Process for the preparation of diethylhexyl butanoylaminotriazinone

Abstract

The application provides a preparation method of diethylhexyl butyrylaminotriazinone, which comprises the following steps: (1) reacting cyanuric chloride and p-aminobenzoic acid to obtain an intermediate I; (2) reacting the intermediate I with thionyl chloride to obtain an intermediate II; and (3) reacting the intermediate II with tert-butylamine and isooctanol to obtain diethylhexyl butyrylaminotriazinone. The process has the following advantages: raw materials are easy to obtain, the yield is high, the operation is simple, the cost is low, and the process is easy to industrialize.

Description

Technical Field

[0001] This invention pertains to the preparation method of sunscreen agents, specifically relating to a method for synthesizing the sunscreen agent diethylhexylbutamidotriazinone. Background Technology

[0002] Ultraviolet radiation in sunlight can be divided into three bands based on wavelength: UV-A (315-400nm), UV-B (285-315nm), and UV-C (200-285nm). The sunscreen agent diethylhexylbutyramidotriazinone (HEB) is a triazinone ultraviolet absorber that absorbs ultraviolet light in the 280-320nm range, with an absorption peak at 311nm. Its structural formula is as follows:

[0003]

[0004] HEB, as a novel triazine-based ultraviolet absorber, has the following advantages: it absorbs a wide range of ultraviolet wavelengths and possesses excellent thermal and photostable stability. Currently, it has been included in the permitted sunscreen agent lists of countries and regions such as the United States, Australia, the European Union, and Japan.

[0005] The synthetic routes for HEB reported domestically and internationally fall into two categories:

[0006] Method 1: Patents US5346691A and CN105130918A propose the following: using cyanuric chloride and 4-amino-N-tert-butylbenzamide as raw materials, intermediate A: N-tert-butyl-4-[(4,6-dichloro-1,3,5-triazin-2-yl)amino]benzamide is synthesized at low temperature in acetone solvent.

[0007] The target product HEB was then synthesized using the intermediate and isooctyl p-aminobenzoate.

[0008]

[0009] Method 2: Patent WO2013156270 proposes the following method: Using cyanuric chloride and 4-aminobenzoic acid as raw materials, intermediate B, 4-(4,6-dichloro-1,3,5-triazin-2-yl)aminobenzoic acid, is synthesized at low temperature in acetone. Intermediate B and isooctyl p-aminobenzoate are then used to synthesize intermediate C, 4-(4,6-di(4-((2-ethylhexyloxy)carbonyl)phenylamino)-1,3,5-triazin-2-ylamino)benzoic acid. Intermediate C is then reacted with thionyl chloride and tert-butylamine to synthesize the target product HEB.

[0010]

[0011] The above synthetic route has the following problems:

[0012] 1) Both synthetic routes use cyanuric chloride as a raw material to synthesize monosubstituted intermediates. Cyanuric chloride is highly chemically reactive, making it difficult for the reaction to stop at producing only monosubstituted intermediates; disubstituted and trisubstituted products are inevitably generated, leading to purification difficulties. Currently, the purity of commercially available HEB products, both domestically and internationally, is generally low, which is caused by this process.

[0013] 2) To minimize the formation of disubstituted and trisubstituted products, both synthetic routes employ low-temperature reactions (-30℃ to 0℃), limiting the use of acetone as the solvent. Acetone is expensive and volatile, increasing production costs.

[0014] 3) Both synthetic routes use isooctyl p-aminobenzoate as a raw material. This compound is expensive, which makes the production cost of HEB high. Summary of the Invention

[0015] The purpose of this invention is to provide a method for preparing the sunscreen agent diethylhexylbutamidotriazine ketone suitable for industrial production, which has the advantages of readily available raw materials, high purity, simple operation, low cost, and ease of industrialization.

[0016] The preparation method of diethylhexylbutamidotriazinone includes the following steps:

[0017] (1) Intermediate I was prepared by reacting cyanuric chloride with p-aminobenzoic acid;

[0018] (2) Intermediate I reacts with thionyl chloride to give intermediate II;

[0019] (3) Intermediate II reacts with tert-butylamine and isooctyl alcohol to give diethylhexylbutamidotriazinone;

[0020] The reaction formula is as follows:

[0021]

[0022]

[0023] This invention uses cyanuric chloride as a raw material to obtain the sunscreen agent diethylhexylbutamidotriazinone through a three-step reaction. This invention presents a novel process route that effectively solves the problems of poor reaction selectivity, high cost, and long reaction time in existing processes. First, cyanuric chloride is reacted with excess p-aminobenzoic acid to directly synthesize intermediate I of the trisubstituted product, resulting in fewer impurities and easier purification. Second, since intermediate I is a trisubstituted product, its reaction conditions are easily controlled; the synthesis temperature can be increased to reflux temperature, and inexpensive aromatic hydrocarbons can be used as solvents, making it easily achievable in production.

[0024] In this invention, in order to improve the efficiency of the reaction, the reaction pressure in step (1) is 5-10 kPa, for example 5 kPa, 6 kPa, 7 kPa, 8 kPa, 9 kPa, or 10 kPa.

[0025] In this invention, to improve reaction efficiency and shorten reaction time, the reaction temperature in step (1) is the reflux temperature. In specific embodiments, the micro-reflux temperature in step (1) generally refers to a reaction temperature of 100-125℃.

[0026] Preferably, the specific steps of step (1) are as follows: add p-aminobenzoic acid and solvent to the reactor, heat to 70-75°C, reduce pressure to a vacuum of 5-10 kPa, add cyanuric chloride, and heat to reflux and maintain the temperature for reaction.

[0027] The study found that in the route of step (1), the reaction of cyanuric chloride with three molecules of p-aminobenzoic acid does not have a selectivity problem. The addition of a slight excess of p-aminobenzoic acid is completely converted into intermediate I, which produces the trisubstituted product. Therefore, it is not necessary to control the reaction under low temperature conditions, which greatly improves the reaction rate and efficiency and saves reaction time.

[0028] In a specific embodiment, the reaction time of step (1) is 1-3 hours, preferably 2 hours.

[0029] In a specific embodiment, the solvent in step (1) is one of toluene, xylene, cyclohexane, n-hexane, and n-heptane; preferably, the solvent is xylene.

[0030] In a specific embodiment, the molar ratio of cyanuric chloride to p-aminobenzoic acid in step (1) is 1:3.0 to 5.0, for example, 1:3, 1:3.2, 1:3.5, 1:3.8, 1:4, 1:4.5, 1:4.8, or 1:5. Preferably, the molar ratio of cyanuric chloride to p-aminobenzoic acid is 1:3.2 to 3.5.

[0031] To obtain a purer intermediate I, after the reaction in step (1) is completed, a post-processing step is also included: acid washing, water washing, solvent removal, and crystallization to obtain intermediate I.

[0032] In a specific embodiment, the crystallization solvent of intermediate I of product in step (1) is a mixture of organic solvent and water. The organic solvent is one of methanol, ethanol, isopropanol, tetrahydrofuran, and 1,6-dioxane; preferably, the solvent is ethanol; wherein the ratio of organic solvent to water is 1:1.0 to 3.0, for example, 1:1, 1:1.5, 1:2, 1:2.5, 1:2.8, 1:3, and preferably 1:1.5.

[0033] In this invention, in step (2), the reaction temperature is 50-70℃ and the reaction time is 1-2h.

[0034] In this invention, in step (2), thionyl chloride and xylene are added to the reactor, the temperature is raised to 50-70°C, intermediate I is added, and the reaction is kept at the temperature after the addition is completed.

[0035] Step (2) synthesizes intermediate II. The reaction is simple and the yield is high. Its concentrate does not need to be purified and can be directly used for the synthesis in step 3.

[0036] In a specific embodiment, the solvent in step (2) is one of toluene, xylene, cyclohexane, n-hexane, and n-heptane, with xylene being the preferred solvent. In a specific embodiment, the addition of intermediate I is a slow dropwise addition of a xylene suspension of intermediate I.

[0037] In a specific embodiment, a small amount of N,N-dimethylformamide can be added as a catalyst to accelerate the reaction rate of step (2).

[0038] In a specific embodiment, in step (2), the molar ratio of intermediate I to thionyl chloride is 1:3.0 to 4.5; for example, 1:3, 1:3.2, 1:3.3, 1:3.5, 1:3.7, 1:3.8, 1:4.0, 1:4.5. Preferably, the molar ratio of intermediate I to thionyl chloride is 1:3.3 to 3.8.

[0039] In this invention, in step (3), intermediate II first reacts with tert-butylamine and then with isooctyl alcohol;

[0040] Preferably, the reaction temperature for intermediate II to react with tert-butylamine is 30-70°C; and the reaction temperature for reacting with isooctyl alcohol is 50-110°C.

[0041] More preferably, the specific steps of step (3) are as follows: add xylene solution of intermediate II obtained in step 2 to the reactor, add tert-butylamine dropwise at 30-50°C, and keep warm for 1-2 hours after the addition is completed; then raise the temperature to 50-70°C, add isooctyl alcohol dropwise, and keep warm for 1-2 hours after the addition is completed; raise the temperature to 90-110°C, keep warm for 1-2 hours, and the reaction ends.

[0042] In a specific embodiment, the molar ratio of intermediate II to tert-butylamine in step (3) is 1:0.9-1.1; for example: 1:0.92, 1:0.95, 1:0.96, 1:0.98, 1:1.0, 1:1.1, with a preferred molar ratio of 1:0.92 to 0.96.

[0043] In a specific embodiment, the molar ratio of intermediate II to isooctanol in step (3) is 1:2.0-2.5; for example: 1:2.0, 1:2.1, 1:2.2, 1:2.3, 1:2.4, 1:2.5, with a preferred molar ratio of 1:2.1 to 2.3.

[0044] In a specific embodiment, the solvent in step (3) is one of toluene, xylene, cyclohexane, n-hexane, and n-heptane; preferably, the solvent is xylene.

[0045] The solvents used in the three-step reaction of this invention are basically the same. In actual production, it is preferred to use the same solvent. After each step of the reaction, only simple processing is required before it can be directly used in the next step of the reaction, which simplifies the production process and improves the overall yield of the reaction.

[0046] Preferably, the post-processing steps of step (3) include: alkali washing, water washing, concentration, and crystallization to obtain the diethylhexylbutamidotriazinone product.

[0047] The present invention has achieved the following positive effects: the synthetic route described herein has high selectivity, with a total yield of over 90% for the sunscreen agent diethylhexylbutamidotriazine and a chromatographic purity of over 99%; the route of the present invention can use the same reaction solvent, and only simple processing is required after each reaction before it can be directly used in the next reaction; the raw materials used in the route of the present invention are widely available and low in cost, the process is simple and easy to industrialize, and the total reaction time is short. Detailed Implementation

[0048] The present invention is described in detail below with reference to specific embodiments. However, it should be noted that the scope of protection of the present invention is not limited by these specific embodiments and principle explanations, but is determined by the claims.

[0049] In this invention, except where expressly stated, any matters or issues not mentioned herein are directly applicable to those known in the art without any modification. Furthermore, any implementation described herein can be freely combined with one or more other implementations described herein, and the resulting technical solutions or concepts are considered part of the original disclosure or original record of this invention, and should not be regarded as new content not disclosed or anticipated herein, unless those skilled in the art consider the combination clearly unreasonable.

[0050] All features disclosed in this invention can be combined arbitrarily, and such combinations should be understood as the contents disclosed or recorded in this invention, unless those skilled in the art consider such combinations to be obviously unreasonable.

[0051] The numerical points disclosed in this specification include not only the numerical points specifically disclosed in the embodiments, but also the endpoints of each numerical range in the specification. Any combination of these numerical points should be regarded as the range disclosed or recorded in this invention.

[0052] The term "droplet addition" as used in this invention refers to slow addition, as understood by those skilled in the art, without strict flow rate limitations, and is intended to avoid affecting the stability and progress of the reaction.

[0053] In this invention, the technical and scientific terms that are given a definition shall be used as defined thereon, and those that are not given a definition shall be understood according to their common meaning in the art.

[0054] The molecular structure of diethylhexylbutamidotriazinone is complex due to the different substituents in its three components. Therefore, the selectivity of reaction conditions is crucial for the yield and purity of the product. As described in the background section, existing synthetic routes often fail to reach a single-substituted intermediate, resulting in di- and tri-substituted products with low purity (less than 99%). Furthermore, the use of acetone as a solvent and isooctyl p-aminobenzoate as a raw material in existing technologies leads to high costs. Since diethylhexylbutamidotriazinone is used as a sunscreen agent in daily chemical products, high purity is required. Improving the purity of the precursor without adding new post-processing steps is a pressing technical problem in this field. Patent CN110229113A also improved the process, achieving a purity of over 99%, but its reaction time exceeds 44 hours, resulting in low production efficiency.

[0055] This invention provides a method for preparing diethylhexylbutamidotriazinone, comprising the following steps:

[0056] (1) Synthesis of intermediate I: Add p-aminobenzoic acid and xylene solvent to the reaction vessel and reduce the pressure to a vacuum of 5-10 kPa. Raise the temperature to 70-75°C and begin adding cyanuric chloride dropwise over 30-60 minutes. After the addition is complete, maintain the temperature. Raise the temperature to 100-110°C and maintain the temperature for 1-2 hours.

[0057] After the reaction was complete, the temperature was lowered to 70-80℃, and the mixture was washed with water until the pH reached 5-6. Xylene was recovered under reduced pressure, and the concentrate was dissolved in ethanol. Then, ethanol and water were added and the mixture was cooled to crystallize, yielding a white solid intermediate I: 2,4,6-tris[(p-carboxyphenyl)amino]-1,3,5-triazinone.

[0058] (2) Synthesis of intermediate II: Thionyl chloride and xylene, along with 2-3 drops of DMF, were added to the reaction vessel. At 60-65℃, a xylene suspension of intermediate I was added dropwise over 1 hour. After the addition was complete, the mixture was kept at this temperature for 1-2 hours. Once the reaction was complete, thionyl chloride was distilled under reduced pressure until some xylene was distilled off, yielding a pale yellow intermediate II: 2,4,6-tris[(p-chlorocarbonylphenyl)amino]-1,3,5-triazinone.

[0059] (3) Synthesis of HEB: The concentrated solution obtained in the previous step was added to the reaction vessel, and tert-butylamine and xylene solvent were added dropwise at 30-40℃. After the addition was complete, the temperature was maintained for 1-2 hours. Then the temperature was raised to 50-60℃, and isooctyl alcohol was added dropwise. After the addition was complete, the temperature was maintained for 1-2 hours. The temperature was raised to 90-100℃ and maintained for 1-2 hours.

[0060] After the reaction is complete, cool to 70-80℃, wash once with water to achieve a pH of 3-4. Adjust the pH to 7-8 with sodium carbonate aqueous solution, and wash once more with water. Recover xylene from the washings under reduced pressure, dissolve the concentrate in ethanol, and then add n-hexane to crystallize. Filter, wash, and dry to obtain a creamy-white product: diethylhexylbutamidotriazinone.

[0061] This invention uses cyanuric chloride and p-aminobenzoic acid as raw materials, eliminating the need for alkaline conditions such as acid-binding agents. A slight negative pressure reduces the hydrogen chloride content, increasing the reaction depth. The resulting intermediate I, after simple crystallization, can be used in the next reaction step. Intermediate I reacts with thionyl chloride, and the reaction solution is purified by removing excess raw materials and solvent to obtain intermediate II, which is then reacted with tert-butylamine and isooctanol to obtain the product. The reaction solvents for all three steps are the same, the intermediates do not require complex post-processing, the overall yield is high, and the product purity can reach over 99%.

[0062] To more clearly and intuitively explain the technical content of the present invention, the following embodiments are provided as examples:

[0063] Example 1

[0064] (1) Synthesis of intermediate I

[0065] Add 59.5 g (0.434 mol) of p-aminobenzoic acid and 150 ml of xylene to a four-necked flask equipped with a thermometer, condenser, constant-pressure dropping funnel, and stirrer. Reduce the pressure to a vacuum of 10 kPa. Raise the temperature to 70-75°C and begin adding a suspension of 25.0 g (0.136 mol) of cyanuric chloride and 60 ml of xylene dropwise over 60 min. After the addition is complete, maintain the temperature for 1 h. Raise the temperature to 100-110°C and maintain the temperature for 2 h.

[0066] After the reaction was complete, the temperature was lowered to 80°C, and the mixture was washed with water until the pH reached 5-6. Xylene was recovered under reduced pressure, and the concentrate was dissolved in ethanol, followed by the addition of water (ethanol:water = 1:1.5). The mixture was then cooled and crystallized to obtain 62.8 g of a white solid. The yield was 95.2%, and the HPLC purity was 99.2%.

[0067] (2) Synthesis of intermediate II

[0068] Under nitrogen protection, add 27.9 g (0.23 mol) of thionyl chloride and 20 ml of anhydrous xylene, along with 2-3 drops of DMF, to a four-necked flask equipped with a thermometer, condenser, constant pressure bottom liquid funnel, and stirrer. At 60-65℃, add 30.0 g (0.062 mol) of intermediate I and 150 ml of anhydrous xylene suspension dropwise over 1 hour. After the addition is complete, maintain the temperature for 1 hour.

[0069] After the reaction was completed, thionyl chloride was distilled under reduced pressure until some xylene was distilled off, yielding a pale yellow intermediate II and a solution of xylene.

[0070] (3) Synthesis of HEB

[0071] Under nitrogen protection, the concentrated solution obtained in the previous step was added to a four-necked flask equipped with a thermometer, condenser, constant pressure bottom liquid funnel, and stirrer. At 30-40℃, 4.3g (0.059mol) of tert-butylamine and 20ml of xylene solution were added dropwise. After the addition was complete, the temperature was maintained for 1-2 hours. Then, the temperature was raised to 50-60℃, and 17.7g (0.136mol) of isooctanol was added dropwise. After the addition was complete, the temperature was maintained for 1-2 hours. The temperature was then raised to 90-100℃ and maintained for 1-2 hours.

[0072] After the reaction was complete, the temperature was lowered to 70-80℃. The mixture was first washed once with water to achieve a pH of 3-4. The pH was then adjusted to 7-8 with a sodium carbonate aqueous solution, followed by a final wash with water. Xylene was recovered from the washings under reduced pressure. The concentrated solution was dissolved in ethanol, and then hexane was added for crystallization. The solution was filtered, washed, and dried to obtain 44.9 g of a off-white product, with a yield of 95.16%.

[0073] HEB total yield 90.6%; liquid chromatography analysis showed purity 99.10%.

[0074] Example 2

[0075] (1) Synthesis of intermediate I

[0076] Add 65.3 g (0.476 mol) of p-aminobenzoic acid and 150 ml of xylene to a four-necked flask equipped with a thermometer, condenser, constant-pressure dropping funnel, and stirrer. Reduce the pressure to a vacuum of 10 kPa. Raise the temperature to 70-75°C and begin adding a suspension of 25.0 g (0.136 mol) of cyanuric chloride and 60 ml of xylene dropwise over 60 min. After the addition is complete, maintain the temperature for 1 h. Raise the temperature to 100-110°C and maintain the temperature for 2 h.

[0077] After the reaction was complete, the temperature was lowered to 70-80℃, and the mixture was washed with water until the pH reached 5-6. Xylene was recovered under reduced pressure, and the concentrate was dissolved in ethanol, followed by the addition of water (ethanol:water = 1:1.5). The mixture was then cooled and crystallized to obtain 62.9 g of a white solid. The yield was 95.3%, and the HPLC purity was 99.0%.

[0078] (2) Synthesis of intermediate II

[0079] Under nitrogen protection, add 27.9 g (0.23 mol) of thionyl chloride and 20 ml of anhydrous xylene, along with 2-3 drops of DMF, to a four-necked flask equipped with a thermometer, condenser, constant pressure bottom liquid funnel, and stirrer. At 60-65℃, add 30.0 g of intermediate I and 150 ml of anhydrous xylene suspension dropwise over 1 hour. After the addition is complete, maintain the temperature for 1 hour.

[0080] After the reaction was completed, thionyl chloride was distilled under reduced pressure until some xylene was distilled off, yielding a pale yellow intermediate II and a solution of xylene.

[0081] (3) Synthesis of HEB

[0082] Under nitrogen protection, the concentrated solution obtained in the previous step was added to a four-necked flask equipped with a thermometer, condenser, constant pressure bottom liquid funnel, and stirrer. At 30-40℃, 4.3g (0.059mol) of tert-butylamine and 20ml of xylene solution were added dropwise. After the addition was complete, the temperature was maintained for 1-2 hours. Then, the temperature was raised to 50-60℃, and 17.7g (0.136mol) of isooctanol was added dropwise. After the addition was complete, the temperature was maintained for 1-2 hours. The temperature was then raised to 90-100℃ and maintained for 1-2 hours.

[0083] After the reaction was complete, the temperature was lowered to 70-80℃. The mixture was first washed once with water to achieve a pH of 3-4. The pH was then adjusted to 7-8 with a sodium carbonate aqueous solution, followed by a final wash with water. Xylene was recovered from the washings under reduced pressure. The concentrated solution was dissolved in ethanol, and then hexane was added for crystallization. The solution was filtered, washed, and dried to obtain 44.9 g of a off-white product, with a yield of 95.16%.

[0084] HEB total yield 90.7%; liquid chromatography analysis showed purity 98.75%.

[0085] Example 3

[0086] (1) Synthesis of intermediate I

[0087] Add 65.3 g (0.476 mol) of p-aminobenzoic acid and 150 ml of xylene to a four-necked flask equipped with a thermometer, condenser, constant-pressure dropping funnel, and stirrer. Reduce the pressure to a vacuum of 10 kPa. Raise the temperature to 70-75°C and begin adding a suspension of 25.0 g (0.136 mol) of cyanuric chloride and 60 ml of xylene dropwise over 60 min. After the addition is complete, maintain the temperature for 1 h. Raise the temperature to 100-110°C and maintain the temperature for 1 h.

[0088] After the reaction was complete, the temperature was lowered to 70-80℃, and the mixture was washed with water until the pH reached 5-6. Xylene was recovered under reduced pressure, and the concentrate was dissolved in ethanol, followed by the addition of water (ethanol:water = 1:1.5). The mixture was then cooled and crystallized to obtain 62.4 g of a white solid. The yield was 94.6%, and the HPLC purity was 98.8%.

[0089] (2) Synthesis of intermediate II

[0090] Under nitrogen protection, add 27.9 g (0.23 mol) of thionyl chloride and 20 ml of anhydrous xylene, along with 2-3 drops of DMF, to a four-necked flask equipped with a thermometer, condenser, constant pressure bottom liquid funnel, and stirrer. At 60-65℃, add 30.0 g of intermediate I and 150 ml of anhydrous xylene suspension dropwise over 1 hour. After the addition is complete, maintain the temperature for 1 hour.

[0091] After the reaction was completed, thionyl chloride was distilled under reduced pressure until some xylene was distilled off, yielding a pale yellow intermediate II and a solution of xylene.

[0092] (3) Synthesis of HEB

[0093] Under nitrogen protection, the concentrated solution obtained in the previous step was added to a four-necked flask equipped with a thermometer, condenser, constant pressure bottom liquid funnel, and stirrer. At 30-40℃, 4.3g (0.059mol) of tert-butylamine and 20ml of xylene solution were added dropwise. After the addition was complete, the temperature was maintained for 1-2 hours. Then, the temperature was raised to 50-60℃, and 17.7g (0.136mol) of isooctanol was added dropwise. After the addition was complete, the temperature was maintained for 1-2 hours. The temperature was then raised to 90-100℃ and maintained for 1-2 hours.

[0094] After the reaction was complete, the temperature was lowered to 70-80℃. The mixture was first washed once with water to achieve a pH of 3-4. The pH was then adjusted to 7-8 with a sodium carbonate aqueous solution, followed by a final wash with water. Xylene was recovered from the washings under reduced pressure. The concentrated solution was dissolved in ethanol, and then hexane was added for crystallization. The solution was filtered, washed, and dried to obtain 44.6 g of a creamy-white product.

[0095] HEB total yield 88.7%; liquid chromatography analysis showed purity 99.00%.

[0096] Example 4

[0097] (1) Synthesis of intermediate I

[0098] Add 59.5 g (0.434 mol) of p-aminobenzoic acid and 150 ml of xylene to a four-necked flask equipped with a thermometer, condenser, constant-pressure dropping funnel, and stirrer. Reduce the pressure to a vacuum of 5-10 kPa. Raise the temperature to 70-75°C and begin adding a suspension of 25.0 g (0.136 mol) of cyanuric chloride and 60 ml of xylene dropwise over 30-60 minutes. After the addition is complete, maintain the temperature for 1 hour. Raise the temperature to 100-110°C and maintain the temperature for 2 hours.

[0099] After the reaction was complete, the temperature was lowered to 70-80℃, and the mixture was washed with water until the pH reached 5-6. Xylene was recovered under reduced pressure, and the concentrate was dissolved in ethanol, followed by the addition of water (ethanol:water = 1:1.5). The mixture was then cooled and crystallized to obtain 62.8 g of a white solid. The yield was 95.2%, and the HPLC purity was 99.2%.

[0100] (2) Synthesis of intermediate II

[0101] Under nitrogen protection, add 29.4 g (0.25 mol) of thionyl chloride and 20 ml of anhydrous xylene, along with 2-3 drops of DMF, to a four-necked flask equipped with a thermometer, condenser, constant pressure bottom liquid funnel, and stirrer. At 60-65℃, add 30.0 g of intermediate I and 150 ml of anhydrous xylene suspension dropwise over 1 hour. After the addition is complete, maintain the temperature for 1 hour.

[0102] After the reaction was completed, thionyl chloride was distilled under reduced pressure until some xylene was distilled off, yielding a pale yellow intermediate II and a solution of xylene.

[0103] (3) Synthesis of HEB

[0104] Under nitrogen protection, the concentrated solution obtained in the previous step was added to a four-necked flask equipped with a thermometer, condenser, constant pressure bottom liquid funnel, and stirrer. At 30-40℃, 4.3g (0.059mol) of tert-butylamine and 20ml of xylene solution were added dropwise. After the addition was complete, the temperature was maintained for 1-2 hours. Then, the temperature was raised to 50-60℃, and 17.7g (0.136mol) of isooctanol was added dropwise. After the addition was complete, the temperature was maintained for 1-2 hours. The temperature was then raised to 90-100℃ and maintained for 1-2 hours.

[0105] After the reaction was complete, the temperature was lowered to 70-80℃. The mixture was first washed once with water to achieve a pH of 3-4. The pH was then adjusted to 7-8 with a sodium carbonate aqueous solution, followed by a final wash with water. Xylene was recovered from the washings under reduced pressure. The concentrated solution was dissolved in ethanol, and then hexane was added for crystallization. The solution was filtered, washed, and dried to obtain 44.3 g (0.058 mol) of a creamy-white product.

[0106] HEB total yield 89.2%; liquid chromatography analysis showed purity 99.00%.

[0107] Example 5

[0108] (1) Synthesis of intermediate I

[0109] Add 59.5 g (0.434 mol) of p-aminobenzoic acid and 150 ml of xylene to a four-necked flask equipped with a thermometer, condenser, constant-pressure dropping funnel, and stirrer. Reduce the pressure to a vacuum of 5-10 kPa. Raise the temperature to 70-75°C and begin adding a suspension of 25.0 g (0.136 mol) of cyanuric chloride and 60 ml of xylene dropwise over 30-60 minutes. After the addition is complete, maintain the temperature for 1 hour. Raise the temperature to 100-110°C and maintain the temperature for 2 hours.

[0110] After the reaction was complete, the temperature was lowered to 70-80℃, and the mixture was washed with water until the pH reached 5-6. Xylene was recovered under reduced pressure, and the concentrate was dissolved in ethanol, followed by the addition of water (ethanol:water = 1:1.5). The mixture was then cooled and crystallized to obtain 62.8 g of a white solid. The yield was 95.2%, and the HPLC purity was 99.2%.

[0111] (2) Synthesis of intermediate II

[0112] Under nitrogen protection, add 27.9 g (0.23 mol) of thionyl chloride and 20 ml of anhydrous xylene, along with 2-3 drops of DMF, to a four-necked flask equipped with a thermometer, condenser, constant pressure bottom liquid funnel, and stirrer. At 60-65℃, add 30.0 g of intermediate I and 150 ml of anhydrous xylene suspension dropwise over 1 hour. After the addition is complete, maintain the temperature for 1 hour.

[0113] After the reaction was completed, thionyl chloride was distilled under reduced pressure until some xylene was distilled off, yielding a pale yellow intermediate II and a solution of xylene.

[0114] (3) Synthesis of HEB

[0115] Under nitrogen protection, the concentrated solution obtained in the previous step was added to a four-necked flask equipped with a thermometer, condenser, constant pressure bottom liquid funnel, and stirrer. At 30-40℃, 4.5g (0.062mol) of tert-butylamine and 20ml of xylene solution were added dropwise. After the addition was complete, the temperature was maintained for 1-2 hours. Then, the temperature was raised to 50-60℃, and 17.7g (0.136mol) of isooctanol was added dropwise. After the addition was complete, the temperature was maintained for 1-2 hours. The temperature was then raised to 90-100℃ and maintained for 1-2 hours.

[0116] After the reaction was complete, the temperature was lowered to 70-80℃. The mixture was first washed once with water to achieve a pH of 3-4. The pH was then adjusted to 7-8 with a sodium carbonate aqueous solution, followed by a final wash with water. Xylene was recovered from the washings under reduced pressure. The concentrated solution was dissolved in ethanol, and then hexane was added for crystallization. The solution was filtered, washed, and dried to obtain 42.5 g (0.056 mol) of a creamy-white product.

[0117] HEB total yield 85.6%; liquid chromatography analysis showed purity 99.01%.

[0118] Example 6

[0119] (1) Synthesis of intermediate I

[0120] Add 59.5 g (0.434 mol) of p-aminobenzoic acid and 150 ml of xylene to a four-necked flask equipped with a thermometer, condenser, constant-pressure dropping funnel, and stirrer. Reduce the pressure to a vacuum of 5-10 kPa. Raise the temperature to 70-75°C and begin adding a suspension of 25.0 g (0.136 mol) of cyanuric chloride and 60 ml of xylene dropwise over 30-60 minutes. After the addition is complete, maintain the temperature for 1 hour. Raise the temperature to 100-110°C and maintain the temperature for 2 hours.

[0121] After the reaction was complete, the temperature was lowered to 70-80℃, and the mixture was washed with water until the pH reached 5-6. Xylene was recovered under reduced pressure, and the concentrate was dissolved in ethanol, followed by the addition of water (ethanol:water = 1:1.5). The mixture was then cooled and crystallized to obtain 62.8 g of a white solid. The yield was 95.2%, and the HPLC purity was 99.2%.

[0122] (2) Synthesis of intermediate II

[0123] Under nitrogen protection, add 27.9 g (0.23 mol) of thionyl chloride and 20 ml of anhydrous xylene, along with 2-3 drops of DMF, to a four-necked flask equipped with a thermometer, condenser, constant pressure bottom liquid funnel, and stirrer. At 60-65℃, add 30.0 g of intermediate I and 150 ml of anhydrous xylene suspension dropwise over 1 hour. After the addition is complete, maintain the temperature for 1 hour.

[0124] After the reaction was completed, thionyl chloride was distilled under reduced pressure until some xylene was distilled off, yielding a pale yellow intermediate II and a solution of xylene.

[0125] (3) Synthesis of HEB

[0126] Under nitrogen protection, the concentrated solution obtained in the previous step was added to a four-necked flask equipped with a thermometer, condenser, constant pressure bottom liquid funnel, and stirrer. At 30-40℃, 4.3g (0.059mol) of tert-butylamine and 20ml of xylene solution were added dropwise. After the addition was complete, the temperature was maintained for 1-2 hours. Then, the temperature was raised to 50-60℃, and 20.1g (0.154mol) of isooctanol was added dropwise. After the addition was complete, the temperature was maintained for 1-2 hours. The temperature was then raised to 90-100℃ and maintained for 1-2 hours.

[0127] After the reaction was complete, the temperature was lowered to 70-80℃. The mixture was first washed once with water to achieve a pH of 3-4. The pH was then adjusted to 7-8 with a sodium carbonate aqueous solution, followed by a final wash with water. Xylene was recovered from the washings under reduced pressure. The concentrated solution was dissolved in ethanol, and then hexane was added for crystallization. The solution was filtered, washed, and dried to obtain 44.8 g (0.058 mol) of a creamy-white product.

[0128] HEB total yield 90.2%; liquid chromatography analysis showed purity 99.10%.

[0129] Example 7

[0130] (1) Synthesis of intermediate I

[0131] Add 59.5 g (0.434 mol) of p-aminobenzoic acid and 150 ml of xylene to a four-necked flask equipped with a thermometer, condenser, constant-pressure dropping funnel, and stirrer. Raise the temperature to 70-75°C under normal pressure, and begin adding a suspension of 25.0 g (0.136 mol) of cyanuric chloride and 60 ml of xylene dropwise over 60 minutes. After the addition is complete, maintain the temperature for 1 hour. Then raise the temperature to 100-110°C and maintain the temperature for 2 hours.

[0132] After the reaction was complete, the temperature was lowered to 80°C, and the mixture was washed with water until the pH reached 5-6. Xylene was recovered under reduced pressure, and the concentrate was dissolved in ethanol, followed by the addition of water (ethanol:water = 1:1.5). The mixture was then cooled and crystallized to obtain 61.5 g of a white solid. The yield was 93.2%, and the HPLC purity was 97.4%.

[0133] (2) Synthesis of intermediate II

[0134] Under nitrogen protection, add 27.9 g (0.23 mol) of thionyl chloride and 20 ml of anhydrous xylene, along with 2-3 drops of DMF, to a four-necked flask equipped with a thermometer, condenser, constant pressure bottom liquid funnel, and stirrer. At 60-65℃, add 30.0 g (0.062 mol) of intermediate I and 150 ml of anhydrous xylene suspension dropwise over 1 hour. After the addition is complete, maintain the temperature for 1 hour.

[0135] After the reaction was completed, thionyl chloride was distilled under reduced pressure until some xylene was distilled off, yielding a pale yellow intermediate II and a solution of xylene.

[0136] (3) Synthesis of HEB

[0137] Under nitrogen protection, the concentrated solution obtained in the previous step was added to a four-necked flask equipped with a thermometer, condenser, constant pressure bottom liquid funnel, and stirrer. At 30-40℃, 4.3g (0.059mol) of tert-butylamine and 20ml of xylene solution were added dropwise. After the addition was complete, the temperature was maintained for 1-2 hours. Then, the temperature was raised to 50-60℃, and 17.7g (0.136mol) of isooctanol was added dropwise. After the addition was complete, the temperature was maintained for 1-2 hours. The temperature was then raised to 90-100℃ and maintained for 1-2 hours.

[0138] After the reaction was complete, the temperature was lowered to 70-80℃. The mixture was first washed once with water to adjust the pH to 3-4. Then, the pH was adjusted to 7-8 with sodium carbonate aqueous solution, and finally washed once with water. Xylene was recovered from the washings under reduced pressure. The concentrated solution was dissolved in ethanol, and then hexane was added for crystallization. The solution was filtered, washed, and dried to obtain 44.9 g of a off-white product, with a yield of 95.16%.

[0139] HEB total yield 88.71%; liquid chromatography analysis showed purity 98.9%.

[0140] Although the present invention has been described in detail above with general descriptions, specific embodiments, and experiments, modifications or improvements can be made to it, which will be obvious to those skilled in the art. Therefore, all such modifications or improvements made without departing from the spirit of the present invention fall within the scope of protection claimed by the present invention.

Claims

1. A method for preparing diethylhexylbutamidotriazinone, comprising the following steps: (1) Intermediate I was prepared by reacting cyanuric chloride with p-aminobenzoic acid; (2) Intermediate I reacts with thionyl chloride to give intermediate II; (3) Intermediate II reacts with tert-butylamine and isooctyl alcohol to give diethylhexylbutamidotriazinone; The reaction formula is as follows: ； In step (3), intermediate II first reacts with tert-butylamine, and then with isooctyl alcohol. In step (2), intermediate II is obtained. Tert-butylamine is added dropwise at 30-50℃. After the addition is completed, the temperature is maintained for 1-2 hours. Then the temperature is raised to 50-70℃, and isooctyl alcohol is added dropwise. After the addition is completed, the temperature is maintained for 1-2 hours. The temperature is raised to 90-110℃ and maintained for 1-2 hours.

2. The preparation method according to claim 1, characterized in that, The reaction pressure in step (1) is 5-10 kPa, and / or the reaction temperature is the reflux temperature.

3. The preparation method according to claim 2, characterized in that, Step (1) includes: adding p-aminobenzoic acid and solvent to the reactor, heating to 70-75℃, reducing the pressure to a vacuum of 5-10 kPa, adding cyanuric chloride, and heating to reflux and maintaining the temperature for reaction.

4. The preparation method according to claim 1 or 2, characterized in that, The reaction time of step (1) is 1-3 h; and / or the solvent in step (1) is at least one of toluene, xylene, cyclohexane, n-hexane, and n-heptane; The molar ratio of raw material cyanuric chloride to p-aminobenzoic acid is 1:3.0~5.

0.

5. The preparation method according to claim 1 or 2, characterized in that, The solvent in step (1) is xylene; the molar ratio of raw material cyanuric chloride to p-aminobenzoic acid is 1:3.2~3.

5.

6. The preparation method according to claim 1, characterized in that, After the reaction in step (1) is completed, intermediate I is obtained by washing with water, removing solvent, and crystallizing.

7. The preparation method according to claim 1, characterized in that, In step (2), the reaction temperature is 50-70℃ and the reaction time is 1-2h.

8. The preparation method according to claim 7, characterized in that, The solvent in step (2) is one of toluene, xylene, cyclohexane, n-hexane, and n-heptane, and / or... In step (2), the molar ratio of reactant intermediate I to thionyl chloride is 1:3.0~4.

5.

9. The preparation method according to claim 8, characterized in that, The solvent in step (2) is xylene; and / or, the molar ratio of intermediate I to thionyl chloride is 1:3.3~3.

8.

10. The preparation method according to claim 1, characterized in that, In step (3), the molar ratio of intermediate II to tert-butylamine is 1:0.9-1.1; and / or, The molar ratio of intermediate II to isooctanol in step (3) is 1:2.0-2.

5.

11. The preparation method according to claim 10, characterized in that, The post-processing steps of step (3) include: alkaline washing, water washing, concentration, and crystallization to obtain diethylhexylbutamidotriazinone.

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