Preparation process of 5-bromonicotinic acid

Abstract

The invention discloses a preparation process of 5-bromonicotinic acid, which comprises the following steps: sequentially adding ethyl nicotinate and pinacol borane into a reaction kettle, heating to react, adding N-bromosuccinimide into the reaction kettle, maintaining the reaction temperature, and filtering to remove a byproduct succinimide after the reaction is finished. And carrying out reduced pressure distillation to recover the solvent to obtain the ethyl 5-bromonicotinate. Adding ethyl 5-bromonicotinate into another reaction kettle, adding an alkali solution, heating, stirring for reaction, cooling reaction liquid after the reaction is finished, dropwise adding hydrochloric acid to adjust the pH value, cooling, crystallizing, filtering, washing a filter cake, and drying to obtain a 5-bromonicotinic acid finished product. The total yield gt of the preparation process of the 5-bromonicotinic acid; the HPLC purity is gt; 99%. The process is simple and convenient to operate and easy to implement, raw materials are cheap and easy to obtain, reaction conditions are mild, high-temperature and high-pressure reaction is not needed, and requirements on equipment are reduced. The whole process is safer to the environment, and green and pollution-free production can be realized.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis, specifically relating to a preparation process for 5-bromonicotinic acid. Background Technology

[0002] 5-Bromonicotinic acid (BNA) is a key intermediate in the synthesis of nitrogen-containing heterocyclic compounds and a crucial raw material for the synthesis of various drugs. In the pharmaceutical field, it is used to synthesize drugs such as JAK inhibitors and HIV protease inhibitors. In the pesticide field, it is used to synthesize selective herbicides against grassy weeds, such as nicotinic acid herbicides. In materials science, a team at the University of Hong Kong discovered that 4-amino-5-bromonicotinic acid can significantly improve battery efficiency and enhance stability. This technological breakthrough makes BNA a key material in the commercialization of perovskites. Therefore, the market demand for BNA continues to grow.

[0003] Currently, the methods for preparing 5-bromonicotinic acid reported both domestically and internationally have the following main shortcomings: 1. Preparation of 5-bromonicotinic acid from nicotinic acid as a starting material: DuPont's patent (WO2004035545A2) uses nicotinic acid as a starting material, converting it to nicotinyl chloride under reflux at 80°C. The subsequent crucial bromination reaction also uses liquid bromine as the bromine source, requiring a reaction time of 8-10 hours at 155°C. Because liquid bromine has a low boiling point and is highly volatile, this method requires equipment that is resistant to high temperatures, high pressures, and corrosion—high demands on the equipment. Furthermore, this method suffers from the highly corrosive and toxic nature of liquid bromine, posing significant operational risks and generating large amounts of acidic wastewater, resulting in high environmental treatment costs.

[0004] 2. Preparation of 5-bromonicotinic acid from 3-cyanopyridine: Chinese patent CN 114181139 A uses 3-cyanopyridine as a starting material and a solid halogenation reagent as a bromine source, followed by hydrolysis of the cyano group in the presence of concentrated hydrochloric acid to prepare 5-bromonicotinic acid. However, the bromination yield is not high with different halogenation reagents. Moreover, this method requires a large amount of concentrated hydrochloric acid for cyano hydrolysis, and the hydrolysis temperature is 95-100℃, which places high demands on the acid corrosion resistance of the equipment.

[0005] 3. Transition metal catalysis: Using 3,5-dibromopyridine as the starting material and palladium dichloride bis(triphenylphosphine) as the catalyst, the carbonylation reaction is carried out in ethanol solvent by introducing carbon monoxide (e.g., Tetrahedron Letters, Vol. 25, No. 51, pp. 5939-5942, 1984). This method uses a noble metal catalyst, which is costly (Pd catalyst dosage is 30 mol% of the starting material), has a yield of only 40%, and uses CO, making it unsuitable for large-scale industrial applications.

[0006] Currently, there is a lack of an industrial-scale preparation process for 5-bromonicotinic acid that utilizes readily available raw materials, has low-cost catalysts, operates under mild reaction conditions, is environmentally friendly, and achieves high yields. Therefore, developing a new process that balances economic efficiency, safety, and environmental friendliness is crucial to overcoming the current technological bottlenecks. Summary of the Invention

[0007] To address the shortcomings of existing technologies, the present invention aims to provide a process for preparing 5-bromonicotinic acid suitable for industrial production, achieving the following objectives: ① using inexpensive and readily available starting materials; ② using low-toxicity and high-efficiency catalysts and bromine sources; ③ mild reaction conditions, eliminating the need for high-temperature and high-pressure equipment; ④ improving reaction selectivity and product purity, with a total yield ≥75% and purity ≥99%; ⑤ recyclable solvents, reducing emissions of waste.

[0008] The core idea of ​​this invention is: using ethyl nicotinate as the starting material, utilizing the catalytic properties of pinacolborane Lewis acid, the active site at the 5-position of the pyridine ring of ethyl nicotinate is activated, thereby... N Using bromosuccinimide as a mild bromine source, ethyl 5-bromonicotinic acid is generated with high selectivity; then, the ester group is converted to a carboxyl group by alkaline hydrolysis, finally yielding 5-bromonicotinic acid.

[0009] To achieve the above objectives, the present invention adopts the following technical solution: A preparation process for 5-bromonicotinic acid, the preparation route is as follows: The specific preparation process is as follows: (1) Preparation of ethyl 5-bromonicotinic acid: Add solvent to the reaction vessel, start stirring, add ethyl nicotinic acid (purity ≥98%), stir until completely dissolved, add pinacol borane, and add at 0~50℃. N 5-Brominated succinimide was used to maintain the reaction temperature. The reaction endpoint was monitored by HPLC (ethyl nicotinic acid residue ≤0.5%). The mixture was filtered. The solvent was recovered by vacuum distillation of the filtrate (recovery rate ≥60%). The filter cake was washed with an appropriate amount of solvent, and the washing liquid was added to the filtrate. The washed filter cake was 5-bromonicotinic acid ethyl ester (yield 74-87%, purity ≥98.5%). (2) Preparation of 5-bromonicotinic acid: Add ethyl 5-bromonicotinic acid obtained in step (1) to another reaction vessel, add alkaline solution to make the pH of the system 7~9, heat to 50~80℃ (preferably 65~75℃), stir until the reaction is complete, monitor the hydrolysis endpoint by HPLC (ethyl 5-bromonicotinic acid residue ≤0.3%), cool the reaction solution to 30~40℃, add hydrochloric acid dropwise to adjust the pH to 2~3, cool to crystallize, filter after complete crystallization, wash the filter cake with purified water and dry to obtain the 5-bromonicotinic acid product.

[0010] Further, in step (1), ethyl nicotinate, pinacol borane andN The molar ratio of 1:(0.05~0.2):(1.1~2) for bromosuccinimide is 1:(0.05~0.2):(1.1~2). In step (1), the solvent is at least one of dichloromethane, acetonitrile, and tetrahydrofuran. The concentration of ethyl nicotinate in the solvent is 0.5~1 mol / L.

[0011] Furthermore, in step (1), the temperature is raised to 30~45℃, and then... N - Bromosuccinimide; after the reaction is complete, cool. Let it cool to room temperature, stand for 0.5 to 1 hour, and then filter.

[0012] Further, in step (2), the alkaline solution is at least one of sodium hydroxide solution, potassium hydroxide solution, and ammonia solution; the mass concentration of the alkaline solution is 28-35%.

[0013] Furthermore, in step (2), the mass concentration of the hydrochloric acid solution is 32-38%, and the hydrochloric acid solution is added at 30-40°C.

[0014] Furthermore, in step (2), the temperature for cooling crystallization is 0~25℃.

[0015] The advantages and positive effects of this invention are as follows: The preparation process of 5-bromonicotinic acid provided by this invention is simple to operate, easy to implement, and operates under mild reaction conditions, avoiding the use of liquid bromine and high-temperature, high-pressure equipment. The entire process is safe and environmentally friendly. The purity of the final product, 5-bromonicotinic acid, can reach 99%. Attached Figure Description

[0016] Figure 1 It is the ethyl 5-bromonicotinic acid obtained in Example 1. 1 H-NMR spectrum; Figure 2 This is the HPLC chromatogram of ethyl 5-bromonicotinic acid obtained in Example 1; Figure 3 It is the final product obtained in Example 1. 1 H-NMR spectrum; Figure 4 This is the HPLC chromatogram of the final product obtained in Example 1.

[0017] The spectral results of Examples 2 and 3 are not significantly different, so no further illustrations are provided. Detailed Implementation

[0018] To further illustrate the content and features of the present invention, the following description is provided in conjunction with embodiments.

[0019] Example 1 A preparation process for 5-bromonicotinic acid is as follows: (1) Preparation of 5-bromonicotinic acid ethyl ester: Add 200 mL of acetonitrile to a 500 mL four-necked reactor, start stirring, add 30 g of nicotinic acid ethyl ester (0.20 mol), and stir for 15 min until completely dissolved; add pinacol borane (2.56 g of 0.02 mol), stir for 10 min, and heat to 35 °C; add in three batches N - Bromosuccinimide (53.5 g, 0.30 mol), maintain temperature 35~40℃; after the addition is complete, continue stirring for 1.5 h, HPLC detection shows 0.3% residual nicotinic acid ester, reaction ends.

[0020] The reaction system was cooled to 20°C and allowed to stand for 1 hour. The solid succinimide was then removed by filtration. The filter cake was washed twice with 15 mL of acetonitrile, and the washings were combined with the filtrate. The filtrate was transferred to a vacuum distillation apparatus (0.08 MPa, 40°C) to recover 150 mL of acetonitrile (65% recovery rate, recyclable after dehydration), yielding a pale yellow oily substance, 40.0 g of ethyl 5-bromonicotinic acid, with a yield of 87.0%.

[0021] The 1H NMR spectrum of ethyl 5-bromonicotinic acid is as follows: Figure 1 As shown, 1 HNMR (Bruker, 400M, CDCl3): δ 9.13(s, 1H),8.84(s, 1H), 8.43(d, 1H, 1.6Hz), 4.42((m, 2H), 1.42(m, 3H). HPLC analysis of ethyl 5-bromonicotinic acid ester Figure 2 As shown, its purity is 99.5%.

[0022] (2) Preparation of 5-bromonicotinic acid: 40.0 g (0.17 mol) of the above-mentioned ethyl 5-bromonicotinic acid was added to a 500 mL four-necked reactor, followed by 70 mL of 30 wt% sodium hydroxide aqueous solution (system pH>9), and stirred until homogeneous. The temperature was then raised to 70 °C and maintained at 70-75 °C with stirring for 2.5 h. HPLC analysis showed that the residual ethyl 5-bromonicotinic acid was 0.2%, indicating the end of hydrolysis.

[0023] The reaction system was cooled to 40°C, and 36wt% hydrochloric acid was added dropwise to adjust the pH to 2.5 (dropwise over 10 min). Stirring was continued for 20 min, and the mixture was cooled to 25°C and allowed to stand for 30 min, resulting in the precipitation of a white solid. The solid was filtered, and the filter cake was washed twice with 50 mL of purified water and placed in a vacuum drying oven at 50°C. o After drying at C for 4 h, 32.6 g of 5-bromonicotinic acid was obtained, with an HPLC purity of 99.2%, a yield of 95%, and an overall yield of 82.7%.

[0024] The 1H NMR spectrum of 5-bromonicotinic acid is as follows: Figure 3 As shown, 1 HNMR (Bruker, 400M, DMSO- d6 ): δ HPLC values ​​of 5-bromonicotinic acid were 13.76 (s, 1H), 9.03 (d, 1H, 1.2Hz), 8.95 (d, 1H, 2.4Hz), and 8.42 (s, 1H). Figure 4 As shown, its purity is 99.48%.

[0025] Example 2 A preparation process for 5-bromonicotinic acid is as follows: (1) Preparation of 5-bromonicotinic acid ethyl ester: 400 mL of dichloromethane was added to a 1000 mL four-necked reactor, followed by 60 g of nicotinic acid ethyl ester (0.40 mol). The mixture was stirred for 25 min until completely dissolved, and then pinacol borane (5.20 g, 0.04 mol) was added. The temperature was raised to 35 °C. NBS (107.2 g, 0.60 mol) was added in 6 batches, with an interval of 10 min between each batch, and the temperature was maintained at 35 °C. After the addition was completed, the reaction was stirred for another 2 h. HPLC analysis showed that 0.4% of nicotinic acid ethyl ester remained, and the reaction was considered complete.

[0026] The reaction system was cooled to 20°C and allowed to stand for 1.5 h. The solid succinimide was then removed by filtration. The filter cake was washed twice with 25 mL of dichloromethane, and the washings were combined with the filtrate. The filtrate was transferred to a vacuum distillation apparatus (0.08 MPa, 40°C) to recover the dichloromethane, yielding a pale yellow oil containing 79.5 g of ethyl 5-bromonicotinic acid (86.0% yield, HPLC purity 98.9%).

[0027] (2) Preparation of 5-bromonicotinic acid: 150 mL of 30 wt% sodium hydroxide aqueous solution (system pH > 9) was added to the above reaction vessel, and the temperature was raised to 70℃ for 3 h. HPLC analysis showed that ethyl 5-bromonicotinic acid residue was 0.2%, indicating the end of hydrolysis. The reaction system was cooled to 40℃, and 36 wt% hydrochloric acid was added dropwise to adjust the pH to 2.5. Stirring was continued for 30 min, and the system was cooled to 0℃. o C crystallization, filtration and washing, vacuum drying oven at 50°C o After drying at C, 65.0 g of 5-bromonicotinic acid was obtained, with a yield of 93%, HPLC purity of 99.5%, and an overall yield of 80%.

[0028] Example 3 A preparation process for 5-bromonicotinic acid is as follows: (1) Preparation of ethyl 5-bromonicotinic acid: Add 300 mL of tetrahydrofuran to a 500 mL reactor, add ethyl nicotinic acid (30 g, 0.20 mol), and stir for 20 min until completely dissolved. Add pinacol borane (2.56 g, 0.02 mol), stir for 10 min, heat to 40 °C, and add in three batches. N - Bromosuccinimide (71.5 g, 0.40 mol), maintained at 40℃; after the addition was complete, the reaction was stirred for another 1.5 h. HPLC analysis showed that the residual ethyl nicotinate was 0.3%, and the reaction was terminated.

[0029] The reaction system was cooled to 20°C and allowed to stand for 1 hour. The solid succinimide was then removed by filtration. The filter cake was washed twice with 10 mL of tetrahydrofuran, and the washings were combined with the filtrate. The filtrate was transferred to a vacuum distillation apparatus to recover 195 mL of tetrahydrofuran (61% recovery rate, which can be recycled after dehydration), yielding a pale yellow oil containing 34.2 g of ethyl 5-bromonicotinic acid (0.149 mol), with a yield of 74.0% and an HPLC purity of 98.5%.

[0030] (2) Preparation of 5-bromonicotinic acid: Add 60 mL of 30wt% sodium hydroxide aqueous solution (system pH>9) and stir until homogeneous. Then raise the temperature to 70℃ and maintain the temperature at 70-75℃ for 2.5 h. HPLC analysis showed that ethyl 5-bromonicotinic acid residue was 0.2%, indicating the end of hydrolysis.

[0031] The reaction system was cooled to 40°C, and 36wt% hydrochloric acid was added dropwise to adjust the pH to 2.5. Stirring was continued for 20 min, followed by cooling to 25°C and standing for 30 min, resulting in the precipitation of a white solid. The solid was filtered, and the filter cake was washed twice with 50 mL of purified water and placed in a vacuum drying oven at 50°C. o After drying at C for 4 h, 32.6 g of 5-bromonicotinic acid was obtained with an HPLC purity of 99.2%, a yield of 95%, and an overall yield of 70%.

[0032] The above embodiments are merely illustrative of the present invention and are not intended to limit the scope of the present invention. All equivalent implementations of the present invention should be included within the scope of the claims of the present invention.

Claims

1. A preparation process for 5-bromonicotinic acid, characterized in that, The preparation route is as follows: The specific preparation process is as follows: (1) Preparation of ethyl 5-bromonicotinic acid: Add solvent to the reaction vessel, start stirring, add ethyl nicotinic acid, stir until completely dissolved, add pinacol borane, and add at 0~50℃. N 5-bromosuccinimide was reacted at a maintained temperature until the reaction was complete, then filtered. The solvent was recovered by vacuum distillation of the filtrate, and the filter cake was ethyl 5-bromonicotinate. (2) Preparation of 5-bromonicotinic acid: Add ethyl 5-bromonicotinic acid obtained in step (1) to another reaction vessel, add alkaline solution to make the pH of the system 7~9, heat to 50~80℃, stir until the reaction is complete, cool the reaction solution to 30~40℃, add hydrochloric acid dropwise to adjust the pH to 2~3, cool and crystallize, filter, wash the filter cake with purified water and dry to obtain the 5-bromonicotinic acid product.

2. The preparation process of 5-bromonicotinic acid according to claim 1, characterized in that, In step (1), ethyl nicotinate, pinacol borane and N The molar ratio of 1:(0.05~0.2):(1.1~2) of bromosuccinimide is 1:(0.05~0.2):(1.1~2).

3. The preparation process of 5-bromonicotinic acid according to claim 1, characterized in that, In step (2), the alkaline solution is at least one of sodium hydroxide solution, potassium hydroxide solution, and ammonia solution; the mass concentration of the alkaline solution is 28-35%.

4. The preparation process of 5-bromonicotinic acid according to claim 1, characterized in that, In step (1), the solvent is at least one of dichloromethane, acetonitrile, and tetrahydrofuran, and the temperature is raised to 30-45°C, then added... N - Bromosuccinimide.

5. The preparation process of 5-bromonicotinic acid according to claim 1, characterized in that, In step (2), the temperature is raised to 65~75℃.

6. The preparation process of 5-bromonicotinic acid according to claim 1, characterized in that, In step (2), the mass concentration of the hydrochloric acid solution is 32-38%, and the hydrochloric acid solution is added at 30-40℃.

7. The preparation process of 5-bromonicotinic acid according to claim 1, characterized in that, In step (2), the cooling crystallization temperature is 0~25℃.

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