Method for synthesizing 5-ethyl-2-amino phenol

Abstract

The invention relates to a method for synthesizing 5-ethyl-2-amino phenol.

Description

[0001] METHOD FOR SYNTHESIZING 5-ETHYL-2-AMINO PHENOL

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to a method for synthesizing 5-ethyl-2-amino phenol, or salts thereof. This compound is also known under COLIPA n° A158. 5-ethyl-2-amino phenol is known to the industry as an important oxidative coupler compound used in oxidative hair dye compositions. It provides with oxidative primaries such as paraphenylendiamine derivatives and other well-known oxidative precursors an important yellowish base coat to support grey coverage and lastingness of any oxidative hair coloration. Due to similar dyeing properies compared with resorcinol or methylresorcinol, it is therefore a suitable candidate for replacing resorcinol and resorcinol derivatives in oxidative hair color formulations. In light of the rapidly changing global regulatory environments, a suitable replacement for resorcinol and methyl-resorcinol will be needed in the near future. Hence, 5-ethyl-2-amino phenol according to formula (I) represents an attractive candidate to achieve this aim.

[0004] BACKGROUND OF THE INVENTION

[0005] 5-ethyl-2-amino phenol (I) has been found a suitable candidate to achieve the aim of providing a solid color backbone in the oxidative hair shade palette. It has been used in the past rarely in market formulations as the yellow color strike was only specifically needed in special light shades but not to address the grey coverage concerns. A big barrier was the cost intensive synthesis for this compound. As the hair color industry is moving out of traditional and cheap resorcinol derivatives compounds such as resorcinol or methyl-resorcinol, the focus is now on providing an advanced and improved synthesis to minimize the financial impact the exit of resorcinol derivatives may have to hair color companies.

[0006] In the past, the industry already published different synthetic routes to manufacture 5-ethyl-2-amino phenol (I) or salts thereof.

[0007] The synthesis route currently used for preparing 5-ethyl-2-amino phenol (I) is the method going back to US5214194A by Eastman-Kodak. As depicted in reaction scheme 1 below, the method starts with commercially available 4-ethyl-nitrobenzene, which is condensed with benzaldehyde in the presence of zinc in acetic acid. This intermediate is reacted with trichloroacetyl chloride to form the desired compound 5-ethyl-2-amino phenol (I) after a rearrangement reaction.

[0008] Reaction Scheme 1 The downsides of this current commercial method are the formation of many byproducts during this operation, and the difficult purification to achieve cosmetic quality. Associated with this fact is the high-cost structure following this synthesis pathway which is truly an enormous burden for the hair color industry in comparison to cheap and readily available resorcinol derivatives or resorcinol itself.

[0009] Therefore, there exists a massive need to provide a new method for preparing 5-ethyl-2-amino phenol (I), or a salt thereof, or mixture thereof which offers an attractive and considerably improved cost structure, particularly in comparison with the current existing synthesis methods or other published and / or commercialized methods. In regard of an increasing global demand, an economical access to 5-ethyl-2-amino phenol (I) would be appreciated. This manufacturing method should also be able to provide a material with a low impurity level in accordance with global regulations. Furthermore, the method should also reduce the risk of non-controllable side reactions and involve inexpensive starting materials and use more standardized chemical reactions versus known methods which are regarded state of the art. Finally, in view of increasing ecological demands, manufacturers should be able to conduct the method under mild reaction conditions, involving moderate temperatures, using ecologically acceptable solvents, and producing a minimum of non-recyclable waste solutions.

[0010] It has surprisingly now been found that a new synthesis concept starting with readily commercially available feedstock materials, will lead to the desired 5-ethyl-2-amino phenol (I) with enhanced economics and significantly decreased use of organic solvents and harsh chemicals / process aids versus the current state of the art. The synthesis routes presented herein may use water, aqueous, alhoholic solutions or recyclable organic solvents in one or more steps of the reaction course.

[0011] SUMMARY OF THE INVENTION

[0012] Subject matter of the present invention ia a method for preparing 5-ethyl-2-amino phenol (I), or a salt thereof, or mixture thereof, as defined in claim 1. The dependent claims relate to particular embodiments thereof.

[0013] Subject matter of the present invention is a method for preparing 5-ethyl-2-amino phenol (I)

[0014] (U or a salt thereof, in particular a cosmetically acceptable salt thereof.

[0015] The method according to the present invention comprises:

[0016] (a) providing 4-ethylaniline (II):

[0017] (b) converting the amino group to an electron-withdrawing system, and halogenating the aromatic ring in ortho-position to form 2-halo-intermediate (III): wherein R1 and R2 are electron-withdrawing moieties, or R1 and R2 together form an electronwithdrawing moiety, and wherein X is fluoro, chloro, bromo, or iodo,

[0018] (c) hydrolyzing 2-halo-intermediate (III) to form 2-hydroxy-intermediate (IV):

[0019] (d) converting the electron-withdrawing system of 2-hydroxy-intermediate (IV) to an amino group, to form 5-ethyl-2-amino phenol (I).

[0020] Converting the amino group to an electron-withdrawing system in step (b) may be done, according to embodiments of the present invention, by oxidation of the amino group to a nitro group, or by reaction of the amino group with either two monovalent electron-withdrawing moieties or one divalent electron-withdrawing moiety. According to particular embodiments, the present invention contemplates reaction of the amino group with a divalent electron-withdrawing moiety, more particularly reaction with an aromatic acid anhydride. Suitable acid anhydrides for use in the present invention encompass for example phthalic acid anhydride, or 1,8-naphthalene dicarboxylic anhydride. Further acid anhydrides principally suitable for use in the present invention are known to the person skilled in the art.

[0021] According to a first specific embodiment of the present invention, the electron-withdrawing system obtained in step (b) is a nitro group. In that case, the first step of the method according to the present invention comprises halogenating 4-ethylaniline (II) in ortho-position, to form 2-halo-4-ethyl- aniline (V). The preferred halogen in this step is bromine. Following halogenation, 2-halo-4-ethyl- aniline (V) is oxidized to form 2-halo-4-ethyl-nitro benzene (VI). Following oxidation to the nitro derivative (VI), the halogen group is hydrolyzed to the hydroxyl group, thereby forming 2-nitro-5- ethyl-phenol (VII). Finally, 2-nitro-5-ethyl-phenol (VII) is reduced to the desired end-product 5-ethyl- 2-amino phenol (I). According to a particular embodiment, the final two steps, i.e. hydrolyzing the halogen group and reducing the nitro group, may be done simultaneously in a one-pot-reaction.

[0022] According to a second specific embodiment of the present invention, the electron-withdrawing system obtained in step (b) is the reaction product of the amino group with an aromatic anhydride, such as phthalic acid anhydride. Other acid anhydrides may be used, as noted above. According to this second specific embodiment (exemplified with phthalic acid anhydride), the method starts as above with halogenating 4-ethylaniline (II) in ortho-position, to form 2-halo-4-ethyl-aniline (V). Again, the preferred halogen in this step is bromine. The method continues with condensing 2-halo-4-ethyl- aniline (V) with phthalic acid anhydride, to form 2-(2-halo-4-ethyl-phenyl)isoindoline-l, 3-dione (IX). Subsequently, 2-(2-halo-4-ethyl-phenyl) isoindoline-1, 3-dione (IX) is hydrolysed to form the hydroxylated intermediate 2-(2-hydroxy-4-ethyl-phenyl)isoindoline-l, 3-dione (X), which in the last method step is converted to the desired end-product 5-ethyl-2-amino phenol (I) by aminolysis.

[0023] According to a third specific embodiment, the electron-withdrawing system incorporated in step (b) again is the reaction product of the amino group with an aromatic anhydride, such as phthalic acid anhydride, but the order of the halogenation and condensing steps is reversed. Other acid anhydrides may be used, as noted above. According to this third specific embodiment (again exemplified with phthalic acid anhydride), the method starts with a condensation of 4-ethylaniline (II) and phthalic acid anhydride, to form 2-(4-ethyl-phenyl)isoindoline-l, 3-dione (VIII). The method continues with halogenating intermediate (VIII), to form 2-(2-halo-4-ethyl-phenyl)isoindoline-l,3- dione (IX). The preferred halogen in the halogenation step again is bromine. Hydrolysis of the halogenated intermediate (IX) to form the hydroxylated phthalimido-derivative 2-(2-hydroxy-4-ethyl- phenyl)isoindoline-l, 3-dione (X), and aminolysis of (X) to form the desired end-product 5-ethyl-2- amino phenol (I) are carried out as in the second specific embodiment.

[0024] DEFINITIONS

[0025] The terms "ambient temperature" and "room temperature" are used herein interchangeably, and refer to a temperature in the range of 20-30°C, in particular to a temperature in the range of 22- 27°C, for example about 25°C.

[0026] The terms "normal pressure" and "atmospheric pressure" are used herein interchangeably, and refer to a pressure of in the range of 0.8-1.2 bar, in particular about 1.0 bar.

[0027] The term "salt", as used herein, comprises salts in the classical meaning, as well as addition salts. Addition salts encompass addition complexes with acid, base and / or solvent(s). Examples of addition salts with an acid include complexes of the target compound or of intermediates disclosed herein, with hydrogen chloride, hydrogen bromide, sulfuric acid, phosphoric acid, acetic acid, citric acid, succinic acid, tartaric acid, lactic acid, tosylic acid, benzenesulfonic acid. Examples of addition salts with a base include complexes of the target compound or of intermediates disclosed herein, with a base such as sodium hydroxide, potassium hydroxide, ammonia, amines or alkanolamines. Examples of addition salts with solvent(s) (solvates) include complexes of the target compound or of intermediates disclosed herein with water (hydrates) or lower alcohols, i.e. methanol, ethanol, isopropanol, n-propanol, isobutanol, n-butanol. Preferred solvates are hydrates.

[0028] The term "cosmetically acceptable salt" encompasses addition salts as exemplified above, and salts in the classical meaning comprising as counter ion a cation selected from lithium, sodium, potassium, beryllium, magnesium, calcium, boron, aluminium, iron, copper, zink, or ammonium, or respectively an anion selected from fluoride, chloride, bromide, jodide, hydroxide, sulfate, sulfonate, or phosphate. Preferred "cosmetically acceptable salts" include hydrates and solvates of the lower alcohols, and as classical salts the sodium, potassium, magnesium, calcium, and ammonium salts, or respectively the chlorides, hydroxides, sulfates, sulfonates, and phosphates. As far as the present invention relates to salts of 5-ethyl-2-amino phenol (I), or of intermediates disclosed herein, cosmetically acceptable salts are preferred.

[0029] DETAILED DESCRIPTION OF THE INVENTION

[0030] The method according to the present invention, including the sequence of steps, intermediates involved in the synthesis, and the large-scale process, is described in detail in the following. It is to be understood that when the present disclosure refers to a particular structure, all of the reasonable additional tautomeric structures are included. In the art tautomeric structures are frequently represented by one single structure and the present disclosure follows this general practice.

[0031] It is to be understood that the steps described to prepare 5-ethyl-2-amino phenol (I) may be performed in a sequential one-pot synthesis, with reagents added to a reactor one at a time and without work-up in-between. The reaction steps require suitable solvents, as indicated below. Sequential one-pot synthesis without work-up in-between is preferred, unless it is preferred to reduce or avoid the presence of by-products from a preceding step in a subsequent step.

[0032] The detailed description that follows exemplifies the methods according to the present invention by referring to, for example, particular reactants and / or reaction conditions. This is done for the sake of exemplification, and the present invention is not limited thereby. For example, reference to chlorine is to be understood as a reference to a suitable halogen, or the reference to a particular solvent is to be understood as a reference to solvents being generally suitable for the respective reaction, and the respective solubilisation intended. Analogously, the reference to a particular acid or base is to be understood as a general reference to a suitable acid or base, respectively.

[0033] The present invention relates to a method for synthesizing 5-ethyl-2-amino phenol (I), or a salt thereof, for example a cosmetically acceptable salt thereof, or mixture thereof, comprising the steps as described in the following.

[0034] 1 General outline of the method according to the present invention

[0035] The method according to the present invention for preparing 5-ethyl-2-amino phenol (I), or a salt thereof (in particular a cosmetically acceptable salt thereof) starts with 4-ethylaniline (II). In a first step, the amino group of 4-ethylaniline (II) is converted to an electron-withdrawing system, and the aromatic ring is halogenated in ortho-position (i.e. position 2), to form 2-halo-intermediate (III):

[0036] Conversion of the amino group to an electron-withdrawing system may be done, according to embodiments of the present invention, by oxidation to a nitro group or by reaction with either two monovalent electron-withdrawing moieties or one divalent electron-withdrawing moiety.

[0037] Depending on the type of electron-withdrawing system, halogenation may be accomplished prior or subsequent to the conversion of the amino group to an electron-withdrawing system. In case the amino group is converted by oxidation, then halogenation in ortho-position is carried out prior to oxidation. In case the amino group is converted by reaction with an electron-withdrawing moiety or electron-withdrawing moieties, then halogenation may be carried out prior to oxidation, or vice versa.

[0038] According to particular embodiments, the present invention contemplates reacting the amino group with a divalent electron-withdrawing moiety. According to more particular embodiments, the present invention contemplates reacting the amino group with an aromatic acid anhydride. Suitable acid anhydrides for use in the present invention encompass for example phthalic acid anhydride, or 1,8-naphthalene dicarboxylic anhydride. Further acid anhydrides principally suitable for use in the present invention are known to the person skilled in the art. According to alternative embodiments, the present invention contemplates reacting the amino group with two monovalent electron-withdrawing moieties. Suitable monovalent electron-withdrawing moieties include trifuoroacetic derivatives, trifluorobenzene derivatives, nitro benzene derivatives, cyano benzene derivatives and indandione moieties.

[0039] The general method continues with hydrolyzing the 2-halo-intermediate (III), to form 2-hydroxy- intermediate (IV):

[0040] In the final step of the general method, the electron-withdrawing system is reacted to re-establish the amino group, thereby forming the desired endproduct 5-ethyl-2-amino phenol (I).

[0041] Specific embodiments of the method according to the present invention are described in the following.

[0042] 2 Synthesis of 5-ethyl-2-amino phenol (I) via oxidation of the amine group

[0043] According to a first specific embodiment of the present invention, the electron-withdrawing system is obtained by oxidizing the amino group, in particular by oxidizing the amino group to a nitro group.

[0044] In that case, the first step of the method according to the present invention comprises halogenating 4-ethylaniline (II) in ortho-position, to form 2-halo-4-ethyl-aniline (V):

[0045] (II) (V)

[0046] The halogenation of 4-ethylaniline (II) may be carried out using NBS (N-bromo succinimide), hydrobromic acid, bromine, chorine gas, sulfuryl chloride or NCLS (N-chloro-succinimide), in particular at a temperature from 0°C up to ambient temperature. The preferred halogen in this step is bromine, and a preferred halogenation agent in this step is NBS. The solvent used in the halogenation step may be, for example, DMF, DMSO, tetrachlorocarbon, chloroform, methylenchloride, 1,2-dichloro ethane, 1,2-dimethoxy-ethane, pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, 1,4-dioxane, diethyl ether, tetrahydrofuran, methyl-tetrahydrofuran, aceto nitrile, ethylenglycol, propylenglycol, polyethylene glycols, methanol, ethanol, iso-propanole and mixtures thereof.

[0047] Following halogenation, 2-halo-4-ethyl-aniline (V) is oxidized to form 2-halo-4-ethyl-nitro benzene (VI):

[0048] Oxidation of 2-halo-4-ethyl-nitro benzene (VI) may be carried out using, for example, peroxy sulfuric acid, peroxy disulfuric acid, sodium peroxodisulfate, potassium peroxy disulfate, ammonium peroxy disulfate. Alternative oxidation agents contemplated by the present invention are inorganic oxidizers, such as for example permanganates, mangan dioxide, and cerium salts such as ammonium cer(IV) nitrate (CAN). Further agents suitable for the oxidation reaction include aqueous solutions of hydrogen peroxide in the presence of a base, or hydrogen peroxide with maleic acid anhydride.

[0049] Further oxidizers are organic peracids such as peracetic acid or 3-chloro-perbenzoic acid, or aqueous solutions of such organic peracids.

[0050] The base for the oxidation using aqueous hydrogen peroxide may be selected, for example, from calcium carbonate, sodium carbonate, potassium carbonate, sodium acetate, DBU, DBN, Huenig Base, DABCO, ammonium sulphate, sodium hydrogencarbonate and potassium hydrogencarbonate. According to a particular embodiment, potassium carbonate is used as the base.

[0051] The solvent used for the oxidation step may be, for example, aceto nitrile, toluene, 1,2- dimethoxyethane, ethyl acetate, pentane, cyclopentane, hexane, cyclohexane, benzene, 1,4-dioxane, diethyl ether, tetrahydrofuran, methyl-tetrahydrofuran, n-pentanol, n-butanol, acetic acid, propionic acid, oxalic acid, iso-pentanol, t-butanol, isopropanol, n-propanol, ethanol, methanol, glycols, aqueous solutions thereof, or mixtures thereof. According to a particular embodiment, the solvent may be selected from ethyl acetate, aceto nitrile, toluene, n-butanol, isopropanol, n-propanol, ethanol and methanol, aqueous solutions thereof, and mixtures thereof. Following oxidation to the nitro derivative (VI), the halogen group is hydrolyzed to the hydroxyl group, thereby forming 2-nitro-5-ethyl-phenol (VII):

[0052] The hydrolysis may be carried out under atmospheric pressure at temperatures in the range of 40- 140°C, preferable between 50 and 90 °C. The base may be selected from calcium carbonate, sodium carbonate, potassium carbonate, sodium acetate, DBU, DBN, Huenig Base, DABCO, ammonium sulphate, sodium hydrogencarbonate and potassium hydrogencarbonate. According to a particular embodiment, potassium hydroxide and / or sodium hydroxide are used as the base.

[0053] The solvent for the hydrolysis reaction may be selected from 1,2-dimethoxyethane, pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, methylacetate, ethylacetate, n-propylacetate, iso-propylacetate, n-butylacetate, methylpropionate, ethylpropionate, n-propylpropionate, isopropylpropionate, n-butylpropionate, 1,4-dioxane, diethyl ether, tetrahydrofuran, methyltetrahydrofuran, n-butanol, isopropanol, n-propanol, ethanol, methanol, an aqueous solution thereof, and a mixture thereof. According to a particular embodiment, the solvent may be selected from the group consisting of methanol, ethanol, ethylacetate, toluene and mixtures thereof. From an ecological viewpoint, the solvent may preferably be selected from methanol, ethanol and / or ethylacetate, or an aqueous solution of methanol and / or ethanol.

[0054] As the next step, 2-nitro-5-ethyl-phenol (VII) is reduced to the desired end-product 5-ethyl-2-amino phenol (I). The reduction of 2-nitro-5-ethyl-phenol (VII) typicaly is carried out by hydrogenation, for example via a procedure using palladium on charcoal as catalyst and hydrogen in ethanol as an environmentally friendly solvent to give 5-ethyl-2-amino phenol (I). The hydrogenation step is principally carried out in the presence of a hydrogen source. The hydrogen source may be selected from hydrazine or Hz with a metal catalyst selected from the group consisting of Fe, Pd / C, Pd / (OH)z, Raney-Ni, Pt / C, PtOz and mixtures thereof. In particular, the hydrogen source may be Hz, and the metal catalyst may be a Pd / C catalyst.

[0055] The solvent(s) used in the hydrogenation step may be selected from 1,2-dimethoxyethane, pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, methylacetate, ethylacetate, n-propylacetate, iso-propylacetate, n-butylacetate, methylpropionate, ethylpropionate, n-propylpropionate, iso- propylpropionate, n-butylpropionate, 1,4-dioxane, diethyl ether, tetrahydrofuran, methyltetrahydrofuran, n-butanol, isopropanol, n-propanol, ethanol, methanol, aqueous solutions thereof, and mixtures thereof. According to particular embodiments, the solvent may be selected from methanol, ethanol, ethylacetate, toluene, and mixtures thereof. From an ecological viewpoint, the solvent may be selected from methanol, ethanol and / or ethylacetate, or an aqueous solution of methanol and / or ethanol.

[0056] According to a particular variant of this first specific embodiment, the final two steps, i.e. hydrolyzing the halogen group and reducing the nitro group, may be done simultaneously in a one-pot-reaction. According to this variant of the first specific embodiment, hydrolysis of 2-nitro-5-ethyl-phenol (VII) while simultaneously converting the halogen atom such as fluoro, chloro or bromo, respectively, to a hydroxyl group may be carried out by alkaline hydrolysis in a tube reactor at a temperature of 180°C or less, for example at a temperature of 140-180°C, and a pressure of 2-20 bar. The conversion of an aromatic halogen atom into the corresponding hydroxy group is part of multiple well-known large scale and industrially well elaborated processes (e.g. Lujian Gongye, Volume: 48, Issue: 10, Pages: 29- 31, 2012, CN 114591175 etc.). It mainly focuses on a formal hydrolysis step of the chloro substituent yielding the hydroxy group using large tube reactors, high temperatures (up to 180°C) under high pressure, optionally in the presence of selective metal catalysts.

[0057] The base for alkaline hydrolysis in a tube reactor may be selected from sodium hydroxide, potassium hydroxide, potassium tert-butylate, or a mixture thereof, or an aqueous solution thereof. Typical solvents used for this hydrolysis conversion are selected from sodium hydroxide, potassium hydroxide, potassium tert-butylate, aqueous solutions thereof, and mixtures thereof. According to particular embodiments, the solvent for the hydrolysis may be selected from sodium hydroxide, potassium hydroxide, and mixtures thereof.

[0058] According to particular embodiments, alkaline hydrolysis in a tube reactor may be carried out in the presence of catalyst, for example a catalyst selected from zirconium, cerium, phosphotungstic acid, phosphomolybdic acid, silicotungstic acid, silicomolybdic acid, or a mixture thereof. According to a particularly preferred embodiment, the material of the tube reactor in contact with the reaction comprises cerium, zirconium, or a composite thereof.

[0059] Key steps of the first specific embodiment according to the present invention may be summarized as follows:

[0060] Halogenation of 4-ethylaniline (II) in ortho-position

[0061] Oxidation of 2-halo-4-ethyl-aniline (V) to form 2-halo-4-ethyl-nitro benzene (VI) o Alkaline hydrolysis of 2-halo-4-ethyl-nitro benzene (VI) to form 2-nitro-5-ethyl phenol

[0062] (VII), and hydrogenation of 2-nitro-5-ethyl phenol (VII) to yield the desired endproduct 5-ethyl-2-amino phenol (I) OR o One-step hydrolysis of 2-halo-4-ethyl-nitro benzene (VI) in a tube reactor, to form the desired endproduct 5-ethyl-2-amino phenol (I)

[0063] 2.1 Synthesis of 5-ethyl-2-amino phenol (I) via bromination in ortho-position, and oxidation of the amino group

[0064] The following describes an example of the first specific embodiment, via bromination of 4- ethylaniline (II) in ortho-position using NBS, and oxidation to the nitro compound.

[0065] Synthesis of 2-bromo-4-ethyl-aniline (Va)

[0066] Commercial 4-ethylaniline (II) is reacted with a halogen source which delivers with clear regioselectivity the ortho-product. The halogenation is particularly beneficial in the case of the bromination as it has been demonstrated that the yields and the purity profile is superior versus fluoro, chloro and iodo substitutions. Whilst 4-ethylaniline (II) represents an activated aromatic system, the core bromination using NBS (N-bromo succinimide) is particularly preferred over other bromination regants such as hydrobromic acid or liquid bromine. Chlorination produces more byproducts as the reactivity of free chlorine and particularly chlorine gas is highly reactive, hence chlorination proceeds less regioselective as compared to bromination. A preferred temperature range is 0°C up to ambient temperature, with a particularly preferred temperature range being 0°C up to 5°C. The ortho-bromination is preferably run within 10 up to 60 min, preferably within 25 and 35 min. The progress of the halogenation is monitored by TLC in process control. Once the starting material is completely consumed and the product spot on the TLC looks uniformly, the reaction is stopped while filtrating off the insoluble succinimide which has been formed during the bromination. Further evaporation of the solvent provides the crude product as residue which will be further purified via recrystallization procedures. The solvent used in the halogenation step may be, for example, DMF, DMSO, tetrachlorocarbon, chloroform, methylenchloride, 1,2-dichloro ethane, 1,2- dimethoxy-ethane, pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, 1,4-dioxane, diethyl ether, tetrahydrofuran, methyl-tetrahydrofuran, aceto nitrile, ethylenglycol, propylenglycol, polyethylene glycols, methanol, ethanol, iso-propanole and mixtures thereof. The solvent(s) used for the purifying recrystallization step may be selected from 1,2-dimethoxyethane, pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, methylacetate, ethylacetate, n-propylacetate, iso-propylacetate, n-butylacetate, methylpropionate, ethylpropionate, n-propylpropionate, isopropylpropionate, n-butylpropionate, 1,4-dioxane, diethyl ether, tetrahydrofuran, methyl- tetrahydrofuran, n-butanol, isopropanol, n-propanol, ethanol, methanol, aqueous solutions thereof, and mixtures thereof. According to particular embodiments, the solvent may be selected from methanol, ethanol, ethyl acetate, toluene, aqueous solutions thereof, and mixtures thereof. From an ecological viewpoint, the solvent may preferably be selected from methyl acetate, methanol, ethanol and / or ethyl acetate, and aqueous solutions thereof.

[0067] Synthesis of 2-bromo-4-ethyl-nitro benzene (Via)

[0068] The oxidation of 2-bromo-4-ethyl-aniline (Va) is particularly beneficial to create an electronwithdrawing group at the aromatic ring system. Such an electron-withdrawing system will activate the leaving group properties of the vicinal halogen atom, which will become important for the next synthesis step. The particular advantage is, that direct hydrolysis of the halogen atom in the presence of the unprotected amino group of the aniline system of 2-bromo-4-ethyl-aniline (VI) would require harsh conditions causing multiple side reactions, so that the conversion will end up with many unwanted byproducts which are difficult to separate from the desired intermediate product. In order to bypass this disadvantage, an additional protection group of the amino group would be beneficial. Protecting the amino group would deactivate the strong donor function of the free amino group to some extent, but the subsequent alkaline hydrolysis reaction would require even more aggressive reaction conditions. In addition, after completion of the hydrolysis, the amino function needs to be deprotected, which would add an additional step to the synthesis concept. Hence, the invention as described herein remains superior over the traditional concept using protection and deprotection steps of the amino function. In addition, the electron-withdrawing acceptor effect of the nitro group formed during the oxidation step towards 2-bromo-4-ethyl-nitro benzene (Via) enables a subsequent alkaline hydrolysis of the halogen atom in ortho-position to the nitro group under mild conditions and very good yields.

[0069] The oxidation requires an oxidative agent which selectively oxidizes the amino function without interacting with the halogen group. A typical oxidizer which has proven to be suitable to support the oxidation of an amino group towards a nitro group is aqueous hydrogen peroxide in the presence of a base. The base is important as the oxidation potential of hydrogen peroxide works best in alkaline medium. The base for the oxidation using aqueous hydrogen peroxide may be selected, for example, from calcium carbonate, sodium carbonate, potassium carbonate, sodium acetate, DBU, DBN, Huenig Base, DABCO, ammonium sulphate, sodium hydrogencarbonate and potassium hydrogencarbonate. The downside however still is, that some side reactions due to the alkaline medium, caused by the presence of the halogen atom as a potent leaving group, cannot be avoided completely. Therefore, according to a particular embodiment, potassium carbonate is used as the base as it works in aqueous medium as a mild base.

[0070] Other oxidative systems which do not require an alkaline medium at this stage have shown to work even better. Hence, the system using 3-chloro-perbenzoic acid as a standard peracid reagent works highly efficient in pure organic medium and causes only little amounts of byproducts. Further oxidizers which show good performance regarding the conversion of the amino group to a nitro function are selected from peroxy sulfuric acid, peroxy disulfuric acid, sodium peroxodisulfate, potassium peroxy disulfate, ammonium peroxy disulfate, organic peracids such as peracetic acid, or inorganic oxidizers such as permanganates, mangan dioxide, cerium salts such as ammonium Cer(IV) nitrate (CAN).

[0071] The solvent used for the oxidation step may be, for example, aceto nitrile, toluene, 1,2- dimethoxyethane, ethyl acetate, pentane, cyclopentane, hexane, cyclohexane, benzene, 1,4-dioxane, diethyl ether, tetrahydrofuran, methyl-tetrahydrofuran, n-pentanol, n-butanol, acetic acid, propionic acid, oxalic acid, iso-pentanol, t-butanol, isopropanol, n-propanol, ethanol, methanol, glycols, mixtures thereof, and aqueous solutions thereof. According to a particular embodiment, the solvent may be selected from ethyl acetate, aceto nitrile, toluene, n-butanol, isopropanol, n-propanol, ethanol and methanol, and aqueous solutions thereof. Synthesis of 2-nitro-5-ethyl-phenol (VII)

[0072] The hydrolysis of 2-bromo-4-ethyl-nitro benzene (Via) conveniently may be carried out in an alkaline medium using a nucleophilic base. There are multiple options available to perform this hydrolysis to convert the halogen substituent to the desired hydroxy group. A well elaborated and industrially scalable process follows the hydrolysis in an autoclave system performing the halogen exchange under conditions enabling strong heat and high pressure. This is particular suitable for less activated halogen leaving groups such as commercially widely used aromatic chloro compounds. According to an embodiment, the conversion of the halogen atom such as fluoro, chloro or bromo, respectively, to a hydroxyl group may be carried out in a tube reactor at a temperature of 180°C or less and a pressure range of 2-20 bar. Such commercially well elaborated processes are described in the literature (e.g. Lujian Gongye, Volume: 48, Issue: 10, Pages: 29-31, 2012, CN 114591175 etc.). Ideally, such autoclave reactions require specific metal catalysts to optimize the yields and to minimize te byproducts while applying harsh reaction conditions. Such an alkaline hydrolysis concept with chlorobenzene as the first model compound was described more than 100 years ago (e.g. Bergius / Meyer, Chemische Berichte, 1914). Suitably, the hydrolyzation may be carried out in the presence of catalyst as described above, which catalyst may be selected from zirconium, cerium, phosphotungstic acid, phosphomolybdic acid, silicotungstic acid, silicomolybdic acid, or a mixture thereof. According to a particularly preferred embodiment, the material of the tube reactor in contact with the reaction comprises cerium, zirconium, or a composite thereof. The base is the particular reagent which drives the hydrolysis reaction and causes the exchange of the halogen leaving group while forming the corresponding hydroxy compound. The base to conveniently yield the desired 2-nitro-5-ethyl-phenol (VII) may be selected from sodium hydroxide, potassium hydroxide, potassium tert-butylate, or a mixture thereof, or an aqueous solution thereof. Typical solvents used for this hydrolysis conversion are selected from sodium hydroxide, potassium hydroxide, potassium tert-butylate, aqueous solutions thereof, and mixtures thereof. Preferably, the solvent for the hydrolysis may be selected from the group consisting of sodium hydroxide, potassium hydroxide, and mixtures thereof. However, as the overall synthesis concept as described herein uses in particular a nitro compound which provides a strong electron-withdrawing effect to enable the alkaline hydrolysis already under mild conditions, as described above, reaction conditions which require less harsh conditions related to temperature and pressure, can be applied advantageously for this particular case. The conversion of 2-bromo-4-ethyl-nitro benzene (Via) to 2-nitro-5-ethyl-phenol (VII) advantageously may be carried out under conditions applying atmospheric pressure, which allows skipping a sophisticated autoclave system in combination with moderate to slightly higher reaction temperatures. The temperature range suitably is 40-140°C, preferably between 50 and 90 °C. The nucleophilic base may be selected from calcium carbonate, sodium carbonate, potassium carbonate, sodium acetate, DBU, DBN, Huenig Base, DABCO, ammonium sulphate, sodium hydrogencarbonate and potassium hydrogencarbonate. According to a particular embodiment, potassium hydroxide and sodium hydroxide are used as the base.

[0073] The solvents typically are selected from 1,2-dimethoxyethane, pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, methylacetate, ethylacetate, n-propylacetate, iso-propylacetate, n- butylacetate, methylpropionate, ethylpropionate, n-propylpropionate, iso-propylpropionate, n- butylpropionate, 1,4-dioxane, diethyl ether, tetrahydrofuran, methyl-tetrahydrofuran, n-butanol, isopropanol, n-propanol, ethanol, methanol, aqueous solutions thereof, and mixtures thereof. Preferably, the solvent may be selected from the group consisting of methanol, ethanol, ethylacetate, toluene and mixtures thereof. From an ecological viewpoint, the solvent may preferably be selected from methanol, ethanol and / or ethylacetate, or an aqueous solution of methanol and / or ethanol.

[0074] Synthesis of 2-amino-5-ethyl-phenol (I)

[0075] The hydrogenation step is principally carried out in the presence of a hydrogen source. The hydrogen source may be selected from ammonium formate, hydrazine or Hz with a metal catalyst selected from the group consisting of Fe, Pd / C, Pd / (OH)?, Raney-Ni, Pt / C, PtO? and mixtures thereof. In particular, the hydrogen source may be H?, and the metal catalyst may be a Pd / C catalyst. The solvent(s) used in this step may be selected from the group consisting of 1,2-dimethoxyethane, pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, methylacetate, ethylacetate, n- propylacetate, iso-propylacetate, n-butylacetate, methylpropionate, ethylpropionate, n- propylpropionate, iso-propylpropionate, n-butylpropionate, 1,4-dioxane, diethyl ether, tetrahydrofuran, methyl-tetrahydrofuran, n-butanol, isopropanol, n-propanol, ethanol, methanol, aqueous solutions thereof, and mixtures thereof. Preferably, the solvent may be selected from the group consisting of methanol, ethanol, ethyl acetate, toluene and mixtures thereof. From an ecological viewpoint, the solvent may preferably be selected from methanol, ethanol and / or ethyl acetate, or an aqueous solution of methanol and / or ethanol.

[0076] The reaction is picking up quickly and being kept with gentle cooling at 25°C. After 5h the reaction is complete, and the consumption of hydrogen stops automatically. The catalyst is filtered off through a celite layer to absorb all unwanted high polar impurities at this stage, washed with small portions of methanol and methyl acetate and the filtrate is concentrated by . The desired product (I) is precipitating and collected by filtration. Further recrystallization yields the pure 5-ethyl-2-amino phenol (I).

[0077] 3 Synthesis of 5-ethyl-2-amino phenol (I) via imide ring formation

[0078] Introducing an electron-withdrawing moiety represents an alternative to the oxidation of 2-halo-4- ethyl-aniline (V) in order to establish the required electron-withdrawing acceptor effect for enabling the subsequent alkaline hydrolysis of the halogen atom in ortho-position under mild conditions.

[0079] According to the present invention, the electron-withdrawing system may be formed by reacting the aniline nitrogen with electron-withdrawing moieties. For example, the aniline nitrogen may be reacted with a divalent moiety, in particular with a divalent carboxylic acid anhydride.

[0080] According to a specific embodiment, 4-ethylaniline (II) may be halogenated, for example using NBS, to form 2-bromo-4-ethyl-aniline (Va). Subsequently, a divalent carboxylic acid anhydride such as for example commercially and readily available phthalic acid anhydride may be condensed with 2- bromo-4-ethyl-aniline (Va) from the first step, to obtain 2-(2-bromo-4-ethyl-phenyl)isoindoline-l,3- dione (IXa). The so-formed imide system represents an equally strong electron withdrawing system as compared to the nitro group:

[0081] The condensation requires a base to enable the condensation at temperatures in the range of 110- 180°C, preferably in the range of 120-150°C under normal pressure. The base may be selected, for example, from calcium carbonate, sodium carbonate, potassium carbonate, sodium acetate, DBU, DBN, Huenig Base, DABCO, ammonium sulphate, sodium hydrogencarbonate and potassium hydrogencarbonate. The solvent used for the condensation step may be, for example, chinoline, glycols, polyethylene glycols, toluene, 1,2-dichloro benzene, 1,4-dichloro benzene, DMF, NMP (N- methyl pyrrolidone), DMSO, DMAcA, ortho-xylene, para-xylene, imidazole, 1,2-dimethoxyethane, and mixtures thereof. According to particular embodiments, the solvent may be selected from imidazole, toluene, 1,4-dichloro benzene, DMSO, DMAcA, ortho-xylene, and mixtures thereof.

[0082] If desired, the order of halogenation and condensation with carboxylic acid anhydride may be reversed. In such case, 4-ethylaniline (II) may be first condensed with a divalent carboxylic acid anhydride such as for example commercially and readily available phthalic acid anhydride, to form 2- (4-ethyl-phenyl)isoindoline-l, 3-dione (VIII). Subsequently, the 2-(4-ethyl-phenyl)isoindoline-l,3- dione (VIII) obtained in the first step may be halogenated, for example using NBS, to obtain 2-(2- bromo-4-ethyl-phenyl)isoindoline-l, 3-dione (IXa).

[0083] Irrespective of the exact order of steps in order to arrive at 2-(2-bromo-4-ethyl-phenyl)isoindoline- 1, 3-dione (IXa), this intermediate is subsequently hydrolyzed in order to convert the bromo substituent (or more generally, the halogen substituent) to a hydroxyl group, thereby forming (in the exemplified specific embodiment) 2-(2-hydroxy-4-ethyl-phenyl)isoindoline-l, 3-dione (X):

[0084] The hydrolysis of 2-(2-bromo-4-ethyl-phenyl)isoindoline-l, 3-dione (IXa) to 2-(2-hydroxy-4-ethyl- phenyl)isoindoline-l, 3-dione (X) conveniently may be carried out in alkaline medium using a nucleophilic base.

[0085] The synthesis concept as described herein uses in particular an aromatic imide ring which provides a strong electron-withdrawing effect to enable the alkaline hydrolysis already under mild conditions, as described above, reaction conditions which require less harsh conditions related to temperature and pressure, can be applied advantageously for this particular case. The conversion of 2-(2-bromo-4- ethyl-phenyl)isoindoline-l, 3-dione (IXa) to 2-(2-hydroxy-4-ethyl-phenyl)isoindoline-l, 3-dione (X) typically may be carried out under conditions applying atmospheric pressure which allows skipping a sophisticated autoclave system in combination with moderate to slightly higher reaction temperatures. The temperature range typically is 40-140°C, preferably between 50 and 90 °C. The nucleophilic base conveniently may be selected from calcium carbonate, sodium carbonate, potassium carbonate, sodium acetate, DBU, DBN, Huenig Base, DABCO, ammonium sulphate, sodium hydrogencarbonate and potassium hydrogencarbonate. According to particular embodiments, potassium hydroxide and sodium hydroxide are used as the base.

[0086] The solvents for the hydrolysis typically are selected from 1,2-dimethoxyethane, pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, methylacetate, ethylacetate, n-propylacetate, iso-propylacetate, n-butylacetate, methylpropionate, ethylpropionate, n-propylpropionate, isopropylpropionate, n-butylpropionate, 1,4-dioxane, diethyl ether, tetrahydrofuran, methyltetrahydrofuran, n-butanol, isopropanol, n-propanol, ethanol, methanol, aqueous solutions thereof, and mixtures thereof. Preferably, the solvent may be selected from methanol, ethanol, ethylacetate, toluene and mixtures thereof. From an ecological viewpoint, the solvent may preferably be selected from methanol, ethanol and / or ethylacetate, or an aqueous solution of methanol and / or ethanol. In the next step of this specific embodiment, the isoindoline-1, 3-dione moiety (i.e. the remainder of the phthalic acid anhydride) is removed by aminolysis:

[0087] (X) (i)

[0088] The aminolysis to effectively remove the phthalimide ring system is typically done via a comfortable hydrazinolysis. Such reactions are known, for instance as final step in the Gabriel synthesis to form primary amines. An excess of commercially available aqueous hydrazine solution is used to perform the reductive ring opening reaction and complete conversion of the imide ring into the desired amino compound 5-ethyl-2-amino phenol (I) and the typical reaction product 3-dihydrophthalazine- 1, 4-dione.

[0089] The solvent(s) used in this step may be selected from 1,2-dimethoxyethane, pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, methylacetate, ethylacetate, n-propylacetate, isopropylacetate, n-butylacetate, methylpropionate, ethylpropionate, n-propylpropionate, isopropylpropionate, n-butylpropionate, 1,4-dioxane, diethyl ether, tetrahydrofuran, methyltetrahydrofuran, n-butanol, isopropanol, n-propanol, ethanol, methanol, aqueous solutions thereof, and mixtures thereof. Preferably, the solvent may be selected from the group consisting of methanol, ethanol, ethyl acetate, toluene and mixtures thereof. From an ecological viewpoint, the solvent may preferably be selected from methanol, ethanol and / or ethyl acetate, or an aqueous solution of methanol and / or ethanol.

[0090] EXAMPLES

[0091] The following non-limiting examples further illustrate the present invention. The examples are given solely for the purpose of illustration and are not to be construed as limitations of the present invention, as many variations thereof are possible without departing from the spirit and scope of the invention, which would be recognized by one of ordinary skill in the art. All concentrations are listed as weight percent, unless otherwise specified. Example 1: Synthesis of 2 bromo-4-ethyl-aniline (Va)

[0092] To a solution of 4-ethylaniline (II) (7.0 g, 58 mmol) in 270 mL aceto nitrile, 10.32 g (58 mmol) N- bromo- succinimide (NBS) are added slowly at 0°C and the formed reaction mixture is stirred for further 30 min. The formed succinimide is filtered off and the filtrate is evaporated to recycle the aceto nitrile completely. The formed residue is recrystallized in methanol to obtain 10.8 g pure 2 bromo-4-ethyl-aniline (Va) in 93% yield.

[0093] Example 2: Synthesis of 2-bromo-4-ethyl-nitro benzene (Via)

[0094] 5.0 g (25 mmol) bromo-4-ethyl-aniline (Va) and 33 g m-CPBA (3-chloro-perbenzoic acid) 70wt %, 134 mmol) are dissolved in 100 mL toluene and heated under reflux for 6 h. The reaction mixture then is allowed to cool to room temperature. The formed solid is collected by filtration and washed with a 10% sodium hydroxide solution. After evaporation of the remaining solvent, the precipitate is recrystallized in ethyl acetate to obtain 4.83 g 2-bromo-4-ethyl nitro benzene (Via) in 84% yield.

[0095] Example 3: Synthesis of 2-nitro-5-ethyl phenol (VII)

[0096] A solution containing 90 mL methanol and 10 mL water is prepared, and 13.4 g potassium hydroxide are dissolved slowly. Once a clear solution is obtained, the solution is heated to reflux, and 10.0 g (43.5 mmol) 2-bromo-4-ethyl-nitro benzene (Via) are added quickly. After 4h stirring at reflux, the solution turns deep red, and a precipitate is formed which corresponds to the potassium salt of the nitro-phenol derivative. After cooling down to room temperature, the precipitate is collected and washed with methanol and water, respectively. The red solid is stirred with 20 mL sulfuric acid (20 wt%) at 75°C for further 3 h. The free phenol is formed, and precipitated from the acidic solution. The solid is collected, washed with methanol, and recrystallized with toluene / ethylacetate mixtures to obtain 5.82 g 2-nitro-5-ethyl phenol (VII) in 80% yield.

[0097] Example 4: Synthesis of 5-ethyl-2-amino phenol (I)

[0098] To a solution of 2-nitro-5-ethyl phenol (VII) (2.0 g, 12 mmol) in methanol (20 mL) at 25° C is added 800 mg Pd / C (10 wt %), and the reaction mixture is deoxygenated under vacuum, then purged with hydrogen. After stirring for 5 h, the reaction mixture is filtered through a pad of Celite followed by rinsing with cold methanol and ethyl acetate (200 mL in total). The filtrate is concentrated in vacuum to obtain 1.5 g 5-ethyl-2-amino phenol (I) in 95% yield. Example 5: 2-(2-bromo-4-ethyl-phenyl)isoindoline-l, 3-dione (IXa)

[0099] 5.0 g (25 mmol) 2-bromo-4-ethyl-aniline (Va), 120 mg zinc acetate, 5.55 g (37.5 mmol) phthalic acid anhydride and 50 g imidazole are placed in a reaction vessel and the mixture is stirred at 130°C for 2h. The hot reaction mixture is diluted with 50 ml ethanol and poured into 200 mL 2N hydrochloric acid, stirred for further 30 min, and allow to cool to ambient temperature. The precipitate is filtered off and washed with cold methanol. The solid is added to a satured aqueous solution of sodium carbonate and heated to reflux for 15-20 min. The hot suspension is filtered off to obtain 7.50 g 2-(2- bromo-4-ethyl-phenyl)isoindoline-l, 3-dione (IXa) in 91% yield.

[0100] Example 6: 2-(2-hydroxy-4-ethyl-phenyl)isoindoline-l, 3-dione (X)

[0101] A solution containing 90 mL methanol and 10 mL water is prepared and 13.4 g potassium hydroxide was dissolved slowly. Once a clear solution is obtained, the solution is heated to reflux, and 10 g (30.2 mmol) 2-(2-bromo-4-ethyl-phenyl)isoindoline-l, 3-dione (IXa) are added quickly. After 4h stirring at reflux, the solution turns reddish, and a precipitate is formed which corresponds to the potassium salt of the formed phenolate derivative. After cooling down to room temperature, the precipitate is collected and washed with methanol and water, respectively. The reddish solid is stirred with 20 mL sulphuric acid (20 wt %) at 75°C for further 3 h. The free phenol is formed and precipitated from the acidic solution. The solid is collected, washed with methanol, and recrystallized with toluene / ethylacetate mixtures to obtain 6.93 g 2-(2-hydroxy-4-ethyl-phenyl)isoindoline-l,3- dione (X) in 86% yield.

[0102] Example 7: Synthesis of 5-ethyl-2-amino phenol (I)

[0103] 5.0 g (18.72 mmol) 2-(2-hydroxy-4-ethyl-phenyl)isoindoline-l, 3-dione (X) is dissolved in 180 mL ethanol, and 1.75 mL (56.16 mmol = 3 eq) hydrazine monohydrate are added. After stirring at 80°C for 2 h, the mixture is cooled to ambient temperature. The reaction solution is filtered through a pad of Celite and concentrated in vacuum. The residue is collected and recrystallized in toluene / ethylacetate mixtures, to obtain 2.28 g 5-ethyl-2-amino phenol (I) in 89% yield. EMBODIMENTS

[0104] The following embodiments further describe the present invention.

[0105] 1 Method for preparing 5-ethyl-2-amino phenol (I) , or a salt thereof, the method comprising: ne (II):

[0106] (b) converting the amino group to an electron-withdrawing system, and halogenating the aromatic ring in ortho-position to form 2-halo-intermediate (III): wherein R1 and R2 are electron-withdrawing moieties, or R1 and R2 together form an electron-withdrawing moiety, and wherein X is fluoro, chloro, bromo, or iodo,

[0107] (c) hydrolyzing 2-halo-intermediate (III) to form 2-hydroxy-intermediate (IV): , and (d) converting the electron-withdrawing system of 2-hydroxy-intermediate (IV) to an amino group, to form 5-ethyl-2-amino phenol (I). The method according to embodiment 1, wherein step (b) comprises:

[0108] (bl) halogenating 4-ethylaniline (II) in ortho-position to form 2-halo-4-ethyl-aniline (V):

[0109] ® (V) , and

[0110] (b2) ozidizing said 2-halo-4-ethyl-aniline (V) in the presence of at least one oxidizing agent, to form 2-halo-4-ethyl-nitro benzene (VI): The method according to embodiment 2, wherein oxidation of the amino group to a nitro group is carried out using peroxy sulfuric acid, peroxy disulfuric acid, sodium peroxodisulfate, potassium peroxy disulfate, ammonium peroxy disulfate; inorganic oxidizers such as permanganates, mangan dioxide, cerium salts such as ammonium cer(IV) nitrate (CAN); an aqueous solution of hydrogen peroxide in the presence of a base; hydrogen peroxide with maleic acid anhydride; or organic peracids such as peracetic acid or 3-chloro-perbenzoic acid, or aqueous solutions of organic peracids. The method according to embodiment 3, wherein the oxidation is carried out in the presence of a solvent selected from aceto nitrile, toluene, 1,2-dimethoxyethane, ethyl acetate, pentane, cyclopentane, hexane, cyclohexane, benzene, 1,4-dioxane, diethyl ether, tetrahydrofuran, methyl-tetrahydrofuran, n-pentanol, n-butanol, acetic acid, propionic acid, oxalic acid, isopentanol, t-butanol, isopropanol, n-propanol, ethanol, methanol, glycols, an aqueous solution thereof, and a mixture thereof. The method according to embodiment 4, wherein the solvent is selected from ethyl acetate, aceto nitrile, toluene, n-butanol, isopropanol, n-propanol, ethanol and methanol, an aqueous solution thereof, and a mixture thereof. The method according to any of embodiments 2 to 5, wherein step (c) comprises:

[0111] (cl) hydrolyzing 2-halo-4-ethyl-nitro benzene (VI) to form 2-nitro-5-ethyl-phenol (VII): , and wherein step (d) comprises reducing 2-nitro-5-ethyl-phenol (VII), to form 5-ethyl-2-amino phenol (I). The method according to embodiment 6, wherein hydrolysis of 2-halo-4-ethyl-nitro benzene (VI) to 2-nitro-5-ethyl-phenol (VII) is carried out under alkaline conditions, at a temperature in the range of 40-140°C and normal pressure. The method according to embodiment 6 or 7, wherein reduction of 2-nitro-5-ethyl-phenol (VII) to 5-ethyl-2-amino phenol (I) is carried out in the presence of a hydrogen source selected from hydrazine or H2. The method according to embodiment 8, wherein the reduction is carried out in the presence of metal catalyst selected from the group consisting of Fe, Pd / C, Pd / (OH)2, Raney-Ni, Pt / C, PtO2, and a mixture thereof. The method according to embodiment 8 or 9, wherein the reduction is carried out in the presence of a solvent selected from 1,2-dimethoxyethane, pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, methylacetate, ethylacetate, n-propylacetate, isopropylacetate, n-butylacetate, methylpropionate, ethylpropionate, n-propylpropionate, isopropylpropionate, n-butylpropionate, 1,4-dioxane, diethyl ether, tetrahydrofuran, methyltetrahydrofuran, n-butanol, isopropanol, n-propanol, ethanol, methanol, an aqueous solution thereof, and a mixture thereof. The method according to any of embodiments 2 to 5, wherein steps (c) and (d) are carried out simultaneously, by hydrolyzing 2-halo-4-ethyl-nitro benzene (VI) under alkaline conditions in a tube reactor at a temperature of 140°C to 180°C and a pressure of 2-20 bar, in a solvent selected from sodium hydroxide, potassium hydroxide, potassium tert-butylate, or a mixture thereof, or an aqueous solution thereof, to form 5-ethyl-2-amino phenol (I). The method according to embodiment 11, wherein the hydrolysis is carried out in the presence of at least one catalyst selected from zirconium, cerium, phosphotungstic acid, phosphomolybdic acid, silicotungstic acid and silicomolybdic acid. The method according to embodiment 11 or 12, wherein the material of the tube reactor in contact with the reaction comprises cerium, zirconium, or a composite thereof The method according to embodiment 1, wherein step (b) comprises condensing the amino group with an aromatic acid anhydride, and wherein step (d) comprises aminolysis of said electron-withdrawing system. The method according to embodiment 14, wherein said acid anhydride is selected from phthalic acid anhydride and 1,8-naphthalene dicarboxylic anhydride. The method according to embodiment 14 or 15, wherein step (b) comprises:

[0112] (bl) halogenating 4-ethylaniline (II) in ortho-position, to form 2-halo-4-ethyl-aniline (V):

[0113] (b3) condensing 2-halo-4-ethyl-aniline (V) with phthalic acid anhydride, to form 2-(2-halo-4- ethyl-phenyl)isoindoline-l, 3-dione (IX): wherein step (c) comprises hydrolyzing 2-(2-halo-4-ethyl-phenyl) isoindoline-1, 3-dione (IX) in alkaline medium, to form 2-(2-hydroxy-4-ethyl-phenyl)isoindoline-l, 3-dione (X): and wherein step (d) comprises aminolyzing 2-(2-hydroxy-4-ethyl-phenyl)isoindoline-l, 3-dione (X), to form 5-ethyl-2-amino phenol (I). The method according to embodiment 14 or 15, wherein step (b) comprises:

[0114] (b4) condensing 4-ethyl-aniline (II) with phthalic acid anhydride, to form 2-(4-ethyl-phenyl) isoindoline-1, 3-dione (VIII):

[0115] (b5) halogenating 2-(4-ethyl-phenyl) isoindoline-1, 3-dione (VIII) in ortho-position, to form 2-

[0116] (2-halo-4-ethyl-phenyl) isoindoline-1, 3-dione (IX): wherein step (c) comprises hydrolyzing 2-(2-halo-4-ethyl-phenyl) isoindoline-1, 3-dione (IX) in alkaline medium, to form 2-(2-hydroxy-4-ethyl-phenyl)isoindoline-l, 3-dione (X):

[0117] and wherein step (d) comprises aminolyzing 2-(2-hydroxy-4-ethyl-phenyl)isoindoline-l, 3-dione (X), to form 5-ethyl-2-amino phenol (I). The method according to any of embodiments 14 to 17, wherein condensing the amino group with the aromatic acid anhydride is carried out under alkaline conditions, at a temperature in the range of 110-180°C and normal pressure. The method according to embodiment 18, wherein condensing the amino group with the aromatic acid anhydride is carried out in the presence of a base selected from calcium carbonate, sodium carbonate, potassium carbonate, sodium acetate, DBU, DBN, Huenig Base, DABCO, ammonium sulphate, sodium hydrogencarbonate and potassium hydrogencarbonate. The method according to embodiment 18 or 19, wherein condensing the amino group with the aromatic acid anhydride is carried out in the presence of a solvent selected from chinoline, glycols, polyethylene glycols, toluene, 1,2-dichloro benzene, 1,4-dichloro benzene, DMF, NMP (N-methyl pyrrolidone), DMSO, DMAcA, ortho-xylene, para-xylene, imidazole, 1,2- dimethoxyethane, and a mixture thereof. The method according to any of embodiments 14 to 20, wherein aminolysis is carried out by hydrazinolysis. The method according to any of the preceding embodiments, wherein halogenation at position 4 is carried out using a halogenation agent selected from NBS (N-bromo succinimide), hydrobromic acid, bromine, chorine gas, sulfuryl chloride or NCLS (N-chloro-succinimide). The method according to any of the preceding embodiments, wherein halogenation is carried out at a temperature in the range of 0°C to ambient temperature and normal pressure, preferably for 10-90 minutes. The method according to any of the preceding embodiments, wherein the solvent used in the halogenation is selected from DMF, DMSO, tetrachlorocarbon, chloroform, methylenchloride, 1,2-dichloro ethane, 1,2-dimethoxy-ethane, pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, 1,4-dioxane, diethyl ether, tetrahydrofuran, methyl-tetrahydrofuran, aceto nitrile, ethylenglycol, propylenglycol, polyethylene glycols, methanol, ethanol, iso-propanol, and mixtures thereof. The method according to any of the preceding embodiments, wherein the halogen introduced at position 2 is bromo. The method of any of embodiments 1-10 and 14-25, wherein hydrolysis of the halogen at position 2 to hydroxyl is carried out in alkaline medium in the presence of a nucleophilic base. The method according to embodiment 26, wherein the hydrolysis is carried out in the presence of a base selected from calcium carbonate, sodium carbonate, potassium carbonate, sodium acetate, DBU, DBN, Huenig Base, DABCO, ammonium sulphate, sodium hydrogencarbonate and potassium hydrogencarbonate. The method according to embodiment 26 or 27, wherein the hydrolysis is carried out in the presence of a solvent selected from 1,2-dimethoxyethane, pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, methylacetate, ethylacetate, n-propylacetate, isopropylacetate, n-butylacetate, methylpropionate, ethylpropionate, n-propylpropionate, isopropylpropionate, n-butylpropionate, 1,4-dioxane, diethyl ether, tetrahydrofuran, methyl- tetrahydrofuran, n-butanol, isopropanol, n-propanol, ethanol, methanol, an aqueous solution thereof, and a mixture thereof. The method according to embodiment 28, wherein the solvent is selected from methanol, ethanol, ethylacetate, toluene, an aqueous solution thereof, and a mixture thereof. The method according to embodiment 28, wherein the solvent is selected from methanol, ethanol, and / or ethylacetate, or an aqueous solution of methanol and / or ethanol.

Claims

CLAIMS1 Method for preparing 5-ethyl-2-amino phenol (I), or a salt thereof, the method comprising:(a) providing 4-ethylaniline (II):(b) converting the amino group to an electron-withdrawing system, and halogenating the aromatic ring in ortho-position to form 2-halo-intermediate (III):wherein R1 and R2 are electron-withdrawing moieties, or R1 and R2 together form an electron-withdrawing moiety, and wherein X is fluoro, chloro, bromo, or iodo,(c) hydrolyzing 2-halo-intermediate (III) to form 2-hydroxy-intermediate (IV):, and(d) converting the electron-withdrawing system of 2-hydroxy-intermediate (IV) to an amino group, to form 5-ethyl-2-amino phenol (I).The method according to claim 1, wherein step (b) comprises:(bl) halogenating 4-ethylaniline (II) in ortho-position to form 2-halo-4-ethyl-aniline (V):® (V) , and(b2) ozidizing said 2-halo-4-ethyl-aniline (V) in the presence of at least one oxidizing agent, to form 2-halo-4-ethyl-nitro benzene (VI):(V) (VI) The method according to claim 2, wherein oxidation of the amino group to a nitro group is carried out using peroxy sulfuric acid, peroxy disulfuric acid, sodium peroxodisulfate, potassium peroxy disulfate, ammonium peroxy disulfate; inorganic oxidizers such as permanganates, mangan dioxide, cerium salts such as ammonium cer(IV) nitrate (CAN); an aqueous solution of hydrogen peroxide in the presence of a base; hydrogen peroxide with maleic acid anhydride; or organic peracids such as peracetic acid or 3-chloro-perbenzoic acid, or aqueous solutions of organic peracids, optionally wherein the oxidation is carried out in the presence of a solvent selected from aceto nitrile, toluene, 1,2-dimethoxyethane, ethyl acetate, pentane, cyclopentane, hexane, cyclohexane, benzene, 1,4-dioxane, diethyl ether, tetrahydrofuran, methyl-tetrahydrofuran, n-pentanol, n-butanol, acetic acid, propionic acid, oxalic acid, iso-pentanol, t-butanol, isopropanol, n-propanol, ethanol, methanol, glycols, an aqueous solution thereof, and a mixture thereof, in particular wherein the solvent is selected from ethyl acetate, aceto nitrile, toluene, n-butanol, isopropanol, n-propanol, ethanol and methanol, an aqueous solution thereof, and a mixture thereof.The method according to claim 2 or 3, wherein step (c) comprises:(cl) hydrolyzing 2-halo-4-ethyl-nitro benzene (VI) to form 2-nitro-5-ethyl-phenol (VII):wherein step (d) comprises reducing 2-nitro-5-ethyl-phenol (VII), to form 5-ethyl-2-amino phenol (I). The method according to claim 4, wherein hydrolysis of 2-halo-4-ethyl-nitro benzene (VI) to 2- nitro-5-ethyl-phenol (VII) is carried out under alkaline conditions, at a temperature in the range of 40-140°C and normal pressure. The method according to claim 4 or 5, wherein reduction of 2-nitro-5-ethyl-phenol (VII) to 5- ethyl-2-amino phenol (I) is carried out in the presence of a hydrogen source selected from hydrazine or H2, for example wherein the reduction is carried out in the presence of metal catalyst selected from the group consisting of Fe, Pd / C, Pd / (OH)2, Raney-Ni, Pt / C, PtO2, and a mixture thereof, optionally in the presence of a solvent selected from 1,2-dimethoxyethane, pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, methylacetate, ethylacetate, n-propylacetate, iso-propylacetate, n-butylacetate, methylpropionate, ethylpropionate, n- propylpropionate, iso-propylpropionate, n-butylpropionate, 1,4-dioxane, diethyl ether, tetrahydrofuran, methyl-tetrahydrofuran, n-butanol, isopropanol, n-propanol, ethanol, methanol, an aqueous solution thereof, and a mixture thereof. The method according to claim 2 or 3, wherein steps (c) and (d) are carried out simultaneously, by hydrolyzing 2-halo-4-ethyl-nitro benzene (VI) under alkaline conditions in a tube reactor at a temperature of 140°C to 180°C and a pressure of 2-20 bar, in a solvent selected from sodium hydroxide, potassium hydroxide, potassium tert-butylate, or a mixture thereof, or an aqueous solution thereof, to form 5-ethyl-2-amino phenol (I). The method according to claim 7, wherein the hydrolysis is carried out in the presence of at least one catalyst selected from zirconium, cerium, phosphotungstic acid, phosphomolybdic acid, silicotungstic acid and silicomolybdic acid, optionally wherein the material of the tube reactor in contact with the reaction comprises cerium, zirconium, or a composite thereofThe method according to claim 1, wherein step (b) comprises condensing the amino group with an aromatic acid anhydride, in particular phthalic acid anhydride or 1,8-naphthalene dicarboxylic anhydride, and wherein step (d) comprises aminolysis of said electronwithdrawing system. The method according to claim 9, wherein step (b) comprises:(bl) halogenating 4-ethylaniline (II) in ortho-position, to form 2-halo-4-ethyl-aniline (V):(II) (V)(b3) condensing 2-halo-4-ethyl-aniline (V) with phthalic acid anhydride, to form 2-(2-halo-4- ethyl-phenyl)isoindoline-l, 3-dione (IX):wherein step (c) comprises hydrolyzing 2-(2-halo-4-ethyl-phenyl) isoindoline-1, 3-dione (IX) in alkaline medium, to form 2-(2-hydroxy-4-ethyl-phenyl)isoindoline-l, 3-dione (X):and wherein step (d) comprises aminolyzing 2-(2-hydroxy-4-ethyl-phenyl)isoindoline-l, 3-dione (X), to form 5-ethyl-2-amino phenol (I).The method according to claim 9, wherein step (b) comprises:(b4) condensing 4-ethyl-aniline (II) with phthalic acid anhydride, to form 2-(4-ethyl-phenyl) isoindoline-1, 3-dione (VIII):(b5) halogenating 2-(4-ethyl-phenyl) isoindoline-1, 3-dione (VIII) in ortho-position, to form 2-(2-halo-4-ethyl-phenyl) isoindoline-1, 3-dione (IX):wherein step (c) comprises hydrolyzing 2-(2-halo-4-ethyl-phenyl) isoindoline-1, 3-dione (IX) in alkaline medium, to form 2-(2-hydroxy-4-ethyl-phenyl)isoindoline-l, 3-dione (X):and wherein step (d) comprises aminolyzing 2-(2-hydroxy-4-ethyl-phenyl)isoindoline-l, 3-dione (X), to form 5-ethyl-2-amino phenol (I).The method according to any of claims 9 to 11, wherein condensing the amino group with the aromatic acid anhydride is carried out under alkaline conditions, at a temperature in the range of 110-180°C and normal pressure, optionally in the presence of a base selected from calcium carbonate, sodium carbonate, potassium carbonate, sodium acetate, DBU, DBN, Huenig Base, DABCO, ammonium sulphate, sodium hydrogencarbonate and potassium hydrogencarbonate, optionally in the presence of a solvent selected from chinoline, glycols, polyethylene glycols, toluene, 1,2-dichloro benzene, 1,4-dichloro benzene, DMF, NMP (N-methyl pyrrolidone), DMSO, DMAcA, ortho-xylene, para-xylene, imidazole, 1,2-dimethoxyethane, and a mixture thereof. The method according to any of claims 9 to 12, wherein aminolysis is carried out by hydrazinolysis. The method according to any of the preceding claims, wherein halogenation is carried out at a temperature in the range of 0°C to ambient temperature and normal pressure, preferably for 10-90 minutes, in particular wherein the halogen introduced at position 2 is bromo. The method of any of claims 1 to 6 and 9 to 14, wherein hydrolysis of the halogen at position 2 to hydroxyl is carried out in alkaline medium in the presence of a nucleophilic base, optionally in the presence of a base selected from calcium carbonate, sodium carbonate, potassium carbonate, sodium acetate, DBU, DBN, Huenig Base, DABCO, ammonium sulphate, sodium hydrogencarbonate and potassium hydrogencarbonate, optionally in the presence of a solvent selected from 1,2-dimethoxyethane, pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, methylacetate, ethylacetate, n-propylacetate, iso-propylacetate, n-butylacetate, methylpropionate, ethylpropionate, n-propylpropionate, iso-propylpropionate, n- butylpropionate, 1,4-dioxane, diethyl ether, tetrahydrofuran, methyl-tetrahydrofuran, n- butanol, isopropanol, n-propanol, ethanol, methanol, an aqueous solution thereof, and a mixture thereof.

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