A method for synthesizing nicotinamide from 3-methylpyridine
Nicotinamide was successfully synthesized under mild conditions through a catalytic oxidation reaction of N-chlorosuccinimide, tert-butyl hydrogen peroxide, and iron salt catalyst, combined with a hydrogenation reduction reaction using a Pd/C catalyst. This solved the safety and equipment requirements issues associated with high-temperature and high-pressure synthesis of nicotinamide, achieving low-cost and highly selective synthesis of nicotinamide.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- JIUJIANG SHANSHUI TECH
- Filing Date
- 2023-09-14
- Publication Date
- 2026-05-26
AI Technical Summary
Existing methods for synthesizing nicotinamide from 3-methylpyridine suffer from problems such as high energy consumption under high temperature and high pressure conditions, high equipment requirements, and safety hazards.
Nicotinamide was synthesized by catalytic oxidation of N-chlorosuccinimide (NCS), tert-butyl hydroperoxide (TBHP) and iron salt catalyst at room temperature, followed by hydrogenation reduction at room temperature and pressure using Pd/C as catalyst.
The method achieves highly selective synthesis of nicotinamide under mild conditions, with fewer byproducts, simpler post-processing, lower cost, and reduced equipment requirements, making it suitable for industrial production.
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Abstract
Description
Technical Field
[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a method for synthesizing nicotinamide from 3-methylpyridine. Background Technology
[0002] Niacinamide, also known as 3-pyridinecarboxamide, is readily soluble in water and ethanol. It exhibits excellent stability in solutions at pH 6, demonstrating both solution and photostability. As a vitamin derivative, niacinamide plays a crucial role in intracellular protein and sugar metabolism. Deficiency can impair normal cellular respiration and metabolism, leading to conditions such as pellagra. Furthermore, studies have demonstrated its effectiveness in inhibiting melanin deposition and reducing inflammation. Based on these characteristics, niacinamide is widely used in cosmetics for its skin-whitening and moisturizing effects, as well as its ability to reduce melanin deposition and remove age spots.
[0003] To date, there are several synthetic routes for nicotinamide, including those using 3-methylpyridine, 3-cyanopyridine, nicotinic acid, 2-methyl-1,5-pentanediamine, and quinoline as raw materials. Among these, the first two have been reported more extensively. Comparatively, 3-methylpyridine is the cheapest. While the synthesis of nicotinamide using 3-cyanopyridine has a higher yield and is widely documented in literature and patents, the synthesis of 3-cyanopyridine generally requires a catalyst and high-temperature conditions (200-300℃) through the ammoxidation of 3-methylpyridine. This process has drawbacks such as high energy consumption and the need for self-made catalysts. Research on the synthesis of nicotinamide from 3-methylpyridine dates back to 1988 with B. Mahipal Reddy. [1] Some researchers proposed a one-step synthesis of nicotinamide from 3-methylpyridine at 375°C using ammonia and oxygen as nitrogen and oxygen sources, catalyzed by copper oxide or molybdenum oxide; in 2016, Liu Shanhe et al. [2] A similar approach has been proposed, which involves synthesizing nicotinamide in a one-step process at 150°C using urea and oxygen as nitrogen and oxygen sources under the catalysis of manganese dioxide. However, the one-step synthesis of nicotinamide from 3-methylpyridine typically involves high reaction temperatures, requires sophisticated equipment, and carries certain risks.
[0004] Therefore, a low-cost, safe, and environmentally friendly method for synthesizing nicotinamide from 3-methylpyridine is urgently needed. Summary of the Invention
[0005] To address the shortcomings of existing technologies, this invention provides a method for synthesizing nicotinamide from 3-methylpyridine.
[0006] To solve the above-mentioned technical problems, the present invention provides the following technical solution:
[0007] This invention provides a method for synthesizing nicotinamide from 3-methylpyridine, the synthetic route of which is as follows:
[0008]
[0009] Wherein, NCS is N-chlorosuccinimide, TBHP is tert-butyl hydroperoxide, and NAM is nicotinamide;
[0010] The iron salt is one of Fe(OAc)2, FeCl2, FeSO4, and FeCl3.
[0011] Preferably, it includes the following steps:
[0012] 1) Catalytic oxidation reaction: Acetonitrile, benzylamine, and NCS were mixed and reacted at room temperature for 3-4 hours. Then, 3-methylpyridine, TBHP, and iron salt were added to the reaction solution, and the catalytic oxidation reaction was carried out under reflux conditions. The reaction progress was monitored by high performance liquid chromatography. The reaction was stopped when the content of 3-methylpyridine was consumed to 1% or less. After the reaction was completed, the solvent was removed by vacuum distillation. The reaction mixture was washed with saturated NaHCO3 solution, and the product was extracted with saturated Na2S2O3 solution and ethyl acetate. The organic layer was dried and vacuum distilled to obtain the intermediate product N-benzylnicotinamide.
[0013] 2) Hydrogenation reduction reaction: Using Pd / C as a catalyst and hydrogen as a reducing agent, N-benzylnicotinamide is hydrogenated and reduced to nicotinamide in methanol under normal temperature and pressure conditions.
[0014] Preferably, in step 1), the molar ratio of benzylamine, NCS, 3-methylpyridine, TBHP, and iron salt is 1:(1.1-1.5):1:1:(0.05-0.2).
[0015] Preferably, in step 1), the amount of NCS used is 1.3 times the equivalent of benzylamine.
[0016] Preferably, in step 1), the amount of iron salt used is 0.1 equivalents of benzylamine.
[0017] Preferably, the reflux temperature in step 1) is 82-86℃.
[0018] Preferably, step 2) specifically includes: dissolving N-benzylnicotinamide in methanol solvent, adding a certain amount of Pd / C catalyst, continuously bubbling hydrogen gas into the reaction solution at room temperature to carry out the reaction, distilling off the methanol solvent after the reaction, extracting the product with water, filtering, and distilling the filtrate under reduced pressure to obtain a white nicotinamide solid final product, wherein the molar ratio of N-benzylnicotinamide to Pd / C is 1:0.06-0.12.
[0019] Compared with the prior art, the present invention has the following beneficial effects:
[0020] The synthesis method of this invention has mild reaction conditions, low equipment requirements and low energy consumption, high reaction selectivity, few by-products, and simple post-processing. The purity of the product obtained by distillation meets the requirements of industrial production. At the same time, this invention uses low-cost iron salt catalysts and easily recyclable Pd / C catalysts, which helps to save production costs. Detailed Implementation
[0021] The preferred embodiments of the present invention are described below. It should be understood that the preferred embodiments described herein are for illustration and explanation only and are not intended to limit the present invention.
[0022] Example 1
[0023] Synthesis of N-benzylnicotinamide: Benzylamine (10.7 g, 0.10 mol) and NCS (17.2 g, 0.13 mol) were added to a 100 mL four-necked flask, followed by 20 mL of acetonitrile as the reaction solvent. The reaction mixture was stirred at room temperature for 3 h. After the reaction was complete, 3-methylpyridine (9.3 g, 0.10 mol), TBHP (9.0 g, 0.10 mol), and Fe(OAc)2 (1.91 g, 10 mmol) were added directly to the reaction mixture. The reaction mixture was refluxed at 82 °C for approximately 25 h with mechanical stirring. After the reaction was complete, the acetonitrile solvent was removed by vacuum distillation. The reaction mixture was washed twice with 50 mL of saturated NaHCO3 solution, and then extracted with saturated Na2S2O3 solution (50 mL) and ethyl acetate (50 mL). The resulting organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. After drying, the purity of the N-benzylnicotinamide obtained was 96.3% as determined by high performance liquid chromatography (HPLC), and the reaction yield was 92%. The product was directly used in the next reaction step.
[0024] Example 2
[0025] Synthesis of N-benzylnicotinamide: Benzylamine (10.7 g, 0.10 mol) and NCS (17.2 g, 0.13 mol) were added to a 100 mL four-necked flask, followed by 20 mL of acetonitrile as the reaction solvent. The reaction mixture was stirred at room temperature for 3 h. After the reaction was complete, 3-methylpyridine (9.3 g, 0.10 mol), TBHP (9.0 g, 0.10 mol), and FeCl2 (1.27 g, 10 mmol) were added directly to the reaction mixture. The reaction mixture was refluxed at 82 °C for approximately 25 h under mechanical stirring. After the reaction was complete, the acetonitrile solvent was removed by vacuum distillation. The reaction mixture was washed twice with 50 mL of saturated NaHCO3 solution, and then extracted with saturated Na2S2O3 solution (50 mL) and ethyl acetate (50 mL). The resulting organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. After drying, the purity of the obtained N-benzylnicotinamide was 95.5% as determined by high performance liquid chromatography (HPLC), and the reaction yield was 51%.
[0026] Example 3
[0027] Synthesis of N-benzylnicotinamide: Benzylamine (10.7 g, 0.10 mol) and NCS (17.2 g, 0.13 mol) were added to a 100 mL four-necked flask, followed by 20 mL of acetonitrile as the reaction solvent. The reaction mixture was stirred at room temperature for 3 h. After the reaction was complete, 3-methylpyridine (9.3 g, 0.10 mol), TBHP (9.0 g, 0.10 mol), and FeSO4 (1.52 g, 10 mmol) were added directly to the reaction mixture. The reaction mixture was refluxed at 82 °C for approximately 25 h with mechanical stirring. After the reaction was complete, the acetonitrile solvent was removed by vacuum distillation. The reaction mixture was washed twice with 50 mL of saturated NaHCO3 solution, and then extracted with saturated Na2S2O3 solution (50 mL) and ethyl acetate (50 mL). The resulting organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. After drying, the purity of the obtained N-benzylnicotinamide was 95.2% as determined by high performance liquid chromatography (HPLC), and the reaction yield was 46%.
[0028] Example 4
[0029] Synthesis of N-benzylnicotinamide: Benzylamine (10.7 g, 0.10 mol) and NCS (17.2 g, 0.13 mol) were added to a 100 mL four-necked flask, followed by 20 mL of acetonitrile as the reaction solvent. The reaction mixture was stirred at room temperature for 3 h. After the reaction was complete, 3-methylpyridine (9.3 g, 0.10 mol), TBHP (9.0 g, 0.10 mol), and FeCl3 (1.62 g, 10 mmol) were added directly to the reaction mixture. The reaction mixture was refluxed at 86 °C for approximately 25 h under mechanical stirring. After the reaction was complete, the acetonitrile solvent was removed by vacuum distillation. The reaction mixture was washed twice with 50 mL of saturated NaHCO3 solution, and then extracted with saturated Na2S2O3 solution (50 mL) and ethyl acetate (50 mL). The resulting organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. After drying, the purity of the obtained N-benzylnicotinamide was 95.6% as determined by high performance liquid chromatography (HPLC), and the reaction yield was 38%.
[0030] Example 5
[0031] Synthesis of nicotinamide: A certain amount of N-benzylnicotinamide (2.12 g, 10 mmol), Pd / C (63.9 mg, 0.6 mmol, 6 mol%) and 20 mL of methanol solvent were added to a 100 mL four-necked flask. Hydrogen gas was continuously bubbled into the reaction solution, and the reaction was carried out at room temperature with mechanical stirring for 20 h. After the reaction was completed, the methanol solvent was removed by distillation. The distillate was added with purified water to extract the nicotinamide product. The Pd / C catalyst was then recovered by filtration. The filtrate was distilled to remove water, and a nicotinamide product with a purity of 95.3% was obtained, with a yield of 88%.
[0032] Example 6
[0033] Synthesis of nicotinamide: A certain amount of N-benzylnicotinamide (2.12 g, 10 mmol), Pd / C (85.1 mg, 0.8 mmol, 8 mol%) and a certain amount of methanol solvent were added to a 100 mL four-necked flask. Hydrogen gas was continuously bubbled into the reaction solution, and the reaction was carried out at room temperature with mechanical stirring for 20 h. After the reaction was completed, the methanol solvent was removed by distillation. The distillate was added with purified water to extract the nicotinamide product. The Pd / C catalyst was then recovered by filtration. The filtrate was distilled to remove water, and a nicotinamide product with a purity of 98.5% was obtained, with a yield of 96%.
[0034] Example 7
[0035] Synthesis of nicotinamide: A certain amount of N-benzylnicotinamide (2.12 g, 10 mmol), Pd / C (106.4 mg, 1.0 mmol, 10 mol%) and a certain amount of methanol solvent were added to a 100 mL four-necked flask. Hydrogen gas was continuously bubbled into the reaction solution, and the reaction was carried out at room temperature with mechanical stirring for 20 h. After the reaction was completed, the methanol solvent was removed by distillation. The distillate was added with purified water to extract the nicotinamide product. The Pd / C catalyst was then recovered by filtration. The filtrate was distilled to remove water, and a nicotinamide product with a purity of 98.2% was obtained, with a yield of 97%.
[0036] Example 8
[0037] Synthesis of nicotinamide: A certain amount of N-benzylnicotinamide (2.12 g, 10 mmol), Pd / C (127.7 mg, 1.2 mmol, 12 mol%) and a certain amount of methanol solvent were added to a 100 mL four-necked flask. Hydrogen gas was continuously bubbled into the reaction solution, and the reaction was carried out at room temperature with mechanical stirring for 20 h. After the reaction was completed, the methanol solvent was removed by distillation. The distillate was added with purified water to extract the nicotinamide product. The Pd / C catalyst was then recovered by filtration. The filtrate was distilled to remove water, and the nicotinamide product with a purity of 98.1% was obtained, with a yield of 97%.
[0038] Table 1 shows the effect of different variables on the reaction in the examples.
[0039]
[0040] As shown in Table 1, Fe(OAc)2 exhibits significantly better catalytic performance than the other three iron salts in the catalytic oxidation reaction. However, for the hydrogenation reduction reaction, increasing the amount of Pd / C can accelerate the reaction process to some extent. Further increasing the amount of Pd / C does not significantly improve the reaction yield. Therefore, considering the cost in industrial production, the optimal amount of Pd / C for this reaction step is 8 mol.
[0041] Finally, it should be noted that the above descriptions are merely preferred embodiments of the present invention and are not intended to limit the present invention. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art can still modify the technical solutions described in the foregoing embodiments or make equivalent substitutions for some of the technical features. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.
Claims
1. A method for synthesizing nicotinamide from 3-methylpyridine, characterized in that, The synthesis route is as follows: ； Wherein, NCS is N-chlorosuccinimide, TBHP is tert-butyl hydroperoxide, and NAM is nicotinamide; The iron salt is one of Fe(OAc)2, FeCl2, FeSO4, and FeCl3.
2. The method for synthesizing nicotinamide from 3-methylpyridine according to claim 1, characterized in that, Includes the following steps: 1) Catalytic oxidation reaction: Acetonitrile, benzylamine, and NCS were mixed and reacted at room temperature for 3-4 h. Then, 3-methylpyridine, TBHP, and iron salt were added to the reaction solution, and catalytic oxidation was carried out under reflux conditions. The reaction progress was monitored by high performance liquid chromatography. The reaction was stopped when the content of 3-methylpyridine was consumed to 1% or less. After the reaction was completed, the solvent was removed by vacuum distillation. The reaction mixture was washed with saturated NaHCO3 solution, and the product was extracted with saturated Na2S2O3 solution and ethyl acetate. The organic layer was dried and vacuum distilled to obtain the intermediate product N-benzylnicotinamide. 2) Hydrogenation reduction reaction: Using Pd / C as a catalyst and hydrogen as a reducing agent, N-benzylnicotinamide is hydrogenated and reduced to nicotinamide in methanol under normal temperature and pressure conditions.
3. The method for synthesizing nicotinamide from 3-methylpyridine according to claim 2, characterized in that, In step 1), the molar ratio of benzylamine, NCS, 3-methylpyridine, TBHP, and iron salt is 1 : (1.1-1.5) : 1 : 1 : (0.05-0.2).
4. The method for synthesizing nicotinamide from 3-methylpyridine according to claim 2, characterized in that, The reflux temperature in step 1) is 82-86℃.
5. The method for synthesizing nicotinamide from 3-methylpyridine according to claim 2, characterized in that, Step 2) specifically includes: dissolving N-benzylnicotinamide in methanol solvent, adding a certain amount of Pd / C catalyst, continuously bubbling hydrogen gas into the reaction solution at room temperature to carry out the reaction, distilling off the methanol solvent after the reaction is completed, adding water to extract the product, filtering, and distilling the filtrate under reduced pressure to obtain a white nicotinamide solid final product, wherein the molar ratio of N-benzylnicotinamide to Pd / C is 1:0.06-0.12.