Preparation process of methyl nicotinate

Abstract

The invention discloses a preparation process for synthesizing methyl nicotinate, and belongs to the field of chemical synthesis. The methyl nicotinate synthesis method provided by the invention comprises the following steps: taking nicotinamide as an initial raw material and water as a solvent, reacting nicotinamide with methanol under the catalysis of solid alkali to generate a methyl nicotinate crude product, adding the obtained crude product into a toluene solution, heating to dissolve the crude product, filtering while the crude product is hot, slowly cooling filtrate until white crystals are separated out, and drying to obtain the methyl nicotinate. The crystals are washed with cold methylbenzene, the washed crystals are dried at low temperature, methyl nicotinate is obtained, the yield is 95.56%, and the purity is 95.22%. The synthesis method disclosed by the invention has the advantages of reasonable process, high reaction yield, low production cost, less three wastes and simple post-treatment.

Description

Technical Field

[0001] The invention relates to the technical field of pharmaceutical raw material synthesis, and in particular to a preparation process of methyl nicotinate. Background Art

[0002] Nicotinate methyl ester, also known as pyridine-3-carboxylic acid methyl ester or 3-pyridinecarboxylic acid methyl ester, is an organic compound with a chemical formula of C7H7NO2, a molecular weight of 137.14, and a density of 1.2528 g / cm 3 , boiling point 204℃, melting point 38-44℃, flash point 95℃, colorless crystals or white crystals with a slight sour taste and a unique tobacco smell.

[0003] Methyl nicotinate has a wide range of uses. It is often used in the fields of medicine and cosmetics in daily life. In the medical field, it is mainly used to dilate skin capillaries, increase blood flow, and thus promote blood circulation. At the same time, it can also dilate blood vessels, improve local blood flow, reduce inflammation and pain, and is suitable for muscle soreness, joint pain, etc. In the field of cosmetics, methyl nicotinate helps other ingredients penetrate the skin better and improve product effects. In addition, in the field of drug synthesis, methyl nicotinate can also increase blood flow, which may help improve the appearance of the skin.

[0004] The literature (Canadian Journal of Chemistry, 1994, 72(1):142-145.) reported that nicotinate methyl ester was obtained by refluxing in a hydrochloric acid (1.0 equiv) aqueous solution for 1.2 h using TiCl4 as a catalyst.

[0005]

[0006] This method has a simple reaction, but the required catalyst TiCl4 is highly active and easily reacts with air and water, making the experimental conditions more harsh. It is also highly toxic and is not conducive to industrial production.

[0007] The literature (European Journal of Organic Chemistry, 2007, 6: 1026-1030) reports a process for converting nicotinamide into the corresponding nicotinic acid methyl ester via a sulfenamide intermediate in the presence of excess methanol using thionyl chloride as a catalyst.

[0008]

[0009] This method has complex reactions and numerous processes, and the required catalyst SOCl2 is highly toxic, corrosive and irritating. It reacts violently with water and easily decomposes and releases toxic gases at high temperatures, which is not conducive to industrial production.

[0010] The literature (Bulletin of the Chemical Society of Japan. 1994, 67(6): 1750 - 1761.) reported that using tetraethoxytellurium [Te(OEt)4] as a catalyst, a primary amide was converted into a mixture of nitrile and ester through two intermediates [C - triethoxytelluroxyimine (1) and N - triethoxytelluramide (2)]. The oxygen - linked intermediate provided nitrile upon thermal decomposition, while the nitrogen - linked intermediate gave an ester upon addition of an alcohol.

[0011]

[0012] The reaction conditions are complex and are extremely sensitive to temperature. At 80 °C, esters are mainly formed, and at higher temperatures, nitriles are formed.

[0013] The literature (Tetrahedron Lett, 1997, 38(13): 2367 - 2368) reported that nicotinamide reacted with N,N - dimethylformamide dimethyl acetal (DMF - DMA) to obtain the corresponding N - acylformamidine, and then methyl nicotinate was obtained by treating it with methanol at room temperature.

[0014]

[0015] The reaction conditions of this reaction are complex, and the required raw materials are difficult to prepare, which is not conducive to industrial production.

[0016] In summary, the existing synthesis methods generally have problems such as high toxicity of the catalyst, harsh reaction conditions, and many by - products, making it difficult to meet the requirements of industrial production. There is a need to develop more economical, effective, and safe synthesis technologies. Summary of the Invention

[0017] The novel method for synthesizing methyl nicotinate provided by the present invention is to use nicotinamide as the starting material and react with methanol under the catalysis of a solid - base catalyst to produce methyl nicotinate.

[0018]

[0019] The present invention provides a preparation process for methyl nicotinate, which is realized through the following technical solutions:

[0020] (1) Using nicotinamide as the raw material, water as the solvent, stirring to dissolve it fully, reacting with methanol at 45 °C - 55 °C for 10 hours under the catalysis of a solid base, and after the reaction is completed, filtering and separating to obtain the crude product of methyl nicotinate;

[0021] (2) Add the obtained crude product into toluene solvent, heat to dissolve it, and filter while it is hot. Slowly cool the filtrate until white crystals precipitate. Wash the crystals with a small amount of cold toluene to remove the adsorbed substances on the surface, and dry the washed crystals at low temperature overnight to obtain methyl nicotinate product;

[0022] (3) After washing and drying the filter cake obtained by filtration with distilled water, the recovered solid base catalyst can be obtained.

[0023] In the step (1), the addition amount of solvent water is 2 - 3 times the molar amount of nicotinamide, preferably 2.5 times; the reaction temperature in the step (1) is 45°C - 55°C; the molar ratio of nicotinamide to methanol in the step (1) is 1:1.5 - 2.0; the solid base catalyst in the step (1) is LaCoO3 or La 0.8 Ce 0.2 CoO3, and the addition amount of the solid base catalyst is 0.1 - 1% of the mass of nicotinamide.

[0024] The traditional method for preparing methyl nicotinate from nicotinamide has harsh reaction conditions, a complex reaction process, and a highly toxic catalyst, which is not conducive to industrial production. The reaction of the present invention is safe and reliable, with low cost. The raw materials and catalysts used are simple and easily available, and the obtained product has high purity, showing good industrial prospects.

[0025] The beneficial effects of the present invention:

[0026] (1) Mild reaction conditions and environmentally friendly. The present invention uses a La-based solid base catalyst to replace the traditional highly toxic catalyst (such as TiCl4). The reaction is carried out under normal pressure at 45 - 55°C, without the need for strong acids or high temperatures, significantly reducing the safety risk and environmental pollution, and meeting the requirements of green chemical industry.

[0027] (2) High product yield and high purity. By optimizing the solvent ratio and reaction parameters, the yield of methyl nicotinate can reach 95.56%, the purity can reach 95.22%, and there are few by-products, without the need for complex purification steps, meeting the requirements of the pharmaceutical and cosmetic fields for high-purity raw materials.

[0028] (3) The catalyst can be recycled, with prominent cost advantages. The solid base catalyst can be recycled by simple filtration, washing with water and drying. After being reused 5 times, the activity decay is <5%, significantly reducing the consumption of precious metals and waste emissions, reducing the comprehensive production cost, and having significant industrial application value. Specific embodiments

[0029] Preparation of solid base catalyst:

[0030] Weigh 0.32 g of lanthanum nitrate and 0.18 g of cobalt nitrate, dissolve them separately in deionized water, and then mix and stir well. Add 1.17 g of EDTA and stir until completely dissolved. Stir continuously at 80 °C until a gel is formed. Dry the gel in an oven at 120 °C for 12 hours to obtain a dry gel, and grind it into a fine powder. Pre-calcine the powder at 300 °C for 3 hours. Calcinate the pre-calcined powder at a high temperature of 700 °C for 5 hours. Naturally cool the calcined sample to room temperature. Grind it into a fine powder to obtain the final LaCoO3 catalyst.

[0031] Weigh 0.32 g of lanthanum nitrate, 0.32 g of cerium nitrate and 0.18 g of cobalt nitrate, dissolve them separately in deionized water, and then mix and stir well. Add 1.75 g of EDTA and stir until completely dissolved. Adjust the pH value of the solution to neutral with ammonia water. Heat and stir the solution to 80 °C to form a gel. Dry the gel in an oven at 120 °C for 12 hours to obtain a dry gel, and grind it into a fine powder. Pre-calcine the powder at 300 °C for 3 hours. Calcinate the pre-calcined powder at 700 °C for 5 hours. Naturally cool the calcined sample to room temperature. Grind it into a fine powder to obtain the La 0.8 Ce 0.3 CoO3 catalyst.

[0032] Example 1: Add nicotinamide (6.11 g, 0.05 mol, 1.0 eq) and distilled water (5 mL) to a 100 mL three-necked flask and dissolve them completely. Add the solid base catalyst La 0.8 Ce 0.2 CoO3 (0.06 g) and methanol (2.4 g, 0.075 mol, 1.5 eq), and react at 55 °C for 10 h. After the reaction is completed, filter and dry to obtain a crude product of methyl nicotinate. Recrystallize the obtained crude product with toluene (50 mL) to obtain methyl nicotinate with a yield of 91.16% and a purity of 92.58%

[0033] Example 2: Add nicotinamide (6.11 g, 0.05 mol, 1.0 eq) and distilled water (5 mL) to a 100 mL three-necked flask and dissolve them completely. Add the solid base catalyst La 0.8 Ce 0.2 CoO3 (0.06 g) and methanol (3.2 g, 0.1 mol, 2.0 eq), and react at 55 °C for 10 h. After the reaction is completed, filter and dry to obtain a crude product of methyl nicotinate. Recrystallize the obtained crude product with toluene (50 mL) to obtain methyl nicotinate with a yield of 95.14% and a purity of 95.68%

[0034] Example 3: Add nicotinamide (6.11 g, 0.05 mol, 1.0 eq) and distilled water (5 mL) to a 100 mL three-necked flask and dissolve them completely. Add the solid base catalyst La 0.8 Ce 0.2CoO3 (0.06 g) and methanol (3.2 g, 0.1 mol, 2.0 eq) were reacted at 45 °C for 10 h. After the reaction was completed, the crude product of methyl nicotinate was obtained by filtration and drying. The obtained crude product was recrystallized with toluene (50 mL) to obtain methyl nicotinate with a yield of 94.26% and a purity of 94.72%

[0035] Example 4: Add nicotinamide (6.11 g, 0.05 mol, 1.0 eq) and distilled water (5 mL) to a 100 mL three-necked flask and completely dissolve it. Add the solid base catalyst LaCoO3 (0.06 g) and methanol (2.4 g, 0.075 mol, 1.5 eq), and react at 45 °C for 10 h. After the reaction was completed, the crude product of methyl nicotinate was obtained by filtration and drying. The obtained crude product was recrystallized with toluene (50 mL) to obtain methyl nicotinate with a yield of 90.42% and a purity of 92.14%

[0036] Example 5: Add nicotinamide (6.11 g, 0.05 mol, 1.0 eq) and distilled water (5 mL) to a 100 mL three-necked flask and completely dissolve it. Add the solid base catalyst La 0.8 Ce 0.2 CoO3 (0.06 g) and methanol (2.4 g, 0.075 mol, 2.0 eq), and react at 55 °C for 10 h. After the reaction was completed, the crude product of methyl nicotinate was obtained by filtration and drying. The obtained crude product was recrystallized with toluene (50 mL) to obtain methyl nicotinate with a yield of 95.02% and a purity of 95.20%

[0037] Comparative Example 1: Add nicotinamide (6.11 g, 0.05 mol, 1.0 eq) and distilled water (5 mL) to a 100 mL three-necked flask and completely dissolve it. Add the solid base catalyst La 0.8 Ce 0.2 CoO3 (0.06 g) and methanol (3.2 g, 0.1 mol, 2.0 eq), and react at 35 °C for 10 h. After the reaction was completed, the crude product of methyl nicotinate was obtained by filtration and drying. The obtained crude product was recrystallized with toluene (50 mL) to obtain methyl nicotinate with a yield of 76.06% and a purity of 81.56%. Comparative Example 2: Add nicotinamide (6.11 g, 0.05 mol, 1.0 eq) and distilled water (5 mL) to a 100 mL three-necked flask and completely dissolve it. Add the solid base catalyst La 0.8 Ce 0.2CoO3 (0.06 g) and methanol (1.6 g, 0.05 mol, 1.0 eq) were reacted at 45 °C for 10 h. After the reaction was completed, the crude product of methyl nicotinate was obtained by filtration and drying. The obtained crude product was recrystallized with toluene (50 mL) to obtain methyl nicotinate with a yield of 61.02% and a purity of 76.16%. Comparative Example 3: Nicotinamide (6.11 g, 0.05 mol, 1.0 eq) and distilled water (5 mL) were added to a 100 mL three-necked flask and completely dissolved. Methanol (3.2 g, 0.1 mol, 2.0 eq) was added and reacted at 45 °C for 10 h. After the reaction was completed, the crude product of methyl nicotinate was obtained by filtration and drying. The obtained crude product was recrystallized with toluene (50 mL) to obtain methyl nicotinate with a yield of 43.70% and a purity of 51.52%

[0038] Comparative Example 4: Nicotinamide (6.11 g, 0.05 mol, 1.0 eq) and distilled water (5 mL) were added to a 100 mL three-necked flask and completely dissolved. TiCl4 (0.06 g), HCl (1.825 g, 0.05 mol, 1.0 eq) and methanol (3.2 g, 0.1 mol, 2.0 eq) were added and reacted at 45 °C for 10 h. After the reaction was completed, the crude product of methyl nicotinate was obtained by filtration and drying. The obtained crude product was recrystallized with toluene (50 mL) to obtain methyl nicotinate with a yield of 76.86% and a purity of 85.44%

[0039] Although the specific embodiments of the present invention have been described above, it is not a limitation to the protection scope of the present invention. Those skilled in the art should understand that various modifications or deformations that can be made without creative labor on the basis of the technical solution of the present invention are still within the protection scope of the present invention.

Claims

1. A method for preparing methyl nicotinate, characterized in that, The preparation method includes: (1) Using nicotinamide as the raw material, water as the solvent, stirring to fully dissolve it, reacting with methanol for 8 - 12 h under the catalysis of solid base, and filtering and separating after the reaction to obtain the crude product of methyl nicotinate; (2) Adding the obtained crude product into toluene solvent, heating to dissolve it, filtering while it is hot, slowly cooling the filtrate until white crystals precipitate, washing the crystals with cold toluene to remove the surface adsorbed substances, and drying the washed crystals at low temperature overnight to obtain the methyl nicotinate product; (3) After washing and drying the filter cake obtained by filtration, the recovered solid base catalyst can be obtained.

2. The preparation method of methyl nicotinate according to claim 1, wherein, The amount of water added as the solvent in step (1) is 2 - 3 times the molar amount of nicotinamide.

3. The preparation method of methyl nicotinate according to claim 1, characterized in that, The reaction temperature in step (1) is 45 °C - 55 °C.

4. The preparation method of methyl nicotinate according to claim 1, characterized in that, The molar ratio of nicotinamide to methanol in step (1) is 1:1.5 - 2.

0.

5. The preparation method of methyl nicotinate according to claim 1, characterized in that, The solid base catalyst in the step (1) is LaCoO3 or La 0.8 Ce 0.2 CoO3, and the addition amount of the solid base catalyst is 0.1-1% of the mass of nicotinamide.

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