Preparation method of diethylhexyl butyrylamide triazinone

Abstract

The invention discloses a preparation method of diethylhexyl butyrylamide triazinone, which comprises the following steps: S1, reacting a first intermediate N-tert-butyl-4-[(4, 6-dichloro-1, 3, 5-triazine) amino] benzamide with p-aminobenzonitrile in a solvent to obtain a second intermediate 4-(4, 6-bis ((4-cyanophenyl) amino)-1, 3, 5-triazine) amino] benzamide; the preparation method comprises the following steps: adding 2-(3, 5-triazine-2-yl) amino)-N-(tert-butyl) benzamide; s2, enabling the second intermediate to react with isooctanol under the condition of acid catalysis to obtain the diethylhexyl butyrylamide triazinone. According to the preparation method, common impurities in other routes can be avoided, the product purity is high, the method is environmentally friendly, the solvent is easy to recycle and reuse, the production cost is low, and the method is suitable for large-scale industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of compound synthesis, and particularly relates to a novel preparation method of diethylhexyl butyramido triazone. Background Art

[0002] Triazine UV absorbers are a new type of high-efficiency and broad-spectrum UV absorbers developed in recent years. They have a large molecular structure and high UV absorption efficiency and antioxidant function, and are the development direction of UV absorbers. As a new type of triazine UV absorber, diethylhexyl butyramido triazone has a large molecular structure and high UV absorption efficiency, and has a broad-spectrum sunscreen effect, which can protect against both UVB and UVA UV rays. It is a type of triazine UV absorber currently allowed for use in the European Union, Australia, China and Japan.

[0003] The prior art has reported a compound called diethylhexyl butyramido triazone and some of its synthesis methods, mainly including two synthesis methods.

[0004] In the first synthesis method, first, N-tert-butyl-4-aminobenzamide is reacted with cyanuric chloride in a solvent such as acetone, and sodium carbonate is used as an acid binding agent to synthesize a substituted intermediate N-tert-butyl-4-[(4,6-dichloro-1,3,5-triazine)amino]benzamide (Formula I). ​​The reaction formula of this step is as follows:

[0005]

[0006] Then, the substituted intermediate is reacted with isooctyl p-aminobenzoate to obtain diethylhexyl butyramido triazone (Formula III), which is then sanded with a toluene / cyclohexane mixed solvent to obtain the product. The reaction formula of this step is as follows:

[0007]

[0008] However, this method has the problem that the product is difficult to crystallize and the reaction impurities are not easy to remove, resulting in low purity of the final product.

[0009] The synthetic route of the second synthetic method is as follows:

[0010]

[0011] However, in this method, the solubility of the raw materials in the first step is poor, there are many side reactions, and the last step uses acyl chloride followed by amidation, resulting in poor product color.

[0012] Therefore, it is urgent to develop a method for preparing diethylhexyl butyramido triazone which can reduce impurities in the synthesis process and has high product purity. Summary of the invention

[0013] In view of the above problems, the present invention is proposed to provide a method for preparing diethylhexylbutanamide triazone which overcomes the above problems or at least partially solves the above problems.

[0014] One object of the present invention is to provide a novel method for preparing diethylhexyl butyramido triazone which can reduce impurities in the synthesis process and has high product purity.

[0015] A further object of the present invention is to further reduce the impurities generated by the reaction of the second intermediate with isooctyl alcohol and simplify the product purification operation.

[0016] In particular, the present invention provides a method for preparing diethylhexyl butyramido triazone, comprising the following steps:

[0017] Step S1: reacting the first intermediate N-tert-butyl-4-[(4,6-dichloro-1,3,5-triazine)amino]benzamide as shown in formula I with p-aminobenzonitrile in a solvent to obtain the second intermediate 4-(4,6-bis((4-cyanophenyl)amino)-1,3,5-triazine-2-yl)amino)-N-(tert-butyl)benzamide as shown in formula II:

[0018]

[0019]

[0020] Step S2: reacting the second intermediate with isooctyl alcohol under acid catalysis to obtain diethylhexyl butyramido triazone as shown in formula III:

[0021]

[0022] Optionally, the acid is HCl, and step S2 comprises:

[0023] Add isooctyl alcohol to the second intermediate obtained in step S1, cool to a specified temperature, and introduce dry HCl gas to react, wherein the specified temperature is in the range of -20°C to 40°C.

[0024] Optionally, the specified temperature is in the range of -10°C to 30°C.

[0025] Optionally, in step S2, the molar ratio of the second intermediate to isooctyl alcohol is 1:(2.5-40).

[0026] Optionally, the step S2 further includes:

[0027] After the reaction is completed, the reaction product is washed with water to separate the phases, and the solvent is removed from the organic phase obtained by the phase separation to obtain a diethylhexyl butyramido triazone product.

[0028] Optionally, the step S1 includes:

[0029] The solvent, the first intermediate and p-aminobenzonitrile are added into a reactor, and the mixture is stirred and reacted at a temperature of 10 to 150° C. for 3 to 12 hours.

[0030] Optionally, in step S1, the molar ratio of the first intermediate to p-aminobenzonitrile is 1:(2.0-2.1).

[0031] Optionally, the solvent in step S1 is toluene, xylene, trimethylbenzene, dichloroethane or chloroform.

[0032] Optionally, the first intermediate is synthesized by reacting N-tert-butyl-4-aminobenzamide with cyanuric chloride.

[0033] The invention provides a method for preparing diethylhexyl butyramido triazone, which comprises the following steps: a first intermediate N-tert-butyl-4-[(4,6-dichloro-1,3,5-triazine)amino]benzamide is reacted with p-aminobenzonitrile to synthesize a second intermediate 4-(4,6-bis((4-cyanophenyl)amino)-1,3,5-triazine-2-yl)amino)-N-(tert-butyl)benzamide, and then the second intermediate is reacted with isooctyl alcohol to obtain a synthetic route of a target product, diethylhexyl butyramido triazone. The method can avoid common impurities in other routes, has high product purity, is environmentally friendly, and has easy solvent recovery and reuse, has low production cost, and is suitable for large-scale industrial production.

[0034] Furthermore, in the step of reacting the second intermediate with isooctyl alcohol, dry HCl gas is introduced for catalysis, which can further reduce impurities generated by the reaction of the second intermediate with isooctyl alcohol and simplify the product purification operation.

[0035] The diethylhexyl butyramido triazone prepared by the invention is a UVB ultraviolet light absorber and can be used as a sunscreen in cosmetic formulas.

[0036] The above description is only an overview of the technical solution of the present invention. In order to more clearly understand the technical means of the present invention, it can be implemented according to the contents of the specification. In order to make the above and other purposes, features and advantages of the present invention more obvious and easy to understand, the specific implementation methods of the present invention are listed below. DETAILED DESCRIPTION

[0037] The technical solution of the present invention is further described below in conjunction with specific embodiments, but it should be understood that the present invention is not limited to these specific embodiments.

[0038] The invention provides a method for preparing diethylhexyl butyramido triazone.

[0039] The following shows a reaction synthesis route of a method for preparing diethylhexyl butyramido triazone according to an embodiment of the present invention:

[0040]

[0041] The preparation method of diethylhexyl butyramido triazone of the present invention is described below in conjunction with the reaction synthesis route shown above.

[0042] The preparation method may at least comprise the following steps:

[0043] Step S1: reacting the first intermediate N-tert-butyl-4-[(4,6-dichloro-1,3,5-triazine)amino]benzamide as shown in formula I with p-aminobenzonitrile in a solvent to obtain the second intermediate 4-(4,6-bis((4-cyanophenyl)amino)-1,3,5-triazine-2-yl)amino)-N-(tert-butyl)benzamide as shown in formula II:

[0044] Step S2: reacting the second intermediate with isooctyl alcohol under acid catalysis to obtain diethylhexyl butyramido triazone as shown in formula III.

[0045] The method for preparing diethylhexyl butyramido triazone provided in an embodiment of the present invention adopts a first intermediate N-tert-butyl-4-[(4,6-dichloro-1,3,5-triazine)amino]benzamide to react with p-aminobenzonitrile to synthesize a second intermediate 4-(4,6-bis((4-cyanophenyl)amino)-1,3,5-triazine-2-yl)amino)-N-(tert-butyl)benzamide, and then the second intermediate is reacted with isooctyl alcohol to obtain a synthetic route of the target product diethylhexyl butyramido triazone. The method can avoid common impurities in other routes, has high product purity, is environmentally friendly, and has easy solvent recovery and reuse. The production cost is low and the method is suitable for large-scale industrial production.

[0046] In some embodiments of the present invention, step S1 may specifically include:

[0047] Add the solvent, the first intermediate and p-aminobenzonitrile into the reactor, and stir the reaction at 10 to 150° C. for 3 to 12 hours.

[0048] Specifically, the reaction temperature in step S1 can be 10°C, 20°C, 30°C, 40°C, 50°C, 60°C, 70°C, 80°C, 90°C, 100°C, 110°C, 120°C, 130°C, 140°C, etc. The reaction time in step S1 can be, for example, 4h, 6h, 8h, 10h to ensure sufficient reaction.

[0049] In some embodiments of the present invention, the molar ratio of the first intermediate to p-aminobenzonitrile in step S1 may be 1:(2.0-2.1) to ensure that the first intermediate and p-aminobenzonitrile react fully.

[0050] In some embodiments of the present invention, the solvent in step S1 may be one selected from toluene, xylene, trimethylbenzene, dichloroethane or chloroform.

[0051] In some optional embodiments, step S1 may further include:

[0052] After the first intermediate and p-aminobenzonitrile react, the reaction product is purified.

[0053] Specifically, whether the reaction is completed can be determined by monitoring whether the first intermediate is completely converted through central control.

[0054] In one embodiment, the purification treatment comprises: adding water to the reaction system, washing and separating the phases under alkaline conditions, removing the solvent from the organic phase obtained by the phase separation, and then crystallizing with another solvent (such as ethanol, etc.) to obtain a second intermediate solid.

[0055] In another embodiment, the purification process includes: cooling the reaction product and then directly filtering and drying it.

[0056] In some embodiments of the present invention, the acid used for catalysis in step S2 is HCl.

[0057] In a preferred embodiment, dry HCl gas is introduced into the reaction system in step S2 for catalytic reaction. In the step of reacting the second intermediate with isooctyl alcohol in this embodiment, dry HCl gas is introduced for catalysis, thereby avoiding the presence of water, further reducing impurities generated by the reaction of the second intermediate with isooctyl alcohol, and simplifying the product purification operation.

[0058] In some embodiments of the present invention, step S2 may specifically include:

[0059] Add isooctyl alcohol to the second intermediate obtained in step S1, cool to a specified temperature, and introduce dry HCl gas to react.

[0060] In some specific embodiments, the designated temperature is in the range of -20°C to 40°C, for example, the designated temperature is -10°C, 0°C, 10°C, 20°C, 30°C, etc.

[0061] In some preferred embodiments, the designated temperature is in the range of -10°C to 30°C.

[0062] In some embodiments of the present invention, the molar ratio of the second intermediate to isooctyl alcohol in step S2 is 1:(2.5-40), for example, 1:5, 1:10, 1:15, 1:20, 1:25, 1:30, 1:35, or 1:40.

[0063] In step S2, excess isooctyl alcohol can be used as a solvent to promote the reaction and dissolve the reaction product. Of course, in some cases, an organic solvent such as toluene, xylene, trimethylbenzene, ethylene dichloride, chloroform, etc. can also be added.

[0064] In some optional embodiments, step S2 may further include:

[0065] After the reaction is completed, the reaction product is washed with water to separate the phases, and the solvent is removed from the organic phase obtained by the phase separation to obtain a diethylhexyl butyramido triazone product. The solvent here refers to excess isooctyl alcohol. When another organic solvent is added in step S2, the solvent here also includes the additional organic solvent.

[0066] Specifically, the reaction can be judged to be complete by monitoring whether the second intermediate is completely converted through the central control. When washing and separating the phases, wash with water until neutral.

[0067] Specifically, the solvent can be removed by distillation under reduced pressure and the removed solvent can be recycled.

[0068] In some embodiments of the present invention, the first intermediate can be synthesized by reacting N-tert-butyl-4-aminobenzamide with cyanuric chloride. In other words, in some embodiments, before step S1, the preparation method may further include a step of reacting N-tert-butyl-4-aminobenzamide with cyanuric chloride to synthesize the first intermediate, as shown in the aforementioned reaction synthesis route. The specific synthesis process of the first intermediate synthesized by reacting N-tert-butyl-4-aminobenzamide with cyanuric chloride can refer to the records of the prior art, and in order not to obscure the improvement points of the present invention, it is not further described herein.

[0069] Of course, the first intermediate N-tert-butyl-4-[(4,6-dichloro-1,3,5-triazine)amino]benzamide can also be prepared by any other method in the present invention.

[0070] The following is an explanation of the embodiments of the present invention by specific embodiments. Those skilled in the art can easily understand other advantages and effects of the present invention from the contents disclosed in this specification. The present invention can also be implemented or applied through other different specific embodiments, and the details in this specification can also be modified or changed in various ways based on different viewpoints and applications without departing from the spirit of the present invention.

[0071] Embodiment 1

[0072] Step S1: Synthesis of the second intermediate

[0073] Put 580g of dichloroethane and 68.04g (0.2mol) of the first intermediate into a reaction bottle, add 49.6g (0.42mol) of p-aminobenzonitrile, stir and heat to 80-86°C, and reflux for 12h. After the conversion of the control is complete, add 300g of water and 21g of sodium carbonate to adjust the pH>7.5, stir for 30 minutes and let stand to separate the water; then add water to wash until neutral. After removing the solvent from the organic phase obtained by phase separation, add ethanol to dissolve, cool and wash the crystals, filter and dry to obtain 99.5g of the second intermediate as a white solid. After testing, the yield of the second intermediate is 96%; HPLC purity: 99.3%.

[0074] Embodiment 2

[0075] Step S1: Synthesis of the second intermediate

[0076] 240g of trimethylbenzene and 34g (0.10mol) of the first intermediate were put into a reaction bottle, and a solution containing 24.2g (0.205mol) of p-aminobenzonitrile dissolved in 200g of trimethylbenzene was added, and the mixture was stirred and heated to 140-150°C, and refluxed for 3h. After the conversion was complete, the temperature was lowered, and 44.2g of the second intermediate solid was obtained by filtration and drying. After testing, the yield of the second intermediate was 85%, and the HPLC purity was 99.5%.

[0077] Embodiment 3

[0078] Step S2: Synthesis of diethylhexylbutyramidotriazineone

[0079] Mix 51.8g (0.1mol) of the second intermediate and 200g (1.54mol) of isooctyl alcohol, cool to 10°C, introduce HCl gas, and react for 3h before the intermediate control conversion is complete. Add 100g of water, continue stirring for 1h, let stand, and separate the aqueous phase. Wash the organic phase with water once more. After completion, separate the phases, distill the organic phase under reduced pressure to remove the solvent, and add cyclohexane for crystallization. Filter and dry at room temperature to obtain 72.8g of diethylhexyl butyramido triazone product. After testing, the yield of diethylhexyl butyramido triazone was 95% and the HPLC purity was 99.2%.

[0080] Embodiment 4

[0081] Step S2: Synthesis of diethylhexylbutyramidotriazineone

[0082] Mix 26g (0.05mol) of the second intermediate, 32g (0.25mol) of isooctyl alcohol and 100g of toluene, cool to 0°C, introduce HCl gas, react for 6h, and complete the intermediate control conversion. Add 70g of water and continue stirring for 1h. Then let it stand and separate the aqueous phase. Wash the organic phase with water once more. After completion, separate the phases, distill the organic phase under reduced pressure to remove the solvent, and add cyclohexane for crystallization. Filter and dry at room temperature to obtain 34.5g of diethylhexyl butyramido triazone product. After testing, the yield of diethylhexyl butyramido triazone was 90% and the HPLC purity was 99.0%.

[0083] Embodiment 5

[0084] Add 76 g (0.41 mol) of cyanuric chloride and 49.7 g (0.41 mol) of N,N-dimethylaniline to 500 g of toluene, maintain the kettle temperature at 25-35°C in a water bath, dropwise add 76.9 g (0.4 mol) of N-tert-butyl-4-aminobenzamide dissolved in 400 g of toluene, stir and react for 1 hour, filter after the conversion is complete, wash once with 150 g of toluene and twice with 250 g of water to obtain the first intermediate wet product.

[0085] The first intermediate prepared by the above process was put into a reaction bottle, 500g toluene was added, the temperature was raised to 110°C and refluxed to remove the water contained in the wet product, and then 99.2g (0.84mol) of p-aminobenzonitrile was added, and the reaction was continued at 110°C for 8h. After the intermediate control reaction was complete, the temperature was lowered to 15°C, 521g (4.0mol) of isooctyl alcohol was added, HCl gas was introduced, and the intermediate control conversion was completed after 6h of reaction. 700g of water was added, and the stirring was continued for 1h and then the phases were separated. The organic phase was washed with sodium bicarbonate solution to adjust the pH to pH=7.0. After the phases were separated, the organic phase was decompressed to remove the solvent, cyclohexane was added for crystallization, and 306.4g of diethylhexyl butyramido triazone product was obtained.

[0086] In this example, the HPLC purity of the diethylhexyl butyramido triazone product is 98.9% and the yield is 90%.

[0087] Experimental data show that the preparation method of the present invention can effectively reduce impurities in the synthesis process and obtain a high-purity diethylhexyl butyramido triazone product.

[0088] In the description provided herein, a large number of specific details are described. However, it is understood that embodiments of the present invention can be practiced without these specific details. In some instances, well-known methods, structures and techniques are not shown in detail so as not to obscure the understanding of this description.

[0089] At this point, those skilled in the art should recognize that, although multiple exemplary embodiments of the present invention have been shown and described in detail herein, many other variations or modifications that conform to the principles of the present invention can still be directly determined or derived based on the content disclosed in the present invention without departing from the spirit and scope of the present invention. Therefore, the scope of the present invention should be understood and recognized as covering all these other variations or modifications.

Claims

1. A method for preparing diethylhexyl butyramido triazone, comprising the following steps: Step S1: reacting the first intermediate N-tert-butyl-4-[(4,6-dichloro-1,3,5-triazine)amino]benzamide as shown in formula I with p-aminobenzonitrile in a solvent to obtain the second intermediate 4-(4,6-bis((4-cyanophenyl)amino)-1,3,5-triazine-2-yl)amino)-N-(tert-butyl)benzamide as shown in formula II: Step S2: reacting the second intermediate with isooctyl alcohol under acid catalysis to obtain diethylhexyl butyramido triazone as shown in formula III:

2. The method for preparing diethylhexyl butyramido triazone according to claim 1, wherein The acid is HCl, and step S2 comprises: Add isooctyl alcohol to the second intermediate obtained in step S1, cool to a specified temperature, and introduce dry HCl gas to react, wherein the specified temperature is in the range of -20°C to 40°C.

3. The method for preparing diethylhexyl butyramido triazone according to claim 2, wherein The specified temperature is in the range of -10°C to 30°C.

4. The method for preparing diethylhexyl butyramido triazone according to claim 1, wherein In the step S2, the molar ratio of the second intermediate to isooctyl alcohol is 1:(2.5-40).

5. The method for preparing diethylhexyl butyramido triazone according to claim 2, wherein The step S2 further comprises: After the reaction is completed, the reaction product is washed with water to separate the phases, and the solvent is removed from the organic phase obtained by the phase separation to obtain a diethylhexyl butyramido triazone product.

6. The method for preparing diethylhexyl butyramido triazone according to claim 1, wherein The step S1 comprises: The solvent, the first intermediate and p-aminobenzonitrile are added into a reactor, and the mixture is stirred and reacted at a temperature of 10 to 150° C. for 3 to 12 hours.

7. The method for preparing diethylhexyl butyramido triazone according to claim 1, wherein In the step S1, the molar ratio of the first intermediate to p-aminobenzonitrile is 1:(2.0-2.1).

8. The method for preparing diethylhexyl butyramido triazone according to claim 1, wherein The solvent in step S1 is toluene, xylene, trimethylbenzene, dichloroethane or chloroform.

9. The method for preparing diethylhexyl butyramido triazone according to claim 1, wherein The first intermediate is synthesized by reacting N-tert-butyl-4-aminobenzamide with cyanuric chloride.

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