A method for preparing avobenzone

Abstract

This invention relates to the field of pharmaceutical technology, and more particularly to a method for preparing avobenzone. The invention uses lithium bis(trimethylsilyl)amino as a catalyst, ensuring safe operation. Furthermore, lithium bis(trimethylsilyl)amino is inexpensive and readily available, resulting in low cost. The avobenzone product prepared by this invention has a purity >99.7%, good color (appearing as a light color), with other individual impurities all less than 0.10%, and total impurities less than 0.3%. The quality exceeds the requirements of the pharmacopoeia standard USP-NF2025 (Pharmacopoeia standard: other individual impurities ≤3.0%, total impurities ≤4.5%), while also exhibiting a high yield >80%.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and in particular to a method for preparing avobenzone. Background Technology

[0002] Avobenzone, chemically known as 1-4-(1,1-dimethylethyl)phenyl-3-(4-methoxyphenyl)-1,3-propanedione, has the molecular formula C1. 20 H 22 O3, with a molecular weight of 310.40 and CAS number 70356-09-1, has the structure shown in Formula 1. Avobenzone is a type of UV-A absorber developed by Roche in 1978 specifically for use in skincare and cosmetic products.

[0003] Formula 1.

[0004] Currently, the mainstream preparation method for avobenzone is the Claisen condensation method, which involves reacting p-methoxyacetophenone with methyl p-tert-butylbenzoate or p-tert-butylbenzoyl chloride to obtain the product. Its advantages are: short route and easy operation. However, this method generally uses sodium amide, sodium hydride, or sodium as catalysts. Sodium amide is prone to side reactions such as ammonolysis during the reaction. Sodium hydride and sodium react violently with water, posing significant safety hazards during production and requiring sophisticated equipment. Furthermore, sodium amide and sodium hydride are expensive, resulting in high costs for large-scale production and a lack of price competitiveness in the market. The yield of this method is relatively low and needs improvement (reported in literature is generally 48-78%); the purity and color are also poor. Summary of the Invention

[0005] In view of this, the purpose of this invention is to provide a method for preparing avobenzone. The preparation method of this invention is low-cost, safe and controllable, and yields avobenzone with high quality.

[0006] To achieve the above-mentioned objectives, the present invention provides the following technical solution: This invention provides a method for preparing avobenzone, comprising the following steps: mixing methyl p-tert-butylbenzoate, p-methoxyacetophenone, a water-soluble organic solvent and lithium bis(trimethylsilyl)amino, and carrying out a Clersen condensation reaction under a protective atmosphere to obtain avobenzone; wherein the temperature of the Clersen condensation reaction is 20~30℃.

[0007] Preferably, the molar ratio of methyl p-tert-butylbenzoate and lithium bis(trimethylsilyl)aminoacetate is 1:(1.3~1.7).

[0008] Preferably, the molar ratio of methyl p-tert-butylbenzoate to p-methoxyacetophenone is 1:(1.1~1.5).

[0009] Preferably, the Clersen condensation reaction takes 6 to 8 hours.

[0010] Preferably, the water-soluble organic solvent includes alcohols and / or ethers.

[0011] Preferably, the volume-to-mass ratio of the water-soluble organic solvent to methyl p-tert-butylbenzoate is 6-8 L / kg.

[0012] Preferably, after completing the Clesen condensation reaction, the product system is further subjected to post-processing. The post-processing includes the following steps: controlling the temperature of the product system to 0-20°C, adding dilute hydrochloric acid to adjust the pH to 2-4, then adding water and stirring, then adding a water-immiscible organic solvent, stirring to separate the layers, and collecting the organic phase; concentrating the organic phase under reduced pressure until no more liquid drips out to obtain an oily substance; adding an alcohol solvent to the oily substance and heating to 50-60°C to dissolve it, cooling to 5-10°C to precipitate the solid, separating the solid and liquid to obtain crude avobenzone.

[0013] Preferably, after obtaining crude avobenzone, the method further includes decolorizing the crude avobenzone.

[0014] Preferably, the decolorization process includes: dissolving the crude avobenzone in an alcohol solvent, adding activated carbon to the resulting solution for decolorization, separating the solid and liquid, and then concentrating, crystallizing, separating, and drying the resulting decolorized solution to obtain the finished avobenzone product.

[0015] Preferably, the purity of the avobenzone product is >99.7%, the purity of each individual impurity is less than 0.10%, and the total impurities are less than 0.3%.

[0016] This invention uses bis(trimethylsilyl)aminolithium as a catalyst, which is more stable and safer to operate than sodium amino, sodium hydride, and sodium. In addition, the raw material bis(trimethylsilyl)aminolithium is inexpensive and readily available. The avobenzone product prepared by this invention has a purity >99.7%, good color (indicated by light color), and other individual impurities are all less than 0.10%, with total impurities less than 0.3%. The quality exceeds the requirements of the pharmacopoeia standard USP-NF2025 (pharmacopoeia standard: other individual impurities ≤3.0%, total impurities ≤4.5%), while also having a high yield >80%. Attached Figure Description

[0017] Figure 1 Gas chromatogram and peak table of crude avobenzone prepared in Example 1; Figure 2 Gas chromatogram and peak table of the avobenzone product prepared in Example 1; Figure 3 The infrared spectrum of the avobenzone product prepared in Example 1; Figure 4The infrared spectrum of avobenzone reference standard; Figure 5 The 1H NMR spectrum of the avobenzone product prepared in Example 1; Figure 6 The 1H NMR spectrum of avobenzone reference standard; Figure 7 Photos of crude and finished avobenzone prepared in Example 1; Figure 8 Gas chromatogram and peak table of crude avobenzone prepared in Example 2; Figure 9 Gas chromatogram and peak table of the avobenzone product prepared in Example 2; Figure 10 Gas chromatogram and peak table of crude avobenzone prepared in Example 3; Figure 11 The gas chromatogram and peak table of the avobenzone product prepared in Example 3 are shown. Detailed Implementation

[0018] This invention provides a method for preparing avobenzone, comprising the following steps: mixing methyl p-tert-butylbenzoate, p-methoxyacetophenone, a water-soluble organic solvent and lithium bis(trimethylsilyl)amino, and carrying out a Clersen condensation reaction under a protective atmosphere to obtain avobenzone; wherein the temperature of the Clersen condensation reaction is 20~30℃.

[0019] In this invention, unless otherwise specified, all raw materials and equipment used are commercially available products well known in the art.

[0020] In this invention, methyl p-tert-butylbenzoate, p-methoxyacetophenone, a water-soluble organic solvent, and lithium bis(trimethylsilyl)aminoacetonitrile are mixed and subjected to a Clersen condensation reaction under a protective atmosphere to obtain the product system.

[0021] In this invention, the molar ratio of methyl p-tert-butylbenzoate to lithium bis(trimethylsilyl)aminoacetate is preferably 1:(1.3~1.7), and in specific embodiments it can be 1:1.3, 1:1.4, 1:1.5, 1:1.6 or 1:1.7. In this invention, the lithium bis(trimethylsilyl)aminoacetate is preferably used in the form of a tetrahydrofuran solution of lithium bis(trimethylsilyl)aminoacetate; the concentration of the tetrahydrofuran solution of lithium bis(trimethylsilyl)aminoacetate is preferably 1 mol / L.

[0022] In this invention, the molar ratio of methyl p-tert-butylbenzoate to p-methoxyacetophenone is preferably 1:(1.1~1.5), and in specific embodiments it can be 1:1.1, 1:1.2, 1:1.3, 1:1.4 or 1:1.5.

[0023] In this invention, the water-soluble organic solvent preferably includes alcohols and / or ethers; the alcohol preferably includes methanol and / or ethanol; and the ether preferably includes tetrahydrofuran. In this invention, the volume-to-mass ratio of the water-soluble organic solvent to methyl p-tert-butylbenzoate is preferably 6-8 L / kg (abbreviated as 6-8 times), and in specific embodiments it can be 6, 7, or 8 times.

[0024] In this invention, the mixing preferably includes: adding methyl p-tert-butylbenzoate and p-methoxyacetophenone to the water-soluble organic solvent at room temperature, then dropwise adding a tetrahydrofuran solution of lithium bis(trimethylsilyl)aminoacetone to the resulting mixture, controlling the temperature at 0-10°C during the dropwise addition, and then raising the temperature to the Cresson condensation reaction temperature after the addition is complete. The addition of lithium bis(trimethylsilyl)aminoacetone causes the system temperature to rise; this invention controls the temperature at 0-10°C during the dropwise addition to prevent a drastic temperature rise and the generation of more byproducts.

[0025] In this invention, the protective atmosphere is preferably a nitrogen atmosphere. In this invention, the temperature of the Clesen condensation reaction is 20-30°C, preferably 22, 24, 26, 28, or 30°C; the time of the Clesen condensation reaction is preferably 6-8 hours, and in specific embodiments, it can be 6, 6.5, 7, 7.5, or 8 hours. In this invention, the Clesen condensation reaction is preferably carried out under stirring conditions.

[0026] After obtaining the product system, the present invention performs post-processing on the product system to obtain crude avobenzone.

[0027] In this invention, the post-processing preferably includes the following steps: controlling the temperature of the product system to 0~20℃, adding dilute hydrochloric acid to adjust the pH value to 2~4, then adding water and stirring, then adding a water-immiscible organic solvent, stirring to separate the layers, and collecting the organic phase; concentrating the organic phase under reduced pressure until no liquid drips out to obtain an oily substance; adding an alcohol solvent to the oily substance and heating to 50~60℃ to dissolve it, cooling to 5~10℃ to precipitate the solid, separating the solid and liquid to obtain crude avobenzone.

[0028] In this invention, the mass concentration of the dilute hydrochloric acid is preferably 15%. The purpose of adjusting the pH of the product system to 2-4 in this invention is to release avobenzone. The purpose of adding water in this invention is to ensure complete precipitation of avobenzone and to separate it from the organic solvent that dissolves the avobenzone. In this invention, the volume-to-mass ratio of water to methyl p-tert-butylbenzoate is preferably 6-8 L / kg. In this invention, the stirring time after adding water is preferably 10-20 min.

[0029] In this invention, the water-immiscible organic solvent is preferably one or more of dichloromethane, trichloromethane, and ethyl acetate; the volume-to-mass ratio of the water-immiscible organic solvent to methyl p-tert-butylbenzoate is 8-10 L / kg. Avobenzone will dissolve in the water-immiscible organic solvent and separate into layers with water.

[0030] In this invention, the alcohol solvent is preferably one or more selected from ethanol, isopropanol, and n-butanol. In this invention, the volume-to-mass ratio of the alcohol solvent to methyl p-tert-butylbenzoate is 8-10 L / kg. After cooling to 5-10°C, this invention preferably involves stirring at this temperature for 2-3 hours. This invention promotes the crystallization of avobenzone by stirring at this temperature for 2-3 hours. This invention does not impose special requirements on the solid-liquid separation method; any solid-liquid separation method well-known in the art, such as filtration, can be used.

[0031] In this invention, the purity of the crude avobenzone is >98.5%. The crude avobenzone has the advantages of high purity and good color. Even without subsequent decolorization, the crude avobenzone has a higher purity than the finished avobenzone prepared by the process mentioned in the background art.

[0032] After obtaining the crude avobenzone, the present invention performs a decolorization treatment on the crude avobenzone.

[0033] In this invention, the decolorization process preferably includes: dissolving the crude avobenzone in an alcohol solvent, adding activated carbon to the resulting solution for decolorization, separating the solid and liquid, and then concentrating, crystallizing, separating and drying the resulting decolorized solution to obtain the finished avobenzone product.

[0034] In this invention, the alcohol solvent is preferably one or more of ethanol, isopropanol, and n-butanol; the dissolution temperature is preferably 60-70°C. In this invention, the mass of the activated carbon is preferably 3-5% of the crude avobenzone mass, and in specific embodiments, it can be 3%, 4%, or 5%. In this invention, the decolorization temperature is preferably 75-80°C, and the time is preferably 1-2 hours. The decolorization is preferably carried out under stirring conditions. After the decolorization is completed, this invention preferably lowers the temperature of the decolorized system to 60-70°C for solid-liquid separation. This invention does not specifically limit the method of solid-liquid separation; any solid-liquid separation method well known in the art can be used, such as filtration. This invention reduces the volume of the decolorized liquid by vacuum concentration, facilitating subsequent crystallization. In this invention, the crystallization temperature is preferably 5-10°C, and the time is preferably 2-3 hours. In this invention, the drying is preferably vacuum drying, and the vacuum drying temperature is preferably 40-50°C.

[0035] This invention further improves the purity and color of avobenzone through a decolorization process.

[0036] The avobenzone product prepared by this invention has high purity (>99.7%), good color (light color), and all other individual impurities are less than 0.10%, with total impurities less than 0.3%. The quality exceeds the requirements of USP-NF2025 (Pharmacopoeia standard: other individual impurities ≤3.0%, total impurities ≤4.5%). At the same time, the yield is high (>80%).

[0037] The preparation method of avobenzone provided by the present invention will be described in detail below with reference to the embodiments, but these should not be construed as limiting the scope of protection of the present invention.

[0038] Example 1 (1) A dry and clean reactor was prepared under nitrogen protection, and stirring was started. At room temperature, 8 L of methanol was added, followed by 1.0 kg of methyl p-tert-butylbenzoate and 0.86 kg of p-methoxyacetophenone. Nitrogen was used to purge twice. At room temperature, 7.6 kg of a tetrahydrofuran solution of lithium bis(trimethylsilyl)aminoacetate (concentration 1 mol / L) was pressurized into the reactor under nitrogen and added over approximately 3 hours, with the temperature controlled at 0-10°C during the addition process. After the addition was complete, the temperature was raised to 25°C and stirring was continued for 8 hours. The molar ratio of methyl p-tert-butylbenzoate to p-methoxyacetophenone was 1:1.1; the molar ratio of methyl p-tert-butylbenzoate to lithium bis(trimethylsilyl)aminoacetate was 1:1.7.

[0039] (2) Control the temperature at 0~20℃, adjust the pH to 2 with 15% dilute hydrochloric acid, then add 6L of water, stir for 15min, add 10L of chloroform, stir to separate the layers, and collect the organic phase. Concentrate the organic phase under reduced pressure until no more liquid drips out, obtaining an oily substance. Add 8L of ethanol to the above oily substance, heat to 60℃ to dissolve, then slowly cool to 5℃ to precipitate a solid, keep warm for 3h, filter, and obtain the crude product. The GC purity (area normalization method) is 99.08%. See details. Figure 1 .

[0040] (3) Add 8L of ethanol to the crude product above, heat to 70℃ to dissolve, add 50.0g of activated carbon, heat to 78℃, stir for 2h, then cool to 60℃ and filter. Transfer the filtrate to a reaction vessel, concentrate under reduced pressure to the remaining 5L, then slowly cool to 5℃, stir for 3h to crystallize, filter, and dry under vacuum. Dry under vacuum at 40℃ to obtain white to pale yellow avobenzone with a yield of 80.5% and a GC purity (area normalization method) of 99.87%. See details. Figure 2 .

[0041] For the infrared spectrum of the product, please refer to [link / reference]. Figure 3 For the infrared spectrum of avobenzone reference standard, please refer to [link / reference]. Figure 4 For detailed 1H NMR spectra of the products, please refer to [link / reference needed]. Figure 5 For the reference standard's 1H NMR spectrum, please refer to [link / reference]. Figure 6 .Depend on Figures 3 to 6It can be seen that the obtained product is the target product, avobenzone.

[0042] Figure 7 The photos show the crude and finished products of avobenzone prepared in Example 1. It can be seen that both the crude and finished products have a light color, indicating good color.

[0043] Example 2 (1) A dry and clean reactor was prepared under nitrogen protection, and stirring was started. At room temperature, 8 L of tetrahydrofuran was added, followed by 1 kg of methyl p-tert-butylbenzoate and 1.02 kg of p-methoxyacetophenone. Nitrogen was used to purge twice. At room temperature, 6.7 kg of a tetrahydrofuran solution of bis(trimethylsilyl)aminolithium (concentration 1 mol / L) was pressurized into the reactor under nitrogen and added over approximately 4 hours, with the temperature controlled at 0-10°C during the addition process. After the addition was complete, the temperature was raised to 20°C and stirring was continued for 7 hours. The molar ratio of methyl p-tert-butylbenzoate to p-methoxyacetophenone was 1:1.3; the molar ratio of methyl p-tert-butylbenzoate to bis(trimethylsilyl)aminolithium was 1:1.5.

[0044] (2) The temperature was controlled at 0~20℃, and the pH was adjusted to 3 with 15% dilute hydrochloric acid. Then 6L of water was added, and the mixture was stirred for 15 min. 10L of dichloromethane was added, and the mixture was stirred to separate the layers. The organic phase was collected. The organic phase was concentrated under reduced pressure until no more liquid dripped out, resulting in an oily substance. 8L of n-butanol was added to the above oily substance, and the mixture was heated to 50℃ to dissolve it. Then the temperature was slowly lowered to 8℃, and a solid precipitated. The solid was kept at this temperature for 3 h, filtered, and the crude product was obtained. The GC purity (area normalization method) was 99.24%. The chromatogram and peak table are shown below. Figure 8 .

[0045] (3) Add 8 L of n-butanol to the crude product, heat to 65 °C to dissolve, add 50.0 g of activated carbon, heat to 80 °C, stir for 2 h, then cool to 60 °C and filter. Transfer the filtrate to a reaction vessel, concentrate under reduced pressure to the remaining 5 L, then slowly cool to 7 °C, stir for 3 h to crystallize, filter, and dry under vacuum. Dry under vacuum at 50 °C to obtain white to pale yellow avobenzone with a yield of 85.7% and a GC purity (area normalization method) of 99.91%. See the chromatogram and peak table below. Figure 9 .

[0046] Example 3 (1) A dry and clean reactor was prepared under nitrogen protection, and stirring was started. At room temperature, 8 L of ethanol was added, followed by 1.0 kg of methyl p-tert-butylbenzoate and 1.17 kg of p-methoxyacetophenone. Nitrogen was used to purge twice. At room temperature, 5.8 kg of a tetrahydrofuran solution of lithium bis(trimethylsilyl)aminoacetate (concentration 1 mol / L) was pressurized into the reactor under nitrogen and added over approximately 5 hours, with the temperature controlled at 0-10°C during the addition process. After the addition was complete, the temperature was raised to 30°C and stirring was continued for 6 hours. The molar ratio of methyl p-tert-butylbenzoate to p-methoxyacetophenone was 1:1.5; the molar ratio of methyl p-tert-butylbenzoate to lithium bis(trimethylsilyl)aminoacetate was 1:1.3.

[0047] (2) The temperature was controlled at 0~20℃, and the pH was adjusted to 4 with 15% dilute hydrochloric acid. Then 6L of water was added, and the mixture was stirred for 15 min. 10L of ethyl acetate was added, and the mixture was stirred to separate the layers. The organic phase was collected. The organic phase was concentrated under reduced pressure until no more liquid dripped out, resulting in an oily substance. 8L of isopropanol was added to the above oily substance, and the mixture was heated to 60℃ to dissolve it. Then the temperature was slowly lowered to 5℃, and a solid precipitated. The mixture was kept at this temperature for 3 h, filtered, and the crude product was obtained. The GC purity (area normalization method) was 98.64%. The chromatogram and peak table are shown below. Figure 10 .

[0048] (3) Add 8 L of isopropanol to the crude product above, heat to 70 °C to dissolve, add 50.0 g of activated carbon, heat to 80 °C, stir for 2 h, then cool to 65 °C and filter. Transfer the filtrate to a reaction vessel, concentrate under reduced pressure to the remaining 5 L, then slowly cool to 6 °C, stir for 3 h to crystallize, filter, and dry under vacuum. Dry under vacuum at 45 °C to obtain white to pale yellow avobenzone, with a yield of 82.1% and a GC purity (area normalization method) of 99.82%. See the chromatogram and peak table below. Figure 11 .

[0049] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A method for preparing avobenzone, characterized in that, Includes the following steps: Methyl p-tert-butylbenzoate, p-methoxyacetophenone, a water-soluble organic solvent, and lithium bis(trimethylsilyl)amino were mixed and subjected to a Clesen condensation reaction under a protective atmosphere to obtain avobenzone; the temperature of the Clesen condensation reaction was 20-30°C.

2. The preparation method according to claim 1, characterized in that, The molar ratio of methyl p-tert-butylbenzoate and lithium bis(trimethylsilyl)aminoacetate is 1:(1.3~1.7).

3. The preparation method according to claim 1, characterized in that, The molar ratio of methyl p-tert-butylbenzoate to p-methoxyacetophenone is 1:(1.1~1.5).

4. The preparation method according to claim 1, characterized in that, The Clersen condensation reaction takes 6-8 hours.

5. The preparation method according to claim 1, characterized in that, The water-soluble organic solvents include alcohols and / or ethers.

6. The preparation method according to claim 1 or 5, characterized in that, The volume-to-mass ratio of the water-soluble organic solvent to methyl p-tert-butylbenzoate is 6-8 L / kg.

7. The preparation method according to claim 1, characterized in that, After the Clersen condensation reaction is completed, the resulting product system is further subjected to post-treatment; the post-treatment includes the following steps: The temperature of the product system is controlled at 0~20℃. Dilute hydrochloric acid is added to adjust the pH value to 2~4. Then water is added and stirred. A water-immiscible organic solvent is added and stirred to separate the layers. The organic phase is collected. The organic phase is concentrated under reduced pressure until no liquid drips out to obtain an oily substance. An alcohol solvent is added to the oily substance and the temperature is raised to 50~60℃ to dissolve it. The temperature is lowered to 5~10℃ to precipitate the solid. Solid-liquid separation is performed to obtain crude avobenzone.

8. The preparation method according to claim 7, characterized in that, After obtaining crude avobenzone, the process also includes decolorizing the crude avobenzone.

9. The preparation method according to claim 8, characterized in that, The decolorization process includes: dissolving the crude avobenzone in an alcohol solvent, adding activated carbon to the resulting solution for decolorization, separating the solid and liquid, and then concentrating, crystallizing, separating, and drying the resulting decolorized solution to obtain the finished avobenzone product.

10. The preparation method according to claim 9, characterized in that, The purity of the avobenzone product is >99.7%, with each individual impurity less than 0.10% and the total impurities less than 0.3%.

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