Preparation method for obtaining nicotinamide through emulsion layer of nicotinoyl reaction product

Abstract

The invention discloses a preparation method for obtaining nicotinamide through an emulsion layer of a nicotinoyl reaction product, which comprises the following treatment steps by utilizing the emulsion layer of the nicotinoyl reaction product: carrying out water washing treatment on the nicotinoyl reaction product for multiple times to effectively remove inorganic salt from the reaction product to obtain a relatively pure organic phase, and then, carrying out solid-liquid separation on the organic phase to obtain the nicotinamide through the emulsion layer of the nicotinoyl reaction product. The method comprises the following steps: dissolving an organic phase in a solvent, adding an emulsifier, carrying out emulsification treatment to form a stable emulsification system, carrying out layering operation, collecting an emulsification layer containing a target product nicotinamide, carrying out chemical treatment on the emulsification layer, and carrying out solvent extraction to preliminarily extract a solution containing nicotinamide to obtain the nicotinamide. Removing impurities in a solution containing nicotinamide through hydrochloric acid, carrying out chemical reaction with impurities in an emulsion layer by utilizing acidity and temperature conditions of the hydrochloric acid to form an easily separated acid layer, disappearing the emulsion layer by utilizing standing, separating out the acid layer, and then carrying out water washing treatment on an organic layer once again to thoroughly remove residual impurities.

Description

Technical Field

[0001] The present invention relates to the technical field of chemical drugs, and in particular to a preparation method for obtaining nicotinamide through an emulsified layer of a nicotinyl reaction product. Background Art

[0002] Nowadays, nicotinamide, also known as nicotinamide, is an amide compound of nicotinic acid and is widely used in biomedicine, cosmetics and other fields. Its traditional synthesis methods mainly include chemical and biological methods, while emulsification technology is a technology that forms a uniform dispersion system by mechanical or chemical methods with two or more immiscible liquids. In the preparation process, emulsifiers are usually used to reduce the interfacial tension between liquids and promote the stability of the dispersion system.

[0003] The existing traditional preparation method of nicotinamide will produce some impurities that are difficult to separate, and the purity of the product is low. In addition, the traditional multi-step synthesis method has complicated process steps, low production efficiency and extraction efficiency, and the traditional preparation process generates waste and causes pollutant emissions. Summary of the invention

[0004] The object of the present invention is to provide a method for preparing nicotinamide through an emulsified layer of a nicotinyl reaction product, so as to solve the problems that the conventional method for preparing nicotinamide proposed in the above-mentioned background technology will produce some impurities that are difficult to separate, the purity of the product is low, and the conventional multi-step synthesis method has complicated process steps, low production efficiency and extraction efficiency, and waste generated in the conventional preparation process and pollutant emissions.

[0005] To achieve the above object, the present invention provides the following technical solution: a preparation method for obtaining nicotinamide through an emulsified layer of a nicotinyl reaction product, comprising the preparation method utilizing the emulsified layer of a nicotinyl reaction product and undergoing the following chemical treatment and purification steps:

[0006] S1. Pretreatment: The nicotinoyl reaction product is washed with water for multiple times to effectively remove inorganic salts from the reaction product and obtain a relatively pure organic phase;

[0007] Afterwards, the organic phase is dissolved in a solvent, an emulsifier is added and emulsified to form a stable emulsified system, and an emulsified layer containing the target product nicotinamide is collected through a layering operation;

[0008] S2. Preliminary extraction: chemically treating the emulsified layer and preliminarily extracting a solution containing nicotinamide by a solvent extraction method;

[0009] S3. Impurity removal:

[0010] a. Add a sufficient amount of hydrochloric acid to the solution containing nicotinamide, wherein the concentration of hydrochloric acid is not less than 3%, while controlling the solution temperature in the range of 60 to 65 ° C, and stirring sufficiently (at least half an hour);

[0011] b. During the stirring process of step a, the hydrochloric acid reacts chemically with the impurities in the emulsified layer (especially the N-substituted amine generated by the substitution of 2,4-difluoroaniline and nicotinamide 2-chloro) by utilizing the acidity and temperature conditions to form an acid layer that is easily separated;

[0012] c. Allow the emulsified layer to disappear by standing, separate the acid layer, and then wash the organic layer again to completely remove the remaining impurities;

[0013] S4. Crystallization purification: The organic layer after impurity removal treatment is subjected to a cooling crystallization operation, and nicotinamide is precipitated in the form of crystals by utilizing the difference in solubility of nicotinamide at different temperatures;

[0014] S5. Drying and packaging: The separated niacinamide crystals are filtered and dried to remove residual moisture and solvent to obtain a granular, high-purity niacinamide product.

[0015] Furthermore, in the pretreatment of step S1, the inorganic salt is potassium carbonate, potassium chloride, etc., and the method for removing the inorganic salt is to utilize the high solubility of inorganic salts such as potassium carbonate and potassium chloride in water.

[0016] Furthermore, in the pretreatment of step S1, the solvent is a mixed solvent of one or more of ethanol, acetone or methanol, and the amount of the solvent is 1 to 3 times the mass of the organic phase.

[0017] Furthermore, in the pretreatment of step S1, the emulsifier is one or more of sodium dodecyl sulfate, polysorbate 80 or Tween 80, and the amount of the emulsifier is 0.5% to 2% of the mass of the organic phase.

[0018] Furthermore, in the preliminary extraction of step S2, the solvent extraction method adopts multiple extractions, and the solvent used in each extraction is one or more of ethyl acetate, dichloromethane or chloroform, and the amount of solvent used in each extraction is 0.8 to 1.2 times the volume of the emulsion layer.

[0019] Furthermore, in the impurity removal of step S3, the concentration of the hydrochloric acid in step a is 3% to 5%, and the solution temperature is controlled within the range of 60° C. to 65° C., and the stirring time is 0.5 to 1 hour;

[0020] In the impurity removal of step S3, the standing time in step c is 1 to 2 hours to ensure that the emulsified layer disappears completely and the acid layer and the organic layer are clearly separated.

[0021] Furthermore, in the crystallization purification of step S4, the temperature range of the cooling crystallization operation is -5°C to 5°C, and the crystallization time is 4 to 8 hours, during which nicotinamide crystals of different particle sizes and morphologies are obtained by controlling the crystallization temperature and crystallization time.

[0022] Furthermore, in the drying and packaging of step S5, the drying process adopts vacuum drying or hot air drying, and the drying temperature is 40° C. to 60° C., and the drying time is 2 to 4 hours to ensure that the residual moisture and solvent in the nicotinamide crystals are completely removed.

[0023] Compared with the prior art, the beneficial effects of the present invention are: the preparation method of obtaining nicotinamide through the emulsified layer of the nicotinyl reaction product has significant advantages and technical advantages in terms of efficient extraction, purity improvement, impurity removal, controllable crystallization, process optimization, environmental protection and energy saving, and provides a new, more efficient and environmentally friendly method for the preparation of nicotinamide;

[0024] 1. The present invention has efficient extraction and purification: through the emulsified layer technology, efficient extraction of nicotinamide is achieved, avoiding the cumbersome separation steps in the traditional method; multiple water washing treatments and solvent extraction methods effectively remove inorganic salts and impurities, thereby improving the purity of the product.

[0025] 2. The present invention can completely remove impurities: the specific hydrochloric acid concentration and temperature conditions, as well as sufficient stirring time, ensure the effective removal of impurities in the emulsion layer, especially the difficult-to-separate N-substituted amines. The residual impurities can be further completely removed by standing and washing again.

[0026] 3. The present invention has controllable crystallization and purification: the cooling crystallization operation utilizes the difference in solubility of nicotinamide at different temperatures to achieve controllable precipitation of nicotinamide crystals; by controlling the crystallization temperature and crystallization time, nicotinamide crystals of different particle sizes and shapes can be obtained to meet different application requirements.

[0027] 4. The present invention has process optimization and innovation: the selection and dosage of the emulsifier are optimized to improve the stability of the emulsification system and ensure the effective separation of the emulsified layer; multiple extractions of the solvent extraction method and optimization of the solvent dosage improve the extraction efficiency of nicotinamide.

[0028] 5. The present invention is environmentally friendly and sustainable: the method reduces the use of solvents and the generation of waste, which is beneficial to environmental protection; by optimizing process conditions and raw material selection, the production cost and environmental burden are reduced. DETAILED DESCRIPTION

[0029] In the description of the present invention, unless otherwise specified, "plurality" means two or more than two; the terms "upper", "lower", "left", "right", "inner", "outer", "front end", "rear end", "head", "tail" and the like indicate positions or positional relationships, which are only for the convenience of describing the present invention and simplifying the description, and do not indicate or imply that the device or element referred to must have a specific orientation, be constructed and operate in a specific orientation, and therefore cannot be understood as limiting the present invention. In addition, the terms "first", "second", "third" and the like are only used for descriptive purposes and cannot be understood as indicating or implying relative importance.

[0030] In the description of the present invention, it should be noted that, unless otherwise clearly specified and limited, the terms "connected" and "connection" should be understood in a broad sense, for example, it can be a fixed connection, a detachable connection, or an integral connection; it can be a mechanical connection or an electrical connection; it can be a direct connection or an indirect connection through an intermediate medium. For ordinary technicians in this field, the specific meanings of the above terms in the present invention can be understood according to specific circumstances.

[0031] The present invention provides a technical solution: a preparation method for obtaining nicotinamide through an emulsified layer of a nicotinyl reaction product, comprising the preparation method utilizing the emulsified layer of a nicotinyl reaction product and undergoing the following chemical treatment and purification steps:

[0032] S1. Pretreatment: The nicotinoyl reaction product is washed with water for multiple times to effectively remove inorganic salts from the reaction product and obtain a relatively pure organic phase;

[0033] Afterwards, the organic phase is dissolved in a solvent, an emulsifier is added and emulsified to form a stable emulsified system, and an emulsified layer containing the target product nicotinamide is collected through a layering operation;

[0034] S2. Preliminary extraction: chemically treating the emulsified layer and preliminarily extracting a solution containing nicotinamide by a solvent extraction method;

[0035] S3. Impurity removal:

[0036] a. Add a sufficient amount of hydrochloric acid to the solution containing nicotinamide, wherein the concentration of hydrochloric acid is not less than 3%, while controlling the solution temperature in the range of 60 to 65 ° C, and stirring sufficiently (at least half an hour);

[0037] b. During the stirring process of step a, the hydrochloric acid reacts chemically with the impurities in the emulsified layer (especially the N-substituted amine generated by the substitution of 2,4-difluoroaniline and nicotinamide 2-chloro) by utilizing the acidity and temperature conditions to form an acid layer that is easily separated;

[0038] c. Allow the emulsified layer to disappear by standing, separate the acid layer, and then wash the organic layer again to completely remove the remaining impurities;

[0039] S4. Crystallization purification: The organic layer after impurity removal treatment is subjected to a cooling crystallization operation, and nicotinamide is precipitated in the form of crystals by utilizing the difference in solubility of nicotinamide at different temperatures;

[0040] S5. Drying and packaging: filtering and drying the separated nicotinamide crystals to remove residual water and solvent to obtain a granular, high-purity nicotinamide product;

[0041] Through a specific emulsification treatment step, the nicotinamide-rich emulsion layer can be effectively separated from the nicotinyl reaction product. Subsequently, through a series of fine chemical extraction and impurity removal steps, nicotinamide can be efficiently purified, avoiding the cumbersome separation steps in traditional methods; multiple water washing treatments and solvent extraction methods effectively remove inorganic salts and impurities, thereby improving the purity of the product;

[0042] For impurities that are difficult to remove in the emulsion layer, such as N-substituted amines generated by substitution of 2,4-difluoroaniline and nicotinamide 2-chloro, specific hydrochloric acid concentration and temperature conditions, as well as sufficient stirring time, ensure the effective removal of impurities in the emulsion layer, especially N-substituted amines that are difficult to separate. By standing and washing again, the residual impurities are further thoroughly removed, which not only improves the purity of the product, but also ensures the safety and stability of the product.

[0043] The cooling crystallization operation utilizes the difference in solubility of niacinamide at different temperatures to achieve controllable precipitation of niacinamide crystals; by controlling the crystallization temperature and crystallization time, niacinamide crystals of different particle sizes and shapes can be obtained to meet different application requirements.

[0044] The selection and dosage of emulsifiers are optimized to improve the stability of the emulsification system and ensure the effective separation of the emulsified layer; multiple extractions and optimization of solvent dosage in the solvent extraction method improve the extraction efficiency of niacinamide. The preparation method has a stable process, simple operation, and is easy to realize industrial production; by optimizing the parameters and conditions of each step, the consistency and stability of product quality can be ensured to meet the needs of large-scale production.

[0045] This method reduces the use of solvents and the generation of waste, which is beneficial to environmental protection; by optimizing process conditions and raw material selection, it reduces production costs and environmental burdens, which is in line with the concepts of environmental protection and sustainable development; at the same time, through efficient purification and impurity removal steps, it also reduces the consumption of raw materials and improves resource utilization.

[0046] It is to be understood that the above embodiments are merely exemplary embodiments used to illustrate the principles of the present invention, but the present invention is not limited thereto. For those of ordinary skill in the art, various modifications and improvements can be made without departing from the spirit and essence of the present invention, and these modifications and improvements are also considered to be within the scope of protection of the present invention.

Claims

1. A method for preparing nicotinamide by an emulsified layer of a nicotinyl reaction product, characterized in that: The preparation method comprises utilizing an emulsified layer of a nicotinyl reaction product and undergoing the following chemical treatment and purification steps: S1. Pretreatment: The nicotinoyl reaction product is washed with water for multiple times to effectively remove inorganic salts from the reaction product and obtain a relatively pure organic phase; Afterwards, the organic phase is dissolved in a solvent, an emulsifier is added and emulsified to form a stable emulsified system, and an emulsified layer containing the target product nicotinamide is collected through a layering operation; S2. Preliminary extraction: chemically treating the emulsified layer and preliminarily extracting a solution containing nicotinamide by a solvent extraction method; S3. Impurity removal: a. Add a sufficient amount of hydrochloric acid to the solution containing nicotinamide, wherein the concentration of hydrochloric acid is not less than 3%, while controlling the solution temperature in the range of 60 to 65 ° C, and stirring sufficiently (at least half an hour); b. During the stirring process of step a, the hydrochloric acid reacts chemically with the impurities in the emulsified layer (especially the N-substituted amine generated by the substitution of 2,4-difluoroaniline and nicotinamide 2-chloro) by utilizing the acidity and temperature conditions to form an acid layer that is easily separated; c. Allow the emulsified layer to disappear by standing, separate the acid layer, and then wash the organic layer again to completely remove the remaining impurities; S4. Crystallization purification: The organic layer after impurity removal treatment is subjected to a cooling crystallization operation, and nicotinamide is precipitated in the form of crystals by utilizing the difference in solubility of nicotinamide at different temperatures; S5. Drying and packaging: The separated niacinamide crystals are filtered and dried to remove residual moisture and solvent to obtain a granular, high-purity niacinamide product.

2. The method for preparing nicotinamide through an emulsified layer of a nicotinyl reaction product according to claim 1, characterized in that: In the pretreatment of step S1, the inorganic salt is potassium carbonate, potassium chloride, etc., and the method for removing the inorganic salt is to utilize the high solubility of inorganic salts such as potassium carbonate and potassium chloride in water.

3. The method for preparing nicotinamide through an emulsified layer of a nicotinyl reaction product according to claim 1, characterized in that: In the pretreatment of step S1, the solvent is a mixed solvent of one or more of ethanol, acetone or methanol, and the amount of the solvent is 1 to 3 times the mass of the organic phase.

4. The method for preparing nicotinamide through an emulsified layer of a nicotinyl reaction product according to claim 1, characterized in that: In the pretreatment of step S1, the emulsifier is one or more of sodium lauryl sulfate, polysorbate 80 or Tween 80, and the amount of the emulsifier is 0.5% to 2% of the mass of the organic phase.

5. The method for preparing nicotinamide through the emulsified layer of nicotinyl reaction products according to claim 1, characterized in that: In the preliminary extraction of step S2, the solvent extraction method adopts multiple extractions, and the solvent used in each extraction is one or more of ethyl acetate, dichloromethane or chloroform, and the amount of solvent used in each extraction is 0.8 to 1.2 times the volume of the emulsion layer.

6. The method for preparing nicotinamide through an emulsified layer of nicotinyl reaction products according to claim 1, characterized in that: In the impurity removal of step S3, the concentration of hydrochloric acid in step a is 3% to 5%, and the solution temperature is controlled in the range of 60° C. to 65° C., and the stirring time is 0.5 to 1 hour; In the impurity removal of step S3, the standing time in step c is 1 to 2 hours to ensure that the emulsified layer disappears completely and the acid layer and the organic layer are clearly separated.

7. The method for preparing nicotinamide through an emulsified layer of nicotinyl reaction products according to claim 1, characterized in that: In the crystallization purification of step S4, the temperature range of the cooling crystallization operation is -5°C to 5°C, and the crystallization time is 4 to 8 hours. During this period, nicotinamide crystals of different particle sizes and morphologies are obtained by controlling the crystallization temperature and crystallization time.

8. The method for preparing nicotinamide through an emulsified layer of nicotinyl reaction products according to claim 1, characterized in that: In the drying and packaging of step S5, the drying process adopts vacuum drying or hot air drying, and the drying temperature is 40° C. to 60° C., and the drying time is 2 to 4 hours to ensure that the residual moisture and solvent in the nicotinamide crystals are completely removed.

9. A method for preparing nicotinamide by using an emulsified layer of nicotinyl reaction products according to any one of claims 1 to 9, characterized in that: The method further includes filtering the nicotinoyl reaction product before step S1 to remove large particle impurities therein, thereby further improving subsequent processing efficiency and product quality.