Preparation method of dihydrooat alkaloid

Abstract

The invention provides a preparation method of dihydrooat alkaloid, and belongs to the technical field of organic synthesis.The preparation method comprises the steps that S1, p-hydroxyphenylpropionic acid and methyl anthranilate serve as raw materials, and an acid amine intermediate is generated through a condensation reaction in a high-boiling-point solvent environment under the action of a catalyst; s2, sequentially carrying out hydrolysis reaction and acidification reaction on the acid amine intermediate to obtain dihydrooat alkaloid; the yield of the dihydrooat alkaloid is more than 80%; the high-boiling-point solvent is xylene; the catalyst is substituted arylboronic acid. The method has the advantages of short synthetic route, safe and stable reaction conditions, avoidance of use of high-toxicity reagents, few byproducts, easy recovery, high product yield of 80% or more, easy refining and purification of the product, high product purity, high refined product purity of 99% or more, recovery and cyclic utilization of the solvent and part of reagents, low emission of generated three wastes, environmental friendliness and reduction of the production cost.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, and in particular to a method for preparing dihydroavenate alkaloids. Background Art

[0002] Dihydroavenate alkaloids, also known as: hydroxyphenylpropionamide benzoic acid, dihydroavenate alkaloids D, etc., CAS number is 697235-49-7, molecular formula is C 16 H 15 NO4, molecular weight is 285.29. Dihydroavenate alkaloid D has multiple biological activities such as antioxidant, anti-allergic, anti-irritant and antipruritic, and has no side effects of steroid hormones. It has broad market prospects and is widely used in daily chemical products such as skin care products, cosmetics, etc. It can also be added to medical ointments to play an anti-inflammatory and erythema-reducing effect, effectively improving skin itching symptoms. However, due to the low content of dihydroavenate alkaloids in crops such as oats, relying solely on natural product sources cannot meet the growing demand for industrial production. Therefore, dihydroavenate alkaloids are prepared through organic synthesis processes to replace natural oat alkaloids to meet people's daily needs.

[0003] At present, there are few reports on the synthesis of dihydroavenate alkaloids. Among the more commonly used methods, method 1: in WO2005016870, its synthesis route is as follows:

[0004]

[0005] Dihydroavenate alkaloids were first prepared by amide condensation using p-hydroxyphenylpropionic acid and o-aminobenzoic acid as raw materials, N,N-carbonyldiimidazole as a condensation agent, and pyridine as an acid-binding agent. However, this method used relatively expensive condensation reagents, such as dicarbonylimidazole, and consumed a large amount of organic base, resulting in high raw material costs. In addition, imidazole, pyridine, etc. are not easy to recover and reuse during post-treatment, and a large amount of three wastes are generated. Similar examples have a yield of only about 17%, which is low in yield and difficult to separate and purify, making it unsuitable for industrial promotion.

[0006] Method 2: As disclosed in CN106631865, CN112939803, and CN104418764, a phenylpropionic acid derivative is converted into an acyl chloride, which is reacted with an anthranilic acid derivative under the action of a base to obtain the target product. This method is a traditional method for synthesizing amides, and its synthetic route is as follows:

[0007]

[0008] However, in the above method, direct preparation of acyl chloride using p-hydroxyphenylpropionic acid as a raw material will cause a large amount of self-condensation of p-hydroxyphenylpropionic acid, which is easy to generate by-products; the acyl chloride reagents used are all hazardous chemicals and highly toxic chemicals, and the by-products include strongly acidic hydrogen chloride gas and toxic and harmful sulfur dioxide, carbon monoxide, etc., which not only have a great corrosive effect on equipment, but also pose a very serious threat to the personal safety of production personnel. At the same time, the treatment of these gases will generate a large amount of three wastes; in this method, the phenolic hydroxyl group and carboxyl esterification on the benzene ring must also be protected to ensure the reaction yield, so a large amount of organic base needs to be used as an acid binding agent, resulting in a significant increase in the treatment of the three wastes and production costs.

[0009] In summary, the synthetic routes of dihydroavenate alkaloids reported so far generally have the problems of low yield, long synthetic route, more by-products, large environmental pollution, high production cost, and unsuitability for industrial production. In view of this, it is necessary to develop a new preparation method of dihydroavenate alkaloids to solve the above technical problems. Summary of the invention

[0010] The invention provides a method for preparing dihydroavenate alkaloids, which is used to solve the problems of low yield, long synthesis route, more by-products, great environmental pollution, and unsuitability for industrial production in the existing synthesis route of dihydroavenate alkaloids.

[0011] To achieve the above object, the present invention provides a method for preparing dihydroavenate alkaloids, comprising:

[0012] S1, using p-hydroxyphenylpropionic acid and methyl anthranilate as raw materials, in a high boiling point solvent environment, under the action of a catalyst, a condensation reaction is performed to generate an acid amine intermediate;

[0013] S2. The acid amine intermediate is subjected to a hydrolysis reaction and an acidification reaction in sequence to obtain a dihydroavenate alkaloid; the yield of the dihydroavenate alkaloid is more than 80%; the high boiling point solvent is xylene; and the catalyst is a substituted aryl boronic acid.

[0014] In the invention, p-hydroxyphenylpropionic acid and methyl anthranilate are used as raw materials for condensation reaction, and then hydrolyzed by inorganic alkali and acidified with inorganic acid to obtain dihydroavenous alkaloids. The raw materials are cheap and easy to obtain, the synthesis route is short, the reaction conditions are safe and stable, the use of highly toxic reagents is avoided, the invention is equipment-friendly, the by-products are few and easy to recycle, the product yield is as high as more than 80%, the product is easy to refine and purify, the product purity is high, the refined product purity can reach more than 99%, the solvent and part of the reagents can be recycled, the three wastes are less, the invention is environmentally friendly, the production cost is reduced, the invention is suitable for the industrial production of dihydroavenous alkaloids and derivatives thereof, and can meet the growing market demand.

[0015] Furthermore, the molar ratio of methyl anthranilate to p-hydroxyphenylpropionic acid is 1:(1.1-1.5).

[0016] Furthermore, the usage amount of the high boiling point solvent is 5-8 times the weight of methyl anthranilate; and the usage amount of the catalyst is 1-1.2% of the weight of methyl anthranilate.

[0017] Water is generated when methyl anthranilate and p-hydroxyphenylpropionic acid are condensed. Compared with other processes that use reflux water separation to remove the generated water, the high boiling point solvent xylene of the present invention can form an azeotrope with water, and can accelerate the forward progress of the condensation reaction while removing the reaction water, thereby shortening the reaction time. After the reaction is completed, xylene and water can be concentrated under negative pressure, and the concentrated xylene can be reused.

[0018] Furthermore, the catalyst substituted aryl boronic acid is at least one of o-nitrophenyl boronic acid, 3,4,5-trifluorophenyl boronic acid, phenyl boronic acid, and 1,4-phenyl diboronic acid. The catalyst using substituted aryl boronic acid can directly catalyze the raw material to undergo amidation reaction, with a high raw material conversion rate, a low usage amount, a significant catalytic effect, and can be reused.

[0019] More preferably, the catalyst is 3,4,5-trifluorophenylboric acid. The catalyst 3,4,5-trifluorophenylboric acid is water-soluble and has good solubility, which makes its recovery and treatment simple, and facilitates the application of the catalyst. At the same time, it does not introduce other impurities into the acid amine intermediate and dihydroavenate alkaloid, and also facilitates its refining and purification.

[0020] Furthermore, the reaction temperature of the condensation reaction is 130-145° C., and the time is 3.5-4.5 h.

[0021] Under the action of high-boiling point solvents and catalysts, condensation generates an acid amine intermediate. In the condensation reaction, no additional reagents are required to protect the phenolic hydroxyl groups on the benzene rings in the raw materials, thereby reducing the operation steps and reagent costs. Azeotropic dehydration is also used in the condensation reaction to accelerate the forward reaction. The generated acid amine intermediate is a methyl ester derivative of dihydroaatine alkaloids. The process route is clear, which provides a basis for subsequent hydrolysis and acidification, and also enables the preparation of dihydroaatine alkaloids to be completed in two steps. The synthetic route is simple, coherent and easy to operate.

[0022] Furthermore, the reaction temperature of the hydrolysis reaction is 80-85° C., the time is 2.5-4 hours, and the content of the acid amine intermediate in the hydrolysis reaction system is less than 0.2 wt %.

[0023] Furthermore, the hydrolysis reaction system also includes ethanol, water and sodium hydroxide; the amount of ethanol added is 1.6-2 times the weight of methyl anthranilate; the amount of water added is 1-1.4 times the weight of methyl anthranilate; and the amount of sodium hydroxide added is 45-60% of the weight of methyl anthranilate. The acid amine intermediate is hydrolyzed by an inorganic base in an ethanol solution, and the removed methanol is dissolved in the ethanol solution and can be separated. After the reaction is completed, the ethanol is concentrated and can be recycled.

[0024] Furthermore, the reaction temperature of the acidification reaction is 20-30°C and the time is 1-2h.

[0025] Furthermore, the reaction system of the acidification reaction also includes a hydrochloric acid solution with a concentration of 36wt% and water; the amount of the hydrochloric acid solution added is 1.4-1.7 times the weight of methyl anthranilate; and the amount of water added is 11-13 times the weight of methyl anthranilate. In the acidification reaction, inorganic acid is used for neutralization to obtain dihydroavenous alkaloids and sodium chloride. After the reaction system of the acidification reaction is filtered, the sodium chloride is removed by elution to obtain dihydroavenous alkaloids with high purity.

[0026] Furthermore, the preparation method further comprises: S3, sequentially recrystallizing, decolorizing, filtering and drying the dihydroavenate alkaloids obtained in S2 to obtain a refined dihydroavenate alkaloid product.

[0027] The dihydroaatmeal alkaloids synthesized by the two-step method are usually crude products with relatively high purity. When the purity requirements of the downstream industry are relatively high, the crude products need to be refined and purified. The refining operation of recrystallization using ethanol and decolorization using activated carbon can be repeated many times to continuously improve the purity of the refined dihydroaatmeal alkaloids. Similarly, the ethanol in the refining operation can be recovered and reused, saving production costs and avoiding the generation of a large amount of three wastes.

[0028] Furthermore, the solvent used for recrystallization is ethanol; the amount of ethanol used is 3.5-4 times the weight of methyl anthranilate.

[0029] Furthermore, activated carbon is used for decolorization, and the amount of activated carbon used is 2.5-4% of the weight of methyl anthranilate.

[0030] Furthermore, the purity of the refined dihydroavenate alkaloid product is not less than 99%.

[0031] The preparation method of dihydroavenate alkaloids provided by the present invention comprises the following steps: carrying out a condensation reaction with p-hydroxyphenylpropionic acid and methyl anthranilate as raw materials, and then hydrolyzing with an inorganic base and acidifying with an inorganic acid to obtain the dihydroavenate alkaloids. The process is easy to control, the yield is high, the by-products are few, the products are easy to refine and purify, the product purity is high, the solvents and some reagents can be recycled, the three wastes are less, the method is environmentally friendly, and has a wide range of applications. The method is suitable for the industrial production of dihydroavenate alkaloids and derivatives thereof, and the production cost can be reduced.

[0032] The preparation method does not require additional reagents to protect the phenolic hydroxyl groups on the benzene rings in the raw materials during the condensation reaction, thus reducing the number of operation steps and reagent costs. The high-boiling-point solvent xylene can form an azeotrope with water, which can accelerate the forward progress of the condensation reaction while removing the reaction water, thus shortening the reaction time. The catalyst replaces the aromatic boronic acid, which is easy to recover and apply. The use of highly toxic reagents is avoided during the preparation process, which is in line with the concept of green chemical engineering.

[0033] The preparation method can synthesize dihydroavenate alkaloids with high purity by a two-step method, and can also use ethanol and activated carbon to refine and purify the dihydroavenate alkaloids, thereby obtaining a refined dihydroavenate alkaloid product with a purity of not less than 99%. The solvents used for refining can be recovered and reused, saving production costs and avoiding the generation of a large amount of three wastes. DETAILED DESCRIPTION

[0034] In order to make the purpose, technical solution and advantages of the embodiments of the present invention clearer, the technical solution in the embodiments of the present invention is clearly and completely described below. Obviously, the described embodiments are 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 also fall within the scope of protection of the present invention.

[0035] The following examples use conventional instruments and equipment in the art. Unless otherwise specified, the test materials and reagents used in the following examples can be obtained from commercial sources, and their specifications are conventional specifications in the art. If no specific techniques or conditions are specified in the following examples, they can be carried out according to the techniques or conditions described in the literature in the art or according to the product instructions.

[0036] It should be noted that, in the present invention and the following embodiments, concentrations, ratios, etc. not otherwise specified are all weight concentrations, weight ratios, etc., "%" means weight percentage, and "parts" means parts by weight, which are common writing habits used by those skilled in the art and are therefore not described in detail in the present invention.

[0037] As an embodiment, a method for preparing dihydroavenate alkaloids comprises the following steps:

[0038] S1. Add hydroxyphenylpropionic acid and methyl anthranilate to a reaction kettle, then add xylene, a high boiling point solvent, and a catalyst, raise the temperature, and react at 130-145° C. for 3.5-4.5 hours. After the reaction is completed, xylene is concentrated under negative pressure to obtain a concentrated solution with an acid amine intermediate content of more than 98.5%.

[0039] The catalyst-substituted aryl boronic acid is at least one of o-nitrophenylboric acid, 3,4,5-trifluorophenylboric acid, phenylboric acid and 1,4-phenylenediboric acid. The molar ratio of methyl anthranilate to p-hydroxyphenylpropionic acid is 1:(1.1-1.5), the amount of high boiling point solvent used is 5-8 times the weight of methyl anthranilate; the amount of catalyst used is 1-1.2% of the weight of methyl anthranilate.

[0040]

[0041] The above condensation reaction route is as follows:

[0042] S2, add ethanol, water and sodium hydroxide to the concentrated solution containing the acid amine intermediate obtained in S1, raise the temperature to 80-85°C, so that the hydrolysis reaction system forms a micro-reflux, and after reacting for 2.5-4h, the content of the acid amine intermediate in the hydrolysis reaction system is less than 0.2wt%, and the hydrolysis reaction ends. Concentrate the ethanol. Then add a 36wt% hydrochloric acid solution and water to the reactor, cool to 20-30°C, acidify and react for 1-2h, filter and rinse, and obtain dihydroavenate alkaloids.

[0043] The amount of ethanol added is 1.6-2 times the weight of methyl anthranilate; the amount of water added is 1-1.4 times the weight of methyl anthranilate; the amount of sodium hydroxide added is 45-60% of the weight of methyl anthranilate; the amount of hydrochloric acid solution added is 1.4-1.7 times the weight of methyl anthranilate; and the amount of water added is 11-13 times the weight of methyl anthranilate.

[0044] The above hydrolysis reaction and acidification reaction route are as follows:

[0045]

[0046] As a preferred embodiment, a method for preparing dihydroavenate alkaloids includes a refining operation, specifically comprising the following steps:

[0047] S1. Add hydroxyphenylpropionic acid and methyl anthranilate to a reaction kettle, then add xylene, a high boiling point solvent, and a catalyst, raise the temperature, and react at 130-145° C. for 3.5-4.5 hours. After the reaction is completed, xylene is concentrated under negative pressure to obtain a concentrated solution with an acid amine intermediate content of more than 98.5%.

[0048] S2, add ethanol, water and sodium hydroxide to the concentrated solution containing the acid amine intermediate obtained in S1, raise the temperature to 80-85°C, so that the hydrolysis reaction system forms a micro-reflux, and after reacting for 2.5-4h, the content of the acid amine intermediate in the hydrolysis reaction system is less than 0.2wt%, and the hydrolysis reaction ends. Concentrate the ethanol. Then add a 36wt% hydrochloric acid solution and water to the reactor, cool to 20-30°C, acidify and react for 1-2h, filter and rinse, and obtain dihydroavenate alkaloids.

[0049] S3, adding ethanol to dissolve the dihydroavenate alkaloids obtained in step S2, then adding activated carbon, filtering with suction, and drying to obtain a refined dihydroavenate alkaloid with a purity of more than 99%.

[0050] The usage amount of the ethanol is 3.5-4 times of the weight of methyl anthranilate. The usage amount of the activated carbon is 2.5-4% of the weight of methyl anthranilate.

[0051] As another preferred embodiment, a method for preparing dihydroavenate alkaloids, which includes two refining operations, specifically includes the following steps:

[0052] S1. Add hydroxyphenylpropionic acid and methyl anthranilate to a reaction kettle, then add xylene, a high boiling point solvent, and a catalyst, raise the temperature, and react at 130-145° C. for 3.5-4.5 hours. After the reaction is completed, xylene is concentrated under negative pressure to obtain a concentrated solution with an acid amine intermediate content of more than 98.5%.

[0053] S2, add ethanol, water and sodium hydroxide to the concentrated solution containing the acid amine intermediate obtained in S1, raise the temperature to 80-85°C, so that the hydrolysis reaction system forms a micro-reflux, and after reacting for 2.5-4h, the content of the acid amine intermediate in the hydrolysis reaction system is less than 0.2wt%, and the hydrolysis reaction ends. Concentrate the ethanol. Then add a 36wt% hydrochloric acid solution and water to the reactor, cool to 20-30°C, acidify and react for 1-2h, filter and rinse, and obtain dihydroavenate alkaloids.

[0054] S3.1. Add ethanol to dissolve the dihydroavenate alkaloids obtained in step S2, then add activated carbon, filter and obtain a primary refined product of dihydroavenate alkaloids with a purity of more than 99%.

[0055] S3.2, adding ethanol to dissolve the primary refined dihydroavenate alkaloid obtained in step S3.1, then adding activated carbon, filtering, and drying to obtain a white crystalline powder, which is a secondary refined dihydroavenate alkaloid with a purity of more than 99.5%. The amounts of ethanol and activated carbon used in S3.1 and S3.2 are the same.

[0056] The present invention is further described in detail below in conjunction with the examples. However, it should be understood that the examples are for illustrative purposes only and are not intended to limit the scope of the present invention.

[0057] Embodiment 1:

[0058] A method for preparing dihydroavenate alkaloids comprises the following steps:

[0059] S1. Add hydroxyphenylpropionic acid and methyl anthranilate to the reactor, then add high boiling point solvent xylene and catalyst 1,4-phenylenediboronic acid, raise the temperature, and react at 130°C for 3.5 hours. After the reaction is completed, xylene is concentrated under negative pressure to obtain a concentrated solution with an acid amine intermediate content of more than 98.5%.

[0060] The molar ratio of the above-mentioned methyl anthranilate to p-hydroxyphenylpropionic acid is 1:1.1, the usage amount of the high boiling point solvent is 5 times the weight of the methyl anthranilate; and the usage amount of the catalyst is 1% of the weight of the methyl anthranilate.

[0061] S2, add ethanol, water and sodium hydroxide to the concentrated solution containing the acid amine intermediate obtained in S1, heat it to 80°C, so that the hydrolysis reaction system forms a micro-reflux, and after reacting for 2.5 hours, the content of the acid amine intermediate in the hydrolysis reaction system is less than 0.2wt%, and the hydrolysis reaction ends. Concentrate the ethanol. Then add a 36wt% hydrochloric acid solution and water to the reactor, cool it to 20°C, acidify and react for 1h, filter it with suction, and rinse it to obtain a dihydroavenous alkaloid with a yield of 85.3%.

[0062] The amount of ethanol added is 1.6 times the weight of methyl anthranilate; the amount of water added is 1 times the weight of methyl anthranilate; the amount of sodium hydroxide added is 45% of the weight of methyl anthranilate; the amount of hydrochloric acid solution added is 1.4 times the weight of methyl anthranilate; and the amount of water added is 11 times the weight of methyl anthranilate.

[0063] Embodiment 2:

[0064] A method for preparing dihydroavenate alkaloids comprises the following steps:

[0065] S1. Add hydroxyphenylpropionic acid and methyl anthranilate to the reactor, then add high boiling point solvent xylene and catalyst o-nitrobenzene boric acid, raise the temperature, and react at 145° C. for 4.5 hours. After the reaction is completed, the xylene is concentrated under negative pressure to obtain a concentrated solution with an acid amine intermediate content of more than 98.5%.

[0066] The molar ratio of the above-mentioned methyl anthranilate to p-hydroxyphenylpropionic acid is 1:1.5, the usage amount of the high boiling point solvent is 8 times the weight of the methyl anthranilate; and the usage amount of the catalyst is 1.2% of the weight of the methyl anthranilate.

[0067] S2, add ethanol, water and sodium hydroxide to the concentrated solution containing the acid amine intermediate obtained in S1, heat it to 85°C, so that the hydrolysis reaction system forms a micro-reflux, and after reacting for 4 hours, the content of the acid amine intermediate in the hydrolysis reaction system is less than 0.2wt%, and the hydrolysis reaction ends. Concentrate the ethanol. Then add a 36wt% hydrochloric acid solution and water to the reactor, cool it to 30°C, acidify and react for 2 hours, filter it with suction, and rinse it to obtain dihydroavenous alkaloids.

[0068] The amount of ethanol added is 2 times the weight of methyl anthranilate; the amount of water added is 1.4 times the weight of methyl anthranilate; the amount of sodium hydroxide added is 60% of the weight of methyl anthranilate; the amount of hydrochloric acid solution added is 1.7 times the weight of methyl anthranilate; and the amount of water added is 13 times the weight of methyl anthranilate.

[0069] S3, adding ethanol to dissolve the dihydroavenate alkaloids obtained in step S2, then adding activated carbon, filtering with suction, and drying to obtain a refined dihydroavenate alkaloid with a yield of 83.7%. The purity of the refined dihydroavenate alkaloids obtained by HPLC is 99.3%. The amount of the ethanol used is 4 times the weight of methyl anthranilate. The amount of activated carbon used is 4% of the weight of methyl anthranilate.

[0070] Embodiment 3:

[0071] A method for preparing dihydroavenate alkaloids comprises the following steps:

[0072] S1. Add hydroxyphenylpropionic acid and methyl anthranilate to the reactor, then add high boiling point solvent xylene and catalyst phenylboric acid, raise the temperature, and react at 138° C. for 4 hours. After the reaction is completed, the xylene is concentrated under negative pressure to obtain a concentrated solution with an acid amine intermediate content of more than 98.5%.

[0073] The molar ratio of the above-mentioned methyl anthranilate to p-hydroxyphenylpropionic acid is 1:1.3, the usage amount of the high boiling point solvent is 6.5 times the weight of the methyl anthranilate; and the usage amount of the catalyst is 1.1% of the weight of the methyl anthranilate.

[0074] S2, add ethanol, water and sodium hydroxide to the concentrated solution containing the acid amine intermediate obtained in S1, heat it to 84°C, so that the hydrolysis reaction system forms a micro-reflux, and after reacting for 3.5 hours, the content of the acid amine intermediate in the hydrolysis reaction system is less than 0.2wt%, and the hydrolysis reaction ends. Concentrate the ethanol. Then add a 36wt% hydrochloric acid solution and water to the reactor, cool it to 25°C, acidify and react for 1.5 hours, filter, rinse, and obtain dihydroaven alkaloids.

[0075] The amount of ethanol added is 1.8 times the weight of methyl anthranilate; the amount of water added is 1.2 times the weight of methyl anthranilate; the amount of sodium hydroxide added is 55% of the weight of methyl anthranilate; the amount of hydrochloric acid solution added is 1.5 times the weight of methyl anthranilate; and the amount of water added is 12 times the weight of methyl anthranilate.

[0076] S3.1, add ethanol to dissolve the dihydroavenate alkaloids obtained in step S2, then add activated carbon, filter and obtain a primary refined product of dihydroavenate alkaloids. The amount of the ethanol used is 3.7 times the weight of methyl anthranilate. The amount of activated carbon used is 3% of the weight of methyl anthranilate.

[0077] S3.2, add ethanol to dissolve the dihydroavenate alkaloid primary refined product obtained in step S3.1, then add activated carbon, filter with suction, and dry to obtain a white crystalline powder, which is the dihydroavenate alkaloid secondary refined product, with a yield of 82.1%. The purity of the obtained dihydroavenate alkaloid secondary refined product determined by HPLC is 99.8%. The amount of the above ethanol used is 3.7 times the weight of methyl anthranilate. The amount of activated carbon used is 3% of the weight of methyl anthranilate.

[0078] Embodiment 4:

[0079] A method for preparing dihydroavenate alkaloids comprises the following steps:

[0080] S1. Add 445 g of hydroxyphenylpropionic acid and 303 g of methyl anthranilate to the reactor, then add 2130 g of high boiling point solvent xylene and 3.3 g of catalyst 3,4,5-trifluorophenylboric acid, raise the temperature, and react at 135° C. for 3.5 hours. After the reaction is completed, xylene is concentrated under negative pressure to obtain a concentrated solution with an acid amine intermediate content of more than 98.5%.

[0081] S2, add 567g ethanol, 395g water and 170g sodium hydroxide to the concentrated solution containing the acid amine intermediate obtained in S1, heat to 85°C, make the hydrolysis reaction system form micro-reflux, after reaction for 3.5h, the acid amine intermediate content in the hydrolysis reaction system is less than 0.2wt%, and the hydrolysis reaction ends. Concentrate ethanol. Then add 485g hydrochloric acid solution and 3785g water with a concentration of 36wt% to the reactor, cool to 20°C and then acidify for 1.5h, filter, rinse, dry, and obtain 603.6g dihydroavenous alkaloids, with a yield of 91.3%, and the purity of the obtained dihydroavenous alkaloids determined by HPLC is 86.3%.

[0082] In this embodiment, the above-mentioned two-step synthesis route is used to obtain dihydroavenate alkaloids with a yield of more than 90% and a purity of more than 80% through condensation reaction, hydrolysis reaction and acidification reaction. There are few by-products and they are easy to separate and remove. No additional reagents are required in the reaction to protect the phenolic hydroxyl groups on the benzene ring in the raw material, which reduces the operation steps and reagent costs, generates less three wastes, is environmentally friendly, and reduces production costs.

[0083] Embodiment 5:

[0084] A method for preparing dihydroavenate alkaloids comprises the following steps:

[0085] S1. Add 325 g of hydroxyphenylpropionic acid and 225 g of methyl anthranilate to the reactor, then add 1240 g of high boiling point solvent xylene and 2.3 g of catalyst 3,4,5-trifluorophenylboric acid, raise the temperature, and react at 140°C for 4.5 hours. After the reaction is completed, xylene is concentrated under negative pressure to obtain a concentrated solution with an acid amine intermediate content of more than 98.5%.

[0086] S2, add 383g ethanol, 260g water and 120g sodium hydroxide to the concentrated solution containing the acid amine intermediate obtained in S1, heat to 80°C, so that the hydrolysis reaction system forms a micro-reflux, after reacting for 3.5h, the acid amine intermediate content in the hydrolysis reaction system is less than 0.2wt%, and the hydrolysis reaction ends. Concentrate ethanol. Then add 350g hydrochloric acid solution with a concentration of 36wt% and 2590g water to the reactor, cool to 30°C and then acidify for 1.5h, filter, rinse, and dry to obtain 474.0g dihydroavenous alkaloids, with a yield of 93.7%, and the purity of the obtained dihydroavenous alkaloids determined by HPLC is 84.6%.

[0087] S3. Add 865 g of ethanol to dissolve the dihydroavenate alkaloids obtained in step S2, then add 8 g of activated carbon, filter with suction, and dry to obtain 375.7 g of a refined dihydroavenate alkaloid with a yield of 87.1%. The purity of the refined dihydroavenate alkaloids obtained by HPLC is 99.2%.

[0088] In this embodiment, after the dihydroavenate alkaloids were subjected to one refining operation of ethanol recrystallization and activated carbon decolorization, the yield decreased slightly, but the yield was still maintained at more than 85%, and the purity of the refined product could reach more than 99%. It can be seen that the crude dihydroavenate alkaloids are easy to refine and purify, saving the refining cost.

[0089] Embodiment 6:

[0090] A method for preparing dihydroavenate alkaloids comprises the following steps:

[0091] S1. Add 98g of hydroxyphenylpropionic acid and 80g of methyl anthranilate to the reactor, then add 560g of high boiling point solvent xylene and 0.8g of catalyst 3,4,5-trifluorophenylboric acid, raise the temperature, and react at 137°C for 4h. After the reaction is completed, xylene is concentrated under negative pressure to obtain a concentrated solution with an acid amine intermediate content of more than 98.5%.

[0092] S2, add 148g ethanol, 94g water and 40g sodium hydroxide to the concentrated solution containing the acid amine intermediate obtained in S1, heat to 83°C, so that the hydrolysis reaction system forms a micro-reflux, after reacting for 3h, the acid amine intermediate content in the hydrolysis reaction system is less than 0.2wt%, and the hydrolysis reaction ends. Concentrate ethanol. Then add 120g hydrochloric acid solution with a concentration of 36wt% and 900g water to the reactor, cool to 25°C and then acidify for 1h, filter and rinse to obtain 154.0g dihydroavenous alkaloids, with a yield of 94.1%, and the purity of the obtained dihydroavenous alkaloids determined by HPLC is 83.7%.

[0093] S3.1. Add 300 g of ethanol to dissolve the dihydroavenate alkaloids obtained in step S2, then add 2 g of activated carbon, filter and obtain 121.8 g of a refined dihydroavenate alkaloid with a yield of 88.3%. The purity of the refined dihydroavenate alkaloids obtained by HPLC is 99.3%.

[0094] S3.2. Add 300 g of ethanol to dissolve the primary refined product of dihydroavenate alkaloid obtained in step S3.1, then add 2 g of activated carbon, filter and dry to obtain 118.6 g of white crystalline powder, which is the secondary refined product of dihydroavenate alkaloid. The yield is 86.5%. The purity of the secondary refined product of dihydroavenate alkaloid obtained by HPLC is 99.8%.

[0095] In this embodiment, the crude dihydroaatmeal alkaloids were subjected to two repetitions of ethanol recrystallization and activated carbon decolorization, and the yield and output decreased slightly, but the yield was still maintained at more than 85%, and the purity of the secondary refined product could reach 99.8%. It can be seen that the crude dihydroaatmeal alkaloids were easy to purify, and the purity of the refined product after purification was also significantly improved. The ethanol and the like in the refining operation could be recovered and reused, saving the refining cost.

[0096] It should be noted that in the present invention, the detailed steps of some operations are not described in detail, but belong to the prior art known to those skilled in the art, so they will not be repeated here. In addition, in the present invention, all features such as values, quantities, contents and concentrations defined in the form of numerical ranges or percentage ranges are only for simplicity and convenience. Accordingly, the description of numerical ranges or percentage ranges should be deemed to have covered and specifically disclosed all possible secondary ranges and individual values ​​(including integers and fractions) within the range.

[0097] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit them. In the present invention, not all possible combinations of the various technical features in the various embodiments or embodiments are described. As long as there is no contradiction in the combination of these technical features, the various technical features in the various embodiments or embodiments can be arbitrarily combined, and all possible combinations should be considered to be within the scope of this specification. Although the present invention has been described in detail with reference to the aforementioned embodiments, a person of ordinary skill in the art should understand that the technical solutions described in the aforementioned embodiments can still be modified, or some or all of the technical features therein can be replaced by equivalents; and these modifications or replacements do not make the essence of the corresponding technical solutions deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for preparing dihydroavenate alkaloids, characterized in that: include: S1, using p-hydroxyphenylpropionic acid and methyl anthranilate as raw materials, in a high boiling point solvent environment, under the action of a catalyst, a condensation reaction is performed to generate an acid amine intermediate; S2, sequentially subjecting the acid amine intermediate to a hydrolysis reaction and an acidification reaction to obtain the dihydroavenate alkaloid; the yield of the dihydroavenate alkaloid is more than 80%; The high boiling point solvent is xylene; and the catalyst is substituted aryl boronic acid.

2. The method for preparing dihydroavenate alkaloids according to claim 1, characterized in that: The molar ratio of methyl anthranilate to p-hydroxyphenylpropionic acid is 1:(1.1-1.5); the catalyst substituted aromatic boronic acid is at least one of o-nitrophenylboric acid, 3,4,5-trifluorophenylboric acid, phenylboric acid, and 1,4-phenyldiboric acid.

3. The method for preparing dihydroavenate alkaloids according to claim 1, characterized in that: The usage amount of the high boiling point solvent is 5-8 times the weight of methyl anthranilate; the usage amount of the catalyst is 1-1.2% of the weight of methyl anthranilate.

4. The method for preparing dihydroavenate alkaloids according to claim 1, characterized in that: The reaction temperature of the condensation reaction is 130-145° C. and the reaction time is 3.5-4.5 hours.

5. The method for preparing dihydroavenate alkaloids according to claim 1, characterized in that: The reaction temperature of the hydrolysis reaction is 80-85° C., the time is 2.5-4 hours, and the content of the acid amine intermediate in the hydrolysis reaction system is less than 0.2 wt %.

6. The method for preparing dihydroavenate alkaloids according to claim 5, characterized in that: The hydrolysis reaction system also includes ethanol, water and sodium hydroxide; the added amount of the ethanol is 1.6-2 times the weight of methyl anthranilate; the added amount of the water is 1-1.4 times the weight of methyl anthranilate; and the added amount of the sodium hydroxide is 45-60% of the weight of methyl anthranilate.

7. The method for preparing dihydroavenate alkaloids according to claim 1, characterized in that: The reaction temperature of the acidification reaction is 20-30° C. and the reaction time is 1-2 h.

8. The method for preparing dihydroavenate alkaloids according to claim 7, characterized in that: The reaction system of the acidification reaction also includes a hydrochloric acid solution with a concentration of 36wt% and water; the amount of the hydrochloric acid solution added is 1.4-1.7 times the weight of methyl anthranilate; and the amount of water added is 11-13 times the weight of methyl anthranilate.

9. The method for preparing dihydroavenate alkaloids according to any one of claims 1 to 8, characterized in that: The preparation method further comprises: S3. The dihydroavenate alkaloids obtained in S2 are sequentially recrystallized, decolorized, filtered and dried to obtain a refined dihydroavenate alkaloids product.

10. The method for preparing dihydroavenate alkaloids according to claim 9, characterized in that: The solvent used in the recrystallization is ethanol; and the solvent used in the decolorization is activated carbon.

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