A method for synthesizing 4-bromo-3-cyanopyridine
The method of synthesizing 4-bromo-3-cyanopyridine through a step-by-step reaction solves the problems of complexity and pollution in existing synthesis methods, and provides a synthetic route with readily available raw materials, mild reaction, and recyclable catalyst, which is suitable for industrial production.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- HENAN UNIVERSITY
- Filing Date
- 2023-11-22
- Publication Date
- 2026-05-26
AI Technical Summary
Existing technologies lack efficient methods for synthesizing 4-bromo-3-cyanopyridine, and also present problems such as heavy metal pollution and complex post-processing of the product.
2-hydroxy-3-cyano-4-methoxypyridine is produced by reacting 2-hydroxy-3-cyano-4-methoxypyridine with phosphorus oxychloride and triethylamine. Then, it is reduced with palladium on carbon and hydrogen, and finally reacted with phosphorus tribromooxypyridine to obtain 4-bromo-3-cyanopyridine. The catalyst can be recycled and reused, and the reaction conditions are mild.
It achieves readily available raw materials, mild reaction conditions, recoverable catalyst, no heavy metal pollution, and simple product post-processing, making it suitable for industrial production.
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Abstract
Description
Technical Field
[0001] This invention belongs to the field of fine organic chemical synthesis, specifically relating to a method for synthesizing the fine chemical intermediate 4-bromo-3-cyanopyridine. Background Technology
[0002] The molecular formula of 4-bromo-3-cyanopyridine is C6H3BrN2, its molecular weight is 183.01, and its structural formula is:
[0003]
[0004] 4-Bromo-3-cyanopyridine (abbreviated as 4-bromonicotinamide), also known as 4-bromo-3-cyanopyridine, is an important fine chemical intermediate widely used in the pharmaceutical and pesticide fields. It is a key raw material for the neonicotinoid insecticide flonicamid; it can also be used as a livestock feed additive and insecticide. However, no synthetic method for 4-bromo-3-cyanopyridine has been found. Therefore, it is essential to find an efficient synthetic method for 4-bromo-3-cyanopyridine. This application discloses the specific synthetic route and method for this structure. Summary of the Invention
[0005] The purpose of this invention is to provide a method for synthesizing 4-bromo-3-cyanopyridine, which has advantages such as readily available raw materials, mild reaction conditions, recyclable catalyst, no heavy metal pollution, and simple product post-processing. The synthetic route is as follows:
[0006]
[0007] (a) 2-hydroxy-3-cyano-4-methoxypyridine and phosphorus oxychloride were mixed and triethylamine was added under stirring at room temperature. The mixture was heated to reflux until the reaction was complete. The reaction solution was evaporated to dryness, added to ice water, the pH was adjusted, filtered, and the precipitate was dried to obtain the intermediate product 2-chloro-3-cyano-4-methoxypyridine.
[0008] (b) Dissolve the product 2-chloro-3-cyano-4-methoxypyridine obtained in step (a) in ethanol, add palladium on carbon and triethylamine, and introduce hydrogen into the reaction system. Stir at room temperature until the reaction is complete; filter palladium on carbon, evaporate the mother liquor to dryness, and recrystallize to obtain the intermediate product 3-cyano-4-methoxypyridine.
[0009] (c) The product 3-cyano-4-methoxypyridine obtained in step (b) was added in portions to phosphorus tribromooxy, and the mixture was heated to reflux until the reaction was complete; it was then added to ice water, the pH was adjusted, the mixture was extracted, the organic phases were combined, and the mixture was recrystallized to obtain the target product 4-bromo-3-cyanopyridine.
[0010] Further, in step (a), the molar ratio of 2-hydroxy-3-cyano-4-methoxypyridine, phosphorus oxychloride and triethylamine is (1.2~2):(4~6):1.
[0011] Furthermore, the pH range for adjusting in step (a) and step (c) is 7 to 8. In step (a), ammonia is used to adjust the pH, and in step (c), sodium bicarbonate is used to adjust the pH.
[0012] Further, in step (b), the palladium on carbon is 10% palladium on carbon.
[0013] Further, in step (b), the molar ratio of 2-chloro-3-cyano-4-methoxypyridine to triethylamine is 1.2~2:1, and the mass ratio of 2-chloro-3-cyano-4-methoxypyridine to 10% palladium on carbon is 7~15:1.
[0014] Further, in step (c), the molar ratio of 3-cyano-4-methoxypyridine to phosphorus tribromooxypyridine is (1.8~2.0):1.
[0015] Furthermore, in step (b), ethyl acetate is used for recrystallization; in step (c), a mixed solvent of ethyl acetate and petroleum ether is used for recrystallization, and the volume ratio of ethyl acetate to petroleum ether is (3~5):1.
[0016] The synthesis method used in this invention has advantages such as readily available raw materials, mild reaction conditions, recyclable catalysts, no heavy metal pollution, and simple product post-processing, making it suitable for industrial production. Attached Figure Description
[0017] Figure 1 The 1H NMR spectrum of compound 2 obtained in Example 1;
[0018] Figure 2 The 1H NMR spectrum of compound 3 obtained in Example 1;
[0019] Figure 3 The 1H NMR spectrum of the target product 4-bromo-3-cyanopyridine obtained in Example 1 is shown below. Detailed Implementation
[0020] The technical solution of the present invention will be further described in detail below with reference to the accompanying drawings and embodiments, but the scope of protection of the present invention is not limited thereto.
[0021] Example 1
[0022] The synthesis method of 4-bromo-3-cyanopyridine is as follows:
[0023]
[0024] Adding starting material 1 (50 g, 0.34 mol) and phosphorus oxychloride (100 ml, 1.1 mol) to a flask, and slowly adding triethylamine (30 ml, 0.22 mol) with stirring, the mixture was heated to 80 °C and refluxed. The reaction progress was monitored by TLC. After 2 h, the starting material was essentially completely reacted. Heating was stopped, the solvent was removed, and the remaining mixture was added to 1 kg of ice water. The pH was adjusted to 7-8 with commercially available concentrated ammonia. A precipitate formed; the precipitate was filtered and dried at 50 °C to obtain brown crude product 2 (41 g, yield = 72%), with a purity of 97%. The 1H NMR spectrum of compound 2 is shown below. Figure 1 As shown, 1 H NMR (500 MHz, Chloroform-d) δ 8.41 (d, J = 6.0 Hz, 0H), 6.89 (d, J = 6.0 Hz, 0H), 4.03 (s, 1H).
[0025]
[0026] Crude product 2 (30 g, 0.178 mol) was dissolved in ethanol (200 ml), and 10% palladium on carbon (4 g) and triethylamine (15 ml, 0.11 mol) were added. Hydrogen gas was continuously bubbled through the solution, and the reaction was carried out at room temperature for 18 h. The reaction progress was monitored by TLC. After 18 h, the palladium on carbon was filtered off, the mother liquor was evaporated to dryness, and recrystallized from ethyl acetate to obtain yellow solid 3 (13 g, yield = 54.5%) with a purity of 95%. The 1H NMR spectrum of compound 3 is shown below. Figure 2 As shown, 1 H NMR (500 MHz, Chloroform-d) δ 8.67 (s, 1H), 8.62 (d,J=6.0Hz, 1H), 6.90 (d,J=6.0Hz, 1H), 3.99 (s, 3H).
[0027]
[0028] Compound 3 (50 g, 0.37 mol) was dissolved in acetonitrile (600 ml), and phosphorus tribromooxy (200 g, 0.7 mol) was slowly added. The mixture was heated to 85 °C under reflux, and the reaction progress was monitored by TLC. After 12 h of reaction, heating was stopped, and the remaining mixture was added to 1 kg of ice water. The pH was adjusted to 7-8 with sodium bicarbonate solids, and the mixture was extracted with ethyl acetate. The organic phases were combined and recrystallized (V... 乙酸乙酯 :V 石油醚 The mixture of compound 4 (4:1) yielded a yellow solid, which was dried at 50 °C to obtain the target product 4-bromo-3-cyanopyridine (41 g, yield = 61%), with a purity of 95%. The 1H NMR spectrum of compound 4 is shown below. Figure 3 As shown, 1 H NMR (500 MHz, Chloroform-d) δ 8.82 (s,1H), 7.68 (d,J=6.0Hz, 1H), 6.90 (d,J=6.0Hz, 1H).
[0029] Example 2
[0030] The synthesis method of 4-bromo-3-cyanopyridine is as follows:
[0031] Add raw material 1 (1 kg, 6.8 mol) and phosphorus oxychloride (2 L, 22 mol) to a flask, and slowly add triethylamine (0.5 L, 5.5 mol). Heat to 80 °C and reflux. Monitor the reaction progress by TLC. After 3.5 h, the raw materials have basically reacted completely. Stop heating, evaporate the solvent, and add the remaining mixture to 30 kg of ice water. Adjust the pH to 7-8 with commercially available concentrated ammonia. A precipitate will form. Filter the precipitate and dry it at 50 °C to obtain brown crude product 2 (0.77 kg, Yield = 67.6%) with a purity of 96%.
[0032] Crude product 2 (1 kg, 5.9 mol) was dissolved in ethanol (5 L), and 10% palladium on carbon (80 g) and triethylamine (0.4 L, 4.4 mol) were added. Hydrogen gas was continuously introduced, and the reaction was carried out at room temperature. The reaction progress was monitored by TLC. After 20 h of reaction, palladium on carbon was filtered, the mother liquor was evaporated to dryness, and recrystallized from ethyl acetate to obtain yellow solid 3 (0.36 kg, Yield = 50.3%) with a purity of 94%.
[0033] Compound 3 (1 kg, 7.5 mol) was dissolved in acetonitrile (6 L), and phosphorus tribromooxyphosphate (4 kg, 14 mol) was slowly added. The mixture was heated to 85 °C under reflux, and the reaction progress was monitored by TLC. After 12 h of reaction, heating was stopped, and the remaining mixture was added to 40 kg of ice water. The pH was adjusted to 7-8 with sodium bicarbonate solids, and the mixture was extracted with ethyl acetate. The organic phases were combined and recrystallized (V... 乙酸乙酯 :V 石油醚 The mixture of 4:1 yielded a yellow solid, which was dried at 50 °C to obtain the target product 4-bromo-3-cyanopyridine (0.76 kg, Yield = 56.5%) with a purity of 97%.
[0034] The above description represents the preferred embodiments of the present invention. It should be noted that those skilled in the art can make various improvements and modifications without departing from the principles of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.
Claims
1. A method for synthesizing 4-bromo-3-cyanopyridine, characterized in that, The synthesis route is as follows: Specifically, the following steps are included: (a) 2-hydroxy-3-cyano-4-methoxypyridine and phosphorus oxychloride were mixed, and triethylamine was added under stirring at room temperature. The mixture was heated to reflux until the reaction was complete. The reaction solution was evaporated to dryness, added to ice water, the pH was adjusted, filtered, and the precipitate was dried to obtain the intermediate product 2-chloro-3-cyano-4-methoxypyridine. The molar ratio of 2-hydroxy-3-cyano-4-methoxypyridine, phosphorus oxychloride and triethylamine was (1.2~2):(4~6):
1. (b) Dissolve the product 2-chloro-3-cyano-4-methoxypyridine obtained in step (a) in ethanol, add palladium on carbon and triethylamine, and purge hydrogen into the reaction system. Stir at room temperature until the reaction is complete; filter palladium on carbon, evaporate the mother liquor to dryness, and recrystallize to obtain the intermediate product 3-cyano-4-methoxypyridine; the palladium on carbon is 10% palladium on carbon; the molar ratio of 2-chloro-3-cyano-4-methoxypyridine to triethylamine is 1.2~2:1, and the mass ratio of 2-chloro-3-cyano-4-methoxypyridine to 10% palladium on carbon is 7~15:1; (c) The product 3-cyano-4-methoxypyridine obtained in step (b) was added in portions to phosphorus tribromooxypyridine, and the mixture was heated to reflux until the reaction was complete; it was added to ice water, the pH was adjusted, the mixture was extracted, the organic phases were combined, and the mixture was recrystallized to obtain the target product 4-bromo-3-cyanopyridine; the molar ratio of 3-cyano-4-methoxypyridine to phosphorus tribromooxypyridine was (1.8~2.0):
1.
2. The synthesis method according to claim 1, characterized in that, In step (a) and step (c), the pH range is adjusted to 7-8. In step (a), ammonia is used to adjust the pH, and in step (c), sodium bicarbonate is used to adjust the pH.
3. The synthesis method according to claim 1, characterized in that, In step (b), ethyl acetate is used for recrystallization; in step (c), a mixed solvent of ethyl acetate and petroleum ether is used for recrystallization, and the volume ratio of ethyl acetate to petroleum ether is (3~5):1.