Preparation method of high-purity nicotinamide

Abstract

The application provides a preparation method of high-purity nicotinamide. The method comprises the following steps: mixing a solution containing nicotinamide and nicotinic acid with an alkali to obtain a mixed solution; wherein the alkali comprises one or more of alkali metal hydroxide, alkali metal carbonate and alkali metal bicarbonate; and concentrating and crystallizing the mixed solution to obtain high-purity nicotinamide. The method can reduce the content of nicotinic acid in nicotinamide and improve the purity of nicotinamide.

Description

Technical Field

[0001] This invention relates to the field of chemical synthesis technology, specifically to a method for preparing high-purity nicotinamide. Background Technology

[0002] Niacinamide and niacin are collectively known as vitamin PP. Niacin is converted into niacinamide in the human body, which is a precursor to coenzyme I (nicotinamide adenine dinucleotide, NAD) and coenzyme II (nicotinamide adenosine dinucleotide phosphate, NADP). Niacinamide can penetrate into human skin. After topical application of niacinamide, the level of coenzyme I in skin cells increases, which is evidence of transdermal absorption. As a precursor of the NADP family of coenzymes, niacinamide plays a significant role in skin improvement, manifested in the following six aspects (Bissett DL, Oblong JE, Saud A, et al. Topical niacinamide provides skin aging appearance benefits while enhancing barrier function[J]. J Clin Dermatol 2003, 32S:9–18): (1) Antioxidant capacity; (2) Epidermal barrier function: After topical application of niacinamide, the epidermal barrier function is also improved along with the improvement of keratin differentiation. At the same time, the improvement of barrier function is also reflected in reducing epidermal water loss and increasing the moisture of the stratum corneum, that is, improving moisturizing ability; (3) Improvement of erythema and pigmentation; (4) Inhibition of skin yellowing: The effect of topical niacinamide is to inhibit the oxidation process, such as protein oxidation, glycation and Maillard reaction (the increase of human skin collagen oxidation products increases 5 times from age 20 to 80), thereby inhibiting skin yellowing; (5) Fine lines and wrinkles: Niacinamide increases the level of epidermal proteins keratin, filaggrin and epidermal proteins, and increases the production of dermal matrix collagen; (6) Pigmentation: Topical application of niacinamide can effectively reduce epidermal pigmentation and reduce pigmentation spots.

[0003] Niacin interacts with receptors in the skin, resulting in a superior therapeutic effect on the skin compared to niacinamide. However, niacin receptors are G-protein-coupled receptors, and stimulation of these receptors leads to peripheral vasodilation, causing skin flushing. Most users strongly dislike this. To minimize the irritation of niacin, the niacin content in niacinamide used in cosmetics must be sufficiently low. Currently, commercially available niacinamides typically contain relatively high concentrations of niacin, for example, around 6000-8000 ppm. Therefore, reducing the niacin content in niacinamide becomes particularly important. US Patent 3678060 describes a resin method for removing niacin, but this process is complex and uneconomical.

[0004] Therefore, an effective method is still needed to remove nicotinic acid from nicotinamide to improve its purity. Summary of the Invention

[0005] To address one of the aforementioned technical problems in the prior art, this invention provides a method for preparing high-purity nicotinamide. This application has discovered that at 25°C, nicotinamide has a solubility of over 30% in water and methanol, but only 2% in anhydrous ethanol and ethyl acetate. Nicotinic acid has a solubility of approximately 1% in water. This application further discovered that the salt formed by nicotinic acid and ammonia is unstable, decomposing into nicotinic acid and ammonia at temperatures above 35°C, but its salts with alkali metals (e.g., sodium nicotinate) are very stable. Since sodium nicotinate has a solubility of over 30% in water, retaining 15-20% water in the concentrated solution during crystallization, with sodium nicotinate ultimately remaining in the mother liquor, yields nicotinamide with a low nicotinic acid content, thus improving the purity of nicotinamide. Furthermore, this invention also found that using a lower concentration of sodium hydroxide can further prevent the hydrolysis of nicotinamide.

[0006] The technical solution of the present invention is as follows:

[0007] This invention provides a method for preparing high-purity nicotinamide, the method comprising the following steps:

[0008] A feed solution containing nicotinamide and nicotinic acid is mixed with an alkali to obtain a mixture; wherein the alkali includes one or more of alkali metal hydroxides, alkali metal carbonates, and alkali metal bicarbonates.

[0009] The mixture was concentrated and crystallized to obtain high-purity nicotinamide.

[0010] In this invention, the alkali metal includes, but is not limited to, lithium, sodium, and potassium. In some embodiments, the alkali includes one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, and potassium bicarbonate. In some embodiments, the alkali includes one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, and potassium carbonate. In some embodiments, the alkali includes sodium hydroxide.

[0011] The alkali in this invention can be an aqueous solution of alkali, and the mass concentration of the alkali solution is preferably 1-10%, for example 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10% or any value between them, more preferably 3-8%.

[0012] According to some embodiments of the present invention, the amount of alkali used is such that the pH value of the mixture is 6.8-7.5.

[0013] According to some embodiments of the present invention, in the feed solution containing nicotinamide and nicotinic acid, the mass content of nicotinamide is 50-60%, and the mass content of nicotinic acid is 5000-8000 ppm.

[0014] According to some embodiments of the present invention, the concentration includes: concentrating the mixture to a nicotinamide content of 75%-90%, for example, 75%, 78%, 80%, 82%, 85%, 88%, 90% or any value between therewith, preferably 80%-88%, more preferably 82%-88%.

[0015] According to some embodiments of the present invention, the crystallization includes mixing the concentrated solution obtained after concentration with a low-carbon alcohol, and then cooling for crystallization. In the present invention, the low-carbon alcohol includes, but is not limited to, methanol. In some embodiments, the amount of the low-carbon alcohol is 3-5 times the mass of nicotinamide in the concentrated solution. In some embodiments, crystallization is carried out at a temperature of 10-30°C.

[0016] According to some embodiments of the present invention, the feed solution containing nicotinamide and nicotinic acid comprises a reaction solution obtained by reacting 3-cyanopyridine under the catalysis of cyanohydrase.

[0017] According to some embodiments of the present invention, when the feed solution containing nicotinamide and nicotinic acid is a reaction solution obtained by reacting 3-cyanopyridine under the catalysis of cyanohydrase, the method further includes: heating the mixture and subjecting it to filtration and decolorization before concentrating the mixture. In some embodiments, the heating temperature is 80-90°C. In some embodiments, the filtration includes membrane filtration, preferably using a ceramic membrane with a pore size of 100nm-200nm. In some embodiments, the decolorization treatment includes decolorization using activated carbon. In some embodiments, the decolorization treatment temperature is 60-70°C.

[0018] According to some embodiments of the present invention, the method further includes: drying the crystallized crystals to obtain the nicotinamide product; preferably, the drying is carried out under vacuum conditions.

[0019] According to some embodiments of the present invention, the method includes the following steps:

[0020] (S1) The pH of the solution containing nicotinamide and nicotinic acid is adjusted to 6.8-7.5 using a sodium hydroxide solution with a mass concentration of 1-10%, preferably 3-8%, to obtain a mixture;

[0021] (S2) The mixture is heated to 80-90℃ and filtered using a ceramic membrane with a pore size of 100nm-200nm to obtain filtrate;

[0022] (S3) The filtrate is decolorized by activated carbon and then vacuum concentrated to a nicotinamide content of 75%-90%, preferably 80%-88%. Methanol is added and the solution is cooled and crystallized to obtain wet nicotinamide. The wet nicotinamide is then vacuum dried to obtain high-purity nicotinamide.

[0023] Compared with the prior art, the present invention has the following beneficial effects:

[0024] The method of the present invention reduces the nicotinic acid content in nicotinamide by adding alkaline substances such as alkali metal hydroxides or weak acid salts to a feed solution containing nicotinamide and nicotinic acid, thereby forming nicotinic acid alkali metal salts in nicotinamide. These salts have high solubility in water and are stable and not easily decomposed at high temperatures, thus obtaining nicotinamide with high purity. Detailed Implementation

[0025] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to embodiments. The specific embodiments described herein are for illustrative purposes only and are not intended to limit the scope of the invention in any way.

[0026] Unless otherwise specified, all reagents used in the following experiments of this invention are commercially available products or reagents prepared according to conventional methods. Unless otherwise specified, all methods used in the experiments are conventional experimental methods. Unless otherwise specified, all instruments used in the experiments are commercially available.

[0027] This invention provides a method for preparing high-purity nicotinamide, comprising the following steps:

[0028] A solution containing nicotinamide and nicotinic acid is mixed with an alkali to obtain a mixture; wherein the alkali includes one or more of alkali metal hydroxides, alkali metal carbonates, and alkali metal bicarbonates.

[0029] The mixture was concentrated and crystallized to obtain high-purity nicotinamide.

[0030] In one specific embodiment, the feed solution containing nicotinamide and nicotinic acid is a reaction solution obtained by reacting 3-cyanopyridine under the catalysis of cyanohydrase.

[0031] As one specific embodiment, the preparation method includes:

[0032] (1) Adjust the pH of the solution containing nicotinamide and nicotinic acid to 7.2-7.5 using sodium hydroxide solution, and then heat it to 80-90℃ to obtain a mixed solution;

[0033] (2) Membrane filtration: While still hot, use a ceramic membrane with a pore size of 100 nm to filter and intercept the catalytic enzyme protein in the mixture to obtain filtrate;

[0034] (3) Activated carbon adsorption: Add activated carbon to the filtrate to adsorb impurities, then decarbonize and filter to obtain a clear filtrate;

[0035] (4) The filtered liquid is vacuum concentrated to a nicotinamide content of 82%-88%, then methanol is added and stirred evenly before cooling and crystallization.

[0036] Further, in step (1), the concentration of nicotinamide in the liquid containing nicotinamide and nicotinic acid is 550-600 g / L, and the content of nicotinic acid is 5000-8000 ppm.

[0037] Further, in step (3), the mass ratio of the filtrate to activated carbon is (0.5-1):100, and the decolorization temperature is 60-70℃.

[0038] Furthermore, in step (4), the ratio of the amount of methanol used to the mass of nicotinamide in the concentrated solution is (3-5):1.

[0039] Furthermore, in step (4), after stirring evenly, the temperature is lowered to 10-30℃ for crystallization.

[0040] Furthermore, in step (4), after cooling and crystallization, the wet nicotinamide product is obtained by filtration, and after vacuum drying, the finished nicotinamide product is obtained. The mother liquor can be concentrated and reused for crystallization.

[0041] The "nicotinamide enzyme catalytic solution" used in the following examples and comparative examples of the present invention is a reaction solution obtained by catalyzing 3-cyanopyridine under the catalysis of cyanohydrase (also known as "nitrile hydratase").

[0042] Example 1

[0043] Take 600 kg of nicotinamide enzyme catalytic solution (nicotinic acid content 6800 ppm, nicotinamide content 56%), adjust the pH to 6.8-7.2 using 5% sodium hydroxide solution; then heat to 80-90℃, and filter through a 100 nm ceramic membrane while hot to intercept the catalytic enzyme protein; add 5 kg of activated carbon to the obtained clear solution, stir evenly while hot, continue stirring for 0.5 h, then decarbonize and filter to obtain a clear filtrate. The decolorization temperature is 60-70℃. Vacuum concentrate the clear filtrate until the nicotinamide content is 85%, then add 1000 kg of methanol and stir evenly, then begin cooling and crystallization at 10-30℃; after cooling and crystallization, filter to obtain wet nicotinamide, which is then vacuum dried to obtain the finished nicotinamide product. The mother liquor can be concentrated and reused for crystallization. The obtained nicotinamide has a purity of 99.8%, with 13 ppm of residual nicotinic acid.

[0044] Example 2

[0045] Take 600 kg of nicotinamide enzyme catalytic solution (nicotinic acid content 6800 ppm, nicotinamide content 56%), adjust the pH to 6.8-7.2 using 5% sodium hydroxide solution; then heat to 80-90℃, and filter the solution while hot using a 100 nm ceramic membrane to intercept the catalytic enzyme protein; add 5 kg of activated carbon to the obtained clear solution, stir evenly while hot, continue stirring for 0.5 h, then decarbonize and filter to obtain a clear filtrate. The decolorization temperature is 60-70℃. Vacuum concentrate the clear filtrate until the nicotinamide content is 90%, then add 1000 kg of methanol and stir evenly, then begin cooling and crystallization at 10-30℃; after cooling and crystallization, filter to obtain wet nicotinamide, which is then vacuum dried to obtain the finished nicotinamide product. The mother liquor can be concentrated and reused for crystallization. The obtained nicotinamide has a purity of 98.3%, and the residual nicotinic acid is 1650 ppm.

[0046] Example 3

[0047] Take 600 kg of nicotinamide enzyme catalytic solution (nicotinic acid content 6800 ppm, nicotinamide content 56%), adjust the pH to 6.8-7.2 using 5% sodium hydroxide solution; then heat to 80-90℃, and filter through a 100 nm ceramic membrane while hot to intercept the catalytic enzyme protein; add 5 kg of activated carbon to the obtained clear solution, stir evenly while hot, continue stirring for 0.5 h, then decarbonize and filter to obtain a clear filtrate. The decolorization temperature is 60-70℃. Vacuum concentrate the clear filtrate until the nicotinamide content is 80%, then add 1000 kg of methanol and stir evenly, then begin cooling and crystallization at 10-30℃; after cooling and crystallization, filter to obtain wet nicotinamide, which is then vacuum dried to obtain the finished nicotinamide product. The mother liquor can be concentrated and reused for crystallization. The obtained nicotinamide has a purity of 97.1% and nicotinic acid residue of 11 ppm.

[0048] Example 4

[0049] Take 600 kg of nicotinamide enzyme catalytic solution (nicotinic acid content 6800 ppm, nicotinamide content 56%), adjust the pH to 6.8-7.2 using 5% sodium hydroxide solution; then heat to 80-90℃, and filter through a 100 nm ceramic membrane while hot to intercept the catalytic enzyme protein; add 5 kg of activated carbon to the obtained clear solution, stir evenly while hot, continue stirring for 0.5 h, then decarbonize and filter to obtain a clear filtrate. The decolorization temperature is 60-70℃. Vacuum concentrate the clear filtrate until the nicotinamide content is 75%, then add 1000 kg of methanol and stir evenly, then begin cooling and crystallization at 10-30℃; after cooling and crystallization, filter to obtain wet nicotinamide, which is then vacuum dried to obtain the finished nicotinamide product. The mother liquor can be concentrated and reused for crystallization. The obtained nicotinamide has a purity of 96.5%, with 12 ppm of residual nicotinic acid.

[0050] Example 5

[0051] Take 600 kg of nicotinamide enzyme catalytic solution (nicotinic acid content 6800 ppm, nicotinamide content 56%), adjust the pH to 6.8-7.2 using 5% sodium hydroxide solution; then heat to 80-90℃, and filter through a 100 nm ceramic membrane while hot to intercept the catalytic enzyme protein; add 5 kg of activated carbon to the obtained clear solution, stir evenly while hot, continue stirring for 0.5 h, then decarbonize and filter to obtain a clear filtrate. The decolorization temperature is 60-70℃. Vacuum concentrate the clear filtrate until the nicotinamide content is 95%, then add 1000 kg of methanol and stir evenly, then begin cooling and crystallization at 10-30℃; after cooling and crystallization, filter to obtain wet nicotinamide, which is then vacuum dried to obtain the finished nicotinamide product. The mother liquor can be concentrated and reused for crystallization. The obtained nicotinamide has a purity of 96.5%, and the residual nicotinic acid is 5600 ppm.

[0052] Example 6

[0053] Take 600 kg of nicotinamide enzyme catalytic solution (nicotinic acid content 6800 ppm, nicotinamide content 56%), adjust the pH to 6.8-7.2 using a 5% sodium carbonate solution; then heat to 80-90℃, and filter through a 100 nm ceramic membrane while hot to intercept the catalytic enzyme protein; add 5 kg of activated carbon to the obtained clear solution, stir evenly while hot, continue stirring for 0.5 h, then decarbonize and filter to obtain a clear filtrate. The decolorization temperature is 60-70℃. Vacuum concentrate the clear filtrate until the nicotinamide content is 85%, then add 1000 kg of methanol and stir evenly, then begin cooling and crystallization at 10-30℃; after cooling and crystallization, filter to obtain wet nicotinamide, which is then vacuum dried to obtain the finished nicotinamide product. The mother liquor can be concentrated and reused for crystallization. The obtained nicotinamide has a purity of 99.7%, with 13 ppm of residual nicotinic acid.

[0054] Example 7

[0055] Take 600 kg of nicotinamide enzyme catalytic solution (nicotinic acid content 6800 ppm, nicotinamide content 56%), adjust the pH to 6.8-7.2 using a 5% potassium hydroxide solution; then heat to 80-90℃, and filter through a 100 nm ceramic membrane while hot to intercept the catalytic enzyme protein; add 5 kg of activated carbon to the obtained clear solution, stir evenly while hot, continue stirring for 0.5 h, then decarbonize and filter to obtain a clear filtrate. The decolorization temperature is 60-70℃. Vacuum concentrate the clear filtrate until the nicotinamide content is 85%, then add 1000 kg of methanol and stir evenly, then begin cooling and crystallization at 10-30℃; after cooling and crystallization, filter to obtain wet nicotinamide, which is then vacuum dried to obtain the finished nicotinamide product. The mother liquor can be concentrated and reused for crystallization. The obtained nicotinamide has a purity of 99.8%, with 13 ppm of residual nicotinic acid.

[0056] Example 8

[0057] Take 600 kg of nicotinamide enzyme catalytic solution (nicotinic acid content 6800 ppm, nicotinamide content 56%), adjust the pH to 6.8-7.2 using 20% ​​sodium hydroxide solution; then heat to 80-90℃, and filter through a 100 nm ceramic membrane while hot to intercept the catalytic enzyme protein; add 5 kg of activated carbon to the obtained clear solution, stir evenly while hot, continue stirring for 0.5 h, then decarbonize and filter to obtain a clear filtrate. The decolorization temperature is 60-70℃. Vacuum concentrate the clear filtrate until the nicotinamide content is 85%, then add 1000 kg of methanol and stir evenly, then begin cooling and crystallization at 10-30℃; after cooling and crystallization, filter to obtain wet nicotinamide, which is then vacuum dried to obtain the finished nicotinamide product. The mother liquor can be concentrated and reused for crystallization. The obtained nicotinamide has a purity of 96.6%, and the residual nicotinic acid is 5361 ppm.

[0058] Comparative Example 1

[0059] Take 600 kg of nicotinamide enzyme catalytic solution (nicotinic acid content 6800 ppm, nicotinamide content 56%), adjust the pH to 6.8-7.2 using 5% ammonia water; then heat to 80-90℃, and filter through a 100 nm ceramic membrane while hot to intercept the catalytic enzyme protein; add 5 kg of activated carbon to the obtained clear solution, stir evenly while hot, continue stirring for 0.5 h, then decarbonize and filter to obtain a clear filtrate. The decolorization temperature is 60-70℃. Vacuum concentrate the clear filtrate until the nicotinamide content is 85%, then add 1000 kg of methanol and stir evenly, then begin cooling and crystallization at 10-30℃; after cooling and crystallization, filter to obtain wet nicotinamide, which is then vacuum dried to obtain the finished nicotinamide product. The mother liquor can be concentrated and reused for crystallization. The obtained nicotinamide has a purity of 96.3%, and the residual nicotinic acid is 13652 ppm.

[0060] Comparative Example 2

[0061] Take 600 kg of nicotinamide enzyme catalytic solution (nicotinic acid content 6800 ppm, nicotinamide content 56%), adjust the pH to 8.0 using a 5% potassium hydroxide solution; then heat to 80-90℃, and filter through a 100 nm ceramic membrane while hot to intercept the catalytic enzyme protein; add 5 kg of activated carbon to the obtained clear solution, stir evenly while hot, continue stirring for 0.5 h, then decarbonize and filter to obtain a clear filtrate. The decolorization temperature is 60-70℃. Vacuum concentrate the clear filtrate until the nicotinamide content is 85%, then add 1000 kg of methanol and stir evenly, then begin cooling and crystallization at 10-30℃; after cooling and crystallization, filter to obtain wet nicotinamide, which is then vacuum dried to obtain the finished nicotinamide product. The mother liquor can be concentrated and reused for crystallization. The obtained nicotinamide has a purity of 93.6%, and the residual nicotinic acid is 36352 ppm.

[0062] The technical solutions of the present invention are not limited to the specific embodiments described above. Any technical modifications made in accordance with the technical solutions of the present invention fall within the protection scope of the present invention.

Claims

1. A method for preparing high-purity nicotinamide, comprising the following steps: A solution containing nicotinamide and nicotinic acid is mixed with an alkali to obtain a mixture; the mixture is concentrated, and the concentrated solution is mixed with a low-carbon alcohol, and then cooled and crystallized to obtain high-purity nicotinamide. in, The feed solution containing nicotinamide and nicotinic acid is a reaction solution obtained by reacting 3-cyanopyridine under the catalysis of cyanohydrase; in the feed solution containing nicotinamide and nicotinic acid, the mass content of nicotinamide is 50-60%, and the mass content of nicotinic acid is 5000-8000 ppm. The alkali is one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, and potassium carbonate; The amount of alkali used is sufficient to make the pH of the mixture 6.8-7.5; The mass concentration of the alkali is 1-10%; The concentration involves concentrating the mixture to a nicotinamide mass content of 75%-88%. The low-carbon alcohol is methanol; the amount of the low-carbon alcohol used is 3-5 times the mass of nicotinamide in the concentrated solution; Cool down to 10-30℃ to crystallize.

2. The preparation method according to claim 1, characterized in that, The alkali is sodium hydroxide.

3. The preparation method according to claim 1, characterized in that, The mass concentration of the alkali is 3-8%; the concentration is to concentrate the mixture to a nicotinamide mass content of 82%-88%.

4. The preparation method according to claim 1, characterized in that, The method further includes heating the mixture and filtering and decolorizing it before concentrating it.

5. The preparation method according to claim 4, characterized in that, The heating temperature is 80-90℃.

6. The preparation method according to claim 4, characterized in that, The filtration includes membrane filtration; filtration is performed using a ceramic membrane with a pore size of 100nm-200nm.

7. The preparation method according to claim 4, characterized in that, The decolorization process includes decolorization using activated carbon.

8. The preparation method according to claim 4, characterized in that, The decolorization process is carried out at a temperature of 60-70℃.

9. The preparation method according to claim 4, characterized in that, The method further includes drying the crystals after crystallization to obtain the nicotinamide product.

10. The preparation method according to claim 1, characterized in that, The method includes the following steps: (S1) Adjust the pH of the solution containing nicotinamide and nicotinic acid to 6.8-7.5 using a sodium hydroxide solution with a mass concentration of 1-10% to obtain a mixed solution; (S2) The mixture is heated to 80-90℃ and filtered using a ceramic membrane with a pore size of 100nm-200nm to obtain filtrate; (S3) The filtrate is decolorized by activated carbon and then vacuum concentrated to a nicotinamide content of 82%-88%. After adding methanol, it is cooled and crystallized to obtain wet nicotinamide. The wet nicotinamide is then vacuum dried to obtain high-purity nicotinamide.

11. The preparation method according to claim 10, characterized in that, The mass concentration of the sodium hydroxide solution is 3-8%.