Synthesis method of dihydrooat alkaloid

Abstract

The invention relates to the technical field of fine chemical synthesis, and discloses a method for synthesizing dihydrooat alkaloid, which comprises the following steps: step (1): dissolving raw materials; (2) carrying out primary heating reaction; (3) carrying out secondary heating and tert-butyl removal reaction; (4) carrying out quenching reaction and alkali dissolution treatment; (5) adjusting the pH value, and separating and purifying the product; according to the method, a high-toxicity acylation reagent in a traditional synthesis route is abandoned, the equipment maintenance frequency and the cost investment are reduced, the production continuity and stability are guaranteed, moreover, as the high-toxicity reagent is not used any more, the safety in the production process is greatly improved, the potential threat to the health of operators is reduced, the investment in the aspect of labor protection is reduced, and the method is suitable for industrial production. Compared with a method needing lengthy oxidation and acylation condensation treatment, the method has the advantages that the reaction steps and conditions are optimized, the reaction time is shortened, the synthesis period as long as several hours or even dozens of hours is greatly shortened, and the production efficiency is effectively improved.

Description

Technical Field

[0001] The invention relates to the technical field of fine chemical synthesis, in particular to a method for synthesizing dihydroavenate alkaloids. Background Art

[0002] In modern society, with the significant improvement of living standards, consumers are paying more and more attention to skin health, and the demand for daily chemical products that can protect the skin and solve skin problems is becoming more diversified and refined. Dihydroavenate alkaloids, precious extracts from natural oats, have become a hot star ingredient in the field of daily chemical products due to their excellent biological activity.

[0003] Its chemical structure is exquisite and unique, and it has a very similar structure to the antihistamine drug troniest, which is well-known in the medical field and widely used in anti-allergy treatment. This structural homology gives dihydrooatmeal alkaloids remarkable efficacy: on the one hand, it can accurately target the skin's histamine receptors, just like pressing the "pause button" for the histamine reaction, effectively blocking the allergic cascade caused by histamine, soothing the skin's itching, redness and swelling and other allergic symptoms from the root, bringing immediate comfort to people with sensitive skin; on the other hand, on the anti-oxidation front, it is like a loyal guard, always alert to the invasion of free radicals from the outside world. Free radicals, as one of the "culprits" of skin aging, are always trying to destroy the normal structure and function of skin cells. Dihydrooatmeal alkaloids, with their own antioxidant properties, can capture and neutralize these free radicals in time, effectively delay the aging process of the skin, and maintain the youthful vitality of the skin. Furthermore, when the skin is stimulated by external factors such as ultraviolet rays, pollution particles, irritating chemical ingredients, etc., dihydrooat alkaloids quickly activate the anti-irritation mechanism, strengthen the skin's own barrier function, help the skin resist damage, and quickly recover to a stable state. At the same time, it also has excellent anti-inflammatory and antipruritic abilities, which can effectively reduce the skin's inflammatory response, relieve the unbearable itching caused by inflammation, and significantly improve the symptoms of erythema, allowing the skin to return to a uniform and translucent state. Based on these excellent effects, dihydrooat alkaloids are widely used in daily chemical products such as skin care products and cosmetics, and have become the core ingredient for creating highly effective anti-allergic and soothing products, and are deeply trusted and favored by consumers.

[0004] However, there are always two sides to a coin. While dihydroavenate alkaloids have attracted much attention, their synthesis process faces severe challenges. The current mainstream synthesis route in the industry is in deep trouble and has many defects that cannot be ignored.

[0005] First, we focus on the traditional synthesis method using p-hydroxyphenylpropionic acid and methyl anthranilate as raw materials. In actual operation, this route has to rely on highly toxic acylating agents to promote the reaction process. These acylating agents are like a "double-edged sword" in the chemical world. While helping chemical reactions to occur, they also bring devastating blows to production equipment. They are extremely corrosive, like "demons" hidden in the dark, quietly corroding the metal surface of the equipment, causing serious corrosion pits and thinning of the pipe wall in the key components of the equipment, greatly shortening the normal service life of the equipment. In order to maintain production, companies have to frequently repair and replace parts of the equipment, which undoubtedly makes the equipment maintenance cost soar like a rocket. What's more tricky is that the raw material conversion rate of this method is extremely low. A large amount of precious raw materials cannot be effectively converted into the target product during the reaction process, and can only be treated as waste helplessly, resulting in serious waste of raw materials, which directly leads to high production costs and continuous compression of corporate profit margins.

[0006] Then we turn our attention to another synthetic route using p-hydroxyphenylpropionaldehyde and methyl anthranilate as raw materials. This route seems to be a different approach, but it actually hides a mystery. It requires the use of an oxidizing agent at the beginning of the reaction to first oxidize the aldehyde group to a carboxyl group before entering the key step of acylation condensation. This process is like a tedious chemical "marathon". The entire reaction process is long and complicated, involving many intermediate steps and fine control of operating conditions. Each step of the reaction takes a lot of time to ensure that the reaction is fully carried out. From the pretreatment of raw materials, the precise regulation of the oxidation reaction, to the long wait for the subsequent acylation condensation, the accumulated reaction time is often several hours or even longer. Such a slow production rhythm has greatly reduced production efficiency, making it difficult for enterprises to face the growing demand for dihydrooat alkaloids in the market. It is difficult to supply high-quality products on time and in sufficient quantities, which seriously restricts the pace of development of the industry and puts many daily chemical companies in a passive situation in product innovation and market competition. Therefore, a method for synthesizing dihydrooat alkaloids is proposed to solve the above problems. Summary of the invention

[0007] 1. Technical issues to be resolved

[0008] In view of the deficiencies of the prior art, the present invention provides a method for synthesizing dihydroavenate alkaloids, which solves the problems raised in the above-mentioned background technology.

[0009] (II) Technical solution

[0010] To achieve the above object, the present invention provides the following technical solution: a method for synthesizing dihydroavenate alkaloids, comprising the following steps:

[0011] The reaction equation is as follows:

[0012]

[0013] Step (1): Dissolving the raw materials

[0014] Accurately weigh appropriate amounts of methyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl) propionate, anthranilic acid and a catalyst; wherein the molar ratio of methyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl) propionate to anthranilic acid to the catalyst must be strictly controlled within the range of 1:1.0-1.5:0.1-0.3;

[0015] Select an organic solvent. The organic solvent can be selected from toluene, xylene, N,N-dimethylformamide, N,N-dimethylacetamide and other solvents, and one or more thereof can be mixed for use; add the weighed methyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate, o-aminobenzoic acid and catalyst into a clean, dry three-necked flask equipped with a stirring device and a thermometer, and then add an appropriate amount of organic solvent to ensure that the solute can be fully dissolved in the solvent; in order to accelerate the dissolution process, the stirring device can be turned on and the stirring speed can be set to [X] rpm (adjusted according to actual conditions) so that the reactants are evenly dispersed in the organic solvent to form a uniform and stable reaction solution;

[0016] Step (2): Initial temperature rise reaction

[0017] After the raw materials are completely dissolved, place the three-necked flask on a temperature-controllable heating device, such as an oil bath or a heated magnetic stirrer;

[0018] Slowly raise the temperature of the reaction solution to 40°C at an appropriate heating rate (e.g., [X]°C / min, which can be adjusted according to equipment performance and experimental conditions), and turn on the stirring device. The stirring speed can be maintained at [X] rpm to ensure that the reaction solution is in a well-mixed state;

[0019] At this temperature, continue the reaction for 2 hours; during the reaction, closely observe the reaction phenomena, such as the color change of the solution, whether bubbles are generated or whether precipitation is formed, etc., and make detailed records; at the same time, use gas chromatography, liquid chromatography or other appropriate analytical methods to regularly (for example, every 30 minutes) take samples to monitor the progress of the reaction to ensure that the reaction proceeds to the desired extent; if the reaction does not meet expectations, the reaction time can be appropriately extended according to the reaction situation, but the maximum time shall not exceed 6 hours;

[0020] Step (3): Second heating and de-tert-butylation reaction

[0021] After the aminolysis reaction is completed (which can be determined by detecting the amount of aminolysis product generated or the change in specific properties of the reaction solution), the reaction solution is heated to 80°C at a heating rate of [X]°C / min;

[0022] The de-tert-butyl catalyst is added to the reaction solution in batches according to a molar ratio of 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionic acid methyl ester to the de-tert-butyl catalyst of 1:1.0-3.0; the de-tert-butyl catalyst can be selected from one or more catalysts such as aluminum chloride, ferric chloride, perchloric acid, ZSM-5 molecular sieve, etc., and the amount added in each batch should be appropriate to avoid excessive addition at one time causing the reaction to run away;

[0023] After adding the catalyst, the reaction temperature is further increased to 100°C and stirring is maintained. The stirring speed can be adjusted to [X] rpm. At this temperature, the reaction will continue for 2-10 hours. Similarly, during the reaction, the reaction progress is monitored regularly (e.g., every hour) using appropriate analytical techniques to determine whether the reaction is complete based on indicators such as the amount of reaction product generated, the amount of reactant consumed, and changes in the properties of the solution. If the reaction is not complete, the reaction time can be appropriately extended, but attention should be paid to observing the state of the solution to prevent the generation of by-products due to overreaction.

[0024] Step (4): Quenching reaction and alkaline dissolution treatment

[0025] When the reaction in step (3) is completed, the heating is immediately stopped, and the reaction apparatus is moved to an ice water bath, and an appropriate amount of ice water is slowly added to the reaction solution to quench the reaction; the amount of ice water added should be sufficient to terminate the reaction, but it should also be avoided that the subsequent processing process is too complicated due to excessive addition; when adding ice water, it is necessary to add it dropwise while stirring, and the dropping speed should be kept uniform to prevent local overheating or overcooling;

[0026] After the reaction is quenched, the reaction solution is transferred to a separatory funnel and allowed to stand for a period of time (generally [X] minutes, which can be adjusted according to the stratification of the solution) to allow the organic phase and the aqueous phase to be fully separated;

[0027] After the layers are clearly separated, the lower organic phase is carefully separated and slowly added dropwise to another clean container containing a pre-prepared 10-30% NaOH aqueous solution; during the addition process, the reaction temperature must be strictly controlled within the range of 35-55°C, which can be achieved by adjusting the dropwise speed and using a cooling device (such as a cold water bath);

[0028] During the entire dropwise addition process, stirring is maintained and the stirring speed is controlled at [X] rpm to ensure that the organic phase and the alkaline solution are fully in contact. The reaction time is 1-3 hours. During the alkaline dissolution process, the pH value of the solution, color changes, and whether new precipitation is generated can be monitored to ensure the normal progress of the alkaline dissolution reaction. At the same time, the stirring speed and temperature should be reasonably adjusted according to the volume of the solution and the reaction conditions to ensure the uniformity and safety of the reaction.

[0029] Step (5): pH adjustment and product separation and purification

[0030] After the alkaline dissolution reaction is completed, the reaction solution is transferred to the separatory funnel again and allowed to stand for [X] minutes to allow the aqueous phase and the organic phase to separate fully; the lower aqueous phase is separated and placed in a clean container;

[0031] Prepare the acid required for adjusting the pH. The acid can be one or more of hydrochloric acid, sulfuric acid, phosphoric acid, etc.; slowly drop the acid into the aqueous phase under stirring, and monitor the pH value of the solution with a precision pH meter until it reaches the range of 2-4; when dropping the acid, pay attention to controlling the dropping speed to avoid the local pH being too low, which will lead to uneven precipitation of the product or the generation of impurities;

[0032] As the pH value decreases, white solid will gradually precipitate from the solution. When the pH value stabilizes in the range of 2-4, stop adding acid;

[0033] The solution containing the white solid is filtered using a Buchner funnel and filter paper or other suitable filtering equipment; during filtering, the filter cake is washed several times with an appropriate amount of distilled water until the filtrate is neutral to remove impurity ions and residual acid;

[0034] Finally, the filtered white solid product is placed in a drying oven, and a suitable drying temperature (generally [X]°C, determined according to the stability of the product) and drying time ([X] hours) are set for drying to obtain a finished dihydroavenate alkaloid product with a purity greater than 99%. During the drying process, care should be taken to prevent the product from decomposing or undergoing other chemical changes due to excessive temperature, and the product can be monitored by regularly checking the appearance, quality and other indicators of the product.

[0035] Preferably, the organic solvent in step (1) includes, but is not limited to, one or more of toluene, xylene, N,N-dimethylformamide, N,N-dimethylacetamide, etc.

[0036] Preferably, the molar ratio of methyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate to anthranilic acid and the catalyst in step (1) is 1:1.0-1.5:0.1-0.3.

[0037] Preferably, the catalyst in step (1) includes but is not limited to one or more of concentrated sulfuric acid, trifluoroacetic acid, phosphotungstic acid, p-toluenesulfonic acid, acidic ion resin, etc.

[0038] Preferably, the type of catalyst in step (3) includes, but is not limited to, one or more of aluminum chloride, ferric chloride, perchloric acid, ZSM-5 molecular sieve, etc.

[0039] Preferably, in step (3), the molar ratio of methyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate to the catalyst is 1:1.0 to 3.0.

[0040] Preferably, in step (4), the molar ratio of methyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate to sodium hydroxide is 1:2.0-5.0.

[0041] Preferably, the concentration of NaOH in step (4) is 10-30%.

[0042] Preferably, the acid used to adjust the pH in step (5) includes, but is not limited to, one or more of hydrochloric acid, sulfuric acid, phosphoric acid, etc.

[0043] (III) Beneficial effects

[0044] Compared with the prior art, the present invention provides a method for synthesizing dihydroavenate alkaloids, which has the following beneficial effects:

[0045] Compared with the prior art, the present invention has significant advantages. On the one hand, the present invention abandons the highly toxic acylating agent in the traditional synthesis route, greatly reduces the degree of corrosion to the production equipment, effectively prolongs the service life of the equipment, reduces the frequency of equipment maintenance and cost investment, and avoids production interruptions caused by frequent equipment maintenance, thereby ensuring the continuity and stability of production. Moreover, since highly toxic reagents are no longer used, the safety of the production process is greatly improved, the potential threat to the health of operators is reduced, and the investment of enterprises in labor protection is reduced. On the other hand, compared with the traditional method requiring lengthy oxidation and acylation condensation treatment, the present invention significantly shortens the reaction time by optimizing the reaction steps and conditions, greatly compresses the original synthesis cycle of several hours or even more than ten hours, effectively improves the production efficiency, and enables the enterprise to produce more high-purity dihydroaven alkaloid products per unit time, so as to meet the urgent needs of the market and enhance the competitiveness of the enterprise in the market. Furthermore, the purity of the dihydroaven alkaloid prepared by the present invention is as high as 99% or more, far exceeding the purity of the products obtained by some traditional synthesis methods, and the product quality is excellent. When high-purity products are used in the field of daily chemical products, they can more efficiently exert their anti-histamine, antioxidant, anti-irritation, anti-inflammatory and antipruritic, and erythema improvement effects, providing consumers with a better skin care experience and improving the quality and market competitiveness of related daily chemical products. BRIEF DESCRIPTION OF THE DRAWINGS

[0046] Figure 1 This is the hydrogen nuclear magnetic resonance spectrum of the amine ester exchange intermediate prepared by this method;

[0047] Figure 2 This is the nuclear magnetic resonance hydrogen spectrum of the dihydroavenate alkaloid prepared by the method;

[0048] Figure 3 This is a high performance liquid chromatogram of the amine ester exchange intermediate prepared by this method;

[0049] Figure 4 The figure is the high performance liquid chromatogram of dihydroavenate alkaloids prepared by the method. DETAILED DESCRIPTION

[0050] The following will be combined with the drawings in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0051] See also Figure 1-4 ,.

[0052] A method for synthesizing dihydroavenate alkaloids, characterized in that it comprises the following steps:

[0053] The reaction equation is as follows:

[0054]

[0055] (1) Dissolve methyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl) propionate, anthranilic acid and a catalyst in an organic solvent; (2) Heat to 40-60°C and react at this temperature for 2-6 hours; (3) After the aminolysis is completed, heat to 80-100°C, add the de-tert-butylation catalyst in batches, and react at this temperature for 2-10 hours; (4) After the reaction is completed, add ice water to quench the reaction. After standing and separating the liquids, the organic phase is slowly added dropwise to a 10-30% NaOH aqueous solution, and the temperature is controlled at 35-55°C to react for 1-3 hours; (5) After the alkaline dissolution is completed, stand and separate the liquids, and slowly add acid to the aqueous phase to adjust the pH to 2-4. A white solid is precipitated, filtered, washed with water until neutral, and dried to obtain a dihydroavenate alkaloid with a purity greater than 99%. The organic solvent in step (1) includes, but is not limited to, one or more of toluene, xylene, N,N-dimethylformamide, N,N-dimethylacetamide, etc. The molar ratio of 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate to anthranilic acid and the catalyst in step (1) is 1:1.0-1.5:0.1-0.3. The catalyst in step (1) includes, but is not limited to, one or more of concentrated sulfuric acid, trifluoroacetic acid, phosphotungstic acid, p-toluenesulfonic acid, acidic ion resin, etc. The type of catalyst in step (3) includes but is not limited to one or more of aluminum chloride, ferric chloride, perchloric acid, ZSM-5 molecular sieve, etc., the molar ratio of methyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate to the catalyst in step (3) is 1:1.0-3.0, the molar ratio of methyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate to sodium hydroxide in step (4) is 1:2.0-5.0, the concentration of NaOH in step (4) is 10-30%, and the acid used to adjust the pH in step (5) includes but is not limited to one or more of hydrochloric acid, sulfuric acid, phosphoric acid, etc.

[0056] Example 1 A method for synthesizing dihydroavenous alkaloids

[0057] Under nitrogen protection, add toluene (146.2ml, 5.0Vols) to a 500ml four-necked flask, stir, add methyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl) propionate (29.24g, 100mmol), anthranilic acid (15.09g, 110mmol), p-toluenesulfonic acid (3.44g, 20mmol), heat to 50℃, and keep warm at this temperature for 5h. After the reaction is completed, heat to 80℃, add aluminum chloride (20g, 150mmol) in batches, and keep warm at this temperature for 8h. After the reaction is completed, cool to below 10℃, slowly add ice water (146.2g, 5.0wt%) to the reaction solution and stir for 0.5h, quench the reaction and separate the liquid at rest. Slowly add 15% NaOH solution (80g, 300mmol) to the organic phase, heat to 40℃, and react at this temperature for 2h. After the reaction was completed, the liquid was separated at rest, and concentrated hydrochloric acid (43.86 g, 444 mmol) was slowly added dropwise to the aqueous phase. After the addition was completed, a white solid was precipitated, which was filtered, washed with water until neutral, and dried to obtain 22.43 g of dihydroavenate alkaloids with a yield of 78.62%, HPLC ≥ 98%.

[0058] Example 2 A method for synthesizing dihydroavenous alkaloids

[0059] Under nitrogen protection, add toluene (146.2ml, 5.0Vols) to a 500ml four-necked flask, stir, add methyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl) propionate (29.24g, 100mmol), anthranilic acid (15.09g, 110mmol), trifluoroacetic acid (2.28g, 20mmol), heat to 50℃, and keep the temperature at this temperature for 5h. After the reaction is completed, heat to 90℃, add aluminum chloride (20g, 150mmol) in batches, and keep the temperature at this temperature for 8h. After the reaction is completed, cool to below 10℃, slowly add ice water (146.2g, 5.0wt%) to the reaction solution and stir for 0.5h, quench the reaction and separate the liquid at rest. Slowly add 15% NaOH solution (80g, 300mmol) to the organic phase, heat to 40℃, and react at this temperature for 2h. After the reaction was completed, the liquid was separated at rest, and concentrated hydrochloric acid (43.86 g, 444 mmol) was slowly added dropwise to the aqueous phase. After the addition was completed, a white solid was precipitated, which was filtered, washed with water until neutral, and dried to obtain 20.57 g of dihydroavenate alkaloids with a yield of 72.11%, HPLC ≥ 98%.

[0060] Example 3 A method for synthesizing dihydroavenous alkaloids

[0061] Under nitrogen protection, add toluene (146.2ml, 5.0Vols) to a 500ml four-necked flask, stir, add methyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl) propionate (29.24g, 100mmol), anthranilic acid (15.77g, 115mmol), p-toluenesulfonic acid (3.44g, 20mmol), heat to 50℃, and keep warm at this temperature for 5h. After the reaction is completed, heat to 80℃, add aluminum chloride (20g, 150mmol) in batches, and keep warm at this temperature for 8h. After the reaction is completed, cool to below 10℃, slowly add ice water (146.2g, 5.0wt%) to the reaction solution and stir for 0.5h, quench the reaction and separate the liquid at rest. Slowly add 15% NaOH solution (80g, 300mmol) to the organic phase, heat to 40℃, and react at this temperature for 2h. After the reaction is completed, the liquid is separated at rest, and concentrated hydrochloric acid (43.86 g, 444 mmol) is slowly added dropwise to the aqueous phase. After the addition is completed, a white solid is precipitated, which is filtered, washed with water until neutral, and dried to obtain 23.11 g of dihydroavenate alkaloids, with a yield of 81.01%, HPLC ≥ 99%.

[0062] Example 4 A method for synthesizing dihydroavenous alkaloids

[0063] Under nitrogen protection, add toluene (584.8ml, 5.0Vols) to a 2000ml four-necked flask, stir, add methyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl) propionate (116.96g, 400mmol), anthranilic acid (63.08g, 460mmol), p-toluenesulfonic acid (13.78g, 80mmol), heat to 50℃, and keep the temperature at this temperature for 5h. After the reaction is completed, heat to 100℃, add aluminum chloride (106.66g, 800mmol) in batches, and keep the temperature at this temperature for 8h. After the reaction is completed, cool to below 10℃, slowly add ice water (584.8g, 5.0wt%) to the reaction solution and stir for 0.5h, quench the reaction and separate the liquid. Slowly drop 15% NaOH solution (342.83 g, 800 mmol) into the organic phase, heat to 40°C, and react at this temperature for 2 h. After the reaction is completed, separate the liquids at rest, and slowly drop concentrated hydrochloric acid (175.44 g, 1778 mmol) into the aqueous phase. After the addition is completed, a white solid is precipitated, which is filtered, washed with water until neutral, and dried to obtain 97.52 g of dihydroavenate alkaloids, with a yield of 85.46%, HPLC ≥ 99%.

[0064] Comparative Example 1 A method for synthesizing dihydroavenous alkaloids

[0065] Under nitrogen protection, dichloromethane (300ml, 3.0Vols), DMF (2.20g, 30mmol), p-hydroxyphenylpropionic acid (100g, 600mmol) were added to a 1000ml four-necked flask, and the temperature was lowered to below 0℃. SOCl2 (108g, 900mmol) was slowly added dropwise at a temperature below 5℃. After the addition was completed, the reaction was carried out at this temperature for 8h. After the reaction was completed, reaction liquid A was obtained; under nitrogen protection, dichloromethane (300g, 3.0Vols), triethylamine (152g, 1500mmol), and methyl anthranilate (92.79g, 610mmol) were added to a 2000ml four-necked flask. The temperature was raised to reflux, and reaction liquid A was slowly added dropwise. After the addition was completed, the reaction was continued at this temperature for 10h. After the reaction was completed, the liquid was washed with water, and the organic phase was concentrated to dryness to obtain the intermediate. Add 14% NaOH (515.82 g, 1810 mmol) to a 1000 ml four-necked flask and add the intermediate under stirring, heat to 40°C, stir until all dissolved, cool to room temperature, slowly drop sulfuric acid to adjust the pH to 2-3 to precipitate solids. Filter, wash with water until neutral, and dry to obtain dihydroavenous alkaloid g, with a yield of 61.08%, HPLC ≥ 95%.

[0066] It can be seen from the above examples that the method for synthesizing dihydroavenate alkaloids is more convenient to operate than the traditional method, and does not require filtering and purifying intermediates. In addition, the method does not require the use of acylating agents and strong oxidizing agents, which effectively improves the efficiency of industrial production.

[0067] It should be noted that, in this document, relational terms such as first and second, etc. are merely used to distinguish one entity or operation from another entity or operation, and do not necessarily require or imply any actual relationship or order between these entities or operations.

[0068] Moreover, the terms "comprises," "comprising," or any other variation thereof are intended to encompass non-exclusive inclusion, such that a process, method, article, or apparatus that includes a list of elements includes not only those elements, but also other elements not explicitly listed, or elements inherent to such process, method, article, or apparatus. In the absence of further limitations, an element defined by the phrase "comprising a" does not exclude the presence of additional identical elements in the process, method, article, or apparatus that includes the element.

[0069] Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions and variations may be made to the embodiments without departing from the principles and spirit of the present invention, and that the scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. A method for synthesizing dihydroavenate alkaloids, characterized in that: The following steps are involved: reaction The equation is as follows: Step (1): Dissolving the raw materials Accurately weigh appropriate amounts of methyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl) propionate, anthranilic acid and a catalyst; wherein the molar ratio of methyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl) propionate to anthranilic acid to the catalyst must be strictly controlled within the range of 1:1.0-1.5:0.1-0.3; Select an organic solvent. The organic solvent can be selected from toluene, xylene, N,N-dimethylformamide, N,N-dimethylacetamide and other solvents, and one or more thereof can be mixed for use; add the weighed methyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate, o-aminobenzoic acid and catalyst into a clean, dry three-necked flask equipped with a stirring device and a thermometer, and then add an appropriate amount of organic solvent to ensure that the solute can be fully dissolved in the solvent; in order to accelerate the dissolution process, the stirring device can be turned on and the stirring speed can be set to [X] rpm (adjusted according to actual conditions) so that the reactants are evenly dispersed in the organic solvent to form a uniform and stable reaction solution; Step (2): Initial temperature rise reaction After the raw materials are completely dissolved, place the three-necked flask on a temperature-controllable heating device, such as an oil bath or a heated magnetic stirrer; Slowly raise the temperature of the reaction solution to 40°C at an appropriate heating rate (e.g., [X]°C / min, which can be adjusted according to equipment performance and experimental conditions), and turn on the stirring device. The stirring speed can be maintained at [X] rpm to ensure that the reaction solution is in a well-mixed state; At this temperature, continue the reaction for 2 hours; during the reaction, closely observe the reaction phenomena, such as the color change of the solution, whether bubbles are generated or whether precipitation is formed, etc., and make detailed records; at the same time, use gas chromatography, liquid chromatography or other appropriate analytical methods to regularly (for example, every 30 minutes) take samples to monitor the progress of the reaction to ensure that the reaction proceeds to the desired extent; if the reaction does not meet expectations, the reaction time can be appropriately extended according to the reaction situation, but the maximum time shall not exceed 6 hours; Step (3): Second heating and de-tert-butylation reaction After the aminolysis reaction is completed (which can be determined by detecting the amount of aminolysis product generated or the change in specific properties of the reaction solution), the reaction solution is heated to 80°C at a heating rate of [X]°C / min; The de-tert-butyl catalyst is added to the reaction solution in batches according to a molar ratio of 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionic acid methyl ester to the de-tert-butyl catalyst of 1:1.0-3.0; the de-tert-butyl catalyst can be selected from one or more catalysts such as aluminum chloride, ferric chloride, perchloric acid, ZSM-5 molecular sieve, etc., and the amount added in each batch should be appropriate to avoid excessive addition at one time causing the reaction to run away; After adding the catalyst, the reaction temperature is further increased to 100°C and stirring is maintained. The stirring speed can be adjusted to [X] rpm. At this temperature, the reaction will continue for 2-10 hours. Similarly, during the reaction, the reaction progress is monitored regularly (e.g., every hour) using appropriate analytical techniques to determine whether the reaction is complete based on indicators such as the amount of reaction product generated, the amount of reactant consumed, and changes in the properties of the solution. If the reaction is not complete, the reaction time can be appropriately extended, but attention should be paid to observing the state of the solution to prevent the generation of by-products due to overreaction. Step (4): Quenching reaction and alkaline dissolution treatment When the reaction in step (3) is completed, the heating is immediately stopped, and the reaction apparatus is moved to an ice water bath, and an appropriate amount of ice water is slowly added to the reaction solution to quench the reaction; the amount of ice water added should be sufficient to terminate the reaction, but it should also be avoided that the subsequent processing process is too complicated due to excessive addition; when adding ice water, it is necessary to add it dropwise while stirring, and the dropping speed should be kept uniform to prevent local overheating or overcooling; After the reaction is quenched, the reaction solution is transferred to a separatory funnel and allowed to stand for a period of time (generally [X] minutes, which can be adjusted according to the stratification of the solution) to allow the organic phase and the aqueous phase to be fully separated; After the layers are clearly separated, the lower organic phase is carefully separated and slowly added dropwise to another clean container containing a pre-prepared 10-30% NaOH aqueous solution; during the addition process, the reaction temperature must be strictly controlled within the range of 35-55°C, which can be achieved by adjusting the dropwise speed and using a cooling device (such as a cold water bath); During the entire dropwise addition process, stirring is maintained and the stirring speed is controlled at [X] rpm to ensure that the organic phase and the alkaline solution are fully in contact. The reaction time is 1-3 hours. During the alkaline dissolution process, the pH value of the solution, color changes, and whether new precipitation is generated can be monitored to ensure the normal progress of the alkaline dissolution reaction. At the same time, the stirring speed and temperature should be reasonably adjusted according to the volume of the solution and the reaction conditions to ensure the uniformity and safety of the reaction. Step (5): pH adjustment and product separation and purification After the alkaline dissolution reaction is completed, the reaction solution is transferred to the separatory funnel again and allowed to stand for [X] minutes to allow the aqueous phase and the organic phase to be fully separated; the lower aqueous phase is separated and placed in a clean container; Prepare the acid required for adjusting the pH. The acid can be one or more of hydrochloric acid, sulfuric acid, phosphoric acid, etc.; slowly drop the acid into the aqueous phase under stirring, and monitor the pH value of the solution with a precision pH meter until it reaches the range of 2-4; when dropping the acid, pay attention to controlling the dropping speed to avoid the local pH being too low, which will lead to uneven precipitation of the product or the generation of impurities; As the pH value decreases, white solid will gradually precipitate from the solution. When the pH value stabilizes in the range of 2-4, stop adding acid; The solution containing the white solid is filtered using a Buchner funnel and filter paper or other suitable filtering equipment; during filtering, the filter cake is washed several times with an appropriate amount of distilled water until the filtrate is neutral to remove impurity ions and residual acid; Finally, the filtered white solid product is placed in a drying oven, and a suitable drying temperature (generally [X]°C, determined according to the stability of the product) and drying time ([X] hours) are set for drying to obtain a finished dihydroavenate alkaloid product with a purity greater than 99%. During the drying process, care should be taken to prevent the product from decomposing or undergoing other chemical changes due to excessive temperature, and the product can be monitored by regularly checking the appearance, quality and other indicators of the product.

2. The method for synthesizing dihydroavenate alkaloids according to claim 1, characterized in that: The organic solvent in step (1) includes, but is not limited to, one or more of toluene, xylene, N,N-dimethylformamide, N,N-dimethylacetamide, etc.

3. The method for synthesizing dihydroavenate alkaloids according to claim 1, characterized in that: The molar ratio of methyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate to anthranilic acid and the catalyst in the step (1) is 1:1.0-1.5:0.1-0.

3.

4. The method for synthesizing dihydroavenate alkaloids according to claim 1, characterized in that: The catalyst in step (1) includes but is not limited to one or more of concentrated sulfuric acid, trifluoroacetic acid, phosphotungstic acid, p-toluenesulfonic acid, acidic ion resin, etc.

5. The method for synthesizing dihydroavenate alkaloids according to claim 1, characterized in that: The types of catalysts in step (3) include, but are not limited to, one or more of aluminum chloride, ferric chloride, perchloric acid, ZSM-5 molecular sieve, etc.

6. The method for synthesizing dihydroavenate alkaloids according to claim 1, characterized in that: In the step (3), the molar ratio of methyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate to the catalyst is 1:1.0-3.

0.

7. The method for synthesizing dihydroavenate alkaloids according to claim 1, characterized in that: In the step (4), the molar ratio of methyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate to sodium hydroxide is 1:2.0-5.

0.

8. The method for synthesizing dihydroavenate alkaloids according to claim 1, characterized in that: The concentration of NaOH in step (4) is 10-30%.

9. The method according to claim 1, characterized in that: The acid used to adjust the pH in step (5) includes, but is not limited to, one or more of hydrochloric acid, sulfuric acid, phosphoric acid, etc.

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