Preparation method of main component octocrylene of sun-screening agent

Abstract

The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of octocrylene serving as a main component of a sun-screening agent. The invention provides a preparation method of octocrylene serving as a main component of a sun-screening agent, which comprises the following steps: dissolving benzophenone in a polar aprotic solvent, adding zinc powder, heating to 50-70 DEG C under an inert condition, and dropwise adding 2-bromo-2-ethyl cyanoacetate for reaction to obtain a solution containing an intermediate etocrylene; under an ice bath condition, acidifying the solution containing the intermediate etocrilene by using a protonic acid aqueous solution, adding isooctanol, and slowly heating to 15-30 DEG C for reaction; and after the reaction is finished, extracting, washing, drying, filtering and concentrating the reaction liquid to obtain the octocrylene. According to the preparation method, reaction steps are reduced, the preparation process is simple, the operation method is convenient and fast, high-purity octocrylene can be obtained without purifying an intermediate, and large-scale industrial production is facilitated.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and in particular relates to a method for preparing octocrylene, a main component of a sunscreen agent. Background Art

[0002] As the global climate continues to warm, the high temperature time in summer is prolonged and increasing year by year, which directly leads to the increasingly serious ultraviolet radiation from the sun to the surface. Ultraviolet rays are rays with a wavelength between 100-400nm in the sun's rays, which have immeasurable potential harm to the human body. Specifically, ultraviolet rays have strong penetrating power and biological activity. Long-term and large-scale exposure to ultraviolet rays may induce skin cancer. At the same time, ultraviolet rays are more likely to cause sunburn and inflammation of the skin, which may promote the occurrence of skin cancer. The mechanism of ultraviolet carcinogenesis mainly involves direct damage to skin cells. Ultraviolet rays can directly or indirectly act on biological macromolecules such as DNA, proteins and cell membranes of skin cells, leading to gene mutations, abnormal cell proliferation and decreased immune function, thereby increasing the risk of skin cancer. Therefore, the market demand for sunscreens that mainly absorb ultraviolet rays is also increasing, and the market prospects are very broad.

[0003] Octocrylene is the main ingredient of sunscreen. It is a liquid UV absorber, mainly used as a UV filter for sunscreen and topical pharmaceutical preparations. Octocrylene is also known as 2-cyano-3,3-diphenylacrylate isooctyl ester or octoquilene, which belongs to the cinnamic acid class of UV absorbers. Its maximum absorption wavelength for UV rays is 308nm, and it has a strong absorption capacity for UV rays (UVB) in the range of 280-320nm.

[0004] The existing preparation method of octocrylene usually uses benzophenone and ethyl cyanoacetate as raw materials, and prepares the intermediate of etocrylene through the catalysis of inorganic weak base ammonium acetate and Knoevenagel condensation reaction, and then obtains the final product octocrylene through the catalysis of inorganic base potassium carbonate and isooctyl ester exchange reaction. However, the Knoevenagel condensation reaction in the first step of this route has the problems of long reaction time and incomplete reaction, and ammonium acetate will sublime during the heating process to block the pipeline, which may cause serious production safety accidents; the second step of the base-catalyzed ester exchange reaction is a reversible reaction in nature, and there is also the problem of incomplete reaction, and the presence of the base will also cause the ester to hydrolyze in the post-treatment, which directly leads to an increase in production costs; in addition, the existing preparation method often requires the intermediate etocrylene to be crystallized and purified before being used in the next step of synthesizing octocrylene, otherwise the quality of the obtained octocrylene is difficult to meet the use requirements. Therefore, it is very necessary to develop a new preparation method for octocrylene to solve the problems existing in the above process.

[0005] Summary of the invention

[0006] In view of this, the present invention provides a method for preparing octocrylene, the main ingredient of a sunscreen agent. The preparation method effectively improves the conversion rate of the reaction, reduces the reaction steps, has a simple preparation process, a convenient operation method, and can obtain high-purity octocrylene without purifying the intermediate, which is conducive to large-scale industrial production.

[0007] In order to solve the above technical problems, the first aspect of the present invention provides a method for preparing octocrylene, a main ingredient of a sunscreen agent, comprising the following steps:

[0008] S1, dissolving benzophenone in a polar aprotic solvent, adding zinc powder and heating to 50-70° C. under inert conditions, adding ethyl 2-bromo-2-cyanoacetate dropwise to react, and obtaining a solution containing the intermediate etocrylene;

[0009] S2, acidifying the solution containing the intermediate etocrylene with an aqueous solution of a protonic acid under ice bath conditions, adding isooctyl alcohol and slowly heating the temperature to 15-30° C. to cause an esterification reaction with the intermediate etocrylene;

[0010] S3. After the reaction is completed, the reaction solution is extracted, washed, dried, filtered and concentrated to obtain octocrylene.

[0011] The invention provides a method for preparing octocrylene, a main component of a sunscreen agent. Benzophenone is used as a raw material. Benzophenone reacts with ethyl 2-bromo-2-cyanoacetate under the action of zinc powder to obtain a reaction intermediate etocrylene. The etocrylene then undergoes an ester exchange reaction with isooctyl alcohol under acidic conditions to obtain octocrylene.

[0012] The preparation method provided by the present invention effectively improves the conversion rate of the reaction raw materials by specifically selecting the reaction conditions and the reaction raw materials, and the reaction is more thorough; moreover, the preparation method causes etocrylene and isooctyl alcohol to undergo an ester exchange reaction under acidic conditions, avoiding the hydrolysis of the ester under alkaline conditions, thereby ensuring that the product octocrylene has a high yield (the total yield of the two-step reaction is greater than 83%). In addition, the preparation method provided by the present invention has a simpler process, and after obtaining the intermediate etocrylene, it can be directly used in the next ester exchange reaction without purification operation, and the purity of the obtained octocrylene is greater than 99%.

[0013] Illustratively, the reaction temperature in step 1 can be 50°C, 60°C, 65°C, 70°C or any value therebetween, and the reaction temperature in step 2 can be 15°C, 20°C, 25°C, 30°C or any value therebetween.

[0014] Preferably, the reaction temperature in step 1 is 65°C, and the reaction temperature in step 2 is 25°C.

[0015] In combination with the first aspect, the polar aprotic solvent includes at least one of tetrahydrofuran, 1,4-dioxane and N,N-dimethylformamide.

[0016] Preferably, the polar aprotic solvent is 1,4-dioxane.

[0017] In combination with the first aspect, each gram of the benzophenone is dissolved in 5 to 15 mL of the polar aprotic solvent.

[0018] Each gram of the benzophenone can be dissolved in any volume of 5 to 15 mL of a polar aprotic solvent, for example, 5, 7, 9, 11, 13, 15 mL or any value between any two of them.

[0019] Preferably, each gram of the benzophenone is dissolved in 10 mL of the polar aprotic solvent.

[0020] In combination with the first aspect, the molar ratio of the zinc powder to benzophenone is 1.1-1.8:1.

[0021] Illustratively, the molar ratio of the zinc powder to benzophenone may be 1.1:1, 1.2:1, 1.3:1, 1.5:1, 1.8:1 or any value therebetween.

[0022] Preferably, the molar ratio of the zinc powder to benzophenone is 1.5:1.

[0023] In combination with the first aspect, the molar ratio of ethyl 2-bromo-2-cyanoacetate to benzophenone is 1.1-1.8:1.

[0024] Illustratively, the molar ratio of ethyl 2-bromo-2-cyanoacetate to benzophenone may be 1.1:1, 1.2:1, 1.3:1, 1.5:1, 1.8:1 or any value in between.

[0025] Preferably, the molar ratio of ethyl 2-bromo-2-cyanoacetate to benzophenone is 1.5:1.

[0026] In combination with the first aspect, the molar ratio of isooctyl alcohol to benzophenone is 1.1-1.8:1.

[0027] Illustratively, the molar ratio of isooctyl alcohol to benzophenone may be 1.1:1, 1.2:1, 1.3:1, 1.5:1, 1.8:1 or any value therebetween.

[0028] Preferably, the molar ratio of isooctyl alcohol to benzophenone is 1.5:1.

[0029] In combination with the first aspect, the reaction time in step S1 is 6 to 12 hours, and the reaction time in step S2 is 1 to 3 hours.

[0030] Exemplarily, the reaction time in step S1 can be 6, 8, 10, 12 h or any value therebetween, and the reaction time in step S2 can be 1, 1.5, 2, 2.5, 3 h or any value therebetween.

[0031] Preferably, the reaction time in step S1 is 8 hours, and the reaction time in step S2 is 2 hours.

[0032] In combination with the first aspect, the protonic acid aqueous solution includes hydrochloric acid solution, sulfuric acid solution and nitric acid solution.

[0033] Preferably, the concentration of the protonic acid aqueous solution is 4 mol / L.

[0034] In combination with the first aspect, the pH of the solution containing the intermediate is adjusted to 3-4 with a protonic acid aqueous solution.

[0035] Adjusting the pH to acidic before conducting the transesterification reaction can effectively avoid the hydrolysis of the generated esters, improve the utilization rate of raw materials and reduce production costs.

[0036] For example, the volume (in milliliters) of the protonic acid aqueous solution used can be 5 to 8 times the mass (in grams) of benzophenone, such as 5, 6, 7, 8 times or any value in between, preferably 6 times.

[0037] The second aspect of the present invention provides a main ingredient of a sunscreen, octocrylene, which is prepared according to the above preparation method and has a purity of at least 99%, meeting the production requirements.

[0038] The preparation method of octocrylene provided by the present invention has simple process and convenient operation, and octocrylene with a yield and purity that meet production requirements can be obtained by only using a "one-pot method", which is of great significance for realizing large-scale and rapid production of octocrylene. BRIEF DESCRIPTION OF THE DRAWINGS

[0039] Figure 1 This is the H NMR spectrum of octocrylene obtained in Example 1 of the present invention;

[0040] Figure 2 This is the HPLC spectrum of octocrylene obtained in Example 1 of the present invention;

[0041] Figure 3 The HPLC spectrum of octocrylene obtained in Example 2 of the present invention. DETAILED DESCRIPTION

[0042] In order to make the purpose, technical solution and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with specific embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0043] There are many methods for preparing octocrylene, but most of them have problems such as long reaction time, high energy consumption, low production capacity, and complicated preparation steps. In view of this, the present invention provides a new method for preparing octocrylene, which effectively improves the conversion rate of reactants, simplifies the reaction steps, has lower energy consumption, and eliminates the purification operation of intermediates, greatly reduces production costs, improves production efficiency, and is conducive to large-scale production.

[0044] The preparation method provided by the present invention is described below through specific examples.

[0045] The reaction reagents and equipment used in the present invention are conventional commercially available common reagents and common equipment.

[0046] The reaction scheme of the preparation method provided by the present invention is as follows:

[0047]

[0048] Example 1

[0049] This embodiment provides a method for preparing octocrylene, a main ingredient of a sunscreen agent, and the specific steps include:

[0050] Add 1.8L 1,4-dioxane to a 5L three-necked flask, then add benzophenone (182.0g, 1.0mol) and zinc powder (97.5g, 1.5mol) in sequence, replace nitrogen three times, heat to 65℃, slowly add ethyl 2-bromo-2-cyanoacetate (288.1g, 1.5mol) dropwise at a rate of 10mL / min, and keep at 65℃ for 8h after addition. After TLC monitoring, add 1100mL 4mol / L hydrochloric acid aqueous solution dropwise under ice bath to adjust the pH of the reaction solution to 3-4. Then add isooctyl alcohol (195.2g, 1.5mol), remove the ice bath after the addition of isooctyl alcohol, slowly raise the temperature to 25℃, and continue to keep at 65℃ for 2h. After the reaction was completed as monitored by TLC, the reaction solution was extracted with ethyl acetate, 1500 mL of ethyl acetate was added each time, and the extraction was performed 3 times in total. Then, the ethyl acetate phases were combined, washed with water and saturated sodium chloride in turn, and finally dried over anhydrous sodium sulfate for 0.5 h, filtered, and concentrated. The obtained oil was then distilled under reduced pressure by a vacuum oil pump to finally obtain a viscous light yellow clear oily liquid octocrylene (a total of 318.10 g, a yield of 88.00%). The purity was determined to be 99.21% by HPLC. Its nuclear magnetic spectrum is shown as follows: Figure 1As shown in (δ7.47-7.36, m, 8H; δ7.25-7.13, d, 2H; δ4.02-3.99, d, 2H; δ1.55, s, 1H; δ1.24-1.19, m, 8H; δ0.89-0.85, m, 3H; δ0.83-0.79, m, 3H), HPLC spectrum as shown in Figure 2 shown.

[0051] The yield is calculated as follows:

[0052] Octocrylene yield (%) = mass of octocrylene obtained (g) / molecular weight of octocrylene (g / mol) / molar amount of benzophenone input (mol) * 100; wherein, the molecular weight of octocrylene is 361.48 g / mol.

[0053] Example 2

[0054] This embodiment provides a method for preparing octocrylene, a main ingredient of a sunscreen agent, and the specific steps include:

[0055] Add 1.45L tetrahydrofuran to a 5L three-necked flask, then add benzophenone (182.0g, 1.0mol) and zinc powder (78.0g, 1.2mol) in sequence, replace nitrogen three times, heat to 65°C, slowly add ethyl 2-bromo-2-cyanoacetate (230.1g, 1.2mol) dropwise, the drop rate is 10mL / min, and the reaction is kept at 65°C for 10h. After the reaction is complete by TLC monitoring, add 900mL 2mol / L sulfuric acid aqueous solution dropwise under ice bath, and adjust the pH of the reaction solution to 3-4. Then add isooctyl alcohol (155.9g, 1.2mol), remove the ice bath after the addition of isooctyl alcohol, slowly raise the temperature to 30°C, and continue to keep the temperature for 1h. After the reaction was completed as monitored by TLC, the reaction solution was extracted with ethyl acetate, 1200 mL of ethyl acetate was added each time, and the extraction was performed 3 times in total. The ethyl acetate phases were then combined, washed with water and saturated sodium chloride in turn, and finally dried over anhydrous sodium sulfate for 0.5 h, filtered, and concentrated. The obtained oil was then distilled under reduced pressure by a vacuum oil pump to finally obtain a viscous light yellow clear oily liquid octocrylene (a total of 301.52 g, a yield of 83.41%). The purity was determined to be 99.37% by HPLC. The HPLC spectrum is shown in FIG. Figure 3 shown.

[0056] Example 3

[0057] This embodiment provides a method for preparing octocrylene, a main ingredient of a sunscreen agent, and the specific steps include:

[0058] Add 2.5L N,N-dimethylformamide to a 5L three-necked flask, then add benzophenone (182.0g, 1.0mol) and zinc powder (84.5g, 1.3mol) in sequence, replace nitrogen three times, heat to 50℃, slowly add ethyl 2-bromo-2-cyanoacetate (249.3g, 1.3mol) dropwise, the drop rate is 10mL / min, and the reaction is kept at 50℃ for 12h after the addition. After the reaction is complete by TLC monitoring, add 1100mL 4mol / L hydrochloric acid aqueous solution dropwise under ice bath to adjust the pH of the reaction solution to 3-4. Then add isooctyl alcohol (169.2g, 1.3mol), remove the ice bath after the addition of isooctyl alcohol, slowly raise the temperature to 15℃, and continue to keep the temperature for 3h. After the reaction was completed as monitored by TLC, the reaction solution was extracted with ethyl acetate, 1000 mL of ethyl acetate was added each time, and the extraction was performed 3 times in total. Then, the ethyl acetate phases were combined, washed with water and saturated sodium chloride in turn, and finally dried over anhydrous sodium sulfate for 0.5 h, filtered, and concentrated. The obtained oil was then distilled under reduced pressure by a vacuum oil pump to finally obtain viscous light yellow clear oily liquid octocrylene (a total of 320.03 g, yield 88.53%), and the purity was determined to be 99.21% by HPLC.

[0059] Example 4

[0060] This embodiment provides a method for preparing octocrylene, a main ingredient of a sunscreen agent, and the specific steps include:

[0061] Add 1L 1,4-dioxane to a 5L three-necked flask, then add benzophenone (182.0g, 1.0mol) and zinc powder (71.5g, 1.1mol) in sequence, replace nitrogen three times, heat to 70℃, slowly add ethyl 2-bromo-2-cyanoacetate (210.9g, 1.1mol) dropwise at a rate of 10mL / min, and keep at 70℃ for 6h after addition. After TLC monitoring, add 900mL 2mol / L sulfuric acid aqueous solution dropwise under ice bath, and adjust the pH of the reaction solution to 3-4. Then add isooctyl alcohol (142.9g, 1.2mol), remove the ice bath after the addition of isooctyl alcohol, slowly raise the temperature to 20℃, and continue to keep at 70℃ for 2.5h. After the reaction was completed as monitored by TLC, the reaction solution was extracted with ethyl acetate, 1100 mL of ethyl acetate was added each time, and the extraction was performed 3 times in total. Then, the ethyl acetate phases were combined, washed with water and saturated sodium chloride in turn, and finally dried over anhydrous sodium sulfate for 0.5 h, filtered, and concentrated. The obtained oil was then distilled under reduced pressure by a vacuum oil pump to finally obtain viscous light yellow clear oily liquid octocrylene (a total of 325.00 g, yield 89.91%), and the purity was determined to be 99.15% by HPLC.

[0062] Example 5

[0063] This embodiment provides a method for preparing octocrylene, a main ingredient of a sunscreen agent, and the specific steps include:

[0064] Add 2.37L tetrahydrofuran to a 5L three-necked flask, then add benzophenone (182.0g, 1.0mol) and zinc powder (117g, 1.8mol) in sequence, replace nitrogen three times, heat to 60°C, slowly add ethyl 2-bromo-2-cyanoacetate (315.1g, 1.8mol) dropwise, the drop rate is 10mL / min, and the reaction is kept at 60°C for 8h. After the reaction is complete, 910mL 2mol / L sulfuric acid aqueous solution is added dropwise under an ice bath to adjust the pH of the reaction solution to 3-4. Then add isooctyl alcohol (214.4g, 1.8mol), remove the ice bath after the addition of isooctyl alcohol, slowly raise the temperature to 25°C, and continue to keep the temperature for 1.5h. After the reaction was completed as monitored by TLC, the reaction solution was extracted with ethyl acetate, 1100 mL of ethyl acetate was added each time, and the extraction was performed 3 times in total. Then, the ethyl acetate phases were combined, washed with water and saturated sodium chloride in turn, and finally dried over anhydrous sodium sulfate for 0.5 h, filtered, and concentrated. The obtained oil was then distilled under reduced pressure by a vacuum oil pump to finally obtain viscous light yellow clear oily liquid octocrylene (a total of 319.20 g, yield 88.30%), and the purity was determined to be 99.33% by HPLC.

[0065] Example 6

[0066] This embodiment provides a method for preparing octocrylene, a main ingredient of a sunscreen agent, and the specific steps include:

[0067] Add 2.1L 1,4-dioxane to a 5L three-necked flask, then add benzophenone (182.0g, 1.0mol) and zinc powder (117g, 1.8mol) in sequence, replace nitrogen three times, heat to 60℃, slowly add ethyl 2-bromo-2-cyanoacetate (262.6g, 1.5mol) dropwise, with a drop rate of 10mL / min, and keep warm at 60℃ for 8h after addition. After TLC monitoring, add 900mL 2mol / L sulfuric acid aqueous solution dropwise under ice bath, and adjust the pH of the reaction solution to 3-4. Then add isooctyl alcohol (190.6g, 1.6mol), remove the ice bath after the addition of isooctyl alcohol, slowly raise the temperature to 25℃, and continue to keep warm for 2h. After the reaction was completed as monitored by TLC, the reaction solution was extracted with ethyl acetate, 1000 mL of ethyl acetate was added each time, and the extraction was performed 3 times in total. Then, the ethyl acetate phases were combined, washed with water and saturated sodium chloride in turn, and finally dried over anhydrous sodium sulfate for 0.5 h, filtered, and concentrated. The obtained oil was then distilled under reduced pressure by a vacuum oil pump to finally obtain viscous light yellow clear oily liquid octocrylene (a total of 333.01 g, yield 92.12%), and the purity was determined to be 99.23% by HPLC.

[0068] Comparative Example 1

[0069] This comparative example provides a method for preparing octocrylene, a main ingredient of a sunscreen agent, and the specific steps include:

[0070] Add 273g of cyclohexane to a 5L three-necked flask, and then add benzophenone (182.0g, 1.0mol), ethyl cyanoacetate (226.0g, 2.0mol), di-n-butylamine (10.00g, 0.08mol), and 5.7g of propionic acid (5.7g, 0.08mol) in sequence. After the addition, heat to reflux and separate water. After the separation of water, distill and concentrate to obtain a concentrated solution of etocrilin. Add 200mL of 2mol / L sulfuric acid aqueous solution to the concentrated solution under an ice bath, and adjust the pH of the reaction solution to 3-4. Then add isooctyl alcohol (190.6g, 1.6mol). After the addition of isooctyl alcohol, remove the ice bath and slowly heat to 25°C, and continue to keep the temperature for 2h. After the reaction was completed as monitored by TLC, the reaction solution was extracted with ethyl acetate, 1000 mL of ethyl acetate was added each time, and the extraction was performed 3 times in total. Then, the ethyl acetate phases were combined, washed with water and saturated sodium chloride in turn, and finally dried over anhydrous sodium sulfate for 0.5 h, filtered, and concentrated. The obtained oil was then distilled under reduced pressure by a vacuum oil pump to finally obtain viscous light yellow clear oily liquid octocrylene (a total of 300.01 g, yield 82.99%), and the purity was determined to be 94.23% by HPLC.

[0071] What is described above is only a preferred specific implementation manner of the present invention, but the protection scope of the present invention is not limited thereto. Any technician familiar with the technical field can make equivalent replacements or changes according to the technical scheme and inventive concept of the present invention within the technical scope disclosed by the present invention, which should be covered by the protection scope of the present invention.

Claims

1. A method for preparing octocrylene, the main ingredient of a sunscreen, characterized in that the steps include: S1, dissolving benzophenone in a polar aprotic solvent, adding zinc powder and heating to 50-70° C. under inert conditions, adding ethyl 2-bromo-2-cyanoacetate dropwise to react, and obtaining a solution containing the intermediate etocrylene; S2, acidifying the solution containing the intermediate etocrylene with an aqueous solution of a protonic acid under ice bath conditions, adding isooctyl alcohol and slowly heating the temperature to 15-30° C. to cause an esterification reaction with the intermediate etocrylene; S3. After the reaction is completed, the reaction solution is extracted, washed, dried, filtered and concentrated to obtain octocrylene.

2. The method for preparing octocrylene as the main ingredient of the sunscreen agent according to claim 1, characterized in that: The polar aprotic solvent includes at least one of tetrahydrofuran, 1,4-dioxane and N,N-dimethylformamide.

3. The method for preparing octocrylene as the main ingredient of the sunscreen agent according to claim 1 or 2, characterized in that: Each gram of the benzophenone is dissolved in 5 to 15 mL of the polar aprotic solvent.

4. The method for preparing octocrylene as the main ingredient of the sunscreen agent according to claim 1, characterized in that: The molar ratio of the zinc powder to benzophenone is 1.1-1.8:

1.

5. The method for preparing octocrylene as the main ingredient of the sunscreen agent according to claim 1, characterized in that: The molar ratio of ethyl 2-bromo-2-cyanoacetate to benzophenone is 1.1-1.8:

1.

6. The method for preparing octocrylene as the main ingredient of sunscreen according to claim 1, characterized in that: The molar ratio of isooctyl alcohol to benzophenone is 1.1-1.8:

1.

7. The method for preparing octocrylene as the main ingredient of sunscreen according to claim 1, characterized in that: The reaction time in step S1 is 6 to 12 hours, and the reaction time in step S2 is 1 to 3 hours.

8. The method for preparing octocrylene as the main ingredient of sunscreen according to claim 1, characterized in that: The protonic acid aqueous solution includes hydrochloric acid solution, sulfuric acid solution and nitric acid solution.

9. The method for preparing octocrylene as the main ingredient of the sunscreen agent according to claim 8, characterized in that: The pH of the solution containing the intermediate etocrylene is adjusted to 3-4 with a protonic acid aqueous solution.

10. Octocrylene, the main ingredient of sunscreen, characterized in that: Prepared according to the preparation method according to any one of claims 1 to 9.

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