent will lead to a decrease in yield. Comparative Example 1

[0048] Preparation of 3-amino-2-chloropropionitrile: 2-chloroacrylonitrile (9.12 g, 104 mmol) was dissolved in 80 ml MeOH in a 500 ml four-necked reaction flask. Under nitrogen protection in an ice bath, a methanol solution of ammonia (39 ml, 156 mmol) was slowly added dropwise using a constant pressure dropping funnel. The reaction time was shortened to 2 h, and the yield was only 54%. Comparative Example 2

[0049] Preparation of 3-amino-2-chloropropionitrile: 2-Chloroacrylonitrile (9.12 g, 104 mmol) was dissolved in 80 ml DCM in a 500 ml four-necked reaction flask. Under nitrogen protection in an ice bath, ammonia (29.16 g, 156 mmol) was slowly added dropwise using a constant pressure dropping funnel. The reaction was carried out in an ice bath for 8 h. Gas chromatography was used to monitor the completeness of the reaction. After standing and separating the layers, the aqueous phase was extracted with DCM. The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give a pale yellow oily product, 3-amino-2-chloropropionitrile (8.48 g, yield: 78%).

[0050] It should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit it. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications or equivalent substitutions can be made to the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention, and all such modifications or substitutions should be covered within the scope of the claims of the present invention.

Claims

1. A four-step method for preparing 4-trifluoromethylnicotinic acid from 2-chloroacrylonitrile, characterized in that: include, 2-Chloroacrylonitrile of Formula I was reacted with an amination reagent to obtain 3-amino-2-chloropropionitrile of Formula II. (Formula I); (Formula II); The 3-amino-2-chloropropionitrile shown in Formula II was reacted with the 4-ethoxy-1,1,1-trifluorobut-3-en-2-one shown in Formula III to give the compound shown in Formula IV. (Formula III); (Formula IV); The compound shown in Formula IV was subjected to a cyclization hydrolysis reaction under the action of a base to obtain the target compound 4-trifluoromethylnicotinic acid shown in Formula V. (Formula V).

2. The method for preparing 4-trifluoromethylnicotinic acid from 2-chloroacrylonitrile in four steps as described in claim 1, characterized in that: The reaction is carried out in solvent A under the action of an amination reagent, and solvent A is any one or two of chloroform, toluene, ethyl acetate, acetonitrile, tetrahydrofuran, dioxane, N,N-dimethylformamide, dimethyl sulfoxide, methanol, dichloromethane, isopropanol, acetic acid, water, dichloroethane, and chlorobenzene.

3. The method for preparing 4-trifluoromethylnicotinic acid from 2-chloroacrylonitrile in four steps as described in claim 2, characterized in that: The amination reagent is any one or two of ammonia water, a methanol solution of ammonia, liquid ammonia, sodium amide, and an ethanol solution of ammonia. The molar ratio of 2-chloroacrylonitrile to the amination reagent shown in Formula I is 1:1~3; The reaction temperature is 0~40 ℃, and the reaction time is 6~24 h.

4. The method for preparing 4-trifluoromethylnicotinic acid from 2-chloroacrylonitrile in four steps as described in claim 1, characterized in that: The reaction of 3-amino-2-chloropropionitrile (Formula II) with 4-ethoxy-1,1,1-trifluorobut-3-en-2-one (Formula III) is carried out in solvent B, wherein solvent B is any one or two of dichloromethane, chloroform, toluene, ethyl acetate, acetonitrile, tetrahydrofuran, dioxane, N,N-dimethylformamide, dimethyl sulfoxide, methanol, ethanol, water, or hexamethylphosphoric triamine.

5. The method for preparing 4-trifluoromethylnicotinic acid from 2-chloroacrylonitrile in four steps as described in claim 1, characterized in that: In the reaction, the molar ratio of 4-ethoxy-1,1,1-trifluorobut-3-en-2-one shown in Formula III to 3-amino-2-chloropropionitrile shown in Formula II is 1~3:1; The reaction temperature is 0~40 ℃, and the reaction time is 30~60 min.

6. The method for preparing 4-trifluoromethylnicotinic acid from 2-chloroacrylonitrile in four steps as described in claim 1, characterized in that: The ring-closing hydrolysis reaction occurs in a solvent C, which is a mixture of any one of dichloromethane, chloroform, toluene, ethyl acetate, acetonitrile, tetrahydrofuran, dioxane, N,N-dimethylformamide, dimethyl sulfoxide, methanol, and ethanol with water.

7. The method for preparing 4-trifluoromethylnicotinic acid from 2-chloroacrylonitrile in four steps as described in claim 1, characterized in that: The base is a base used for cyclization and a base used for hydrolysis; The base used for cyclization includes any one or two of sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, or sodium hydride. The base used for hydrolysis includes any one or two of the following: triethylamine, N,N-diisopropylethylamine, N,N-dimethylaniline, pyridine, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, or sodium hydride. The molar ratio of the compound shown in Formula IV to the base used for cyclization is 1:1 to 3; The molar ratio of the compound shown in Formula IV to the base used for hydrolysis is 1:1 to 10; The reaction temperature is 25~100 ℃, and the reaction time is 12~24 h.

8. The method for preparing 4-trifluoromethylnicotinic acid from 2-chloroacrylonitrile in four steps as described in claim 7, characterized in that: The compound represented by Formula IV undergoes a ring-closing hydrolysis reaction under the action of an alkali. First, the compound represented by Formula IV undergoes a ring-closing reaction with the alkali used for the cyclization reaction. The reaction temperature is 60~100℃ and the reaction time is 2~5 h. Then, the alkali used for hydrolysis is added to carry out the hydrolysis reaction at a temperature of 80~120 ℃ for 15~20 h.

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