Preparation method of diethylhexyl butyrylamide triazinone

Abstract

The invention provides a preparation method of diethyl hexyl butyrylamide triazinone. The preparation method comprises the following steps: (1) reacting cyanuric chloride with para aminobenzoic acid to prepare 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 the diethylhexyl butyrylamide triazinone. The process disclosed by the invention has the advantages of easily available raw materials, high yield, simplicity in operation, low cost and easiness in industrialization.

Description

Technical Field

[0001] The invention belongs to a method for preparing a sunscreen agent, and specifically relates to a method for synthesizing diethylhexyl butyramido triazone, a sunscreen agent. Background Art

[0002] The ultraviolet rays in sunlight can be divided into three bands according to different wavelengths: UV-A (315-400nm), UV-B (285-315nm), and UV-C (200-285nm). Sunscreen agent diethylhexyl butyramido triazone, referred to as HEB, is a triazone ultraviolet absorber that can absorb 280-320nm ultraviolet light with an absorption peak of 311nm. The structural formula is as follows:

[0003]

[0004] HEB is a new type of triazine UV absorber with the following advantages: wide wavelength range of UV absorption, excellent thermal stability and photostability. Currently, it has been included in the list of sunscreen varieties allowed for use in countries and regions such as the United States, Australia, the European Union, and Japan.

[0005] There are two synthetic routes of HEB reported domestically and abroad:

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

[0007] The intermediate is then used with isooctyl p-aminobenzoate to synthesize the target product HEB.

[0008]

[0009] Method 2: Patent WO2013156270 proposes: using raw materials cyanuric chloride and 4-aminobenzoic acid, intermediate B is synthesized at low temperature in acetone: 4-(4,6-dichloro-1,3,5-triazine-2-yl)aminobenzoic acid. Intermediate B and isooctyl p-aminobenzoate are used to synthesize intermediate C: 4-(4,6-bis(4-((2-ethylhexyloxy)carbonyl)phenylamino)-1,3,5-triazine-2-ylamino)benzoic acid. Intermediate C is then combined 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 synthesis routes use cyanuric chloride as the raw material to synthesize monosubstituted intermediates. Cyanuric chloride has a high chemical activity, and it is difficult for the reaction to stop at generating only monosubstituted intermediates. It will inevitably generate disubstituted and trisubstituted products, which are difficult to purify. At present, the HEB products sold at home and abroad are generally of low purity, which is caused by this process.

[0013] 2) In order to minimize the formation of disubstituted and trisubstituted products, the two synthetic routes use low temperature reactions (-30℃~0℃), which means that only acetone can be used as the solvent. Acetone is relatively expensive and volatile, which increases production costs.

[0014] 3) Both synthesis routes use isooctyl p-aminobenzoate as a raw material, and the price of this compound is relatively high, which makes the production cost of HEB relatively high. Summary of the invention

[0015] The purpose of the present invention is to provide a method for preparing diethylhexyl butyramido triazone, a sunscreen agent, which is suitable for industrial production and has the advantages of easy availability of raw materials, high purity, simple operation, low cost, easy industrialization, and the like.

[0016] The preparation method of diethylhexyl butyramido triazone comprises the following steps:

[0017] (1) reacting cyanuric chloride with p-aminobenzoic acid to obtain intermediate I;

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

[0019] (3) intermediate II reacts with tert-butylamine and isooctyl alcohol to obtain diethylhexyl butyramido triazone;

[0020] The reaction formula is as follows:

[0021]

[0022]

[0023] The present invention uses cyanuric chloride as a raw material and obtains a sunscreen agent diethylhexyl butyramido triazone through a three-step reaction. The present invention is a new process route, which can effectively solve the problems of poor reaction selectivity, high cost and long reaction time in the existing process. First, cyanuric chloride is reacted with an excess of p-aminobenzoic acid to directly synthesize an intermediate I of a trisubstituted product, which has few impurities and is easy to purify. Secondly, the intermediate I is a trisubstituted product, and its reaction conditions are easy to control, the synthesis temperature can be increased to the reflux temperature, and the solvent can use a low-priced aromatic hydrocarbon as a solvent, which is easy to achieve in production.

[0024] In the present 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, 10 kPa.

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

[0026] Preferably, the specific steps of step (1) are: adding p-aminobenzoic acid and solvent into the reactor, heating to 70-75°C, reducing the pressure to a vacuum degree of 5-10 kPa, adding cyanuric chloride, heating to reflux state and keeping the reaction.

[0027] Research has found that in the route of step (1), there is no selectivity problem in the reaction of cyanuric chloride with three molecules of p-aminobenzoic acid. The addition of a slight excess of p-aminobenzoic acid converts all of it into intermediate I that produces a trisubstituted product. Therefore, it does not need to be controlled under low temperature conditions, which greatly improves the reaction speed 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 the raw materials cyanuric chloride to p-aminobenzoic acid in the step (1) is 1:3.0-5.0, for example 1:3, 1:3.2, 1:3.5, 1:3.8, 1:4, 1:4.5, 1:4.8, 1:5. Preferably, the molar ratio of the raw materials cyanuric chloride to p-aminobenzoic acid is 1:3.2-3.5.

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

[0032] In a specific embodiment, the crystallization solvent of the product intermediate I of step (1) is a mixture of an organic solvent and water, the organic solvent is one of methanol, ethanol, isopropanol, tetrahydrofuran, and 1,6-dioxane; the preferred solvent is ethanol; wherein the ratio of the 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 the preferred ratio is 1:1.5.

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

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

[0035] Step (2) synthesizes intermediate II, the reaction is simple and the yield is high; the concentrated solution does not need to be purified and can be directly used in the synthesis of step 3.

[0036] In a specific embodiment, the solvent of step (2) is one of toluene, xylene, cyclohexane, n-hexane, and n-heptane, and the preferred solvent is xylene. In a specific embodiment, the adding of intermediate I is to slowly dropwise add a xylene suspension of intermediate I.

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

[0038] In a specific embodiment, in step (2), the molar ratio of intermediate I to thionyl chloride is 1:3.0-4.5; 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 1:3.3-3.8.

[0039] In the present invention, in the step (3), the intermediate II is first reacted with tert-butylamine and then reacted with isooctyl alcohol;

[0040] Preferably, the reaction temperature of the intermediate II first reacting with tert-butylamine is 30-70°C; the reaction temperature of the intermediate II reacting with isooctyl alcohol is 50-110°C;

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

[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, and the preferred molar ratio is 1:0.92-0.96.

[0043] In a specific embodiment, the molar ratio of intermediate II to isooctyl alcohol 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, and the preferred molar ratio is 1:2.1-2.3.

[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 applicable to the three-step reactions of the present invention are basically the same. In actual production, the same solvent is preferably used. After each step of reaction, only simple treatment is required before the solvent can be directly used for the next step of reaction, thereby simplifying the production process and improving the overall yield of the reaction.

[0046] Preferably, the post-treatment step of step (3) comprises: alkali washing, water washing, concentration, and crystallization to obtain the diethylhexyl butyramido triazone product.

[0047] The present invention has achieved the following positive effects: the synthetic method has high selectivity, the total yield of the sunscreen diethylhexyl butyramido triazone is more than 90%, and the chromatographic purity is more than 99%; the same reaction solvent can be used in the route of the present invention, and only simple treatment is required after each step of reaction before it can be directly used for the next step of 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 DESCRIPTION

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

[0049] In the present invention, except for the contents explicitly described, any matters or items not mentioned are directly applicable to those known in the art without any changes. Moreover, any embodiment described herein can be freely combined with one or more other embodiments described herein, and the technical solutions or technical ideas formed thereby are regarded as part of the original disclosure or original record of the present invention, and should not be regarded as new contents not disclosed or anticipated herein, unless a person skilled in the art considers that the combination is obviously unreasonable.

[0050] All features disclosed in the present invention may be arbitrarily combined, and these combinations should be understood as contents disclosed or recorded in the present invention, unless a person skilled in the art considers that the combination is 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 scope disclosed or recorded in the present invention.

[0052] The "dropwise addition" mentioned in the present invention is a slow addition that can be understood by those skilled in the art, and there is no strict limit on the flow rate, so as not to affect the stability and progress of the reaction.

[0053] The technical and scientific terms in the present invention shall be based on their definitions if they are defined, and shall be understood according to the general meaning in the art if no definitions are given.

[0054] In the molecular structure of diethylhexyl butyramido triazone, because of three different substituents, the selectivity of reaction conditions is very critical for the yield and purity of the product. As described in the background technology, the synthetic route in the prior art is difficult to stay at the monosubstituted intermediate, and disubstituted and trisubstituted products will be produced, and the purity is difficult to reach 99%. And the prior art selects acetone as solvent and uses isooctyl p-aminobenzoate as raw material price, resulting in high product cost. Diethylhexyl butyramido triazone is used in daily chemical products as a sunscreen, and has higher requirements for its purity. How to improve the purity of the product without adding the precursor of the new post-processing step is a technical problem that needs to be solved in this area. Patent CN110229113A has also improved the process of this product, so that its purity reaches more than 99%, but its reaction time exceeds 44 hours, and the production efficiency is low.

[0055] The present invention provides a method for preparing diethylhexyl butyramido triazone, comprising the following steps:

[0056] (1) Synthesis of intermediate I: Add p-aminobenzoic acid and xylene solvent to the reaction vessel, reduce the pressure to a vacuum degree of 5-10 KPa. Raise the temperature to 70-75°C, and start to drop cyanuric chloride for 30-60 min. After the dropwise addition is completed, keep the temperature. Raise the temperature to 100-110°C and keep the temperature for 1-2 h.

[0057] After the reaction is finished, the temperature is lowered to 70-80°C, and water is added to wash until the pH is 5-6. Xylene is recovered under reduced pressure, ethanol is added to the concentrate to dissolve, and then ethanol water is added to cool and crystallize to obtain a white solid intermediate I: 2,4,6-tris[(p-carboxyphenyl)amino]-1,3,5-triazine ketone.

[0058] (2) Synthesis of Intermediate II: Add thionyl chloride and xylene, and 2-3 drops of DMF into the reaction vessel. Add the xylene suspension of Intermediate I dropwise at 60-65°C for 1 hour. After the addition is complete, keep warm for 1-2 hours. After the reaction is complete, distill the thionyl chloride under reduced pressure until some xylene is distilled out to obtain a light yellow intermediate II: 2,4,6-tris[(p-chlorocarbonylphenyl)amino]-1,3,5-triazinone.

[0059] (3) Synthesis of HEB: Add the concentrated solution obtained in the previous step to the reaction vessel, and add tert-butylamine and xylene solvent dropwise at 30-40°C. After the addition is complete, keep the temperature for 1-2 hours. Then raise the temperature to 50-60°C and add isooctyl alcohol dropwise. After the addition is complete, keep the temperature for 1-2 hours. Raise the temperature to 90-100°C and keep the temperature for 1-2 hours.

[0060] After the reaction is finished, the temperature is lowered to 70-80°C, and the product is washed once with water to a pH of 3-4. Then, the pH is adjusted to 7-8 with an aqueous sodium carbonate solution, and the product is washed once with water. The washing liquid is decompressed to recover xylene, and ethanol is added to the concentrated liquid to dissolve it, and then n-hexane is added to crystallize it. Filter, wash, and dry to obtain an off-white product: diethylhexyl butyramido triazone.

[0061] The present invention first uses cyanuric chloride and p-aminobenzoic acid as raw materials, does not require alkaline conditions such as acid binding agents, and uses a slight negative pressure to reduce the content of hydrogen chloride and improve the reaction depth. The intermediate I obtained can be used for the next reaction after simple crystallization. The intermediate I reacts with thionyl chloride, and the reaction liquid is subjected to removal of excess raw materials and solvent to obtain the intermediate II, which is then reacted with tert-butylamine and isooctyl alcohol to obtain the product. The reaction solvents of the above three reactions are the same, the intermediate does not require complicated post-treatment, the total yield is high, and the product purity can reach more than 99%.

[0062] In order to explain the technical content of the present invention more clearly and intuitively, the following embodiments are used as examples:

[0063] Example 1

[0064] (1) Synthesis of Intermediate I

[0065] Add 59.5g (0.434mol) of p-aminobenzoic acid and 150ml of xylene to a four-necked bottle equipped with a thermometer, condenser, constant pressure dropping funnel and stirring, and reduce the pressure to a vacuum degree of 10Kpa. Raise the temperature to 70-75℃, and start dripping a suspension of 25.0g (0.136mol) of cyanuric chloride and 60ml of xylene for 60 minutes. After the dripping is completed, keep warm for 1 hour. Raise the temperature to 100-110℃ and keep warm for 2 hours.

[0066] After the reaction was completed, the temperature was lowered to 80°C, and water was added to wash until the pH value was 5-6. Xylene was recovered under reduced pressure, ethanol was added to the concentrate to dissolve it, and then water (ethanol: water = 1:1.5) was added to cool and crystallize to obtain 62.8 g of 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 27.9g (0.23mol) of thionyl chloride and 20ml of anhydrous xylene and 2-3 drops of DMF to a four-necked flask equipped with a thermometer, condenser, constant pressure bottom funnel and stirring. At a temperature of 60-65°C, add 30.0g (0.062mol) of intermediate I and 150ml of anhydrous xylene suspension dropwise for 1 hour. After the addition is complete, keep warm for 1 hour;

[0069] After the reaction is completed, thionyl chloride is distilled under reduced pressure until part of xylene is distilled off to obtain a light yellow solution of intermediate II and xylene.

[0070] (3) Synthesis of HEB

[0071] Under nitrogen protection, add the concentrate obtained in the previous step to a four-necked flask equipped with a thermometer, condenser, constant pressure bottom funnel and stirring, and drop 4.3g (0.059mol) of tert-butylamine and 20ml of xylene solution at 30-40°C. After the addition is complete, keep the temperature for 1-2h. Then raise the temperature to 50-60°C and drop 17.7g (0.136mol) of isooctyl alcohol. After the addition is complete, keep the temperature for 1-2h. Raise the temperature to 90-100°C and keep the temperature for 1-2h.

[0072] After the reaction is finished, the temperature is lowered to 70-80°C, and the product is washed once with water to a pH of 3-4. Then, the pH is adjusted to 7-8 with an aqueous sodium carbonate solution, and finally, the product is washed once with water. The washing liquid is decompressed to recover xylene, and the concentrated liquid is dissolved in ethanol, and then n-hexane is added for crystallization. Filtering, washing, and drying give 44.9 g of an off-white product with a yield of 95.16%.

[0073] The total yield of HEB was 90.6%; the purity was 99.10% according to liquid chromatography analysis.

[0074] Example 2

[0075] (1) Synthesis of Intermediate I

[0076] Add 65.3g (0.476mol) of p-aminobenzoic acid and 150ml of xylene to a four-necked bottle equipped with a thermometer, condenser, constant pressure dropping funnel and stirring, and reduce the pressure to a vacuum degree of 10Kpa. Raise the temperature to 70-75℃, and start dripping a suspension of 25.0g (0.136mol) of cyanuric chloride and 60ml of xylene for 60 minutes. After the dripping is completed, keep warm for 1 hour. Raise the temperature to 100-110℃ and keep warm for 2 hours.

[0077] After the reaction is finished, the temperature is lowered to 70-80°C, and water is added to wash until the pH is 5-6. Xylene is recovered under reduced pressure, ethanol is added to the concentrate to dissolve, and then water (ethanol: water = 1:1.5) is added to cool and crystallize to obtain 62.9 g of white solid. The yield is 95.3%, and the HPLC purity is 99.0%.

[0078] (2) Synthesis of Intermediate II

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

[0080] After the reaction is completed, thionyl chloride is distilled under reduced pressure until part of xylene is distilled off to obtain a light yellow solution of intermediate II and xylene.

[0081] (3) Synthesis of HEB

[0082] Under nitrogen protection, add the concentrate obtained in the previous step to a four-necked flask equipped with a thermometer, condenser, constant pressure bottom funnel and stirring, and drop 4.3g (0.059mol) of tert-butylamine and 20ml of xylene solution at 30-40°C. After the addition is complete, keep the temperature for 1-2h. Then raise the temperature to 50-60°C and drop 17.7g (0.136mol) of isooctyl alcohol. After the addition is complete, keep the temperature for 1-2h. Raise the temperature to 90-100°C and keep the temperature for 1-2h.

[0083] After the reaction is finished, the temperature is lowered to 70-80°C, and the product is washed once with water to a pH of 3-4. Then, the pH is adjusted to 7-8 with an aqueous sodium carbonate solution, and finally, the product is washed once with water. The washing liquid is decompressed to recover xylene, and the concentrated liquid is dissolved in ethanol, and then n-hexane is added for crystallization. Filtering, washing, and drying give 44.9 g of an off-white product with a yield of 95.16%.

[0084] The total yield of HEB was 90.7%; the purity was 98.75% according to liquid chromatography analysis.

[0085] Example 3

[0086] (1) Synthesis of Intermediate I

[0087] Add 65.3g (0.476mol) of p-aminobenzoic acid and 150ml of xylene to a four-necked bottle equipped with a thermometer, condenser, constant pressure dropping funnel and stirring, and reduce the pressure to a vacuum degree of 10Kpa. Raise the temperature to 70-75℃, and start dripping a suspension of 25.0g (0.136mol) of cyanuric chloride and 60ml of xylene for 60 minutes. After the dripping is completed, keep warm for 1 hour. Raise the temperature to 100-110℃ and keep warm for 1 hour.

[0088] After the reaction is finished, the temperature is lowered to 70-80°C, and water is added to wash until the pH is 5-6. Xylene is recovered under reduced pressure, ethanol is added to the concentrate to dissolve, and then water (ethanol: water = 1:1.5) is added to cool and crystallize to obtain 62.4 g of white solid. The yield is 94.6%, and the HPLC purity is 98.8%.

[0089] (2) Synthesis of Intermediate II

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

[0091] After the reaction is completed, thionyl chloride is distilled under reduced pressure until part of xylene is distilled off to obtain a light yellow solution of intermediate II and xylene.

[0092] (3) Synthesis of HEB

[0093] Under nitrogen protection, add the concentrate obtained in the previous step to a four-necked flask equipped with a thermometer, condenser, constant pressure bottom funnel and stirring, and drop 4.3g (0.059mol) of tert-butylamine and 20ml of xylene solution at 30-40°C. After the addition is complete, keep the temperature for 1-2h. Then raise the temperature to 50-60°C and drop 17.7g (0.136mol) of isooctyl alcohol. After the addition is complete, keep the temperature for 1-2h. Raise the temperature to 90-100°C and keep the temperature for 1-2h.

[0094] After the reaction is finished, the temperature is lowered to 70-80°C, and the product is washed once with water to a pH of 3-4. Then, the pH is adjusted to 7-8 with an aqueous sodium carbonate solution, and finally, the product is washed once with water. The washing liquid is decompressed to recover xylene, and ethanol is added to the concentrated liquid to dissolve it, and then n-hexane is added to crystallize it. Filter, wash, and dry to obtain 44.6 g of an off-white product.

[0095] The total yield of HEB was 88.7%; the purity was 99.00% according to liquid chromatography analysis.

[0096] Example 4

[0097] (1) Synthesis of Intermediate I

[0098] Add 59.5g (0.434mol) of p-aminobenzoic acid and 150ml of xylene to a four-necked bottle equipped with a thermometer, condenser, constant pressure dropping funnel and stirring, and reduce the pressure to a vacuum degree of 5-10Kpa. Raise the temperature to 70-75℃, and start dripping a suspension of 25.0g (0.136mol) of cyanuric chloride and 60ml of xylene for 30-60min. After the dripping is completed, keep warm for 1h. Raise the temperature to 100-110℃ and keep warm for 2h.

[0099] After the reaction is finished, the temperature is lowered to 70-80°C, and water is added to wash until the pH is 5-6. Xylene is recovered under reduced pressure, ethanol is added to the concentrate to dissolve, and then water (ethanol: water = 1:1.5) is added to cool and crystallize to obtain 62.8 g of white solid. The yield is 95.2%, and the HPLC purity is 99.2%.

[0100] (2) Synthesis of Intermediate II

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

[0102] After the reaction is completed, thionyl chloride is distilled under reduced pressure until part of xylene is distilled off to obtain a light yellow intermediate II and a xylene solution.

[0103] (3) Synthesis of HEB

[0104] Under nitrogen protection, add the concentrate obtained in the previous step to a four-necked flask equipped with a thermometer, condenser, constant pressure bottom funnel and stirring, and drop 4.3g (0.059mol) of tert-butylamine and 20ml of xylene solution at 30-40°C. After the addition is complete, keep the temperature for 1-2h. Then raise the temperature to 50-60°C and drop 17.7g (0.136mol) of isooctyl alcohol. After the addition is complete, keep the temperature for 1-2h. Raise the temperature to 90-100°C and keep the temperature for 1-2h.

[0105] After the reaction is finished, the temperature is lowered to 70-80°C, and the product is washed once with water to a pH of 3-4. Then, the pH is adjusted to 7-8 with an aqueous sodium carbonate solution, and finally, the product is washed once with water. The washing liquid is decompressed to recover xylene, and ethanol is added to the concentrated liquid to dissolve it, and then n-hexane is added to crystallize it. Filter, wash, and dry to obtain 44.3 g (0.058 mol) of an off-white product.

[0106] The total yield of HEB was 89.2%; the purity was 99.00% according to liquid chromatography analysis.

[0107] Example 5

[0108] (1) Synthesis of Intermediate I

[0109] Add 59.5g (0.434mol) of p-aminobenzoic acid and 150ml of xylene to a four-necked bottle equipped with a thermometer, condenser, constant pressure dropping funnel and stirring, and reduce the pressure to a vacuum degree of 5-10Kpa. Raise the temperature to 70-75℃, and start dripping a suspension of 25.0g (0.136mol) of cyanuric chloride and 60ml of xylene for 30-60min. After the dripping is completed, keep warm for 1h. Raise the temperature to 100-110℃ and keep warm for 2h.

[0110] After the reaction is finished, the temperature is lowered to 70-80°C, and water is added to wash until the pH is 5-6. Xylene is recovered under reduced pressure, ethanol is added to the concentrate to dissolve, and then water (ethanol: water = 1:1.5) is added to cool and crystallize to obtain 62.8 g of white solid. The yield is 95.2%, and the HPLC purity is 99.2%.

[0111] (2) Synthesis of Intermediate II

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

[0113] After the reaction is completed, thionyl chloride is distilled under reduced pressure until part of xylene is distilled off to obtain a light yellow solution of intermediate II and xylene.

[0114] (3) Synthesis of HEB

[0115] Under nitrogen protection, add the concentrate obtained in the previous step to a four-necked flask equipped with a thermometer, condenser, constant pressure bottom funnel and stirring, and drop 4.5g (0.062mol) of tert-butylamine and 20ml of xylene solution at 30-40°C. After the addition is complete, keep warm for 1-2h. Then raise the temperature to 50-60°C and drop 17.7g (0.136mol) of isooctyl alcohol. After the addition is complete, keep warm for 1-2h. Raise the temperature to 90-100°C and keep warm for 1-2h.

[0116] After the reaction is finished, the temperature is lowered to 70-80°C, and the product is washed once with water to a pH of 3-4. Then, the pH is adjusted to 7-8 with an aqueous sodium carbonate solution, and finally, the product is washed once with water. The washing liquid is decompressed to recover xylene, and ethanol is added to the concentrated liquid to dissolve it, and then n-hexane is added to crystallize it. Filter, wash, and dry to obtain 42.5 g (0.056 mol) of an off-white product.

[0117] The total yield of HEB was 85.6%; the purity was 99.01% according to liquid chromatography analysis.

[0118] Example 6

[0119] (1) Synthesis of Intermediate I

[0120] Add 59.5g (0.434mol) of p-aminobenzoic acid and 150ml of xylene to a four-necked bottle equipped with a thermometer, condenser, constant pressure dropping funnel and stirring, and reduce the pressure to a vacuum degree of 5-10Kpa. Raise the temperature to 70-75℃, and start dripping a suspension of 25.0g (0.136mol) of cyanuric chloride and 60ml of xylene for 30-60min. After the dripping is completed, keep warm for 1h. Raise the temperature to 100-110℃ and keep warm for 2h.

[0121] After the reaction is finished, the temperature is lowered to 70-80°C, and water is added to wash until the pH is 5-6. Xylene is recovered under reduced pressure, ethanol is added to the concentrate to dissolve, and then water (ethanol: water = 1:1.5) is added to cool and crystallize to obtain 62.8 g of white solid. The yield is 95.2%, and the HPLC purity is 99.2%.

[0122] (2) Synthesis of Intermediate II

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

[0124] After the reaction is completed, thionyl chloride is distilled under reduced pressure until part of xylene is distilled off to obtain a light yellow solution of intermediate II and xylene.

[0125] (3) Synthesis of HEB

[0126] Under nitrogen protection, add the concentrate obtained in the previous step to a four-necked flask equipped with a thermometer, condenser, constant pressure bottom funnel and stirring, and drop 4.3g (0.059mol) of tert-butylamine and 20ml of xylene solution at 30-40°C. After the addition is complete, keep the temperature for 1-2h. Then raise the temperature to 50-60°C and drop 20.1g (0.154mol) of isooctyl alcohol. After the addition is complete, keep the temperature for 1-2h. Raise the temperature to 90-100°C and keep the temperature for 1-2h.

[0127] After the reaction is finished, the temperature is lowered to 70-80°C, and the product is washed once with water to a pH of 3-4. Then, the pH is adjusted to 7-8 with an aqueous sodium carbonate solution, and finally, the product is washed once with water. The washing liquid is decompressed to recover xylene, and ethanol is added to the concentrated liquid to dissolve it, and then n-hexane is added to crystallize it. Filter, wash, and dry to obtain 44.8 g (0.058 mol) of an off-white product.

[0128] The total yield of HEB was 90.2%; the purity was 99.10% according to liquid chromatography analysis.

[0129] Example 7

[0130] (1) Synthesis of Intermediate I

[0131] Add 59.5g (0.434mol) of p-aminobenzoic acid and 150ml of xylene to a four-necked bottle equipped with a thermometer, condenser, constant pressure dropping funnel and stirring. Raise the temperature to 70-75℃ under normal pressure, and start dripping a suspension of 25.0g (0.136mol) of cyanuric chloride and 60ml of xylene for 60 minutes. After the dripping is completed, keep warm for 1 hour. Raise the temperature to 100-110℃ and keep warm for 2 hours.

[0132] After the reaction was completed, the temperature was lowered to 80°C, and water was added to wash until the pH value was 5-6. Xylene was recovered under reduced pressure, ethanol was added to the concentrate to dissolve it, and then water (ethanol: water = 1:1.5) was added to cool and crystallize to obtain 61.5 g of 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 27.9g (0.23mol) of thionyl chloride and 20ml of anhydrous xylene and 2-3 drops of DMF to a four-necked flask equipped with a thermometer, condenser, constant pressure bottom funnel and stirring. At a temperature of 60-65°C, add 30.0g (0.062mol) of intermediate I and 150ml of anhydrous xylene suspension dropwise for 1 hour. After the addition is complete, keep warm for 1 hour;

[0135] After the reaction is completed, thionyl chloride is distilled under reduced pressure until part of xylene is distilled off to obtain a light yellow intermediate II and a xylene solution.

[0136] (3) Synthesis of HEB

[0137] Under nitrogen protection, add the concentrate obtained in the previous step to a four-necked flask equipped with a thermometer, condenser, constant pressure bottom funnel and stirring, and drop 4.3g (0.059mol) of tert-butylamine and 20ml of xylene solution at 30-40°C. After the addition is complete, keep the temperature for 1-2h. Then raise the temperature to 50-60°C and drop 17.7g (0.136mol) of isooctyl alcohol. After the addition is complete, keep the temperature for 1-2h. Raise the temperature to 90-100°C and keep the temperature for 1-2h.

[0138] After the reaction is finished, the temperature is lowered to 70-80°C, and the product is washed once with water to a pH of 3-4. Then, the pH is adjusted to 7-8 with an aqueous sodium carbonate solution, and finally, the product is washed once with water. The washing liquid is decompressed to recover xylene, and the concentrated liquid is dissolved in ethanol, and then n-hexane is added for crystallization. Filtering, washing, and drying give 44.9 g of an off-white product with a yield of 95.16%.

[0139] The total yield of HEB was 88.71%; the purity was 98.9% according to liquid chromatography analysis.

[0140] Although the present invention has been described in detail above by means of general description, specific implementation methods and tests, it is obvious to those skilled in the art that some modifications or improvements may be made to the present invention. Therefore, these modifications or improvements made without departing from the spirit of the present invention all fall within the scope of protection claimed by the present invention.

Claims

1. A method for preparing diethylhexyl butyramido triazone, comprising the following steps: (1) reacting cyanuric chloride with p-aminobenzoic acid to obtain intermediate I; (2) intermediate I reacts with thionyl chloride to obtain intermediate II; (3) intermediate II reacts with tert-butylamine and isooctyl alcohol to obtain diethylhexyl butyramido triazone; The reaction formula is as follows:

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 reflux temperature; Preferably, step (1) comprises: adding p-aminobenzoic acid and a solvent into a reactor, heating to 70-75° C., reducing the pressure to a vacuum degree of 5-10 kPa, adding cyanuric chloride, and heating to reflux for reaction.

3. The preparation method according to claim 1 or 2, characterized in that: The reaction time of step (1) is 1-3h; and / or the solvent in step (1) is at least one of toluene, xylene, cyclohexane, n-hexane and n-heptane; preferably the solvent is xylene; The molar ratio of the raw materials cyanuric chloride to p-aminobenzoic acid is 1:3.0-5.0, preferably 1:3.2-3.

5.

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

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

6. The preparation method according to claim 5, characterized in that: The solvent of step (2) is one of toluene, xylene, cyclohexane, n-hexane and n-heptane, preferably xylene, and / or In step (2), the molar ratio of the intermediate I to thionyl chloride is 1:3.0-4.5, preferably, the molar ratio of the intermediate I to thionyl chloride is 1:3.3-3.

8.

7. The preparation method according to claim 6, characterized in that: In step (3), intermediate II is first reacted with tert-butylamine and then with isooctyl alcohol; Preferably, the reaction temperature of the intermediate II first reacting with tert-butylamine is 30-70°C; the reaction temperature of the intermediate II reacting with isooctyl alcohol is 50-110°C; More preferably, in step (2), intermediate II is obtained, tert-butylamine is added dropwise at 30-50°C, and after the addition is completed, the temperature is kept for 1-2 hours; then the temperature is raised to 50-70°C, isooctyl alcohol is added dropwise, and after the addition is completed, the temperature is kept for 1-2 hours; the temperature is raised to 90-110°C and kept for 1-2 hours.

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

5.

9. The preparation method according to claim 7 or 8, characterized in that: The post-treatment steps of step (3) include: alkali washing, water washing, concentration, and crystallization to obtain diethylhexyl butyramido triazone.

10. Diethylhexyl butyramido triazone prepared by the preparation method according to any one of claims 1 to 9.

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