Method for synthesizing nicotinamide by using nicotine and nicotinamide prepared by method
Niacin is prepared by oxidizing nicotine by potassium permanganate, and then reacting with amidating reagent to prepare nicotine amide, which solves the problems of low nicotine oxidation efficiency and safety hazards of oxidant in the prior art, achieves high yield and low cost nicotine amide production, and expands its application in the food and pharmaceutical fields.
Patent Information
- Application Number
- CN202410111833.9
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-01-25
- Publication Date
- 2025-07-25
AI Technical Summary
In the prior art, nicotine oxidation is inefficient in preparing niacin and the oxidants used such as nitric acid and chromium trioxide have safety risks, which limits the application of nicotinamide in the food and medicine field.
Nicotinamide is prepared by oxidizing potassium permanganate under neutral or acidic conditions to form niacin, and then reacting with the amidating reagent under the action of a condensing agent. By controlling the reaction conditions and post-treatment steps, the yields of niacin and niacinamide are improved and impurity residues are reduced.
It improves the yield and application safety of nicotinamide, reduces production costs, facilitates industrial production, and expands the application of nicotinamide in the food and pharmaceutical fields.
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Figure CN120365213A_ABST
Abstract
Description
Technical Field
[0001] The present application relates to a method for synthesizing nicotinamide from nicotine and the obtained nicotinamide, belonging to the technical field of nicotinamide preparation. Background Art
[0002] Nicotinamide is an amide compound of nicotinic acid. As a member of the vitamin B group, nicotinamide participates in the formation of coenzyme I and coenzyme II, and plays a crucial role in the lipid metabolism, cell respiration, and glycogenolysis processes in the human body. Its deficiency may have a negative impact on the normal respiration and metabolism of cells, and thus trigger diseases such as pellagra.
[0003] In clinical applications, nicotinamide is mainly used for preventing and treating diseases such as pellagra, oral inflammation, sick sinus syndrome, and atrioventricular block. In the medical and cosmetic fields, nicotinamide is highly regarded for its good anti-aging and whitening effects and is widely used in many daily chemical products with whitening effects. In livestock and poultry production, nicotinamide is added to feed as an important nutrient component, which can promote the growth and development of livestock and poultry, improve the quality of skin and hair, and increase the utilization rate of feed, effectively enhancing the production performance and immunity of livestock and poultry.
[0004] The traditional synthesis methods of nicotinamide include chemical methods and biological methods. The chemical method mainly consists of two steps. The first step is to synthesize nicotinic acid first, and the second step is to synthesize nicotinamide from nicotinic acid; the biological method is mainly to generate 3-cyanopyridine through the catalytic reaction of 3-methylpyridine under high temperature and high pressure, and then obtain nicotinamide by hydrolyzing 3-cyanopyridine with biological enzymes. Some studies have shown that nicotine can be oxidized to nicotinic acid, and the oxidation reagents currently used for the oxidation of nicotine to nicotinic acid include nitric acid and chromium trioxide. However, the reaction efficiency of oxidizing nicotine with nitric acid is low (the molar yield is less than 20%); in addition, chromium (VI) compounds are recognized as class I carcinogens by the World Health Organization and the International Agency for Research on Cancer, and the nicotinic acid prepared with chromium trioxide has potential chromium (VI) residues, so there are serious obstacles to its application in the food and pharmaceutical fields.
[0005] Therefore, due to the limitations of the current technology, it is very crucial to develop a method for preparing nicotinamide with high yield and no harm using nicotine as a raw material for laboratory preparation and industrial production. Summary of the Invention
[0006] To solve the above problems, a method for synthesizing nicotinamide from nicotine is provided. This method oxidizes nicotine with potassium permanganate under neutral or acidic conditions to obtain nicotinic acid, and then prepares nicotinamide from nicotinic acid, which can improve the yield of nicotinamide, reduce the harmfulness of nicotinamide preparation, and improve the application safety of nicotinamide.
[0007] According to one aspect of the present application, a method for synthesizing nicotinamide from nicotine is provided, including the following steps:
[0008] (1) Nicotine and potassium permanganate are subjected to an oxidation reaction under neutral or acidic conditions to prepare nicotinic acid;
[0009] (2) The nicotinic acid is subjected to an amidation reaction with an amidating agent under the activation of a condensing agent to prepare nicotinamide.
[0010] In the present application, potassium permanganate is used to oxidize nicotine to obtain nicotinic acid. As the oxidation by potassium permanganate proceeds, manganese dioxide precipitate will gradually form. The presence of the precipitate will affect the continuous oxidation of nicotine. Therefore, oxidizing nicotine under acidic conditions can dissolve the manganese dioxide precipitate, thereby increasing the reaction rate and reactivity of nicotine, ultimately increasing the yield of nicotinic acid and reducing the residue of nicotine; and in the case of the same solvent, acidic conditions can improve the solubility of nicotine in the aqueous solution, thereby producing more nicotinic acid, reducing production costs, and facilitating industrial production and processing.
[0011] The manganese dioxide precipitate obtained under neutral conditions is removed by filtration during post-treatment. Under acidic conditions, the manganese dioxide precipitate dissolves into manganese ions and will also be removed during post-treatment. Therefore, using potassium permanganate will not introduce new impurities. Moreover, as an excellent antibacterial agent and disinfectant, potassium permanganate is widely used in the medical and health fields for debridement and disinfection of the skin surface. Potassium and manganese are also essential macroelements and trace elements for the human body, thus improving the application safety of nicotinamide.
[0012] Optionally, the temperature of the oxidation reaction is 70 - 100 °C and the time is 4 - 8 h.
[0013] This reaction temperature and reaction time can, firstly, increase the oxidation rate of nicotine and save reaction time, and secondly, reduce production energy consumption, thus facilitating industrial batch production. If the reaction temperature is too low or the time is too short, the reaction rate and degree of nicotine with potassium permanganate will decrease, the residue of nicotine will increase, and the yield of nicotinic acid will decline; if the temperature is too high or the time is too long, the increase in the yield of nicotinic acid is not significant, but the reaction energy consumption increases, resulting in an increase in production costs.
[0014] Optionally, the oxidation reaction in step (1) is carried out in an aqueous solution.
[0015] Optionally, the pH value of the acidic condition in step (1) is below 2, and the hydrogen ion concentration in the solution does not exceed 2 mol / L.
[0016] When the pH is greater than 2, the dissolution of manganese dioxide precipitate is incomplete, which is not conducive to improving the yield of nicotinic acid. If the hydrogen ion concentration in the solution exceeds 2 mol / L, first, it will cause the solution to be too acidic, reducing the reaction activity of nicotine and potassium permanganate; second, it will increase the cost of subsequent treatment; third, it will affect the amidation reaction of nicotinic acid and reduce the yield of nicotinamide.
[0017] Optionally, the molar ratio of nicotine to potassium permanganate is 1:4 to 10.
[0018] The above molar ratio is conducive to the oxidation of nicotine by potassium permanganate and improves the formation rate of nicotinic acid. If the amount of potassium permanganate is too small, the oxidation of nicotine is insufficient, resulting in an increase in nicotine residue and a decrease in the yield of nicotinic acid; if the amount of potassium permanganate is too large, the precipitation of manganese dioxide increases, affecting the oxidation of nicotine. The precipitate may adsorb the product nicotinic acid, which also leads to a decrease in the yield of nicotinic acid.
[0019] Optionally, in step (1), after the oxidation reaction of nicotine and potassium permanganate under acidic conditions, the pH is adjusted to 4 - 7, and then the nicotinic acid is obtained by vacuum distillation.
[0020] Since the nicotinic acid is prepared under acidic conditions, the pH is adjusted to near neutral after obtaining the nicotinic acid. If the pH is not adjusted, the nicotinic acid obtained by vacuum distillation may contain acidic components, which will reduce the amidation reaction of nicotinic acid in step (2), thereby reducing the yield of nicotinamide. Therefore, this step of adjusting the pH can avoid excessive acidic residues in the finished product of nicotinic acid, thereby improving the yield and purity of the final nicotinamide.
[0021] Optionally, the acidic condition in step (1) is provided by at least one of sulfuric acid, phosphoric acid or perchloric acid. Using the above non-reducing acid to adjust the pH will not react with nicotine and potassium permanganate, and can avoid introducing reactive impurities, thereby improving the yield and purity of nicotinic acid.
[0022] Optionally, the temperature of the amidation reaction in step (2) is 20 - 40 °C and the time is 6 - 8 h.
[0023] This reaction temperature and reaction time can, first, improve the formation rate of nicotinamide and the reaction efficiency; second, reduce the production energy consumption, thus facilitating industrial batch production. If the reaction temperature is too low or the time is too short, the formation rate of nicotinamide will decrease, resulting in a decrease in the yield of nicotinamide; if the temperature is too high, it will exceed the boiling point of the solvent, and the solvent will evaporate too fast, requiring an additional condensation reflux device, making the synthesis equipment more complex and not conducive to industrial production; if the time is too long, the improvement of the product yield is not significant, but the time consumption increases, thereby increasing the production cost.
[0024] Optionally, the condensing agent is selected from at least one of 4-(4,6-dimethoxytriazin)-4-methylmorpholine hydrochloride, dicyclohexylcarbodiimide, 1-hydroxybenzotriazole, and thionyl chloride.
[0025] Optionally, the amidating agent is selected from at least one of ammonia water, ammonium chloride, and triethylamine.
[0026] Optionally, the solvent used in the amidation reaction in step (2) is selected from at least one of water, tetrahydrofuran, ethanol, dichloromethane, and N,N-dimethylformamide.
[0027] Optionally, the condensing agent is selected from 4-(4,6-dimethoxytriazin)-4-methylmorpholine hydrochloride, the amidating agent is selected from ammonia water, and the molar ratio of nicotinic acid, 4-(4,6-dimethoxytriazin)-4-methylmorpholine hydrochloride, and ammonia water is 1:1-2:2-3.
[0028] Optionally, the condensing agent is selected from 4-(4,6-dimethoxytriazin)-4-methylmorpholine hydrochloride, the amidating agents are selected from ammonium chloride and triethylamine, and the molar ratio of nicotinic acid, 4-(4,6-dimethoxytriazin)-4-methylmorpholine hydrochloride, ammonium chloride, and triethylamine is 1:1-2:1-2:1-2.
[0029] Optionally, the condensing agents are selected from dicyclohexylcarbodiimide and 1-hydroxybenzotriazole, the amidating agent is selected from ammonia water, and the molar ratio of nicotinic acid, dicyclohexylcarbodiimide, 1-hydroxybenzotriazole, and ammonia water is 1:1-2:0.5-1:2-4.
[0030] Optionally, the molar ratio of nicotinic acid, thionyl chloride, and ammonia water is 1:5-50:5-20.
[0031] If the amount of the above condensing agent and amidating agent is too small, the yield of nicotinamide will be reduced. If the amount is too large, it will lead to an increase in production cost and greater difficulty in post-treatment.
[0032] Optionally, the yield of nicotinic acid in step (1) is not less than 80%, and the yield of nicotinamide in step (2) is not less than 58%.
[0033] Preferably, in step (1), the residual amount of nicotine is not more than 7%, and in step (2), the residual amount of nicotinic acid is not more than 21%.
[0034] According to another aspect of the present application, there is provided a nicotinamide prepared by using the method described in any one of the above.
[0035] The beneficial effects of the present application include but are not limited to:
[0036] 1. The method for synthesizing nicotinamide from nicotine in this application helps to reduce production costs and also improve the comprehensive utilization rate of tobacco extracts, thereby increasing the economic benefits of tobacco.
[0037] 2. The method for synthesizing nicotinamide from nicotine in this application uses potassium permanganate to oxidize nicotine, which not only improves the yields of nicotinic acid and subsequent nicotinamide but also avoids introducing impurities and improves the application safety of nicotinamide.
[0038] 3. Nicotine in this application is cheap and easily available, can be directly extracted from tobacco or tobacco waste, and the prepared nicotinamide has higher purity and safety, and can be widely used in the food and pharmaceutical fields, expanding the hierarchical utilization of tobacco or tobacco waste. Description of the Drawings
[0039] The drawings described herein are used to provide a further understanding of this application and form a part of this application. The schematic embodiments of this application and their descriptions are used to explain this application and do not constitute an improper limitation of this application. In the drawings:
[0040] Figure 1 It is a schematic diagram of the reaction equation involved in Examples 1-20 of this application.
[0041] Figure 2 It is the chromatogram of nicotinic acid obtained in Example 1 of this application.
[0042] Figure 3 It is the chromatogram of nicotinic acid obtained in Example 5 of this application.
[0043] Figure 4 It is the chromatogram of nicotinic acid obtained in Comparative Example 1 of this application.
[0044] Figure 5 It is the chromatogram of nicotinic acid obtained in Comparative Example 2 of this application.
[0045] Figure 6 It is the chromatogram of the crude product in Example 1 of this application.
[0046] Figure 7 It is the chromatogram of the crude product in Example 2 of this application.
[0047] Figure 8 It is the chromatogram of the crude product in Example 3 of this application.
[0048] Figure 9 It is the chromatogram of the crude product in Example 4 of this application. Detailed Embodiments
[0049] The following describes this application in detail with reference to the embodiments, but this application is not limited to these embodiments.
[0050] Unless otherwise specified, the raw materials in the embodiments of the present application are all purchased through commercial channels.
[0051] In the following embodiments, DMT-MM is the abbreviation of 4-(4,6-dimethoxytriazin)-4-methylmorpholine hydrochloride, DCC is the abbreviation of dicyclohexylcarbodiimide, and HOBt is the abbreviation of 1-hydroxybenzotriazole. The reaction equations in the following Examples 1-20 are as Figure 1 shown.
[0052] Example 1
[0053] This example relates to a method for synthesizing nicotinamide from nicotine, which includes the following steps:
[0054] (1) Add 10 mL of water to a reaction flask, add 1 mmol of nicotine under stirring, heat the reaction to 80 °C, slowly add 5 mmol of potassium permanganate solid thereto, react for 6 h, black manganese dioxide precipitate gradually forms during the reaction, filter off the precipitate after the reaction and wash it thoroughly with water, and distill off the water under reduced pressure from the filtrate to obtain nicotinic acid. The chromatogram is as Figure 2 shown;
[0055] (2) Add 1.2 mmol of DMT-MM and 5 mL of ethanol to the nicotinic acid, slowly add 2 mmol of ammonia water under stirring, and react at 25 °C for 6 h. After the reaction is completed, add water and ethanol to dissolve it fully, filter, and dry the filtrate to obtain a crude product. The chromatogram of the crude product is as Figure 6 shown. The crude product is dissolved by heating with the least amount of ethanol and recrystallized to obtain the product nicotinamide.
[0056] Example 2
[0057] This example relates to a method for synthesizing nicotinamide from nicotine, which includes the following steps:
[0058] (1) The same as in Example 1;
[0059] (2) Add 1.2 mmol of DMT-MM, 1.5 mmol of ammonium chloride, 1.5 mmol of triethylamine, and 5 mL of ethanol to the nicotinic acid, and react at 30 °C for 6 h. After the reaction is completed, add water and ethanol to dissolve it fully, filter, and dry the filtrate to obtain a crude product. The chromatogram of the crude product is as Figure 7 shown. The crude product is dissolved by heating with the least amount of ethanol and recrystallized to obtain the product nicotinamide.
[0060] Example 3
[0061] This example relates to a method for synthesizing nicotinamide from nicotine, which includes the following steps:
[0062] (1) The same as in Example 1;
[0063] (2) Add 1.2 mmol of DCC, 0.6 mmol of HOBt, 2.0 mmol of ammonia water, 4 ml of dichloromethane, and 1 mL of N,N-dimethylformamide to nicotinic acid, and react at 25 °C for 6 h. After the reaction, filter, and after the filtrate is dried, a crude product is obtained. The chromatogram of the crude product is as shown in Figure 8 shown. The crude product is dissolved in the minimum amount of ethanol by heating and recrystallized to obtain the product nicotinamide.
[0064] Example 4
[0065] This example relates to a method for synthesizing nicotinamide from nicotine, which includes the following steps:
[0066] (1) The same as in Example 1;
[0067] (2) Add 13.8 mmol of thionyl chloride to nicotinic acid and react at 25 °C for 6 h. After the reaction, remove thionyl chloride, and the precipitate reacts and undergoes ammonolysis in 14.0 mmol of ammonia water for 2 h. After the reaction, remove the ammonia water solution to obtain a crude product. The chromatogram of the crude product is as shown in Figure 9 shown. The crude product is dissolved in the minimum amount of ethanol by heating the residue and recrystallized to obtain the product nicotinamide.
[0068] Example 5
[0069] This example relates to a method for synthesizing nicotinamide from nicotine, which includes the following steps:
[0070] (1) Add 10 mL of water to a reaction flask, add sulfuric acid until the final concentration of hydrogen ions is 2 mol / L, add 1 mmol of nicotine with stirring, raise the reaction temperature to 80 °C, slowly add 5 mmol of potassium permanganate solid thereto, react for 6 h, and no precipitate is produced during the reaction. After the reaction, detect and adjust the pH value to about 4, distill off water under reduced pressure, dissolve the product in ethanol, filter, and distill off ethanol under reduced pressure to obtain nicotinic acid. The chromatogram is as shown in Figure 3 shown;
[0071] (2) The same as in Example 1, and the product nicotinamide is obtained.
[0072] Example 6
[0073] This example relates to a method for synthesizing nicotinamide from nicotine, which includes the following steps:
[0074] (1) Add 10 mL of water to a reaction flask, add phosphoric acid until the final concentration of hydrogen ions is 2 mol / L, add 1 mmol of nicotine with stirring, raise the reaction temperature to 80 °C, slowly add 5 mmol of potassium permanganate solid thereto, react for 6 h, and no precipitate is produced during the reaction. After the reaction, detect and adjust the pH value to about 4, distill off water under reduced pressure, dissolve the product in ethanol, filter, and distill off ethanol under reduced pressure to obtain nicotinic acid;
[0075] (2) It is the same as Example 2, and the product nicotinamide is obtained.
[0076] Example 7
[0077] This example relates to a method for synthesizing nicotinamide from nicotine, which includes the following steps:
[0078] (1) Add 10 mL of water to a reaction flask, add perchloric acid until the final hydrogen ion concentration is 2 mol / L, add 1 mmol of nicotine under stirring, raise the reaction temperature to 80 °C, slowly add 5 mmol of potassium permanganate solid thereto, react for 6 h, and no precipitate is produced during the reaction. After the reaction, detect and adjust the pH value to about 4, distill off the water under reduced pressure, dissolve the product with ethanol, filter, and distill off the ethanol under reduced pressure to obtain nicotinic acid;
[0079] (2) It is the same as Example 3, and the product nicotinamide is obtained.
[0080] Example 8
[0081] This example relates to a method for synthesizing nicotinamide from nicotine, which includes the following steps:
[0082] (1) It is the same as Example 5;
[0083] (2) Add 13.8 mmol of thionyl chloride to nicotinic acid and react at 25 °C for 6 h. After the reaction, distill off the thionyl chloride, and the precipitate reacts and undergoes ammonolysis in 14.0 mmol of ammonia water for 2 h. After the reaction, distill off the ammonia water solution to obtain the crude product, and the crude product is heated and dissolved with the least amount of ethanol and recrystallized to obtain the product nicotinamide.
[0084] Example 9
[0085] The difference between this example and Example 5 is that sulfuric acid is added until the final hydrogen ion concentration is 0.0001 mol / L, that is, the pH is 4, and the other steps are the same as those in Example 5, and the product nicotinamide is obtained.
[0086] Example 10
[0087] The difference between this example and Example 1 is that the amount of potassium permanganate is 3 mmol, and the other steps are the same as those in Example 1, and the product nicotinamide is obtained.
[0088] Example 11
[0089] The difference between this example and Example 1 is that the amount of potassium permanganate is 15 mmol, and the other steps are the same as those in Example 1, and the product nicotinamide is obtained.
[0090] Example 12
[0091] The difference between this example and Example 1 is that the oxidation temperature in step (1) is 60°C, and the other steps are the same as in Example 1, obtaining the product nicotinamide.
[0092] Example 13
[0093] The difference between this example and Example 1 is that the oxidation temperature in step (1) is 110°C, and a condensation reflux device is added. The other steps are the same as in Example 1, obtaining the product nicotinamide.
[0094] Example 14
[0095] The difference between this example and Example 1 is that the amidation temperature in step (2) is 50°C, and a condensation reflux device is added. The other steps are the same as in Example 1, obtaining the product nicotinamide.
[0096] Example 15
[0097] The difference between this example and Example 1 is that the amount of DMT-MM in step (2) is 0.5 mmol, and the amount of ammonia water is 4 mmol. The other steps are the same as in Example 1, obtaining the product nicotinamide.
[0098] Example 16
[0099] The difference between this example and Example 2 is that the amount of DMT-MM in step (2) is 0.5 mmol, the amount of ammonium chloride is 2.5 mmol, and the amount of triethylamine is 2.5 mmol. The other steps are the same as in Example 2, obtaining the product nicotinamide.
[0100] Example 17
[0101] The difference between this example and Example 3 is that the amount of DCC in step (2) is 0.5 mmol, the amount of HOBt is 0.6 mmol, and the amount of ammonia water is 1.5 mmol. The other steps are the same as in Example 3, obtaining the product nicotinamide.
[0102] Example 18
[0103] The difference between this example and Example 4 is that the amount of thionyl chloride in step (2) is 4 mmol, and the amount of ammonia water is 5 mmol. The other steps are the same as in Example 4, obtaining the product nicotinamide.
[0104] Example 19
[0105] This example designs a method for synthesizing nicotinamide from nicotine, including the following steps:
[0106] (1) Add 10 mL of water to a reaction flask, add 1 mmol of nicotine with stirring, raise the reaction temperature to 70 °C, slowly add 10 mmol of solid potassium permanganate thereto, react for 8 h. During the reaction, black manganese dioxide precipitate gradually forms. After the reaction, filter off the precipitate and wash it thoroughly with water. Distill off the water under reduced pressure from the filtrate to obtain nicotinic acid;
[0107] (2) Add 2.0 mmol of DMT-MM and 5 mL of ethanol to the nicotinic acid, slowly add 3 mmol of ammonia water with stirring, and react at 30 °C for 8 h. After the reaction is completed, add water and ethanol to dissolve it fully, filter, and dry the filtrate to obtain a crude product. The crude product is heated and dissolved in the least amount of ethanol and recrystallized to obtain the product nicotinamide.
[0108] Example 20
[0109] This example designs a method for synthesizing nicotinamide from nicotine, which includes the following steps:
[0110] (1) Add 10 mL of water to a reaction flask, add 1 mmol of nicotine with stirring, raise the reaction temperature to 90 °C, slowly add 4 mmol of solid potassium permanganate thereto, react for 4 h. During the reaction, black manganese dioxide precipitate gradually forms. After the reaction, filter off the precipitate and wash it thoroughly with water. Distill off the water under reduced pressure from the filtrate to obtain nicotinic acid;
[0111] (2) Add 2.0 mmol of DMT-MM, 2.0 mmol of ammonium chloride, 2.0 triethylamine and 5 mL of ethanol to the nicotinic acid, and react at 20 °C for 6 h. After the reaction is completed, add water and ethanol to dissolve it fully, filter, and dry the filtrate to obtain a crude product. The crude product is heated and dissolved in the least amount of ethanol and recrystallized to obtain the product nicotinamide.
[0112] Comparative Example 1
[0113] This example designs a method for synthesizing nicotinamide from nicotine, which includes the following steps:
[0114] (1) Add 1 mmol of nicotine to a reaction flask, slowly add 1 mL of nitric acid, stir and raise the reaction temperature to 90 °C, react for 4 h. The reaction solution gradually turns brownish-red. After the reaction, adjust the pH to about 4 with 2M NaOH, orange-red precipitate forms, filter, distill off the water under reduced pressure from the filtrate, dissolve the product with ethanol, filter, and distill off the ethanol under reduced pressure to obtain nicotinic acid and by-products. The detection chromatogram is as Figure 4 shown, and this product is used for the next reaction;
[0115] (2) Similar to Example 1, the difference is that the product needs to be purified by column chromatography to obtain the product nicotinamide.
[0116] Comparative Example 2
[0117] This embodiment designs a method for synthesizing nicotinamide from nicotine, which includes the following steps:
[0118] (1) Add 10 mL of water to a reaction flask, add 1 mmol of nicotine under stirring, add sulfuric acid until the final concentration of hydrogen ions is 2 mol / L, raise the reaction temperature to 80 °C, slowly add 15 mmol of chromium trioxide solid thereto, react for 8 h, distill off the water under reduced pressure from the filtrate, detect and adjust the pH value to about 4 after the reaction, filter, distill off the water under reduced pressure from the filtrate, dissolve the product with ethanol, filter, and distill off the ethanol under reduced pressure to obtain nicotinic acid and by-products. The detected chromatogram is as Figure 5 shown, and this product is used for the next reaction;
[0119] (2) The same as in Example 1, namely, the product nicotinamide is obtained.
[0120] Test Example 1
[0121] Calculate the yield and purity of nicotinic acid, the residual amount of nicotine in step (1) in the above-mentioned examples and comparative examples, the yield and purity of nicotinamide before recrystallization, and the residual amount of nicotinic acid in step (2). The results are shown in Table 1 below. The yield of nicotinamide in Table 1 refers to the yield of the final nicotinamide obtained by combining the calculations of step (1) and step (2).
[0122] Table 1
[0123]
[0124]
[0125] In Table 1, the residual amount of nicotinic acid in Comparative Example 1 could not be detected. The reason is that since the feeding amount of nicotine in step (1) is 1 mmol, the yield of nicotinic acid obtained by nitric acid oxidation is very low, only 19%, so the amount of nicotinic acid is 0.19 mmol, and the rest are impurities. The amidating reagent in step (2) is fed according to 1 mmol in the first step. Therefore, in step (2), for nicotinic acid, the amidating reagent is greatly in excess, so the conversion efficiency of step (2) will be very complete, and thus almost no nicotinic acid can be detected.
[0126] According to the data in Table 1, compared with Example 1, the reaction temperature in Examples 13 and 14 is increased, but the increase in temperature has little effect on the yield. However, a condensation reflux device needs to be added, and the complexity of the overall reaction increases.
[0127] Test Example 2
[0128] Because no inorganic metal elements are introduced in step (2) in each example, using inductively coupled plasma spectrometry, measure the residual amounts of potassium, manganese, and chromium elements in the crude nicotinic acid obtained by oxidizing nicotine in step (1) of Examples 1, 5, Comparative Example 1, and Comparative Example 2 above. The results are shown in Table 2 below.
[0129] Table 2
[0130] Number Residual amount of manganese element Residual amount of potassium element Residual amount of chromium element Example 1 9.09 ng / mg 154.19 ng / mg 2.61 ng / mg Example 5 7.98 μg / mg 3.35 ng / mg 8.18 ng / mg Comparative Example 1 5.90 ng / mg 0.83 ng / mg 3.20 ng / mg Comparative Example 2 0.18 ng / mg 0.06 ng / mg 323.89 μg / mg
[0131] According to the data in Table 2, it can be seen that the residual amount of manganese element in Example 5 is relatively high. However, since the recommended intake of niacin is about 300 mg, after conversion, the Mn element is about 2 mg, and this content is still within the safe range. Moreover, this manganese element can be removed by further recrystallization. Therefore, the safety performance of nicotinamide in Example 5 is still relatively high. In Comparative Example 2, the content of chromium element is relatively large. Since chromium cannot be removed by simple methods such as ethanol dissolution and recrystallization and remains in large amounts in the product, there are potential safety hazards in the nicotinamide synthesized in Comparative Example 2.
[0132] As described above, only the embodiments of the present application are given. The protection scope of the present application is not limited by these specific embodiments, but is determined by the claims of the present application. For those skilled in the art, various changes and modifications can be made to the present application. Any modification, equivalent replacement, improvement, etc. made within the technical idea and principle of the present application shall be included in the protection scope of the present application.
Claims
1. A method for synthesizing nicotinamide from nicotine, characterized in that, It includes the following steps: (1) Nicotinic acid is prepared by an oxidation reaction of nicotine and potassium permanganate under neutral or acidic conditions; (2) The nicotinic acid is subjected to an amidation reaction with an amidating agent under the activation of a condensing agent to prepare nicotinamide.
2. The method for synthesizing nicotinamide from nicotine according to claim 1, characterized in that, The temperature of the oxidation reaction in step (1) is 70 - 100 °C, and the time is 4 - 8 h.
3. The method for synthesizing nicotinamide using nicotine according to claim 1, wherein The pH value of the acidic condition in step (1) is below 2, and the hydrogen ion concentration in the solution does not exceed 2 mol / L.
4. The method for synthesizing nicotinamide using nicotine according to claim 1, characterized in that, The molar ratio of the nicotine to the potassium permanganate is 1:4 - 10.
5. The method for synthesizing nicotinamide using nicotine according to claim 1, characterized in that, The temperature of the amidation reaction in step (2) is 20 - 40 °C, and the time is 6 - 8 h.
6. The method for synthesizing nicotinamide from nicotine according to claim 1, characterized in that, The condensing agent is selected from at least one of 4-(4,6-dimethoxytriazin)-4-methylmorpholine hydrochloride, dicyclohexylcarbodiimide, 1-hydroxybenzotriazole, and thionyl chloride.
7. The method for synthesizing nicotinamide from nicotine according to claim 1, wherein The amidating agent is selected from at least one of ammonia water, ammonium chloride, and triethylamine.
8. The method for synthesizing nicotinamide from nicotine according to claim 1, wherein, The solvent used in the amidation reaction in step (2) is selected from at least one of water, tetrahydrofuran, ethanol, dichloromethane, and N,N-dimethylformamide.
9. The method for synthesizing nicotinamide from nicotine according to claim 1, wherein, The yield of the nicotinic acid in step (1) is not less than 80%, and the yield of the nicotinamide in step (2) is not less than 58%; Preferably, in step (1), the residual amount of the nicotine is not more than 7%, and in step (2), the residual amount of the nicotinic acid is not more than 21%.
10. A nicotinamide prepared by using the method according to any one of claims 1 - 9.