Preparation method of sun-screening agent MCE400

Abstract

The invention provides a sun-screening agent MCE400 preparation method, which comprises: 1, adding 1, 3-cyclohexanedione, 3-methoxypropylamine and toluene into a reaction container, carrying out a heating reflux reaction, and steaming out toluene after the reaction is completed to obtain an intermediate I; step 2, adding the intermediate I into a microchannel reactor, then adding sulfuric acid diester, heating and cooling, and then adding an organic solvent to prepare an intermediate solution; step 3, dissolving ethoxyethyl cyanoacetate in an organic solvent to prepare an ethoxyethyl cyanoacetate solution; and 4, adding alkali and an ethoxyethyl cyanoacetate solution into the intermediate solution, carrying out heating reaction, cooling to room temperature after the reaction is finished, adding water and ethyl acetate, carrying out liquid separation, carrying out reduced pressure distillation on the organic phase filtrate to remove the solvent, and recrystallizing with the solvent to obtain MCE400. According to the method, the raw materials are low in price, a continuous reaction technology is adopted, the operation process and equipment investment are reduced, and the production cost is reduced.

Description

Technical Field

[0001] This invention belongs to the field of cosmetic technology, specifically relating to a method for preparing sunscreen agent MCE400. Background Technology

[0002] MCE400 (Mexoryl 400), a novel sunscreen agent, expands the UV protection range by 30 nanometers, effectively protecting the skin from ultra-long-wave UVA radiation in the 380-400 nanometer range. Compared to traditional sunscreens, only 0.5% MCE400 can increase the UVA protection factor of a formula from 14 to 29, providing a wider absorption range and stronger UVA protection. MCE400 received EU approval at the end of 2020, and subsequently, La Roche-Posay UVMune 400, a sunscreen product based on MCE400 technology, was officially launched in some countries in March 2022.

[0003] MCE400 and its derivatives have great market prospects and economic value. There is little information disclosed in the existing technology regarding the preparation method of MCE400. This invention aims to design a method suitable for industrial production, achieving high yield and low cost in the preparation of MCE400. Summary of the Invention

[0004] To address the problems existing in the prior art, this invention aims to provide a method for preparing sunscreen agent MCE400. This method has a simple production process, high yield, fast reaction speed, low cost, and is easy to industrialize.

[0005] The technical solution adopted by the present invention to solve the problems existing in the prior art is as follows: A method for preparing sunscreen agent MCE400, comprising the following steps: Step 1: Add 1,3-cyclohexanedione, 3-methoxypropylamine, and toluene to a reaction vessel, heat under reflux, and after the reaction is complete, distill off the toluene to obtain intermediate I. Intermediate I does not require purification and can be directly used in the next reaction. The chemical formula of intermediate I is as follows: Step 2: Add intermediate I obtained in step 1 to a microchannel reactor, then add sulfate diester, react at -2~0℃ for 10 min, then heat the reaction for 15-20 min at a pressure of 0.5-2.0 MPa, cool to room temperature, and then add organic solvent to prepare a 0.01 mol / L intermediate solution; Step 3: Dissolve ethoxyethyl cyanoacetate in an organic solvent to prepare a 0.01 mol / L ethoxyethyl cyanoacetate solution; Step 4: Add alkali and the ethoxyethyl cyanoacetate solution prepared in Step 3 to the intermediate solution in Step 2, heat the reaction for 10-60 min at a pressure of 0.5-2.0 MPa, cool to room temperature after the reaction is complete, add water and ethyl acetate, separate the liquid and liquid phases, remove the solvent by vacuum distillation of the organic phase filtrate, and recrystallize with the solvent to obtain MCE400. The reaction equations for the production process are shown below, where MCE400 has two isomers: E / Z and E / E. .

[0006] In step 1, the molar ratio of 1,3-cyclohexanedione to 3-methoxypropylamine is 1:1-1:1.2, with a preferred molar ratio of 1:1-1:1.05; the mass ratio of 1,3-cyclohexanedione to toluene is 1:1-1:6, with a preferred mass ratio of 1:2-1:3; the reaction temperature is 80-140 ℃, with a preferred temperature of 110-120 ℃; the specific reaction time is determined based on the conversion rate detected by the central control system, and samples are taken every 30 minutes after the reaction has been going on for 30 minutes. The reaction is stopped when the conversion rate no longer increases. The reaction time is 1-4 hours, with a preferred reaction time of 2-3 hours.

[0007] In step 1, toluene is distilled under reduced pressure at 50-60 °C, and the distilled toluene can be recovered and reused.

[0008] A water separator is connected to the reaction vessel in step 1 to remove the water generated in the reaction and improve the reaction conversion rate.

[0009] The sulfate diester in step 2 is either dimethyl sulfate or diethyl sulfate, preferably diethyl sulfate.

[0010] The feed rate of the disulfate in step 2 is 0.3 g / min-0.8 g / min, and the preferred dropping rate is 0.5 g / min-0.6 g / min.

[0011] The molar ratio of the sulfate diester in step 2 to the 1,3-cyclohexanedione added in step 1 is 1.2:1-1:1, preferably 1.05:1-1:1; the heating temperature is 50-90 ℃, preferably 70-80 ℃; the reaction time is 10-60 min, preferably 20-30 min.

[0012] In step 3, the catalyst is one of sodium tert-butoxide, potassium tert-butoxide, triethylamine, sodium carbonate, and sodium ethoxide. The molar ratio of the catalyst to the 1,3-cyclohexanedione added in step 1 is 1.5:1 to 1:1, and the preferred molar ratio is 1.1:1 to 1:1.

[0013] The organic solvent used in steps 2 and 3 is one of n-heptane, toluene, 1,4-dioxane, tetrahydrofuran, and methyl tert-butyl ether.

[0014] In step 4, the molar ratio of ethoxyethyl cyanoacetate to 1,3-cyclohexanedione added in step 1 is 1.2:1-1:1, preferably 1.05:1-1:1; the heating temperature in step 4 is 60-120 ℃, preferably 90-100 ℃; the reaction time is 10-60 min, preferably 20-30 min; after the reaction, the mass ratio of water to 1,3-cyclohexanedione is 1:1-10:1, preferably 4:1-5:1; the mass ratio of ethyl acetate to 1,3-cyclohexanedione is 2:1-10:1, preferably 5:1-6:1.

[0015] The solvent used for recrystallization in step 4 is one or two of the following: ethanol, ethyl acetate, acetone, n-hexane, and methyl tert-butyl ether. Preferably, the solvent is a mixed solution of ethyl acetate and methyl tert-butyl ether. The mass ratio of ethyl acetate to 1,3-cyclohexanedione added in step 1 is 1:2 to 1:1, and the mass ratio of methyl tert-butyl ether to 1,3-cyclohexanedione added in step 1 is 8:1 to 5:1.

[0016] Both steps 2 and 4 are carried out in an inert atmosphere.

[0017] The microchannel reactor is a stainless steel channel with an inner diameter of 0.5-1.0 mm.

[0018] The present invention has the following advantages: (1) The present invention proposes a method for preparing sunscreen agent MCE400, using inexpensive 1,3-cyclohexanedione and 3-methoxypropylamine as starting materials.

[0019] (2) By adopting continuous reaction technology, intermediate I does not need to be separated and purified, and can directly proceed to the next reaction, which reduces the operation process, reduces equipment investment, and lowers production costs.

[0020] (3) The microchannel reactor has advantages such as small inner diameter, large specific surface area, and instantaneous uniform mixing of materials, which greatly shortens the reaction time and results in high reaction yield. At the same time, the process is simple to operate and easy to industrialize. Attached Figure Description

[0021] Figure 1 The 1H NMR spectrum of MCE400 synthesized by the method in Example 1 of this invention; Figure 2 This is a high-resolution mass spectrum of MCE400 synthesized by the method in Example 1 of this invention; Figure 3 The infrared spectrum of MCE400 synthesized by the method in Example 1 of this invention; Figure 4 This is a liquid chromatogram of MCE400 synthesized by the method in Example 1 of the present invention. Detailed Implementation

[0022] The technical solution of the present invention will be further described in detail below through embodiments and in conjunction with the accompanying drawings.

[0023] Example 1 44.9 g of 1,3-cyclohexanedione, 35.7 g of 3-methoxypropylamine and 90 g of toluene were added to a 250 mL reaction flask and heated to 110 °C for 2 h. After the reaction was completed, the toluene was distilled under reduced pressure at 60 °C to obtain intermediate I. HPLC analysis showed that the purity of intermediate I was greater than 95%.

[0024] Intermediate I was added to a microchannel reactor, and then 61.7 g of diethyl sulfate was added at a flow rate of 0.5 g / min via a syringe pump under nitrogen atmosphere at -2 to 0 °C. The mixture was then heated to 70 °C and reacted for 30 min. After the reaction was completed, the mixture was cooled to room temperature, and 40 mL of toluene was added to prepare the intermediate solvent. Then, 42 g of sodium tert-butoxide was added.

[0025] 62.9 g of ethoxyethyl cyanoacetate was dissolved in 40 mL of toluene to prepare an ethoxyethyl cyanoacetate solution. At 100 °C and 2.0 MPa, the ethoxyethyl cyanoacetate solution was added to the mixture via a syringe pump at a flow rate of 2.0–3.0 mL / min. The reaction was allowed to proceed for 30 min, after which the mixture was cooled to room temperature. 200 g of water and 225 g of ethyl acetate were added, and the mixture was separated. The filtrate was distilled under reduced pressure to obtain a crude product, which was then recrystallized from 23 g of ethyl acetate and 270 g of methyl tert-butyl ether to give 116 g of a yellow solid, with a yield of 90% and a melting point of 87.2–89.5 °C. The purity, as determined by HPLC, was 99.9%.

[0026] The MCE400 synthesized by the method in Example 1 was subjected to NMR testing using a Bruker 400 MHz nuclear magnetic resonance spectrometer. Figure 1 MCE400 synthesized by the method in Example 1 1 H NMR spectrum, with the ratio of E / Z isomers to E / E isomers being 6.25:1: spectral information is as follows: 1H NMR (400 MHz, CDCl3): δ 7.08 (br, 1H), 5.47–6.47 (m, 1H), 4.13 – 4.34 (m, 2H), 3.69 – 3.72 (m, 2H), 3.53 – 3.61 (m, 4H), 3.36 – 3.40 (m, 5H), 2.70 – 3.11 (m, 2H), 2.30 – 2.37 (m, 2H), 1.82 – 1.93 (m, 4H), 1.19 – 1.33(m, 3H). The MCE400 synthesized by the method in Example 1 was tested using high-resolution mass spectrometry. Figure 2 The HRMS spectrum of MCE400 prepared in Example 1 is shown below. The spectrum information is as follows: C 17 H 27 N₂O₄, calculated value (measured value), 323.1965 (323.1960) [M+H] + C 17 H 26 N₂O₄Na, calculated value (measured value), 345.1785 (345.1778) [M+Na] + .

[0027] Figure 3 This is the infrared spectrum of MCE400 synthesized by the method in Example 1 of this invention. Figure 2 3256 cm -1 The broad peak at 2862-3108 cm⁻¹ is the stretching vibration peak of N–H. -1 This is the absorption peak for the stretching vibration of the C=C skeleton, at 2187 cm⁻¹. -1 The absorption peak for the stretching vibration of CN is 1683 cm⁻¹. -1 The peak at 1057-1275 cm⁻¹ is the characteristic absorption peak of the carbonyl group in the ester. -1 This is a characteristic absorption peak of C–O.

[0028] The MCE400 product in Example 1 has a purity of 99.9%, fully meeting the requirements of the cosmetics and materials industries. HPLC analysis results are as follows: Figure 4 As shown.

[0029] Example 2 44.9 g of 1,3-cyclohexanedione, 35.7 g of 3-methoxypropylamine and 120 g of toluene were added to a 250 mL reaction flask and heated to 120 °C for 3 h. After the reaction was completed, the toluene was distilled under reduced pressure at 60 °C to obtain intermediate I. HPLC analysis showed that the purity of intermediate I was greater than 95%.

[0030] Intermediate I was added to a microchannel reactor, and then 50.5 g of dimethyl sulfate was added at a flow rate of 0.8 g / min via a syringe pump under nitrogen atmosphere at -2 to 0 °C. The mixture was then heated to 60 °C and reacted for 20 min. After the reaction was completed, the mixture was cooled to room temperature, and 40 mL of toluene was added to prepare the intermediate solvent. Then, 47 g of potassium tert-butoxide was added.

[0031] 62.9 g of ethoxyethyl cyanoacetate was dissolved in 40 mL of toluene to prepare an ethoxyethyl cyanoacetate solution. At 100 °C and 2.0 MPa, the ethoxyethyl cyanoacetate solution was added to the mixture via a syringe pump at a flow rate of 2.0–3.0 mL / min. The reaction was allowed to proceed for 10 min, after which the solution was cooled to room temperature. 200 g of water and 225 g of ethyl acetate were added, and the mixture was separated. The filtrate was distilled under reduced pressure to obtain a crude product, which was then recrystallized from 23 g of ethyl acetate and 270 g of methyl tert-butyl ether to give 106 g of a yellow solid, with a yield of 82% and a purity of 99.5% as determined by HPLC.

[0032] Example 3 44.9 g of 1,3-cyclohexanedione, 39 g of 3-methoxypropylamine and 90 g of toluene were added to a 250 mL reaction flask and heated to 110 °C for 1 h. After the reaction was completed, the toluene was distilled under reduced pressure at 60 °C to obtain intermediate I. HPLC analysis showed that the purity of intermediate I was greater than 90%.

[0033] Intermediate I was added to a microchannel reactor, and then 61.7 g of dimethyl sulfate was added at a flow rate of 0.5 g / min via a syringe pump under nitrogen atmosphere at -2 to 0 °C. The mixture was then heated to 70 °C and reacted for 20 min. After the reaction was completed, the mixture was cooled to room temperature, and 40 mL of 1,4-dioxane was added to prepare the intermediate solvent. Then, 44 g of triethylamine was added.

[0034] 69 g of ethoxyethyl cyanoacetate was dissolved in 44 mL of 1,4-dioxane to prepare an ethoxyethyl cyanoacetate solution. At 120 °C and 2.0 MPa, the ethoxyethyl cyanoacetate solution was added to the mixture via a syringe pump at a flow rate of 2.0–3.0 mL / min. The reaction was allowed to proceed for 60 min, after which the solution was cooled to room temperature. 200 g of water and 225 g of ethyl acetate were added, and the mixture was separated. The filtrate was distilled under reduced pressure to obtain a crude product, which was then recrystallized from 23 g of ethyl acetate and 270 g of methyl tert-butyl ether to give 95.4 g of a yellow solid, with a yield of 74% and a purity of 99.0% as determined by HPLC.

[0035] Example 4 44.9 g of 1,3-cyclohexanedione, 35.7 g of 3-methoxypropylamine and 90 g of toluene were added to a 250 mL reaction flask and heated to 110 °C for 2 h. After the reaction was completed, the toluene was distilled under reduced pressure at 60 °C to obtain intermediate I. HPLC analysis showed that the purity of intermediate I was greater than 95%.

[0036] Intermediate I was added to a microchannel reactor, and then 61.7 g of diethyl sulfate was added at a flow rate of 0.8 g / min via a syringe pump under nitrogen atmosphere at -2 to 0 °C. The mixture was then heated to 70 °C and reacted for 30 min. After the reaction was completed, the mixture was cooled to room temperature, and 40 mL of n-heptane was added to prepare the intermediate solvent. Then, 30 g of sodium ethoxide was added.

[0037] 62.9 g of ethoxyethyl cyanoacetate was dissolved in 40 mL of n-heptane to prepare an ethoxyethyl cyanoacetate solution. At 100 °C and 2.0 MPa, the ethoxyethyl cyanoacetate solution was added to the mixture via a syringe pump at a flow rate of 2.0–3.0 mL / min. The reaction was allowed to proceed for 60 min, after which the mixture was cooled to room temperature. 200 g of water and 225 g of ethyl acetate were added, and the mixture was separated. The filtrate was distilled under reduced pressure to obtain a crude product, which was then recrystallized from 23 g of ethyl acetate and 270 g of methyl tert-butyl ether to give 83.8 g of a yellow solid, with a yield of 65% and a purity of 98.5% as determined by HPLC.

[0038] Example 5 44.9 g of 1,3-cyclohexanedione, 35.7 g of 3-methoxypropylamine and 90 g of toluene were added to a 250 mL reaction flask and heated to 110 °C for 2 h. After the reaction was completed, the toluene was distilled under reduced pressure at 60 °C to obtain intermediate I. HPLC analysis showed that the purity of intermediate I was greater than 95%.

[0039] Intermediate I was added to a microchannel reactor, and then 61.7 g of diethyl sulfate was added at a flow rate of 0.5 g / min via a syringe pump under nitrogen atmosphere at -2 to 0 °C. The mixture was then heated to 70 °C and reacted for 20 min. After the reaction was completed, the mixture was cooled to room temperature, and 40 mL of tetrahydrofuran was added to prepare the intermediate solvent. Then, 42 g of sodium tert-butoxide was added.

[0040] 61.7 g of ethoxyethyl cyanoacetate was dissolved in 39 mL of tetrahydrofuran to prepare an ethoxyethyl cyanoacetate solution. At 100 °C and 2.0 MPa, the ethoxyethyl cyanoacetate solution was added to the mixture via a syringe pump at a flow rate of 2.0–3.0 mL / min. The reaction was allowed to proceed for 60 min, after which the mixture was cooled to room temperature. 200 g of water and 225 g of ethyl acetate were added, and the mixture was separated. The filtrate was distilled under reduced pressure to obtain a crude product, which was then recrystallized from 23 g of ethyl acetate and 270 g of methyl tert-butyl ether to give 73.5 g of a yellow solid, with a yield of 57% and a purity of 99.1% as determined by HPLC.

[0041] The embodiments listed in this application all employ the method proposed in this application, and all demonstrate superior overall performance. This method effectively improves the product yield and purity by optimizing key process steps and parameter settings such as alkali, solvent, and feeding rate. Although each embodiment adopts the core technical route of this application, differences in process parameters, raw material ratios, and reaction conditions lead to certain differences in the final results during specific implementation. For example, in Example 1, diethyl sulfate was used as the raw material, sodium tert-butoxide as the alkali, toluene as the solvent, and the reaction temperature was 100°C, resulting in a more complete reaction, significantly improved product yield, and the highest product quality. In contrast, Example 2 used dimethyl sulfate as the raw material and potassium tert-butoxide as the alkali, resulting in a slight decrease in both product yield and purity. Furthermore, Example 3 used dimethyl sulfate as the raw material, triethylamine as the alkali, and 1,4-dioxane as the solvent, with a reaction temperature of 120°C. Although this reduced costs, it decreased reaction efficiency, and the product purity was correspondingly affected. Comparative analysis of the above embodiments shows that factors such as raw materials, alkali, solvent, and reaction temperature have a significant impact on the performance of the final product. Example 1 demonstrates superior performance compared to traditional methods in terms of yield, energy consumption control, and final product quality, validating the feasibility and advancement of the proposed method. Therefore, in practical applications, it is recommended to preferentially use diethyl sulfate as the raw material, sodium tert-butoxide as the alkali, toluene as the solvent, and a reaction temperature of 100°C.

[0042] In summary, the method of this application has shown good adaptability under different implementation conditions, and by further optimizing the key process parameters, the product performance can be further improved, showing good prospects for promotion and application.

[0043] The scope of protection of this invention is not limited to the embodiments described above. Obviously, those skilled in the art can make various modifications and variations to this invention without departing from its scope and spirit. If these modifications and variations fall within the scope of the claims of this invention and their equivalents, then the intent of this invention also includes these modifications and variations.

Claims

1. A method for preparing sunscreen agent MCE400, characterized in that: Includes the following steps: Step 1: Add 1,3-cyclohexanedione, 3-methoxypropylamine, and toluene to a reaction vessel, heat under reflux, and after the reaction is complete, distill off the toluene to obtain intermediate I. Intermediate I does not require purification and can be directly used in the next reaction. The chemical formula of intermediate I is as follows: ； Step 2: Add intermediate I obtained in step 1 to a microchannel reactor, then add sulfate diester, react at -2~0℃ for 10 min, then heat the reaction for 15-20 min at a pressure of 0.5-2.0 MPa, cool to room temperature, and then add organic solvent to prepare a 0.01 mol / L intermediate solution; Step 3: Dissolve ethoxyethyl cyanoacetate in an organic solvent to prepare a 0.01 mol / L ethoxyethyl cyanoacetate solution; Step 4: Add alkali and the ethoxyethyl cyanoacetate solution prepared in Step 3 to the intermediate solution in Step 2, heat the reaction for 10-60 min at a pressure of 0.5-2.0 MPa, cool to room temperature after the reaction is complete, add water and ethyl acetate, separate the liquid and liquid phases, remove the solvent by vacuum distillation of the organic phase filtrate, and recrystallize with the solvent to obtain MCE400. The reaction equations for the production process are shown below, where MCE400 has two isomers: E / Z and E / E. 。 2. The method for preparing sunscreen agent MCE400 as described in claim 1, characterized in that: In step 1, the molar ratio of 1,3-cyclohexanedione to 3-methoxypropylamine is 1:1-1:1.2, preferably 1:1-1:1.05; the mass ratio of 1,3-cyclohexanedione to toluene is 1:1-1:6, preferably 1:2-1:3; the reaction temperature is 80-140 ℃, preferably 110-120 ℃; the specific reaction time is determined based on the conversion rate detected by the central control system, and samples are taken every 30 minutes after the reaction has been going on for 30 minutes. The reaction is stopped when the conversion rate no longer increases. The reaction time is 1-4 hours, preferably 2-3 hours. In step 1, toluene is distilled under reduced pressure at 50-60 ℃, and the distilled toluene can be recovered and reused.

3. The method for preparing sunscreen agent MCE400 as described in claim 1, characterized in that: The sulfate diester in step 2 is either dimethyl sulfate or diethyl sulfate, preferably diethyl sulfate.

4. The method for preparing sunscreen agent MCE400 as described in claim 1, characterized in that: The feed rate of the disulfate in step 2 is 0.3 g / min-0.8 g / min, and the preferred dropping rate is 0.5 g / min-0.6 g / min.

5. The method for preparing sunscreen agent MCE400 as described in claim 1, characterized in that: The molar ratio of the sulfate diester in step 2 to the 1,3-cyclohexanedione added in step 1 is 1.2:1-1:1, preferably 1.05:1-1:1; the heating temperature is 50-90 ℃, preferably 70-80 ℃; the reaction time is 10-60 min, preferably 20-30 min.

6. The method for preparing sunscreen agent MCE400 as described in claim 1, characterized in that: In step 3, the catalyst is one of sodium tert-butoxide, potassium tert-butoxide, triethylamine, sodium carbonate, and sodium ethoxide. The molar ratio of the catalyst to the 1,3-cyclohexanedione added in step 1 is 1.5:1 to 1:1, and the preferred molar ratio is 1.1:1 to 1:

1.

7. The method for preparing sunscreen agent MCE400 as described in claim 1, characterized in that: The organic solvent used in steps 2 and 3 is one of n-heptane, toluene, 1,4-dioxane, tetrahydrofuran, and methyl tert-butyl ether.

8. The method for preparing sunscreen agent MCE400 as described in claim 1, characterized in that: In step 4, the molar ratio of ethoxyethyl cyanoacetate to 1,3-cyclohexanedione added in step 1 is 1.2:1-1:1, preferably 1.05:1-1:1; the heating temperature in step 4 is 60-120 ℃, preferably 90-100 ℃; the reaction time is 10-60 min, preferably 20-30 min; after the reaction, the mass ratio of water to 1,3-cyclohexanedione is 1:1-10:1, preferably 4:1-5:1; the mass ratio of ethyl acetate to 1,3-cyclohexanedione is 2:1-10:1, preferably 5:1-6:

1.

9. The method for preparing sunscreen agent MCE400 as described in claim 1, characterized in that: The solvent used for recrystallization in step 4 is one or two of the following: ethanol, ethyl acetate, acetone, n-hexane, and methyl tert-butyl ether. Preferably, the solvent is a mixed solution of ethyl acetate and methyl tert-butyl ether. The mass ratio of ethyl acetate to 1,3-cyclohexanedione added in step 1 is 1:2 to 1:1, and the mass ratio of methyl tert-butyl ether to 1,3-cyclohexanedione added in step 1 is 8:1 to 5:

1.

10. The method for preparing sunscreen agent MCE400 as described in claim 1, characterized in that: A water separator is connected to the reaction vessel in step 1 to remove the water generated in the reaction and improve the reaction conversion rate. The microchannel reactor in step 2 is a stainless steel channel with an inner diameter of 0.5-1.0 mm. Both steps 2 and 4 are carried out in an inert atmosphere.

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