Novel superposition synthesis of 5-ethyl-2-amino-phenol

Abstract

The present invention relates to a process for the preparation of 5-ethyl-2-aminophenol.

Description

Technical Field

[0001] The present invention relates to a novel telescoping synthesis of 5-ethyl-2-aminophenol or its salts. This compound is also known as COLIPA 158. 5-ethyl-2-aminophenol is an important oxidative coupler compound well known in the industry for oxidative hair dyeing compositions. It provides an important light yellow base coating together with oxidative primary colors (such as p-phenylenediamine derivatives and other well-known oxidative precursors) to support the gray coverage and durability of any oxidative hair dyeing. Due to similar dyeing properties compared to resorcinol or methyl-resorcinol, it is a candidate suitable for replacing resorcinol and resorcinol derivatives in oxidative hair dyeing preparations. In view of the rapidly changing global regulatory environment, suitable replacements for resorcinol and methyl-resorcinol will be needed in the near future. Therefore, 5-ethyl-2-aminophenol according to formula (I) represents an attractive candidate to achieve this goal.

[0002] Background Art

[0003] 5-ethyl-2-aminophenol (I) has been found to be a suitable candidate for achieving the goal of providing a solid color backbone in the oxidative hair color palette. It has been rarely used in commercial formulations in the past because a yellow color strike was specifically desired only in special light shades, rather than to address the problem of gray coverage. A large obstacle is the high cost of synthesizing this compound. As the hair coloring industry is moving away from traditional and inexpensive resorcinol derivative compounds (such as resorcinol or methyl-resorcinol), the focus is now on providing advanced and improved syntheses to minimize the financial impact that the withdrawal of resorcinol derivatives may have on hair coloring companies.

[0004] In the past, different synthetic routes for producing 5-ethyl-2-aminophenol (I) or its salts have been published.

[0005] The current commercial synthesis route uses commercially available 4-ethyl-nitrobenzene, which is condensed with benzaldehyde in acetic acid in the presence of zinc. This intermediate reacts with trichloroacetyl chloride to form the desired compound 5-ethyl-2-aminophenol (I) after a rearrangement reaction. Disadvantages are the formation of various by-products during this operation and the difficulty in purification to cosmetic quality. Associated with this fact is the high cost structure following this synthesis route, which is a real burden for the hair dyeing industry compared to the cheap and readily available resorcinol derivatives or resorcinol itself.

[0006] Therefore, it is urgent to provide a novel method for preparing 5-ethyl-2-aminophenol (I) or its salt or their mixture, which provides an attractive and significantly improved cost structure, particularly compared with existing synthetic methods or other published and / or commercial methods. In view of the growing global demand, economically obtaining 5-ethyl-2-aminophenol (I) will be taken seriously. The production method should also be able to provide materials with low impurity levels that meet global regulations. In addition, the method should also reduce the risk of uncontrolled side reactions, and involve cheap starting materials, and use more standardized chemical reactions compared with the known methods that are considered to be the state of the art. Finally, considering the growing ecological needs, the manufacturer should be able to implement the method under mild reaction conditions, including moderate temperature, using ecologically acceptable solvents, and producing a minimum amount of non-recyclable waste solution.

[0007] It has now been unexpectedly discovered that a novel synthetic route starting from readily commercially available raw materials will produce the desired 5-ethyl-2-aminophenol (I) with improved economy and significantly reduced use of organic solvents and harsh chemicals / process aids compared to the current state of the art. The synthetic routes provided herein can use water, aqueous solutions, alcoholic solutions or recyclable organic solvents in one or more steps of the reaction process. Summary of the invention

[0008] The subject of the invention is a process for preparing 5-ethyl-2-aminophenol (I) or its salts or mixtures thereof as defined in claims 1 and 9. The dependent claims relate to specific embodiments thereof.

[0009] According to one embodiment of the present invention, a method for preparing 5-ethyl-2-aminophenol (I) or a salt thereof,

[0010]

[0011] include:

[0012] (a1) providing ethylphenol (II),

[0013]

[0014] (b1) diazotizing an aromatic primary amine (IV) having the formula NH2-R1 in the presence of at least one nitrosating agent, and coupling the reaction product with ethylphenol (II) to form a diazo compound (III), wherein R1 is an aromatic moiety,

[0015]

[0016] (c1) The diazo compound (III) is cleaved under reducing conditions to form 5-ethyl-2-aminophenol (I) and an aromatic amine (IV).

[0017] The exact nature of the aromatic amine (IV) is not particularly critical, and a wide variety of compounds can be used as aromatic amine (IV). However, it is preferred that the polarity of 5-ethyl-2-aminophenol (I) and the polarity of the aromatic amine (IV) are significantly different, because such a polarity difference facilitates the separation of 5-ethyl-2-aminophenol (I) and aromatic amine (IV) in the final step of the method according to the invention. The polarity of 5-ethyl-2-aminophenol (I) expressed as the distribution coefficient LogPow is 1.37, which is determined according to EU method A.8 (36°C). According to a preferred embodiment, the distribution coefficient logPow of the aromatic amine (IV) determined by EU method A.8 is less than -1.5, for example less than -2, such as less than -3.

[0018] According to a specific embodiment, the aromatic moiety of the aromatic amine (IV) having the formula H2N-R1 can be, for example, selected from the aromatic moieties R2 to R15:

[0019]

[0020]

[0021] Preferred aromatic amines (IV) include aromatic amines with acidic moieties, such as R2-NH2, R3-NH2, R10-NH2, R14-NH2, R15-NH2. Another preferred aromatic amine (IV) includes phthalic acid as the aromatic moiety. Also preferred but less preferred are aromatic amines (IV) with nitro groups, such as R11-NH2.

[0022] A particularly preferred aromatic amine (IV) of the formula NH2-R1 is p-aminobenzenesulfonic acid (IX).

[0023] According to one embodiment, the aromatic amine (IV) is diazotized in an aqueous solution under acidic conditions. The nitrosating agent may be, for example, selected from: sodium nitrite, potassium nitrite, nitrogen pentoxide, nitrosylsulfuric acid or a mixture thereof. The acid present in the diazotization step is at least one inorganic acid or organic acid. Conveniently, the acid may be selected from: hydrogen chloride, trifluoroacetic acid, sulfuric acid, sulfurous acid, carbonic acid, nitric acid, acetic acid, propionic acid, phosphoric acid or a mixture thereof. The solvent used in the diazotization step may be, for example: 1,2-dimethoxy-ethane, pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, 1,4-dioxane, diethyl ether, tetrahydrofuran, methyl-tetrahydrofuran, n-pentanol, n-butanol, acetic acid, propionic acid, oxalic acid, malonic acid, sulfuric acid, phosphoric acid, isoamyl alcohol, tert-butyl alcohol, isopropanol, n-propanol, ethanol, methanol, glycol, hydrogen chloride, their aqueous solution or a mixture thereof.

[0024] According to one embodiment, the process may comprise isolating the diazo compound (III).

[0025] The cleavage of the diazo compound (III) is generally carried out using a hydrogen source in the presence of a metal catalyst, particularly using ammonium formate, hydrazine hydrate and / or H2 as a hydrogen source. According to a specific embodiment, the hydrogen source is ammonium formate, and the metal catalyst is Pd / C. Alternatively, the cleavage of the diazo compound (III) can be carried out using an electrochemical method.

[0026] According to one embodiment, the cleavage of the diazo compound (III) under reducing conditions can be carried out in a solvent selected from the following: 1,2-dimethoxyethane, pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, methyl propionate, ethyl propionate, n-propyl propionate, isopropyl propionate, n-butyl propionate, 1,4-dioxane, diethyl ether, tetrahydrofuran, methyl-tetrahydrofuran, n-butanol, isopropanol, n-propanol, ethanol, methanol, their aqueous solutions or their mixtures.

[0027] According to one embodiment, the solvent used in this step is methanol, ethanol, ethyl acetate or a mixture thereof, or an aqueous solution of methanol and / or ethanol.

[0028] Conveniently, the method can also include filtering the reaction mixture to obtain a solution of 5-ethyl-2-aminophenol (I). The target compound 5-ethyl-2-aminophenol (I) can be separated from the filtrate by solvent evaporation subsequently. Typically, the precipitate from the filter will be collected to reclaim metal catalyst and aromatic amine (IV). Especially, aromatic amine (IV) can be recycled to step (b1).

[0029] According to a specific embodiment, the method according to the present invention is carried out under conditions where the hydroxyl group of the starting material ethylphenol (II) is further protected. According to this specific embodiment, step (a1) comprises: reacting ethylphenol (I) with a protecting group R16-X to form O-protected ethylphenol (X), wherein X is OH or Cl,

[0030] Wherein R16 is a protecting group.

[0031] Step (b1) comprises: diazotizing the aromatic primary amine (IV), and coupling the reaction product with O-protected ethylphenol (X) through a reaction therebetween to form an O-protected diazo compound (XI),

[0032]

[0033] Step (c1) comprises: cleaving the O-protected diazo compound (XI) under the reducing conditions to form an O-protected ethylaminophenol (XII) and an aromatic amine (IV), respectively;

[0034]

[0035] The method further comprises: deprotecting the O-protected ethylaminophenol (XII) to obtain the target compound 5-ethyl-2-aminophenol (I).

[0036] The protecting group R16 of this embodiment is a standard group for protecting hydroxyl groups. For example, the protecting group R16 can be selected from:

[0037]

[0038] According to one specific embodiment, the protecting group may be, for example, an acyl group (ie, R17).

[0039] According to another embodiment of the present invention, a method for preparing 5-ethyl-2-aminophenol (I) or a salt thereof,

[0040]

[0041] include:

[0042] (a2) reacting 4-ethylaniline (V) with benzyl chloroformate (XVI) in the presence of a base,

[0043]

[0044] To form protected N-(4-ethylphenyl) benzyl carbamate (VI),

[0045]

[0046] (b2) reacting benzyl N-(4-ethylphenyl)carbamate (VI) with a chlorinating agent in the presence of a secondary amine as an organic catalyst to form benzyl N-(2-chloro-4-ethyl-phenyl)carbamate (VII),

[0047]

[0048] (c2) hydrolyzing benzyl N-(2-chloro-4-ethyl-phenyl)carbamate (VII) to form benzyl N-(4-ethyl-2-hydroxy-phenyl)carbamate (VIII),

[0049]

[0050] (d2) Benzyl N-(4-ethyl-2-hydroxy-phenyl)carbamate (VIII) is cleaved under reducing conditions to form 5-ethyl-2-aminophenol (I).

[0051] According to one embodiment, the base present during the reaction of 4-ethylaniline (V) with benzyl chloroformate (XVI) is selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium bicarbonate, calcium carbonate, sodium carbonate, potassium carbonate, sodium acetate, DBU, DBN, Huenig's base, ammonium sulfate, sodium bicarbonate and potassium bicarbonate. According to a specific embodiment, the base is sodium hydroxide, potassium hydroxide or a mixture thereof.

[0052] According to one embodiment, the reaction of 4-ethylaniline (V) and benzyl chloroformate (XVI) can be carried out in a solvent selected from the group consisting of THF, 1,2-dimethoxyethane, pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, methyl propionate, ethyl propionate, n-propyl propionate, isopropyl propionate, n-butyl propionate, 1,4-dioxane, diethyl ether, tetrahydrofuran, methyl-tetrahydrofuran or a mixture thereof. According to a specific embodiment, the solvent is THF, ethyl acetate, toluene or a mixture thereof.

[0053] The chlorinating agent used in the reaction with N-(4-ethylphenyl)benzyl carbamate (VI) is one of the standard chlorinating agents used. For example, the chlorinating agent is N-chlorosuccinimide, sulfonyl chloride, thionyl chloride or chlorine. Conveniently, the chlorinating agent can be N-chlorosuccinimide or sulfonyl chloride.

[0054] The solvent used in the chlorination reaction can be selected from: toluene, THF, 1,2-dimethoxyethane, pentane, cyclopentane, hexane, cyclohexane, benzene, methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, methyl propionate, ethyl propionate, n-propyl propionate, isopropyl propionate, n-butyl propionate, 1,4-dioxane, diethyl ether, tetrahydrofuran, methyl-tetrahydrofuran or a mixture thereof. According to a specific embodiment, the solvent is toluene, THF, ethyl acetate or a mixture thereof.

[0055] The organic catalyst secondary amine used in the chlorination reaction can be, for example, diisopropylamine, dimethylamine, diethylamine, dibutylamine, dipentylamine, N-isopentyl-3-methyl-butan-1-amine. According to a specific embodiment, the secondary amine is diisopropylamine.

[0056] The hydrolysis of benzyl N-(2-chloro-4-ethyl-phenyl)carbamate (VII) can be conveniently carried out in a tubular reactor at a temperature below 180° C. and a pressure of 2-20 bar. Typical solvents used in the hydrolysis are sodium hydroxide, potassium hydroxide, potassium tert-butylate, mixtures thereof and aqueous solutions thereof.

[0057] According to a specific embodiment, the hydrolysis can be carried out in the presence of a catalyst, for example in the presence of a catalyst selected from the following: zirconium, cerium, phosphotungstic acid, phosphomolybdic acid, silicotungstic acid, silicomolybdic acid or mixtures thereof. According to a particularly preferred embodiment, the material of the tubular reactor in contact with the reaction comprises cerium, zirconium or a composite thereof.

[0058] As is well known in the art, the cleavage of N-(4-ethyl-2-hydroxy-phenyl)benzylcarbamate (VIII) under reducing conditions to obtain the target compound 5-ethyl-2-aminophenol (I) is carried out using a hydrogen source in the presence of a metal catalyst, for example using ammonium formate, hydrazine hydrate and / or H2 as a hydrogen source. According to a specific embodiment, the hydrogen source is ammonium formate and the metal catalyst is Pd / C. Alternatively, the cleavage of the diazo compound (III) can be carried out using an electrochemical method.

[0059] The solvent used in the step of cleaving the diazo compound (III) under reducing conditions can be selected, for example, from: 1,2-dimethoxyethane, pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, methyl propionate, ethyl propionate, n-propyl propionate, isopropyl propionate, n-butyl propionate, 1,4-dioxane, diethyl ether, tetrahydrofuran, methyl-tetrahydrofuran, n-butanol, isopropanol, n-propanol, ethanol, methanol, their aqueous solutions or mixtures thereof. According to a specific embodiment, the solvent is methanol, ethanol, methyl acetate, ethyl acetate or mixtures thereof or their aqueous solutions.

[0060] Conveniently, the method can also include filtering the reaction mixture to obtain a solution of 5-ethyl-2-aminophenol (I). The target compound 5-ethyl-2-aminophenol (I) can be separated from the filtrate by solvent evaporation subsequently. Typically, the precipitate from the filter will be collected to reclaim the metal catalyst.

[0061] The subject of the present invention is a novel process for preparing 5-ethyl-2-aminophenol (I) or its salts or mixtures thereof. The process according to the invention is described further below.

[0062] The first method for preparing 5-ethyl-2-aminophenol (I) is illustrated by reaction schemes 1A and 1B. Reaction scheme 1A shows that 3-ethylphenol (II) is subjected to azo coupling with a suitable aromatic amine of general formula (IV) as a nitrogen donor to obtain the azo intermediate sodium salt of general formula (III). Reaction scheme 1B shows that the azo intermediate sodium salt of general formula (III) is subjected to reductive cleavage by standard hydrogenation methods using ammonium formate, hydrazine hydrate, hydrogen gas, etc. with a metal catalyst (such as palladium supported on carbon (Pd / C)) or electrochemical electrolysis methods to form 5-ethyl-2-aminophenol (I), which can be easily separated from the aromatic nitrogen donor compound of general formula (IV).

[0063] Reaction Scheme 1A

[0064]

[0065] Reaction Scheme 1B

[0066]

[0067] An embodiment according to the first aspect of the present invention, which also involves the protection of the hydroxyl group, is shown in reaction schemes 1C to 1E. This embodiment begins with the conversion of 3-ethylphenol (II) into O-protected ethylphenol (X) using typical protecting groups known to be commonly used for alcohols. The remainder of these protecting groups is represented by R16:

[0068]

[0069] Reaction Scheme 1C shows that O-protected ethylphenol (X) undergoes azo coupling with a suitable aromatic amine of general formula (IV) as a nitrogen donor to obtain an O-protected azo intermediate salt of general formula (XI), such as a sodium salt. Reaction Scheme 1D shows that the O-protected azo intermediate sodium salt of general formula (XI) undergoes azo cleavage by standard hydrogenation methods using ammonium formate, hydrazine hydrate, hydrogen gas, etc. with a metal catalyst such as palladium supported on carbon (Pd / C) or electrochemical electrolysis methods to form an O-protected intermediate (XII), which can be easily separated from the aromatic nitrogen donor compound of general formula (IV). Reaction Scheme 1E shows that after reductive azo cleavage according to literature procedures, the O-protected compound (XII) is deprotected while finally cleaving the protecting group as the last step to obtain the desired product 5-ethyl-2-aminophenol (I).

[0070] Reaction Scheme 1C

[0071]

[0072] Reaction Scheme 1D

[0073]

[0074] Reaction Scheme 1E

[0075]

[0076] According to this 2-step (4-step respectively) method of the present invention, a kind of easy synthesis concept is provided, and it meets the requirement of the green synthesis of mainly using aqueous reaction solution and avoids unnecessary heating step as far as possible.In addition, whenever using organic solvent, the recovery rate is up to 80%.The recovery rate of the aromatic amine of introducing nitrogen used during the diazotization step can be up to 90%.

[0077] The key steps of the first method according to the present invention can be summarized as follows:

[0078] · Azo coupling of 3-ethylphenol (II) with a suitable aromatic amine of general formula (IV)

[0079] Alternatively: 3-ethylphenol (II) is protected to form the starting material of general formula (X) prior to azo coupling with a suitable aromatic amine of general formula (IV) to give the sodium salt of the azo intermediate of general formula (XI)

[0080] The sodium salt of the azo intermediate of general formula (III) undergoes azo cleavage to obtain the desired 5-ethyl-2-aminophenol (I)

[0081] - Alternatively: Azo intermediate (XI) undergoes azo cleavage to give protected compound (XII), followed by deprotection to give the desired compound 5-ethyl-2-aminophenol (I).

[0082] A second method for preparing 5-ethyl-2-aminophenol (I) is shown by Reaction Schemes 2A to 2D.

[0083] Reaction Scheme 2A shows the conversion of commercially available 4-ethylaniline (V) to the N-protected derivative benzyl N-(4-ethylphenyl)carbamate (VI) using commercially available benzyl chloroformate (XVI), for example in THF in the presence of sodium hydroxide or potassium hydroxide.

[0084] Reaction Scheme 2B shows the ortho-chlorination of benzyl N-(4-ethylphenyl)carbamate (VI) using sulfonyl chloride in toluene in the presence of diisopropylamine as a catalyst to form benzyl N-(2-chloro-4-ethyl-phenyl)carbamate (VII).

[0085] Reaction Scheme 2C shows that N-(2-chloro-4-ethyl-phenyl)benzyl carbamate (VII) is converted to the desired compound N-(4-ethyl-2-hydroxy-phenyl)benzyl carbamate (VIII) with a hydroxyl group in the ortho position by alkaline hydrolysis of the chlorine to obtain the corresponding hydroxyl group. The conversion of aromatic chlorine atoms to the corresponding hydroxyl groups is part of a variety of well-known large-scale and industrially well-established processes (e.g., Lujian Gongye, Vol. 48, No. 10, pp. 29-31, 2012, CN 114591175, etc.). It mainly focuses on the formal hydrolysis of chlorine atoms to produce hydroxyl groups using large tubular reactors at high temperatures (up to 180° C.) and high pressures, optionally in the presence of a selective metal catalyst. This method for obtaining N-(4-ethyl-2-hydroxy-phenyl)benzyl carbamate (VIII) is generally very efficient and cost-effective, and will significantly reduce the number of steps.

[0086] Reaction Scheme 2D shows that benzyl N-(4-ethyl-2-hydroxy-phenyl)carbamate (VIII) is then converted by a standard hydrogenation procedure in methyl acetate / methanol as an environmentally friendly solvent mixture using palladium on carbon as a catalyst and hydrogen gas, while efficiently removing the protecting groups to give the desired 5-ethyl-2-aminophenol (I).

[0087] Reaction Scheme 2A

[0088]

[0089] Reaction Scheme 2B

[0090]

[0091] Reaction Scheme 2C

[0092]

[0093] Reaction Scheme 2D

[0094]

[0095] As far as the present invention relates to salts of the form of 5-ethyl-2-aminophenol (I) or salts of intermediates disclosed herein, cosmetically acceptable salts are preferred. Preferred cosmetically acceptable salts are lithium salts, sodium salts, potassium salts, ammonium salts, magnesium salts and calcium salts of the form of 5-ethyl-2-aminophenol (I) or intermediates discussed herein, respectively. As used herein, the term salt includes salts in the traditional sense as well as addition salts. Addition salts encompass addition complexes with acids, bases and / or one or more solvents. Examples of addition salts with acids include complexes of the target compound or intermediates disclosed herein with hydrogen chloride, hydrogen bromide, sulfuric acid, phosphoric acid, acetic acid, citric acid, succinic acid, tartaric acid, lactic acid, toluenesulfonic acid (tosylic acid), benzenesulfonic acid. Examples of addition salts with bases include complexes of the target compound or intermediates disclosed herein with bases such as sodium hydroxide, potassium hydroxide, ammonia, amines or alkanolamines. Examples of addition salts (solvates) with one or more solvents include complexes (hydrates) of the target compound or the intermediate disclosed herein with water or complexes with lower alcohols, i.e., methanol, ethanol, isopropanol, n-propanol, isobutanol, n-butanol. Preferred solvates are hydrates. DETAILED DESCRIPTION

[0096] The order of the steps involved in the telescoping synthesis and large-scale process is described in detail below, including all determined intermediates. It should be understood that when the disclosure refers to a specific structure, all reasonable other tautomeric structures are included. In the art, tautomeric structures are usually represented by a single structure, and the disclosure follows this general practice.

[0097] Should be understood that the step described as preparing 5-ethyl-2-aminophenol (I) can be carried out with continuous one-pot synthesis, wherein reagent is added in the reactor in a mode of once, and does not process (work-up) therebetween. As indicated below, reactions steps requires suitable solvent. It is preferred that the continuous one-pot synthesis not process therebetween is carried out, unless preferably in subsequent steps, avoid the by product from the previous step.

[0098] The present invention relates to a telescoping process for preparing 5-ethyl-2-aminophenol (I), its salts (e.g. its cosmetically acceptable salts) or mixtures thereof, which process comprises the steps as described below.

[0099] The following detailed description illustrates the method according to the present invention by, for example, mentioning specific reactants and / or reaction conditions. This is done for illustrative purposes, and the present invention is not limited thereto. For example, a reference to chlorine should be understood as a reference to a suitable halogen, or a reference to a specific solvent should be understood as a reference to a solvent that is generally suitable for the corresponding reaction and the corresponding target dissolution. Similarly, a reference to a specific acid or base should be understood as a general reference to a suitable acid or base, respectively.

[0100] 1 Synthesis of 5-ethyl-2-aminophenol (I) using 3-ethylphenol (II) as starting material

[0101] 1.1 Synthesis of 4-[(E)-(4-ethyl-2-hydroxy-phenyl)azo]benzenesulfonate (XVII) (sodium salt)

[0102] Reaction Scheme 1A

[0103]

[0104] Commercially available p-aminobenzenesulfonic acid (IX) was suspended in water and then 32% sodium hydroxide solution was added to obtain a clear solution of the corresponding sodium salt. The solution was then diazotized using sodium nitrite and hydrochloric acid at 0°C under standard conditions to produce a colorless and low-viscosity suspension after 60 minutes. At the same time, a solution of 3-ethylphenol (II) in water was prepared. The diazo suspension was then added to the clear aqueous solution under cooling at 0-5°C within 30 minutes. After stirring at a maximum of 7-8°C for 3 hours, the formation of the corresponding diazo compound 4-[(E)-(4-ethyl-2-hydroxy-phenyl)azo]-benzene-sodium sulfonate (XVII) was completed by TLC. The product was obtained by precipitation. Compound (XVII) was collected by filtration in a yield of 96%, and it was washed with a small amount of ethyl acetate and dried under air conditions. In addition, the intermediate (XVII) appeared to be stable, so nitrogen-supported drying was not required.

[0105] The diazotization step is carried out in the presence of at least one nitrosating agent. The one or more nitrosating agents may be selected from the group consisting of sodium nitrite, potassium nitrite, dinitrogen pentoxide, nitrosylsulfuric acid and mixtures thereof.

[0106] This step is carried out in the presence of at least one mineral acid or organic acid. The mineral acid or organic acid can be selected from the group consisting of the following: hydrogen chloride, trifluoroacetic acid, sulfuric acid, sulfurous acid, carbonic acid, nitric acid, acetic acid, propionic acid, phosphoric acid and their mixture. Alternatively, the mineral acid or organic acid can be selected from the group consisting of the following: hydrogen chloride, sulfuric acid, sulfurous acid, acetic acid and their mixture. Alternatively, the mineral acid or organic acid can be sulfuric acid.

[0107] The one or more solvents used in this step can be selected from the group consisting of: 1,2-dimethoxy-ethane, pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, 1,4-dioxane, diethyl ether, tetrahydrofuran, methyl-tetrahydrofuran, n-pentanol, n-butanol, acetic acid, propionic acid, oxalic acid, malonic acid, sulfuric acid, phosphoric acid, isoamyl alcohol, tert-butanol, isopropanol, n-propanol, ethanol, methanol, glycols, hydrogen chloride, their aqueous solutions and mixtures thereof, alternatively selected from the group consisting of: n-butanol, isopropanol, n-propanol, ethanol, methanol, acetic acid, propionic acid, oxalic acid, malonic acid, hydrogen chloride, sulfuric acid, phosphoric acid, their aqueous solutions and mixtures thereof, preferably selected from the group consisting of: n-propanol, acetic acid, propionic acid, oxalic acid, malonic acid, hydrogen chloride, sulfuric acid, phosphoric acid, their aqueous solutions and mixtures thereof.

[0108] 1.2 Synthesis of 5-ethyl-2-aminophenol (I)

[0109] Reaction Scheme 1B

[0110]

[0111] 4-[(E)-(4-ethyl-2-hydroxy-phenyl)azo]-benzene-sodium sulfonate (XVII) is suspended in methyl acetate and stirred to form a uniform yellow suspension. Pd / C (wetted with 50% water) is then added to the mixture and the container is purged with nitrogen before adding hydrogen. The hydrogenation step is mainly carried out in the presence of a hydrogen source. The hydrogen source can be selected from: ammonium formate, hydrazine or H2, and the metal catalyst is selected from the group consisting of: Fe, Pd / C, Pd / (OH)2, Raney nickel (Raney-Ni), Pt / C, PtO2 and mixtures thereof. In particular, the hydrogen source can be H2, and the metal catalyst can be a Pd / C catalyst. The one or more solvents used in this step can be selected from the group consisting of the following: 1,2-dimethoxyethane, pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, methyl propionate, ethyl propionate, n-propyl propionate, isopropyl propionate, n-butyl propionate, 1,4-dioxane, diethyl ether, tetrahydrofuran, methyl-tetrahydrofuran, n-butanol, isopropanol, n-propanol, ethanol, methanol, water and their mixture. Preferably, the solvent can be selected from the group consisting of the following: methanol, ethanol, ethyl acetate, toluene and their mixture. From an ecological point of view, the solvent can be preferably selected from methanol, ethanol and / or ethyl acetate, or an aqueous solution of methanol and / or ethanol. The reaction is carried out rapidly and is maintained at 20°C for slow cooling. After 1.5 hours, the reaction is complete, and the consumption of hydrogen stops automatically. The catalyst and the precipitated p-aminobenzenesulfonic acid (IX) are filtered out, washed with a small portion of methyl acetate, and the filtrate is evaporated. The desired product (I) precipitates and is collected by filtration. Further recrystallization affords pure 5-ethyl-2-aminophenol (I).

[0112] By pH adjustment, p-aminobenzenesulfonic acid (IX) is separated from charcoal and palladium catalyst. In this article, the material mixture filtered is processed with 32% sodium hydroxide aqueous solution. The material containing sulfonic acid (for example p-aminobenzenesulfonic acid (IX)) is converted into the corresponding sodium salt, and is easily dissolved in the aqueous phase, while the charcoal and palladium catalyst can be filtered out, separated, and reused in other chemical operations. The catalyst can be reused for at least 10 continuous chemical operations, such as hydrogenation as described herein. Then the aqueous phase is acidified with hydrochloric acid. After being cooled to 0-5 ℃, p-aminobenzenesulfonic acid (IX) is precipitated, and it can be easily collected by filtering. It is observed that the maximum recovery is about 80%. The isolated p-aminobenzenesulfonic acid (IX) can be used again for chemical operations, such as diazotization as described herein, to drive the economy of chemical method as described herein.

[0113] The azo cleavage step is mainly carried out in the presence of a hydrogen source. The hydrogen source can be selected from: ammonium formate, hydrazine or H2, and the metal catalyst is selected from the group consisting of the following: Fe, Pd / C, Pd / (OH)2, Raney nickel (Raney-Ni), Pt / C, PtO2 and their mixture. In particular, the hydrogen source can be H2, and a Pd / C catalyst is used. The one or more solvents used in this step can be selected from the group consisting of the following: 1,2-dimethoxyethane, pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, methyl propionate, ethyl propionate, n-propyl propionate, isopropyl propionate, n-butyl propionate, 1,4-dioxane, diethyl ether, tetrahydrofuran, methyl-tetrahydrofuran, n-butanol, isopropyl alcohol, n-propyl alcohol, ethanol, methanol, water and their mixture. Preferably, the solvent may be selected from the group consisting of methanol, ethanol, water, ethyl acetate, toluene and mixtures thereof. From an ecological point of view, the solvent may be preferably selected from methyl acetate, methanol, ethanol and / or ethyl acetate, or aqueous solutions thereof.

[0114] 2 Synthesis of 5-ethyl-2-aminophenol (I) using ethylphenol (II) as starting material while protecting the hydroxyl group

[0115] The following illustrates an embodiment of the first method according to the present invention, wherein acetic acid (3-ethylphenyl) ester (XIII) is used as the starting material with an acyl protecting group. This improvement of the first method according to the present invention typically improves the yield. Compound (XIII) can be prepared by standard operations using acetyl chloride or acetic anhydride as acetylating agents.

[0116] 2.1 Synthesis of 4-[(E)-(2-acetoxy-4-ethyl-phenyl)azo]benzenesulfonic acid (XIV) (sodium salt)

[0117] Reaction Scheme 1C

[0118]

[0119] The azo coupling was carried out while commercially available p-aminobenzenesulfonic acid (IX) was suspended in water and then 32% sodium hydroxide solution was added to obtain a clear solution of the corresponding sodium salt. The solution was then diazotized using sodium nitrite and hydrochloric acid at 0°C under standard conditions to produce a colorless and low-viscosity suspension after 60 minutes. At the same time, a solution of acetic acid (3-ethylphenyl) ester (XIII) in an aqueous alcohol solution was prepared. The diazo suspension was then added to the clear aqueous solution under cooling at 0-5°C within 30 minutes. After stirring at a maximum of 7-8°C for 3 hours, the formation of the corresponding diazo compound 4-[(E)-(2-acetoxy-4-ethyl-phenyl)azo]-sodium benzenesulfonate (XIV) was completed by TLC. The product was obtained by precipitation. Compound (XIV) was collected by filtration with a yield of 92%, and it was washed with a small amount of ethyl acetate and dried under air conditions. In addition, the intermediate (XIV) appeared to be stable, so nitrogen-supported drying was not required.

[0120] The diazotization step is carried out in the presence of at least one nitrosating agent. The one or more nitrosating agents may be selected from the group consisting of sodium nitrite, potassium nitrite, dinitrogen pentoxide, nitrosylsulfuric acid and mixtures thereof.

[0121] This step is carried out in the presence of at least one mineral acid or organic acid. The mineral acid or organic acid can be selected from the group consisting of the following: hydrogen chloride, trifluoroacetic acid, sulfuric acid, sulfurous acid, carbonic acid, nitric acid, acetic acid, propionic acid, phosphoric acid and their mixture. Alternatively, the mineral acid or organic acid can be selected from the group consisting of the following: hydrogen chloride, sulfuric acid, sulfurous acid, acetic acid and their mixture. Alternatively, the mineral acid or organic acid can be sulfuric acid.

[0122] The one or more solvents used in this step may be selected from the group consisting of: 1,2-dimethoxy-ethane, pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, 1,4-dioxane, diethyl ether, tetrahydrofuran, methyl-tetrahydrofuran, n-pentanol, n-butanol, acetic acid, propionic acid, oxalic acid, malonic acid, sulfuric acid, phosphoric acid, isoamyl alcohol, tert-butanol, isopropanol, n-propanol, ethanol, methanol, glycol, hydrogen chloride, water and mixtures thereof, alternatively selected from the group consisting of: n-butanol, isopropanol, n-propanol, ethanol, methanol, acetic acid, propionic acid, oxalic acid, malonic acid, hydrogen chloride, sulfuric acid, phosphoric acid and mixtures thereof, preferably selected from the group consisting of: n-propanol 、 Acetic acid, propionic acid, oxalic acid, malonic acid, hydrogen chloride, sulfuric acid, phosphoric acid, water and mixtures thereof.

[0123] 2.2 Synthesis of intermediate (2-amino-5-ethyl-phenyl) acetate (XV)

[0124] Reaction Scheme 1D

[0125]

[0126] Sodium 4-[(E)-(2-acetoxy-4-ethyl-phenyl)azo]benzenesulfonate (XIV) is suspended in methyl acetate and stirred to form a uniform yellow suspension. Pd / C (wetted with 50% water) is then added to the mixture and the container is purged with nitrogen before adding hydrogen. The hydrogenation step is mainly carried out in the presence of a hydrogen source. The hydrogen source can be selected from: ammonium formate, hydrazine or H2, and the metal catalyst is selected from the group consisting of: Fe, Pd / C, Pd / (OH)2, Raney-Ni, Pt / C, PtO2 and mixtures thereof. In particular, the hydrogen source can be H2, and the metal catalyst can be a Pd / C catalyst. The one or more solvents used in this step can be selected from the group consisting of the following: 1,2-dimethoxyethane, pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, methyl propionate, ethyl propionate, n-propyl propionate, isopropyl propionate, n-butyl propionate, 1,4-dioxane, diethyl ether, tetrahydrofuran, methyl-tetrahydrofuran, n-butanol, isopropanol, n-propanol, ethanol, methanol, water and their mixture. Preferably, the solvent can be selected from the group consisting of the following: methanol, ethanol, ethyl acetate, toluene and their mixture. From an ecological point of view, the solvent can be preferably selected from methanol, ethanol and / or ethyl acetate, or an aqueous solution of methanol and / or ethanol. The reaction is carried out rapidly and is maintained at 20°C for slow cooling. After 1.5 hours, the reaction is complete, and the consumption of hydrogen stops automatically. The catalyst and the precipitated p-aminobenzenesulfonic acid (IX) are filtered out, washed with a small portion of methyl acetate, and the filtrate is evaporated. The intermediate (2-amino-5-ethyl-phenyl) acetate (XV) precipitated and was collected by filtration.

[0127] By pH adjustment, p-aminobenzenesulfonic acid (IX) is separated from charcoal and palladium catalyst. In this article, the material mixture filtered is processed with 32% sodium hydroxide aqueous solution. The material containing sulfonic acid (for example p-aminobenzenesulfonic acid (IX)) is converted into the corresponding sodium salt, and easily dissolved in the aqueous phase, while the charcoal and palladium catalyst can be filtered out, separated, and reused in other chemical operations. The catalyst can be reused for at least 10 continuous chemical operations, such as hydrogenation as described herein. Then the aqueous phase is acidified with hydrochloric acid. After being cooled to 0-5 ℃, p-aminobenzenesulfonic acid (IX) is precipitated, and it can be easily collected by filtering. It is observed that the maximum recovery is about 80%. The isolated p-aminobenzenesulfonic acid (IX) can be used again for chemical operations, such as diazotization as described herein, to drive the economy of chemical method as described herein.

[0128] The azo cleavage step is mainly carried out in the presence of a hydrogen source. The hydrogen source can be selected from: ammonium formate, hydrazine or H2, and the metal catalyst is selected from the group consisting of the following: Fe, Pd / C, Pd / (OH)2, Raney nickel (Raney-Ni), Pt / C, PtO2 and their mixture. In particular, the hydrogen source can be H2, and a Pd / C catalyst is used. The one or more solvents used in this step can be selected from the group consisting of the following: 1,2-dimethoxyethane, pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, methyl propionate, ethyl propionate, n-propyl propionate, isopropyl propionate, n-butyl propionate, 1,4-dioxane, diethyl ether, tetrahydrofuran, methyl-tetrahydrofuran, n-butanol, isopropyl alcohol, n-propyl alcohol, ethanol, methanol, water and their mixture. Preferably, the solvent may be selected from the group consisting of methanol, ethanol, water, ethyl acetate, toluene and mixtures thereof. From an ecological point of view, the solvent may be preferably selected from methyl acetate, methanol, ethanol and / or ethyl acetate, or aqueous solutions thereof.

[0129] 2.3 Synthesis of 5-ethyl-2-aminophenol (I)

[0130] Reaction Scheme 1E

[0131]

[0132] Finally, the intermediate (2-amino-5-ethyl-phenyl) acetate (XV) is treated in an alkaline solution at high temperature (about 80-90° C.) to completely remove the protecting group, thereby obtaining the desired target compound 5-ethyl-2-aminophenol (I). The base can be selected from: sodium hydroxide, potassium hydroxide, sodium bicarbonate, calcium carbonate, sodium carbonate, potassium carbonate, sodium acetate, DBU, DBN, Huenig base, ammonium sulfate, sodium bicarbonate and potassium bicarbonate. According to one embodiment, sodium hydroxide and potassium hydroxide are used as bases.

[0133] 3 Synthesis of 5-ethyl-2-aminophenol (I) using 4-ethylaniline (V) as starting material

[0134] 3.1 Synthesis of N-(4-ethylphenyl)benzyl carbamate (VI) Scheme 2A

[0135]

[0136] The second method according to the present invention begins with utilizing benzyl chloroformate (XVI) to transform commercially available 4-ethylaniline (V) in THF in the presence of potassium carbonate as a base to obtain N-(4-ethylphenyl) benzyl carbamate (VI). Compound (VI) is a protected intermediate, which has been proven to effectively protect the amino functional group from forming any undesirable by-products in subsequent steps. In addition, the protecting group is stable for pH changes and other physical treatments (such as conditions under high pressure (autoclave conditions) or high temperature (up to 180-200 ℃)), and it can be easily removed by standard hydrogenation methods. The reaction is started at 0 ℃ for 10 minutes, then it is warmed to ambient temperature, and stirred for another 24 hours to complete the reaction. The solvent is evaporated, and the organic phase is washed 3 times with salt water and dried. The evaporation of the solvent obtains N-(4-ethylphenyl) benzyl carbamate (VI), which is further recrystallized.

[0137] The base may be selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium bicarbonate, calcium carbonate, sodium carbonate, potassium carbonate, sodium acetate, DBU, DBN, Huenig's base, ammonium sulfate, sodium bicarbonate and potassium bicarbonate. According to one embodiment, sodium carbonate and potassium carbonate are used as bases.

[0138] The one or more solvents used in the step including the final recrystallization step may be selected from the group consisting of THF, 1,2-dimethoxyethane, pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, methyl propionate, ethyl propionate, n-propyl propionate, isopropyl propionate, n-butyl propionate, 1,4-dioxane, diethyl ether, tetrahydrofuran, methyl-tetrahydrofuran and mixtures thereof. Preferably, the solvent may be selected from the group consisting of THF, ethyl acetate, toluene and mixtures thereof.

[0139] 3.2 Synthesis of N-(2-chloro-4-ethyl-phenyl)carbamic acid benzyl ester (VII) Scheme 2B

[0140]

[0141] In the next step, N-(4-ethylphenyl) benzyl carbamate (VI) is chlorinated at the ortho position of the nitrogen group. This conversion is carried out in an organic solvent using a reagent commonly used in aromatic ring chlorination (such as sulfonyl chloride or N-chlorosuccinimide). Therefore, N-(4-ethylphenyl) benzyl carbamate (VI) is suspended in toluene, and then 10 mol % of a secondary amine as an organic catalyst is added to improve the regioselectivity to the ortho position. For this operation, commercially available diisopropylamine is used as an easily available and inexpensive secondary amine. Then sulfonyl chloride is slowly added at room temperature within 10 minutes. The reaction is then stirred at room temperature for 24 hours to complete. Any excess sulfonyl chloride is neutralized by adding 10 volume % of sodium sulfite aqueous solution. The organic phase is separated from the aqueous phase and the solvent is evaporated, thereby achieving a recovery rate of at least 80%. The product N-(2-chloro-4-ethyl-phenyl) benzyl carbamate (VII) is precipitated by recrystallization, and the yield is 94%.

[0142] The one or more solvents used in this step can be selected from the group consisting of: toluene, THF, 1,2-dimethoxyethane, pentane, cyclopentane, hexane, cyclohexane, benzene, methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, methyl propionate, ethyl propionate, n-propyl propionate, isopropyl propionate, n-butyl propionate, 1,4-dioxane, diethyl ether, tetrahydrofuran, methyl-tetrahydrofuran and mixtures thereof. Preferably, the solvent can be selected from the group consisting of: toluene, THF, ethyl acetate and mixtures thereof.

[0143] The secondary amine may be selected from the group of diisopropylamine, dimethylamine, diethylamine, dibutylamine, dipentylamine, N-isopentyl-3-methyl-butan-1-amine. According to one embodiment, diisopropylamine is used as organic catalyst.

[0144] The chlorinating agent is selected from the group consisting of: N-chlorosuccinimide, sulfuryl chloride, thionyl chloride, chlorine. According to one embodiment, N-chlorosuccinimide and sulfuryl chloride are used as chlorinating agents.

[0145] 3.3 Synthesis of N-(4-ethyl-2-hydroxy-phenyl)carbamic acid benzyl ester (VIII)

[0146] Reaction Scheme 2C

[0147]

[0148] N-(2-chloro-4-ethyl-phenyl)benzyl carbamate (VII) is then converted to the desired compound N-(4-ethyl-2-hydroxy-phenyl)benzyl carbamate (VIII) by alkaline hydrolysis of the chlorine atom to obtain the corresponding hydroxyl group. The conversion of aromatic chlorine atoms to the corresponding hydroxyl groups is part of a variety of well-known large-scale and industrially well-established processes (e.g., Lujian Gongye, Vol. 48, No. 10, pp. 29-31, 2012, CN 114591175, etc.). They mainly focus on the formal hydrolysis step of the chlorine atoms using large tubular reactors at high temperatures (up to 180° C.) and high pressures, optionally in the presence of selective metal catalysts.

[0149] This method of obtaining benzyl N-(4-ethyl-2-hydroxy-phenyl)carbamate (VIII) is generally very efficient and cost-effective and will significantly reduce the number of steps.

[0150] Typical solvents for the hydrolysis conversion are selected from: sodium hydroxide, potassium hydroxide, potassium tert-butoxide, their mixtures and their aqueous solutions. Preferably, the solvent for the hydrolysis can be selected from the group consisting of the following: sodium hydroxide, potassium hydroxide and their aqueous mixtures. Metal catalysts include: zirconium, cerium, acid catalysts such as phosphotungstic acid, phosphomolybdic acid, silicotungstic acid and silicomolybdic acid. The material for the tubular autoclave in contact with the material in the reaction system includes one of the following: cerium, zirconium or its composite.

[0151] 3.4 Synthesis of 5-ethyl-2-aminophenol (I)

[0152] Reaction Scheme 2D

[0153]

[0154] The last step includes cleaving the protecting group under reducing conditions. This step is mainly carried out in the presence of a hydrogen source. The hydrogen source can be selected from: ammonium formate, hydrazine or H2, and the metal catalyst is selected from the group consisting of: Fe, Pd / C, Pd / (OH)2, Raney nickel (Raney-Ni), Pt / C, PtO2 and their mixtures. In particular, the hydrogen source can be H2, and a Pd / C catalyst is used.

[0155] The one or more solvents used in this step can be selected from the group consisting of: 1,2-dimethoxyethane, pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, methyl propionate, ethyl propionate, n-propyl propionate, isopropyl propionate, n-butyl propionate, 1,4-dioxane, diethyl ether, tetrahydrofuran, methyl-tetrahydrofuran, n-butanol, isopropyl alcohol, n-propanol, ethanol, methanol, water and mixtures thereof. Preferably, the solvent can be selected from the group consisting of: methanol, ethanol, water, ethyl acetate, toluene and mixtures thereof.

[0156] From an ecological point of view, the solvent may preferably be selected from methyl acetate, methanol, ethanol and / or ethyl acetate, or aqueous solutions thereof.

[0157] Once hydrogen is blown into the solution of N-(4-ethyl-2-hydroxy-phenyl) benzyl carbamate (VIII), the reaction proceeds rapidly and is maintained at 20°C for slow cooling. After 1.5 hours, the reaction is complete and the consumption of hydrogen stops automatically. The catalyst is filtered out, washed with a small portion of methyl acetate, and the filtrate is evaporated. The desired product (I) is precipitated and collected by filtration. Further recrystallization gives pure 5-ethyl-2-aminophenol (I).

[0158] The following embodiments further describe the present invention.

[0159] 1. A method for preparing 5-ethyl-2-aminophenol (I) or a salt thereof,

[0160]

[0161] The method comprises:

[0162] (a1) Providing ethylphenol (II)

[0163]

[0164] (b1) diazotizing an aromatic primary amine (IV) having the formula NH2-R1 in the presence of at least one nitrosating agent, and coupling the reaction product with ethylphenol (II) to form a diazo compound (III), wherein R1 is an aromatic moiety,

[0165]

[0166] (c1) The diazo compound (III) is cleaved under reducing conditions to form 5-ethyl-2-aminophenol (I) and an aromatic amine (IV).

[0167] 2. The method according to embodiment 1, wherein the aromatic amine (IV) has a distribution coefficient logPow determined by EU method A.8 of less than -1.5.

[0168] 3. The method according to embodiment 1 or 2, wherein the R1 part of the aromatic amine (IV) is selected from R2 to R15:

[0169]

[0170] 4. The method according to embodiment 3, wherein the R1 part of the aromatic amine (IV) is selected from R2, R3, R10, R14, R15.

[0171] 5. The method according to any one of the preceding embodiments, wherein the aromatic primary amine (IV) is p-aminobenzenesulfonic acid (IX).

[0172] 6. The method according to any one of the preceding embodiments, wherein the diazotization is carried out in aqueous solution under acidic conditions.

[0173] 7. The method according to any one of the preceding embodiments, wherein the nitrosating agent is selected from the group consisting of sodium nitrite, potassium nitrite, nitrogen pentoxide, nitrosylsulfuric acid, or mixtures thereof.

[0174] 8. The method according to any one of the preceding embodiments, wherein the diazotization is carried out in the presence of at least one inorganic or organic acid selected from the group consisting of hydrogen chloride, trifluoroacetic acid, sulfuric acid, sulfurous acid, carbonic acid, nitric acid, acetic acid, propionic acid, phosphoric acid or mixtures thereof.

[0175] 9. The method according to embodiment 7 or 8, wherein the diazotization is carried out in a solvent selected from the group consisting of: 1,2-dimethoxy-ethane, pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, 1,4-dioxane, diethyl ether, tetrahydrofuran, methyl-tetrahydrofuran, n-pentanol, n-butanol, acetic acid, propionic acid, oxalic acid, malonic acid, sulfuric acid, phosphoric acid, isopentanol, tert-butanol, isopropanol, n-propanol, ethanol, methanol, glycols, hydrogen chloride, their aqueous solutions or their mixtures.

[0176] 10. The method according to any one of the preceding embodiments, further comprising isolating the diazo compound (III).

[0177] 11. The method according to any one of the preceding embodiments, wherein the cleavage of the diazo compound (III) is carried out in the presence of a metal catalyst using a hydrogen source, in particular using ammonium formate, hydrazine hydrate and / or H2 as a hydrogen source.

[0178] 12. The method of embodiment 11, wherein the hydrogen source is ammonium formate and the metal catalyst is Pd / C.

[0179] 13. The method according to any one of embodiments 1 to 10, wherein the cleavage of the diazo compound (III) is performed using an electrochemical method.

[0180] 14. A method according to any one of embodiments 11 to 13, wherein the cleavage of the diazo compound (III) under reducing conditions is carried out in a solvent selected from the group consisting of: 1,2-dimethoxyethane, pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, methyl propionate, ethyl propionate, n-propyl propionate, isopropyl propionate, n-butyl propionate, 1,4-dioxane, diethyl ether, tetrahydrofuran, methyl-tetrahydrofuran, n-butanol, isopropanol, n-propanol, ethanol, methanol, an aqueous solution thereof, or a mixture thereof.

[0181] 15. The method according to embodiment 14, wherein the solvent is selected from: methanol, ethanol, ethyl acetate or a mixture thereof, or wherein the solvent is an aqueous solution of methanol and / or ethanol.

[0182] 16. The method according to any one of embodiments 11 to 15, further comprising filtering the reaction mixture to obtain a solution of 5-ethyl-2-aminophenol (I), and isolating 5-ethyl-2-aminophenol (I) by solvent evaporation.

[0183] 17. The method according to embodiment 16 further comprises: collecting the precipitate from the filter and recovering the metal catalyst and aromatic amine (IV).

[0184] 18. The method according to embodiment 17, further comprising: recycling the aromatic amine (IV) to step (b1).

[0185] 19. The method according to any one of the preceding embodiments, wherein step (a1) comprises: reacting ethylphenol (I) with a protecting group R16-X to form O-protected ethylphenol (X), wherein X is OH or Cl,

[0186]

[0187] Wherein R16 is a protecting group,

[0188] wherein step (b1) comprises: diazotizing the aromatic primary amine (IV), and coupling the reaction product with an O-protected ethylphenol (X) through a reaction therebetween to form an O-protected diazo compound (XI),

[0189]

[0190] wherein step (c1) comprises: cleaving the O-protected diazo compound (XI) under the reducing conditions to form an O-protected ethylaminophenol (XII) and an aromatic amine (IV),

[0191]

[0192] The method further comprises: deprotecting the O-protected ethylaminophenol (XII) to form 5-ethyl-2-aminophenol (I).

[0193] 20. The method according to embodiment 19, wherein the protecting group R16 is selected from:

[0194]

[0195] 21. The method of embodiment 21, wherein the protecting group is an acyl group.

[0196] 22. A process for preparing 5-ethyl-2-aminophenol (I) or a salt thereof,

[0197]

[0198] The method comprises:

[0199] (a2) reacting 4-ethylaniline (V) with benzyl chloroformate (XVI) in the presence of a base,

[0200]

[0201] To form protected N-(4-ethylphenyl) benzyl carbamate (VI),

[0202]

[0203] (b2) reacting benzyl N-(4-ethylphenyl)carbamate (VI) with a chlorinating agent in the presence of a secondary amine as an organic catalyst to form benzyl N-(2-chloro-4-ethyl-phenyl)carbamate (VII),

[0204]

[0205] (c2) hydrolyzing benzyl N-(2-chloro-4-ethyl-phenyl)carbamate (VII) to form benzyl N-(4-ethyl-2-hydroxy-phenyl)carbamate (VIII),

[0206]

[0207] (d2) Benzyl N-(4-ethyl-2-hydroxy-phenyl)carbamate (VIII) is cleaved under reducing conditions to form 5-ethyl-2-aminophenol (I).

[0208] 23. A method according to embodiment 22, wherein the base present during the reaction of 4-ethylaniline (V) with benzyl chloroformate (XVI) is selected from: sodium hydroxide, potassium hydroxide, sodium bicarbonate, calcium carbonate, sodium carbonate, potassium carbonate, sodium acetate, DBU, DBN, Huenig's base, ammonium sulfate, sodium bicarbonate and potassium bicarbonate.

[0209] 24. The method of embodiment 23, wherein the base is sodium hydroxide, potassium hydroxide, or a mixture thereof.

[0210] 25. A method according to any one of embodiments 22 to 24, wherein the reaction of 4-ethylaniline (V) with benzyl chloroformate (XVI) is carried out in a solvent selected from the group consisting of THF, 1,2-dimethoxyethane, pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, methyl propionate, ethyl propionate, n-propyl propionate, isopropyl propionate, n-butyl propionate, 1,4-dioxane, diethyl ether, tetrahydrofuran, methyl-tetrahydrofuran or a mixture thereof.

[0211] 26. The method of embodiment 25, wherein the solvent is THF, ethyl acetate, toluene, or a mixture thereof.

[0212] 27. The method according to any one of embodiments 22 to 26, wherein the chlorinating agent is selected from: N-chlorosuccinimide, sulfonyl chloride, thionyl chloride and chlorine gas.

[0213] 28. The method of embodiment 27, wherein the chlorinating agent is N-chlorosuccinimide or sulfonyl chloride.

[0214] 29. A method according to embodiment 27 or 28, wherein the chlorination reaction is carried out in a solvent selected from the following: toluene, THF, 1,2-dimethoxyethane, pentane, cyclopentane, hexane, cyclohexane, benzene, methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, methyl propionate, ethyl propionate, n-propyl propionate, isopropyl propionate, n-butyl propionate, 1,4-dioxane, diethyl ether, tetrahydrofuran, methyl-tetrahydrofuran or a mixture thereof.

[0215] 30. The method of embodiment 29, wherein the solvent is toluene, THF, ethyl acetate, or a mixture thereof.

[0216] 31. The method according to any one of embodiments 22 to 30, wherein the secondary amine is selected from: diisopropylamine, dimethylamine, diethylamine, dibutylamine, dipentylamine, N-isopentyl-3-methyl-butan-1-amine, in particular wherein the secondary amine is diisopropylamine.

[0217] 32. A method according to any one of embodiments 22 to 31, wherein the hydrolysis of benzyl N-(2-chloro-4-ethyl-phenyl)carbamate (VII) is carried out in a tubular reactor at a temperature below 180°C and a pressure of 2-20 bar in a solvent selected from the group consisting of sodium hydroxide, potassium hydroxide, potassium tert-butoxide, mixtures thereof and aqueous solutions thereof.

[0218] 33. The method according to embodiment 32, wherein the hydrolysis is carried out in the presence of at least one catalyst selected from the group consisting of zirconium, cerium, phosphotungstic acid, phosphomolybdic acid, silicotungstic acid and silicomolybdic acid.

[0219] 34. A method according to embodiment 32 or 33, wherein the material of the tubular reactor in contact with the reaction comprises cerium, zirconium or a composite thereof.

[0220] 35. A method according to any one of embodiments 22 to 34, wherein the cleavage of benzyl N-(4-ethyl-2-hydroxy-phenyl)carbamate (VIII) is carried out in the presence of a metal catalyst using a hydrogen source, in particular using ammonium formate, hydrazine hydrate and / or H2 as a hydrogen source.

[0221] 36. A method according to embodiment 35, wherein the hydrogen source is ammonium formate and the metal catalyst is Pd / C.

[0222] 37. The method according to any one of embodiments 22 to 34, wherein the cleavage of the diazo compound (III) is performed using an electrochemical method.

[0223] 38. A method according to any one of embodiments 35 to 37, wherein the cleavage of the diazo compound (III) under reducing conditions is carried out in a solvent selected from the group consisting of: 1,2-dimethoxyethane, pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, methyl propionate, ethyl propionate, n-propyl propionate, isopropyl propionate, n-butyl propionate, 1,4-dioxane, diethyl ether, tetrahydrofuran, methyl-tetrahydrofuran, n-butanol, isopropanol, n-propanol, ethanol, methanol, an aqueous solution thereof, or a mixture thereof.

[0224] 39. The method according to embodiment 38, wherein the solvent is selected from: methanol, ethanol, methyl acetate, ethyl acetate, or a mixture thereof or an aqueous solution thereof.

[0225] 40. The method according to any one of embodiments 35 to 39, further comprising filtering the reaction mixture to obtain a solution of 5-ethyl-2-aminophenol (I), and isolating 5-ethyl-2-aminophenol (I) by solvent evaporation.

[0226] 41. The method according to embodiment 40 further comprises: collecting the precipitate from the filter and recovering the metal catalyst.

Claims

1. A method for preparing 5-ethyl-2-aminophenol (I) or a salt thereof, The method comprises: (a1) providing ethylphenol (II), (b1) diazotizing an aromatic primary amine (IV) having the formula NH2-R1 in the presence of at least one nitrosating agent, and coupling the reaction product with ethylphenol (II) to form a diazo compound (III), wherein R1 is an aromatic moiety, (c1) The diazo compound (III) is cleaved under reducing conditions to form 5-ethyl-2-aminophenol (I) and an aromatic amine (IV).

2. The method according to claim 1, wherein the R1 portion of the aromatic amine (IV) is selected from R2 to R15:

3. The method according to claim 2, wherein the R1 portion of the aromatic amine (IV) is selected from R2, R3, R10, R14, R15.

4. A process according to any one of the preceding claims, wherein the diazotization is carried out in aqueous solution under acidic conditions.

5. The method according to any one of the preceding claims, wherein the nitrosating agent is selected from: sodium nitrite, potassium nitrite, nitrogen pentoxide, nitrosylsulfuric acid or mixtures thereof.

6. The process according to any one of the preceding claims, wherein the diazotization is carried out in the presence of at least one inorganic or organic acid selected from the group consisting of hydrogen chloride, trifluoroacetic acid, sulfuric acid, sulfurous acid, carbonic acid, nitric acid, acetic acid, propionic acid, phosphoric acid or mixtures thereof.

7. The method according to any one of the preceding claims, wherein step (a1) comprises: Reacting ethylphenol (I) with a protecting group R16-X to form O-protected ethylphenol (X), wherein X is OH or Cl, Wherein R16 is a protecting group, wherein step (b1) comprises: diazotizing the aromatic primary amine (IV), and coupling the reaction product with an O-protected ethylphenol (X) through a reaction therebetween to form an O-protected diazo compound (XI), wherein step (c1) comprises: cleaving the O-protected diazo compound (XI) under the reducing conditions to form an O-protected ethylaminophenol (XII) and an aromatic amine (IV), The method further comprises: deprotecting the O-protected ethylaminophenol (XII) to form 5-ethyl-2-aminophenol (I).

8. The method according to claim 7, wherein the protecting group R16 is selected from:

9. A process for preparing 5-ethyl-2-aminophenol (I) or a salt thereof, The method comprises: (a2) reacting 4-ethylaniline (V) with benzyl chloroformate (XVI) in the presence of a base, To form protected N-(4-ethylphenyl) benzyl carbamate (VI), (b2) reacting benzyl N-(4-ethylphenyl)carbamate (VI) with a chlorinating agent in the presence of a secondary amine as an organic catalyst to form benzyl N-(2-chloro-4-ethyl-phenyl)carbamate (VII), (c2) hydrolyzing benzyl N-(2-chloro-4-ethyl-phenyl)carbamate (VII) to form benzyl N-(4-ethyl-2-hydroxy-phenyl)carbamate (VIII), (d2) Benzyl N-(4-ethyl-2-hydroxy-phenyl)carbamate (VIII) is cleaved under reducing conditions to form 5-ethyl-2-aminophenol (I).

10. The process according to claim 9, wherein the base present during the reaction of 4-ethylaniline (V) with benzyl chloroformate (XVI) is selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium bicarbonate, calcium carbonate, sodium carbonate, potassium carbonate, sodium acetate, DBU, DBN, Huenig's base, ammonium sulfate, sodium bicarbonate and potassium bicarbonate.

11. The method according to claim 9 or 10, wherein the secondary amine is selected from the group consisting of diisopropylamine, dimethylamine, diethylamine, dibutylamine, dipentylamine, N-isopentyl-3-methyl-butan-1-amine, in particular wherein the secondary amine is diisopropylamine.

12. The process according to any one of claims 9 to 11, wherein the hydrolysis of benzyl N-(2-chloro-4-ethyl-phenyl)carbamate (VII) is carried out in a tubular reactor at a temperature below 180°C and a pressure of 2 to 20 bar in a solvent selected from the group consisting of sodium hydroxide, potassium hydroxide, potassium tert-butoxide, mixtures thereof and aqueous solutions thereof.

13. The process according to claim 12, wherein the hydrolysis is carried out in the presence of at least one catalyst selected from the group consisting of zirconium, cerium, phosphotungstic acid, phosphomolybdic acid, silicotungstic acid and silicomolybdic acid.

14. The process according to any one of claims 9 to 13, wherein the cleavage of benzyl N-(4-ethyl-2-hydroxy-phenyl)carbamate (VIII) is carried out in the presence of a metal catalyst using a hydrogen source, in particular using ammonium formate, hydrazine hydrate and / or H2 as a hydrogen source.

15. The method according to claim 14, wherein the cleavage of the diazo compound (III) under reducing conditions is carried out in a solvent selected from the group consisting of: 1,2-dimethoxyethane, pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, methyl propionate, ethyl propionate, n-propyl propionate, isopropyl propionate, n-butyl propionate, 1,4-dioxane, diethyl ether, tetrahydrofuran, methyl-tetrahydrofuran, n-butanol, isopropanol, n-propanol, ethanol, methanol, their aqueous solutions or their mixtures.

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