Process for producing 2-(4'-diethylamino-2'-hydroxybenzoyl)hexyl benzoate

Abstract

The present invention relates to a process for producing 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoic acid hexyl ester having a Gardner value of less than or equal to 8.2, comprising adjusting the reaction mixture obtained by reacting 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoic acid with n-hexanol to a pH greater than 7, followed by at least one extraction with an aqueous phase, and adsorbing the dissolved 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoic acid hexyl ester on at least two different adsorbents.

Description

Technical Field

[0001] The present invention relates to a process for producing hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate having a low Gardner value.

Background Art

[0002] UV radiation causes harmful effects on human skin. In addition to the acute effect of sunburn on the skin, it is also known to increase the risk of skin cancer. Furthermore, long-term exposure to UV-A light and UV-B light may cause phototoxic and photoallergic reactions in the skin and may accelerate skin aging.

[0003] To protect human skin from UV radiation, there are various sunscreen UV filters (also referred to as UV absorbers) including UV-A filters, UV-B filters and broadband filters. These filters are added to sunscreen or cosmetic compositions. UV filters are organic or inorganic, particulate or non-particulate compounds, all of which have high absorption efficacy in the UV light region. Generally, UV light can be divided into UV-A radiation (320 - 400 nm) and UV-B radiation (280 - 320 nm). UV filters are divided into UV-A filters and UV-B filters according to the position of the absorption maximum. When a UV filter absorbs both UV-A light and UV-B light, it is called a broadband absorber.

[0004] Since 2006, the European Commission has recommended that all sunscreen or cosmetic compositions should have a UV-A protection index of at least one third of the indicated sun protection factor (SPF), where the sun protection factor mainly refers to UV-B protection.

[0005] 2-(4'-diethylamino-2'-hydroxybenzoyl)hexyl benzoate is an effective UV-A filter and is used (e.g., in sunscreens) to protect the skin from UV radiation. 2-(4'-diethylamino-2'-hydroxybenzoyl)hexyl benzoate is represented below and is also referred to hereafter as DHHB or the compound of formula (I). [ka]

[0006] The process for producing 2-(4'-diethylamino-2'-hydroxybenzoyl)hexyl benzoate is publicly known, for example, by German Patent Application Publication No. 10011317, European Patent No. 2155660, and International Publication No. 2003097578. Several challenges have been identified in this regard. During the synthesis process of 2-(4'-diethylamino-2'-hydroxybenzoyl)hexyl benzoate, rhodamine B-type dyes (e.g., [9-(2-carboxyphenyl)-6-diethylamino-3-xanthenylidene]-diethylammonium salt) and their corresponding esters are formed as impurities, resulting in undesirable discoloration of the final product. Additional purification steps are required to purify the final product (rhodamine B-type dye at less than 5 ppm). Conventionally, this purification process involves dissolving impure 2-(4'-diethylamino-2'-hydroxybenzoyl) hexyl benzoate in a nonpolar solvent, adsorbing it onto an adsorbent, passing it through the layer, and then evaporating the solvent.

[0007] Subsequently, 2-(4'-diethylamino-2'-hydroxybenzoyl)hexyl benzoate is isolated by separating the solvent by distillation, and the clean final product is filled into bottles as a melt and optionally further solidified according to European Patent No. 2155660. [Prior art documents] [Patent Documents]

[0008] [Patent Document 1] German Patent Application Publication No. 10011317 [Patent Document 2] European Patent No. 2155660 [Patent Document 3] International Publication No. 2003097578 [Overview of the Initiative] [Problems that the invention aims to solve]

[0009] Therefore, there is a continuing need for a process to rapidly and efficiently produce 2-(4'-diethylamino-2'-hydroxybenzoyl)hexyl benzoate, particularly with reduced coloring impurities. In particular, the objective was to reduce coloring impurities that cause undesirable reddish and brownish discoloration of 2-(4'-diethylamino-2'-hydroxybenzoyl)hexyl benzoate. Furthermore, an object of the present invention was to provide an efficient and economically improved process for isolating crystalline 2-(4'-diethylamino-2'-hydroxybenzoyl)hexyl benzoate. [Means for solving the problem]

[0010] Surprisingly, it has been found that at least one of the above objectives can be achieved by the process according to the present invention. The process of the present invention provides hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate with a low rhodamine content (less than 5 ppm, particularly less than 1 ppm) and a low content of potential further non-red coloring impurities.

[0011] In particular, the inventors of this invention have discovered a process for efficiently producing the compound of formula (I).

[0012] Therefore, in the first aspect, the present invention is a process for producing 2-(4'-diethylamino-2'-hydroxybenzoyl) hexyl benzoate, a) A step of reacting phthalic anhydride with 3-N,N-diethylaminophenol to obtain 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoic acid, b) A step in which the 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoic acid obtained in step a) is reacted with n-hexanol to obtain 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate hexyl ester, c) The reaction mixture obtained in step b) is adjusted to a pH greater than 7, and then extracted at least once with the aqueous phase. d) A step of adsorbing the dissolved 2-(4'-diethylamino-2'-hydroxybenzoyl)hexyl benzoate on at least two different adsorbents. Regarding processes that include this.

[0013] The following describes in more detail preferred embodiments of the process according to the first embodiment. It should be understood that each preferred embodiment is suitable both on its own and in combination with other preferred embodiments.

[0014] In a preferred embodiment A1 of the first aspect, the 3-N,N-diethylaminophenol applied in step a) is distilled before reacting with the phthalic anhydride and / or has a Gardner value of 20 or less, a yellowness index of 80 or less, and / or a Hess-Ives of 350 or less.

[0015] In a preferred embodiment A2 of the first aspect, the pH of the reaction mixture in extraction step c) is adjusted with an alkaline aqueous solution.

[0016] In preferred embodiment A3 of the first aspect, the pH of the reaction mixture in extraction step c) is 8 to 14, preferably 9 to 13, and particularly 10.5 to 12.5.

[0017] In a preferred embodiment A4 of the first aspect, in step c), the reaction mixture obtained in step b) is adjusted to a pH greater than 7 by adding a base to the reaction mixture obtained in step b).

[0018] In the preferred embodiment A5 of the first aspect, the process is cII) a step of crystallizing hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate from the organic phase obtained in the extraction step c) further comprises.

[0019] In the preferred embodiment A6 of the first aspect, in the crystallization step cII), the crystallized hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate is dissolved in an organic solvent before the adsorption step d), preferably, the crystallized hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate is dissolved in a non-polar solvent, more preferably toluene.

[0020] In the preferred embodiment A7 of the first aspect, at least two different adsorbents are selected from the group consisting of activated carbon, aluminum oxide, zeolite and silica gel, preferably activated carbon and silica gel.

[0021] In the preferred embodiment A8 of the first aspect, in the adsorption step d), the dissolved hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate is first adsorbed on silica gel and then adsorbed on activated carbon.

[0022] In the preferred embodiment A9 of the first aspect, the solution of the adsorption step d) contains 10 to 80% by weight, preferably 20 to 60% by weight, particularly 25 to 40% by weight of hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate based on the total weight of the solution of the adsorption step d).

[0023] In the preferred embodiment A10 of the first aspect, the esterification step b) is carried out in the presence of an acidic catalyst, preferably, the acidic catalyst is sulfuric acid.

[0024] In the preferred embodiment A11 of the first aspect, the process is e) A step of removing the solvent, preferably the solvent is removed by distillation. It also includes.

[0025] In a preferred embodiment A12 of the first aspect, the prepared hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate ester has a Gardner value of 8.2 or less, a yellowness index of less than 89, and a Hess-Ives of less than 19, and / or contains rhodamine and its ester in a concentration of less than 5 ppm, preferably less than 2 ppm, and particularly less than 1 ppm.

[0026] In a second aspect, the present invention relates to a hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate ester having a Gardner value of 8.2 or less, preferably less than 7.9, and particularly less than 7.5, and containing rhodamine and its ester in a concentration of less than 5 ppm, preferably less than 2 ppm, and particularly less than 1 ppm, and preferably obtained by a process according to the first aspect.

[0027] In the preferred embodiment B1 of the second aspect, 2-(4'-diethylamino-2'-hydroxybenzoyl)hexyl benzoate further has a yellowness index of less than 89, preferably less than 86, and / or Hess-Ives of less than 19, preferably less than 17. [Modes for carrying out the invention]

[0028] Before describing exemplary embodiments of the present invention in detail, we will provide some important definitions necessary for understanding the invention.

[0029] As used herein and in the appended claims, the singular forms “one (a)” and “one (an)” also encompass their respective plural forms unless explicitly indicated in the context. In relation to the present invention, the terms “about” and “approximately” refer to a range of precision that a person skilled in the art would recognize as ensuring the technical effect of the feature in question is still maintained. This term typically refers to a deviation of ±20%, preferably ±15%, more preferably ±10%, and even more preferably ±5% from the given numerical value. The term “including” should be understood to be non-limiting. For the purposes of the present invention, the term “consisting of” is considered a preferred embodiment of the term “including.” Hereinafter, where a group is defined as containing at least a certain number of embodiments, it preferably also means that a group consisting only of these embodiments is also included. Furthermore, terms such as “first,” “second,” “third,” or “(a),” “(b),” “(c),” “(d)” in this specification and in the claims are used to distinguish similar elements and do not necessarily describe a consecutive or chronological order. It should be understood that the terms used in this manner are interchangeable under appropriate circumstances, and that the embodiments of the invention described herein may be carried out in an order other than that described or illustrated herein. Where terms such as “first,” “second,” “third,” or “(a),” “(b),” “(c),” “(d),” “i,” “ii” relate to a method, use, or assay step, unless otherwise specified herein, there may be no time interval between these steps, or the time interval may be inconsistent, as described or described herein, i.e., these steps may be carried out simultaneously, or there may be time intervals of a few seconds, a few minutes, a few hours, a few days, a few weeks, a few months, or even a few years between such steps. It should be understood that the invention is not limited to the specific methods, procedures, reagents, etc. described herein, as they may vary. It should also be understood that the terms used herein are used solely for the purpose of describing specific embodiments and are not intended to limit the scope of the invention, and the scope of the invention is limited only by the appended claims.Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art.

[0030] The terms "compound according to the present invention" or "compound of formula (I)" refer to hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate.

[0031] The term "halogen" refers to fluorine, bromine, chlorine, or iodine in each case, and especially to fluorine, chlorine, or bromine.

[0032] The term "body care products" refers to any product suitable for application to the human body, such as sunscreen compositions, bath and shower products, formulations containing fragrances and aromatic substances, hair care products, toothpastes, cosmetic formulations, and cosmetic formulations containing active ingredients. Sunscreen compositions are preferred.

[0033] The terms “sunscreen composition,” “sunscreen,” or “skincare product” refer to any topical agent that reflects and / or absorbs specific portions of UV radiation. Therefore, it should be understood that the term “sunscreen composition” includes not only sunscreen compositions but also any cosmetic compositions that provide UV protection. The term “topical agent” refers to a product applied to the skin, which may be, for example, a spray, lotion, cream, oil, foam, powder, or gel. According to the present invention, a sunscreen composition may include one or more activators, such as organic UV filters, and other components or additives, such as emulsifiers, emollients, viscosity modifiers, stabilizers, preservatives, or fragrances.

[0034] The term "daily care composition" refers to any topical agent that reflects or absorbs specific portions of UV radiation and is used as a daily care product for the human body, such as the face, body, or hair. A daily care composition may contain one or more activators, such as organic or inorganic UV filters, and other ingredients or additives, such as emulsifiers, softeners, viscosity modifiers, stabilizers, preservatives, or fragrances.

[0035] Suitable bath and shower additives include, for example, shower gels, bath salts, bubble baths, and soaps.

[0036] Suitable formulations containing fragrances and aromatic substances are, in particular, perfumes, fragrances, lotions, and shaving lotions (aftershave formulations).

[0037] Suitable hair care products include, for example, shampoos for humans and animals, especially dogs; hair conditioners; hair styling and treatment products; perming agents; hair sprays and lacquers; hair styling gels; hair fixatives; and hair dyes or bleaching agents.

[0038] Suitable toothpastes include, for example, tooth creams, toothpastes, mouthwashes, oral rinses, tartar prevention preparations, and denture cleaners.

[0039] Suitable cosmetic formulations include, for example, lipstick, nail polish, eyeshadow, mascara, dry and moist makeup, lipstick, powder, depilatory agents, and sunscreen.

[0040] Suitable cosmetic formulations containing active ingredients include, for example, hormone preparations, vitamin preparations, vegetable extract preparations, and antibacterial preparations.

[0041] The body care products mentioned may be in the form of creams, ointments, pastes, foams, gels, lotions, powders, makeup, sprays, sticks, or aerosols. Thus, the compound of formula (I) may act as a light stabilizer.

[0042] The term "critical wavelength" is defined as the wavelength at which the area under the UV protection curve (protection rate relative to wavelength) is 90% of the total area under the curve in the UV region (280-400 nm). For example, a critical wavelength of 370 nm indicates that the protection of a sunscreen composition is not limited to UV-B wavelengths, i.e., wavelengths of 280-320 nm, but is extended to 370 nm in such a way that 90% of the total area under the UV protection curve is achieved at 370 nm.

[0043] As used herein, the term “ultraviolet filter” or “UV filter” refers to an organic or inorganic compound capable of absorbing and / or reflecting UV radiation produced by sunlight. UV filters can be classified as UV-A, UV-B, or broadband filters based on their UV protection curve. In relation to this application, broadband filters can also be listed as UV-A filters because they also provide UV-A protection. In other words, preferred UV-A filters also include broadband filters.

[0044] The definition of "broadband" protection (also called broad-spectrum protection or broad protection) is based on the "critical wavelength." To achieve broadband coverage, protection against UV-B and UV-A is necessary. According to US standards, a critical wavelength of at least 370 nm is required to achieve broad-spectrum protection. Furthermore, the European Commission recommends that all sunscreen or cosmetic compositions should have a UVA protection index of at least one-third of their stated sun protection index (SPF) (for example, if a sunscreen composition has an SPF of 30, the UVA protection index must be at least 10).

[0045] Preferred embodiments of the process according to the present invention are described below. It should be understood that preferred embodiments of the present invention are preferred individually or in combination with each other.

[0046] As shown above, in one embodiment, the present invention is a process for producing 2-(4'-diethylamino-2'-hydroxybenzoyl) hexyl benzoate, a) A step of reacting phthalic anhydride with 3-N,N-diethylaminophenol to obtain 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoic acid, b) A step in which the 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoic acid obtained in step a) is reacted with n-hexanol to obtain 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate hexyl ester, c) The reaction mixture obtained in step b) is adjusted to a pH greater than 7, and then extracted at least once with the aqueous phase. d) A step of adsorbing the dissolved 2-(4'-diethylamino-2'-hydroxybenzoyl)hexyl benzoate on at least two different adsorbents. Regarding processes that include this.

[0047] A preferred embodiment of the process is defined below.

[0048] In a preferred embodiment of the present invention, the 3-N,N-diethylaminophenol applied in step a) is distilled before reacting with the phthalic anhydride. Distillation can be carried out by any method known in the art.

[0049] Preferably, the distillation of 3-N,N-diethylaminophenol applied in step a) is carried out within 72 hours, more preferably within 48 hours, even more preferably within 24 hours, and particularly within 12 hours prior to the reaction in step a). In certain preferred embodiments, the distillation of 3-N,N-diethylaminophenol applied in step a) is carried out within 6 hours, more preferably within 3 hours, even more preferably within 1 hour, and still more preferably within 30 minutes prior to the reaction in step a).

[0050] In a preferred embodiment of the present invention, the 3-N,N-diethylaminophenol applied in step a) has a Gardner value (measured according to ASTM D1544-04) of 20 or less, more preferably 18 or less, even more preferably 15 or less, even more preferably 10 or less, and particularly 7 or less.

[0051] In another preferred embodiment of the present invention, the 3-N,N-diethylaminophenol applied in step a) has a yellowness index (measured according to ASTM D5386-93b with respect to a CIE XYZ tristimulus value, standard light source C and 2° standard observer) of 80 or less, more preferably 70 or less, even more preferably 60 or less, even more preferably 50 or less, and particularly 40 or less.

[0052] In another preferred embodiment of the present invention, the 3-N,N-diethylaminophenol applied in step a) has a Hess-Ives value (measured according to DGK method number F 050.2) of 350 or less, more preferably 280 or less, even more preferably 150 or less, even more preferably 50 or less, and particularly 20 or less.

[0053] Preferably, the 3-N,N-diethylaminophenol applied in step a) has a Gardner value of 20 or less (measured by ASTM D1544-04), a yellowness index of 80 or less (measured according to ASTM D5386-93b with CIE XYZ tristimulus values, standard light source C and 2° standard observer as references), and a Hess-Ives value of 350 or less (measured according to DGK method number F 050.2).

[0054] In preferred embodiments of the present invention, esterification step b) is carried out in the presence of an acidic catalyst. Suitable acidic catalysts include, for example, hydrogen chloride, sulfuric acid, nitric acid, phosphoric acid, sulfonic acid, such as benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, or mixtures thereof, but also sulfonic acid group-containing ion exchangers such as Lewatits S100 (Bayer). Preferred acidic catalysts are hydrogen chloride, sulfuric acid, methanesulfonic acid, and p-toluenesulfonic acid, particularly sulfuric acid.

[0055] Preferably, the reactions in steps a) and b) are carried out in a solvent. The solvent can be selected from the group consisting of aromatic hydrocarbons such as benzene, toluene, and xylene; aliphatic C5-C12 hydrocarbons such as octane, petroleum ether, isooctane, and decane; ethers such as diethyl ether, dibutyl ether, and tetrahydrofuran; ketones such as acetone and acetophenone; esters such as ethyl acetate and isopropyl acetate; alcohols such as methanol, ethanol, isopropanol, and hexanol; chlorinated hydrocarbons such as perchloroethylene and chlorobenzene; cyclohexane; and mixtures thereof. Particularly preferred solvents are toluene and xylene in step a) and hexanol in step b).

[0056] In step c), the pH can be adjusted with any suitable base known in the art. Preferably, the pH is adjusted with an alkaline solution derived from a nitrogen-containing base containing alkali metal hydroxides and alkaline earth metal hydroxides, alkali metal oxides and alkaline earth metal oxides, alkali metal carbonates and alkaline earth metal carbonates, alkali metal bicarbonates and alkaline earth metal bicarbonates, alkali metal alkoxides and alkaline earth metal alkoxides, and tertiary amines, pyridines and bicyclic amines. In particular, the pH is adjusted with an alkaline aqueous solution.

[0057] A suitable alkaline aqueous solution may be an alkaline aqueous solution containing at least one hydroxide of at least one metal selected from the group consisting of alkali metals and alkaline earth metals. Sodium hydroxide aqueous solutions and potassium hydroxide aqueous solutions are preferred. Preferably, the alkaline aqueous solution is a 0.5-5%, more preferably 1-4%, and particularly 2-3% sodium hydroxide aqueous solution.

[0058] In a preferred embodiment of the present invention, the pH of the reaction mixture in extraction step c) is greater than 7.5, preferably greater than 8, more preferably greater than 8.5, and particularly greater than 9.

[0059] In a preferred embodiment of the present invention, the pH of the reaction mixture in extraction step c) is 8 to 14, more preferably 9 to 13, and particularly 10.5 to 12.5. Alternatively, the pH is adjusted by adding water to the reaction mixture obtained in step b) and adding a higher concentration of base, such as a 25% aqueous sodium hydroxide solution or a 25% aqueous potassium hydroxide solution. In this regard, the addition of the higher concentration of base is stopped when the pH reaches above 7, preferably 8 to 14, more preferably 9 to 13, and particularly 10.5 to 12.5.

[0060] In a preferred embodiment of the present invention, in step c), the reaction mixture obtained in step b) is adjusted to a pH greater than 7 by adding a base to the reaction mixture obtained in step b). In this regard, it should be understood that the reaction mixture obtained in step b) is not further diluted with an organic solvent before adjusting the pH to a pH greater than 7.

[0061] In a preferred embodiment of the present invention, the process is: cII) A step to crystallize 2-(4'-diethylamino-2'-hydroxybenzoyl)hexyl benzoate from the organic phase obtained in extraction step c). It also includes.

[0062] Preferably, in crystallization step cII), the crystallized 2-(4'-diethylamino-2'-hydroxybenzoyl) hexyl benzoate is dissolved in an organic solvent before adsorption step d).

[0063] Suitable organic solvents to be applied in step cII) to dissolve the crystallized 2-(4'-diethylamino-2'-hydroxybenzoyl) hexyl benzoate are ketones; ethers; esters such as ethyl acetate and isopropyl acetate; alcohols such as methanol, ethanol, isopropanol and n-hexanol; nonpolar aliphatic and aromatic hydrocarbons such as toluene, xylene, cyclohexane and petroleum ether; and mixtures thereof.

[0064] Preferably, the crystallized 2-(4'-diethylamino-2'-hydroxybenzoyl) hexyl benzoate is soluble in a nonpolar solvent.

[0065] It should be understood that nonpolar solvents have a dielectric constant (ε) of less than 15. Nonpolarity can also be expressed by a dipole moment (μ) of 0 to 2, either alternatively or additionally. In this regard, it is particularly preferable when the nonpolar solvent is selected from the group consisting of petroleum ether, ligroin, n-hexane, cyclohexane, heptane, di-n-butyl ether, xylene, toluene, benzene, and mixtures thereof.

[0066] According to certain preferred embodiments of the present invention, crystallized 2-(4'-diethylamino-2'-hydroxybenzoyl) hexyl benzoate is dissolved in toluene.

[0067] In adsorption step d), the dissolved 2-(4'-diethylamino-2'-hydroxybenzoyl)hexyl benzoate is preferably dissolved in an organic solvent. The organic solvent is preferably selected from the group consisting of ketones; ethers; esters such as ethyl acetate and isopropyl acetate; alcohols such as methanol, ethanol, isopropanol and n-hexanol; nonpolar aliphatic and aromatic hydrocarbons such as toluene, xylene, cyclohexane and petroleum ether; and mixtures thereof. More preferably, the dissolved 2-(4'-diethylamino-2'-hydroxybenzoyl)hexyl benzoate is dissolved in a nonpolar solvent. In particular, the solvent in adsorption step d) is selected from the group consisting of toluene, xylene and mixtures thereof.

[0068] In a preferred embodiment of the present invention, at least two different adsorbents are selected from the group consisting of activated carbon, aluminum oxide, zeolite, and silica gel, preferably activated carbon and silica gel. In a more preferred embodiment of the present invention, at least two different adsorbents have different chemical compositions; that is, if the first adsorbent is activated carbon, the second adsorbent is selected from the group consisting of aluminum oxide, zeolite, and silica gel, preferably activated carbon and silica gel.

[0069] When activated carbon and silica gel are used as at least two adsorbents, they can be applied in any ratio. Preferably, they are applied with a weight ratio of activated carbon to silica gel of 0.001 to 2, more preferably 0.005 to 1.5, even more preferably 0.01 to 1.0, and particularly 0.02 to 0.5.

[0070] Suitable silica gels as adsorbents are described, in particular, in CD Rompp Chemie Lexikon-Version 1.0, keyword:silica gels, Stuttgart / New York: Georg Thieme Verlag 1995 and the literature cited therein. Preferred silica gels are Silica Gel 60 from Merck (Darmstadt) and Silica Gel 123 from Grace.

[0071] Activated carbon can be used in powder form, granular form, or as cylindrical particles. In this regard, activated carbon is advantageously used in granular form (granular activated carbon) in fixed-bed filters or fluidized-bed filters. Examples of preferred carbons include activated carbon CPG(R)LF, CAL(R), and APC(R) from Chemviron Carbon, or Norit C Gran and Norit GAC 1240 Plus from Cabot, or Acticarbone BGE from Ceca.

[0072] Further details regarding the properties and grades of activated carbon used are provided in Ullmann's Encyclopedia, Sixth Edition, 2000 Electronic Release, Chapter 5.

[0073] In a preferred embodiment of the present invention, in adsorption step d), the dissolved 2-(4'-diethylamino-2'-hydroxybenzoyl) hexyl benzoate is first adsorbed on silica gel and then on activated carbon.

[0074] In a more preferred embodiment of the present invention, in adsorption step d), the dissolved 2-(4'-diethylamino-2'-hydroxybenzoyl)hexyl benzoate is first adsorbed on silica gel, then adsorbed on activated carbon, and then adsorbed again on silica gel.

[0075] In another preferred embodiment of the present invention, in adsorption step d), the dissolved 2-(4'-diethylamino-2'-hydroxybenzoyl)hexyl benzoate is first adsorbed on activated carbon, then adsorbed on silica gel, and preferably subsequently further adsorbed on activated carbon.

[0076] Preferably, the adsorption step d) is carried out at a temperature in the range of 15 to 80°C, more preferably 18 to 70°C, even more preferably 19 to 60°C, even more preferably 20 to 50°C, and particularly 20 to 25°C.

[0077] Preferably, the solution in adsorption step d) contains 10 to 80% by weight, more preferably 20 to 60% by weight, even more preferably 22 to 50% by weight, and especially 25 to 40% by weight of hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate based on the total weight of the solution in adsorption step d).

[0078] Preferably, adsorption is carried out continuously in a stationary layer (column). However, it can also be carried out discontinuously by adding the adsorbent to a solution of 2-(4'-diethylamino-2'-hydroxybenzoyl) hexyl benzoate in a solvent, preferably an organic solvent as described above, followed by stirring and filtering of the adsorbent.

[0079] In a preferred embodiment of the present invention, the process is: e) A step of removing the solvent, preferably the solvent is removed by distillation. It also includes.

[0080] It should be understood that step e) is performed after the adsorption step d). It is preferable to perform an additional stripping step to remove any potential residual solvent after step e).

[0081] In a preferred embodiment of the present invention, the prepared hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate ester has a Gardner value of 8.2 or less, preferably less than 7.9, more preferably less than 7.6, and particularly less than 7.5; a yellowness index of less than 89, preferably less than 86, more preferably less than 84, and particularly less than 82; and a Hess-Ives of less than 19, preferably less than 17, more preferably less than 16, and particularly less than 15, and / or contains less than 5 ppm, preferably less than 2 ppm, and particularly less than 1 ppm of rhodamine and its ester.

[0082] Generally, the Gardner value is considered particularly suitable for representing brownish discoloration impurities because a lower Gardner value indicates less brownish discoloration. Reddish, undesirable discoloration impurities in the final product, 2-(4'-diethylamino-2'-hydroxybenzoyl)hexyl benzoate, are preferably represented using Hess-Ives, as a lower Hess-Ives value indicates less reddish discoloration.

[0083] In a second aspect, the present invention relates to hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate containing rhodamine and its esters having a Gardner value of 8.2 or less, preferably less than 7.9, more preferably less than 7.6, and particularly less than 7.5, and less than 5 ppm, preferably less than 2 ppm, and particularly less than 1 ppm.

[0084] Preferably, the hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate further has a yellowness index of less than 89, preferably less than 86, more preferably less than 84, and especially less than 82, and / or Hess-Ives of less than 19, preferably less than 17, more preferably less than 16, and especially less than 15.

[0085] Preferably, the present invention relates to hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate containing rhodamine and its esters, having a Gardner value of 8.2 or less, preferably less than 7.9, more preferably less than 7.6, and particularly less than 7.5, a yellowness index of less than 89, preferably less than 86, more preferably less than 84, and particularly less than 82, and a Hess-Ives of less than 19, preferably less than 17, more preferably less than 16, and particularly less than 15, and less than 5 ppm, preferably less than 2 ppm, and particularly less than 1 ppm.

[0086] In a preferred embodiment, 2-(4'-diethylamino-2'-hydroxybenzoyl)hexyl benzoate ester having a Gardner value of 8.2 or less, preferably less than 7.9, more preferably less than 7.6, and particularly less than 7.5, and containing rhodamine and its ester in a concentration of less than 5 ppm, preferably less than 2 ppm, and particularly less than 1 ppm, is obtained by the process according to the first embodiment. Preferably, the 2-(4'-diethylamino-2'-hydroxybenzoyl)hexyl benzoate ester obtained by the process according to the first embodiment further has a yellowness index of less than 89, preferably less than 86, more preferably less than 84, and particularly less than 82, and / or a Hess-Ives of less than 19, preferably less than 17, more preferably less than 16, and particularly less than 15.

[0087] In certain preferred embodiments, hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate containing rhodamine and its esters, having a Gardner value of 8.2 or less, preferably less than 7.9, more preferably less than 7.6, and particularly less than 7.5, a yellowness index of less than 89, preferably less than 86, more preferably less than 84, and particularly less than 82, and a Hess-Ives of less than 19, preferably less than 17, more preferably less than 16, and particularly less than 15, is obtained by a process according to the first embodiment.

[0088] 2-(4'-diethylamino-2'-hydroxybenzoyl)hexyl benzoate obtained according to the claimed process may be included in body care products or daily care compositions. In particular, 2-(4'-diethylamino-2'-hydroxybenzoyl)hexyl benzoate obtained according to the claimed process may be included in sunscreen compositions.

[0089] 2-(4'-diethylamino-2'-hydroxybenzoyl)hexyl benzoate obtained according to the claimed process may be used as a UV filter in body care products or daily care compositions, particularly in sunscreen compositions.

[0090] The present invention is further illustrated by the following embodiments.

[0091] Experiment Section method HPLC method for measuring 2-(4'-diethylamino-2'-hydroxybenzoyl) hexyl benzoate and rhodamine-type impurities HPLC chromatograph with DAD / UV detector (Agilent 1100 or similar). HPLC chromatography column: Symmetry C18 5μm 250×4.6mm Waters. Solvent A: Water + 85% 0.1% v / v o-phosphate, Solvent B: Acetonitrile. Flow rate 1.2 ml / min. Injection volume 5 μL, T = 20°C. Gradient: t=0 min 80%A, 20%B / t=20 min 0%A, 100%B / t=30 min 0%A, 100%B / t=32 min 80%A, 20%B. Rhodamine B: RT=8.8 min (558 nm), Rhodamine-hexyl ester: RT=11.9 min (558 nm), 2-(4'-diethylamino-2'-hydroxybenzoyl) hexyl benzoate: RT=21.7 min (360 nm). External standards: Rhodamine B, rhodamine hexyl ester, 2-(4'-diethylamino-2'-hydroxybenzoyl) hexyl benzoate.

[0092] Color evaluation Color values ​​were measured using a Lico 690 colorimeter (Hach-Lange) in an 11 mm round cuvette. Samples were prepared by heating 2-(4'-diethylamino-2'-hydroxybenzoyl) hexyl benzoate to 65°C, homogenizing it, and transferring it to the cuvette. After cooling for 5-7 minutes, the color values ​​were measured.

[0093] Gardner values ​​were measured according to ASTM D1544-04.

[0094] The yellowness index was measured according to ASTM D5386-93b, using CIE XYZ tristimulus values, standard light source C, and 2° standard observer as references.

[0095] Hess-Ives values ​​were measured according to DGK method number F 050.2.

[0096] The analytical standards for calibration were determined using standard, up-to-date methods.

[0097] Silica 123 (Grace) was used as the silica adsorbent.

[0098] Norit C GRAN (Cabot Norit) was used as the activated carbon adsorbent. [Examples]

[0099] General Procedure 2-(4'-diethylamino-2'-hydroxybenzoyl) hexyl benzoate (DHHB) was synthesized based on the process described in International Publication No. 03097578 (Examples 1 and 2). Several parameters (Table 2) were changed as follows: i) 3-N,N-diethylaminophenol (DEMAP) was distilled / not distilled before use, and / or ii) the pH during extraction was set to pH 7 or approximately pH 11.5. The process included the following general steps.

[0100] General process 1: Synthesis of 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoic acid 3-N,N-diethylaminophenol (DEMAP) was reacted with phthalic anhydride in toluene under reflux, followed by filtration. The filtrate was washed with hexanol to isolate 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoic acid. The wet filtrate was used in the second step.

[0101] General process 2: Synthesis of 2-(4'-diethylamino-2'-hydroxybenzoyl)hexyl benzoate In the presence of an acidic catalyst, preferably sulfuric acid, the acid was esterified in hexanol under reflux while azeotropically removing water to obtain hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate. After the reaction, the pH of the reaction mixture was adjusted to the pH shown in the following examples using a 2.3% aqueous sodium hydroxide solution. The organic phase was washed again with water, and after extraction, the ester was crystallized from the organic phase. The filtrate was washed with hexanol, and the wet filtrate was used for adsorption.

[0102] Digitization of DEMAP Distillation was carried out at low pressure using a general distillation apparatus, such as a distillation bridge or short-stroke distillation (thin film evaporator). A distillation column is also suitable.

[0103] Distillation (bridging): 450 g of DEMAP (dark brown, 97.1% by weight as determined by HPLC) was distilled on a Claisenbridge at 160-170°C (heated jacket) / 0.7 mmbar. The following four fractions were collected: 1) 92.1 g; 2) 18.4 g; 3) 7.7 g; and 4) 330.6 g. Fractions 1-3 were pale yellow, and fraction 4 was yellow. The fourth fraction, with a DEMAP content of 99.1% by weight (HPLC), was used for the synthesis of DHHB.

[0104] Examples of thin-film evaporation: 353.5 g of DEMAP (94.2% by weight as determined by HPLC) was melted at 80°C, and 21.2 g of polypropylene glycol (Pluriol P 600) was added. Approximately 310 g of the mixture was distilled by thin-film evaporation at 5 mmbar and 156°C (jacket temperature) (0.016 m 2 (450 U / min). The mixture was added by pump (250 g / hour). All parts, including the condenser in contact with DEMAP, except for the recovered product, were heated to 80°C. After distillation, 281.8 g of DEMAP (97.7 wt%, HPLC) was obtained as a yellow molten product (sample: 24.6 g).

[0105] General process 3: Purification of 2-(4'-diethylamino-2'-hydroxybenzoyl) hexyl benzoate (DHHB) Adsorption was performed using a 3.6 cm diameter column. The volume of the adsorbent (silica, activated carbon (also called charcoal), or both) was always kept constant (adsorbent height approximately 10 cm). The column was either packed with a slurry of the adsorbent in toluene, or the column was flushed with toluene after packing with the adsorbent before adsorption began.

[0106] Crystalline 2-(4'-diethylamino-2'-hydroxybenzoyl) hexyl benzoate (hexanol-wet, approximately 15% hexanol), prepared according to general procedure 2, was dissolved in toluene and purified by adsorption on silica and / or activated charcoal. The solution concentration was 30% DHHB (cal. 100%). A total of 100 g of DHHB (cal. 100%) was added to the column in several portions of 33.4 g each (10 g of DHHB cal. 100%, approximately 38 ml of solution) as the solution (and residual hexanol) in toluene. The product was recovered by fractionation. A new fractionation was started each time a new volume was added, and only the first two fractions were recovered together. A total of nine fractions were recovered. The time taken to add one fraction was approximately 40 minutes. Each fraction was concentrated at 50°C to a pressure of 4 millibars and then dried at <1 millibar (room temperature) for 30 minutes. To evaluate the different parameters used in the synthesis, the number of comparable fractions of color was measured (reference: total grams of ester after adsorption, cal. 100%).

[0107] Examples of adsorption (specific steps in general process 3) IE1: (Table 2, No. 1): Purification of 2-(4'-diethylamino-2'-hydroxybenzoyl)hexyl benzoate A column (φ3.6cm) was packed with: 1) 1cm of sand, 2) 5.4g of Silica 123 (Grace), 5.2g of Norit C GRAN (Cabot Norit), 3) 37g of Silica 123, and 4) 1cm of sand (with filter paper between each layer). The column was flushed with 100g of toluene (discarded).

[0108] 125.4 g of the ester prepared in step 2 was dissolved in 226 g of toluene to obtain a solution of approximately 30% by weight of the ester in a mixture of toluene and residual hexanol. This solution was added to the column in 33.4 g in 10 separate additions (40 minutes / addition). At the start of each new addition, the new fraction was collected, excluding the first two fractions which were recovered together, as the first fraction was necessary to load the column. Each product fraction was concentrated at 50°C to a pressure of 4 mmbar (using a membrane pump) and then dried at <1 mmbar for 30 minutes.

[0109] Further experiments Based on the general process described in general steps 1-3, several parameters were modified: i) distillation of DEMAP, ii) pH during extraction, and iii) adsorbent. The total volume of adsorbent was always maintained as described in IE1 (total height of adsorbent approximately 10 cm; φ = 3.6 cm).

[0110] Examples IE2, C3, and C4 were all synthesized according to general steps 1-3, and only the modified parameters are listed (Table 2).

[0111] DHHB samples were synthesized according to general steps 1 and 2 without prior distillation of IE2, C3, and C4:DEMAP.

[0112] For IE2, the pH during extraction after esterification in general step 2 was set to pH=11.5. After crystallization, 122.4 g (83.7 wt%) of the crystalline product was dissolved in 219 g of toluene and filtered through a column packed with 1) 1 cm of sand, 2) 5.4 g of Silica 123 (Grace), 5.2 g of Norit C GRAN (Cabot Norit), 3) 37 g of Silica 123, and 4) 1 cm of sand (filter paper between each layer, with the column flushed with 100 g of toluene). The fractions were collected and concentrated as described in IE1 (Table 1).

[0113] For C3 and C4, the pH during extraction after esterification in general step 2 was set to pH=7. After crystallization, 133 g (76.0 wt%) of the crystalline product was dissolved in 204 g of toluene and filtered through a column packed with 1) 1 cm of sand, 2) 19 g of Norit C GRAN (Cabot Norit; for experiment C3) or 61.0 g of Silica 123 (Grace; for experiment C4), and 3) 1 cm of sand (filter paper between each layer, with the column flushed with 100 g of toluene). The fractions were collected and concentrated as described in IE1 (Table 1).

[0114] [Table 1]

[0115] [Table 2]

[0116] As can be seen from Table 2, the process of the present invention provides DHHB in which the amount of coloring impurities is reduced.

Claims

1. A process for producing 2-(4'-diethylamino-2'-hydroxybenzoyl)hexyl benzoate, a) A step of reacting phthalic anhydride with 3-N,N-diethylaminophenol to obtain 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoic acid, b) A step of reacting the 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoic acid obtained in step a) with n-hexanol to obtain 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoic acid hexyl ester, c) Adjust the pH of the reaction mixture obtained in step b) to a pH greater than 7, and then extract it at least once with the aqueous phase. d) A step of adsorbing the dissolved 2-(4'-diethylamino-2'-hydroxybenzoyl)hexyl benzoate on at least two different adsorbents. A process that includes this.

2. The 3-N,N-diethylaminophenol applied in step a) is distilled before reacting with the phthalic anhydride, and / or The manufacturing process according to claim 1, having a Gardner value of 20 or less, a yellowness index of 80 or less, and / or a Hess-Ives of 350 or less.

3. The manufacturing process according to claim 1 or 2, wherein the pH of the reaction mixture in the extraction step c) is adjusted with an alkaline aqueous solution.

4. The manufacturing process according to any one of claims 1 to 3, wherein the pH of the reaction mixture in extraction step c) is 8 to 14.

5. The manufacturing process according to any one of claims 1 to 4, wherein in step c), the reaction mixture obtained in step b) is adjusted to a pH greater than 7 by adding a base to the reaction mixture obtained in step b).

6. c) The manufacturing process according to any one of claims 1 to 5, further comprising the step of crystallizing the 2-(4'-diethylamino-2'-hydroxybenzoyl) hexyl benzoate from the organic phase obtained in the extraction step c).

7. The manufacturing process according to claim 6, wherein in the crystallization step cII), the crystallized 2-(4'-diethylamino-2'-hydroxybenzoyl) hexyl benzoate is dissolved in an organic solvent before the adsorption step d).

8. The manufacturing process according to any one of claims 1 to 7, wherein the at least two different adsorbents are selected from the group consisting of activated carbon, aluminum oxide, zeolite, and silica gel.

9. The manufacturing process according to any one of claims 1 to 8, wherein in the adsorption step d), the dissolved 2-(4'-diethylamino-2'-hydroxybenzoyl) hexyl benzoate is first adsorbed on silica gel and then adsorbed on activated carbon.

10. The manufacturing process according to any one of claims 1 to 9, wherein the solution in adsorption step d) contains 10 to 80% by weight of 2-(4'-diethylamino-2'-hydroxybenzoyl) hexyl benzoate based on the total weight of the solution in adsorption step d).

11. The manufacturing process according to any one of claims 1 to 10, wherein the esterification step b) is carried out in the presence of an acidic catalyst.

12. e) The manufacturing process according to any one of claims 1 to 11, further comprising the step of removing the solvent.

13. The manufacturing process according to any one of claims 1 to 12, wherein the manufactured hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate ester has a Gardner value of 8.2 or less, a yellowness index of less than 89, and a Hess-Ives of less than 19, and / or comprises less than 5 ppm of rhodamine and its ester.

14. A hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate ester having a Gardner value of less than 7.9 and containing less than 5 ppm of rhodamine and its ester.

15. The 2-(4'-diethylamino-2'-hydroxybenzoyl) hexyl benzoate ester according to claim 14, further comprising a yellowness index of less than 89 and / or a Hess-Ives of less than 19.

16. The manufacturing process according to any one of claims 1 to 3, wherein the pH of the reaction mixture in extraction step c) is 9 to 13.

17. The manufacturing process according to any one of claims 1 to 3, wherein the pH of the reaction mixture in extraction step c) is 10.5 to 12.

5.

18. The manufacturing process according to claim 6, wherein in the crystallization step cII), the crystallized 2-(4'-diethylamino-2'-hydroxybenzoyl) hexyl benzoate is dissolved in a nonpolar solvent before the adsorption step d).

19. The manufacturing process according to claim 6, wherein in the crystallization step cII), the crystallized 2-(4'-diethylamino-2'-hydroxybenzoyl) hexyl benzoate is dissolved in toluene before the adsorption step d).

20. The manufacturing process according to any one of claims 1 to 7, wherein the at least two different adsorbents are selected from the group consisting of activated carbon and silica gel.

21. The manufacturing process according to any one of claims 1 to 9, wherein the solution in adsorption step d) contains 20 to 60% by weight of 2-(4'-diethylamino-2'-hydroxybenzoyl) hexyl benzoate based on the total weight of the solution in adsorption step d).

22. The manufacturing process according to any one of claims 1 to 9, wherein the solution in adsorption step d) contains 25 to 40% by weight of 2-(4'-diethylamino-2'-hydroxybenzoyl) hexyl benzoate based on the total weight of the solution in adsorption step d).

23. The manufacturing process according to any one of claims 1 to 10, wherein the acidic catalyst is sulfuric acid.

24. e) The manufacturing process according to any one of claims 1 to 11, further comprising the step of removing the solvent, wherein the solvent is removed by distillation.

25. The manufacturing process according to any one of claims 1 to 12, wherein the manufactured hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate ester has a Gardner value of 8.2 or less, a yellowness index of less than 89, and a Hess-Ives of less than 19, and / or comprises less than 2 ppm of rhodamine and its ester.

26. The manufacturing process according to any one of claims 1 to 12, wherein the manufactured hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate ester has a Gardner value of 8.2 or less, a yellowness index of less than 89, and a Hess-Ives of less than 19, and / or comprises less than 1 ppm of rhodamine and its ester.

27. ​​A hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate ester having a Gardner value of less than 7.5 and containing less than 5 ppm of rhodamine and its ester.

28. A hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate ester having a Gardner value of less than 7.5 and containing less than 2 ppm of rhodamine and its ester.

29. A hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate ester having a Gardner value of less than 7.5 and containing less than 1 ppm of rhodamine and its ester.

30. Hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate ester having a Gardner value of less than 7.9 and containing less than 2 ppm of rhodamine and its ester.

31. Hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate ester having a Gardner value of less than 7.9 and containing less than 1 ppm of rhodamine and its ester.

32. The 2-(4'-diethylamino-2'-hydroxybenzoyl) hexyl benzoate according to claim 14, further comprising a yellowness index of less than 86 and / or a Hess-Ives of less than 19.

33. The 2-(4'-diethylamino-2'-hydroxybenzoyl) hexyl benzoate according to claim 14, further comprising a yellowness index of less than 86 and / or a Hess-Ives of less than 17.

34. The 2-(4'-diethylamino-2'-hydroxybenzoyl) hexyl benzoate according to claim 14, further comprising a yellowness index of less than 89 and / or a Hess-Ives of less than 17.

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