Method for separating 2-(4 '-diethylamino-2'-hydroxybenzoyl) hexyl benzoate

Abstract

The invention relates to a method for separating 2-(4 '-diethylamino-2'-hydroxybenzoyl) hexyl benzoate with high purity and low content of dialkyl phthalate.

Description

[0001] This application is a divisional application of the patent application with the application number 202180017491.9. The filing date of the original application is February 25, 2021, and the invention title is "Method for Separating Hexyl 2-(4'-Diethylamino-2'-hydroxybenzoyl) Benzoate".

[0002] The present invention relates to a method for separating hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl) benzoate with high purity and low dialkyl phthalate content.

[0003] Ultraviolet radiation has harmful effects on human skin. In addition to the acute effect of skin sunburn, ultraviolet radiation is also known to increase the risk of skin cancer. In addition, long-term exposure to UV-A and UV-B light can cause phototoxic and photosensitive reactions to the skin and accelerate skin aging.

[0004] To protect human skin from ultraviolet radiation, there are various sunscreen ultraviolet filters (also known as ultraviolet absorbers), including UV-A filters, UV-B filters, and broadband filters. These filters are added to sunscreen or cosmetic compositions. Ultraviolet filters are organic or inorganic, particulate or non-particulate compounds, all of which have high absorption efficacy in the ultraviolet range. Generally, ultraviolet light can be divided into UV-A radiation (320 - 400 nm) and UV-B radiation (280 - 320 nm). According to the position of the absorption maximum, ultraviolet filters are divided into UV-A filters and UV-B filters. In the case where an ultraviolet filter absorbs both UV-A and UV-B light, it is called a broadband absorber.

[0005] Since 2006, the European Commission has recommended that all sunscreen or cosmetic compositions should have a UV-A protection factor of at least 1 / 3 of the marked sun protection factor (SPF), where the sun protection factor mainly relates to UV-B protection.

[0006] Hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl) benzoate is an effective UV-A filter and is used to protect the skin from ultraviolet radiation (for example, in sunscreens). Hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl) benzoate is depicted as follows and is also referred to hereinafter as the compound of formula (I).

[0007]

[0008] Methods for manufacturing hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl) benzoate are known from, for example, DE 10011317, EP2155660, and WO 2003097578. In this regard, several challenges have been observed.

[0009] During the synthesis, the by-product dihexyl phthalate (also known as PSDHE, dihexylphthalate) is formed. The final product may still contain up to 50 - 150 ppm of PSDHE. According to recent findings, the PSDHE content should be as low as possible because this substance may impair fertility and may harm the unborn baby according to the harmonized classification and labelling (ATP05).

[0010] In addition, during the synthesis of hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate, a rhodamine B type dye (e.g. [9-(2-carboxyphenyl)-6-diethylamino-3-xanthenylidene]-diethylammonium salt) and the corresponding ester are formed as impurities, which cause an undesired discoloration of the final product. To purify the final product (less than 10 ppm of rhodamine B type dye), an additional purification step is required. So far, the purification step has consisted of dissolving the contaminated hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate in a non-polar solvent such as cyclohexane or toluene, adsorbing it on an activated carbon or silica bed and evaporating the solvent after passing through the bed.

[0011] After separating toluene and / or 1-hexanol by distillation and subsequently separating hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate, the clean final product is bottled as a melt. Since the product bottles as a melt and initial crystal growth occurs after storage at room temperature for about 6 weeks, the user has to heat the entire package to a temperature above the melting point of hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate in order to be able to remove the liquid product from the package. To provide a safe and easy-to-handle form of the crystallized final product, additional processing steps are required: a) providing a clear melt of hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate at a temperature above 57 °C, b) crystallizing hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate at a temperature below 57 °C, c) crushing the crystallized hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate to the desired particle size.

[0012] Therefore, there is still a need for a rapid and efficient purification method for hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate. In this regard, an object of the present invention is to provide an optimized method for separating and crystallizing hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate. In particular, an object is to provide a method for separating and crystallizing hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate in which the amount of dihexyl phthalate is reduced. In addition, an object of the present invention is to provide a method for separating and crystallizing hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate in which the amount of colored impurities is reduced. Finally, an object of the present invention is to provide a rapid method for separating and crystallizing hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate which further provides a safe and easy-to-operate final product.

[0013] It has surprisingly been found that at least one of the above objects can be achieved by the method according to the present invention. The method of the present invention provides hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate in the form of free-flowing crystals with a low PSDHE content (less than 15 ppm) and a low colored impurity content.

[0014] In particular, the inventors of the present invention have found a method for effectively purifying the compound of formula (I).

[0015] The present invention thus relates in a first aspect to a method for separating and crystallizing hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate, which comprises the following steps:

[0016] a) dissolving a mixture comprising hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate in a solvent having a boiling point of at most 110 °C to obtain a solution;

[0017] b) cooling the solution to a temperature of 20 to 40 °C;

[0018] c) optionally adding seeds of hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate to the solution;

[0019] d) cooling the solution to a temperature below 5 °C to obtain a suspension;

[0020] e) filtering the suspension to separate hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate in crystalline form.

[0021] Preferred embodiments of the method of the first aspect are described in more detail below. It is to be understood that each preferred embodiment is relevant alone and in combination with other preferred embodiments.

[0022] In a preferred embodiment A1 of the first aspect, the mixture in step a) comprises at least 85% by weight of hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate and at most 15% of impurities, including solvent residues of solvents with a boiling point greater than 110 °C and dialkyl phthalates, where the % by weight amounts are in each case based on the total weight of the mixture.

[0023] In a preferred embodiment A2 of the first aspect, the impurities include 1-hexanol in an amount of at most 14% by weight and dialkyl phthalates in an amount of 50 to 200 ppm, based on the total weight of the mixture.

[0024] In a preferred embodiment A3 of the first aspect, the solvent in step a) has a boiling point of at most 85 °C.

[0025] In a preferred embodiment A4 of the first aspect, the solvent in step a) is polar and / or is selected from methanol, ethanol, 1-propanol, and isopropanol.

[0026] In a preferred embodiment A5 of the first aspect, the mixture is dissolved in step a) at a temperature of 45 to 55 °C.

[0027] In a preferred embodiment A6 of the first aspect, the solution is cooled to a temperature of 25 to 30 °C in step b) over a period of at least 10 minutes.

[0028] In a preferred embodiment A7 of the first aspect, the solution is cooled to a temperature below -5 °C in step d) over a period of at least 3 hours, preferably at least 5 hours.

[0029] In a preferred embodiment A8 of the first aspect, cooling is carried out with a linear or non-linear cooling rate.

[0030] In a preferred embodiment A9 of the first aspect, step d) further comprises stirring the resulting suspension at a temperature below 0 °C for at least 3 hours, preferably at least 6 hours.

[0031] In a preferred embodiment A10 of the first aspect, the method further comprises the following steps:

[0032] f) washing the separated hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate with a solvent, optionally an aqueous base, optionally a surfactant, and optionally water.

[0033] In a preferred embodiment A11 of the first aspect, the solvent in washing step f) is the same solvent as used in step a) of the method.

[0034] In a preferred embodiment A12 of the first aspect, in the washing step f), an aqueous base is present and is a potassium carbonate or sodium carbonate solution, a potassium bicarbonate or sodium bicarbonate solution, a potassium hydroxide or sodium hydroxide solution, or an aqueous ammonia solution.

[0035] In a preferred embodiment A13 of the first aspect, a surfactant is present in the washing step f) and is selected from alkylbenzene sulfonates, sodium dodecyl sulfate, ammonium lauryl polyether sulfate, sodium dodecyl sulfosuccinate, cocamidopropyl betaine carboxyglycinate, decyl polyglucoside, cetearyl alcohol, stearyl alcohol, cocamidopropyl betaine, decyl glucoside, glyceryl cocoate, sodium cocoyl isethionate, almond glyceride, sodium dodecyl sulfacetate, sodium lauroyl sarcosinate, sodium methyl cocoyl taurate, sucrose cocoate, polysorbate 20, and polysorbate 80, preferably sodium dodecylbenzenesulfonate.

[0036] In a preferred embodiment A14 of the first aspect, the method further comprises the following step:

[0037] g) drying the separated hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate.

[0038] In another preferred embodiment A15 of the first aspect, the separated hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate has a purity of at least 99%, a dialkyl phthalate content of less than 15 ppm, a 1-hexanol content of less than 400 ppm, and a Gardner value of 8.3 or lower, wherein preferably the separated hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate has a purity of at least 99%, a dialkyl phthalate content of less than 1 ppm, a 1-hexanol content of less than 200 ppm, a Gardner value of 8.3 or lower, and a rhodamine content of less than 1 ppm.

[0039] In a second aspect, the present invention relates to hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate having a purity of at least 99%, a dialkyl phthalate content of less than 15 ppm, a 1-hexanol content of less than 400 ppm, and a Gardner value of 8.3 or lower, preferably wherein the hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate has a purity of at least 99%, a dihexyl phthalate content of less than 5 ppm, a 1-hexanol content of less than 200 ppm, a Gardner value of 8.3 or lower, and a rhodamine content of less than 1 ppm. Detailed Description of the Invention

[0041] Before describing the exemplary embodiments of the present invention in detail, definitions important for understanding the present invention are given. As used in this specification and the appended claims, the singular forms "a", "an", and "the" also include their respective plurals unless the context clearly dictates otherwise. In the present invention, the terms "about" and "substantially" refer to the range of precision that would be understood by a person skilled in the art and still ensure the technical effect of the element involved. This term generally refers to a deviation of ±20% from the indicated value, preferably ±15%, more preferably ±10%, and even more preferably ±5%. It is to be understood that the term "comprising" is not restrictive. For the present invention, the term "consisting of" is considered a preferred embodiment of the term "comprising". If in the following a group is defined as comprising at least a certain number of embodiments, it is intended to also include a group consisting preferably only of these embodiments. Further, the terms "first", "second", "third" or "(a)", "(b)", "(c)", "(d)" etc. and similar terms in the specification and claims are used to distinguish similar elements and are not necessarily used to describe an order of precedence or a temporal order. It is to be understood that the terms so used may be interchanged where appropriate, and the embodiments of the present invention described herein are capable of operating in an order different from that described or illustrated herein. In the case where the terms "first", "second", "third" or "(a)", "(b)", "(c)", "(d)", "i", "ii" etc. relate to steps of a method or use or detection, there is no temporal or time interval coherence between these steps, that is, these steps may be carried out simultaneously or there may be a time interval of seconds, minutes, hours, days, weeks, months or even years between these steps, unless otherwise indicated in the application as set forth in the context. It is to be understood that the present invention is not limited to the specific methods, procedures, reagents, etc. described herein as these may vary. It is also to be understood that the terms used herein are only for the purpose of describing specific embodiments and are not intended to limit the scope of the present invention, which is 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.

[0042] The term "compound according to the invention" or "compound of formula (I)" means hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate.

[0043] The term "halogen" in each case means fluorine, bromine, chlorine or iodine, especially fluorine, chlorine or bromine.

[0044] As used herein, the term "alkyl" in each case refers to a straight-chain or branched alkyl group having generally 1 to 20 carbon atoms, preferably 2 to 18 carbon atoms, more preferably 4 to 12 carbon atoms. Examples of alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-butyl, isobutyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl and n-dodecyl. Isobutyl and n-hexyl are preferred, especially n-hexyl.

[0045] As used herein, the term "(Cn-Cm-alkyl)" in each case refers to a linking group structural moiety, wherein the structural moiety attached thereto is attached to the terminal carbon.

[0046] The term "body care product" refers to any product suitable for application to the human body, such as sunscreen compositions, bath and shower products, preparations containing fragrances and odoriferous substances, hair care products, dentifrices, decorative preparations and cosmetic preparations containing active ingredients. Sunscreen compositions are preferred.

[0047] The term "sunscreen composition" or "sunscreen agent" or "skin care product" refers to any topical product that reflects and / or absorbs certain portions of ultraviolet radiation. Thus, the term "sunscreen composition" should be understood to include not only sunscreen compositions, but also any cosmetic composition that provides UV protection. The term "topical product" refers to a product applied to the skin and can refer, for example, to sprays, lotions, creams, oils, foams, powders or gels. According to the present invention, the sunscreen composition may comprise one or more active agents, such as organic UV filters, and other ingredients or additives, such as emulsifiers, emollients, viscosity regulators, stabilizers, preservatives or fragrances.

[0048] The term "daily care composition" refers to a product that reflects or absorbs certain portions of ultraviolet radiation and is used as a daily care product for the human body, such as any topical product for the face, body or hair. The daily care composition may comprise one or more active agents, such as organic or inorganic UV filters, and other ingredients or additives, such as emulsifiers, emollients, viscosity regulators, stabilizers, preservatives or fragrances.

[0049] Suitable bath and shower additives are, for example, bath gels, bath salts, bubble baths and soaps.

[0050] Suitable preparations containing fragrances and odoriferous substances are especially perfumes, fragrances, eau de toilettes and shaving lotions (aftershave preparations).

[0051] Suitable hair care products are, for example, shampoos, hair conditioners, products for hair styling and treatment, hair perming agents, hairsprays and hair gels, hair styling agents, hair dyes or bleaches for humans and animals, especially dogs.

[0052] Suitable dentifrices are, for example, tooth powders, toothpastes, mouthwashes, gargles, antiplaque agents and denture cleaners.

[0053] Suitable decorative preparations are, for example, lipsticks, nail polishes, eye shadows, mascaras, dry and wet makeup products, rouges, face powders, depilatory agents and sunscreens.

[0054] Suitable cosmetic preparations containing active ingredients are, for example, hormone preparations, vitamin preparations, plant extract preparations and antibacterial preparations.

[0055] The body care products listed can be in the form of creams, ointments, pastes, foams, gels, lotions, powders, makeup products, sprays, sticks or aerosols. They preferably contain the compound of formula (I) in an aqueous phase. Thereby, the compound of formula (I) can act as a light stabilizer.

[0056] The term "light stability" refers to the ability of a UV filter or any other molecule exposed to sunlight to remain stable upon irradiation. In particular, this means that the compound does not undergo a degradation process under UV radiation.

[0057] The term "critical wavelength" is defined as the wavelength at which the area under the UV protection curve (% protection vs. wavelength) represents 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 the sunscreen composition is not limited to the wavelengths of UV - B, i.e., 280 - 320 nm, but extends to 370 nm such that 90% of the total area under the protection curve in the UV region is reached at 370 nm.

[0058] As used herein, the term "ultraviolet filter" or "UV filter" refers to an organic or inorganic compound that can absorb and / or reflect ultraviolet radiation caused by sunlight. Ultraviolet filters can be classified as UV - A filters, UV - B filters or broadband filters based on their UV protection curves. In the present application, broadband filters may be classified as UV - A filters because they also provide UV - A protection. In other words, preferred UV - A filters also include broadband filters.

[0059] The definition of “broadband” protection (also known as broad-spectrum or wide-spectrum protection) is based on the “critical wavelength”. For broadband coverage, both UV-B and UV-A protection must be provided. According to the requirements in the United States, a critical wavelength of at least 370 nm is required to achieve broad-spectrum protection. In addition, the European Commission recommends that all sunscreens or cosmetic compositions should have a UVA protection factor of at least 1 / 3 of the marked sun protection factor (SPF). For example, if the SPF of a sunscreen composition is 30, the UVA protection factor must be at least 10.

[0060] The preferred embodiments of the method according to the present invention are described below. It is to be understood that the preferred embodiments of the present invention are preferred either alone or in combination with each other.

[0061] As shown above, in one embodiment, the present invention relates to a method for separating crystalline hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate, which comprises the following steps:

[0062] a) Dissolving a mixture containing hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate in a solvent having a boiling point of at most 110 °C to obtain a solution;

[0063] b) Cooling the solution to a temperature of 20 to 40 °C;

[0064] c) Optionally adding seeds of hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate to the solution;

[0065] d) Cooling the solution to a temperature below 5 °C to obtain a suspension;

[0066] e) Filtering the suspension to separate hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate in crystalline form.

[0067] The preferred embodiments of the method are specified below.

[0068] In a preferred embodiment of the present invention, the mixture applied in step a) is pretreated in vacuo. Preferably, the mixture applied in step a) is pretreated by drying the mixture at a temperature of 70 to 150 °C, more preferably 90 to 140 °C, especially 100 to 130 °C in vacuo before being dissolved in a solvent having a boiling point of at most 110 °C. Preferably, this pretreatment is carried out at a pressure of 0.1 to 800 mbar, more preferably 1 to 700 mbar, especially 5 to 600 mbar. Preferably, this pretreatment is carried out for 5 to 360 minutes, more preferably 10 to 250 minutes, especially 20 to 120 minutes.

[0069] In one embodiment of the present invention, the mixture in step a) comprises at least 85% by weight, preferably at least 90% by weight, of hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate and at most 15%, preferably at most 10%, of impurities, including solvent residues of solvents having a boiling point greater than 110 °C and dialkyl phthalates, where the % by weight amounts are in each case based on the total weight of the mixture.

[0070] In one embodiment of the present invention, the impurities comprise, based on the total weight of the mixture, at most 14% by weight, preferably at most 12% by weight, more preferably at most 10% by weight, still more preferably at most 9% by weight, especially at most 8% by weight, of a solvent having a boiling point greater than 110 °C and 50 to 200 ppm, preferably 55 to 150 ppm, of dialkyl phthalate.

[0071] In this regard, it is to be understood that, according to the present invention, dialkyl phthalates are defined as having the formula (A)

[0072]

[0073] where R 1 and R 2 are C4-C 12 -alkyl, preferably where R 1 and R 2 are both n-hexyl.

[0074] In a preferred embodiment of the present invention, the impurities include 1-hexanol. In another preferred embodiment of the present invention, the impurities comprise, based on the total weight of the mixture, at most 14% by weight, preferably at most 12% by weight, more preferably at most 10% by weight, still more preferably at most 9% by weight, especially at most 8% by weight, of 1-hexanol and 50 to 200 ppm, preferably 55 to 150 ppm, of dihexyl phthalate.

[0075] Toluene may also be an impurity according to the present invention, which may be included in the mixture applied in step a) in an amount of at most 10% by weight, preferably at most 5% by weight, especially at most 3% by weight, based on the total weight of the mixture.

[0076] Furthermore, according to the present invention, it is to be understood that the impurities also include colored impurities. In particular, Rhodamine B (depicted by formula (B)) and Rhodamine B derivatives. C6-alkyl ester type Rhodamine B derivatives (depicted by formula (C)) may be designated as exemplary Rhodamine B derivatives.

[0077]

[0078] In one embodiment of the present invention, the mixture in step a) has a Gardner value greater than 9.

[0079] In one embodiment of the present invention, the solvent in step a) has a boiling point of at most 100 °C, preferably at most 90 °C, more preferably at most 85 °C, even more preferably at most 83 °C, and particularly at most 80 °C. In one embodiment of the present invention, the solvent in step a) has a boiling point in the range of 30 to 110 °C, preferably 40 to 100 °C, more preferably 45 to 90 °C, even more preferably 50 to 85 °C, and particularly 60 to 85 °C.

[0080] In one embodiment of the present invention, the solvent in step a) is polar. It is understood that a polar solvent has a dielectric constant (ε) of 15 or greater, preferably 18 or greater. In a preferred embodiment of the present invention, the solvent in step a) has a dielectric constant (ε) of 15 to 100. Polarity can alternatively or additionally be represented by a dipole moment (μ) greater than 1, preferably greater than 2. In one embodiment of the present invention, the solvent in step a) has a dipole moment (μ) of 1 to 10, preferably greater than 2 to 10, more preferably 3 to 8. The dipole moment (μ ) is expressed in Debye. In a preferred embodiment of the present invention, the solvent in step a) has a dielectric constant (ε) of 15 to 100 and a dipole moment (μ) of 1 to 10.

[0081] In one embodiment of the present invention, the solvent in step a) has low toxicity and is preferably miscible with water. Solvents with low toxicity are described, for example, in "international council for harmonisation of technical requirements for pharmaceuticals for human use, ICH harmonised guideline, impurities: guideline for residual solvents, Q3C(R6) and toxicological data for class 3 solvents, Q3C support document 3". Acetone, isopropyl acetate, methyl acetate, 2-butanol, methyl ethyl ketone, tert-butyl methyl ether, ethanol, ethyl acetate, 1-propanol, diethyl ether, 2-propanol, ethyl formate, propyl acetate, formic acid, and trimethylamine can be designated as suitable solvents.

[0082] In one embodiment of the present invention, the solvent in step a) is an alcohol, preferably selected from methanol, ethanol, 2-methyl-2-propanol, 1-propanol, and isopropanol, which may be further substituted by halogen (to obtain 2,2,2-trifluoromethanol, 2,2,2-trifluoroethanol, or 2-fluoroethanol). In a particular embodiment of the present invention, the solvent in step a) is selected from methanol, ethanol, 1-propanol, and isopropanol, preferably ethanol. It is to be understood that, according to the present invention, the solvent in step a) may be a mixture of the above solvents.

[0083] In one embodiment of the present invention, the mixture in step a) is dissolved at a temperature of at least 30 °C, preferably at least 35 °C, more preferably at least 40 °C, still more preferably at least 45 °C. In a preferred embodiment of the present invention, the mixture is dissolved in step a) at a temperature of 35 to 80 °C, preferably 40 to 60 °C, more preferably 45 to 55 °C, particularly 48 to 52 °C.

[0084] In one embodiment of the present invention, in step a), the mixture has a ratio of 1:1.5 to 1:3.5, preferably 1:1.7 to 1:3.1, more preferably 1:1.8 to 1:3, particularly 1:1.9 to 1:2.9 with a solvent having a boiling point of at most 110 °C.

[0085] In one embodiment of the present invention, the solvent in step a) is not a non-polar solvent. It is to be understood that a non-polar solvent has a dielectric constant (ε) of less than 15. Non-polarity may alternatively or additionally be represented by a dipole moment (μ) of 0 to 0.5.

[0086] In one embodiment of the present invention, the solvent in step a) is not selected from petroleum ether, Ligroin, n-hexane, cyclohexane, heptane, di-n-butyl ether, xylene, toluene, and benzene. In a further embodiment of the present invention, the method does not include adding a solvent selected from petroleum ether, Ligroin, n-hexane, cyclohexane, heptane, di-n-butyl ether, xylene, toluene, and benzene.

[0087] In step b), the solution is cooled to a temperature of 20 to 40 °C, preferably 20 to 35 °C, more preferably 20 to 30 °C.

[0088] In one embodiment of the present invention, in step b), the solution is cooled to a temperature of 20 °C to 40 °C, preferably 22 to 35 °C, more preferably 25 to 30 °C over a period of at least 10 minutes, preferably at least 15 minutes, more preferably at least 20 minutes, particularly at least 25 minutes. In a preferred embodiment of the present invention, in step b), the solution is cooled to a temperature of 20 °C to 30 °C, preferably 22 °C to 28 °C over a period of at least 10 minutes, preferably at least 15 minutes, more preferably at least 20 minutes, particularly at least 25 minutes.

[0089] In one embodiment of the present invention, in step b), the solution is cooled to a temperature of 20°C to 40°C, preferably 22°C to 35°C, more preferably 25°C to 30°C, at a cooling rate of 10 to 100°C per hour, preferably 15 to 90°C per hour, more preferably 20 to 70°C per hour, especially 25 to 60°C per hour. In a preferred embodiment of the present invention, in step b), the solution is cooled to a temperature of 20°C to 30°C, preferably 22°C to 28°C, at a cooling rate of 10 to 100°C per hour, preferably 15 to 90°C per hour, more preferably 20 to 70°C per hour, especially 25 to 60°C per hour.

[0090] In one embodiment of the present invention, the cooling in step b) is carried out with a linear or non-linear cooling rate.

[0091] In one embodiment of the present invention, in step c), crystals of hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate are added to the solution.

[0092] In one embodiment of the present invention, the seeded solution in step c) is stirred for 1 to 60 minutes, preferably 1 to 50 minutes, more preferably 2 to 40 minutes, especially 3 to 25 minutes, at a temperature greater than 20°C to less than 40°C, preferably 22°C to 35°C, more preferably 25°C to 30°C.

[0093] In one embodiment of the present invention, in step d), the solution is cooled to a temperature below 5°C, preferably below 0°C, more preferably below -3°C, still more preferably below -5°C, especially below -7°C, over a period of at least 2 hours, preferably at least 3 hours, more preferably at least 4 hours, especially at least 5 hours.

[0094] In one embodiment of the present invention, in step d), the solution is cooled to a temperature below 5°C, preferably below 0°C, more preferably below -3°C, still more preferably below -5°C, especially below -7°C, at a cooling rate greater than 4 to less than 20°C per hour, preferably 4.5 to 15°C per hour, more preferably 5 to 11°C per hour, especially 5 to 10°C per hour.

[0095] In one embodiment of the present invention, the cooling in step d) is carried out with a linear or non-linear cooling rate.

[0096] In one embodiment of the present invention, step d) further includes stirring the resulting suspension at a temperature below 5°C, preferably below 0°C, more preferably below -3°C, still more preferably below -5°C, especially below -7°C, for at least 3 hours, preferably at least 4 hours, more preferably at least 5 hours, especially at least 6 hours.

[0097] In one embodiment of the present invention, step e) is carried out at a temperature below 5°C, preferably below 0°C, more preferably below -3°C, still more preferably below -5°C, especially below -7°C.

[0098] In one embodiment of the present invention, after step e), the hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate separated in crystalline form is suspended in a solvent at least once again at a temperature below 5°C, preferably below 0°C, more preferably below -3°C, still more preferably below -5°C, especially below -7°C. In one embodiment of the present invention, the at least one additional suspension step is carried out at the same temperature as in step e). In this regard, the solvent used is a solvent having a boiling point of at most 110°C, wherein the solvent is preferably the same solvent as used previously in step a), more preferably, wherein the solvent is selected from methanol, ethanol, 1-propanol, and isopropanol, especially ethanol. After the at least one additional suspension step, the hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate separated in crystalline form is filtered at a temperature below 5°C, preferably below 0°C, more preferably below -3°C, still more preferably below -5°C, especially below -7°C.

[0099] In one embodiment of the present invention, the method further comprises the following step:

[0100] f) washing the separated hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate with a solvent, optionally an aqueous base, optionally a surfactant, and optionally water.

[0101] It is to be understood that the washing step f) can be carried out with any suitable known solvent as outlined in more detail above. Preferably, the solvent in step f) is the solvent used in step a) of the method.

[0102] In one embodiment of the present invention, an aqueous base is present in step f) and is a potassium carbonate or sodium carbonate solution, a potassium bicarbonate or sodium bicarbonate solution, a potassium hydroxide or sodium hydroxide solution, or an ammonia water solution. In a particular embodiment of the present invention, an aqueous base is present in step f) and is a sodium carbonate solution.

[0103] In one embodiment of the present invention, step f) further comprises washing with an acid solution. In this regard, inorganic acids such as aqueous hydrochloric acid and organic acids such as aqueous citric acid can be mentioned.

[0104] In one embodiment of the present invention, a surfactant is present in step f) and is selected from anionic surfactants, cationic surfactants, amphoteric surfactants, and non-ionic surfactants.

[0105] Preferably, surfactants are used that are derived from natural products and / or are biodegradable and are for cosmetic formulations.

[0106] In one embodiment of the invention, a surfactant is present in step f) and is selected from alkylbenzene sulfonates, sodium dodecyl sulfate, ammonium lauryl ether sulfate, disodium lauryl sulfosuccinate, cocoyl amphocarboxyglycinate, decyl glucoside, cetearyl alcohol, stearyl alcohol, cocamidopropyl betaine, decyl glucoside, glyceryl cocoate, sodium cocoyl isethionate, almond glyceride, sodium dodecyl sulfacetate, sodium lauroyl sarcosinate, sodium methyl cocoyl taurate, sucrose cocoate, polysorbate 20, and polysorbate 80, preferably sodium dodecylbenzenesulfonate.

[0107] In one embodiment of the invention, step f) is carried out at a temperature of at least -5°C, preferably at least -2°C, more preferably at least 0°C, and especially at least 3°C.

[0108] In one embodiment of the invention, the method further comprises the following step:

[0109] g) drying the separated hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate. It is understood that each suitable drying method can be employed.

[0110] In one embodiment of the invention, drying step g) is carried out in vacuo at a temperature of less than 55°C, preferably less than 50°C. In one embodiment of the invention, drying step g) is carried out in vacuo at a temperature of 25 to 55°C, preferably 25 to 50°C, and especially 30 to 45°C.

[0111] In one embodiment of the invention, the method does not include the addition of activated carbon.

[0112] In one embodiment of the invention, the method does not include adsorption on a silica bed.

[0113] In a particular embodiment of the invention, the method does not include adsorption on an activated carbon or silica bed.

[0114] After drying, a free-flowing crystalline solid of hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate is obtained.

[0115] In one embodiment of the present invention, the method provides crystalline 2-(4'-diethylamino-2'-hydroxybenzoyl) benzoic acid hexyl ester having a dialkyl phthalate content of less than 40 ppm, preferably less than 30 ppm, more preferably less than 15 ppm, still more preferably less than 10 ppm, particularly less than 5 ppm. In a particular preferred embodiment of the present invention, the method provides crystalline 2-(4'-diethylamino-2'-hydroxybenzoyl) benzoic acid hexyl ester having a dialkyl phthalate content of less than 4 ppm, preferably less than 3 ppm, more preferably less than 2 ppm, particularly less than 1 ppm.

[0116] In this regard, it is to be understood that the present invention provides a method for separating crystalline 2-(4'-diethylamino-2'-hydroxybenzoyl) benzoic acid hexyl ester having a reduced dihexyl phthalate (also known as dihexyl phthalate) content, preferably having a dihexyl phthalate content of less than 15 ppm, more preferably less than 10 ppm, still more preferably less than 5 ppm, still more preferably less than 2 ppm, particularly less than 1 ppm.

[0117] In one embodiment of the present invention, the method provides crystalline 2-(4'-diethylamino-2'-hydroxybenzoyl) benzoic acid hexyl ester having a colored impurity content of less than 5 ppm, preferably less than 3 ppm, particularly less than 1 ppm.

[0118] In this regard, the present invention provides a method for separating crystalline 2-(4'-diethylamino-2'-hydroxybenzoyl) benzoic acid hexyl ester having a reduced rhodamine B content, preferably having a rhodamine B content of less than 5 ppm, more preferably less than 3 ppm, particularly less than 1 ppm.

[0119] In one embodiment of the present invention, the method provides crystalline 2-(4'-diethylamino-2'-hydroxybenzoyl) benzoic acid hexyl ester having a Gardner value of 9 or lower, preferably 8.8 or lower, more preferably 8.6 or lower, still more preferably 8.4 or lower, particularly 8.3 or lower.

[0120] In one embodiment of the present invention, the method provides crystalline 2-(4'-diethylamino-2'-hydroxybenzoyl) benzoic acid hexyl ester having a solvent content of less than 500 ppm, preferably less than 400 ppm, more preferably less than 300 ppm, still more preferably less than 200 ppm, still more preferably less than 100 ppm, particularly less than 50 ppm. In this regard, it is to be understood that the solvent content mentioned includes impurities of solvent residues originating from solvents having a boiling point greater than 110 °C.

[0121] In one embodiment of the present invention, the method provides crystalline 2-(4'-diethylamino-2'-hydroxybenzoyl) benzoic acid hexyl ester having a 1-hexanol content of less than 400 ppm, preferably less than 200 ppm, more preferably less than 150 ppm, still more preferably less than 100 ppm, still more preferably less than 50 ppm, particularly less than 40 ppm.

[0122] In a preferred embodiment of the present invention, the method provides crystalline 2-(4'-diethylamino-2'-hydroxybenzoyl) benzoic acid hexyl ester having a toluene content of less than 300 ppm, preferably less than 200 ppm, more preferably less than 150 ppm, still more preferably less than 100 ppm, still more preferably less than 40 ppm, particularly less than 20 ppm.

[0123] In one embodiment of the present invention, the isolated 2-(4'-diethylamino-2'-hydroxybenzoyl) benzoic acid hexyl ester has a purity of at least 99%, preferably at least 99.2%, more preferably at least 99.4%, still more preferably at least 99.6%, particularly greater than 99.8%.

[0124] In one embodiment of the present invention, the isolated 2-(4'-diethylamino-2'-hydroxybenzoyl) benzoic acid hexyl ester has a purity of at least 99%, a dialkyl phthalate content of less than 15 ppm, a solvent content of less than 400 ppm, and a Gardner value of 8.3 or lower, wherein preferably the isolated 2-(4'-diethylamino-2'-hydroxybenzoyl) benzoic acid hexyl ester has a purity of at least 99%, a dialkyl phthalate content of less than 5 ppm, a solvent content of less than 400 ppm, a Gardner value of 8.3 or lower, and a rhodamine B content of less than 1 ppm. The solvent is preferably selected from 1-hexanol, toluene, and mixtures thereof.

[0125] In one embodiment of the present invention, the isolated 2-(4'-diethylamino-2'-hydroxybenzoyl) benzoic acid hexyl ester has a purity of at least 99%, a dialkyl phthalate content of less than 1 ppm, a solvent content of less than 400 ppm, a Gardner value of 8.3 or lower, and a rhodamine B content of less than 1 ppm.

[0126] In one embodiment of the present invention, the isolated 2-(4'-diethylamino-2'-hydroxybenzoyl) benzoic acid hexyl ester has a purity of at least 99%, a dialkyl phthalate content of less than 3 ppm, a toluene content of less than 300 ppm, a 1-hexanol content of less than 400 ppm, a rhodamine B content of less than 1 ppm, and / or a Gardner value of 8.3 or lower.

[0127] In one embodiment of the present invention, the isolated hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate has a purity of at least 99%, a dialkyl phthalate content of less than 5 ppm, a solvent content of less than 100 ppm, and a Gardner value of 8.3 or lower. The solvent is preferably selected from 1-hexanol, toluene, and mixtures thereof.

[0128] In one embodiment of the present invention, the isolated hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate has a purity of at least 99%, a dihexyl phthalate content of less than 15 ppm, a 1-hexanol content of less than 400 ppm, and a Gardner value of 8.3 or lower, wherein preferably the isolated hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate has a purity of at least 99%, a dihexyl phthalate content of less than 5 ppm, a 1-hexanol content of less than 200 ppm, a Gardner value of 8.3 or lower, and a rhodamine B content of less than 1 ppm.

[0129] In one embodiment of the present invention, the isolated hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate has a purity of at least 99%, a dihexyl phthalate content of less than 5 ppm, a 1-hexanol content of less than 400 ppm, a toluene content of less than 300 ppm, and a Gardner value of 8.3 or lower.

[0130] In one embodiment of the present invention, the isolated hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate has a purity of at least 99%, a dialkyl phthalate content of less than 15 ppm, a solvent content of less than 200 ppm, and a Gardner value of 8.3 or lower, wherein preferably the isolated hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate has a purity of at least 99%, a dialkyl phthalate content of less than 5 ppm, a solvent content of less than 200 ppm, a Gardner value of 8.3 or lower, and a rhodamine B content of less than 1 ppm.

[0131] In one embodiment of the present invention, the isolated hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate has a purity of at least 99%, a dialkyl phthalate content of less than 1 ppm, a solvent content of less than 200 ppm, a Gardner value of 8.3 or lower, and a rhodamine B content of less than 1 ppm.

[0132] In one embodiment of the present invention, the isolated hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate has a purity of at least 99%, a dialkyl phthalate content of less than 3 ppm, a toluene content of less than 1 ppm, a 1-hexanol content of less than 200 ppm, a rhodamine B content of less than 1 ppm, and a Gardner value of 8.3 or lower.

[0133] In one embodiment of the present invention, the isolated hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate has a purity of at least 99%, a dialkyl phthalate content of less than 1 ppm, a solvent content of less than 200 ppm, and a Gardner value of 8.3 or lower.

[0134] In one embodiment of the present invention, the isolated hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate has a purity of at least 99%, a dihexyl phthalate content of less than 15 ppm, a solvent content of less than 200 ppm, and a Gardner value of 8.3 or lower, wherein preferably the isolated hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate has a purity of at least 99%, a dihexyl phthalate content of less than 5 ppm, a solvent content of less than 200 ppm, a Gardner value of 8.3 or lower, and a rhodamine B content of less than 1 ppm.

[0135] In one embodiment of the present invention, the isolated hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate has a purity of at least 99%, a dihexyl phthalate content of less than 1 ppm, a solvent content of less than 200 ppm, a Gardner value of 8.3 or lower, and a rhodamine B content of less than 1 ppm.

[0136] In one embodiment, the present invention relates to crystals of hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate obtained according to the claimed method. The obtained crystals preferably have a purity of at least 99%, a dialkyl phthalate content of less than 15 ppm, a solvent content of less than 200 ppm, and a Gardner value of 8.3 or lower, more preferably a purity of at least 99%, a dihexyl phthalate content of less than 5 ppm, a solvent content of less than 200 ppm, a Gardner value of 8.3 or lower, and a rhodamine content of less than 1 ppm. In another preferred embodiment, the obtained crystals have a purity of at least 99%, a dialkyl phthalate content of less than 15 ppm, a 1-hexanol content of less than 400 ppm, and a Gardner value of 8.3 or lower, more preferably a purity of at least 99%, a dihexyl phthalate content of less than 5 ppm, a 1-hexanol content of less than 200 ppm, a Gardner value of 8.3 or lower, and a rhodamine content of less than 1 ppm.

[0137] The process according to the invention provides 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoic acid hexyl ester with a particularly low impurity content. Surprisingly, the process according to the invention provides 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoic acid hexyl ester with a particularly low dialkyl phthalate content. According to the invention, the determination of phthalates and rhodamine-type impurities is preferably carried out by HPLC analysis. The determination of solvent residues is preferably carried out by GC analysis.

[0138] In one embodiment, the invention relates to 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoic acid hexyl ester having a dialkyl phthalate content of less than 15 ppm, preferably less than 10 ppm, more preferably less than 5 ppm, still more preferably less than 2 ppm, and especially less than 1 ppm.

[0139] In a particular embodiment, the invention relates to 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoic acid hexyl ester having a dihexyl phthalate content of less than 15 ppm, preferably less than 10 ppm, more preferably less than 5 ppm, still more preferably less than 2 ppm, and especially less than 1 ppm.

[0140] In one embodiment, the invention relates to 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoic acid hexyl ester having a purity of at least 99%, a dialkyl phthalate content of less than 15 ppm, a 1-hexanol content of less than 400 ppm, and a Gardner value of 8.3 or lower, wherein preferably 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoic acid hexyl ester has a purity of at least 99%, a dihexyl phthalate content of less than 5 ppm, a 1-hexanol content of less than 200 ppm, a Gardner value of 8.3 or lower, and a rhodamine content of less than 1 ppm.

[0141] In a preferred embodiment, the invention relates to 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoic acid hexyl ester having a purity of at least 99%, a dialkyl phthalate content of less than 15 ppm, a 1-hexanol content of less than 400 ppm, a toluene content of less than 300 ppm, and a Gardner value of 8.3 or lower, wherein preferably 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoic acid hexyl ester has a purity of at least 99%, a dihexyl phthalate content of less than 5 ppm, a 1-hexanol content of less than 200 ppm, a toluene content of less than 100 ppm, and a Gardner value of 8.3 or lower.

[0142] In one embodiment, the present invention relates to hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate having a purity of at least 99%, a dialkyl phthalate content of less than 15 ppm, a solvent content of less than 200 ppm, and a Gardner value of 8.3 or lower, wherein preferably hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate has a purity of at least 99%, a dihexyl phthalate content of less than 5 ppm, a solvent content of less than 200 ppm, a Gardner value of 8.3 or lower, and a rhodamine content of less than 1 ppm.

[0143] In one embodiment, the present invention relates to a body care product or a daily care composition comprising crystals of hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate obtained according to the claimed method. In particular, the present invention relates to a sunscreen composition comprising crystals of hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate obtained according to the claimed method.

[0144] In one embodiment, the present invention relates to the use of crystals of hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate obtained according to the claimed method as an ultraviolet filter in a body care product or a daily care composition, particularly in a sunscreen composition.

[0145] The present invention is further illustrated by the following examples. Examples

[0146] Method

[0147] The determination of hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate and solvent residues was carried out using GC analysis.

[0148] Agilent 6890Plus GC with FID (flame ionization detector). Fused silica capillary column (100% dimethyl polysiloxane film (0.33 μm), e.g., Agilent 19091-60321, 12 m × 0.2 mm). Helium, constant flow rate, split ratio 150:1, injector temperature 250 °C, detector temperature 320 °C, injection volume 1 μL. Gradient: 2 min T = 80 °C, 10 °C / min (80 - 320 °C), 4 min T = 320 °C.

[0149] External standards: toluene, n-hexanol, hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate, ethanol, 2-propanol.

[0150] The determination of phthalates and rhodamine-type impurities was carried out using HPLC analysis.

[0151] Agilent 1290 HPLC with a diode array detector (190 - 640 nm). Zorbax Eclipse XDB C8 3x100 mm, 1.8 μm (Agilent Nr. 993967 - 906) HPLC column.

[0152] Solvent A: water / acetonitrile 9:1 + TBAHS (tetrabutylammonium hydrogen sulfate) 2 g / L. Solvent B: acetonitrile (0.8 mL / min). Injection volume 5 μL, T = 50 °C. Gradient: t = 0 min 100% A, 0% B / t = 21 min, 0% A, 100% B / t = 23 min, 0% A, 100% B / t = 24 min, 100% A, 0% B (post time 4 min).

[0153] Rhodamine B: RT = 8.2 min (558 nm), di-n-hexyl phthalate: RT (retention time) = 17.3 min (200 nm, subtracting 356 nm signal). External standards: Rhodamine B, di-n-hexyl phthalate.

[0154] The Gardner value was determined by measuring the spectral color of clear molten 2-(4'-diethylamino-2'-hydroxybenzoyl) benzoic acid hexyl ester (Lico 500 colorimeter, Hach Lange GmbH, Germany).

[0155] Analytical standards that have been calibrated by standard prior art methods.

[0156] Example 1

[0157] According to US2005 / 0165099, Example 2, prepare hexanol-wetted pink crude 2-(4'-diethylamino-2'-hydroxybenzoyl) benzoic acid hexyl ester. The crude product was suction dried.

[0158] Composition of the crude product: 93% 2-(4'-diethylamino-2'-hydroxybenzoyl) benzoic acid hexyl ester, 7% solvent residues and impurities (81 ppm PSDHE, Gardner value > 9).

[0159] The crude hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate (299.8 g) was dissolved in ethanol (836.4 g) at 50 °C and then cooled to 25 °C over 30 - 50 minutes (linear cooling ramp). Thereafter, seeds of pure hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate (0.012 g) were added and the mixture was stirred at 25 °C for 5 - 10 minutes. After cooling to -10 °C (10 hours, linear cooling ramp), a crystal suspension was obtained and further stirred at -10 °C for 7 hours. The solid was separated by filtration at -10 °C. The crystals were suspended in cold ethanol (167 g) and separated by vacuum filtration (-10 °C). Subsequently, the temperature was raised to 5 °C and the crystalline solid was successively washed with aqueous Na2CO3 solution (668 g, 2% Na2CO3), aqueous citric acid solution (670 g, 1% citric acid) and water. The product was dried in vacuo (45 °C) to yield pure hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate (258.1 g) as an almost white free-flowing crystalline solid.

[0160] Composition of the pure product: 99.9% hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate, 190 ppm 1-hexanol, 250 ppm toluene, 6 ppm PSDHE, Gardner value 8.1.

[0161] Example 2

[0162] According to US2005 / 0165099, Example 2, hexanol-wetted pink crude hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate was prepared. The crude product was suction dried.

[0163] Composition of the crude product: 92% hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate, 8% solvent residues and impurities (81 ppm PSDHE, Gardner value >9).

[0164] The crude hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate (302.7 g) was dissolved in ethanol (630.1 g) at 50 °C and then cooled to 25 °C within 30 - 50 minutes (linear cooling ramp). Thereafter, a seed crystal of pure hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate (0.012 g) was added and the mixture was stirred at 25 °C for 5 - 10 minutes. After cooling to -10 °C (10 hours, linear cooling ramp), a crystal suspension was obtained and further stirred at -10 °C for 6 hours. The solid was separated by filtration at -10 °C. The crystals were suspended in cold ethanol (130 - 190 g) and separated by vacuum filtration (-10 °C, repeated four times). Subsequently, the temperature was raised to 5 °C and the crystalline solid was successively washed with an aqueous solution of Na2CO3 / sodium dodecylbenzenesulfonate (504 g, 2% Na2CO3, 0.007 g sodium dodecylbenzenesulfonate), an aqueous solution of citric acid (504 g, 1% citric acid), and water. The product was dried in vacuo (45 °C) to yield pure hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate (262.7 g) as an almost white, free-flowing crystalline solid.

[0165] Composition of the pure product: 99.9% hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate, 310 ppm 1-hexanol, 38 ppm toluene, 2 ppm PSDHE, Gardner value 8.3.

[0166] Example 3

[0167] According to US2005 / 0165099, Example 2, hexanol-wetted pink crude hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate was prepared. The crude product was dried in vacuo at 120 °C (rotary evaporator).

[0168] Composition of the crude product: 99.1% hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate, 0.5% 1-hexanol, 0.2% toluene, 39.4 ppm rhodamine B, 62 ppm PSDHE, Gardner value 9.

[0169] The crude hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate (448.7 g) was dissolved in ethanol (547.9 g) at 37 - 50 °C and then cooled from 37 °C to 25 °C over 70 minutes (linear cooling ramp). Thereafter, seeds of pure hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate (9.0 g) were added and the mixture was stirred at 25 °C for 220 minutes. After cooling to -10 °C (300 minutes, linear cooling ramp), a crystal suspension was obtained and further stirred at -10 °C for 6 - 8 hours. The solid was separated by filtration at -10 °C. The crystals were suspended in cold ethanol (330 g) and separated by vacuum filtration (-10 °C, repeated three times). The product was dried in vacuo (45 °C) to yield pure hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate (425.1 g) as an almost white free-flowing crystalline solid.

[0170] Composition of the pure product: 99.9% hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate, <10 ppm 1-hexanol, 10 ppm toluene, 0.8 ppm PSDHE, 0.8 ppm rhodamine B, Gardner value 7.0.

[0171] Example 4

[0172] According to US2005 / 0165099, Example 2, hexanol-wetted pink crude hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate was prepared. The crude product was dried in vacuo at 120 °C (rotary evaporator).

[0173] Composition of the crude product: 99.1% hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate, 0.5% 1-hexanol, 0.2% toluene, 39.4 ppm rhodamine B, 62 ppm PSDHE, Gardner value 9.

[0174] The crude hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate (449.0 g) was dissolved in ethanol (548.0 g) at 37 - 50 °C and then cooled from 37 °C to 25 °C over 70 minutes (linear cooling ramp). Thereafter, seeds of pure hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate (9.1 g) were added and the mixture was stirred at 25 °C for 220 minutes. After cooling to -10 °C (300 minutes, linear cooling ramp), a crystal suspension was obtained and further stirred at -10 °C for 6 - 8 hours. The solid was separated by filtration at -10 °C. The crystals were suspended in cold ethanol (452 g) and separated by vacuum filtration (-10 °C, repeated three times). The product was dried in vacuo (45 °C) to yield pure hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate (426.0 g) as an almost white, free-flowing crystalline solid.

[0175] Composition of the pure product: 99.7% hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate, <10 ppm 1-hexanol, 10 ppm toluene, 0.8 ppm PSDHE, 0.8 ppm rhodamine B, Gardner value 7.0.

[0176] Example 5

[0177] According to US2005 / 0165099, Example 2, hexanol-wetted pink crude hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate was prepared. The crude product was dried in vacuo at 120 °C (rotary evaporator).

[0178] Composition of the crude product: 98.5% hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate, 1.0% 1-hexanol, 0.1% toluene, 34.0 ppm rhodamine B, 80 ppm PSDHE, Gardner value 8.7.

[0179] Crude hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate (449.0 g) was dissolved in ethanol (550.1 g) at 37 - 50 °C and then cooled from 37 °C to 25 °C over 70 minutes (linear cooling ramp). Thereafter, seeds of pure hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate (9.0 g) were added and the mixture was stirred at 25 °C for 220 minutes. After cooling to -10 °C (300 minutes, linear cooling ramp), a crystal suspension was obtained and further stirred at -10 °C for 6 - 8 hours. The solid was separated by filtration at -10 °C. The crystals were suspended in cold ethanol (450 g) and separated by vacuum filtration (-10 °C, repeated three times). Subsequently, the temperature was raised to 5 - 10 °C and the crystalline solid was washed with water (750 g). The product was dried in vacuo (45 °C) to yield pure hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate (428.1 g) as an almost white free-flowing crystalline solid.

[0180] Composition of the pure product: 99.8% hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate, 30 ppm 1-hexanol, 7 ppm toluene, 0.9 ppm PSDHE, 0.6 ppm rhodamine B, Gardner value 7.1.

[0181] Example 6

[0182] According to US2005 / 0165099, Example 2, hexanol-wetted pink crude hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate was prepared. The crude product was dried in vacuo at 120 °C (rotary evaporator).

[0183] Composition of the crude product: 98.5% hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate, 1.0% 1-hexanol, 0.1% toluene, 34.0 ppm rhodamine B, 80 ppm PSDHE, Gardner value 8.7.

[0184] The crude hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate (449.0 g) was dissolved in 2-propanol (550 g) at 37 - 50 °C and then cooled from 37 °C to 25 °C over 70 minutes (linear cooling ramp). Thereafter, seeds of pure hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate (9.1 g) were added and the mixture was stirred at 25 °C for 220 minutes. After cooling to 0 °C (300 minutes, linear cooling ramp), a crystal suspension was obtained and further stirred at 0 °C for 6 - 8 hours. The solid was separated by filtration at 0 °C. The crystals were suspended in cold 2-propanol (307 - 338 g) and separated by vacuum filtration (-10 °C, repeated three times). Subsequently, the temperature was raised to 5 - 15 °C and the crystalline solid was washed with water (615 g). The product was dried in vacuo (45 °C) to yield pure hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate (432.4 g) as an almost white free-flowing crystalline solid.

[0185] Composition of the pure product: 99.8% hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate, 65 ppm 1-hexanol, 15 ppm toluene, 1.7 ppm PSDHE, 2.2 ppm rhodamine B, Gardner value 7.1.

Claims

1. A method for separating crystalline hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate, which comprises the following steps: a) Dissolving a mixture comprising hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate in a solvent having a boiling point of at most 110 °C to obtain a solution; b) Cooling the solution to a temperature of 20 to 40 °C; c) Optionally adding seeds of hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate to the solution; d) Cooling the solution to a temperature below 5 °C to obtain a suspension; e) Filtering the suspension to separate hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate in crystalline form.

2. The method according to claim 1, wherein the mixture in step a) comprises at least 85% by weight of hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate and at most 15% of impurities, including solvent residues of solvents having a boiling point greater than 110 °C and dialkyl phthalates, wherein the % by weight amounts are in each case based on the total weight of the mixture, preferably wherein the impurities comprise at most 14% by weight of 1-hexanol and 50 to 200 ppm of dialkyl phthalates based on the total weight of the mixture.

3. The method according to claim 1 or 2, wherein the solvent in step a) has a boiling point of at most 85 °C.

4. The method according to any one of claims 1-3, wherein the solvent in step a) is polar and / or selected from methanol, ethanol, 1-propanol and isopropanol.

5. The method according to any one of claims 1-4, wherein the mixture is dissolved in step a) at a temperature of 45 to 55 °C.

6. The method according to any one of claims 1-5, wherein in step b) the solution is cooled to a temperature of 25 to 30 °C over a period of at least 10 minutes.

7. The method according to any one of claims 1-6, wherein in step d) the solution is cooled to a temperature below -5 °C over a period of at least 3 hours, preferably at least 5 hours.

8. The method according to claim 6 or 7, wherein the cooling is effected at a linear or non-linear cooling rate.

9. The method according to any one of claims 1-8, wherein step d) further comprises stirring the resulting suspension at a temperature below 0 °C for at least 3 hours, preferably at least 6 hours.

10. The method according to any one of claims 1-9, wherein the method further comprises the following step: f) Washing the separated hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate with a solvent, optionally an aqueous base, optionally a surfactant and optionally water, preferably wherein the solvent is the same solvent as used in step a) of the method.

11. The method according to claim 10, wherein the aqueous base is a potassium carbonate or sodium carbonate solution, a potassium bicarbonate or sodium bicarbonate solution, a potassium hydroxide or sodium hydroxide solution or an ammonia solution.

12. The method according to claim 10 or 11, wherein the surfactant is selected from alkylbenzene sulfonates, sodium dodecyl sulfate, ammonium lauryl polyether sulfate, sodium dodecyl sulfosuccinate, cocamidopropyl betaine carboxyglycinate, decyl polyglucoside, cetearyl alcohol, stearyl alcohol, cocamidopropyl betaine, decyl glucoside, glyceryl cocoate, sodium cocoyl isethionate, almond glyceride, sodium dodecylsulfacetate, sodium lauroyl sarcosinate, sodium methyl cocoyl taurate, sucrose cocoate, polysorbate 20, polysorbate 80, and mixtures thereof, preferably wherein the surfactant is sodium dodecylbenzenesulfonate.

13. The method according to any one of claims 1-12, wherein the method further comprises the following steps: g) drying the separated hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate.

14. The method according to any one of claims 1-13, wherein the separated hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate has a purity of at least 99%, a dialkyl phthalate content of less than 15 ppm, a 1-hexanol content of less than 400 ppm, and a Gardner value of 8.3 or lower, preferably wherein the separated hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate has a purity of at least 99%, a dialkyl phthalate content of less than 1 ppm, a 1-hexanol content of less than 200 ppm, a Gardner value of 8.3 or lower, and a rhodamine content of less than 1 ppm.

15. Hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate, which has a purity of at least 99%, a dialkyl phthalate content of less than 15 ppm, a 1-hexanol content of less than 400 ppm, and a Gardner value of 8.3 or lower, preferably wherein the hexyl 2-(4'-diethylamino-2'-hydroxybenzoyl)benzoate has a purity of at least 99%, a dihexyl phthalate content of less than 5 ppm, a 1-hexanol content of less than 200 ppm, a Gardner value of 8.3 or lower, and a rhodamine content of less than 1 ppm.

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