Process for the production of a triazine derivative

Abstract

A process for the isolation of a compound of formula (I) wherein R, R1 and R2 are, each individually, a C1 -C18 linear or branched alkyl or a C5 - C12 cycloalkyl optionally substituted with one or more C1 -C4 alkyl; wherein the compound of formula (I) is isolated from a medium, wherein the medium comprises an ester and an ether.

Description

[0001] DSM IP Assets B.V. 2024P00028WO

[0002] PROCESS FOR THE PRODUCTION OF A TRIAZINE DERIVATIVE

[0003] Field of the invention

[0004]

[0001] The present invention relates to an improved process for the production of a triazine derivative, preferably diethylhexyl butamido triazone. The invention further relates to a composition comprising a triazine derivative, preferably diethylhexyl butamido triazone and to the use of such a composition.

[0005] Background of the invention

[0006]

[0002] Diethylhexyl butamido triazone, also known as “bis (2-Ethylhexyl) 4, 4’-((6-((4-(tert-butylcarbamoyl) phenyl) amino)- 1 , 3, 5-triazine-2, 4-diyl) diimino) dibenzoate”, “bis(2-ethylhexyl) 4,4’-[(6-{[4-(tert- butylcarbamoyl)phenyl]amino}-1 , 3, 5-triazine-2, 4-diyl) bis (azanediyl) dibenzoate” or “Iscotrizinol” and also abbreviated as “DBT”, is a UV-B filter used in sunscreen products and other cosmetic products.

[0007]

[0003] US5346691A relates to S-triazine derivatives as light stabilizers and claims compounds having formula (I): in which R , Ri and R2 can, each individually, be a Ci -Cis linear or branched alkyl or a C5 -C12 cycloalkyl optionally substituted with one or more Ci -C4 alkyl; and X can be oxygen or an -NH- group.

[0008]

[0004] US5346691A mentions that the claimed compounds can be prepared by reacting triazine derivatives of formula (III) wherein Z can be bromine or chlorine and R can be as described above with p-a mi no benzoic acid esters of formula (IV) wherein R1 can have the same meaning as R.

[0005] US5346691A states that the compounds of formulae (III) and (IV) are known or they can be prepared according to known methods. It is stated that the reaction can be carried out at a temperature from 50° to 200° C in a suitable solvent. As suitable solvents in which the reaction can be carried out are mentioned acetonitrile; ketones, such as acetone, methyl ethyl ketone; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane; aliphatic or aromatic hydrocarbons such as pentane, heptane, cyclohexane, benzene, toluene, xylene or mixtures thereof; aliphatic carboxylic acid esters such as ethyl acetate.

[0009]

[0006] In example 40 of US5346691A, the compound of example 30, a reaction product of trichlorotriazine and tert-butyl p-aminobenzamide, and 2-ethyl-exyl p-aminobenzoate from example 24 are stirred under reflux in xylene for 4 hour. Thereafter the xylene is distilled off and the residue is recrystallized from a toluene and hexane mixture. It is stated that a compound of formula (I) was obtained (R=(CH3)3C-, Ri =R2 =C4Hg-CH(C2 HS)--CH2 --; X=O) as a white substance with a melting point range m.p. 101 °-103° C.

[0010]

[0007] CN110229113 describes preparation methods for ultraviolet absorber HEB. In the examples of CN110229113 it is described that the reaction product is extracted with water and vacuum distilled to obtain a crude diethylhexylbutanamidotriazinone (HEB), which subsequently was recrystallized with a mixture of ethanol and water.

[0011]

[0008] CN105130918A describes a method for producing a UV absorber diethylhexylbutyramide triazon. In the examples of CN105130918A it is described that the reaction product is crystallized media comprising respectively MeOH, EtOH and hexane.

[0012]

[0009] EP2838885, also published as WO2013 / 156272, refers to processes for the preparation of trisubstituted 1 ,3,5-triazine involving the introduction of substituents onto the triazine ring in a suitable sequence by reacting a cyanuryl halide, generally cyanuryl chloride, with suitable pre -prepared amines. It is explained that with these prior art processes the products obtained may not have sufficient purity and other properties such as colour, odour and stability may be insufficient for use. EP2838886, also published as WO 2013 / 156270, in particular discusses the process of US5346691 and indicates there is a need for triazine derivatives with high purity at high yields and lower costs. EP2838886 1 WO 2013 / 156270 implies that this is partly due to the fact that it is almost impossible to obtain a product with a low content of the intermediate 2-ethylhexyl-4-aminobenzoate, used in the last step. According to the comparative examples in EP2838886 / WO 2013 / 156270, the process of US5346691 results in a product with a purity of 97.55%, and a 2-ethylhexyl-4-aminobenzoate content of 4800 ppm.

[0013]

[0010] EP2838885 / WO2013 / 156272 and EP28388861 WO 2013 / 156270 suggest an alternative process. EP2838886 1 WO 2013 / 156270 subsequently claims amongst others a diethylhexyl butamido triazone with a 2-ethylhexyl-4-aminobenzoate content ranging from 1 to 700 ppm. According to example 4 of EP2838886 I WO 2013 / 156270 a product with a chromatographic purity of 98.65%, comprising a 2-ethylhexy1-4- aminobenzoate content of 600 ppm is prepared.

[0011] Unfortunately the market has indicated that the product, obtainable via the methods of EP2838885 / WO2013 / 156272 and EP2838886 / WO 2013 / 156270 still suffers from an insufficient quality

[0014]

[0012] Hence, there remains a need for an improved process to produce a triazine derivative with high purity at high yields and acceptable costs. Desirably the produced triazine derivative would further have an economically acceptable odour.

[0015] Summary of the invention

[0016]

[0013] Inventors have now advantageously found an improved process to generate triazine derivatives with high purity and / or high yield and / or reduced smell.

[0017]

[0014] Accordingly, in a first aspect, the invention provides a process for the isolation of a compound of formula (I): wherein R, R1 and R2 are, each individually, a Ci -Cis linear or branched alkyl or a C5 -C12 cycloalkyl optionally substituted with one or more Ci -C4 alkyl; wherein the compound of formula (I) is isolated from a medium, wherein the medium comprises an ester and an ether.

[0018]

[0015] In a second aspect, the invention provides a process for the production of a compound of formula (I): wherein R, R1 and R2 are, each individually, a Ci -Cis linear or branched alkyl or a C5 -C12 cycloalkyl optionally substituted with one or more Ci -C4 alkyl; comprising the steps of:

[0019] (a) producing a compound of formula (I); and

[0020] (b) contacting the compound of formula (I) with and retrieving the compound of formula (I) from a medium, wherein the medium comprises an ester and an ether.

[0021]

[0016] Additionally, in a third aspect, the invention provides a composition comprising, based on the total weight of the composition: - equal to or more than 99.0 wt%, more preferably equal to or more than 99.5 wt%, most preferably equal to or more than 99.6 wt%, of a compound having formula (l-A):

[0022] (l-A) wherein R and Ri are, each individually, a Ci -Cis linear or branched alkyl or a C5 -C12 cycloalkyl optionally substituted with one or more Ci -C4 alkyl; and

[0023] - equal to or less than 300 ppm more preferably equal to or less than 250 ppm, of a p-aminobenzoic acid ester of formula (V)

[0024] In a fourth aspect the invention further provides a composition comprising:

[0025] - a compound having formula (l-A):

[0026] (I -A) wherein R and R1 are, each individually, a Ci -Cis linear or branched alkyl or a C5 -C12 cycloalkyl optionally substituted with one or more Ci -C4 alkyl; and

[0027] - a p-aminobenzoic acid ester of formula (V) wherein the composition comprises a weight ratio of the compound of formula (l-A) to the compound of formula (V) of equal to or more than 2000:1 , more preferably equal to or more than 3000:1 , even more preferably equal to or more than 3500:1 , still more preferably equal to or more than 4000:1 , yet more preferably equal to or more than 5000:1 and most preferably equal to or more than 10000:1 .

[0028]

[0017] Finally, in a sixth aspect, the invention provides the use of any one of the above compositions for the preparation of a cosmetic product, respectively a cosmetic product comprising the above composition. Detailed description of the invention

[0029] Definitions

[0030]

[0018] Unless defined otherwise or clearly indicated by context, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

[0031]

[0019] The articles “a” and “an” are used herein to refer to one or to more than one (i.e. to one or at least one) of the grammatical object of the article. By way of example, “an element” may mean one element or more than one element. When referring to a noun (e.g. a compound, an additive, etc.) in the singular, the plural is meant to be included. Thus, when referring to a specific moiety, e.g. a "compound", this means "at least one" of that compound, e.g. "at least one compound", unless specified otherwise.

[0032]

[0020] Throughout the present specification and the accompanying claims, all transitional phrases such as ‘comprising,’ ‘including,’ ‘carrying,’ ‘having,’ ‘containing,’ ‘involving,’ ‘holding,’ ‘composed of, and variations such as "comprises", "comprise", "includes" and "include" are to be interpreted inclusively and to be understood to be open-ended, i.e., to mean including but not limited to. That is, these words are intended to convey the possible inclusion of other elements or integers not specifically recited, where the context allows. Only the transitional phrases ‘consisting of and ‘consisting essentially of shall be closed or semiclosed transitional phrases, respectively.

[0033]

[0021] The term 'consisting essentially of as used herein means that the total amount of the listed ingredients ideally sums up to 100 wt. % (weight percent). It is however not excluded that small amount of impurities derived from the ingredients and / or the production process may be present.

[0034]

[0022] Unless explicitly indicated otherwise, the various embodiments of the invention described herein can be cross-combined.

[0035]

[0023] The terms "cosmetic composition ", “cosmetic product” or “cosmetic preparation” refer in the present document to a composition, respectively product or preparation, suitable for cosmetic purposes. Suitably a cosmetic composition, respectively product or preparation, is herein understood to be a composition, respectively product or preparation, for cosmetic, that is, non-therapeutic, use.

[0036]

[0024] More preferably the term "cosmetic composition " or “cosmetic preparation” refers in the present document to a composition which is applied to the surface of a mammalian keratinous tissue. The terms "cosmetic composition " or “cosmetic preparation” can comprise or consist of those cosmetic compositions as defined under the heading "Kosmetika" in Rompp Lexikon Chemie, 10th edition 1997, Georg Thieme Verlag Stuttgart, New York as well as to cosmetic compositions as disclosed in A. Domsch, "Cosmetic Compositions", Verlag fur chemische Industrie (ed. H. Ziolkowsky), 4thedition, 1992. More preferably the "cosmetic composition " or “cosmetic preparation” is a cosmetic preparation, respectively a cosmetic composition, that can be topically applied to mammalian keratinous tissue such as e.g. human skin or hair (including eyelashes, the eyebrows, the nails or the lips), particularly human skin. Hence, the cosmetic composition is preferably a topical composition.

[0037]

[0025] By a topical composition is herein understood a composition for, preferably external, use on keratinous tissue such as the skin.

[0026] The term “keratinous tissue" as used in this document refers to tissue containing keratine, more preferably it means the skin (body, face, contour of the eyes, scalp), head hair, eyelashes, eyebrows, bodily hairs, nails and / or lips. Preferably, the keratinous tissue is the skin and hair.

[0038]

[0027] The term cosmetically acceptable carrier herein refers to all carriers and / or diluents conventionally used in cosmetic preparations. Preferably the cosmetically acceptable carrier comprises or consists of water, oil or a combination of water and oil.

[0039] Compounds of formula (I)

[0040]

[0028] In the aspects of this invention, the compounds of formula (I) are suitably compounds wherein R, R1 and R2 are, each individually, a Ci -Cis linear or branched alkyl group or a C5 -C12 cycloalkyl group, optionally substituted with one or more Ci -C4 alkyl group(s). Examples of such a Ci -C4 alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tertbutyl.

[0041]

[0029] In all aspects and embodiments of this invention, preferably R is a Ci -Cis linear or branched alkyl group. Preferably R is not a cycloalkyl group. More preferably R is a Ci -Cs linear or branched alkyl, even more preferably R is a C2 -Ce linear or branched alkyl. Preferably R is a branched alkyl. Even more preferably R is a methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tertbutyl, n-pentyl, isopentyl, n-hexyl, isohexyl, n-heptyl, n-octyl, or ethylhexyl group. Still more preferably R is a methyl, ethyl, isopropyl, tert-butyl or ethylhexyl group. Most preferably R is a tert-butyl group.

[0042]

[0030] In all aspects and embodiments of this invention, R1 and R2 are, each individually, preferably a Ci - Cis linear or branched alkyl group. R1 and R2 are preferably not a cycloalkyl group. More preferably R1 and R2 are, each individually, a C4 -C12 linear or branched alkyl, even more preferably a Ce -C10 linear or branched alkyl. Still more preferably R1 and R2 are, each individually, a branched alkyl.

[0043]

[0031] In one preferred embodiment R1 and R2 are, each individually, methyl, isopropyl or tert-butyl. In such embodiment, more preferably both R1 and R2 are methyl or both R1 and R2 are isopropyl or both R1 and R2 are tert-butyl.

[0044]

[0032] In another preferred embodiment R1 and R2 are, each individually, a linear or branched butyl-, pentyl-, hexyl-, heptyl-, octyl-, nonyl-, decyl-, undecyl-, dodecyl-, tridecyl-, tetradecyl-, pentadecyl-, hexadecyl-, heptadecyl- or octadecyl- group. Even more preferably R1 and R2 are, each individually, a linear or branched hexyl-, heptyl-, octyl-, nonyl-, decyl- group. Of these, octyl-groups are most preferred. Still more preferably R1 and R2 are, each individually, a branched hexyl-, heptyl-, octyl-, nonyl-, decyl- group.

[0045] Preferably the branches in such branched Ce- alkyl groups are C1-4 alkyl groups, most preferably methyl or ethyl. Hence, even more preferably R1 and R2 are, each individually, chosen from the group consisting of methylpentyl-, methylhexyl-, methylheptyl-, methyloctyl-, methylnonyl-, ethylbutyl-, ethylpentyl- , ethylhexyl-, ethylheptyl-, ethyloctyl-. Most preferably R1 and R2 are, each individually, an ethylhexyl- group. Suitable examples of ethylhexyl- groups include 2-ethylhexyl- and 3-ethylhexyl-. More preferably R1 and R2 are an identical group. Most preferably both R1 and R2 are a 2-ethylhexyl-group.

[0046]

[0033] In one preferred embodiment, the compound of formula (I) is a compound wherein:

[0047] R is methyl-, isopropyl- tert-butyl-, or 2-ethylhexyl, and most preferably R is tert-butyl; and

[0048] R1 and R2 are both 2-ethylhexyl-.

[0049]

[0034] In a most preferred embodiment, the compound of formula (I) is a compound wherein:

[0050] R is tert-butyl-; and

[0051] R1 and R2 are both 2-ethylhexyl-.

[0052] In such preferred embodiment the compound of formula (I) is diethylhexyl butamido triazone.

[0053]

[0035] Most preferably the compound of formula (I) is diethylhexyl butamido triazone.

[0054] Isolation of a compound of formula (I)

[0055]

[0036] In a first aspect, the invention provides a process for the isolation of a compound of formula (I): wherein R, R1 and R2 are, each individually, a Ci -Cis linear or branched alkyl or a C5 -C12 cycloalkyl optionally substituted with one or more Ci -C4 alkyl; wherein the compound of formula (I) is isolated from a medium, wherein the medium comprises a mixture of an ester and an ether. Such a process advantageously yields an isolated composition comprising, consisting essentially of or consisting of the compound of formula (I).

[0056]

[0037] By isolation is herein preferably understood the separation of the compound of formula (I) from the medium. The compound of formula (I) may be isolated from the medium by any technique known by the skilled person to be suitable for isolation. More preferably the compound of formula (I) is isolated from the medium by filtration, evaporation, distillation, extraction, chromatography, crystallization, or a combination of one or more of these. More preferably the compound of formula (I) is isolated from the medium with the help of filtration, crystallization, vacuum evaporation and / or a combination of these. Most preferred are the methods as illustrated in the examples.

[0057]

[0038] Preferably the isolation, respectively separation, comprises the removal of the medium, such that the residual content of the medium in the isolated composition is equal to or less than 5.0 % w / w, more preferably equal to or less than 2.0 % w / w, and still more preferably equal to or less than 1 .0 % w / w, based on the total weight of the isolated composition. Even more preferably the isolation, respectively separation, comprises the removal of the medium, such that the residual content of the medium in the isolated composition is equal to or less than 5000 ppm (corresponding to equal to or less than 0.5 % w / w), more preferably equal to or less than 2000 ppm (corresponding to equal to or less than 0.2 % w / w), and still more preferably equal to or less than 1000 ppm (corresponding to equal to or less than 0.1 % w / w), based on the total weight of the isolated composition.

[0058]

[0039] More preferably such isolation, respectively separation, comprises the removal of the medium and / or compounds other than the compound of formula (I), such that the isolated composition comprises the compound of formula (I) in an amount of equal to or more than 95.0 % w / w, more preferably in an amount of equal to or more than 98.0 % w / w, and most preferably in an amount of equal to or more than 99.0 % w / w, based on the total weight of the isolated composition. There is no upper limit. However, for practical purposes such isolation, respectively separation, comprises the removal of the medium and / or compounds other than the compound of formula (I), such that the isolated composition comprises the compound of formula (I) in an amount of equal to or less than 100.0 %, based on the total weight of the isolated composition.

[0059]

[0040] Most preferably the isolated composition comprises, consists essentially of or consists of, based on the total weight of the isolated composition:

[0060] - in the range of equal to or more than 99.00 % w / w to less than 100.00 % w / w of the compound of formula (I); and

[0061] - in the range from equal to or more than 0.00% to equal to or less than 1 .00% of the medium and / or one or more compounds other than the compound of formula (I), more preferably equal to or more than 0.00% to equal to or less than 1 .00% of the medium.

[0062]

[0041] Preferably the isolation comprises contacting the compound of formula (I) with and retrieving the compound of formula (I) from the medium. More preferably, the isolation comprises dissolving the compound of formula (I) in and precipitating, crystallizing or re-crystallizing the compound of formula (I) from the medium.

[0063]

[0042] More preferably the compound of formula (I) is precipitated from, crystallized or re-crystallized in and / or washed with the medium. Most preferably the compound of formula (I) is dissolved in and precipitated from, crystallized or re-crystallized from the medium.

[0064]

[0043] The ether and ester compound(s) of the medium can be contacted with the compound of formula (I) simultaneously or sequentially. That is, the ether and ester compounds do not need to be immediately both present, as long as both ingredients are present together with the compound of formula (I) at least at one point in time.

[0065]

[0044] The isolation may therefore comprise, consist essentially of, or consist of a purification. Preferably the isolation in the aspects of the invention comprises the steps of:

[0066] - dissolving a raw material comprising the compound of formula (I) in an ester, preferably ethyl acetate; and - diluting the solution by addition of an ether, preferably di-isopropyl-ether, wherein the ether is preferably added in a volumetric or weight surplus to the ester, preferably according to the preferences listed below for the medium; and

[0067] - allowing the compound of formula (I) to precipitate.

[0068] During such isolation, optionally a further dilution by addition of an alkane, such as for example n-heptane, or cooling may be applied. Preferences for the ether and the ester are as described below for the medium.

[0045] More preferably the isolation in the aspects of the invention comprising the following substeps:

[0069] (1) dissolving the compound of formula (I) in the ester, preferably ethyl acetate, preferably at a temperature in the range from equal to or more than 25°C, more preferably from equal to or more than 35°C to equal to or less than 70°C, more preferably to equal to or less than 60°C; and

[0070] (2) subsequently adding the ether, preferably di-isoproyl ether, wherein the ether is preferably added in a volumetric or weight surplus to the ester, preferably according to the preferences listed below for the medium; and

[0071] (3) preferably reducing the temperature, allowing the compound of formula (I) to precipitate.

[0072]

[0046] The reduction of the temperature is herein also described as “cooling”. Preferably the temperature in substep (3) is reduced to a temperature below the temperature in substep (1), preferably a temperature in the range from equal to or more than 0°C, more preferably from equal to or more than 4°C, to equal to or less than 25°C, more preferably to equal to or less than 16°C.

[0073]

[0047] Suitably the ester in substep (1) and the ether in substep (2) can together form the medium from which the compound of formula (I) can be isolated.

[0074]

[0048] Substep (2) and substep (3) can advantageously be combined and / or carried out simultaneously. Such a combination of substep (2) and substep (3) advantageously allows for the precipitation and / or crystallization of the compound of formula (I) from the medium.

[0075]

[0049] In the above combination of substep (2) and substep (3) preferably first a first part of the ether is added, whereafter the temperature is reduced, and subsequently a second part of the ether is added. Advantageously the ether may be added continuously, semi-continuously, or stepwise. Also the temperature may be reduced continuously, semi-continuously or stepwise. The addition of the ether and the reduction in temperature may be carried out in parallel. It can be advantageous to add the ether, for example in a continuous manner, and to reduce the temperature, for example in a continuous manner, simultaneously.

[0076]

[0050] Following the above isolation from the medium, the compound of formula (I) may be washed, for example one, two, three, four or five times, with medium, preferably medium with a temperature below the temperature in substep (1), more preferably medium with a temperature in the range from equal to or more than 0°C, more preferably from equal to or more than 4°C to equal to or less than 25°C, more preferably to equal to or less than 16°C.

[0077]

[0051] Preferably the above contacting of the compound of formula (I) with and retrieving the compound of formula (I) from the medium is carried out under an inert atmosphere, more preferably under a nitrogen atmosphere. More preferably the contacting and retrieving from the medium comprises or consists of the dissolving in and precipitation and / or crystallization from the medium. Hence most preferably the dissolving in and precipitation, crystallization or recrystallization from the medium is carried out under an inert atmosphere, more preferably under a nitrogen atmosphere.

[0078]

[0052] The medium or any residue of the medium can be removed, preferably continuously, by a flow of nitrogen. Alternatively, the medium or any residue of the medium can be removed by applying a reduced pressure.

[0079]

[0053] Preferably the compound of formula (I) is dried. Preferably the compound of formula (I) is dried under vacuum or under an inert atmosphere, for example under a nitrogen atmosphere and / or a flow of nitrogen. During the drying the temperature may be raised again. More preferably the drying may be carried out at a temperature in the range from equal to or more than 30°C, more preferably from equal to or more than 40°C to equal to or less than 70°C, more preferably to equal to or less than 60°C.

[0080] The medium

[0081]

[0054] The medium may suitably comprise, consist essentially of, or consist of one or more esters and one or more ethers. The medium is preferably a liquid at a temperature of 20°C and a pressure of 1 bar. More preferably the medium is also a liquid at 30 °C and 1 bar. More preferably the medium is further a liquid -10 °C and 1 bar. Hence preferably the medium is at least liquid in the range from equal to or more than -10 °C to equal to or less than 30 °C, as determined at 1 bar (corresponding to 0.1 MPa).

[0082]

[0055] Preferred esters include C1-C10 alkyl esters of C1-C10 carboxylic acids. More preferably the ester is an aliphatic carboxylic acid ester, even more preferably a C1-C10 alkyl ester of an C1-C10 aliphatic carboxylic acid. More preferred esters are C1-C10 alkyl esters of methanoate, ethanolate (acetate), propanoate (propionate), butanoate, pentanoate and hexanoate and combinations thereof. More preferred are methyl, ethyl, propyl, butyl, pentyl and hexyl esters of C1-C10 carboxylic acids, more preferably C1-C5 carboxylic acids, and combinations thereof. Even more preferred are methyl, ethyl, propyl, butyl, pentyl and hexyl esters of a C1-C10 aliphatic carboxylic acid, more preferably a C1-C5 aliphatic carboxylic acid, and combinations thereof. Still more preferred are methyl ethanoate, ethyl ethanoate (ethyl acetate), propyl ethanoate, butyl ethanoate, methyl propanoate, ethyl propanoate, propyl propanoate, butyl propanoate and combinations thereof. Most preferably the ester(s) at least comprise ethyl acetate. Most preferably the ester is ethyl acetate.

[0083]

[0056] Preferably the one or more ether(s) is / are (a) dialkylether(s). Preferred ethers include C1-C10 dialkyl ethers. More preferably the one or more ethers are selected from the group consisting of dimethyl ether, methyl ethyl ether, diethyl ether, methyl n-propyl ether, ethyl n-propyl ether, methyl isopropyl ether, ethyl isopropyl ether, di-n-propyl ether, n-propyl isopropyl ether, diisopropylether, methyl n-butyl ether, ethyl n-butyl ether, n-propyl n-butyl ether, isopropyl n-butyl ether, di-n-butyl ether, methyl-isobutyl ether, ethyl isobutyl ether, n-prolyl isobutyl ether, isopropyl isobutyl ether, n-butyl isobutyl ether, di-isobutyl ether, methyl-tertbutyl ether (also abbreviated as MTBE), ethyl tertbutyl ether, n-prolyl tertbutyl ether, isopropyl tertbutyl ether, n-butyl tertbutyl ether, iso-butyl tertbutyl ether, di-tertbuty I ether and combinations thereof. Still more preferably the one or more ethers are selected from the group consisting of dimethylether, methylethylether, methyl-tertbutyl ether, diethylether, di-n-propylether, di-isopropyl ethe, di-tertbutyl-ether and combinations thereof. In one very preferred embodiment the ether is methyl-tertbutyl ether or di- isopropyl-ether or a combination thereof. In another very preferred embodiment the ether is diethylether or di-isopropyl-ether or a combination thereof. Most preferably the ether is di-isopropyl-ether (also abbreviated as “DI PE”).

[0084]

[0057] Preferably the medium therefore comprises, consists essentially of, or consists of ethyl acetate and di-isopropyl-ether.

[0085]

[0058] Preferably the medium comprises, based on the total volume of the medium, equal to or less than 10 vol.%, more preferably equal to or less than 5 vol. %, even more preferably equal to or less than 1 vol. %, still more preferably equal to or less than 0.5 vol. %,yet even more preferably equal to or less than 0.1 vol. % and still more preferably equal to or less than 0.05 vol. % of any aromatic solvent. More preferably the medium comprises, based on the total volume of the medium, equal to or less than 10 vol.%, more preferably equal to or less than 5 vol. %, even more preferably equal to or less than 1 vol. %, still more preferably equal to or less than 0.5 vol. %,yet even more preferably equal to or less than 0.1 vol. % and still more preferably equal to or less than 0.05 vol. % of, each individually, benzene, xylene or toluene. Most preferably the total sum of benzene, xylene and toluene in the medium is equal to or less than 10 vol.%, more preferably equal to or less than 5 vol. %, even more preferably equal to or less than 1 vol. %, still more preferably equal to or less than 0.5 vol. %, yet even more preferably equal to or less than 0.1 vol. % and still more preferably equal to or less than 0.05 vol. %, based on the total volume of the medium. Most preferably the medium comprises no or essentially no aromatic solvent.

[0086]

[0059] The medium may or may not comprise certain alkane compounds acting as co-solvent. Examples of such alkane compounds include Ci -Cis linear or branched alkanes. If present, preferred alkane compounds are C4-C10 alkanes, more preferably linear or branched hexane, heptane, octane or a mixture of such. If an alkane compound is present in the medium, a most preferred alkane compound is heptane, preferably n-heptane. Hence, in this preferred embodiment the medium most preferably comprises, consists essentially of, or consists of:

[0087] - an ether, preferably di-isopropyl-ether;

[0088] - an ester, preferably ethyl-acetate; and

[0089] - an alkane, preferably heptane.

[0090]

[0060] In another preferred embodiment the medium comprises, based on the total volume of the medium, equal to or less than 10 vol.%, more preferably equal to or less than 5 vol. %, even more preferably equal to or less than 1 vol. %, still more preferably equal to or less than 0.5 vol. %,yet even more preferably equal to or less than 0.1 vol. % and still more preferably equal to or less than 0.05 vol. % of any alkane solvent. In this embodiment the medium most preferably comprises no or essentially no alkane solvent.

[0061] In another preferred embodiment the medium comprises, based on the total volume of the medium, equal to or less than 10 vol.%, more preferably equal to or less than 5 vol. %, even more preferably equal to or less than 1 vol. %, still more preferably equal to or less than 0.5 vol. %,yet even more preferably equal to or less than 0.1 vol. % and still more preferably equal to or less than 0.05 vol. % of any solvent other than the ether and the ester.

[0091]

[0062] Preferably the medium is a medium that comprises the one or more esters and one or more ethers, wherein the ethers are present in a volumetric surplus to the esters. More preferably the medium is a medium that comprises the one or more ethers and one or more esters in a volume ratio of ethers to esters in the range from 1 :1 to 100:1 , more preferably in the range from 2:1 to 40:1 , even more preferably in the range from 3:1 to 30:1 , most preferably in the range from 4:1 to 25:1. In one preferred embodiment, the medium is a medium that comprises di-isopropyl-ether and one or more esters in a volume ratio of di- isopropyl-ether to esters in the range from 1 :1 to 100:1 , more preferably in the range from 2:1 to 40:1 , even more preferably in the range from 3:1 to 30:1 , most preferably in the range from 4:1 to 25:1. In another preferred embodiment the medium is a medium that comprises the one or more ethers and ethyl-acetate in a volume ratio of ethers to ethyl-acetate in the range from 1 :1 to 100:1 , more preferably in the range from 2:1 to 40:1 , even more preferably in the range from 3:1 to 30:1 , most preferably in the range from 4:1 to 25:1. Most preferably the medium is a medium that comprises di-isopropyl-ether and ethyl-acetate in a volume ratio of di-isopropyl-ether to ethyl-acetate in the range from 1 :1 to 100:1 , more preferably in the range from 2:1 to 40:1 , even more preferably in the range from 3:1 to 30:1 , most preferably in the range from 4:1 to 25:1 .

[0092]

[0063] Preferably the medium is a medium that comprises the one or more esters and one or more ethers, wherein the ethers are present in a weight surplus to the esters. More preferably the medium is a medium that comprises the one or more ethers and one or more esters in a weight ratio of ethers to esters in the range from 1 :1 to 100:1 , more preferably in the range from 2:1 to 40:1 , even more preferably in the range from 3:1 to 30:1 , most preferably in the range from 4:1 to 25:1 . In one preferred embodiment, the medium is a medium that comprises di-isopropyl-ether and one or more esters in a weight ratio of di-isopropyl-ether to esters in the range from 1 :1 to 100:1 , more preferably in the range from 2:1 to 40:1 , even more preferably in the range from 3:1 to 30:1 , most preferably in the range from 4:1 to 25:1 . In another preferred embodiment the medium is a medium that comprises the one or more ethers and ethyl-acetate in a weight ratio of ethers to ethyl-acetate in the range from 1 :1 to 100:1 , more preferably in the range from 2:1 to 40:1 , even more preferably in the range from 3:1 to 30:1 , most preferably in the range from 4:1 to 25:1 . Most preferably the medium is a medium that comprises di-isopropyl-ether and ethyl-acetate in a weight ratio of di-isopropyl- ether to ethyl-acetate in the range from 1 :1 to 100:1 , more preferably in the range from 2:1 to 40:1 , even more preferably in the range from 3:1 to 30:1 , most preferably in the range from 4:1 to 25:1 .

[0093]

[0064] Most preferably the medium is a medium that comprises, consists essentially of or consists of ethyl acetate and di-isopropyl-ether. More preferably the medium is a medium that comprises, consists essentially of, or consists of di-isopropyl-ether and ethyl acetate, wherein the di-isopropyl-ether is present in a volumetric surplus to the ethylacetate. Even more preferably the medium is a medium that that comprises, consists essentially of, or consists of di-isopropyl-ether and ethyl acetate in a volume ratio of di- isopropyl-ether to ethyl acetate in the range from 1 :1 to 100:1 , more preferably in the range from 2:1 to 40:1 , even more preferably in the range from 3:1 to 30:1 , most preferably in the range from 4:1 to 25:1. More preferably the medium is a medium that comprises, consists essentially of, or consists of di-isopropyl- ether and ethyl acetate, wherein the di-isopropyl-ether is present in a weight surplus to the ethylacetate. Even more preferably the medium is a medium that that comprises, consists essentially of, or consists of di-isopropyl-ether and ethyl acetate in a weight ratio of di-isopropyl-ether to ethyl acetate in the range from 1 :1 to 100:1 , more preferably in the range from 2:1 to 40:1 , even more preferably in the range from 3:1 to 30:1 , most preferably in the range from 4:1 to 25:1 .

[0094]

[0065] If the medium comprises one or more alkane solvent(s), such as heptane, the alkane solvent(s) is / are preferably present in a volumetric surplus or in a weight surplus to the ester(s). In such a case the medium can suitably be a medium that comprises, consists essentially of or consists of an ether, an ester and an alkane, wherein the medium comprises the one or more alkanes and one or more esters in a volume ratio of alkanes to esters in the range from 1 :1 to 100:1 , more preferably in the range from 2:1 to 40:1 , even more preferably in the range from 3:1 to 30:1 , most preferably in the range from 4:1 to 25:1 . In such a case, alternatively or additionally, the medium can suitably be a medium that comprises, consists essentially of or consists of an ether, an ester and an alkane, wherein the medium comprises the one or more alkanes and one or more esters in a weight ratio of alkanes to esters in the range from 1 :1 to 100:1 , more preferably in the range from 2:1 to 40:1 , even more preferably in the range from 3:1 to 30:1 , most preferably in the range from 4:1 to 25:1. Further, in such a case, the medium can suitably be a medium that comprises, consists essentially of or consists of an ether, an ester and an alkane, wherein the medium comprises the one or more alkanes and one or more ethers in a volume ratio of alkanes to ethers in the range from 0.1 :1 to 10:1 , more preferably in the range from 0.5:1 to 2:1 , even more preferably in the range from 0.9:1 to 1 :0.9. In such a case, alternatively or additionally, the medium can suitably be a medium that comprises, consists essentially of or consists of an ether, an ester and an alkane, wherein the medium comprises the one or more alkanes and one or more ethers in a weight ratio of alkanes to ethers in the range from 0.1 :1 to 10:1 , more preferably in the range from 0.5:1 to 2:1 , even more preferably in the range from 0.9:1 to 1 :0.9.

[0095]

[0066] Although the medium can contain other compounds, such as other solvents, preferably such other compounds are present, based on the total volume of the medium, in an amount of equal to or less than 10 vol.%, more preferably equal to or less than 5 vol. %, even more preferably equal to or less than 1 vol. %, still more preferably equal to or less than 0.5 vol. %,yet even more preferably equal to or less than 0.1 vol. % and still more preferably equal to or less than 0.05 vol. %. Most preferably the medium comprises no or essentially no aromatic solvent.

[0096]

[0067] If an alkane, such as a heptane is present, a preferred medium is a medium which, based on the total volume of the medium, comprises, consists essentially of, or consists of: - equal to or more than 1 to equal to or less than 30 vol.% of an ester, preferably ethyl acetate; and

[0097] - equal to or more than 10 to equal to or less than 60 vol.% of an ether, preferably di-isopropyl-ether; and

[0098] - equal to or more than 10 to equal to or less than 60 vol.%. of an alkane, preferably heptane; and

[0099] - optionally equal to or more than 0.0001 vol.% to equal to or less than 10 vol.%, more preferably equal to or less than 5 vol. %, even more preferably equal to or less than 1 vol. %, still more preferably equal to or less than 0.5 vol. %,yet even more preferably equal to or less than 0.1 vol. % and still more preferably equal to or less than 0.05 vol. % of another compound.

[0100] Suitably the volume percentages of ester, ether and alkane add up to 100%.

[0101] Alternatively or in addition, the medium could be a medium which, based on the total weight of the medium, comprises, consists essentially of, or consists of:

[0102] - equal to or more than 1 to equal to or less than 30 wt.% of an ester, preferably ethyl acetate; and

[0103] - equal to or more than 10 to equal to or less than 60 wt.% of an ether, preferably di-isopropyl-ether; and

[0104] - equal to or more than 10 to equal to or less than 60 wt.% of an alkane, preferably heptane; and

[0105] - optionally equal to or more than 0.0001 vol.% to equal to or less than 10 wt.%, more preferably equal to or less than 5 wt. %, even more preferably equal to or less than 1 wt. %, still more preferably equal to or less than 0.5 wt. %,yet even more preferably equal to or less than 0.1 wt. % and still more preferably equal to or less than 0.05 wt. % of another compound. Suitably the weight percentages of ester, ether and alkane add up to 100%.

[0106]

[0068] A preferred medium is a medium which, based on the total volume of the medium, comprises, consists essentially of or consists of:

[0107] - equal to or more than 1 to equal to or less than 50 vol.% , more preferably equal to or more than 1 to equal to or less than 30 vol.% of an ester, preferably ethyl acetate; and

[0108] - equal to or more than 50 to equal to or less than 99 vol.%., more preferably equal to or more than 70 to equal to or less than 99 vol.% of an ether, preferably di-isopropyl-ether; and

[0109] - optionally equal to or more than 0.0001 vol.% to equal to or less than 10 vol.%, more preferably equal to or less than 5 vol. %, even more preferably equal to or less than 1 vol. %, still more preferably equal to or less than 0.5 vol. %,yet even more preferably equal to or less than 0.1 vol. % and still more preferably equal to or less than 0.05 vol. % of another compound. Suitably the volume percentages of ester and ether add up to 100%.

[0110]

[0069] Alternatively or in addition, a preferred medium is a medium which, based on the total weight of the medium, comprises, consists essentially of or consists of:

[0111] - equal to or more than 1 to equal to or less than 50 wt.% , more preferably equal to or more than 1 to equal to or less than 30 wt.% of an ester, preferably ethyl acetate; and

[0112] - equal to or more than 50 to equal to or less than 99 wt.%., more preferably equal to or more than 70 to equal to or less than 99 wt.% of an ether, preferably di-isopropyl-ether; and

[0113] - optionally equal to or more than 0.0001 wt.% to equal to or less than 10 wt.%, more preferably equal to or less than 5 wt.%, even more preferably equal to or less than 1 wt.%, still more preferably equal to or less than 0.5 wt.%, yet even more preferably equal to or less than 0.1 wt.% and still more preferably equal to or less than 0.05 wt.% of another compound. Suitably the weight percentages of ester and ether add up to 100%.

[0114]

[0070] Preferably the medium comprises, consists essentially of, or consists of, one or more polar aprotic solvents. Preferably the medium comprises a polarity index in the range from equal to or more than 1 .0 to equal to or less than 5.0, more preferably in the range from equal to or more than 2.0 to equal to or less than 3.5, most preferably in the range from equal to or more than 2.1 to equal to or less than 2.9. Relative polarity is a measure of a solvent’s polarity compared to the polarity of water as a reference solvent (where the relative polarity of water is set at 1 .00). Preferably the medium comprises a relative polarity in the range from equal to or more than 0.100 to equal to or less than 0.500, more preferably in the range from equal to or more than 0.110 to equal to or less than 0.350, most preferably in the range from equal to or more than 0.110 to equal to or less than 0.290.

[0115] Production of a compound of formula (I)

[0116]

[0071] The compound of formula (I) can suitably be produced in any manner known by a person skilled in the art. For example, the compound of formula (I) can be prepared according to the processes of US5346691 , EP2838885, or EP2838886 or WO 2013 / 156270, whereafter the compound of formula (I) so prepared can be contacted with and retrieved from the medium, for example in a manner as described herein.

[0117]

[0072] Hence , the invention also provides a process for the production of a compound having formula (I), comprising the steps of:

[0118] (a) producing a compound of formula (I); and

[0119] (b) contacting the compound of formula (I) with and retrieving the compound of formula (I) from a medium, wherein the medium comprises an ester and an ether.

[0120] Further preferences for the compound of formula (I) and for the medium are as described herein above. Further preferences for step (b) are as described above for the isolation of the compounds of formula (I) and elsewhere in this disclosure.

[0121]

[0073] The compound of formula (I) may be produced in step (a) in a variety of manners. For example, above step (a) may comprise a process as described in US5346691 , EP2838885, or EP2838886 or WO 2013 / 156270.

[0122]

[0074] More preferably, step (a) comprises, and this invention independently provides, a process for the production of a compound of formula (I) comprising one or more of the reaction steps:

[0123] (i) reacting 4-nitrobenzoic acid with a chlorinating reagent, preferably thionylchloride, yielding 4- nitrobenzoylchloride; reacting such 4-nitrobenzoylchloride with an alkyl amine compound, wherein preferably the alkyl group in such alkyl amine is R, yielding a N-alkyl-4-nitro-benzamide compound; and hydrogenating such a N-alkyl-4-nitro-benzamide compound yielding a 4-amino-N-(alkyl) benzamide compound of formula (II); wherein R is a Ci -Cis linear or branched alkyl group or a C5 -C12 cycloalkyl group, optionally substituted with one or more Ci -C4 alkyl group(s); and / or

[0124] (ii) reacting a 4-amino-N-(alkyl) benzamide compound of formula (II) with a triazine derivative compound of formula (III) wherein Z is a leaving group, more preferably a bromine or chlorine group, yielding a substituted triazine compound of formula (IV) wherein Z is a leaving group, more preferably a bromine or chlorine group, and wherein R is a Ci -Cis linear or branched alkyl group or a C5 -C12 cycloalkyl group, optionally substituted with one or more Ci -C4 alkyl group(s); and / or

[0125] (iii) reacting a substituted triazine compound of formula (IV) with a p-aminobenzoic acid ester of formula

[0126] (V) and / or a p-aminobenzoic acid ester of formula (VI) wherein R1 and R2 are, each individually, a Ci -Cis linear or branched alkyl or a C5 -C12 cycloalkyl optionally substituted with one or more Ci -C4 alkyl, yielding a compound of formula (I).

[0075] Preferences for R, R1 and R2 are as described herein above and below. Preferences for leaving group Z are also as described herein above and below. Further preferences are as detailed further in the paragraphs above and below.

[0127]

[0076] If R2 is different from R1, the compound of formula (IV) is preferably first reacted solely with the compound of formula (V), more preferably in a mol ratio of the compound of formula (V) to the compound of formula (IV) in the range from equal to or more than 0.9:1 .0 to equal to or less than 1 .1 :1 .0, resulting in an intermediate compound. Hereafter such intermediate compound can be retrieved from the reaction mixture, optionally purified, and subsequently such intermediate compound can be reacted with the compound of formula (VI).

[0128]

[0077] More preferably, R2 is identical to R1 and step (a), respectively the above process, comprises a process for the production of a compound of formula (IA): wherein R and Ri are, each individually, a Ci -Cis linear or branched alkyl or a C5 -C12 cycloalkyl optionally substituted with one or more Ci -C4 alkyl.

[0129]

[0078] Most preferably the compound of formula (I) is diethylhexyl butamido triazone; and most preferably the p-aminobenzoic acid ester of formula (V) and / or the p-aminobenzoic acid ester of formula (VI) are 2- ethylhexyl-4-amino-benzoate.

[0130]

[0079] Further preferences for each of the reaction steps (i), (ii) and (iii) are provided below.

[0131] (i) Reaction yielding a compound having formula (II):

[0132]

[0080] The process according to the invention can comprise a reaction step (i) to produce a 4-amino-N- (alkyl) benzamide compound of formula (II):

[0133]

[0081] Preferences for group R are as described herein above for compounds of formula (I). Most preferably R is a tert-butyl group.

[0082] The 4-amino-N-(alkyl) benzamide of formula (II), such as applied in reaction step (II), can suitably be produced in any manner known by a person skilled in the art. Examples of such production routes are conveniently provided by US5346691 , incorporated herein by reference.

[0134]

[0083] In a preferred embodiment the 4-amino-N-(alkyl) benzamide of formula (II) is prepared by a process according to reaction step (i) above, more preferably a process comprising :

[0135] (i-a) reacting 4-nitrobenzoic acid with a chlorinating reagent, preferably thionylchloride, yielding 4- nitrobenzoylchloride;

[0136] (i-b) reacting the 4-nitrobenzoylchloride with an alkyl amine compound yielding a N-alkyl-4-nitro- benzamide compound; and

[0137] (i-c) hydrogenating such a N-alkyl-4-nitro-benzamide compound yielding a 4-amino-N-(alkyl) benzamide compound of formula (II).

[0138]

[0084] Above step (i-a) preferably comprises reacting 4-nitrobenzoic acid with a chlorinating reagent to produce 4-nitrobenzoylchloride of formula (VII).

[0139] Examples of suitable chlorinating reagents include thionyl chloride (SOCI2), phosphorus trichloride (PCI3), phosphorus pentachloride (PCI5) and sulfuryl chloride (SO2CI2). Phosgene, diphosgene or triphosgene can be used as chlorinating reagent, but are less preferred. Most preferably the chlorinating reagent is thionyl chloride.

[0140]

[0085] Above step (i-b) preferably comprises reacting a 4-nitrobenzoylchloride of formula (VII), preferably obtained from step (i-a), with an alkyl amine compound of formula (VIII)

[0141] R-NH2 (VIII) to produce an N-alkyl-4-nitro-benzamide compound of formula (IX)

[0142]

[0086] Above step (i-c) preferably comprises hydrogenating the N-alkyl-4-nitro-benzamide compound of formula (IX) to produce a 4-amino-N-(alkyl) benzamide compound of formula (II).

[0087] In the above reaction steps (i-a), (i-b) and (i-c), R is suitably as defined above, i.e. a Ci -Cis linear or branched alkyl group or a Cs -C12 cycloalkyl group, optionally substituted with one or more Ci -C4 alkyl group(s). Preferences for such group R are as mentioned herein above.

[0143]

[0088] Hence, step (a) as described above may preferably comprise a reaction step (i) wherein a 4-amino- N-(alkyl) benzamide compound of formula (II) is prepared by hydrogenating a N-alkyl-4-nitro-benzamide compound of formula (IX). The N-alkyl-4-nitro-benzamide compound of formula (IX), in turn, is preferably prepared by reacting a 4-nitrobenzoylchloride compound of formula (VII) with an alkyl amine compound of formula (VIII). The 4-nitrobenzoylchloride compound of formula (VII), in turn, is preferably prepared by reacting 4-nitrobenzoic acid with a chlorinating reagent, preferably thionylchloride.

[0144]

[0089] The above reactions (i-a) and / or (i-b) can suitably be carried out in the presence of a solvent, more preferably a solvent chosen from the group consisting of ketones, such as acetone, methyl ethyl ketone; ethers such as diethyl ether, diisopropyl ether, methyl-tertbutylether, tetra hydrofuran, dioxane; aliphatic or aromatic hydrocarbons such as pentane, heptane, cyclohexane, benzene, toluene, xylene or mixtures thereof; chloroalkanes such as dichloromethane; aliphatic carboxylic acid esters such as ethyl acetate, and mixtures of one or more of these.

[0145]

[0090] Preferably the reaction step (i-a) and / or the reaction step (i-b) is / are carried out in an aromatic solvent. More preferably the solvent in the above reaction step (i-a) and / or the reaction (i-b) comprises, consists essentially of or consists of toluene. Most preferably the solvent in the above reaction step (i-a) and the solvent in the reaction step (i-b) comprises, consists essentially of or consists of toluene. Preferably the reaction step (i-a) and / or the reaction step (i-b), more preferably both reaction step (i-a) and reaction step (i-b) are carried out in the absence of halogenated solvents. For example, preferably the reaction step (i-a) and / or the reaction step (i-b), more preferably both reaction step (i-a) and reaction step (i-b) are carried out in the absence of dichloromethane.

[0146]

[0091] More preferably the solvent in the reaction of 4-nitrobenzoic acid with the chlorinating reagent, preferably thionylchloride, is applied in a five-fold to thirty-fold volume in millilitres per weight in gram of respective 4-nitrobenzoic acid. That is, the volume in millilitres (v) of solvent, preferably toluene, per weight in gram (w) of respective 4-nitrobenzoic acid preferably lies in the range from equal to or more than 5 v / w to equal to or less than 30 v / w, more preferably in the range from equal to or more than 6 v / w to equal to or less than 20 v / w, even more preferably in the range from equal to or more than 6 v / w to equal to or less than 15 v / w.

[0147]

[0092] More preferably the solvent in the reaction of a 4-nitrobenzoylchloride compound of formula (VII) with an alkyl amine compound of formula (VIII) is applied in a five-fold to thirty-fold volume in millilitres per weight in gram of respective 4-nitrobenzoylchloride compound of formula (VII). That is, the volume in millilitres (v) of solvent, preferably toluene, per weight in gram (w) of respective compound of formula (VII) preferably lies in the range from equal to or more than 5 v / w to equal to or less than 30 v / w, more preferably in the range from equal to or more than 6 v / w to equal to or less than 20 v / w, even more preferably in the range from equal to or more than 6 v / w to equal to or less than 15 v / w.

[0093] The reaction (i-a) of a 4-nitrobenzoic acid with the chlorinating reagent, preferably thionyl chloride, can be carried out at a wide range of temperatures. However, preferably the reaction is carried out at a temperature in the range from equal to or more than 80 °C, more preferably from equal to or more than 90 °C, to equal to or less than 130 °C, more preferably to equal to or less than 120 °C. More preferably the reaction is carried out at the reflux temperature of the solvent. Most preferably the reaction of such 4- nitrobenzoic acid with the chlorinating reagent, preferably thionyl chloride, is carried out in toluene as a solvent at a temperature in the range from equal to or more than 105 °C to equal to or less than 115 °C.

[0148]

[0094] The reaction (i-b) of a 4-nitrobenzoylchloride compound of formula (VII) with an alkyl amine compound of formula (VIII) can be carried out at a wide range of temperatures. However, preferably the reaction is carried out at a temperature in the range from equal to or more than 15 °C, more preferably from equal to or more than 25 °C, to equal to or less than 50 °C, more preferably to equal to or less than 40 °C.

[0095] The reaction (i-a) of a 4-nitrobenzoic acid with the chlorinating reagent, preferably thionyl chloride, is preferably carried out with no or a mere moderate molar surplus of chlorinating reagent. Hence, the mol ratio of moles chlorinating reagent to moles 4-nitrobenzoic acid preferably lies in the range from equal to or more than 0.9:1 .0 to equal to or less than 2.0:1 .0, more preferably in the range from equal to or more than 1 .0:1 .0 to equal to or less than 1 .5:1.0, most preferably in the range from equal to or more than 1.1 : 1 .0 to equal to or less than 1 .2:1 .0. Without wishing to be bound by any kind of theory it is believed that such a mere moderate molar surplus of chlorinating reagent over 4-nitrobenzoic acid may result in a lower amount of impurities when the compound of formula (IV) is used to produce a compound of formula (I).

[0149]

[0096] The reaction (i-b) of a 4-nitrobenzoylchloride compound of formula (VII) with an alkyl amine compound offormula (VIII) is preferably carried out with a molar surplus of alkyl amine compound of formula (VIII). Hence, the mol ratio of moles alkyl amine compound of formula (VIII) to moles 4-nitrobenzoylchloride compound of formula (VII) preferably lies in the range from equal to or more than 1 .0:1.0 to equal to or less than 3.0:1 .0, more preferably in the range from equal to or more than 1 .1 :1 .O to equal to or less than 2.0:1 .0, most preferably in the range from equal to or more than 1 .2: 1 .0 to equal to or less than 1 .5:1 .0.

[0150]

[0097] In reaction (i-c) the N-alkyl-4-nitro-benzamide compound of formula (IX) wherein R is as defined above, i.e. a Ci -Cis linear or branched alkyl group or a Cs -C12 cycloalkyl group, optionally substituted with one or more Ci -C4 alkyl group(s), is hydrogenated.

[0151] Preferences for such group R are as mentioned herein above.

[0098] The hydrogenation reaction (i-c) is preferably carried out with the help of a catalyst, more preferably a palladium on carbon catalyst, a platinum on carbon catalyst or a Raney nickel catalyst. Most preferably the reaction step (i-c) comprises, consists essentially of, or consists of, hydrogenating of a N-alkyl-4-nitro- benzamide compound with the help of a Raney Nickel.

[0152] (ii) Reaction yielding a compound having formula (IV):

[0153]

[0099] The process according to the invention can comprise a reaction step (ii) to produce a substituted triazine compound of formula (IV) wherein Z is a leaving group, more preferably a bromine or chlorine group, and wherein R is a Ci -Cis linear or branched alkyl group or a Cs -C12 cycloalkyl group, optionally substituted with one or more Ci -C4 alkyl group(s).

[0154]

[0100] Preferences for group R are as described herein above for compounds of formula (I). Most preferably R is a tert-butyl group.

[0155]

[0101] Preferences for group Z are as described herein above. Most preferably Z is a chlorine group.

[0156]

[0102] The substituted triazine compound of formula (IV), such as applied in reaction step (iii), can suitably be produced in any manner known by a person skilled in the art. Examples of such production routes are conveniently provided by US5346691 , incorporated herein by reference.

[0157]

[0103] In a preferred embodiment the substituted triazine compound of formula (IV) is prepared by reacting a 4-amino-N-(alkyl) benzamide compound of formula (II) wherein R is as defined above, with a triazine derivative compound of formula (III) (HI) wherein Z is as defined above, to prepare the substituted triazine compound of formula (IV).

[0158]

[0104] Hence, step (a) as described above may preferably comprise a reaction step (ii) wherein a substituted triazine compound of formula (IV) is prepared by reacting a 4-amino-N-(alkyl) benzamide compound of formula (II) with a triazine derivative compound of formula (III).

[0159]

[0105] The above reaction can suitably be carried out in the presence of a solvent, more preferably a solvent chosen from the group consisting of acetonitrile; ketones, such as acetone, methyl ethyl ketone; ethers such as diethyl ether, diisopropyl ether, methyl-tertbutylether, tetra hydrofuran, dioxane; aliphatic or aromatic hydrocarbons such as pentane, heptane, cyclohexane, benzene, toluene, xylene or mixtures thereof; aliphatic carboxylic acid esters such as ethyl acetate, and mixtures of one or more of these.

[0160]

[0106] Preferably the reaction step (ii) is carried out in a polar aprotic solvent. More preferably the reaction step (ii) is carried out in a solvent comprising, consisting essentially of, or consisting of a ketone, more preferably acetone, methyl ethyl ketone, or a mixture thereof. Most preferably the solvent in reaction step (ii) comprises, consists essentially of, or consists of, an aliphatic ketone, preferably acetone. That is, preferably the reaction step (ii) is carried out in acetone as a solvent.

[0161]

[0107] The solvent in such a reaction of a 4-amino-N-(alkyl) benzamide compound of formula (II) with a triazine derivative compound of formula (III) is preferably applied in a five-fold to thirty-fold volume in millilitres per weight in gram of respective compound of formula (II). That is, the volume in millilitres (v) of solvent, preferably acetone, per weight in gram (w) of respective compound of formula (II) preferably lies in the range from equal to or more than 5 v / w to equal to or less than 30 v / w, more preferably in the range from equal to or more than 6 v / w to equal to or less than 20 v / w, even more preferably in the range from equal to or more than 8 v / w to equal to or less than 18 v / w, most preferably in the range from equal to or more than 11 v / w to equal to or less than 15 v / w.

[0162]

[0108] The reaction of a 4-amino-N-(alkyl) benzamide compound of formula (II) with a triazine derivative compound of formula (III) can be carried out at a wide range of temperatures. However, preferably such reaction is carried out at a temperature in the range from equal to or more than -30 °C, more preferably from equal to or more than -20 °C, most preferably from equal to or more than -15 °C, to equal to or less than 30 °C, more preferably to equal to or less than 0 °C, most preferably to equal to or less than -5 °C. More preferably the reaction is carried out at a temperature below 0 °C. It has advantageously been found that when carrying out such reaction at such a temperature below 0 °C, preferably below -5 °C, higher purities can be obtained. Most preferably the reaction is thus carried out at a temperature in the range from equal to or more than -15 °C to equal to or less than -5 °C.

[0163]

[0109] The invention therefore also provides a process for the production of a substituted triazine compound of formula (IV) wherein Z is a leaving group, more preferably a bromine or chlorine group, and wherein R is a Ci -Cis linear or branched alkyl or a C5 -C12 cycloalkyl optionally substituted with one or more Ci -C4 alkyl, wherein the process comprises reacting a 4-amino-N-(alkyl) benzamide compound of formula (II) wherein R is as defined above for the compound of formula (IV) with a triazine derivative compound of formula (III) wherein Z is as defined above for the compound of formula (IV), to prepare the substituted triazine compound of formula (IV), and wherein such reaction is carried out at a temperature in the range from equal to or more than -15 °C to equal to or less than -5 °C.

[0164] Preferably such reaction is carried out in a solvent comprising, consisting essentially of or consisting of acetone. Further preferences are as mentioned herein above for reaction step (ii) and / or the reaction of a 4-amino-N-(alkyl) benzamide compound of formula (II) with a triazine derivative compound of formula (III).

[0110] Preferably the triazine derivative compound of formula (III) is a compound wherein Z is a chlorine group.

[0165] Hence, preferably the triazine derivative compound of formula (III) is a trichlorotriazine (cyanuric chloride).

[0166] Such trichlorotriazine (cyanuric chloride) conveniently has the structure of formula (II IA)

[0167]

[0111] The 4-amino-N-(alkyl) benzamide compound of formula (II) is preferably applied in a molar surplus to the triazine derivative compound of formula (III). Hence, the mol ratio of moles of compound of formula

[0168]

[0111] to moles of compound of formula (II) preferably lies in the range from equal to or more than 0.95:1.0 to equal to or less than 1 .0:1.0, more preferably in the range from equal to or more than 0.97:1 .0 to equal to or less than 0.99:1.0. Without wishing to be bound by any kind of theory it is believed that such a slight molar surplus of the compound of formula (II) over the compound of formula (III) may result in a lower amount of impurities when the compound of formula (IV) is used to produce a compound of formula (I).

[0169]

[0112] The reaction in the above process, respectively in step (ii), can be carried out either in the absence or in the presence of a base, such as triethyl amine, alkali or alkaline-earth metal hydroxides, alkali metal bicarbonates or carbonates (such as sodium bicarbonate or sodium carbonate). Without wishing to be bound by any kind of theory it was found that the reaction works well in the absence of a base. Hence it is preferred the above process, respectively in step (ii), are carried out in the absence of a base, that is, in the absence of fer example triethyl amine, sodium carbonate, sodium bicarbonate or any other base.

[0170]

[0113] At the end of the reaction between the 4-amino-N-(alkyl) benzamide compound of formula (II) with the triazine derivative compound of formula (III), the reaction mixture is preferably quenched with chilled water, preferably to a temperature of equal to or below -10°C, more preferably to a temperature of equal to or below -12°C.

[0171] (iii) Reaction yielding a compound having formula (I):

[0172]

[0114] Conveniently the process according to the invention comprises a step (iii) wherein a compound of formula (I) is produced wherein R, R1 and R2 are, each individually, a Ci -Cis linear or branched alkyl or a C5 -C12 cycloalkyl optionally substituted with one or more Ci -C4 alkyl.

[0173]

[0115] Most preferably in the above R is a tert-butyl group and most preferably R1 and R2 are the same and are both ethylhexyl groups.

[0116] The compound of formula (I) can suitably be produced in any manner known by a person skilled in the art. Examples of such production routes are conveniently provided by US5346691 , incorporated herein by reference.

[0174]

[0117] In a preferred embodiment the compound of formula (I) is prepared by reacting a substituted triazine compound of formula (IV) wherein Z is a leaving group, more preferably a bromine or chlorine group, and wherein R is a Ci -Cis linear or branched alkyl group or a Cs -C12 cycloalkyl group, optionally substituted with one or more Ci -C4 alkyl group(s); with a p-a mi no benzoic acid ester of formula (V) and / or a p-a mi no benzoic acid ester of formula (VI) wherein R1 and R2 are, each individually, a Ci -Cis linear or branched alkyl or a C5 -C12 cycloalkyl optionally substituted with one or more Ci -C4 alkyl, yielding a compound of formula (I).

[0175]

[0118] The above reaction of the substituted triazine compound of formula (IV) with the p-aminobenzoic acid ester(s) can be carried out in the presence of a solvent, more preferably a solvent chosen from the group consisting of acetonitrile; ketones, such as acetone, methyl ethyl ketone; ethers such as diethyl ether, diisopropyl ether, methyl-tertbutylether, tetrahydrofuran, dioxane; aliphatic or aromatic hydrocarbons such as pentane, heptane, cyclohexane, benzene, toluene, xylene or mixtures thereof; aliphatic carboxylic acid esters such as ethyl acetate, and mixtures of one or more of these. More preferably the solvent is an ester, most preferably the solvent is ethylacetate.

[0176]

[0119] Preferably the reaction of the substituted triazine compound of formula (IV) with the p-aminobenzoic acid ester(s) is carried out in a solvent having a polarity index in the range from equal to or more than 2.0 to equal to or less than 7.0, more preferably in the range from equal to or more than 3.0 to equal to or less than 6.0. Preferably the solvent in reaction step (i) comprises a relative polarity in the range from equal to or more than 0.150 to equal to or less than 0.600, more preferably in the range from equal to or more than 0.200 to equal to or less than 0.500, most preferably in the range from equal to or more than 0.200 to equal to or less than 0.400.

[0177]

[0120] Still more preferably the above the reaction of the substituted triazine compound of formula (IV) with the p-aminobenzoic acid ester(s) is carried out using a solvent comprising, consisting essentially of, or consisting of an ester, even more preferably an aliphatic carboxylic acid ester. Preferences for such esters are as described above for the medium. Preferably the ester applied as a solvent in reaction step (i) is the same as the ester applied in the medium in step (b). Most preferably reaction step (i) is carried out using a solvent comprising, consisting essentially of, or consisting of ethyl acetate.

[0178]

[0121] The invention therefore also provides a process for the production of a compound of formula (I) wherein R, R1 and R2 are, each individually, a Ci -Cis linear or branched alkyl group or a C5 - C12 cycloalkyl group, optionally substituted with one or more Ci -C4 alkyl group(s) and wherein preferably R2 is R1, and most preferably R1 and R2 are an ethylhexyl group. comprising the reaction step of: reacting a substituted triazine compound of formula (IV) wherein Z is a leaving group, more preferably a bromine or chlorine group, and R is as described above for compounds of formula (I); with a p-a mi no benzoic acid ester of formula (V) and / or a p-a mi no benzoic acid ester of formula (VI) wherein R1 and R2 are as described above for compounds of formula (I) and most preferably R1 and R2 are, each individually, an ethylhexyl group. wherein the reaction is preferably carried out in a solvent comprising, consisting essentially of, or consisting of an ester; and / or wherein the reaction product or the compound of formula (I) is preferably contacted with and / or retrieved from a medium, wherein the medium comprises a mixture of an ester and an ether.

[0179] Preferences for such ester are as described above and elsewhere herein. Preferably such ester is an aliphatic carboxylic acid ester, most preferably ethylacetate. Other preferences for such a process are as described above and below.

[0180]

[0122] Preferably R1 and R2 are the same. Hence preferably the invention provides a process for the production of a compound having formula (l-A):

[0181] (I -A) wherein R and Ri are, each individually, a Ci -Cis linear or branched alkyl or a Cs -C12 cycloalkyl optionally substituted with one or more Ci -C4 alkyl; comprising: reacting a substituted triazine compound of formula (IV) wherein Z is a leaving group, more preferably a bromine or chlorine group, and R is as described above with a p-a mi no benzoic acid ester of formula (V)

[0182] H2N-A V-COOR1

[0183] (V) wherein R1 is as described above, wherein preferably the reaction is carried out in an ester as a solvent; and / or wherein the reaction product or the compound of formula (l-A) is preferably contacted with and / or retrieved from a medium, wherein the medium comprises a mixture of an ester and an ether.

[0184]

[0123] The solvent in such reaction of the substituted triazine compound of formula (IV) with the p- aminobenzoic acid ester(s) is preferably applied in a volumetric surplus to the compound of formula (IV). More preferably the solvent is applied in a five-fold to thirty-fold volume in millilitres per weight in gram of respective compound of formula (IV). That is, the volume in millilitres (v) of solvent per weight in gram (w) of respective compound of formula (IV) preferably lies in the range from equal to or more than 5 v / w to equal to or less than 30 v / w, more preferably in the range from equal to or more than 6 v / w to equal to or less than 20 v / w, even more preferably in the range from equal to or more than 8 v / w to equal to or less than 18 v / w, most preferably in the range from equal to or more than 10 v / w to equal to or less than 15 v / w.

[0185]

[0124] If R2 is identical to R1, the compound of formula (V) is preferably applied in a molar surplus to the compound of formula (IV). Hence, if R2 is identical to R1, the mol ratio between moles of compound of formula (V) to moles of compound of formula (IV) in the above process, respectively in step (iii), preferably lies in the range from equal to or more than 1.9:1 .0 to equal to or less than 3.0:1.0, more preferably in the range from equal to or more than 2.0:1 .0 to equal to or less than 2.5:1 .0.

[0125] The reaction in the above process, respectively in step (iii), can be carried out either in the absence or in the presence of acid acceptors (also referred to herein as a “base”), such as triethyl amine, alkali or alkaline-earth metal hydroxides, alkali metal bicarbonates or carbonates (such as sodium carbonate). Without wishing to be bound by any kind of theory it was found that the reaction works well in the absence of a base. Hence it is preferred the above process, respectively in step (iii), are carried out in the absence of a base, that is, in the absence of for example triethyl amine, sodium carbonate, sodium bicarbonate or any other base.

[0186]

[0126] The reaction in the above process, respectively in step (iii), can be carried out at a wide range of temperatures. Preferably the reaction in the above process, respectively in step (iii), is carried out at a temperature in the range from equal to or more than 55 °C, more preferably from equal to or more than 65 °C, to equal to or less than 120 °C, more preferably to equal to or less than 110 °C. More preferably the reaction in the above process, respectively in step (iii), is carried out at the reflux temperature of the solvent. Most preferably the reaction in the above process, respectively in step (iii), is carried out in ethylacetate as a solvent at a temperature in the range from equal to or more than 70 °C to equal to or less than 80 °C.

[0187]

[0127] The reaction in the above process, respectively in step (iii), can be carried out batch-wise, semi- continuously or continuously.

[0188]

[0128] Without wishing to be bound by any kind of theory it is believed that higher reaction temperatures allow for shorter reaction times. Preferably the reaction time in the above process, respectively in step (iii), lies in the range from equal to or more than 6 hours to equal to or less than 48 hours.

[0189] Purified compound of formula (I)

[0190]

[0129] The processes of the invention advantageously allow for a very pure compound of formula (I), more preferably a very pure diethylhexyl butamido triazone, to be obtained. In addition, as illustrated by the examples, the processes of the invention advantageously allow for a product, suitably a high purity product, that suitably was not difficult to filter.

[0191]

[0130] The processes of the invention advantageously may allow for a compound of formula (I), more preferably diethylhexyl butamido triazone, having a particle size in the range from equal to or more than 1 micrometer, more preferably from equal to or more than 10 micrometer, even more preferably from equal to or more than 100 micrometer, to equal to or less than 400 micrometer, more preferably equal to or less than 300 micrometer. The particle size may suitably be determined by granulometric analysis with a Ro- Tap Sieve Shaker. This compound of formula (I) having such particle size may suitably be obtained or obtainable with the processes of the invention,

[0192]

[0131] In a preferred embodiment the particle size of the compound of formula (I), more preferably diethylhexyl butamido triazone, is determined by sieve analysis with a 50 mesh filter, where the particle size would be a 50 mesh particle size (i.e. a particle size retained on a filter of 50 mesh).

[0193]

[0132] In another preferred embodiment the particle size of the compound of formula (I), more preferably diethylhexyl butamido triazone, is determined by granulometric analysis with a Ro-Tap Sieve Shaker, and the particle size preferably lies in the range from equal to or more than 1 micrometer, more preferably from equal to or more than 10 micrometer, even more preferably from equal to or more than 100 micrometer, to equal to or less than 400 micrometer, more preferably equal to or less than 300 micrometer.

[0194]

[0133] The invention therefore also provides a composition comprising, based on the total weight of the composition:

[0195] (1) equal to or more than 99.0 wt%, more preferably equal to or more than 99.5 wt%, most preferably equal to or more than 99.6 wt%, of a compound of formula (I): wherein R, R1 and R2are, each individually, a Ci -Cis linear or branched alkyl group or a C5 -C12 cycloalkyl group, optionally substituted with one or more Ci -C4 alkyl group(s) and preferably R2is identical to R1; and

[0196] (2) equal to or less than 300 ppm more preferably equal to or less than 250 ppm of a total amount of p-aminobenzoic acid ester of formula (V) and p-a mi no benzoic acid ester of formula (VI) wherein R1 and R2are as defined above.

[0197]

[0134] More preferably the invention provides a composition comprising, based on the total weight of the composition:

[0198] (1) equal to or more than 99.0 wt%, more preferably equal to or more than 99.5 wt%, most preferably equal to or more than 99.6 wt%, of a compound of formula (I): wherein R, Ri and R2are, each individually, a Ci -Cis linear or branched alkyl group or a C5 -C12 cycloalkyl group, optionally substituted with one or more Ci -C4 alkyl group(s) and preferably R2is identical to R1; and

[0199] (2) no p-ammobenzoic acid ester of formula (V) and / or no p-ammobenzoic acid ester of formula (VI), or , if present, p-aminobenzoic acid ester of formula (V) and / or p-aminobenzoic acid ester of formula (VI) in an amount in the range from equal to or more than 0.1 ppmw (parts per million weight) to equal to or less than 300 ppmw more preferably equal to or less than 250 ppmw of a total amount of p-aminobenzoic acid ester of formula (V) and p-aminobenzoic acid ester of formula (VI) wherein Ri and R2 are as defined above.

[0200]

[0135] Preferences for R, R1 and R2 are as described above. Most preferably in the above R is a tert-butyl group and most preferably R1 and R2 are the same and are both ethylhexyl groups.

[0201]

[0136] Even more preferably R is a tert-butyl group and most preferably R1 and R2 are the same and are both ethylhexyl groups.

[0202]

[0137] Most preferably the compound of formula (I) is diethylhexyl butamido triazone; and most preferably the p-aminobenzoic acid ester of formula (V) and / or p-aminobenzoic acid ester of formula (VI) are 2- ethylhexyl-4-amino-benzoate.

[0203]

[0138] As illustrated by the examples, the processes according to the invention - most preferably processes wherein the medium comprises, consists essentially of, or consists of ethyl acetate and di- isopropyl-ether - advantageously allow for a high purity product that was not difficult to filter. Further preferences for the process, respectively further preferences for the medium are as already described above. The invention therefore also advantageously provides a product, preferably a composition comprising a compound of formula (I), obtained or obtainable by a process as claimed herein.

[0204]

[0139] More preferably the invention provides a composition comprising, based on the total weight of the composition:

[0205] (1) equal to or more than 99.0 wt%, more preferably equal to or more than 99.5 wt%, most preferably equal to or more than 99.6 wt%, of a compound of formula (I): wherein R, R1 and R2 are, each individually, a Ci -Cis linear or branched alkyl group or a C5 -C12 cycloalkyl group, optionally substituted with one or more Ci -C4 alkyl group(s) and preferably R2 is identical to R1; and

[0206] (2) equal to or less than 300 ppm more preferably equal to or less than 250 ppm of a total amount of p-aminobenzoic acid ester of formula (V) and p-a mi no benzoic acid ester of formula (VI) wherein Ri and R2 are as defined above, wherein such composition is obtained or obtainable by means of a process as described herein, more preferably by: a process for the isolation of a compound of formula (I): wherein R, R1 and R2 are, each individually, a Ci -Cis linear or branched alkyl or a C5 -

[0207] C12 cycloalkyl optionally substituted with one or more Ci -C4 alkyl; wherein the compound of formula (I) is isolated from a medium, wherein the medium comprises an ester and an ether, more preferably wherein the medium comprises, consists essentially of, or consists of ethyl acetate and di-isopropyl-ether; and / or a process for the production of a compound of formula (I): wherein R, R1 and R2 are, each individually, a Ci -Cis linear or branched alkyl or a C5 -

[0208] C12 cycloalkyl optionally substituted with one or more Ci -C4 alkyl; comprising the steps of:

[0209] (a) producing a compound of formula (I); and

[0210] (b) contacting the compound of formula (I) with and retrieving the compound of formula (I) from a medium, wherein the medium comprises an ester and an ether, more preferably wherein the medium comprises, consists essentially of, or consists of ethyl acetate and di-isopropyl-ether.

[0211]

[0140] More preferably the invention provides a composition comprising, based on the total weight of the composition:

[0212] (1) equal to or more than 99.0 wt%, more preferably equal to or more than 99.5 wt%, most preferably equal to or more than 99.6 wt%, of a compound of formula (I): wherein R, Ri and R2 are, each individually, a Ci -Cis linear or branched alkyl group or a C5 -C12 cycloalkyl group, optionally substituted with one or more Ci -C4 alkyl group(s) and preferably R2 is identical to R1; and

[0213] (2) no p-aminobenzoic acid ester of formula (V) and / or no p-aminobenzoic acid ester of formula (VI), or , if present, p-aminobenzoic acid ester of formula (V) and / or p-aminobenzoic acid ester of formula (VI) in an amount in the range from equal to or more than 0.1 ppmw (parts per million weight) to equal to or less than 300 ppmw more preferably equal to or less than 250 ppmw of a total amount of p-aminobenzoic acid ester of formula (V) and p-aminobenzoic acid ester of formula (VI) wherein R1 and R2 are as defined above, wherein such composition is obtained or obtainable by means of a process as described herein, more preferably by: a process for the isolation of a compound of formula (I): wherein R, R1 and R2 are, each individually, a Ci -Cis linear or branched alkyl or a C5 -

[0214] C12 cycloalkyl optionally substituted with one or more Ci -C4 alkyl; wherein the compound of formula (I) is isolated from a medium, wherein the medium comprises an ester and an ether, more preferably wherein the medium comprises, consists essentially of, or consists of ethyl acetate and di-isopropyl-ether; and / or a process for the production of a compound of formula (I): wherein R, Ri and R2 are, each individually, a Ci -Cis linear or branched alkyl or a C5 -

[0215] C12 cycloalkyl optionally substituted with one or more Ci -C4 alkyl; comprising the steps of:

[0216] (a) producing a compound of formula (I); and

[0217] (b) contacting the compound of formula (I) with and retrieving the compound of formula (I) from a medium, wherein the medium comprises an ester and an ether, more preferably wherein the medium comprises, consists essentially of, or consists of ethyl acetate and di-isopropyl-ether.

[0218]

[0141] As mentioned before, in a preferred embodiment the above compositions have a particle size as determined by sieve analysis with a 50 mesh filter, wherein the particle size is a 50 mesh particle size.

[0219]

[0142] In another preferred embodiment the above compositions have a particle size, as determined by granulometric analysis with a Ro-Tap Sieve Shaker, wherein the particle size lies in the range from equal to or more than 1 micrometer, more preferably from equal to or more than 10 micrometer, even more preferably from equal to or more than 100 micrometer, to equal to or less than 400 micrometer, more preferably equal to or less than 300 micrometer.

[0220]

[0143] In a preferred embodiment the compound of formula (I) is diethylhexyl butamido triazone and the p-aminobenzoic acid ester of formula (V) and / or p-aminobenzoic acid ester of formula (VI) is 2-ethylhexyl- 4-amino-benzoate.

[0221]

[0144] In an especially preferred embodiment, the invention therefore provides a composition comprising, based on the total weight of the composition:

[0222] (1) equal to or more than 99.0 wt%, more preferably equal to or more than 99.5 wt%, most preferably equal to or more than 99.6 wt% of diethylhexyl butamido triazone; and

[0223] (2) no 2-ethylhexyl-4-amino-benzoate, or, if present, 2-ethylhexyl-4-amino-benzoate in an amount in the range from equal to or more than 0.1 ppmw (parts per million weight) to equal to or less than 300 ppmw more preferably equal to or less than 250 ppmw.

[0224]

[0145] More preferably a composition comprising, based on the total weight of the composition:

[0225] (1) equal to or more than 99.0 wt%, more preferably equal to or more than 99.5 wt%, most preferably equal to or more than 99.6 wt% of diethylhexyl butamido triazone; and

[0226] (2) no 2-ethylhexyl-4-amino-benzoate, or, if present, 2-ethylhexyl-4-amino-benzoate in an amount in the range from equal to or more than 0.1 ppmw (parts per million weight) to equal to or less than 300 ppmw more preferably equal to or less than 250 ppmw. wherein such composition is obtained or obtainable by means of a process as described herein, more preferably by: a process forthe isolation of diethylhexyl butamido triazone wherein diethylhexyl butamido triazone is isolated from a medium, wherein the medium comprises an ester and an ether, more preferably wherein the medium comprises, consists essentially of, or consists of ethyl acetate and di- isopropyl-ether; and / or a process for the production of diethylhexyl butamido triazone comprising the steps of:

[0227] (a) producing diethylhexyl butamido triazone; and

[0228] (b) contacting the diethylhexyl butamido triazone with and retrieving the diethylhexyl butamido triazone from a medium, wherein the medium comprises an ester and an ether, more preferably wherein the medium comprises, consists essentially of, or consists of ethyl acetate and di- isopropyl-ether.

[0229]

[0146] As mentioned before, in a preferred embodiment also these compositions preferably have a particle size as determined by sieve analysis with a 50 mesh filter, wherein the particle size is a 50 mesh particle size.

[0230]

[0147] In another preferred embodiment the above compositions have a particle size, as determined by granulometric analysis with a Ro-Tap Sieve Shaker, wherein the particle size lies in the range from equal to or more than 1 micrometer, more preferably from equal to or more than 10 micrometer, even more preferably from equal to or more than 100 micrometer, to equal to or less than 400 micrometer, more preferably equal to or less than 300 micrometer.

[0231]

[0148] In an especially preferred embodiment, the invention provides a composition comprising, consisting essentially of or consisting of: diethylhexyl butamido triazone; and

[0232] 2-ethylhexyl-4-amino-benzoate wherein preferably the composition comprises equal to or more than 99.0 wt%, more preferably equal to or more than 99.5 wt%, most preferably equal to or more than 99.6 wt% of diethylhexyl butamido triazone; and wherein preferably the weight ratio of weight diethylhexyl butamido triazone to weight 2-ethylhexyl-4-amino- benzoate is equal to or more than 3000:1 , more preferably wherein the weight ratio of weight diethylhexyl butamido triazone to weight 2-ethylhexyl-4-amino-benzoate lies in the range from equal to or more than 2000:1 , more preferably equal to or more than 3000:1 , even more preferably equal to or more than 3500:1 , still more preferably equal to or more than 4000:1 , yet more preferably equal to or more than 5000:1 , yet even more preferably equal to or more than 9000:1 and most preferably equal to or more than 10000:1 to equal to or less than 1000000:1 , suitably equal to or less than 100000.

[0149] In a further especially preferred embodiment, the invention provides a composition comprising, consisting essentially of or consisting of: diethylhexyl butamido triazone; and

[0233] 2-ethylhexyl-4-amino-benzoate

[0234] Wherein preferably the composition comprises equal to or more than 99.0 wt%, more preferably equal to or more than 99.5 wt%, most preferably equal to or more than 99.6 wt% of diethylhexyl butamido triazone; and wherein preferably the mole ratio of mole diethylhexyl butamido triazone to mole 2-ethylhexyl-4-amino- benzoate is equal to or more than 3000:1 , more preferably wherein the mole ratio of mole diethylhexyl butamido triazone to mole 2-ethylhexyl-4-amino-benzoate lies in the range from equal to or more than 2000:1 , more preferably equal to or more than 3000:1 , even more preferably equal to or more than 3500:1 , still more preferably equal to or more than 4000:1 , yet more preferably equal to or more than 5000:1 , yet even more preferably equal to or more than 9000:1 and most preferably equal to or more than 10000:1 to equal to or less than 1000000:1 , suitably equal to or less than 100000.

[0235] Preferably such compositions are obtained or obtainable by means of a process as described herein, more preferably by: a process forthe isolation of diethylhexyl butamido triazone wherein diethylhexyl butamido triazone is isolated from a medium, wherein the medium comprises an ester and an ether, more preferably wherein the medium comprises, consists essentially of, or consists of ethyl acetate and di- isopropyl-ether; and / or a process for the production of diethylhexyl butamido triazone comprising the steps of:

[0236] (a) producing diethylhexyl butamido triazone; and

[0237] (b) contacting the diethylhexyl butamido triazone with and retrieving the diethylhexyl butamido triazone from a medium, wherein the medium comprises an ester and an ether, more preferably wherein the medium comprises, consists essentially of, or consists of ethyl acetate and di- isopropyl-ether.

[0238]

[0150] As mentioned before, in a preferred embodiment also these compositions preferably have a particle size as determined by sieve analysis with a 50 mesh filter, wherein the particle size is a 50 mesh particle size.

[0239]

[0151] In another preferred embodiment the above compositions have a particle size, as determined by granulometric analysis with a Ro-Tap Sieve Shaker, wherein the particle size lies in the range from equal to or more than 1 micrometer, more preferably from equal to or more than 10 micrometer, even more preferably from equal to or more than 100 micrometer, to equal to or less than 400 micrometer, more preferably equal to or less than 300 micrometer.

[0152] The invention further advantageously provides the use of the above composition for the preparation of a cosmetic product and a cosmetic product comprising the above composition. Preferences for such a cosmetic product are provided below.

[0240] Cosmetic compositions

[0241]

[0153] The compound of formula (I) may advantageously be used in a cosmetic composition.

[0242]

[0154] The invention therefore also provides a composition, preferably a cosmetic composition, comprising:

[0243] - a compound of formula (I):

[0244] HN- zb- COOR2

[0245] (I) wherein R, Ri and Rz are, each individually, a Ci -Cis linear or branched alkyl group or a Cs -C12 cycloalkyl group, optionally substituted with one or more Ci -C4 alkyl group(s) and preferably R2 is identical to R1; and

[0246] - a p-aminobenzoic acid ester of formula (V) and / or a p-aminobenzoic acid ester of formula (VI) wherein the weight ratio of weight of compound of formula (I) to the sum of weight of p-aminobenzoic acid ester of formula (V) and p-aminobenzoic acid ester of formula (VI) is equal to or more than 2000:1 , more preferably equal to or more than 3000:1 , even more preferably equal to or more than 3500:1 , still more preferably equal to or more than 4000:1 , yet more preferably equal to or more than 5000:1 , yet even more preferably equal to or more than 9000:1 and most preferably equal to or more than 10000:1 . There is no upper limit for the weight ratio but for practical purposes the weight ratio may be equal to or less than 1000000:1 , suitably equal to or less than 100000.

[0247]

[0155] More preferably the invention thus also provides a composition, preferably a cosmetic composition, comprising:

[0248] - a compound of formula (I): wherein R, Ri and R2 are, each individually, a Ci -Cis linear or branched alkyl group or a C5 -C12 cycloalkyl group, optionally substituted with one or more Ci -C4 alkyl group(s) and preferably R2 is identical to R1; and

[0249] - a p-aminobenzoic acid ester of formula (V) and / or a p-aminobenzoic acid ester of formula (VI) wherein the weight ratio of weight of compound of formula (I) to the sum of weight of p-aminobenzoic acid ester of formula (V) and p-aminobenzoic acid ester of formula (VI) lies in the range from equal to or more than 2000:1 , more preferably equal to or more than 3000:1 , even more preferably equal to or more than 3500:1 , still more preferably equal to or more than 4000:1 , yet more preferably equal to or more than 5000:1 , yet even more preferably equal to or more than 9000:1 and most preferably equal to or more than 10000:1 to equal to or less than 1000000:1 , suitably equal to or less than 100000.

[0250]

[0156] The weight ratio can conveniently be calculated as :

[0251] [weight of compound of formula (I)] / [weight of p-aminobenzoic acid ester of formula (V) + weight of p- aminobenzoic acid ester of formula (VI)]

[0252]

[0157] This may also conveniently be illustrated by the formula:

[0253]

[0158] Preferences for R, R1 and R2 are as described above. Most preferably in the above R is a tert-butyl group and most preferably R1 and R2 are the same and are both ethylhexyl groups. Most preferably the compound of formula I is diethylhexyl butamido triazone. Most preferably the p-aminobenzoic acid ester of formula (V) and / or p-aminobenzoic acid ester of formula (VI) is 2-ethylhexyl 4-amino benzoate.

[0254]

[0159] Preferences for the particle size are as described above.

[0255]

[0160] More preferably therefore the invention therefore also provides a composition, preferably a cosmetic composition, comprising: diethylhexyl butamido triazone; and

[0256] 2-ethylhexyl-4-amino-benzoate wherein the weight ratio of weight of diethylhexyl butamido triazone to weight of 2-ethylhexyl-4-amino- benzoate is equal to or more than 2000:1 , more preferably equal to or more than 3000:1 , even more preferably equal to or more than 3500:1 , still more preferably equal to or more than 4000:1 , yet more preferably equal to or more than 5000:1 , yet even more preferably equal to or more than 9000:1 and most preferably equal to or more than 10000:1. There is no upper limit for the weight ratio but for practical purposes the weight ratio may be equal to or less than 1000000:1 , suitably equal to or less than 100000.

[0257]

[0161] More preferably the invention thus also provides a composition, preferably a cosmetic composition, comprising: diethylhexyl butamido triazone; and

[0258] 2-ethylhexyl-4-amino-benzoate wherein the weight ratio of weight of diethylhexyl butamido triazone to weight of 2-ethylhexyl-4-amino- benzoate lies in the range from equal to or more than 2000:1 , more preferably equal to or more than 3000:1 , even more preferably equal to or more than 3500:1 , still more preferably equal to or more than 4000:1 , yet more preferably equal to or more than 5000:1 , yet even more preferably equal to or more than 9000:1 and most preferably equal to or more than 10000:1 to equal to or less than 1000000:1 , suitably equal to or less than 100000.

[0259]

[0162] Preferably the above composition is a cosmetic composition. More preferably the above composition is a topical composition. Preferably the composition is a non-therapeutic composition.

[0260]

[0163] The above composition can for example be an ingredient composition, more preferably a cosmetic ingredient composition. By an “ingredient composition”, also referred to sometimes as an “ingredient premix”, is herein preferably understood a blend of a specific ingredient, more preferably a cosmetically active ingredient, with one or more other ingredients. Such one or more other ingredients may for example help to dissolve, stabilize and / or preserve such an specific, preferably cosmetically active, ingredient. Such a blend may advantageously make it more easy to allow the specific, preferably cosmetically active, ingredient to be supplied by an ingredient manufacturer to the producer of a certain (end-)product, such as a personal care end-product. Such a “personal care end-product” can for example be a product that is supplied by the producer of the end-product to a consumer, for example to beautify the face or body of such consumer.

[0261]

[0164] More preferably the above composition is a cosmetic product, preferably a personal care endproduct.

[0262]

[0165] More preferably the above composition is a topical cosmetic product, more preferably a topical cosmetic end-product.

[0263]

[0166] Preferably the cosmetic product is a skincare or suncare product, most preferably a sunscreen product.

[0264]

[0167] Preferably the composition is a non-therapeutic composition.

[0265]

[0168] Preferably such a cosmetic product comprises in the range from equal to or more than 1 wt% to equal to or less than 15 wt%, more preferably in the range from equal to or more than 2 wt% to equal to or less than 10 wt% of the compound of formula (I), preferably dimethylhexyl butamido triazone compound, based on the total weight of the cosmetic product.

[0266]

[0169] Advantageously the composition, respectively the cosmetic product, may comprise one or more other UV filters, in addition to the compound of formula (I), to achieve broad spectrum protection against sunlight. Preferred UV filters include Titanium Dioxide, Zinc Oxide, Benzophenone-3 (also referred to as Oxybenzone), Benzophenone-4 (also referred to as Sulisobenzone), Benzophenone-5, Butyl methoxydibenzoylmethane (also referred to as “BMDBM” or “Avobenzone”), Ethylhexyl Methoxycinnamate (also referred to as Octinoxate), Ethylhexyl Salicylate (also referred to as Octisalate), Homosalate, Octocrylene, Terephthalylidene Dicamphor Sulfonic Acid, Drometrizole Trisiloxane, Bis- Ethylhexyloxyphenol Methoxyphenyl Triazine (also referred to as Bemotrizinol or “BEMT”), Methylene Bis- Benzotriazolyl Tetramethylbutylphenol (also referred to as Bisoctrizole, “MBBT”” ), Diethylamino Hydroxybenzoyl Hexyl Benzoate (also referred to as “DHHB”), Ethylhexyl Triazone (also referred to as “EHT”), Polysilicone-15, Isoamyl p-Methoxycinnamate, Phenylbenzimidazole Sulfonic Acid, Bisdisulizole Disodium, Tris-Biphenyl Triazine and / or combinations of one or more of these.

[0267]

[0170] Some UV filters are currently under scrutiny or falling out of favor with consumers due to environmental and / or health concerns. The compositions of the invention therefore may or may not comprise UV filters such as octocrylene, oxybenzone, ethylhexyl methoxycinnamate (also referred to as octinoxate) and / or Isoamyl p-Methoxycinnamate. In a preferred embodiment the compositions according to the invention are therefore free of octocrylene and / or free of oxybenzone and / or free of ethylhexyl methoxycinnamate and / or free of isoamyl p-methoxycinnamate.

[0268]

[0171] Preferably the composition, respectively the cosmetic product, has an SPF of equal to or more than 20, more preferably equal to or more than 30.

[0269]

[0172] The cosmetic composition, respectively the cosmetic product, can conveniently be in the form of a liquid, lotion, cream or spray.

[0270]

[0173] Preferably the cosmetic compositions, respectively the cosmetic products, according to this invention comprise a cosmetically acceptable carrier. The term ‘cosmetically acceptable carrier’ (also referred to herein as carrier) refers to all vehicles / carriers conventionally used in cosmetic compositions, i.e. which are suitable for topical application to the keratinous tissue, have good aesthetic properties, are compatible with the actives present in the composition, and will not cause any unreasonable safety or toxicity concerns. Such carriers are well-known to one of ordinary skill in the art. The exact amount of carrier will depend upon the actual level of the actives (a) to (c) and any other optional ingredients that one of ordinary skill in the art would classify as distinct from the carrier (e.g., other active ingredients).

[0271]

[0174] In an advantageous embodiment, the cosmetic compositions, respectively the cosmetic products, according to the present invention comprise from about 50% to about 99%, preferably from about 60% to about 98%, more preferably from about 70% to about 98%, such as in particular from about 80% to about 95% of a carrier, based on the total weight of the cosmetic composition. In a particular advantageous embodiment, the carrier consists furthermore of at least 40 wt.-%, more preferably of at least 50 wt.-%, most preferably of at least 55 wt.-% of water, such as in particular of about 55 to about 90 wt.-% of water.

[0272]

[0175] The cosmetic compositions, respectively the cosmetic products, of the invention (including the carrier) may comprise conventional adjuvants and additives, such as preservatives / antioxidants, fatty substances / oils, organic solvents, silicones, thickeners, softeners, emulsifiers, antifoaming agents, aesthetic components such as fragrances, surfactants, fillers, anionic, cationic, nonionic or amphoteric polymers or mixtures thereof, propellants, acidifying or basifying agents, dyes, colorings / colorants, abrasives, absorbents, chelating agents and / or sequestering agents, essential oils, skin sensates, astringents, pigments or any other ingredients usually formulated into such compositions.

[0273]

[0176] In accordance with the present invention, the cosmetic compositions, respectively the cosmetic products, according to the invention may also comprise further cosmetically active ingredients conventionally used in cosmetic compositions. Exemplary active ingredients encompass skin lightening agents; additional UV-filters, agents for the treatment of hyperpigmentation; agents for the prevention or reduction of inflammation; firming, moisturizing, soothing, and / or energizing agents as well as agents to improve elasticity and skin barrier.

[0274]

[0177] Examples of cosmetic excipients, diluents, adjuvants, additives as well as active ingredients commonly used in the skin care industry which are suitable for use in the cosmetic compositions of the present invention are for example described in the International Cosmetic Ingredient Dictionary & Handbook by Personal Care Product Council (http: / / www.personalcarecouncil.org / ), accessible by the online INFO BASE (http: / / online.personalcarecouncil.org / jsp / Home.jsp), without being limited thereto.

[0275]

[0178] The cosmetic compositions, respectively the cosmetic products, according to the present invention can be in a wide variety of forms. Non limiting examples include simple solutions (e.g. aqueous, organic solvent, or oil based), emulsion or micro emulsion (in particular of oil-in-water (O / W) or water-in-oil (W / 0) type, silicone-in-water (Si / W) or water-in-silicone (W / Si) type, PIT-emulsion, multiple emulsion (e.g. of oil- in-water-in oil (O / W / O) or water-in-oil-in-water (W / O / W) type) or pickering emulsions), as well as solid forms (e.g. hydrogels, alcoholic gels, lipogels, sticks, flowable solids, or amorphous materials).

[0276]

[0179] If the cosmetic composition is an emulsion, such as in particular an 0 / W-, W / 0-, Si / W-, W / Si-, 0 / W / 0-, W / O / W- or a pickering emulsion, then the amount of the oily phase present in such cosmetic emulsions is preferably at least 10 wt.-%, such as in the range of 10 to 60 wt.-%, preferably in the range of 15 to 50 wt.-%, most preferably in the range of 15 to 40 wt.-%, based on the total weight of the composition.

[0277]

[0180] In one embodiment, the cosmetic compositions, respectively the cosmetic products, according to the present invention are advantageously in the form of an oil-in-water (O / W) emulsion comprising an oily phase dispersed in an aqueous phase in the presence of an O / W emulsifier. The preparation of such O / W emulsions is well known to a person skilled in the art.

[0278]

[0181] The cosmetic compositions, respectively the cosmetic products, according to the present invention advantageously comprise a preservative.

[0182] The cosmetic compositions, respectively the cosmetic products, according to the invention in general have a pH in the range of 3 to 10, preferably a pH in the range of 4 to 8 and most preferably a pH in the range of 5 to 8. The pH can easily be adjusted as desired with suitable acids, such as e.g. citric acid, or bases, such as sodium hydroxide (e.g. as aqueous solution), triethanolamine (TEA Care), Tromethamine (Trizma Base) and Aminomethyl Propanol (AMP-Ultra PC 2000), according to standard methods in the art.

[0279] Examples

[0280] Example 1 - preparation of 4-amino-N-(tert-butyl) benzamide

[0281]

[0183] In this example four consecutive batches (“1-a”, “1-b”, “1-c” and “1-d”) of 4-amino-N-(tert-butyl) benzamide (abbreviated as “A-TB-B”) were prepared.

[0282]

[0184] The volume to weight ratios (v / w) in the below steps of this example 1 , and in later example 4, represent the volume in millilitres, for example of a reactant or solvent, per gram of respective starting compound (4-nitrobenzoic acid for reaction 1-a and work-up 1a; 4-nitrobenzoylchloride for reaction 1-b and work-up 1 b; and N-(tert-butyl)-4-nitro-benzamide for reaction 1-c and work-up 1 c ).

[0283] Reaction 1-a : preparation of 4-nitrobenzoylchloride

[0284]

[0185] As a first step 200 grams of 4-nitrobenzoic acid and 1 mL of dimethyl formamide (0.005 v / w) were charged at a temperature of 30°C under nitrogen atmosphere to a first, 3 liter, round bottom flask (RBF) equipped with a mechanical stirrer, thermo-probe, addition funnel and a nitrogen bubbler. Subsequently 1200 mL toluene (6 v / w) was charged into the flask under nitrogen atmosphere. The flask was held at a temperature of 30°C.

[0285]

[0186] Hereafter 156 grams of thionyl chloride was slowly added, over a period of about 30 minutes, into the reaction mixture under nitrogen atmosphere, at a temperature of 30°C. Hence, thionyl chloride was thus charged to the flask in a 1 .1 :1 .0 molar ratio of thionyl chloride to 4-nitrobenzoic acid.

[0286]

[0187] Subsequently the reaction mixture was heated to 80 °C and stirred for about 1 to 2 hours at 80 °C. Temperature was then increased and the reaction mixture was heated to 90 °C and stirred for about 1 to 2 hours at 90 °C. Subsequently temperature was increased once more and the reaction mixture was heated to 110 °C and stirred for about 2 to 4 hours at 110 °C to prepare a reaction mixture comprising 4-nitro- benzoylchloride.

[0287]

[0188] The reaction mixture was cooled to 80 °C and checked for residual 4-nitrobenzoic acid content (by HPLC) under nitrogen atmosphere. If the 4-nitrobenzoic acid content did not comply yet with a limit of “not more than 1 .0 % w / w residual 4-nitrobenzoic acid as determined by HPLC”, the reaction mixture was heated again to 110 °C and reacted further for about 2 to 4 hours at 110 °C. If thereafter (following cooling to 80 °C) the reaction mixture still did not comply yet with the limit of “not more than 1.0 % w / w residual 4- nitrobenzoic acid as determined by HPLC”, the reaction mixture was cooled to 60 °C and an additional amount of 14.2 grams thionyl chloride was added at 60 °C, whereafter the reaction mixture was heated again to 110 °C and reacted further for about 2 to 4 hours at 110 °C.

[0288]

[0189] Once the 4-nitrobenzoic acid content complied with a limit of “not more than 1 .0 % w / w residual 4- nitrobenzoic acid as determined by HPLC”, the reaction mixture comprising the 4-nitro-benzoylchloride intermediate product was worked-up as described below.

[0289] Work-up 1-a : work-up of 4-nitrobenzoylchloride

[0290]

[0190] The reaction mixture was cooled to 55 °C under nitrogen atmosphere. Solvent was distilled of under vacuum and at a temperature of about 50 to 60 °C.

[0291]

[0191] Subsequently 200 ml toluene (1 v / w) has been added at a temperature below 60 °C, followed each time by distilling off the solvent under vacuum and at a temperature below 60 °C.

[0292]

[0192] Thereafter 400 mL toluene (2 v / w) was charged into the reaction mixture and the reaction mixture was stored at 30 °C in the RBF itself under nitrogen atmosphere for reaction step 1-b described below.

[0293] Reaction 1-b : preparation of N-(tert-butyl)-4-nitro-benzamide

[0294]

[0193] In the second step 190 grams of sodium carbonate was charged at a temperature of about 20°C (room temperature) under nitrogen atmosphere to a second, 3 liter, round bottom flask (RBF) equipped with a mechanical stirrer, thermo-probe, addition funnel and a nitrogen bubbler. Subsequently 1200 mL toluene (6 v / w) was charged into the flask under nitrogen atmosphere.

[0295]

[0194] The mixture in the flask was cooled to 2°C under nitrogen atmosphere, whereafter 132 gram of tert-butyl amine was added to the flask at 2°C.

[0296]

[0195] Then, the solution of 4-nitrobenzoylchloride in toluene as prepared in work-up 1-a, was slowly added over a period of about 60 minutes, into the reaction mixture under nitrogen atmosphere at 2°C. Hence, 4-nitrobenzoylchloride was thus charged to the flask in a 1.0:1.5:1.5 molar ratio of 4- nitrobenzoylchloride to sodium carbonate to tert-butyl amine.

[0297]

[0196] The subsequent reaction mixture was stirred for about 2 to 3 hours at 2 °C. Temperature was then increased and the reaction mixture was heated to 30 °C and stirred for about 3 to 5 hours at 30 °C to prepare a reaction mixture comprising N-(tert-butyl)-4-nitro-benzamide.

[0298]

[0197] The reaction mixture was checked for residual 4-nitrobenzoylchloride content (by HPLC). If the 4- nitrobenzoylchloride content did not comply yet with a limit of “not more than 1.0 % area residual 4- nitrobenzoylchloride as determined by HPLC”, the reaction mixture was reacted further for about 2 to 4 hours at 30 °C. If thereafter the reaction mixture still did not comply yet with the limit of “not more than 1 .0 % area residual 4-nitrobenzoylchloride as determined by HPLC”, an additional amount of 8.8 grams tertbutyl amine was added at 30 °C, whereafter the reaction mixture was reacted further for about 2 to 4 hours at 30 °C.

[0299]

[0198] Subsequently the reaction mixture comprising the N-(tert-butyl)-4-nitro-benzamide intermediate product was worked-up as described below. Work-up 1-b : work-up of N-(tert-butyl)-4-nitro-benzamide

[0300]

[0199] The reaction mixture was cooled to a temperature of 0 °C under nitrogen atmosphere and maintained at 0 °C for about 30 to 60 minutes under nitrogen atmosphere. Thereafter the reaction mixture was filtered at 0 °C under nitrogen atmosphere. The intermediate product was sucked dry until the mother liquor was expelled, obtaining a wet cake.

[0301]

[0200] Subsequently the wet cake was washed with 200 mL pre-cooled toluene (1 v / w) under nitrogen atmosphere, followed by sucking the cake dry again until the mother liquor was expelled again.

[0302]

[0201] The wet N-(tert-butyl)-4-nitro-benzamide intermediate product was dried under vacuum at a drier temperature of about 40°C to 50 °C for about 4 to 5 hours. Hereafter the drier temperature was decreased to about 30 °C under vacuum, the vacuum was released with nitrogen and the N-(tert-butyl)-4-nitro- benzamide intermediate product was de-lumped under nitrogen atmosphere. Subsequently the drier temperature was increased to 50 °C and the N-(tert-butyl)-4-nitro-benzamide intermediate product was again dried under vacuum for about 4 to 6 hours at 50 °C. The N-(tert-butyl)-4-nitro-benzamide intermediate product was tested for compliance with a loss on drying (LOD) limit of “not more than 8 % w / w” and further dried at 50°C with intervals of 4 to 6 hours just as often as needed until the loss on drying (LOD) was equal to or less than 8 % w / w.

[0303]

[0202] Thereafter the drier temperature was lowered to 30 °C and a dry N-(tert-butyl)-4-nitro-benzamide intermediate product was retrieved.

[0304]

[0203] The retrieved dry N-(tert-butyl)-4-nitro-benzamide intermediate product was charged together with 2000 mL demineralized water into a new round bottom flask equipped with a mechanical stirrer, thermoprobe, addition funnel and a nitrogen bubbler. The mixture was stirred at 30 °C during about 2 to 3 hours thereafter cooled to 5 °C and subsequently maintained at 5 °C for about 1 to 2 hours.

[0305]

[0204] Hereafter the N-(tert-butyl)-4-nitro-benzamide intermediate product was filtered at 5 °C and sucked dry until the mother liquor was expelled, obtaining a wet cake.

[0306]

[0205] Subsequently the wet cake was washed with 200 mL of pre-cooled demineralized water of about 5°C, followed by drying under vacuum for about 6 to 8 hours at a temperature of about 40°C to 50 °C. Hereafter the drier temperature was reduced to 30 °C under vacuum. The vacuum was released with nitrogen and the N-(tert-butyl)-4-nitro-benzamide intermediate product was de-lumped under nitrogen atmosphere. Thereafter the drier temperature was increased again to 50 °C under vacuum and the N-(tert- butyl)-4-nitro-benzamide intermediate product was dried again during about 6 to 8 hours at 50 °C.

[0307]

[0206] The water content was checked via a Karl Fischer (KF) determination. If the water content of the N-(tert-butyl)-4-nitro-benzamide intermediate product did not comply with a limit of “not more than 5 % w / w water”, the above vacuum drying at 50 °C was repeated for an interval of about 4 to 6 hours just as often as needed until the N-(tert-butyl)-4-nitro-benzamide intermediate product complied with a limit of “not more than 5 % w / w water”.

[0207] The drier temperature was decreased to about 30 °C and the N-(tert-butyl)-4-nitro-benzamide intermediate product was transferred into a container.

[0308] Reaction 1-c : preparation of 4-Amino-N-(tert-butyl) benzamide

[0309]

[0208] In the third step a slurry of the N-(tert-butyl)-4-nitro-benzamide intermediate product (as prepared above in work-up 1-b) in 1000 mL methanol (5 v / w) was prepared and placed into an autoclave vessel under nitrogen atmosphere. A mixture of 16 grams Raney Nickel in 1000 mL methanol was prepared and also charged into the autoclave vessel under nitrogen atmosphere.

[0310]

[0209] The temperature of the autoclave was increased to 30 °C and the nitrogen was replaced by hydrogen gas.

[0311]

[0210] The hydrogenation reaction was carried out by maintaining the reaction mixture during 5 to 7 hours at 30°C under a hydrogen pressure of about 5 kg / cm2(corresponding to about 4.9 bar and about 0.49 MegaPascal) to obtain a reaction mixture comprising 4-amino-N-(tert-butyl) benzamide.

[0312]

[0211] The reaction mixture was checked for residual N-(tert-butyl)-4-nitro-benzamide content (by HPLC). If the N-(tert-butyl)-4-nitro-benzamide content did not comply yet with a limit of “not more than 0.5% w / w residual N-(tert-butyl)-4-nitro-benzamide as determined by HPLC”, the reaction mixture was reacted further at 30 °C under hydrogen pressure of about 5 kg / cm2(corresponding to about 4.9 bar and about 0.49 MegaPascal) for intervals of each 4 to 6 hours just as long as needed until the reaction mixture complied with the limit of “not more than 0.5% w / w residual N-(tert-butyl)-4-nitro-benzamide as determined by HPLC”

[0313]

[0212] Subsequently the reaction mixture comprising the 4-amino-N-(tert-butyl) benzamide intermediate product was worked-up as described below.

[0314] Work-up 1-c : work-up of 4-Amino-N-(tert-butyl) benzamide

[0315]

[0213] The hydrogen pressure was released from the autoclave and the reaction mixture was cooled until 25°C. Subsequently the reaction mixture was placed under nitrogen atmosphere.

[0316]

[0214] A celite bed was prepared by uniform mixing of 40 grams of celite (also referred to as “diatomaceous earth”) in 200 mL of methanol and filtering the mass to form a celite bed and discarding the filtrate.

[0317]

[0215] The above reaction mixture from the autoclave was filtered through the celite bed under nitrogen atmosphere at 25 °C. Thereafter the celite bed was washed with 400 mL methanol under nitrogen and both filtrates were collected and combined under nitrogen atmosphere.

[0318]

[0216] The above collected filtrates comprising the reaction mixture were subsequently filtered through a micron filter at 30 °C under nitrogen atmosphere and a particle free filtrate was collected.

[0319]

[0217] Subsequently the filtrate was distilled off under vacuum at a temperature about 35 to 45 °C.

[0320]

[0218] Subsequently to the residue comprising the 4-amino-N-(tert-butyl) benzamide 200mL of n-heptane has been added. Each time the n-heptane was charged into the residue and distilled off under vacuum at a temperature about 35 to 45 °C.

[0219] Hereafter 1000 mL of n-heptane was charged to the residue and the temperature was adjusted to 25 °C under nitrogen atmosphere. The mixture was stirred for about 2 to 4 hours at a temperature of 25 °C under nitrogen atmosphere.

[0321]

[0220] Hereafter the mixture was filtered at a temperature of 25 °C under nitrogen atmosphere and sucked dry to expel the mother liquor. A wet cake was obtained.

[0322]

[0221] The wet cake was washed with 200 mL n-heptane at 25°C under nitrogen atmosphere and the 4- amino-N-(tert-butyl) benzamide intermediate product was sucked dry to expel the mother liquor.

[0323]

[0222] The 4-amino-N-(tert-butyl) benzamide intermediate product was transferred to a vacuum oven under nitrogen atmosphere. The 4-amino-N-(tert-butyl) benzamide intermediate product was dried under vacuum at a temperature of 50 °C for about 6 to 8 hours. Hereafter the drier temperature was decreased to about 30 °C under vacuum, the vacuum was released with nitrogen and the 4-amino-N-(tert-butyl) benzamide intermediate product was de-lumped. Subsequently the vacuum was applied again, the drier temperature was increased to 50 °C and the 4-amino-N-(tert-butyl) benzamide intermediate product was again dried under vacuum for about 4 to 6 hours at 50 °C. Subsequently the 4-amino-N-(tert-butyl) benzamide intermediate product was tested for compliance with a loss on drying (LOD) limit of “not more than 0.5 % w / w” and further dried under vacuum at 50°C with intervals of 4 to 6 hours just as often as needed until the loss on drying (LOD) was equal to or less than 0.5 % w / w.

[0324]

[0223] The drier temperature was decreased to about 30 °C and the vacuum was released with nitrogen. The 4-amino-N-(tert-butyl) benzamide intermediate product was transferred into a container under nitrogen atmosphere.

[0325] Analysis

[0326]

[0224] The yield and chromatographic purity by HPLC of each of the four consecutive batches (“1-a”, “1- b”, “1-c” and “1-d”) of 4-amino-N-(tert-butyl) benzamide intermediate product were determined. The yield and purity for each batch is listed in Table 1 below. An overview of product related characteristics, including colour and water content of each batch is provided in Table 2 below.

[0327] Table 1 : Yield and purity of the consecutive batches of example 1

[0328] Table 2 : Analysis data of the consecutive batches

[0329] Example 2 - preparation of N-(tert-Butyl)-4-((4,6-dichloro-1,3,5-triazin-2-yl)amino)benzamide

[0330]

[0225] In this example four consecutive batches (“2-a”, “2-b”, “2-c” and “2-d”) of N-(tert-butyl)-4-((4,6- dichloro-1 ,3,5-triazin-2-yl)amino)benzamide (abbreviated as “TB-DCL-TAB”) were prepared.

[0226] The volume to weight ratios (v / w) in the below steps of this example 2 and in later example 5 represent the volume in milliliters, for example of a reactant or solvent, per gram of starting compound 4- amino-N-(tert-butyl) benzamide. The starting compounds in example 2 were obtained from example 1 , as listed in the below Table 3. Table 3: Starting compounds for the batches of Example 2

[0331] Reaction

[0332]

[0227] As a first step 94 grams of trichloro triazine (also referred to as “cyanuric chloride”) was charged under nitrogen atmosphere to a first, 3 liter, round bottom flask (RBF) equipped with a mechanical stirrer, thermo-probe, addition funnel and a nitrogen bubbler. Subsequently 700 mL acetone (7 v / w) was charged into the flask under nitrogen atmosphere. The mixture was cooled to -10 °C under nitrogen atmosphere.

[0333]

[0228] A solution of 4-amino-N-(tert-butyl) benzamide in acetone was separately prepared by charging 100 grams of the 4-amino-N-(tert-butyl) benzamide obtained from example 1 (as listed in Table 3 above) and 500 mL of acetone in a separate second round bottom flask and stirring the mixture during about 20 to 30 minutes at a temperature of about 25 to 30°C until a solution was obtained.

[0334]

[0229] Subsequently the obtained solution of 4-amino-N-(tert-butyl) benzamide in acetone was slowly added to the mixture of trichloro triazine and acetone in the first round bottom flask, whilst keeping the mixture in the flask at -10 °C under nitrogen atmosphere. Hence, 4-amino-N-(tert-butyl) benzamide was thus charged to the flask in a 1 .00:0.98 molar ratio of 4-amino-N-(tert-butyl) benzamide to trichloro triazine.

[0335]

[0230] The reaction mixture in the first round bottom flask was maintained at -10 °C for about 5 to 7 hours under nitrogen atmosphere.

[0336]

[0231] Subsequently the reaction mixture was checked for residual 4-amino-N-(tert-butyl) benzamide content by HPLC. If the 4-amino-N-(tert-butyl) benzamide content did not comply yet with a limit of “not more than 2.0 % w / w residual 4-amino-N-(tert-butyl) benzamide as determined by HPLC”, the reaction mixture was allowed to continue to react at -10 °C, each time for a period of 2 to 4 hours, until the reaction mixture complied with a limit of “not more than 2.0 % w / w residual 4-amino-N-(tert-butyl) benzamide as determined by HPLC”.

[0337]

[0232] Hereafter the reaction mixture was cooled to a temperature of -15°C, whereafter 500 mL of demineralized water (5 v / w) was slowly added into the reaction mixture under nitrogen atmosphere, whilst keeping the temperature at -15°C. Preferably this “water quenching” step is very closely monitored to prevent the temperature from increasing beyond -10 °C. Without wishing to be bound by any kind of theory it is believed that if the temperature for this water quenching step increases beyond -10 °C, additional impurities may be formed.

[0338]

[0233] The reaction mixture was hereafter stirred for about 1 to 2 hours at a temperature of -15°C under nitrogen atmosphere, whilst the reaction was completed to obtain an unpurified N-(tert-butyl)-4-((4,6- dichloro-1 ,3,5-triazin-2-yl)amino) benzamide intermediate product (herein also abbreviated as “TB-DCL- TAB”).

[0339] Work-up

[0234] Subsequently the above reaction mixture comprising the TB-DCL-TAB was filtered under nitrogen atmosphere and sucked dry until the mother liquor was expelled, obtaining a wet cake.

[0340]

[0235] Subsequently the wet cake was washed twice with 100 ml pre-cooled demineralized water (1 v / w) of about 2°C under nitrogen atmosphere, followed each time by sucking the cake dry again until the mother liquor was expelled again. Filtration and drying herein were performed under a closed atmosphere in a Hastelloy ANFD / Halar coated centrifuge.

[0341]

[0236] The washed TB-DCL-TAB intermediate product was unloaded from the centrifuge and a wet TB- DCL-TAB intermediate product was obtained.

[0342]

[0237] The wet TB-DCL-TAB intermediate product was dried in a vacuum oven under nitrogen atmosphere at a drier temperature of about 50 °C for about 6 to 8 hours. Hereafter the drier temperature was decreased to about 30 °C under vacuum, the vacuum was released with nitrogen and the TB-DCL-TAB intermediate product was de-lumped under nitrogen atmosphere. Subsequently the drier temperature was increased to 50 °C again and the TB-DCL-TAB intermediate product was again dried under vacuum for about 6 to 8 hours at 50 °C. The drier temperature was decreased once more to about 30 °C and the vacuum was released with nitrogen.

[0343]

[0238] The water content was checked via a Karl Fischer (KF) determination under nitrogen atmosphere. If the water content of the TB-DCL-TAB intermediate product did not comply with a limit of “not more than 0.8 % w / w water”, the above vacuum drying at 50 °C was repeated for an interval of about 4 to 6 hours just as often as needed until the TB-DCL-TAB intermediate product complied with a limit of “not more than 0.8 % w / w water”.

[0344]

[0239] The drier temperature was decreased to about 30 °C and the vacuum was released with nitrogen. The TB-DCL-TAB intermediate product was transferred into a container under nitrogen atmosphere.

[0345] Analysis

[0346]

[0240] The yield and chromatographic purity by HPLC of each of the four consecutive batches (“2-a”, “2- b”, “2-c” and “2-d”) of TB-DCL-TAB intermediate product were determined. The yield and purity for each batch is listed in Table 4 below. An overview of product related characteristics, including colour and water content of each batch is provided in Table 5 below.

[0347] Table 4 : Yield and purity of the consecutive batches

[0348] Table 5 : Analysis data of the consecutive batches

[0349] Example 3 - preparation of Diethyl Hexyl Butamido Triazone

[0350]

[0241] In this example three consecutive batches (“3-a”, “3-b”, “3-c”) of diethylhexylbutamido triazone product were prepared under an inert atmosphere (i.e. , nitrogen and / or vacuum). The volume to weight ratios (v / w) in the below steps of this example represent the volume in milliliters, for example of a solvent, per gram of starting compound N-(te / Y-butyl)-4-((4,6-dichloro-1 ,3,5-triazin-2-yl)amino)benzamide (abbreviated as “TB-DCL-TAB”). The batches used starting compound as were not those as mentioned above in example 2, but were prepared in an equivalent manner to the batches in example 2, as listed in the below Table 6.

[0351] Table 6: Starting compounds for the batches of Example 3

[0352] Reaction

[0353]

[0242] As a first step 100 grams of the N-(tert-butyl)-4-((4,6-dichloro-1 ,3,5-triazin-2-yl)amino)benzamide product obtained via a process equivalent to the process described in example 2 (herein also abbreviated as “TB-DCL-TAB”) (1 .0 equivalent) was charged under nitrogen atmosphere to a 3 liter round bottom flask equipped with a mechanical stirrer, thermo-probe, addition funnel and a nitrogen bubbler. Subsequently 1000 millilitre (mL) of ethyl acetate was charged under nitrogen atmosphere to the flask, representing a volume to weight ratio of 10 millilitres of ethyl acetate per 1 gram of TB-DCL-TAB (10v / w). Subsequently the temperature of the flask was set at 30°C and 146.6 grams of 2-Ethylhexyl p-amino benzoate was charged under nitrogen atmosphere to the flask. Hence, 2-ethylhexyl p-amino benzoate was thus charged to the flask in a 2:1 molar ratio of 2-ethyhexyl 4-aminobenzoate to N-(tert-butyl)-4-((4,6-dichloro-1 ,3,5- triazin-2-yl)amino)benzamide).

[0354]

[0243] The temperature of the reaction mixture was raised to reflux temperature, in this case about 73 °C. Subsequently the reaction mixture was maintained under nitrogen atmosphere at such reflux temperature during at least 13 hours, whilst the reaction was carried out to obtain an unpurified diethylhexylbutamido triazone product.

[0355]

[0244] After 13 to 15 hours the reaction mixture was cooled to to 60 °C and checked for residual N-(tert- butyl)-4-((4,6-dichloro-1 ,3,5-triazin-2-yl)amino)benzamide (TB-DCL-TAB) content by HPLC. Ifthe TB-DCL- TAB content did not comply yet with a limit of “not more than 0.2 % w / w residual TB-DCL-TAB as determined by HPLC” and / or a limit of “not more than 0.2 % w / w residual mono-chloro intermediate (with a RRT of 0.59) as determined by HPLC”, the temperature of the reaction mixture was raised again to 73 °C and the reaction was allowed to continue to react at 73 °C under nitrogen, each time for a period of 2 to 4 hours, until the reaction mixture complied with both the limit of “not more than 0.2 % w / w residual TB-DCL-TAB as determined by HPLC” and the limit of not more than 0.2 % w / w residual mono-chloro intermediate (with a RRT of 0.59) as determined by HPLC” or until two consecutive results were consistent.

[0356] Work-up

[0357]

[0245] The reaction mixture was cooled to 25 °C under nitrogen atmosphere and 1000 mL demineralized water (10 v / w) was charged to the reaction mixture at 25 °C, whereafter the mixture was stirred during 30- 40 minutes. Subsequently the mixture was allowed to settle and a bottom water layer and a top organic layer became visible. The bottom water layer was separated off and the top organic layer was retained in the flask.

[0358]

[0246] Hereafter 500 mL ethyl acetate (5 v / w) was charged into this organic layer retained in the flask at 25 °C. Subsequently 500 mL of an 10 wt. % aqueous sodium carbonate solution (5 v / w) was slowly added to the reaction mixture at 25 °C. The reaction mixture was stirred for about 120 to 130 minutes at 25 °C. Subsequently the mixture was allowed to settle and a bottom aqueous sodium carbonate layer and a top organic layer became visible. The bottom aqueous sodium carbonate layer was separated off and the top organic layer was retained in the flask. This washing step was thereafter repeated a second time.

[0359]

[0247] Then, as a washing step, a new portion of 1000 mL demineralized water (10 v / w) was charged at 25 °C to the organic layer in the flask, whereafter the mixture was stirred during 50 to 60 minutes. Again the mixture was allowed to settle and a bottom water layer and a top organic layer became visible. Again, the bottom water layer was separated off and the top organic layer was retained in the flask. This washing step was thereafter repeated a second time. Subsequently the top organic layer was transferred to a dedicated container.

[0360]

[0248] The organic layer was filtered through a micron filter (0.45 / 0.22 ) for particle free at 30 °C and the filtrate, comprising an organic mixture, was distilled off completely under vacuum at about 40 to 50 °C in a clean round bottom flask. Subsequently the organic mixture was degassed for at least 3 hours under vacuum at a temperature about 40 to 50 °C, whereafter the vacuum was released under nitrogen.

[0361] Isolation

[0362]

[0249] To isolate the product, 100 mL ethyl acetate (1 v / w) was charged into the organic mixture at a temperature about 40 to 50 °C. Subsequently 2000 mL di-isopropyl-ether (DIPE) (20 v / w) was charged into the organic mixture at a temperature about 40 to 50 °C under nitrogen atmosphere, whereafter the mixture was stirred for about 20 minutes at a temperature about 40 to 50 °C. It was seen that the mixture became homogeneous. Hereafter the temperature of the mixture was raised to about 50 °C and stirred for another 15 to 30 minutes at 50 °C.

[0363]

[0250] Subsequently the mixture was gradually cooled to a temperature of about 10 °C over a period of about 2 to 3 hours under nitrogen atmosphere.

[0364]

[0251] Hereafter the mixture was filtered under nitrogen atmosphere and sucked dry until the mother liquor was expelled, obtaining a wet cake.

[0365] Purification

[0366]

[0252] The wet cake was washed with 10OmL of a pre-cooled 5 % vol. / vol. solution of ethyl acetate in di- isopropyl-ether (DIPE) (1 v / w) at 10 °C under nitrogen atmosphere. This pre-cooled solution was prepared by mixing 5 mL of ethyl acetate in 95 mL of di-isopropyl-ether (DIPE) and cooling the obtained mixture to 10 °C. The resulting washed cake was sucked dry again until the mother liquor was expelled. A moist product of about 225 gram was obtained.

[0367]

[0253] Subsequently the moist product was dried by drying under vacuum for 4 to 5 hours at about 30°C, followed by drying under vacuum for 4 to 5 hours at about 40°C and drying under vacuum for 8 to 12 hours at about 52°C. Thereafter the product was cooled to 30°C and the vacuum was released with nitrogen.

[0368]

[0254] Subsequently the product was milled and a milled product was obtained. The milled product was again dried under vacuum at about 52°C for 20 to 24 hours, just as long as needed until the loss on drying (LOD) was less than 0.4 wt %.

[0369] Analysis

[0370]

[0255] The chromatographic purity of each batch of product was determined by HPLC.

[0371]

[0256] The yield and purity for each batch is listed in Table 7 below. An overview of product related characteristics, including colour, odour, loss on drying and molar extinction coefficient of each batch is provided in Table 8 below. The molar extinction coefficient (also denoted as e (epsilon)), is a constant that describes how strongly a substance absorbs light at a given wavelength. Table 7 : Yield and purity of the consecutive batches

[0372] Table 8 : Analysis data of the consecutive batches

[0373] Example 4 - Effect of the use of toluene as a solvent in the preparation of 4-amino-N-(tert-butyl) benzamide

[0374]

[0257] The experiments below illustrate that the use of toluene as a solvent in the preparation of N-(tert- Butyl)-4-((4,6-dichloro-1 ,3,5-triazin-2-yl)amino)benzamide can advantageously result in high yields. In addition, the experiments below illustrate that good yields and purity can also be obtained whilst using less than 2.0 equivalents of the chloride compound.

[0375]

[0258] In batches 4-a to 4-f, 4-nitrobenzoylchloride was prepared in a similar manner as described in example 1 , except for the aspects as indicated in Table 9 below. The solvent and the volume in millilitres of solvent per gram of4-nitrobenzoic acid (v / w) was varied. Further the mol ratio of molar equivalents thionyl chloride (SOCI2) to molar equivalents 4-nitrobenozic acid (4NBA) was varied. The purity of the starting compounds, the solvent, volumes and other reaction conditions are listed in Table 9. The yield and purity of the produced batches are given in Table 10. Table 9: Reaction conditions for batches 4-a to 4-f of 4-nitrobenzoylchloride

[0376] Table 10 : Yield and purity of batches 4-a to 4-f of 4-nitrobenzoylchloride

[0377]

[0259] In batches 4-g to 4-i, N-(tert-butyl)-4-nitro-benzamide was prepared in a similar manner as described in example 1 , except for the aspects as indicated in Table 11 below. The solvent and the volume in millilitres of solvent per gram of 4-nitrobenzoylchloride (v / w) was varied. The purity of the starting compounds, the solvent, volumes and other reaction conditions are listed in Table 11. The yield and purity of the produced batches are given in Table 12. Table 11 : Reaction conditions for batches 4-g to 4-i of N-(tert-butyl)-4-nitro-benzamide

[0378] In each of the below experiments the mol ratio of molar equivalents tert-butylamine to molar equivalents 4-nitrobenzoylchloride was 1 .7. In addition sodium carbonate (NaHCOs) was present in a mol ratio of molar equivalents NaHCOsto molar equivalents 4-nitrobenzoylchloride of 3.5. The reactions were run until completeness.

[0379] Table 12 : Yield and purity of batches 4-q to 4-i of N-(tert-butyl)-4-nitro-benzamide

[0380] Example 5 - Effect of the reaction temperature and / or the presence of a base in the preparation of N-(tert-Butyl)-4-((4,6-dichloro-1 ,3,5-triazin-2-yl)amino)benzamide

[0381]

[0260] The experiments below illustrate that a higher yield and purity for the preparation of N-(tert-Butyl)- 4-((4,6-dichloro-1 ,3,5-triazin-2-yl)amino)benzamide (abbreviated as “TB-DCL-TAB”) can be obtained by applying a preferred reaction temperature below 0 °C, more preferably a reaction temperature in the range from equal to or more than -15°C to equal to or less than -5°C. In addition, the experiments below illustrate that good yields and purity can also be obtained in the absence of a base.

[0382]

[0261] Batches 5-a, 5-b, 5-c and 5-d were prepared in a similar manner to example 2, except for the aspects as indicated in Table 13 below. In the batches 5-a, 5-b, 5-c and 5-d, the reaction temperature was varied. The purity of the starting compounds and the reaction temperature for each batch are listed in Table 13. The yield and purity of the produced batches are given in Table 14. Table 13: Reaction conditions for batches 5-a to 5-d of TB-DCL-TAB

[0383] The batches were prepared by reacting 1 molar equivalent of 4-amino-N-(tert-butyl) benzamide with 0.98 molar equivalents of cyanuric chloride in acetone (12 v / w) during 6 hours.

[0384] Table 14 : Yield and purity of batches 5-a to 5-d of TB-DCL-TAB

[0385] * Due to the low reaction temperature this reaction could not be completed within the reaction time.

[0386]

[0262] Batches 5-e, 5-f and 5-g were prepared in a similar manner to example 2, except for the aspects as indicated in Table 15 below. In the batches 5-e, 5-f and 5-g, the presence of a base was varied. The purity of the starting compounds and the presence of a base for each batch are listed in Table 15. The yield and purity of the produced batches are given in Table 16.

[0387] Table 15: Reaction conditions for batches 5-e to 5-g of TB-DCL-TAB

[0388] The batches were prepared by reacting 1 molar equivalent of 4-amino-N-(tert-butyl) benzamide with 0.98 molar equivalents of cyanuric chloride in acetone (11 v / w) during 2 to 4 hours.

[0389] Table 16 : Yield and purity of batches 5-e to 5-g of TB-DCL-TAB

[0390] Example 6 - Effect of the reaction medium on impurities in the preparation of Diethyl Hexyl Butamido Triazone

[0391]

[0263] For these examples N-(tert-butyl)-4-((4,6-dichloro-1 ,3,5-triazin-2-yl)amino)benzamide (with Mw of about 340.2 30 gram) was reacted with 2-ethyhexyl 4-aminobenzoate in a 2:1 molar excess of 2-ethyhexyl 4-aminobenzoate to N-(tert-butyl)-4-((4,6-dichloro-1 ,3,5-triazin-2-yl)amino)benzamide) in a similar manner as described above for example 3, except that the reaction was carried out under a nitrogen atmosphere during 6 to 8 hours at a temperature of 78°C instead of 73 °C. The volumes, for example of the reactants and solvents used in each step, were adapted in order to apply the same volume to weight ratio (v / w) of solvent to starting weight of TB-DCL-TAB as in example 3. For each example two batches were prepared.

[0392]

[0264] The work-up, isolation and purification for the batches “6-a” and “6-b” was carried out as described above for example 3, except that (i) the cooling was carried out to a temperature of about 2 °C instead of a temperature of about 10 °C and (ii) a 10 wt.% solution instead of a 5 wt.% solution of ethyl acetate in di- isopropyl-ether (DI PE) was used. Hence, also for example 4 the reaction product was isolated with a mixture of ethyl acetate and di-isopropyl-ether as described above for example 3, followed by a purification in ethyl acetate and di-isopropyl-ether.

[0265] For the batches “6-c”and “6-d” the reaction product was isolated with a medium comprising ethyl acetate and di-isopropyl-ether and in addition heptane and no additional purification step was carried out.

[0393]

[0266] The reaction conditions for each batch are summarized in Table 17. The purities of the starting compound were as listed in the below Table 18. An overview of yield, purity and impurities is provided in respectively Tables 19 and 20 below.

[0394]

[0267] As illustrated in Table 20 especially by batches 6-a, 6b and 6-c a considerable reduction in the impurity 2-ethylhexyl-4-aminobenzoate has been achieved.

[0395] Table 17: Reaction conditions for Example 6 * In examples 6-c and 6-d, the crude product was dissolved in ethyl acetate (1 volume part) and DIPE (9 volume parts) followed by heptane (8 volume parts) being added, followed by stirring during 30 to 60 minutes and filtering, all steps being carried out at about 2°C. Subsequently the wet material was dried during 12 hours, milled and redried during 24 hours under vacuum at less than 55 °C.

[0396] Table 18: Purity of the starting compounds for the batches of Example 6

[0397] Table 19 : Yield and purity of the consecutive batches

[0398] Table 20 : Impurities of the batches (in HPLC % area) Example 7 - Effect of the medium on isolation of the Diethyl Hexyl Butamido Triazone

[0399]

[0268] For these examples a reaction mixture comprising diethylhexyl butamido triazone was prepared, whereafter such reaction mixture was subjected to water washes and a wash with a 10% sodium carbonate solution, similar to the work-up as described in Example 3 above. The so obtained crude diethylhexyl butamido triazone was subsequently isolated and / or purified with the help of different solvents.

[0400]

[0269] The details of each isolation and / or purification and the results are provided in Table 21 below.

[0401]

[0270] As can be concluded from the results in Table 21 , isolation from a medium comprising ethylacetate(1 v / w) and di-isopropyl-ether (DIPE) (20 v / w) at 10 °C gave the best results and provided a high quality with good yield.

[0402] Table 21 : Batches of example 7 (* are comparative batches)

[0403]

Claims

CLAIMSA process for the isolation of a compound of formula (I):wherein R, Ri and R2 are, each individually, a Ci -Cis linear or branched alkyl or a C5 - C12 cycloalkyl optionally substituted with one or more Ci -C4 alkyl; wherein the compound of formula (I) is isolated from a medium, wherein the medium comprises an ester and an ether.

2. A process for the production of a compound of formula (I):wherein R, R1 and R2 are, each individually, a Ci -Cis linear or branched alkyl or a C5 - C12 cycloalkyl optionally substituted with one or more Ci -C4 alkyl; comprising the steps of:(a) producing a compound of formula (I); and(b) contacting the compound of formula (I) with and retrieving the compound of formula (I) from a medium, wherein the medium comprises an ester and an ether.

3. The process according to claim 2, wherein step (a) comprises one or more of the reaction steps: (i) reacting 4-nitrobenzoic acid with a chlorinating reagent, preferably thiony Ichloride, yielding 4-nitrobenzoylchloride; reacting such 4-nitrobenzoylchloride with an alkyl amine compound yielding a N-alkyl-4-nitro-benzamide compound; and hydrogenating such a N-alkyl-4- nitro-benzamide compound yielding a 4-amino-N-(alkyl) benzamide compound of formula (II);wherein R is a Ci -Cis linear or branched alkyl group or a C5 -C12 cycloalkyl group, optionally substituted with one or more Ci -C4 alkyl group(s); and / or(ii) reacting a 4-amino-N-(alkyl) benzamide compound of formula (II) with a triazine derivative compound of formula (III)wherein Z is a leaving group, more preferably a bromine or chlorine group, yielding a substituted triazine compound of formula (IV)wherein Z is a leaving group, more preferably a bromine or chlorine group, and wherein R is a Ci -Cis linear or branched alkyl group or a C5 -C12 cycloalkyl group, optionally substituted with one or more Ci -C4 alkyl group(s); and / or(iii) reacting a substituted triazine compound of formula (IV) with a p-aminobenzoic acid ester of formula (V) and / or a p-aminobenzoic acid ester of formula (VI)wherein R1 and R2 are, each individually, a Ci -Cis linear or branched alkyl or a C5 -C12 cycloalkyl optionally substituted with one or more Ci -C4 alkyl, yielding a compound of formula (I).

4. The process according to claim 3, wherein reaction step (i) comprises :(i-a) reacting 4-nitrobenzoic acid with a chlorinating reagent, preferably thionylchloride, yielding 4- nitrobenzoylchloride;(i-b) reacting the 4-nitrobenzoylchloride with an alkyl amine compound yielding a N-alkyl-4-nitro- benzamide compound; and(i-c) hydrogenating such a N-alkyl-4-nitro-benzamide compound yielding a 4-amino-N-(alkyl) benzamide compound of formula (II).

5. The process according to any one of claims 3 to 4, wherein the reaction in reaction step (ii) is carried out at a temperature in the range from equal to or more than -15 °C to equal to or less than -5 °C.

6. The process according to any one of claims 3 to 5, wherein the reaction in reaction step (iii) is carried out in a solvent and the solvent comprises, consists essentially of, or consists of, an ester.

7. The process according to any one of claims 1 to 6, wherein the medium further comprises a Ci - Cis linear or branched alkane, preferably n-heptane.

8. The process according to any one of claims 1 to 7, wherein the ester is ethyl acetate.

9. The process according to any one of claims 1 to 8, wherein the ether is di-isopropyl ether.

10. The process according to any one of claims 1 to 9, wherein R is tert-butyl.11 . The process according to any one of claims 1 to 10, wherein R2 is identical to R1 and both R1 andR2 are ethyl-hexyl.

12. A composition comprising, based on the total weight of the composition:- equal to or more than 99.0 wt%, more preferably equal to or more than 99.5 wt%, most preferably equal to or more than 99.6 wt%, of a compound having formula (I-A):(I-A)wherein R and Ri are, each individually, a Ci -Cis linear or branched alkyl or a C5 -C12 cycloalkyl optionally substituted with one or more Ci -C4 alkyl; and- equal to or less than 300 ppm more preferably equal to or less than 250 ppm, of a p- aminobenzoic acid ester of formula (V)13. A composition comprising:- a compound having formula (l-A):(l-A) wherein R and R1 are, each individually, a Ci -Cis linear or branched alkyl or a C5 -C12 cycloalkyl optionally substituted with one or more Ci -C4 alkyl; and- a p-a mi no benzoic acid ester of formula (V)wherein the composition comprises a weight ratio of the compound of formula (l-A) to the compound of formula (V) of equal to or more than 3000:1 .

14. A composition according to claim 13, comprising: diethylhexyl butamido triazone; and2-ethylhexyl-4-amino-benzoate wherein the weight ratio of moles of diethylhexyl butamido triazone to moles of 2-ethylhexyl-4- amino-benzoate is equal to or more than 3000:1 ,15. A composition according to any one of claims 12 to 14, wherein the composition has a particle size in the range from equal to or more than 1 micrometer to equal to or less than 400 micrometer, more preferably in the range from equal to or more than 10 micrometer to equal to or less than 400 micrometer, as determined by granulometric analysis with a Ro-Tap Sieve Shaker.

16. Use of any one of the compositions according to claims 12 to 15 for the preparation of a cosmetic product.

17. A cosmetic product comprising any one of the compositions according to claims 12 to 15.

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