Process for increasing the content of BEMT in a composition comprising 2,4-bis[4-(2-ethylhexyloxy)-2-hydroxyphenol]-6-(4-methoxyphenol)-1,3,5-triazine (BEMT)

Abstract

A method for increasing the BEMT content in a composition comprising 2,4-bis[4-(2-ethylhexyloxy)-2-hydroxyphenol]-6-(4-methoxyphenol)-1,3,5-triazine (BEMT), the method comprising the steps of: a) providing a composition comprising BEMT and impurities; b) dissolving the composition in a solvent mixture at a first dissolution temperature to produce an unsaturated BEMT solution, wherein the solvent mixture comprises at least one polar solvent; c) lowering the temperature of the unsaturated BEMT solution to a saturation temperature, wherein the saturation temperature is below the first dissolution temperature, to produce a saturated BEMT solution; d) further lowering the temperature of the first saturated BEMT solution to a first crystallization temperature, wherein the first crystallization temperature is below the saturation temperature, thereby producing a supersaturated BEMT solution; e) during step d), adding BEMT seed crystals in an amount ranging from 0.00001 wt.-% to 20 wt.-% relative to the total weight of the composition to the supersaturated BEMT solution to produce a first BEMT suspension comprising BEMT particles; f) a) Heating the first BEMT suspension to a second dissolution temperature to produce a second BEMT suspension containing fewer BEMT particles than the first BEMT suspension, wherein the second dissolution temperature is higher than and lower than the first crystallization temperature; g) Cooling the second BEMT suspension to a second crystallization temperature to produce a final BEMT suspension containing BEMT particles larger than those in the first BEMT suspension; h) Separating these BEMT particles from the final BEMT suspension, wherein the second crystallization temperature is lower than the first crystallization temperature.

Description

Technical Field

[0001] This invention relates to an improved method for preparing 2,4-bis[4-(2-ethylhexyloxy)-2-hydroxyphenol]-6-(4-methoxyphenol)-1,3,5-triazine (BEMT, CAS 187393-00-6), and more particularly to a method for producing a composition having an increased BEMT content. The invention further relates to said compositions of BEMT containing fewer impurities than those typically generated in BEMT synthesis. The invention further relates to the use of said compositions for protecting human and animal hair and skin from damage caused by UV radiation.

[0002] Therefore, the present invention also relates to a cosmetic formulation comprising the said composition. Background Technology

[0003] Bis-resorcinol triazine is a highly effective UV absorber, which can be used, for example, as a light stabilizer in plastics or as an alkyl-substituted bis-resorcinol triazine derivative (such as Tinosorb, which is particularly suitable as a sunscreen in cosmetics). ® The intermediate in the preparation of S). The preparation of bis-resorcinyltriazine is known and disclosed, for example, in US 5,955,060. This preparation involves the reaction of cyanuric chloride with a phenyl magnesium bromide compound in a Grignard reaction to form dichlorotriazine. Two resorcinol groups are then introduced by Fried-Krawczythylation with resorcinol in the presence of a Lewis acid, particularly an aluminum halide. In a third step, the etherification of the free 4-hydroxyl group is carried out by alkylation, as known from US 5,955,060.

[0004] However, the former preparation method has complex drawbacks and low yields. In addition, Fried-Krawczynoylation often produces unwanted byproducts that are almost impossible to remove and are subsequently carried into the product.

[0005] Therefore, WO 2016 / 184764 A1 describes a method for preparing bis-resorcinol triazine, which is easy to perform and offers economic and regulatory advantages due to its high yield and high purity.

[0006] Furthermore, the method described in US 5,955,060 is unsatisfactory in terms of reaction time and selectivity. Even more importantly, this method involves chromatographic techniques for separating the products, which are cumbersome, labor-intensive, and time-consuming, and therefore unsuitable for industrial scale due to unacceptable manufacturing costs.

[0007] Therefore, WO 2016 / 184766 A1 describes a method for preparing bis-resorcinol triazine having formula (I), which involves specific bases and reaction conditions, and can be used to scale up to produce high yields and purity.

[0008] However, the method described has the following drawbacks: due to the small particle size obtained during crystallization, the solid-liquid separation and purification of the resulting crystals suffers from long filtration and washing times. This further leads to a lower degree of purification.

[0009] CN 113929636 A1 describes a method for purifying bis-ethylhexyloxyphenol methoxyphenyl triazine by combining silica gel column chromatography with C6 alkane recrystallization. However, due to the chromatographic steps involved, this method lacks technical relevance for industrial multi-tonnage processes.

[0010] IP.com 2017 17(8A) and IP.com 2019 19(6) describe certain methods for producing 2,4-bis[4-(2-ethylhexyloxy)-2-hydroxyphenol]-6-(4-methoxyphenol)-1,3,5-triazine (BEMT), which involve crystallization steps from various solvents, improving the purity of the produced BEMT. However, the problem of long filtration and washing times remains. Summary of the Invention

[0011] Therefore, a first object of the present invention is to find a method for producing 2,4-bis[4-(2-ethylhexyloxy)-2-hydroxyphenol]-6-(4-methoxyphenol)-1,3,5-triazine (BEMT) that is more economically feasible, particularly involving shorter time, preferably during filtration and washing steps, and simultaneously producing high yield and high purity. A further object of the present invention is to prepare compositions comprising BEMT that allow for faster post-synthetic processing at high purity levels.

[0012] It has now been unexpectedly discovered that the above objective can be achieved by a method for increasing the BEMT content in a composition containing 2,4-bis[4-(2-ethylhexyloxy)-2-hydroxyphenol]-6-(4-methoxyphenol)-1,3,5-triazine (BEMT), the method comprising the following steps:

[0013] a) Provide a composition comprising BEMT and impurities;

[0014] b) Dissolving the composition in a solvent mixture at a first dissolution temperature to produce an unsaturated BEMT solution, wherein the solvent mixture contains at least one polar solvent;

[0015] c) The temperature of the unsaturated BEMT solution is lowered to the saturation temperature, which is lower than the first dissolution temperature, to produce a saturated BEMT solution;

[0016] d) Further reduce the temperature of the saturated BEMT solution to a first crystallization temperature, which is lower than the saturation temperature, thereby producing a supersaturated BEMT solution;

[0017] e) During step d), an amount of BEMT seed crystals in the range of 0.00001 wt.-% to 20 wt.-% relative to the total weight of the composition is added to the supersaturated BEMT solution to produce a first BEMT suspension containing BEMT particles;

[0018] f) Heating the first BEMT suspension to a second dissolution temperature to produce a second BEMT suspension containing fewer BEMT particles than the first BEMT suspension, wherein the second dissolution temperature is higher than the first crystallization temperature and lower than the first dissolution temperature;

[0019] g) Reduce the temperature of the second BEMT suspension to a second crystallization temperature to produce a final BEMT suspension containing BEMT particles larger than those in the first BEMT suspension.

[0020] h) Separate these BEMT particles from the final BEMT suspension.

[0021] The second crystallization temperature is lower than the first crystallization temperature.

[0022] It has been further and unexpectedly discovered that the above-mentioned objective can be achieved by a particulate composition comprising at least 98.0 wt.% of 2,4-bis[4-(2-ethylhexyloxy)-2-hydroxyphenol]-6-(4-methoxyphenol)-1,3,5-triazine (BEMT) and at least one of the compounds according to formulas (I) to (VIII), preferably at least two, more preferably at least three, even more preferably at least four, even more preferably at least five, even more preferably at least six, even more preferably at least seven, and most preferably all of them.

[0023]

[0024]

[0025]

[0026]

[0027] in

[0028] R is a 2-ethylhexyl residue;

[0029] The amount of the compound having formula (I) in the composition is less than 0.06 wt.-%, preferably less than 0.05 wt.-%, and most preferably less than 0.03 wt.-% based on the total weight of the composition.

[0030] The amount of the compound having formula (II) in the composition is less than 0.11 wt.-%, preferably less than 0.05 wt.-%, more preferably less than 0.03 wt.-% based on the total weight of the composition;

[0031] The amount of the compound having formula (III) in the composition is less than 0.11 wt.-%, preferably less than 0.07 wt.-%, and most preferably less than 0.05 wt.-% based on the total weight of the composition.

[0032] The amount of the compound having formula (IV) in the composition is less than 0.41 wt.-%, preferably less than 0.23 wt.-%, and most preferably less than 0.12 wt.-% based on the total weight of the composition.

[0033] The amount of the compound having formula (V) in the composition is less than 0.14 wt.-%, preferably less than 0.11 wt.-%, and most preferably less than 0.03 wt.-% based on the total weight of the composition.

[0034] The amount of the compound having formula (VI) in the composition is less than 0.07 wt.-%, preferably less than 0.03 wt.-%, based on the total weight of the composition.

[0035] The amount of the compound having formula (VII) in the composition is less than 0.05 wt.-%, preferably less than 0.03 wt.-%, based on the total weight of the composition.

[0036] The amount of the compound having formula (VIII) in the composition is less than 0.17 wt.-%, preferably less than 0.15 wt.-%, based on the total weight of the composition; and

[0037] The particulate composition has a median particle size D greater than 10 µm, preferably equal to or greater than 12 µm, as determined according to ISO 13320:2020. 50,3 .

[0038] It will be apparent to those skilled in the art that the above method also reduces the amount of any other potential impurities that may be present in the crude BEMT mixture, which are not specifically mentioned.

[0039] More preferably, the particulate composition of the present invention comprises at least one of the compounds according to formulas (IX) to (XII), preferably at least two, more preferably at least three, and most preferably all of them:

[0040]

[0041] in

[0042] R is a 2-ethylhexyl residue.

[0043] The amount of the compound having formula (IX) in the composition is less than 0.05 wt.-%, preferably less than 0.03 wt.-%, based on the total weight of the composition.

[0044] The amount of the compound having formula (X) in the composition is less than 0.05 wt.-%, preferably less than 0.03 wt.-%, based on the total weight of the composition.

[0045] The amount of the compound having formula (XI) in the composition is less than 0.05 wt.-% based on the total weight of the composition; and

[0046] The amount of compounds having formula (XII) in the composition is less than 0.05 wt.-% based on the total weight of the composition.

[0047] It has been further discovered that the above-mentioned objective can be achieved through the use of the particulate composition according to the invention for protecting human and animal hair and skin from damage caused by UV radiation. Furthermore, the objective can also be achieved through cosmetic formulations comprising a carrier and adjuvants compatible with cosmetics, based on the particulate composition according to the invention.

[0048] This invention is particularly advantageous because the crystallization method allows for the controlled growth of larger crystals, resulting in reduced filtration resistance of the filter cake during the filtration and washing steps. Furthermore, the controlled crystal growth has the beneficial effect of producing powders with larger average particle size and extremely high purity, especially considering the byproducts of the synthesis method used. Attached Figure Description

[0049] Figure 1 This is a schematic illustration of the method of the present invention according to a preferred embodiment in a solubility curve.

[0050] Figure Labels

[0051] 1 represents steps a) to b).

[0052] 2 indicates step c)

[0053] 3 represents steps d) and e).

[0054] 4 indicates the preferred end of steps d) and e).

[0055] 5 indicates step f)

[0056] 6 indicates step g)

[0057] definition

[0058] Before describing in detail exemplary embodiments of the present invention, definitions important for understanding the present invention are given.

[0059] As used herein, the term "impurity" refers to a material within a composition that has a molecular structure different from that of the material that forms the highest amount in the composition.

[0060] As used herein, the term "standard pressure" means a pressure in the range of 1,012 to 1,014 millibars, preferably 1,013.25 millibars.

[0061] As used in this specification and the appended claims, unless the context clearly specifies otherwise, the singular form “a / an” also includes the corresponding plural. In the context of this invention, the terms “about” and “approximately” indicate a range of precision that, as will be understood by those skilled in the art, still ensures the technical effect of the discussed features. This term typically indicates a deviation from the indicated value of ±10%, preferably ±8%, more preferably ±5%, and even more preferably ±2%. It should be understood that the terms “comprising” and “encompassing” are not limiting. For the purposes of this invention, the term “consisting of” is considered a preferred embodiment of the term “formulated by”. If a group is defined below as including at least a certain number of embodiments, this means that a group preferably consisting only of those embodiments is also covered. Furthermore, the terms “first,” “second,” “third,” or “(a),” “(b),” “(c),” “(d),” etc., in this specification and claims are used to distinguish similar elements and are not necessarily used to describe a sequential or chronological order. It should be understood that the terms used herein are interchangeable where appropriate, and the embodiments of the invention described herein can be operated in a sequence other than that described or shown herein. Where the terms “first,” “second,” “third,” or “(a),” “(b),” “(c),” “(d),” “i,” “ii,” etc., refer to steps of a method or use or determination, there is no temporal or time interval coherence between these steps; that is, these steps may be performed simultaneously or there may be time intervals of seconds, minutes, hours, days, weeks, months, or even years between such steps, unless otherwise indicated in this application as stated above or below. It should be understood that the invention is not limited to the specific methods, schemes, reagents, etc., described herein, as these can vary. It should also be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of the invention, which will be limited only by the appended claims. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

[0062] As used herein, the terms “does not contain / comprise,” “does not contain,” or “does not contain” in the context mean that the composition of the invention does not contain a specific compound or group of compounds (which may be grouped together under a collective term), meaning that the composition does not contain more than 0.8% of the compound or group of compounds by weight based on the total weight of the composition. Furthermore, it is preferred that the composition according to the invention does not contain more than 0.5% of the compound or group of compounds by weight, and preferably the composition does not contain the compound or group of compounds at all.

[0063] When referring to the composition and the weight percentage of the components contained therein, it should be understood that, according to the invention, the total amount of the components does not exceed 100% (± 1%, due to rounding). Detailed Implementation

[0064] The method and the product of the present invention are described in detail below.

[0065] The method of the present invention

[0066] As described above, the method of the present invention is a method for increasing the BEMT content in a composition containing 2,4-bis[4-(2-ethylhexyloxy)-2-hydroxyphenol]-6-(4-methoxyphenol)-1,3,5-triazine (BEMT), the method comprising the following steps:

[0067] a) Provide a composition comprising BEMT and impurities;

[0068] b) Dissolving the composition in a solvent mixture at a first dissolution temperature to produce an unsaturated BEMT solution, wherein the solvent mixture contains at least one polar solvent;

[0069] c) The temperature of the unsaturated BEMT solution is lowered to the saturation temperature, which is lower than the first dissolution temperature, to produce a saturated BEMT solution;

[0070] d) Further reduce the temperature of the saturated BEMT solution to a first crystallization temperature, which is lower than the saturation temperature, thereby producing a supersaturated BEMT solution;

[0071] e) During step d), an amount of BEMT seed crystals in the range of 0.00001 wt.-% to 20 wt.-% relative to the total weight of the composition is added to the supersaturated BEMT solution to produce a first BEMT suspension containing BEMT particles;

[0072] f) Heating the first BEMT suspension to a second dissolution temperature to produce a second BEMT suspension containing fewer BEMT particles than the first BEMT suspension, wherein the second dissolution temperature is higher than the first crystallization temperature and lower than the first dissolution temperature;

[0073] g) Reduce the temperature of the second BEMT suspension to a second crystallization temperature to produce a final BEMT suspension containing BEMT particles larger than those in the first BEMT suspension.

[0074] h) Separate these BEMT particles from the final BEMT suspension.

[0075] The second crystallization temperature is lower than the first crystallization temperature.

[0076] The method of the present invention produces a particulate composition comprising at least 98 wt.% of 2,4-bis[4-(2-ethylhexyloxy)-2-hydroxyphenol]-6-(4-methoxyphenol)-1,3,5-triazine (BEMT) based on the total weight of the composition of the present invention. The BEMT particles obtained in step h) of the method of the present invention represent the particulate composition of the present invention.

[0077] Step a)

[0078] Preferably, step a) includes the step of synthesizing a composition containing BEMT. Preferably, the step of synthesizing a composition containing BEMT includes reacting 2,4-bis(2,4-dihydroxyphenyl)-(4-methoxyphenyl)-1,3,5-triazine in dimethylformamide with 2-ethylhexyl halide RX (where X is Cl, Br or I and R is 2-ethylhexyl) in the presence of a base selected from the group consisting of sodium carbonate, sodium phosphate and sodium bicarbonate, and the reaction temperature is selected in the range of at least 120°C (at atmospheric pressure).

[0079] It should be fully understood that if pressure / vacuum is applied to the method of the present invention, the reaction temperature must be adjusted accordingly; however, this temperature can be readily adjusted by those skilled in the art, and this embodiment is also incorporated herein.

[0080] Dimethylformamide [CAS 68-12-2] is also known as N,N-dimethylformamide. Suitable 2-ethylhexyl halides particularly cover the corresponding bromides or chlorides, with chlorides being preferred. Most preferably, 2-ethylhexyl chloride [CAS 123-04-6] is used in the method according to the invention.

[0081] Sodium carbonate [CAS 497-19-8], sodium phosphate [CAS 7601-54-9], and sodium bicarbonate [CAS 144-55-8] are well known to those skilled in the art and can be purchased, for example, from Sigma-Aldrich. In all embodiments of the invention, anhydrous sodium carbonate or anhydrous sodium bicarbonate is preferred, with anhydrous sodium carbonate being most preferred. Most preferably, in step a) of the method of the invention, the synthesis of the composition comprising BEMT, anhydrous sodium carbonate with a purity > 99%, preferably > 99.5%, and most preferably > 99.9% (determined, based on dry matter calculations) is used.

[0082] The reaction temperature (at atmospheric pressure, i.e., 1013 mbar) is preferably selected in the range of 120°C-155°C, more preferably in the range of 130°C-155°C, and most preferably in the range of 130°C-145°C. In a very advantageous embodiment, the reaction temperature is selected such that the reaction is maintained under reflux (i.e., a reaction temperature of about 133°C-143°C at atmospheric pressure), which can be readily adjusted by those skilled in the art. If desired, the reaction can also be carried out under reduced or increased pressure, with the temperature adjusted accordingly, as is well known to those skilled in the art. However, preferably, the reaction is carried out at atmospheric pressure.

[0083] The reaction time is typically adjusted such that all 2,4-bis(2,4-dihydroxyphenyl)-(4-methoxyphenyl)-1,3,5-triazine is consumed, and the amount of monoalkylated product is < 8%, preferably < 5%, more preferably < 4% (by HPLC tracking: area %, detected at 230 nm). Advantageously, the reaction time is selected in the range of 3 to 24 h, preferably in the range of 4 to 20 h, and most preferably in the range of 5 to 15 h.

[0084] The molar ratio of the base to 2,4-bis(2,4-dihydroxyphenyl)-(4-methoxyphenyl)-1,3,5-triazine is preferably selected in the range of 2 to 9, and most preferably in the range of 3 to 7. The amount of dimethylformamide is preferably selected such that the amount of 2,4-bis(2,4-dihydroxyphenyl)-(4-methoxyphenyl)-1,3,5-triazine in the dimethylformamide is in the range of 0.5 to 2 mol / L, preferably in the range of 0.75 to 1.5 mol / L, and most preferably in the range of 0.8 to 1 mol / L.

[0085] Preferably, 2-ethylhexyl halide RX is used in a slightly excess. More preferably, the amount of 2-ethylhexyl halide RX relative to 2,4-bis(2,4-dihydroxyphenyl)-(4-methoxyphenyl)-1,3,5-triazine is selected in the range of 1.5 to 6 molar equivalents, even more preferably in the range of 2 to 5 molar equivalents, even more preferably in the range of 2.5 to 4 molar equivalents, and most preferably in the range of 3 to 3.5 molar equivalents.

[0086] Preferably, the alkali is added in two parts. The first part is used to neutralize the solution of 2,4-bis(2,4-dihydroxyphenyl)-(4-methoxyphenyl)-1,3,5-triazine in dimethylformamide to about pH 6.5 to 7.5, preferably to about pH 7. Typically, about 15-30 wt.% of the total amount of alkali is used in the neutralization step, and this amount can be easily adjusted by those skilled in the art.

[0087] Therefore, in a particularly advantageous embodiment, the synthesis step in step a) according to the invention encompasses the following sequential steps, wherein all the definitions and preferences given above also apply:

[0088] (i) 2,4-bis(2,4-dihydroxyphenyl)-(4-methoxyphenyl)-1,3,5-triazine was suspended in dimethylformamide.

[0089] (ii) Heating the resulting suspension to 90°C-155°C, preferably to 95°C-145°C.

[0090] (iii) Neutralize the resulting suspension to approximately pH 7 with the first portion of the alkali.

[0091] (iv) Add the second part of the base, followed by the addition of 2-ethylhexyl halide RX.

[0092] (v) Heat the resulting mixture to reflux.

[0093] Advantageously, the reaction time in step (v) is selected to be in the range of 3 to 24 h, preferably in the range of 4 to 20 h, and most preferably in the range of 5 to 15 h. In another advantageous embodiment, the step a) of synthesizing the composition comprising BEMT in the method of the invention encompasses the following additional steps.

[0094] (vi) Filter the resulting reaction mixture obtained in step (v).

[0095] (vii) Neutralize the reaction mixture obtained in step (vi) with sodium bisulfate and remove the volatile solvent under ambient pressure or reduced pressure.

[0096] Step b)

[0097] In the method according to the invention, the at least one polar solvent is preferably a polar organic solvent, more preferably selected from the group consisting of methanol, ethanol, 1-butanol, 2-butanol, isopropanol, acetone, methyl ethyl ketone, diethyl ketone, and N,N-dimethylformamide, and most preferably acetone. Preferably, the solvent mixture contains only one polar solvent, preferably composed of that polar solvent. More preferably, the solvent mixture is composed of a solvent selected from the group consisting of methanol, ethanol, 1-butanol, 2-butanol, isopropanol, acetone, methyl ethyl ketone, diethyl ketone, and N,N-dimethylformamide, and most preferably, the solvent mixture is composed of acetone. Acetone ensures an optimal solvent system in terms of crystallization, the temperature used, and the controllability of the crystallization process. Furthermore, acetone is readily available and inexpensive. Finally, acetone has a low boiling point and good volatility, allowing for efficient removal of acetone from BEMT crystals.

[0098] Preferably, the unsaturated BEMT solution in step b) is a solution containing 10 to 60 wt.-%, more preferably 20 to 40 wt.-%, and most preferably 25 to 35 wt.-%.

[0099] Preferably, in the method according to the invention, the first dissolution temperature is higher than the clarifying temperature obtained from the solubility profile of the solvent mixture and BEMT at standard pressure, and lower than the boiling point of the solvent mixture at standard pressure. Therefore, the temperature of the unsaturated BEMT solution produced in step b) can be higher than the temperature required to dissolve the implemented amount of BEMT in the implemented amount of solvent mixture. However, more preferably, the first dissolution temperature is the clarifying temperature obtained from the solubility profile of the solvent mixture and BEMT at standard pressure. A first dissolution temperature higher than the clarifying temperature obtained from the solubility profile of the solvent mixture and BEMT at standard pressure requires unnecessary cooling time and energy as the unsaturated BEMT solution is further cooled to eventually reach a supersaturated state. Furthermore, if the first dissolution temperature is equal to or higher than the boiling point of the solvent mixture at standard pressure, an unnecessarily large amount of energy is used, resulting in low energy efficiency of the method.

[0100] It should be further understood that the first dissolution temperature is not the lowest temperature at which any BEMT can dissolve in the solvent mixture under standard pressure, otherwise further cooling would be impossible. Therefore, preferably, the first dissolution temperature is higher than the lowest temperature at which any BEMT can dissolve in the solvent mixture under standard pressure by a temperature XK, where X is 15%, preferably 50%, more preferably 70%, and most preferably 80% of the temperature difference between the lowest temperature at which any BEMT can dissolve in the solvent mixture under standard pressure and the boiling point of the solvent mixture under standard pressure.

[0101] Preferably, step b) includes a final step of removing, preferably filtering, undissolved solids from the saturated BEMT solution.

[0102] Steps c), d), and e)

[0103] BEMT is typically obtained as a mixture of three stereoisomers, namely:

[0104]

[0105] R, R form

[0106]

[0107] S,S form

[0108]

[0109] meso form

[0110] These three distinct stereoisomers are difficult to separate and are therefore often not separated at all. Typically, due to the presence of these three stereoisomers, BEMT tends to exhibit hindered nucleation and growth kinetics, particularly in polar organic solvents such as acetone. Therefore, crystallizing BEMT from solution is generally problematic. Thus, cooling an unsaturated solution of BEMT to a first crystallization temperature to induce a highly supersaturated state, while simultaneously using BEMT crystals as a guide, is often used to force the crystallization of the BEMT solution. However, this forceful method results in a high nucleation rate (for nucleation, generally, "(...) must cross the free energy barrier to form a cluster of [molecules] of a critical size beyond which a new phase grows spontaneously" (Mersmann, A. (ed.) (2001) Crystallization Technology Handbook (2nd edition)), resulting in a large number of very fine crystals and correspondingly small particle sizes, which affect the purity and filtration efficiency of the BEMT composition.

[0111] The present invention introduces a crystal-guiding circuit via steps d), e), and f), wherein a supersaturated solution is formed and seed crystals are used for crystal guiding (see...). Figure 1 (See attached figures 2, 3, and 4). Then, the temperature was increased again (see attached figures 2, 3, and 4). Figure 1 (See figures 4 and 5). Since the dissolution of BEMT is generally not kinetically hindered, the system more or less follows a solubility curve up to the point representing the adjusted temperature. This step ensures a significant reduction in the number of crystallization centers in the BEMT suspension. After the second cooling step, the suspension is controlled to allow complete crystallization.

[0112] The saturation temperature in step c) is preferably at or near a point on the solubility curve of the given BEMT / solvent mixture system (see [reference]). Figure 1 (See attached figure 2).

[0113] As in step d) of the method according to the invention, a supersaturated BEMT solution is formed, and the first crystallization temperature is preferably lower than the clarification temperature generated by the solubility curve of the solvent mixture and BEMT at standard pressure.

[0114] According to the method of any one of the preceding claims, in step e), the seed crystals are added at least once at a temperature below the saturation temperature of the supersaturated BEMT solution, preferably in the range of 1 to 15 K below the saturation temperature of the supersaturated BEMT solution, and more preferably in the range of 1 to 5 K below the saturation temperature of the supersaturated BEMT solution. Preferably, the polar solvent is acetone, and the seed crystals are added at a temperature in the range of 35°C to 20°C, preferably 30°C to 20°C, and most preferably 25°C to 20°C. If the polar solvent is acetone and the seed crystals are added in batches, the batch addition is preferably carried out at 23°C, 22°C, and 21°C.

[0115] Therefore, preferably, in the method according to the invention, in step e), the BEMT seed crystal is added all at once, added in two batches at two different times, added in three batches at three different times, added in four batches at four different times, or added in up to ten batches at ten different times. Most preferably, in the method according to the invention, in step e), the BEMT seed crystal is added all at once.

[0116] Preferably, the total amount of BEMT seed crystals added in step e) is not higher than 15 wt.-%, more preferably not higher than 10 wt.-%, and most preferably not higher than 5 wt.-%. Furthermore, preferably, the total amount of BEMT seed crystals added in step e) is at least 0.00005 wt.-%, more preferably at least 0.0001 wt.-%, and most preferably at least 0.0005 wt.-%.

[0117] In a preferred embodiment of the method of the present invention, in step e), the temperature of the supersaturated BEMT solution is maintained constant at the first crystallization temperature for at least 30 minutes. The purpose of this waiting time is to form a larger number of small BEMT particles.

[0118] Step f)

[0119] It should be noted that the first BEMT suspension in step f) can be either supersaturated or saturated. A supersaturated BEMT suspension is a suspension of BEMT particles in a supersaturated BEMT solution. Due to the kinetic hindrance of the supersaturated BEMT solution, it relaxes over time, thereby causing BEMT crystallization. Once the supersaturated BEMT suspension reaches its thermodynamic equilibrium, it becomes a saturated BEMT suspension (see [link to relevant documentation]). Figure 1 (Ref. 3 to 4 in the attached figures). Preferably, the first BEMT suspension in step f) is a saturated BEMT suspension to ensure that step f) proceeds according to the solubility curve, thereby minimizing the number of crystallization centers.

[0120] Preferably, in the method according to the invention, the second dissolution temperature in step f) is higher than the highest temperature that the first BEMT suspension can reach through the absorption and release of crystallization enthalpy. This ensures that a larger number of crystallization centers dissolve again and a smaller number of crystallization centers remain in the suspension.

[0121] Step g)

[0122] In another preferred embodiment of the method according to the invention, in step g), the second BEMT suspension is kept constant at the second crystallization temperature for at least 30 min. This waiting time serves to complete crystallization and maximize the yield.

[0123] Preferably, step g) of the method of the present invention is carried out progressively at two different cooling rates, preferably three cooling rates. Thus, preferably, the cooling rate remains constant over a certain period of time, thereby forming a cooling ramp with a constant cooling rate. Preferably, the first cooling rate is lower than the second cooling rate. Also preferably, the second cooling rate is lower than the third cooling rate. This ensures that crystallization follows a pattern opposite to the natural pattern, i.e., a smaller amount of BEMT crystallizes at the beginning of step g) and a larger amount of BEMT crystallizes at the end of step g). More preferably, the polar solvent is acetone, and the first cooling rate is in the range of -0.5 to -4 K / h, preferably in the range of -0.7 to -1.5 K / h, and most preferably -1.2 K / h. Even more preferably, the polar solvent is acetone, and the second cooling rate is in the range of -1 to -6 K / h, preferably in the range of -2 to -4 K / h, and most preferably -3 K / h. More preferably, the polar solvent is acetone, and the third cooling rate is in the range of -3 to -10 K / h, preferably in the range of -4 to -8 K / h, and most preferably -5.3 K / h. Also preferably, the polar solvent is acetone, and the time of the first cooling ramp is in the range of 2 to 8 h; more preferably, the polar solvent is acetone, and the time of the second cooling ramp is in the range of 1 to 5 h; even more preferably, the polar solvent is acetone, and the time of the third cooling ramp is in the range of 1 to 5 h. This further enhances the growth of a smaller number of crystal centers and reduces the formation of new nuclei. Therefore, the resulting crystal size increases.

[0124] When comparing the cooling of the corresponding unsaturated BEMT solution in step d) and the second BEMT suspension in step g), it is preferable that the maximum value of any shortest distance from any point on the concentration / temperature curve followed by the unsaturated BEMT solution to the solubility curve of the BEMT / solvent mixture system is greater than the maximum value of any shortest distance from any point on the concentration / temperature curve followed by the second BEMT suspension to the solubility curve of the BEMT / solvent mixture system. This ensures that the crystallization force caused by the cooling of the corresponding solution or suspension is higher in step d) and lower in step g). Therefore, more nuclei are formed in step d) compared to step g). It should be noted that this feature is not essential to the invention due to the presence of the crystallization initiation step e).

[0125] Furthermore, when comparing the cooling rates of steps d) and g), it is preferable that the overall cooling rate of step d) is higher than (i.e., faster than) the overall cooling rate of step g). Even more preferably, the cooling rate of step d) is higher than (i.e., faster than) any one of the first, second, or third cooling rates of step g).

[0126] In the method according to the invention, the second crystallization temperature in step g) is lower than the first crystallization temperature, thereby ensuring a higher BEMT crystal yield. Preferably, the polar solvent is acetone, and the second crystallization temperature is below 10°C; more preferably, the polar solvent is acetone, and the second crystallization temperature is 0°C.

[0127] Step h)

[0128] Preferably, step h) includes solid-liquid separation to separate BEMT particles from the final BEMT suspension, preferably by filtration. Also preferably, step h) includes washing the BEMT particles with a polar solvent. More preferably, step h) includes solid-liquid separation to separate BEMT particles from the final BEMT suspension, preferably by filtration, followed by washing the separated BEMT particles with a suitable polar solvent. Preferably, the polar solvent is acetone.

[0129] Other steps

[0130] In another preferred embodiment of the invention, the method includes an additional step i) of heating the BEMT particles to further remove the solvent mixture.

[0131] Preferably, the method according to the invention comprises one or more repetitions of steps b) to h). Repeating these steps further reduces the amount of compounds according to formulas (I) to (XII) in the final BEMT composition. More preferably, the method according to the invention comprises no more than one repetition. Selecting only one repetition achieves the optimal ratio of the required energy and time to the reduction in the amount of compounds according to formulas (I) to (XII).

[0132] The particulate composition of the present invention

[0133] The present invention further relates to a particulate composition comprising at least 98 wt.% of 2,4-bis[4-(2-ethylhexyloxy)-2-hydroxyphenol]-6-(4-methoxyphenol)-1,3,5-triazine (BEMT) and at least one, preferably at least two, more preferably at least three, even more preferably at least four, even more preferably at least five, even more preferably at least six, even more preferably at least seven, and most preferably all, wherein R is a 2-ethylhexyl residue; the amount of compound of formula (I) in the composition is less than 0.06 wt.-%, preferably less than 0.05 wt.-%, and most preferably less than 0.03 wt.-% based on the total weight of the composition; the amount of compound of formula (II) in the composition is less than 0.11 wt.-%, preferably less than 0.05 wt.-%, and more preferably less than 0.03 wt.-% based on the total weight of the composition; the amount of compound of formula (III) in the composition is less than 98 wt.% of 2,4-bis[4-(2-ethylhexyloxy)-2-hydroxyphenol]-6-(4-methoxyphenol)-1,3,5-triazine (BEMT) and at least one, preferably less than two, more preferably less than three, even more preferably less than four, even more preferably less than five, even more preferably less than six, even more preferably less than seven, and most preferably all, based on the total weight of the composition; the amount of compound of formula (III) in the composition is less than 98 wt.% of 2,4-bis[4-(2-ethylhexyloxy)-2-hydroxyphenol]-6-(4-methoxyphenol)-1,3,5-triazine (BEMT) based on the total weight of the composition; the amount of compound of formula (II) in the composition is less than 0.11 wt.-%, preferably less than 0.05 wt.-%, and more preferably less than 0. The amount of the compound in the composition is less than 0.11 wt.-%, preferably less than 0.07 wt.-%, and most preferably less than 0.05 wt.-% based on the total weight of the composition; the amount of the compound having formula (IV) in the composition is less than 0.41 wt.-%, preferably less than 0.23 wt.-%, and most preferably less than 0.12 wt.-% based on the total weight of the composition; the amount of the compound having formula (V) in the composition is less than 0.14 wt.-%, preferably less than 0.11 wt.-%, and most preferably less than 0.03 wt.-% based on the total weight of the composition; the amount of the compound having formula (VI) in the composition is less than 0.07 wt.-%, preferably less than 0.03 wt.-% based on the total weight of the composition; the amount of the compound having formula (VII) in the composition is less than 0.05 wt.-%, preferably less than 0.03 wt.-% based on the total weight of the composition; the amount of the compound having formula (VIII) in the composition is less than 0.17 wt.-%. wt.-%, preferably less than 0.15 wt.-%; and the particulate composition has a median particle size D greater than 10 µm, preferably equal to or greater than 12 µm, as determined according to ISO 13320:2020.50,3 The amounts of the components (in wt.%) were determined by HPLC according to the present invention, in accordance with USP Monograph Proposal No. 32(4), 1045-1047, 2006.

[0134] When referring to the total weight of the composition, it is immediately apparent that this refers to the total weight of the particulate composition of the present invention.

[0135] In a preferred embodiment of the particulate composition of the present invention, the particulate composition comprises at least one, preferably at least two, more preferably at least three, and most preferably all of the compounds according to formulas (XI) to (XII), wherein R is a 2-ethylhexyl residue; the amount of the compound having formula (IX) in the composition is less than 0.05 wt.-% based on the total weight of the composition; the amount of the compound having formula (X) in the composition is less than 0.05 wt.-% based on the total weight of the composition; the amount of the compound having formula (XI) in the composition is less than 0.05 wt.-% based on the total weight of the composition; and the amount of the compound having formula (XII) in the composition is less than 0.05 wt.-% based on the total weight of the composition.

[0136] Preferably, in the particulate composition according to the invention, the amount of BEMT in the composition is greater than 98 wt.-, preferably greater than 99 wt.-, relative to the total weight of the composition.

[0137] The median particle size D of the particulate composition according to the present invention 50,3 The particle size is greater than 10 µm, preferably equal to or greater than 12 µm, as determined by laser diffraction according to ISO 13320:2020, as described in the 'Measurement Methods' section herein. Larger particle sizes result in lower filter cake resistance during filtration and washing, leading to shorter filtration and washing times.

[0138] Other embodiments

[0139] Another embodiment of the invention is the use of the particulate composition according to the invention for protecting human and animal hair and skin from damage caused by UV radiation.

[0140] Therefore, the present invention also relates to a cosmetic formulation comprising a carrier and adjuvants compatible with cosmetics according to the particulate composition of the present invention.

[0141] Preferably, the cosmetic formulation according to the invention contains other UV-protective substances, which are preferably selected from the group consisting of triazine, oxalaniline, triazole, vinyl-containing amides and cinnamic acid amides. Example

[0142] Measurement methods

[0143] a) Weight percentage of the composition

[0144] The composition of the BEMT samples was determined by HPLC using an internal standard according to USP Monograph Proposal 32(4), 1045-1047, 2006, to obtain wt.% values. The relative retention times of impurities were confirmed by synthesis. Additional impurities were identified by coupled methods (such as HPLC-MS). Byproducts having formulas (I) to (VIII) are listed as NK1 to NK8 in Table 1 below.

[0145] b) Particle size and distribution

[0146] The volume-weighted particle size distribution of the final BEMT suspension was determined by laser diffraction according to ISO 13320:2020 on a Malvern Mastersizer 3000 equipped with a Malvern Hydro SM wet sample dispersion unit and additional cooling to maintain the final BEMT suspension sample at 0°C. The Fraunhofer approximation was chosen as the optical model. The obtained particle size was defined as the equivalent spherical diameter according to ISO 13320:2020. The median particle size D... 50,3 It is as defined in ISO 13320:2020. It should be understood that the terms "particle size" and "particle diameter" are synonyms.

[0147] c) Filter cake resistance

[0148] The cake resistance of the final BEMT suspension was determined according to guideline VDI 2762 Part 2:2010-12 (R2016). The obtained value is expressed as a mathematical product of the cake resistance and viscosity, in mPas / m³. 2 .

[0149] experiment

[0150] Refer to Example 1 (RE1)

[0151] In this example, crude BEMT was produced. All steps were performed under a protective atmosphere (nitrogen). 54 g of sodium carbonate and 260 g of N,N-dimethylformamide were charged into a reactor equipped with a condenser and a water separator. The reaction mixture was heated to 80°C and stirred. 126 g of 2,4-bis(2,4-dihydroxyphenyl)-(4-methoxyphenyl)-1,3,5-triazine (80%, >5% NaCl, <1% water, as determined) was added in one step. Subsequently, 156 g of 2-ethylhexyl chloride was added dropwise, and the reactor temperature was first increased to 90°C, then to 120°C. Finally, the reaction temperature was first increased to 140°C, then to 155°C, while distilling off a mixture of water, 2-ethylhexyl chloride, DMF, and other compounds. The distillate phase was collected and separated. The organic phase was continuously fed back into the reactor. The reaction progress was monitored by HPLC, and alkylation was stopped at maximum yield. The reaction mixture was allowed to cool to 120°C and filtered. The filtrate (F1) was cooled to 90°C and neutralized by adding aqueous sodium bisulfate. Subsequently, the solvent was removed under vacuum to produce crude BEMT. The resulting crude BEMT melt contained approximately 90 wt.% BEMT (measured by calibrated HPLC) and specified byproducts according to the amounts in Table 1. The remainder consisted of solvent and unspecified byproducts.

[0152] Compare with Example 1 (CE1)

[0153] The crude BEMT melt obtained from RE1 was dissolved in acetone. The solution was filtered and heated to 40°C to produce a 29% solution of crude BEMT in acetone. The mixture was rapidly cooled (to 25°C as quickly as possible over approximately 30 min, and from 25°C at 8.6 K / h) to 16°C. During cooling at 23°C, 22°C, and 21°C, solid purified BEMT (approximately 0.06 wt.-% each relative to crude BEMT) was added as seed crystals. After stirring at 16°C for 3 h, the suspension was subsequently cooled to 0°C. After solidification for 2 h, the suspension was filtered, and the residue was washed twice with acetone to produce purified BEMT in 98% yield relative to the amount of crude BEMT. The crystalline BEMT particles were small (D 50,3 = 5.8 µm), and therefore the filtration and washing time is relatively long (filter cake resistance 2 × 10⁻⁶). 13 mPas / m 2 The amounts of byproducts are listed in Table 1.

[0154] Invention Example 1 (IE1)

[0155] The crude BEMT melt obtained from RE1 was dissolved in acetone. The solution was filtered and heated to 40°C to produce a 29 wt.% solution of crude BEMT in acetone. The mixture was rapidly cooled (to 25°C as quickly as possible over approximately 30 min, and from 25°C at 8.6 K / h) to 16°C. During cooling at 23°C, 22°C, and 21°C, solid-state purified BEMT (approximately 0.06 wt.% of crude BEMT, each) was added as seed crystals. After stirring at 16°C for 30 min, the suspension was warmed to 30°C and subsequently cooled to 25°C over a period of 4.2 h (at a cooling rate of -1.2 K / h), and further cooled to 16°C over a period of 3 h (at a cooling rate of -3 K / h). Finally, the suspension was cooled to 0°C over a period of 3 h (at a cooling rate of -5.3 K / h). After curing for 2 h, the suspension was filtered, and the residue was washed twice with a sufficient amount of acetone to produce purified BEMT in a yield of 98 wt.-% relative to the amount of crude BEMT. The crystalline BEMT particles were relatively large (D 50,3 = 11.3 µm), and therefore the filtration and washing times are shorter (filter cake resistance 5.4 × 10⁻⁶). 12 mPas / m 2 In this example, rapid filtration followed by air purging for deep dehumidification resulted in a product with small amounts of soluble byproducts (NK2 and NK5). The amounts of these byproducts are listed in Table 1.

[0156] Invention Example 2 (IE2)

[0157] To further reduce byproducts, the crystallization step of IE1 can be repeated. Therefore, the acetone-wetted product, as obtained in IE1 without an air purging step, is dissolved in acetone and heated to 40°C to produce a 19.6 wt.% solution of the IE1 product in acetone. The mixture is rapidly cooled (to 25°C as quickly as possible over approximately 30 min, and from 25°C at 8.6 K / h) to 16°C. During cooling at 23°C, 22°C, and 21°C, solid-state purified BEMT (approximately 0.06 wt.% of the IE1 product, each) is added as seed crystals. After stirring at 16°C for 30 min, the suspension is warmed to 32°C and subsequently cooled to 25°C over a period of 5.8 h (at a cooling rate of -1.2 K / h), and further cooled to 16°C over a period of 3 h (at a cooling rate of -3 K / h). Finally, the suspension was cooled to 0°C over a 3-hour period (at a cooling rate of -5.3 K / h). After solidification for 2 hours, the suspension was filtered, and the residue was washed twice with a sufficient amount of acetone to produce purified BEMT in a yield of 98 wt.% relative to the amount of crude BEMT. The duration of the filtration and washing steps was comparable to that of IE1 (D 50,3 = 12.0 µm; filter cake resistance 4.5 × 10 12 mPas / m 2 In this case, all byproducts were significantly reduced compared to CE1. The amounts of byproducts are listed in Table 1.

[0158] Table 1: Results of Examples RE1, CE1, and IE1-2

[0159]

[0160] na: Not available because it yields a crude product in melt form.

[0161] Compared to CE1, IE1 and IE2 exhibit significantly improved cake resistance. The accelerated filtration and washing are primarily due to the significantly larger particle size of IE1 and IE2 compared to CE1. Therefore, the method of the present invention is faster and thus cheaper. Additionally, the amount of byproducts contained in the final product is significantly reduced, especially when comparing IE2 with CE1. Higher purity BEMT is advantageous because it produces a healthier product and a less environmentally impactful one.

Claims

1. A method for increasing the BEMT content in a composition comprising 2,4-bis[4-(2-ethylhexyloxy)-2-hydroxyphenol]-6-(4-methoxyphenol)-1,3,5-triazine (BEMT), the method comprising the steps of: a) Provide a composition comprising BEMT and impurities; b) Dissolving the composition in a solvent mixture at a first dissolution temperature to produce an unsaturated BEMT solution, wherein the solvent mixture contains at least one polar solvent; c) The temperature of the unsaturated BEMT solution is lowered to the saturation temperature, which is lower than the first dissolution temperature, to produce a saturated BEMT solution; d) Further reduce the temperature of the saturated BEMT solution to a first crystallization temperature, which is lower than the saturation temperature, thereby producing a supersaturated BEMT solution; e) During step d), an amount of BEMT seed crystals in the range of 0.00001 wt.-% to 20 wt.-% relative to the total weight of the composition is added to the supersaturated BEMT solution to produce a first BEMT suspension containing BEMT particles and the supersaturated BEMT solution; f) Heating the first BEMT suspension to a second dissolution temperature to produce a second BEMT suspension containing fewer BEMT particles than the first BEMT suspension, wherein the second dissolution temperature is higher than the first crystallization temperature and lower than the first dissolution temperature; g) Reduce the temperature of the second BEMT suspension to a second crystallization temperature to produce a final BEMT suspension containing BEMT particles larger than those in the first BEMT suspension. h) Separate these BEMT particles from the final BEMT suspension; The method preferably includes one or more repetitions of steps b) to h), and wherein the second crystallization temperature is lower than the first crystallization temperature.

2. The method according to claim 1, wherein, In step e), the BEMT seed crystals are added in two batches at two different times, preferably in three batches at three different times.

3. The method according to claim 1 or 2, wherein, In step e), the temperature of the supersaturated BEMT solution is kept constant at the first crystallization temperature for at least 30 min.

4. The method according to any one of the preceding claims, wherein, In step g), the temperature of the second BEMT suspension is kept constant at the second crystallization temperature for at least 30 min.

5. The method according to any one of the preceding claims, wherein, The second dissolution temperature is higher than the highest temperature that the first BEMT suspension can reach through the enthalpy of crystallization released in the absorption step (g).

6. The method according to any one of the preceding claims, wherein, The at least one polar solvent is selected from the group consisting of methanol, ethanol, 1-butanol, 2-butanol, isopropanol, acetone, methyl ethyl ketone, diethyl ketone, and N,N-dimethylformamide, preferably acetone.

7. The method according to any one of the preceding claims, wherein, Step g) The cooling process is carried out stepwise at two different cooling rates, preferably three cooling rates.

8. The method according to any one of the preceding claims, wherein, In step d), these seed crystals are added at least once at a temperature in the range of 35°C to 20°C, preferably 30°C to 20°C, and most preferably 25°C to 20°C.

9. The method according to any one of the preceding claims, wherein, Step h) includes a filtration step and / or a washing step.

10. A particulate composition comprising at least 98 wt.% of 2,4-bis[4-(2-ethylhexyloxy)-2-hydroxyphenol]-6-(4-methoxyphenol)-1,3,5-triazine (BEMT) and at least one of the compounds according to formulas (I) to (VIII) based on the total weight of the composition: in R is a 2-ethylhexyl residue; The amount of the compound having formula (I) in the composition is less than 0.06 wt.-%, preferably less than 0.05 wt.-%, and most preferably less than 0.03 wt.-% based on the total weight of the composition. The amount of the compound having formula (II) in the composition is less than 0.11 wt.-%, preferably less than 0.05 wt.-%, more preferably less than 0.03 wt.-% based on the total weight of the composition; The amount of the compound having formula (III) in the composition is less than 0.11 wt.-%, preferably less than 0.07 wt.-%, and most preferably less than 0.05 wt.-% based on the total weight of the composition. The amount of the compound having formula (IV) in the composition is less than 0.41 wt.-%, preferably less than 0.23 wt.-%, and most preferably less than 0.12 wt.-% based on the total weight of the composition. The amount of the compound having formula (V) in the composition is less than 0.14 wt.-%, preferably less than 0.11 wt.-%, and most preferably less than 0.03 wt.-% based on the total weight of the composition. The amount of the compound having formula (VI) in the composition is less than 0.07 wt.-%, preferably less than 0.03 wt.-%, based on the total weight of the composition. The amount of the compound having formula (VII) in the composition is less than 0.05 wt.-%, preferably less than 0.03 wt.-%, based on the total weight of the composition. The amount of the compound having formula (VIII) in the composition is less than 0.17 wt.-%, preferably less than 0.15 wt.-%, based on the total weight of the composition; wherein the particulate composition has a median particle size D greater than 10 µm, preferably equal to or greater than 12 µm, as determined according to ISO 13320:2020. 50,3 .

11. The particulate composition according to claim 10, wherein, The amount of BEMT in the composition is greater than 98 wt.-, preferably greater than 99 wt.-, relative to the total weight of the composition.

12. The particulate composition according to claim 10 or 11, wherein, The composition is obtained by the method according to any one of claims 1 to 9.

13. Use of the particulate composition according to any one of claims 10 to 12 for protecting human and animal hair and skin from the harmful effects of UV radiation.

14. A cosmetic formulation comprising a carrier and an adjuvant compatible with the particulate composition according to any one of claims 10 to 12.

15. The cosmetic formulation according to claim 14, further comprising other UV-protective substances, preferably selected from the group consisting of triazine, oxalaniline, triazole, vinyl-containing amides, and cinnamic acid amides.

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