Method for industrially producing 2-chloronicotinic acid
By using the catalytic chlorination and hydrolysis reaction of ethyl nicotinate, along with the metal benzimidazole ionic liquid IL-1 and tetrachloroglyurea, the problems of low yield and low purity in the production of 2-chloronicotinic acid were solved, achieving efficient and environmentally friendly industrial production.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-12-22
- Publication Date
- 2026-04-03
AI Technical Summary
The industrial production of 2-chloronicotinic acid in the current technology suffers from problems such as low yield, low purity, serious pollution, expensive raw materials, and harsh reaction conditions.
Ethyl nicotinic acid was chlorinated in the presence of the catalyst metal benzimidazole ionic liquid IL-1 and the chlorinating agent tetrachloroglyurea, followed by hydrolysis in the presence of a base to produce 2-chloronicotinic acid.
The production of 2-chloronicotinic acid with high yield and high purity was achieved under mild reaction conditions, which are environmentally friendly and suitable for industrial production.
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Abstract
Description
Technical Field
[0001] This invention belongs to the field of organic synthesis, specifically relating to a method for the industrial production of 2-chloronicotinic acid. Background Technology
[0002] 2-Chloronicotinic acid, also known as 2-chloronicotinic acid, has the chemical name 2-chloro-3-pyridinecarboxylic acid or 2-chloropyridine-3-carboxylic acid, and its structural formula is: 2-Chloronicotinic acid is an important intermediate in pharmaceuticals and pesticides. On the one hand, in the pesticide field, it can be used to synthesize fungicides, insecticides, and herbicides, such as nicosulfuron and diflufenican. On the other hand, in the pharmaceutical field, it can be used to synthesize many medical antibiotics and drugs for treating cardiovascular diseases, such as the anti-AIDS drug nevirapine, the antidepressant mirtazapine, the nonsteroidal anti-inflammatory analgesic niflumicacid, pranoprofen, nicosulfan, and nicosulfan. Currently, the main methods for synthesizing 2-chloronicotinic acid include: 1) Using nicotinic acid or 3-cyanopyridine as raw materials, the mixture is oxidized with hydrogen peroxide and then reacted with phosphorus oxychloride or phosphorus pentachloride under triethylamine catalysis to synthesize 2-chloronicotinic acid. This route is currently widely used in industrial applications, but it suffers from problems such as low product yield and purity. Furthermore, the reaction process involves the large-scale use of chlorinating agents such as phosphorus oxychloride or phosphorus pentachloride, resulting in acidic phosphorus-containing wastewater that is difficult to treat, easily causing eutrophication and severe environmental pollution.
[0003] 2) Oxidation of 2-chloro-3-methylpyridine. This route uses potassium permanganate, a strong oxidant, to oxidize the methyl group to a carboxyl group to prepare 2-chloronicotinic acid with relatively high purity and a yield of 65%. The process is simple, the reaction conditions are mild, and the product has high purity, but the yield is relatively low. Moreover, the raw material 2-chloro-3-methylpyridine is difficult to obtain, making industrial-scale production challenging.
[0004] 3) Cycling Method. The main routes for synthesizing 2-chloronicotinic acid via cyclization reactions are as follows: 1) Chlorination of ethyl cyanoacetate followed by Michael addition with acrolein, followed by hydrolysis to obtain 2-chloronicotinic acid. This method uses acrolein as a starting material, which is highly irritating and toxic, and the synthetic process is complex, making it unsuitable for industrial production; 2) Reaction of tetramethoxypropane with ethyl cyanoacetate in acetic anhydride solvent. The cyclization reaction with HCl requires acetic acid as a solvent, resulting in low cyclization yields. This method requires sophisticated equipment, has high production costs, low yields, and generates large amounts of wastewater; 3) Cyclation of N,N-dimethylaminopropene with ethyl cyanoacetate to synthesize 2-chloronicotinic acid. However, the starting material, aminopropene, is very unstable and needs to be prepared and used immediately. Furthermore, the yield of aminopropene is only 65%; 4) Reaction of solid phosgene and vinyl ether with ammonia to prepare dimethylaminopropene, followed by further reaction with... 2-Chloronicotinic acid was prepared by the reaction of methyl cyanoacetate. This synthetic method solved the problem of synthesizing aminoacrylaldehyde, but the low yield of aminoacrylaldehyde during the reaction resulted in high cost, and the low boiling point of vinyl ether made it difficult to operate.
[0005] In summary, existing technologies suffer from problems such as low yield, low purity, serious pollution, expensive raw materials, and harsh reaction conditions. Therefore, there is an urgent need to develop a new method for preparing 2-chloronicotinic acid suitable for industrial production. Summary of the Invention
[0006] The purpose of this invention is to provide a method for the industrial production of 2-chloronicotinic acid, thereby solving the problems of low yield, low purity, severe pollution, expensive raw materials, and harsh reaction conditions in existing technologies. To address these technical problems, this invention provides the following technical solution: A method for the industrial production of 2-chloronicotinic acid includes the following steps: Step 1: Preparation of ethyl 2-chloronicotinate Ethyl nicotinate undergoes a chlorination reaction in the presence of the catalyst metal benzimidazole ionic liquid IL-1 and the chlorinating agent tetrachloroglyurea to produce 2-chloronicotinate ethyl ester; The structural formula of the catalyst metal benzimidazole ionic liquid IL-1 is: ; Step 2: Preparation of 2-chloronicotinic acid Ethyl 2-chloronicotinic acid undergoes hydrolysis in the presence of a base, and then the pH of the solution is adjusted to 2-4 with acid to obtain 2-chloronicotinic acid.
[0007] In some embodiments, in step 1, the reaction solvent is selected from one or more of chloroform, ethyl acetate, tetrahydrofuran, toluene, DMSO, and DMF.
[0008] In some embodiments, in step 1, the molar ratio of ethyl nicotinate to the catalyst metal benzimidazole ionic liquid IL-1 is 1: (0.05~0.15); the molar ratio of ethyl nicotinate to tetrachloroglycol is 1: (0.2~0.4).
[0009] In some implementation schemes, in step 1, the reaction temperature is 40~80℃ and the reaction time is 1~3h.
[0010] In some embodiments, in step 1, after the reaction is completed, the mixture is cooled to room temperature, quenched with water, and then extracted with 1,2-dichloroethane. The organic phases are combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product is then distilled under reduced pressure to obtain ethyl 2-chloronicotinate.
[0011] In some embodiments, in step 2, the alkali is selected from one or more of NaOH, KOH, sodium carbonate, potassium carbonate, sodium bicarbonate, and potassium bicarbonate.
[0012] In some embodiments, in step 2, the acid is selected from one or more of hydrochloric acid, sulfuric acid, and nitric acid.
[0013] In some implementation schemes, in step 2, the reaction temperature is 80~100℃ and the reaction time is 1~5h.
[0014] In some embodiments, the preparation method of the catalyst metal benzimidazole ionic liquid IL-1 in step 1 includes the following steps: Step S1: Add 1-propylbenzimidazole, 1,2-dichloroethane, and acetonitrile to the reactor, heat to 80-100℃, and reflux under stirring for 12-24 hours. After the reaction is complete, cool to 10-20℃ to precipitate a solid. Filter, wash the residue with acetonitrile, and dry under vacuum to obtain a benzimidazole ionic liquid. The reaction formula is as follows: ; Step S2: Under nitrogen protection, benzimidazole ionic liquid, aluminum chloride, and ethanol are added to the reactor, and the mixture is heated to 60-90℃ and refluxed for 5-15 hours. After the reaction is complete, the solvent is removed by rotary evaporation, and the catalyst metal benzimidazole ionic liquid IL-1 is obtained by vacuum drying. The reaction formula is as follows: .
[0015] The present invention has achieved the following beneficial effects: 1) The ethyl nicotinate of the present invention can undergo a chlorination reaction in the presence of the catalyst metal benzimidazole ionic liquid IL-1 and the chlorinating agent tetrachloroglyurea to generate ethyl 2-chloronicotinate with high yield and high selectivity. Specifically, the metal benzimidazole ionic liquid IL-1, as a Lewis acid, effectively activates ethyl nicotinate, enhancing the electronic defect at the 2-position of the pyridine ring through coordination with the nitrogen atom of pyridine, thereby promoting the electrophilic chlorination reaction at the 2-position. Furthermore, the tetrachloroglyurea used in this invention provides an efficient and mild chlorination environment. The chloride ions released during the reaction selectively attack the 2-position of pyridine under the synergistic effect of the ionic liquid catalyst, overcoming the defect of prior art requiring the oxidation of nitrogen in the starting material during the chlorination reaction.
[0016] 2) The reaction conditions of this invention are mild, avoid the use of hazardous raw materials, are green and environmentally friendly, and have simple post-processing operations. It has high yield and purity, making it very suitable for industrial production. Detailed Implementation
[0017] The technical solution of the present invention will be clearly and completely described below with reference to the embodiments. Obviously, the described embodiments are only some embodiments of the present invention, and 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.
[0018] The endpoints and any values of the ranges described in this invention are not limited to the precise ranges or values, and these ranges or values should be understood to include values close to these ranges or values. For numerical ranges, the endpoint values of the various ranges, the endpoint values of the various ranges and individual point values, and individual point values can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed herein. The raw materials and reagents used in the following examples are commercially available.
[0019] Preparation Example 1: Preparation of the metal benzimidazole ionic liquid IL-1 Step 1: Preparation of benzimidazole ionic liquid 1-Propylbenzimidazole (64.0 g, 0.4 mol), 1,2-dichloroethane (0.21 mol), and acetonitrile (200 mL) were added to a reactor, and the mixture was heated to 85 °C and refluxed with stirring for 24 h. After the reaction was complete, the mixture was cooled to 10 °C to precipitate a solid. The solid was filtered, and the residue was washed with acetonitrile (100 mL x 3). The residue was then dried under vacuum at 100 °C for 12 h to obtain a benzimidazole ionic liquid with a yield of 78.6%.
[0020] 1H-NMR (400 MHz, D2O): δ(ppm): 9.40(s, 2H), 7.90(d, 2H), 7.66 (t, 2H),7.54 (t, 2H), 7.38 (d, 2H), 5.25 (s, 4H), 4.40 (t, 4H), 1.88-1.79 (m, 4H), 0.81 (t, 6H).
[0021] Step 2: Preparation of the metal benzimidazole ionic liquid IL-1 Under nitrogen protection, 0.1 mol of benzimidazole ionic liquid (prepared in step 1), 0.2 mol of aluminum chloride, and 100 mL of ethanol were added to a reactor, and the mixture was heated to 80 °C and refluxed with stirring for 12 h. After the reaction was complete, the solvent was removed by rotary evaporation, and the mixture was dried under vacuum at 100 °C for 12 h to obtain the metallic benzimidazole ionic liquid IL-1, with a yield of 95.5%.
[0022] Example 1 A method for the industrial production of 2-chloronicotinic acid includes the following steps: Step 1: Preparation of ethyl 2-chloronicotinate Ethyl nicotinate (5.0 mol), catalyst benzimidazole ionic liquid IL-1 (obtained in Preparation Example 1) (0.5 mol), chlorinating reagent tetrachloroglycol (2.0 mol), and tetrahydrofuran (1.0 L) were added to a reactor, and the mixture was heated to 60 °C and stirred for 2 h. After the reaction was complete, the mixture was cooled to room temperature, quenched with water (0.5 L), and then extracted with 1,2-dichloroethane (1.5 L x 3). The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was then distilled under reduced pressure (0.1 mmHg, 78 °C) to obtain ethyl 2-chloronicotinate with a yield of 96.2% and an HPLC purity of 99.7%.
[0023] Step 2: Preparation of 2-chloronicotinic acid Ethyl 2-chloronicotinic acid (2.0 mol) and a 2 mol / L NaOH solution (1.5 L) were added to a reactor, and the mixture was heated to 90 °C and stirred for 1.5 h. After the reaction was complete, the mixture was cooled to room temperature, and the pH was adjusted to 2 with hydrochloric acid to precipitate a white solid. The solid was filtered, and the filter cake was washed with water and dried under vacuum to obtain 2-chloronicotinic acid with a yield of 97.5% and an HPLC purity of 99.5%.
[0024] Upon comparison, the HPLC retention time of the product in this embodiment was consistent with that of the 2-chloronicotinic acid standard.
[0025] Example 2 A method for the industrial production of 2-chloronicotinic acid includes the following steps: Step 1: Preparation of ethyl 2-chloronicotinate Ethyl nicotinate (5.0 mol), the catalyst benzimidazole ionic liquid IL-1 (obtained in Preparation Example 1) (0.4 mol), the chlorinating agent tetrachloroglycourea (1.5 mol), and ethyl acetate (1.5 L) were added to a reactor, and the mixture was heated to 70 °C and stirred for 1.5 h. After the reaction was complete, the mixture was cooled to room temperature, quenched with water (0.5 L), and then extracted with 1,2-dichloroethane (1.5 L x 3). The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was then distilled under reduced pressure (0.1 mmHg, 78 °C) to obtain ethyl 2-chloronicotinate with a yield of 94.9% and an HPLC purity of 99.6%.
[0026] Step 2: Preparation of 2-chloronicotinic acid Ethyl 2-chloronicotinic acid (2.0 mol) and a 2 mol / L KOH solution (1.2 L) were added to a reactor, and the mixture was heated to 90 °C and stirred for 2.0 h. After the reaction was complete, the mixture was cooled to room temperature, and the pH was adjusted to 3 with hydrochloric acid, resulting in the precipitation of a white solid. The solid was filtered, and the filter cake was washed with water and dried under vacuum to obtain 2-chloronicotinic acid with a yield of 96.6% and an HPLC purity of 99.4%.
[0027] Upon comparison, the HPLC retention time of the product in this embodiment was consistent with that of the 2-chloronicotinic acid standard.
[0028] Comparative Example 1 Based on Example 1, the chlorination reagent tetrachloroglyurea was used. Replace with N-chlorosuccinimide, a common chlorination reagent The specific steps are as follows: Ethyl nicotinate (5.0 mol), catalyst benzimidazole ionic liquid IL-1 (obtained in Preparation Example 1) (0.5 mol), chlorinating agent N-chlorosuccinimide (8.0 mol), and tetrahydrofuran (1.0 L) were added to a reactor, and the mixture was heated to 60 °C and stirred for 2 h. After the reaction was complete, the mixture was cooled to room temperature, quenched with water (0.5 L), and then extracted with 1,2-dichloroethane (1.5 L x 3). The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was then distilled under reduced pressure to obtain ethyl 2-chloronicotinate with a yield of 82.7% and an HPLC purity of 99.2%.
[0029] Comparative Example 2 Based on Example 1, the catalyst metal benzimidazole ionic liquid IL-1 was replaced with... The specific steps are as follows: Ethyl nicotinic acid (5.0 mol), catalyst 1.0 mol of tetrachloroglyurea (chlorinating agent), 2.0 mol of tetrachlorofuran (chlorinating agent), and 1.0 L of tetrahydrofuran were added to the reactor, and the mixture was heated to 60 °C and stirred for 2 h. After the reaction was complete, the mixture was cooled to room temperature, quenched with water (0.5 L), and then extracted with 1,2-dichloroethane (1.5 L x 3). The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was then distilled under reduced pressure to obtain ethyl 2-chloronicotinate with a yield of 74.1% and an HPLC purity of 99.1%.
[0030] The above embodiments are merely illustrative examples and are not intended to limit the implementation. Those skilled in the art will recognize that other variations or modifications can be made based on the above description. It is neither necessary nor possible to exhaustively list all possible implementations. However, obvious variations or modifications derived therefrom are still within the scope of protection of this invention.
Claims
1. A method for the industrial production of 2-chloronicotinic acid, comprising the following steps: Step 1: Preparation of ethyl 2-chloronicotinate Ethyl nicotinate undergoes a chlorination reaction in the presence of the catalyst metal benzimidazole ionic liquid IL-1 and the chlorinating agent tetrachloroglyurea to produce 2-chloronicotinate ethyl ester; The structural formula of the catalyst metal benzimidazole ionic liquid IL-1 is: ; Step 2: Preparation of 2-chloronicotinic acid Ethyl 2-chloronicotinic acid undergoes hydrolysis in the presence of a base, and then the pH of the solution is adjusted to 2-4 with acid to obtain 2-chloronicotinic acid.
2. The method according to claim 1, characterized in that, In step 1, the reaction solvent is selected from one or more of chloroform, ethyl acetate, tetrahydrofuran, toluene, DMSO, and DMF.
3. The method according to claim 1, characterized in that, In step 1, the molar ratio of ethyl nicotinate to the catalyst metal benzimidazole ionic liquid IL-1 is 1: (0.05~0.15); the molar ratio of ethyl nicotinate to tetrachloroglycol is 1: (0.2~0.4).
4. The method according to claim 1, characterized in that, In step 1, the reaction temperature is 40~80℃ and the reaction time is 1~3h.
5. The method according to claim 1, characterized in that, In step 1, after the reaction is completed, the mixture is cooled to room temperature, quenched with water, and then extracted with 1,2-dichloroethane. The organic phases are combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product is then distilled under reduced pressure to obtain ethyl 2-chloronicotinate.
6. The method according to claim 1, characterized in that, In step 2, the alkali is selected from one or more of NaOH, KOH, sodium carbonate, potassium carbonate, sodium bicarbonate, and potassium bicarbonate.
7. The method according to claim 1, characterized in that, In step 2, the acid is selected from one or more of hydrochloric acid, sulfuric acid, and nitric acid.
8. The method according to claim 1, characterized in that, In step 2, the reaction temperature is 80~100℃ and the reaction time is 1~5h.
9. The method according to claim 1, characterized in that, The preparation method of the catalyst metal benzimidazole ionic liquid IL-1 in step 1 includes the following steps: Step S1: Add 1-propylbenzimidazole, 1,2-dichloroethane, and acetonitrile to the reactor, heat to 80-100℃, and reflux under stirring for 12-24 hours. After the reaction is complete, cool to 10-20℃ to precipitate a solid. Filter, wash the residue with acetonitrile, and dry under vacuum to obtain a benzimidazole ionic liquid. The reaction formula is as follows: ； Step S2: Under nitrogen protection, benzimidazole ionic liquid, aluminum chloride, and ethanol are added to the reactor, and the mixture is heated to 60-90℃ and refluxed for 5-15 hours. After the reaction is complete, the solvent is removed by rotary evaporation, and the catalyst metal benzimidazole ionic liquid IL-1 is obtained by vacuum drying. The reaction formula is as follows: 。