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 is 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] <t or a salt thereof, in particular a cosmetically acceptable salt thereof.

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

[0016] (a) providing 4-ethyl nitro benzene (II):

[0017] (b) partial reduction of 4-ethyl nitro benzene (II) in the presence of a reducing agent, and reaction with chloroformate CIC(O)-OR, to form diester intermediate (III): wherein R is selected from hydrogen, C1-C6 alkyl and C1-C6 hydroxy alkyl,

[0018] (c) sigmatropic rearrangement of diester intermediate (III) to form amidoester intermediate (IV): , and

[0019] (d) hydrolysis of amidoester intermediate (IV) under alkaline conditions, to form 5-ethyl-2-amino phenol (I):

[0020] The step of providing 4-ethyl nitro benzene (II) may comprise reacting an appropriate precursor compound with one or more respective reactant(s), in one or more steps, and optionally separating or isolating 4-ethyl nitro benzene (II).

[0021] With respect to step (b), the chloroformate used in the partial reduction of 4-ethyl nitro benzene (II) may be, according to particular embodiments, methyl chloroformate or ethyl chloroformate.

[0022] The partial reduction of 4-ethyl nitro benzene (II) may be carried out conveniently by electrochemical reduction, which is well-known to the person skilled in the art. Alternatively, the partial reduction may be carried out in the presence of a reducing agent. Suitable reducing agents are well-known to the person skilled in the art. Organic reducing agents suitable for the partial reduction comprise, for example, and comprise for example hydrazine and hydrazine derivatives such as methylhydrazine. Inorganic reducing agents suitable for the partial reduction comprise, for example, base metals, in particular base metals in a reactive form. If the partial reduction is carried out in the presence of a reducing agent, typical reducing agents used are hydrazine or methylhydrazine, or base metal powders, such as zink powder, tin powder, iron powder, or powders of base metals with comparable electronegativities. The term "powder" denotes average particle sizes below 1 mm, typically below 200 pm.

[0023] The partial reduction of 4-ethyl nitro benzene (II), and the subsequent reaction with chloroformate conveniently are carried out in an aqueous solution of organic solvent in the presence of a water- soluble acid.

[0024] The solvent used for the reductive transformational step may be, for example, 1,2-dimethoxy- ethane, pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, 1,2-dichlorobenzene, 1,4- dichlorobenzene, DMSO, DMAcA, NMP, 1,4-dioxane, diethyl ether, methyl-tert-butyl-ether, tetrahydrofuran, methyl-tetrahydrofuran, n-pentanol, n-butanol, iso-pentanol, t-butanol, isopropanol, n-propanol, ethanol, methanol, glycols, an aqueous solution thereof, or a mixture thereof.

[0025] The water-soluble acid conveniently may be selected from weak acids, typically Brbnsted acids such acetic acid and hydrogen halides, or ammonium chloride. According to particular embodiments, the acid is ammonium chloride or aqueous hydrochlorid acid.

[0026] After the partial reduction and subsequent reaction with chloroformate in step (b), the diester intermediate (III) obtained conveniently may be separated from the reaction mixture, typically by extraction. The extraction solvent for diester intermediate (III) may be selected from methyl-tert- butyl-ether, 1,2-dimethoxyethane, methylacetate, ethylacetate, n-propylacetate, iso-propylacetate, n-butylacetate, 1,4-dioxane, diethyl ether, tetrahydrofuran, methyl-tetrahydrofuran, pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, methylpropionate, ethylpropionate, n- propylpropionate, iso-propylpropionate, n-butylpropionate, n-butanol, isopropanol, n-propanol, ethanol, methanol, aqueous solutions thereof, and mixtures thereof.

[0027] According to a particular embodiment, the partial reduction of 4-ethyl nitro benzene (II) and subsequent reaction with chloroformate to form diester intermediate (III) is carried out in the presence of ammonium chloride and an excess of chloroformate at 0°C (preferably freshly prepared, i.e. non-hydrolyzed chloroformate), followed by the addition of organic solvents as denoted above to extract the organic layers. After separation into the extraction solvent, diester intermediate (III) conveniently may be precipitated by addition of a hydrophobic organic solvent. Suitable hydrophobic precipitation solvents comprise pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, 1,2- dichlorobenzene, 1,4-dichlorobenzene, DMSO, DMAcA, NMP, 1,4-dioxane, diethyl ether. According to preferred embodiments, the hydrophobic solvent is hexane or cyclohexane.

[0028] In the next step of the method according to the present invention, diester intermediate (III) undergoes a sigmatropic rearrangement, to form amidoester intermediate (IV).

[0029] According to an embodiment, the sigmatropic rearrangement of diester intermediate (III) to yield amidoester intermediate (IV) is carried out via a thermal rearrangement in high boiling solvents. A suitable temperature may be selected, for example within a temperature range from 100-180°C, in particular within a temperature range of 120-160°C. The thermodynamic reaction requires reaction times of 24-48h to enable essentially complete conversion, or complete conversion of the diester intermediate (III). Microwave-assisted energy supply may significantly reduce the reaction time to a range of 5-10h.

[0030] Suitable solvents used for the rearrangement of diester intermediate intermediate (III) to amidoester intermediate (IV) are high-boiling aprotic organic solvents. The solvent may be selected, for example, from from toluene, o-xylene, m-xylene, p-xylene, nitro benzene, mesitylene, anisoles, 1,2- dichlorobenzene, 1,4-dichlorobenzene, diphenyl ethers, naphthalenes, DMF, DMAcA, NMP, DMSO, chinoline, 1,2-dimethoxyethane, ethylene glycol, glycols, polyethylenglycols, or a mixture thereof.

[0031] Following the rearrangement reaction, amidoester intermediate (IV) may be separated from the reaction mixture. One route for separating amidoester intermediate (IV) comprises concentrating the reaction mixture obtained, cooling down to ambient temperature, and diluting the concenbtrated reaction mixture by addition of aprotic, organic solvents to cause precipitation of amidoester intermediate (IV). Suitable organic aprotic solvents for precipitating amidoester intermediate (IV) include cyclohexane, pentane, cyclopentane, hexane, methyl-tert-butylether, 1,2-dimethoxyethane, methylacetate, ethylacetate, n-propylacetate, iso-propylacetate, n-butylacetate, 1,4-dioxane, diethyl ether, and mixtures thereof.

[0032] In the next step of the method according to the present invention, the formate moieties are cleaved- off from amidoester intermediate (IV), to yield the desired compound 5-ethyl-2-amino phenol (I). Cleaving-off the formate moieties may be carried out via alkaline hydrolysis, in the presence of a nucleophilic base. A typical temperature range for the alkaline hydrolysis is 40-140°C, preferably between 50 and 90 °C. The nucleophilic base may 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 particular embodiments, potassium hydroxide and / or sodium hydroxide are used as the base.

[0033] The solvents for the alkaline hydrolysis may be selected, for example, 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. According to particular embodiments, 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.

[0034] An embodiment of the method according to the present invention for preparing 5-ethyl-2-amino phenol (I) is exemplified below by reaction schemes 2A-2C.

[0035] Reaction scheme 2A illustrates the partial reduction of the nitro function of 4-ethyl nitro benzene (II) to the hydroxyl amin stage, followed by double protection of the nitrogen atom with chloroformate. The exemplified embodiment shows partial reduction in the presence of ammonium chloride and using zinc powder, and subsequent reaction with methyl chloroformate, to give (4-ethyl-N- methoxycarbonyl-anilino)methyl carbonate (V).

[0036] Reaction scheme 2A:

[0037] Reaction scheme 2B illustrates sigmatropic rearrangement of (4-ethyl-N-methoxycarbonyl- anilino)methyl carbonate (V) to form the corresponding [5-ethyl-2- (methoxycarbonylamino)phenyl]methyl carbonate (VI). The exemplified embodiment shows thermally driven sigmatropic rearrangement at high temperatures using xylene as the solvent for the rearragment step. Reaction scheme 2B:

[0038] Reaction scheme 2C illustrates alkaline hydrolysis of the methylformate moieties to obtain the desired endproduct 5-ethyl-2-amino phenol (I). The exemplified embodiment shows alkaline hydrolysis of (4- ethyl-N-methoxycarbonyl-anilino)methyl carbonate (V) in the presence of potassium hydroxide as the base, in methanol.

[0039] Reaction scheme 2C:

[0040] Key steps of the method according to the present invention may be summarized as follows:

[0041] • partial reduction of 4-ethyl nitro benzene (II) to the hydroxyl amin stage followed by subsequent double protection of the nitrogen atom using chloroformate derivatives to form intermediate (III)

[0042] • sigmatropic rearrangement to form intermediate (IV)

[0043] • alkaline hydrolysis of intermediate (IV), to give endproduct 5-ethyl-2-amino phenol (I)

[0044] DEFINITIONS

[0045] 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.

[0046] 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. 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.

[0047] 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.

[0048] DETAILED DESCRIPTION OF THE INVENTION

[0049] 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.

[0050] 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.

[0051] 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.

[0052] 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. The following detailed description exemplifies a particular embodiment of the present invention, specifically using methyl chloroformate, and accordingly involving the specific intermediates (4-ethyl-N-methoxycarbonyl- anilino)methyl carbonate (V) and [5-ethyl-2-(methoxycarbonylamino)phenyl]methyl carbonate (VI).

[0053] 1 Synthesis of (4-ethyl-N-methoxycarbonyl-anilino)methyl carbonate (V)

[0054] Commercial 4-ethyl nitro benzene (II) in a first step is partially reduced to the stage of the corresponding N-hydroxyl amine derivative N-(4-ethylphenyl)hydroxylamine of formula (VII).

[0055] The N-(4-ethylphenyl)hydroxylamine (VII) however, is not isolated and acts only as an intermediate compound which will subsequently react with the highly activated and reactive methyl chloroformate. As the nitrogen of N-(4-ethylphenyl)hydroxylamine (VII) can be substituted at 2 positions, the condensation of the methyl chloroformate will appear directly at the nitrogen substituting the free hydrogen whereas the electron rich hydroxy group may condense with the second methyl chloroformate to form the first isolated intermediate (4-ethyl-N-methoxycarbonyl- anilino)methyl carbonate (V). The reaction is carried out in an aqueous solution of organic solvents in the presence of a water-soluble acid.

[0056] The acid may be selected, for example, from ammonium chloride, acetic acid, or hydrogen halides such as hydrochlorid acid. According to a particular embodiment, ammonium chloride is used as the acid. The acid may be used in amounts from 1-3 molar equivalents, preferably from 1-1.5 molar equivalents.

[0057] The solvent(s) used in this step may be selected from 1,2-dimethoxy-ethane, pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, 1,2-dichlorobenzene, 1,4-dichlorobenzene, DMSO, DMAcA, NMP, 1,4-dioxane, diethyl ether, methyl-tert-butyl-ether, tetrahydrofuran, methyl-tetrahydrofuran, n- pentanol, n-butanol, iso-pentanol, t-butanol, isopropanol, n-propanol, ethanol, methanol, glycols, preferably from tetrahydrofuran, methyl-tert-butyl-ether, methyl-tetrahydrofuran, aqueous solutions thereof, and mixtures thereof.

[0058] The reaction typically is carried out in a temperature range of 0°C -10°C, particularly preferred at 0°C. The product (4-ethyl-N-methoxycarbonyl-anilino)methyl carbonate (V) is isolated via organic extraction into inert ether / ester type solvents. The solvent(s) used in this extraction step may be selected from methyl-tert-butyl-ether, 1,2-dimethoxyethane, methylacetate, ethylacetate, n- propylacetate, iso-propylacetate, n-butylacetate, 1,4-dioxane, diethyl ether, tetrahydrofuran, methyl- tetrahydrofuran, pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, methylpropionate, ethylpropionate, n-propylpropionate, iso-propylpropionate, n-butylpropionate, n-butanol, isopropanol, n-propanol, ethanol, methanol, aqueous solutions thereof, and mixtures thereof. Preferably, the solvent may be selected from ethylacetate, toluene, methyl-tert-butyl-ether and mixtures thereof. After collecting all organic phases and evaporation of the solvent, the product will be precipitated as a white solid with strongly hydrophobic organic solvents. The solvent may be selected from pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, 1,2-dichlorobenzene, 1,4-dichlorobenzene, DMSO, DMAcA, NMP, 1,4-dioxane and diethyl ether. Preferably, the solvent may be selected from hexane, cyclohexane, benzene and toluene.

[0059] 2 Synthesis of [5-ethyl-2-(methoxycarbonylamino)phenyl]methyl carbonate (VI) The sigmatropic rearrangement reaction is driven by thermal activation. The preferred reaction temperature is in the range of 100-200°C, more preferred in the range of 120-180°C. This rearrangement reaction is carried out in the presence of a solvent, preferable under reflux conditions. The solvent in this step is selected from an aprotic solvent, preferably an aromatic aprotic solvent, selected from toluene, o-xylene, m-xylene, p-xylene, nitro benzene, mesitylene, anisoles, 1,2-dichlorobenzene, 1,4-dichlorobenzene, diphenyl ethers, naphthalenes, DMF, DMAcA, NMP, DMSO, chinoline, 1,2-dimethoxyethane, ethylene glycol, glycols, polyethylenglycols. Preferred solvents are xylene derivatives, particularly preferred, according to an embodiment, is p-xylene. The reaction is carried out under normal pressure. The reaction time in order to achieve complete conversion of the typical slower thermodynamics is in the range of 10-55 h, particularly preferred according to an embodiment 42-48h. The rearrangement reaction shall be carried out advantageously in the absence of oxidizers such as air oxygen, as oxidizers typically will cause the formation of unwanted byproducts.

[0060] The product [5-ethyl-2-(methoxycarbonylamino)phenyl]methyl carbonate (VI) is isolated via reducing the aromatic aprotic solvent down to 20-30% by volume, preferable down to 25% by volume and cooling down to ambient temperature, followed by dilution of the obtained reaction mixture with aprotic, organic solvents to cause precipitation of the intermediate [5-ethyl-2- (methoxycarbonylamino)phenyl]methyl carbonate (VI). The organic aprotic solvents used in this step may be selected from cyclohexane, pentane, cyclopentane, hexane, methyl-tert-butyl-ether, 1,2- dimethoxyethane, methylacetate, ethylacetate, n-propylacetate, iso-propylacetate, n-butylacetate, 1,4-dioxane, diethyl ether, and mixtures thereof. Preferably, the solvent may be selected from ethyl acetate, cyclohexane, pentane and mixtures thereof. The intermediate [5-ethyl-2- (methoxycarbonylamino)phenyl]methyl carbonate (VI) is collected by filtration.

[0061] 3 Synthesis of 5-ethyl-2-amino phenol (I)

[0062] (VI) (i) The intermediate [5-ethyl-2-(methoxycarbonylamino)phenyl]methyl carbonate (VI) is transformed to the desired product 5-ethyl-2-amino phenol (I) via an alkaline hydrolysis of the alkyl formate moieties.

[0063] The conversion follows well know standard procedures for cleaving off ester-type and amido-type protection groups under alkaline conditions. This method typically is highly efficient and cost advantageous, as the alkaline hydrolysis can be carried out already under mild conditions. Hence, reaction conditions which require less harsh conditions in terms of temperature and pressure, can be applied advantageously for this particular case. The conversion of [5-ethyl-2- (methoxycarbonylamino)phenyl]methyl carbonate (VI) to 5-ethyl-2-amino phenol (I) 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 is 40-140°C, preferably between 50 and 90 °C. The nucleophilic base may be selected from sodium hydroxide, potassium hydroxide, 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 may be used as the base.

[0064] The solvents for the alkaline hydrolysis may be selected, for example, 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 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.

[0065] The hydrolysis step is typically performed under reflux conditions. The reaction time typically is selected to be in the range of 4-10 h, preferable 5-7 h to allow for essentially complete conversion and cleavage of the formate moieties. Once the reation is complete, the reaction mixture is allowed to cool to ambient temperature, followed by neutralization to pH 7 via addition of mineral acids to form the desired 5-ethyl-2-amino phenol (I) by protonation of the obtained phenolate derivative. The acids conveniently may be selected from hydrochloric acid, acetic acid, sulfuric acid, phosphoric acid, nitric acid, and mixtures thereof. In a particular embodiment, hydrochloric acid may be used as the acid. The precipitated 5-ethyl-2-amino phenol (I) is collected by filtration. Further recrystallization yields the pure 5-ethyl-2-amino phenol (I).

[0066] EXAMPLES

[0067] 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.

[0068] Example 1: Synthesis of (4-ethyl-N-methoxycarbonyl-anilino)methyl carbonate (V)

[0069] 151.16 g (1 mol) of 4-ethyl nitro benzene (II) are dissolved in a solution of 500 mL THF / water (2:1 by volume). 58.3 g (1.1 mol) ammonium chloride are added, and the reaction mixture is cooled to 0°C. 282.0 g (3 mol) chloro methylformate are gradually and slowly added over 15 min, followed by the addition of 130.0 g (2 mol) zinc powder in small portions. The reaction mixture turns greyish and is stirred for further 3 h at 0°C. Once the staring material 4-ethyl nitro benzene (II) is completely consumed, as determined by TLC analysis, the reaction mixture is diluted with 500 mL methyl-tert- butyl-ether. The organic layer is extracted and washed 3-4 times with 500 mL of a saturated aqueous solution of sodium hydrogen carbonate and finally 1-2 times with equal amounts of aqueous NaCI solution. This extraction ensures reducing the salt freight which has been formed during the course of the reaction. The combined organic phases are filtered over a pad of celite and dried over sodium sulfate. After concentrating the solvent to 100-150 mL by evaporation, the product (4-ethyl-N- methoxycarbonyl-anilino)methyl carbonate (V) is precipitated by adding small portions of cyclohexane. The yield of the collected colorless solid is calculated to be 92% (232.7 g).

[0070] Example 2: Synthesis of [5-ethyl-2-(methoxycarbonylamino)phenyl]methyl carbonate (VI)

[0071] 200.0 g (0.79 mol) (4-ethyl-N-methoxycarbonyl-anilino)methyl carbonate (V) are dissolved in 1.8 L p- xylene and heated to reflux for 35h. The reaction progress is monitored by TLC. Once the starting material is completely consumed, as determined by TLC, the reaction mixture is concentrated by evaporation in vacuum to ca. 250 mL and allowed to cool to ambient temperature. The reaction mixture is treated with 250 mL cyclohexane, and cooled to 0°C. The precipitated product [5-ethyl-2- (methoxycarbonylamino)phenyl]methyl carbonate (VI) is collected by filtration and dried over air. The yield is calculated to be 84% (167.9 g). Example 3: Synthesis of 5-ethyl-2-amino phenol (I)

[0072] 150.0 g (0.59 mol) [5-ethyl-2-(methoxycarbonylamino)phenyl]methyl carbonate (VI) are dissolved in 1.2 L methanol and 99.1 g (1.77 mol) solid potassium hydroxide are slowly added to the reaction solution. Once the sodium hydroxide is completely dissolved, the reaction mixture is heated to reflux for further 6 h. After cooling to ambient temperature, the reaction mixture is carefully neutralized to pH 7 by the addition of 2N hydrochloric acid, and cooled to 0°C. The precipitate is collected by filtration and recrystallized from methanol and ethyl acetate to give the desired endproduct 5-ethyl- 2-amino phenol (I) in 94% yield (75.9 g).

Claims

CLAIMS:1 Method for preparing 5-ethyl-2-amino phenol (I), or a salt thereof, the method comprising:(a) providing 4-ethyl nitro benzene (II):(b) partial reduction of 4-ethyl nitro benzene (II), and reaction with chloroformate CIC(O)-OR, to form diester intermediate (III):wherein R is selected from hydrogen, C1-C6 alkyl and C1-C6 hydroxy alkyl,(c) sigmatropic rearrangement of diester intermediate (III) to form amidoester intermediate (IV):(d) hydrolysis of amidoester intermediate (IV) under alkaline conditions, to form 5-ethyl-2- amino phenol (I):The method according to claim 1, wherein the alkyl chloroformate is methyl chloroformate or ethyl chloroformate. The method according to claim 1 or 1, wherein the partial reduction of 4-ethyl nitro benzene (II) is carried out electrochemically, or in the presence of a reducing agent. The method according to any of the preceding claims, wherein the partial reduction of 4-ethyl nitro benzene (II) is carried out in the presence of an organic reducing agent selected from hydrazine or methylhydrazine, or an inorganic reducing agent selected from base metals, in particular base metals in reactive form, such as zinc powder, tin powder, or iron powder. The method according to any of the preceding claims, wherein step (b) is carried out in an aqueous solution of organic solvent in the presence of a water-soluble acid. The method according to claim 5, wherein the water-soluble acid is selected from ammonium chloride, acetic acid and hydrogen halides, in particular wherein the acid is ammonium chloride or aqueous hydrochlorid acid. The method according to any of the preceding claims, wherein step (b) is carried out in a solvent selected from 1,2-dimethoxy-ethane, pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, 1,2-dichlorobenzene, 1,4-dichlorobenzene, DMSO, DMAcA, NMP, 1,4- dioxane, diethyl ether, methyl-tert-butyl-ether, tetrahydrofuran, methyl-tetrahydrofuran, preferably in a solvent selected from tetrahydrofuran, methyl-tert-butyl-ether, methyl- tetrahydrofuran, an aqueous solution thereof, and a mixture thereof. The method according to claim 7, wherein step (b) further comprises extracting diester intermediate (III) into a solvent selected from methyl-tert-butyl-ether, 1,2-dimethoxyethane, methylacetate, ethylacetate, n-propylacetate, iso-propylacetate, n-butylacetate, 1,4-dioxane, diethyl ether, tetrahydrofuran, methyl-tetrahydrofuran, pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, methylpropionate, ethylpropionate, n-propylpropionate, iso-propylpropionate, n-butylpropionate, n-butanol, isopropanol, n-propanol, ethanol, methanol, an aqueous solution thereof, and a mixture thereof. The method according to claim 8, further comprising precipitating diester intermediate (III) by addition of a hydrophobic organic solvent, in particular a solvent selected from pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, 1,2-dichloro benzene, 1,4- dichlorobenzene, DMSO, DMAcA, NMP, 1,4-dioxane and diethyl ether. The method according to any of the preceding claims, wherein the sigmatropic rearrangement reaction is carried out in the presence of an aprotic solvent at a temperature in the range of 100-200°C, in particular at a temperature in the range of 120-180°C. The method according to claim 10, wherein the sigmatropic rearrangement reaction is carried out under normal pressure, for a reaction time of 10-55 hours, in particular 42-48 hours, in an inert atmosphere, preferably in a solvent selected from toluene, o-xylene, m-xylene, p-xylene, nitro benzene, mesitylene, anisoles, 1,2-dichlorobenzene, 1,4-dichlorobenzene, diphenyl ethers, naphthalenes, DMF, DMAcA, NMP, DMSO, chinoline, 1,2-dimethoxyethane, ethylene glycol, glycols, polyethylenglycols, or a mixture thereof. The method according to claim 10 or 11, further comprising precipitating amidoester intermediate (IV) by addition of an aprotic organic solvent, in particular an aprotic organic solvent selected from pentane, cyclopentane, hexane, cyclohexane, methyl-tert-butyl-ether, 1,2-dimethoxyethane, methylacetate, ethylacetate, n-propylacetate, iso-propylacetate, n- butylacetate, 1,4-dioxane, diethyl ether, and a mixture thereof. The method according to any of the preceding claims, wherein conversion of amidoester intermediate (IV) to 5-ethyl-2-amino phenol (I) is carried out by alkaline hydrolysis in the presence of a nucleophilic base at a temperature in the range of 40-140°C, in particular at a temperature in the range of 50-90°C. The method according to claim 13, wherein the nucleophilic base is selected from sodium hydroxide, potassium hydroxide, calcium carbonate, sodium carbonate, potassium carbonate, sodium acetate, DBU, DBN, Huenig Base, DABCO, ammonium sulphate, sodium hydrogencarbonate and potassium hydrogencarbonate and / or wherein the solvent is 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 any of the preceding claims, further comprising recrystallization of 5- ethyl-2-amino phenol (I) from methanol, ethyl acetate, or a mixture thereof.

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