A preparation method of bis-ethylhexyloxyphenol methoxyphenyl triazine

Abstract

The invention discloses a preparation method of bis-ethylhexyloxyphenol methoxyphenyl triazine, and belongs to the technical field of organic synthesis. The present invention uses 4-bromoanisole and cyanuric chloride as raw materials, and obtains 6-(4-methoxyphenyl)-2,4-dichloro-1,3,5-triazine in a one-pot process with zinc powder under nickel catalysis, and then obtains 2,4-bis-(2,4-dihydroxyphenyl)-6-(4-methoxyphenyl)-1,3,5-triazine with resorcinol under the action of Lewis acid catalyst. Finally, etherification with halogenated isooctane obtains bis-ethylhexyloxyphenol methoxyphenyl triazine. The reaction step yield is high, and the obtained product purity is high, and by-products are significantly reduced by zinc reagent Negishi coupling, and the one-pot process operation process is simple, and subsequent reactions are guaranteed, and economy is improved.

Description

Technical Field

[0001] The invention relates to a preparation method of bis-ethylhexyloxyphenol methoxyphenyl triazine, belonging to the technical field of organic synthesis. Background Art

[0002] Bis-ethylhexyloxyphenol methoxyphenyl triazine, CAS: 187393-00-6, English name: Bemotrizinol. Triazine UV absorbers are a new type of high-efficiency UV absorbers developed in recent years. They have high absorption performance, broad spectrum, strong heat resistance, and are used in plastics, coatings, cosmetics and other industries. Due to the depletion of the ozone layer, more and more ultraviolet rays (UVR) are gradually increasing on the earth, which not only causes serious photo-induced loss of organic materials, but also is an important factor leading to human skin aging, erythema, edema, pigmentation, eye diseases and photodegradation. Bis-ethylhexyloxyphenol methoxyphenyl triazine (commercial name: TinosorbS, TS) has a high wide range of absorption and high absorption intensity in the ultraviolet UVA and UVB regions, so it is widely used in hydrophobic sunscreen skin care products and light-stable materials.

[0003] Currently, there are two main methods for synthesizing bis-ethylhexyloxyphenol methoxyphenyl triazine. One is direct alkylation before etherification (such as KR2019 / 136506, 2019, A or KR2021 / 54710, 2021, A), and the other is Grignard coupling before etherification and then alkylation [Journal of Fluorescence, 2018, vol. 28, #2, p. 707-723]. Although the direct alkylation method is simple to operate, it has poor selectivity and limitations, while the Grignard coupling selectivity is relatively better, but not good enough.

[0004] In view of the above problems, the present invention adopts zinc reagent coupling, alkylation and etherification routes to achieve better selectivity and higher yield, thereby reducing costs and fully ensuring product quality, thereby meeting the growing market demand. Summary of the invention

[0005] In order to overcome the above technical defects, the present invention provides a preparation method of bis-ethylhexyloxyphenol methoxyphenyl triazine. 4-bromoanisole and cyanuric chloride are used as raw materials, and 6-(4-methoxyphenyl)-2,4-dichloro-1,3,5-triazine is obtained by one-pot method with zinc powder and nickel catalytic reagent, and then Friedel-Crafts reaction is carried out with resorcinol under the action of Lewis acid catalyst to obtain 2,4-bis(2,4-dihydroxyphenyl)-6-(4-methoxyphenyl)-1,3,5-triazine, and finally etherification with halogenated isooctane to obtain bis-ethylhexyloxyphenol methoxyphenyl triazine. The reaction step has a high yield, and the obtained product has a high purity. Through the zinc reagent Negishi coupling, the selectivity is better improved, and the by-products are significantly reduced. The one-pot operation process is simple, which is guaranteed for subsequent reactions and improves economy.

[0006] The preparation method of bis-ethylhexyloxyphenol methoxyphenyl triazine of the present invention comprises the following steps:

[0007]

[0008] Step 1: 4-bromoanisole, cyanuric chloride, zinc powder, nickel catalyst, triphenylphosphine and tetrahydrofuran are mixed, and an activating agent is added dropwise to obtain 6-(4-methoxyphenyl)-2,4-dichloro-1,3,5-triazine in one pot;

[0009] Step 2: 6-(4-methoxyphenyl)-2,4-dichloro-1,3,5-triazine is mixed with an organic solvent, a Lewis catalyst is added, and then resorcinol is added to undergo Friedel-Crafts reaction to obtain 2,4-bis(2,4-dihydroxyphenyl)-6-(4-methoxyphenyl)-1,3,5-triazine;

[0010] Step 3: 2,4-bis(2,4-dihydroxyphenyl)-6-(4-methoxyphenyl)-1,3,5-triazine, an inorganic base and an organic solvent are mixed, and halogenated isooctane is added under elevated temperature to etherify and obtain bis-ethylhexyloxyphenol methoxyphenyl triazine.

[0011] Furthermore, in the above technical solution, in the first step, the nickel catalytic agent is selected from nickel acetylacetonate or nickel chloride dimethoxyethane.

[0012] Furthermore, in the above technical solution, in the first step, the activator is selected from a combination of trimethylsilyl chloride and ethanol or tert-butyldimethylsilyl chloride and ethanol.

[0013] Furthermore, in the above technical solution, in the first step, the molar ratio of the 4-bromoanisole, cyanuric chloride, zinc powder, nickel catalyst, triphenylphosphine and activator is 1: 0.99-1.00: 1.35-1.50: 0.03-0.04: 0.06-0.08: 0.05-0.10.

[0014] Furthermore, in the above technical solution, in the second step, the organic solvent is selected from a mixed solvent of anisole and sulfolane or a mixed solvent of toluene and sulfolane, and the Lewis acid catalyst is selected from anhydrous aluminum chloride, boron trichloride or tris(pentafluorophenyl)boron.

[0015] Furthermore, in the above technical solution, in the second step, the molar ratio of the 6-(4-methoxyphenyl)-2,4-dichloro-1,3,5-triazine, Lewis catalyst and resorcinol is 1:0.20-3.00:2.00-2.05.

[0016] Furthermore, in the above technical solution, in the third step, the organic solvent is selected from acetonitrile or DMF (N,N-dimethylformamide).

[0017] Furthermore, in the above technical solution, in the third step, the inorganic base is selected from sodium carbonate or potassium carbonate.

[0018] Furthermore, in the above technical solution, in the third step, the halogenated isooctane is selected from brominated isooctane or chloroisooctane.

[0019] Furthermore, in the above technical solution, in the third step, the molar ratio of the 2,4-bis(2,4-dihydroxyphenyl)-6-(4-methoxyphenyl)-1,3,5-triazine, the inorganic base and the halogenated isooctane is 1:2.40-2.80:2.15-2.20.

[0020] Advantageous Effects of the Invention

[0021] 1. The use of zinc reagents for Negishi coupling has a selectivity of more than 91%, and the di- or tri-substitution is significantly reduced, thereby reducing costs and improving raw material utilization. The one-pot method is used to make the operation simple and quick.

[0022] 2. Boron trichloride is used for alkylation to make the post-processing operation more solvent-free and solve the problem of difficult stratification after quenching with aluminum trichloride hydrochloric acid. Specific embodiments

[0023] The present invention is further described below by means of specific examples. These embodiments should be understood to be used only to illustrate the present invention and not to limit the scope of protection of the present invention. After reading the contents described in the present invention, those skilled in the art may make various changes or modifications to the present invention, and these equivalent changes and modifications also fall within the scope defined by the claims of the present invention. Synthesis of Bis-Ethylhexyloxyphenol Methoxyphenyl Triazine

[0024] Example 1

[0025]

[0026] Under nitrogen protection, 18.7 g (0.1 mol) of 4-bromoanisole, 18.4 g (0.1 mol) of cyanuric chloride, 9.2 g (0.14 mol) of zinc powder, 0.8 g (0.003 mol) of nickel acetylacetonate, 1.6 g (0.006 mol) of triphenylphosphine and 190 mL of tetrahydrofuran were added into the reaction bottle, mixed and stirred evenly, and 1.1 g (0.01 mol) of trimethylchlorosilane and 0.4 g (0.01 mol) of ethanol were added dropwise at 10°C. 0095), reacted at room temperature for 7 hours, HPLC raw material remaining 1.3%, added 2M hydrochloric acid to quench, added diatomaceous earth to filter, the filtrate was concentrated under reduced pressure, extracted with dichloromethane, washed with water, the organic phase was concentrated until no liquid, added toluene / n-heptane for recrystallization to obtain 6-(4-methoxyphenyl)-2,4-dichloro-1,3,5-triazine 21.9g, yield 85.6%, HPLC 99.6%, ESI-MS (m / z): 255.0 (M+H)+. 1 HNMR(400M Hz, CDCl3)δ:8.48-8.44(m,2H),7.05-7.01(m,2H),3.90(s,3H).

[0027] Example 2

[0028]

[0029] Under nitrogen protection, 4-bromoanisole 18.7g (0.1mol), cyanuric chloride 18.4g (0.1mol), zinc powder 9.2g (0.14mol), nickel chloride dimethoxyethane 0.9g (0.004mol), triphenylphosphine 2.1g (0.008mol) and tetrahydrofuran 200mL were added to the reaction bottle, stirred evenly and temperature controlled at 10°C, tert-butyldimethylsilyl chloride 0.9g (0.006mol) and ethanol 0.26g were added dropwise, and the reaction was carried out at room temperature for 6 hours. The HPLC raw material remained 2.2%, 2M hydrochloric acid was added to quench, diatomaceous earth was added to filter, the filtrate was concentrated under reduced pressure, extracted with dichloromethane, washed with water, the organic phase was concentrated to no liquid, and a mixed solvent of toluene and n-heptane was added for recrystallization to obtain 6-(4-methoxyphenyl)-2,4-dichloro-1,3,5-triazine 21 with a yield of 82.8% and HPLC99.1%.

[0030] Example 3

[0031]

[0032] Add 25.6 g (0.1 mol) of 6-(4-methoxyphenyl)-2,4-dichloro-1,3,5-triazine, 130 mL of toluene and 100 mL of sulfolane into the reaction bottle, add 36.3 g (0.24 mol) of anhydrous aluminum chloride at room temperature, and then add 22 g (0.2 mol) of resorcinol, then heat to 70 ° C, react for 6 hours, and after HPLC reaction is complete, cool to 0 ° C, add hydrochloric acid to quench, and concentrate under reduced pressure to remove Remove benzene, add water to precipitate the product, filter, rinse the filter cake with water, mix the filter cake with butyl acetate, heat to 90°C, add activated carbon, stir for 1 hour, filter hot, cool the filtrate to precipitate the product, and filter to obtain 35.7 g of 2,4-bis(2,4-dihydroxyphenyl)-6-(4-methoxyphenyl)-1,3,5-triazine, with a yield of 88.6%, HPLC99.3%, ESI-MS (m / z): 403.1 (M+H)+. 1 HNMR(400MHz,DMSO-d6)δ:13.18(s,2H),10.52(s,2H),8.36-8.30(m,4H),7.24-7.21(m,2H),6.55-6.51(m,2H),6.41-6.37(m,2H),3.89(s,3H).

[0033] Example 4

[0034]

[0035] 25.6 g (0.1 mol) of 6-(4-methoxyphenyl)-2,4-dichloro-1,3,5-triazine, 150 mL of anisole and 100 mL of cyclopentane were added to the reaction bottle, 35.2 g (0.3 mol) of boron trichloride was introduced at 10-15 ° C, and 22 g (0.2 mol) of resorcinol was added, and then the temperature was raised to 85 ° C, and the reaction was carried out for 8 hours. After the HPLC reaction was complete, the temperature was lowered to 0 ° C, hydrochloric acid was added to quench, the layers were separated, and the organic phase was extracted with chlorobenzene. The synthetic organic phase was heated to 50 ° C, washed with water, concentrated under reduced pressure to recover chlorobenzene, butyl acetate was added, the temperature was raised to 90 ° C, activated carbon was added, stirred for 1 hour, hot filtered, the filtrate was cooled to precipitate the product, and 2,4-bis (2,4-dihydroxyphenyl) -6- (4-methoxyphenyl) -1,3,5-triazine 34.7 g was obtained by filtration, with a yield of 86.1%, and HPLC 99.5%.

[0036] Under the same conditions, B(C6F5)3 (0.04 mol) was used, the temperature was raised to 40°C for 5 hours, and BCl3 (0.3 mol) was used instead, the temperature was raised to 85°C for 8 hours; the yield was 92.2%, HPLC 99.3%.

[0037] Example 5

[0038]

[0039] Under nitrogen protection, 40.3 g (0.1 mol) of 2,4-bis(2,4-dihydroxyphenyl)-6-(4-methoxyphenyl)-1,3,5-triazine, 29.7 g (0.28 mol) of sodium carbonate and 310 mL of N,N-dimethylformamide were added to the reaction bottle, the temperature was raised to 50°C, 41.5 g (0.215 mol) of isooctane bromide was added dropwise, the temperature was raised to 90-95°C for reaction for 6 hours, and the reaction was complete by HPLC. The reaction was cooled to room temperature, filtered, and the filtrate was added with ethyl acetate and dilute hydrochloric acid to adjust the pH to 6.5-6.8. The layers were separated, the aqueous phase was extracted with ethyl acetate, the organic phases were combined, washed with water, the organic phase was concentrated, replaced with n-heptane, recrystallized and seeded to obtain 50.5 g of bis-ethylhexyloxyphenol methoxyphenyl triazine, with a yield of 80.4%, HPLC 99.8%, ESI-MS (m / z): 627.4 (M+H)+. 1 HNMR(400MHz, CDCl3)δ:13.45(s,2H),8.36-8.32(m,2H),7.61-7.47(m,2H),7.24-7.01(m,2H),6.82-6 .56(m,4H),3.82(s,3H),3.78-3.64(m,4H),1.83-1.78(m,2H),1.57-1.35(m,16H),1.01-0.93(m,12H).

[0040] Example 6

[0041]

[0042] Under nitrogen protection, 40.3 g (0.1 mol) of 2,4-bis(2,4-dihydroxyphenyl)-6-(4-methoxyphenyl)-1,3,5-triazine, 34.6 g (0.25 mol) of potassium carbonate and 450 mL of acetonitrile were added into the reaction bottle, the temperature was raised to 50°C, 32.7 g (0.22 mol) of chloroisoctane was added dropwise, the temperature was raised to 82°C, the reaction was refluxed for 8 hours, and the reaction was complete by HPLC. The temperature was lowered to room temperature, ethyl acetate and dilute hydrochloric acid were added to adjust the pH to 6.5-6.8, the layers were separated, the organic phase was concentrated, the phase was replaced by n-heptane, the temperature was raised to 70°C, the insoluble matter was filtered out, the filtrate was slowly cooled to precipitate the product to obtain 53.7 g of bis-ethylhexyloxyphenol methoxyphenyl triazine, the yield was 85.6%, and the HPLC was 99.5%.

[0043] The above description 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 bis-ethylhexyloxyphenol methoxyphenyl triazine, characterized in that: The steps include: The first step, under nitrogen protection, add 4-bromoanisole 18.7g, cyanuric chloride 18.4g, zinc powder 9.2g, acetylacetonate nickel 0.8g, triphenylphosphine 1.6g and tetrahydrofuran 190mL to the reaction bottle, mix and stir evenly, at 10°C, add trimethylchlorosilane 1.1g and ethanol 0.4g dropwise, react at room temperature for 7 hours; HPLC raw material remaining 1.3%, add 2M hydrochloric acid quenching, add diatomaceous earth to filter, the filtrate is concentrated under reduced pressure, extracted with dichloromethane, washed with water, the organic phase is concentrated to no liquid, and toluene / n-heptane is added for recrystallization to obtain 6-(4-methoxyphenyl)-2,4-dichloro-1,3,5-triazine; Step 2: Add 25.6 g of 6-(4-methoxyphenyl)-2,4-dichloro-1,3,5-triazine, 150 mL of anisole and 100 mL of cyclopentane into the reaction bottle, add 0.04 mol of B(C6F5)3 at 10-15°C, then add 22 g of resorcinol, then heat to 40°C, react for 5 hours, and after the HPLC reaction is complete, cool to 0°C, add hydrochloric acid to quench, separate, extract the organic phase with chlorobenzene, heat the synthetic organic phase to 50°C, wash with water, concentrate under reduced pressure to recover chlorobenzene, add butyl acetate, heat to 90°C, add activated carbon, stir for 1 hour, filter hot, cool the filtrate to precipitate the product, and filter to obtain 2,4-bis(2,4-dihydroxyphenyl)-6-(4-methoxyphenyl)-1,3,5-triazine; Step 3: Under nitrogen protection, add 40.3 g of 2,4-bis(2,4-dihydroxyphenyl)-6-(4-methoxyphenyl)-1,3,5-triazine, 34.6 g of potassium carbonate and 450 mL of acetonitrile into the reaction bottle, heat to 50°C, add 32.7 g of chloroisooctane dropwise, heat to 82°C and reflux for 8 hours. HPLC reaction is complete, cool to room temperature, add ethyl acetate and dilute hydrochloric acid to adjust pH = 6.5-6.8, separate layers, concentrate the organic phase, replace with n-heptane, heat to 70°C, filter out insoluble matter, filter, and slowly cool the filtrate to precipitate the product to obtain bis-ethylhexyloxyphenol methoxyphenyl triazine.

2. A method for preparing bis-ethylhexyloxyphenol methoxyphenyl triazine, characterized in that: The steps include: The first step, under nitrogen protection, add 4-bromoanisole 18.7g, cyanuric chloride 18.4g, zinc powder 9.2g, nickel chloride dimethoxyethane 0.9g, triphenylphosphine 2.1g and tetrahydrofuran 200mL to the reaction bottle, stir evenly and control the temperature at 10°C, add tert-butyldimethylsilyl chloride 0.9g and ethanol 0.26g dropwise, and react at room temperature for 6 hours; HPLC raw material remaining 2.2%, add 2M hydrochloric acid to quench, add diatomaceous earth to filter, the filtrate is concentrated under reduced pressure, extracted with dichloromethane, washed with water, the organic phase is concentrated to no liquid, and a mixed solvent of toluene and n-heptane is added for recrystallization to obtain 6-(4-methoxyphenyl)-2,4-dichloro-1,3,5-triazine; Step 2: Add 25.6 g of 6-(4-methoxyphenyl)-2,4-dichloro-1,3,5-triazine, 150 mL of anisole and 100 mL of cyclopentane into the reaction bottle, add 0.04 mol of B(C6F5)3 at 10-15°C, then add 22 g of resorcinol, then heat to 40°C, react for 5 hours, and after the HPLC reaction is complete, cool to 0°C, add hydrochloric acid to quench, separate, extract the organic phase with chlorobenzene, heat the synthetic organic phase to 50°C, wash with water, concentrate under reduced pressure to recover chlorobenzene, add butyl acetate, heat to 90°C, add activated carbon, stir for 1 hour, filter hot, cool the filtrate to precipitate the product, and filter to obtain 2,4-bis(2,4-dihydroxyphenyl)-6-(4-methoxyphenyl)-1,3,5-triazine; Step 3: Under nitrogen protection, add 40.3 g of 2,4-bis(2,4-dihydroxyphenyl)-6-(4-methoxyphenyl)-1,3,5-triazine, 29.7 g of sodium carbonate and 310 mL of N,N-dimethylformamide into the reaction bottle, heat to 50°C, add 41.5 g of isooctane bromide dropwise, heat to 90-95°C and react for 6 hours. HPLC reaction is complete, cool to room temperature, filter, add ethyl acetate and dilute hydrochloric acid to the filtrate to adjust pH = 6.5-6.8, separate the layers, extract the aqueous phase with ethyl acetate, combine the organic phases, wash with water, concentrate the organic phase, replace with n-heptane, recrystallize and add seed crystals to obtain bis-ethylhexyloxyphenol methoxyphenyl triazine.

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