Method for synthesizing 5-ethyl-2-aminophenol

Abstract

The invention relates to a method for synthesizing 5-ethyl-2-aminophenol (5-ethyl-2-aminophenol).

Description

Technical Field

[0001] The present invention relates to a process for synthesizing 5-ethyl-2-aminophenol or a salt thereof. This compound is also known as COLIPA no. A158. 5-Ethyl-2-aminophenol is known in the industry as an important oxidative coupler compound for oxidative hair dye compositions. It provides an important yellowish primer for oxidative primary dyes (primary dye precursors), such as p-phenylenediamine derivatives and other well-known oxidative precursors, to support gray coverage and the permanence of any oxidative hair coloring. Due to its similar coloring properties compared to resorcinol or methylresorcinol, it is a suitable candidate for replacing resorcinol and resorcinol derivatives in oxidative hair dye formulations. In view of the rapidly changing global regulatory environment, suitable alternatives to resorcinol and methylresorcinol will be needed in the near future. Therefore, 5-ethyl-2-aminophenol according to formula (I) represents an attractive candidate for achieving 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. In the past, it was rarely used in commercial formulations because the yellow strike was only specifically required in special light shades, rather than to address the gray coverage problem. A major obstacle is the cost-intensive synthesis of this compound. As the hair dye industry is phasing out traditional and inexpensive resorcinol derivative compounds such as resorcinol or methylresorcinol, there is now a focus on providing advanced and improved syntheses to minimize the financial impact that the withdrawal of resorcinol derivatives may have on hair dye companies.

[0004] In the past, the industry has published different synthetic routes to produce 5-ethyl-2-aminophenol (I) or its salts.

[0005] The current synthetic route for preparing 5-ethyl-2-aminophenol (I) is a process that goes back to Eastman-Kodak's US Pat. No. 5,214,194A. As shown in the following reaction scheme 1, the process starts with commercially available 4-ethyl-nitrobenzene, which is condensed with benzaldehyde in acetic acid in the presence of zinc. This intermediate is reacted with trichloroacetyl chloride to form the desired compound 5-ethyl-2-aminophenol (I) after a rearrangement reaction.

[0006] Reaction Scheme 1

[0007]

[0008] A drawback of this current commercial process is the numerous by-products formed during this operation, which are difficult to purify to cosmetic quality. Coupled with this fact is the high cost structure of following this synthetic route, which represents a significant burden for the hair dye industry compared to the cheap and readily available resorcinol derivatives or resorcinol itself.

[0009] Therefore, it is highly desirable to provide a novel method for preparing 5-ethyl-2-aminophenol (I) or its salt or its mixture, the method providing an attractive and significantly improved cost structure, particularly compared to current existing synthesis methods or other published and / or commercial methods. In view of growing global demand, obtaining 5-ethyl-2-aminophenol (I) in an economical manner will be appreciated. This manufacturing method should also be able to provide a material with low impurity levels that complies with 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 to the known methods that are considered to be prior art. Finally, in view of growing ecological demands, manufacturers should be able to perform the method under mild reaction conditions (including moderate temperature, use of ecologically acceptable solvents, and generation of minimal non-recyclable waste liquid).

[0010] Surprisingly, it has now been discovered that a new synthetic concept starting from readily commercially available feedstock materials will produce the desired 5-ethyl-2-aminophenol (I) with enhanced economy relative to the current state of the art and significantly reduced use of organic solvents and harsh chemicals / processing aids. The synthetic route proposed herein can use water, aqueous alcoholic solutions or recyclable organic solvents in one or more steps of the reaction process. Summary of the Invention

[0011] The subject matter of the present invention is a process for preparing 5-ethyl-2-aminophenol (I) or its salts or mixtures thereof as defined in claim 1. The dependent claims relate to special embodiments thereof.

[0012] The subject of the present invention is a process for preparing 5-ethyl-2-aminophenol (I) or its salts, in particular its cosmetically acceptable salts

[0013]

[0014] The method according to the present invention comprises:

[0015] (a) Providing 4-ethylnitrobenzene (II):

[0016]

[0017] (b) 4-Ethylnitrobenzene (II) is partially reduced in the presence of a reducing agent and reacted with chloroformate ClC(O)-OR to form a diester intermediate (III):

[0018]

[0019] wherein R is selected from hydrogen, C1-C6 alkyl and C1-C6 hydroxyalkyl,

[0020] (c) subjecting the diester intermediate (III) to a sigma shift rearrangement to form the amide ester intermediate (IV):

[0021] and

[0022] (d) hydrolyzing the amide ester intermediate (IV) under basic conditions to form 5-ethyl-2-aminophenol (I):

[0023]

[0024] The step of providing 4-ethylnitrobenzene (II) may comprise reacting a suitable precursor compound with one or more corresponding reactants in one or more steps, and optionally separating or isolating the 4-ethylnitrobenzene (II).

[0025] As for step (b), according to a particular embodiment, the chloroformate used in the partial reduction of 4-ethylnitrobenzene (II) can be methyl chloroformate or ethyl chloroformate.

[0026] The partial reduction of 4-ethylnitrobenzene (II) can be conveniently carried out by electrochemical reduction, which is well known to those skilled in the art. Alternatively, the partial reduction can be carried out in the presence of a reducing agent. Suitable reducing agents are well known to those skilled in the art. Organic reducing agents suitable for partial reduction include, for example, hydrazine and hydrazine derivatives (such as methylhydrazine). Inorganic reducing agents suitable for partial reduction include, for example, base metals, particularly reactive forms of base metals. If partial reduction is carried out in the presence of a reducing agent, the typical reducing agent used is hydrazine or methylhydrazine, or base metal powders, such as zinc powder, tin powder, iron powder or powders of base metals with considerable electronegativity. The term "powder" means an average particle size less than 1 mm, typically less than 200 μm.

[0027] The partial reduction of 4-ethylnitrobenzene (II) and the subsequent reaction with the chloroformate can be conveniently carried out in aqueous solution of an organic solvent in the presence of a water-soluble acid.

[0028] The solvent used in the reductive conversion step can be, for example, 1,2-dimethoxyethane, 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, methyltetrahydrofuran, n-pentanol, n-butanol, isopentanol, tert-butanol, isopropanol, n-propanol, ethanol, methanol, a diol, an aqueous solution thereof, or a mixture thereof.

[0029] The water-soluble acid may conveniently be selected from a weak acid, typically a Bronsted acid ( Acid) such as acetic acid and hydrogen halide, or ammonium chloride. According to a particular embodiment, the acid is aqueous hydrochloric acid or ammonium chloride.

[0030] After partial reduction and subsequent reaction with chloroformate in step (b), the diester intermediate (III) obtained can be conveniently separated from the reaction mixture, typically by extraction. The extraction solvent for the diester intermediate (III) can be selected from methyl tert-butyl ether, 1,2-dimethoxyethane, methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, 1,4-dioxane, diethyl ether, tetrahydrofuran, methyltetrahydrofuran, pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, methyl propionate, ethyl propionate, n-propyl propionate, isopropyl propionate, n-butyl propionate, n-butanol, isopropyl alcohol, n-propanol, ethanol, methanol, aqueous solutions thereof, and mixtures thereof.

[0031] According to a particular embodiment, the partial reduction of 4-ethylnitrobenzene (II) and the subsequent reaction with chloroformate to form the diester intermediate (III) are carried out at 0° C. in the presence of ammonium chloride and excess chloroformate (preferably freshly prepared, i.e., unhydrolyzed chloroformate), followed by addition of an organic solvent as described above to extract the organic layer.

[0032] After separation into the extraction solvent, the diester intermediate (III) can be conveniently precipitated by adding a hydrophobic organic solvent. Suitable hydrophobic precipitation solvents include pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, 1,2-dichlorobenzene, 1,4-dichlorobenzene, DMSO, DMAcA, NMP, 1,4-dioxane, diethyl ether. According to a preferred embodiment, the hydrophobic solvent is hexane or cyclohexane.

[0033] In the next step of the process according to the invention, the diester intermediate (III) undergoes a sigma shift rearrangement to form the amide ester intermediate (IV).

[0034] According to one embodiment, the σ shift rearrangement of the diester intermediate (III) to produce the amide ester intermediate (IV) is carried out via thermal rearrangement in a high boiling point solvent. Suitable temperatures can be selected, for example, in the temperature range of 100-180° C., particularly in the temperature range of 120-160° C. The thermodynamic reaction requires a reaction time of 24-48 hours to achieve substantially complete conversion or complete conversion of the diester intermediate (III). Microwave-assisted energy supply can significantly shorten the reaction time to a range of 5-10 hours.

[0035] Suitable solvents for the rearrangement of the diester intermediate (III) to the amide ester intermediate (IV) are high boiling aprotic organic solvents. The solvent can be selected from, for example, toluene, o-xylene, m-xylene, p-xylene, nitrobenzene, mesitylene, anisole, 1,2-dichlorobenzene, 1,4-dichlorobenzene, diphenyl ether, naphthalene, DMF, DMAcA, NMP, DMSO, quinoline, 1,2-dimethoxyethane, ethylene glycol, glycol, polyethylene glycol, or a mixture thereof.

[0036] After the rearrangement reaction, the amide ester intermediate (IV) can be separated from the reaction mixture. A kind of approach for separating the amide ester intermediate (IV) includes concentrating the reaction mixture obtained, being cooled to ambient temperature, and diluting the concentrated reaction mixture by adding an aprotic organic solvent, to cause the precipitation of the amide ester intermediate (IV). Suitable organic aprotic solvents for precipitating the amide ester intermediate (IV) include cyclohexane, pentane, cyclopentane, hexane, methyl tert-butyl ether, 1,2-dimethoxyethane, methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, 1,4-dioxane, diethyl ether and mixtures thereof.

[0037] In the next step of the method according to the invention, the formate moiety is cleaved from the amide ester intermediate (IV) to produce the desired compound 5-ethyl-2-aminophenol (I). The cleavage of the formate moiety can be carried out via alkaline hydrolysis in the presence of a nucleophilic base. Typical temperatures for alkaline hydrolysis range from 40 to 140° C., preferably from 50 to 90° C. The nucleophilic base can be selected from, for example, calcium carbonate, sodium carbonate, potassium carbonate, sodium acetate, DBU, DBN, Huenig's base, DABCO, ammonium sulfate, sodium bicarbonate and potassium bicarbonate. According to a particular embodiment, potassium hydroxide and / or sodium hydroxide are used as bases.

[0038] The solvent for alkaline hydrolysis can be selected from, for example, 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, methyltetrahydrofuran, n-butanol, isopropyl alcohol, n-propyl alcohol, ethanol, methanol, its aqueous solution and mixture thereof. According to a particular embodiment, the solvent can be selected from methanol, ethanol, ethyl acetate, toluene and mixture thereof. From an ecological point of view, the solvent can preferably be selected from methanol, ethanol and / or ethyl acetate, or an aqueous solution of methanol and / or ethanol.

[0039] An embodiment of the method for preparing 5-ethyl-2-aminophenol (I) according to the present invention is illustrated below by reaction schemes 2A-2C.

[0040] Reaction Scheme 2A illustrates the partial reduction of the nitro functionality of 4-ethylnitrobenzene (II) to the hydroxylamine stage, followed by double protection of the nitrogen atom with chloroformate. The illustrated embodiment shows the partial reduction in the presence of ammonium chloride and using zinc powder, followed by reaction with methyl chloroformate to give (4-ethyl-N-methoxycarbonyl-anilino)methyl carbonate (V).

[0041] Reaction Scheme 2A:

[0042]

[0043] Reaction Scheme 2B illustrates the sigma shift rearrangement of (4-ethyl-N-methoxycarbonyl-anilino)methyl carbonate (V) to form the corresponding [5-ethyl-2-(methoxycarbonylamino)phenyl]methyl carbonate (VI). The illustrated embodiment shows a thermally driven sigma shift rearrangement at elevated temperature using xylene as the solvent for the rearrangement step.

[0044] Reaction Scheme 2B:

[0045]

[0046] Reaction Scheme 2C illustrates the alkaline hydrolysis of the methyl formate moiety to obtain the desired final product, 5-ethyl-2-aminophenol (I). The illustrated embodiment shows the alkaline hydrolysis of (4-ethyl-N-methoxycarbonyl-anilino)methyl carbonate (V) in methanol in the presence of potassium hydroxide as a base.

[0047] Reaction Scheme 2C:

[0048]

[0049] The key steps of the method according to the present invention can be summarized as follows:

[0050] Partial reduction of 4-ethylnitrobenzene (II) to the hydroxylamine stage followed by subsequent double protection of the nitrogen atom using a chloroformate derivative to form intermediate (III)

[0051] · σ-shift rearrangement to form intermediate (IV)

[0052] Alkaline hydrolysis of intermediate (IV) to obtain the final product 5-ethyl-2-aminophenol (I)

[0053] definition

[0054] The terms "ambient temperature" and "room temperature" are used interchangeably herein and refer to a temperature in the range of 20-30°C, particularly in the range of 22-27°C, such as about 25°C.

[0055] The terms "normal pressure" and "atmospheric pressure" are used interchangeably herein and refer to pressures in the range of 0.8-1.2 bar, in particular about 1.0 bar.

[0056] As used herein, the term "salt" includes salts of the classical meaning and 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 target compounds disclosed herein or intermediates with hydrogen chloride, hydrogen bromide, sulfuric acid, phosphoric acid, acetic acid, citric acid, succinic acid, tartaric acid, lactic acid, toluenesulfonic acid, benzenesulfonic acid. Examples of addition salts with alkalis include complexes of target compounds disclosed herein or intermediates with alkalis such as sodium hydroxide, potassium hydroxide, ammonia, amines or alkanolamines. Examples of addition salts (solvates) with one or more solvents include complexes of target compounds disclosed herein or intermediates with water (hydrates) or lower alcohols (i.e., methanol, ethanol, isopropanol, n-propanol, isobutanol, n-butanol). Preferred solvates are hydrates.

[0057] The term "cosmetically acceptable salts" encompasses addition salts as exemplified above, as well as salts in the classical sense, which contain as counterions cations selected from lithium, sodium, potassium, beryllium, magnesium, calcium, boron, aluminum, iron, copper, zinc or ammonium, or anions selected from fluoride, chloride, bromide, iodide, hydroxide, sulfate, sulfonate or phosphate, respectively. Preferred "cosmetically acceptable salts" include hydrates and solvates of lower alcohols, as well as sodium, potassium, magnesium, calcium and ammonium salts as classical salts, or chlorides, hydroxides, sulfates, sulfonates and phosphates, respectively. Insofar as the present invention relates to salts of 5-ethyl-2-aminophenol (I) or salts of the intermediates disclosed herein, cosmetically acceptable salts are preferred. DETAILED DESCRIPTION

[0058] The method according to the present invention is described in detail below, including the order of steps, the intermediates involved in the synthesis and large-scale processes. Should be understood that when the present disclosure relates to a particular structure, all reasonable other tautomeric structures are included. In the art, tautomeric structures are often represented by a single structure and the present disclosure follows this general practice.

[0059] Should be appreciated that the step of the preparation 5-ethyl-2-aminophenol (I) of description can be carried out in the mode of continuous one-pot synthesis, wherein at each time add a kind of reagent in reactor and need not carry out aftertreatment therebetween.Reactions steps needs suitable solvent, as noted below.It is preferred that continuous one-pot synthesis under the situation of needing no aftertreatment therebetween, unless preferably reduce or avoid in a back step, to have the by product from the previous step.

[0060] The following detailed description illustrates the methods according to the present invention by reference to, for example, specific reactants and / or reaction conditions. This is for illustrative purposes only, 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 generally suitable for the respective reaction and the intended corresponding solubility. Similarly, a reference to a specific acid or base should be understood as a general reference to the appropriate acid or base, respectively.

[0061] The present invention relates to a process for the synthesis of 5-ethyl-2-aminophenol (I) or a salt thereof (e.g., a cosmetically acceptable salt thereof) or a mixture thereof. The following detailed description illustrates a particular embodiment of the invention, specifically using methyl chloroformate, and correspondingly relates to the specific intermediates, namely (4-ethyl-N-methoxycarbonyl-anilino)methyl carbonate (V) and [5-ethyl-2-(methoxycarbonylamino)phenyl]methyl carbonate (VI).

[0062] 1. Synthesis of (4-ethyl-N-methoxycarbonyl-anilino)methyl carbonate (V)

[0063]

[0064] In the first step, commercially available 4-ethylnitrobenzene (II) is partially reduced to the corresponding N-hydroxylamine derivative, ie, N-(4-ethylphenyl)hydroxylamine of the formula (VII).

[0065]

[0066] In the present invention, the reaction of N-(4-ethylphenyl) hydroxylamine (VII) and N-(4-ethylphenyl) hydroxylamine (VII) is carried out.Yet, N-(4-ethylphenyl) hydroxylamine (VII) is not separated, and only serves as intermediate compound, and it will react with highly activated and reactive methylchloroformate subsequently.Because the nitrogen of N-(4-ethylphenyl) hydroxylamine (VII) can be substituted at 2 positions, so the condensation of methylchloroformate will directly appear at the nitrogen place that replaces free hydrogen, and the electron-rich hydroxyl group can be condensed with second methylchloroformate to form first separated intermediate carbonic acid (4-ethyl-N-methoxycarbonyl-anilino) methyl esters (V).Reaction is carried out in the aqueous solution of organic solvent in the presence of water-soluble acid.

[0067] The acid can be selected from, for example, ammonium chloride, acetic acid or a hydrogen halide (such as hydrochloric acid). According to a particular embodiment, ammonium chloride is used as the acid. The acid can be used in an amount of 1-3 molar equivalents, preferably 1-1.5 molar equivalents.

[0068] The one or more solvents used in this step can be selected from 1,2-dimethoxyethane, 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, methyltetrahydrofuran, n-pentanol, n-butanol, isopentanol, tert-butanol, isopropanol, n-propanol, ethanol, methanol, glycols (preferably tetrahydrofuran, methyl tert-butyl ether, methyltetrahydrofuran), aqueous solutions thereof, and mixtures thereof.

[0069] The reaction is typically carried out in the temperature range of 0°C to 10°C, particularly preferably at 0°C. The product (4-ethyl-N-methoxycarbonyl-anilino) methyl carbonate (V) is separated via organic extraction into an inert ether / ester type solvent. The one or more solvents used in this extraction step can be selected from methyl tert-butyl ether, 1,2-dimethoxyethane, methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, 1,4-dioxane, diethyl ether, tetrahydrofuran, methyltetrahydrofuran, pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, methyl propionate, ethyl propionate, n-propyl propionate, isopropyl propionate, n-butyl propionate, n-butanol, isopropyl alcohol, n-propanol, ethanol, methanol, an aqueous solution thereof, and a mixture thereof. Preferably, the solvent can be selected from ethyl acetate, toluene, methyl tert-butyl ether, and a mixture thereof. After collecting all organic phases and evaporating the solvent, the product will precipitate out as a white solid using a strongly hydrophobic organic solvent. 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.

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

[0071]

[0072] The σ shift rearrangement reaction is driven by thermal activation. The preferred reaction temperature is in the range of 100-200°C, more preferably in the range of 120-180°C. This rearrangement reaction is carried out in the presence of a solvent, preferably under reflux conditions. The solvent in this step is selected from aprotic solvents, preferably aromatic aprotic solvents, selected from toluene, o-xylene, m-xylene, p-xylene, nitrobenzene, mesitylene, anisole, 1,2-dichlorobenzene, 1,4-dichlorobenzene, diphenyl ether, naphthalene, DMF, DMAcA, NMP, DMSO, quinoline, 1,2-dimethoxyethane, ethylene glycol, glycols, and polyethylene glycols. Preferred solvents are xylene derivatives, with p-xylene being particularly preferred according to one embodiment. The reaction is carried out at atmospheric pressure. To achieve complete conversion, which is typically slow thermodynamically, the reaction time is in the range of 10-55 hours, with 42-48 hours being particularly preferred according to one embodiment. The rearrangement reaction should advantageously be carried out in the absence of an oxidizing agent such as atmospheric oxygen, since oxidizing agents typically cause the formation of unwanted by-products.

[0073] The product [5-ethyl-2-(methoxycarbonylamino)phenyl]methyl carbonate (VI) is isolated by reducing the aromatic aprotic solvent to 20-30% by volume, preferably to 25% by volume and cooling to ambient temperature, followed by dilution of the obtained reaction mixture with an aprotic organic solvent to cause precipitation of the intermediate [5-ethyl-2-(methoxycarbonylamino)phenyl]methyl carbonate (VI). The organic aprotic solvent used in this step can be selected from cyclohexane, pentane, cyclopentane, hexane, methyl tert-butyl ether, 1,2-dimethoxyethane, methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, 1,4-dioxane, diethyl ether and mixtures thereof. Preferably, the solvent can be selected from ethyl acetate, cyclohexane, pentane and mixtures thereof. The intermediate [5-ethyl-2-(methoxycarbonylamino)phenyl]methyl carbonate (VI) is collected by filtration.

[0074] 3. Synthesis of 5-ethyl-2-aminophenol (I)

[0075]

[0076] The intermediate [5-ethyl-2-(methoxycarbonylamino)phenyl]methyl carbonate (VI) is converted to the desired product 5-ethyl-2-aminophenol (I) via basic hydrolysis of the alkyl formate moiety.

[0077] The conversion follows the well-known standard procedure for cleaving off ester-type and amide-type protecting groups under alkaline conditions. This method is typically highly effective and cost-effective because alkaline hydrolysis can already be carried out under mild conditions. Therefore, reaction conditions that require less stringent conditions in terms of temperature and pressure can be advantageously applied to this particular case. The conversion of [5-ethyl-2-(methoxycarbonylamino)phenyl]methyl carbonate (VI) to 5-ethyl-2-aminophenol (I) can be carried out under conditions of applied atmospheric pressure, which allows skipping the complex autoclave system combined with moderate to slightly high reaction temperatures. The temperature range is 40-140° C., preferably 50 to 90° C. The nucleophilic base can be selected from sodium hydroxide, potassium hydroxide, calcium carbonate, sodium carbonate, potassium carbonate, sodium acetate, DBU, DBN, Huenig's base, DABCO, ammonium sulfate, sodium bicarbonate and potassium bicarbonate. According to a particular embodiment, potassium hydroxide and / or sodium hydroxide can be used as the base.

[0078] The solvent for alkaline hydrolysis can be selected from, for example, 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, methyltetrahydrofuran, n-butanol, isopropyl alcohol, n-propyl alcohol, ethanol, methanol, its aqueous solution and mixture thereof. Preferably, the solvent can be selected from methanol, ethanol, ethyl acetate, toluene and mixture thereof. From an ecological point of view, the solvent can preferably be selected from methanol, ethanol and / or ethyl acetate, or an aqueous solution of methanol and / or ethanol.

[0079] The hydrolysis step is typically carried out under reflux conditions. The reaction times is typically selected as in the scope of 4-10 hour, preferably 5-7 hour, to allow for substantially complete conversion and cracking of the formate moiety. Once the reaction is complete, the reaction mixture is cooled to ambient temperature, then neutralized to pH 7 via adding a mineral acid, to form required 5-ethyl-2-aminophenol (I) with the protonation of the phenolate derivative obtained. Acid can be easily selected from hydrochloric acid, acetic acid, sulfuric acid, phosphoric acid, nitric acid and composition thereof. In a special embodiment, hydrochloric acid can be used as acid. By filtering and collecting the precipitated 5-ethyl-2-aminophenol (I). Further recrystallization obtains pure 5-ethyl-2-aminophenol (I).

[0080] Example

[0081] The following non-limiting examples further illustrate the present invention. These examples are given for illustrative purposes only and should not be construed as limiting the present invention, as many variations are possible without departing from the spirit and scope of the present invention, as will be appreciated by those skilled in the art. Unless otherwise indicated, all concentrations are listed as weight percent.

[0082] Example 1: Synthesis of (4-ethyl-N-methoxycarbonyl-anilino)methyl carbonate (V)

[0083] 151.16g (1mol) of 4-ethylnitrobenzene (II) is dissolved in a solution of 500mL THF / water (2: 1 by volume). 58.3g (1.1mol) of ammonium chloride is added, and the reaction mixture is cooled to 0°C. In 15 minutes, 282.0g (3mol) of methyl chloroformate are gradually and slowly added, followed by addition of 130.0g (2mol) of zinc powder in small portions. The reaction mixture becomes light grey and is stirred for another 3 hours at 0°C. Once the starting material 4-ethylnitrobenzene (II) is completely consumed (as determined by TLC analysis), the reaction mixture is diluted with 500mL of methyl tert-butyl ether. The organic layer is extracted and washed 3-4 times with 500mL of saturated sodium bicarbonate aqueous solution, and finally washed 1-2 times with an equal amount of NaCl aqueous solution. This extraction ensures that the salt load formed during the reaction process is reduced. The organic phase merged is filtered with diatomaceous earth pad and dried over sodium sulfate. After the solvent was concentrated to 100-150 mL by evaporation, the product (4-ethyl-N-methoxycarbonyl-anilino)methyl carbonate (V) was precipitated by adding small portions of cyclohexane. The yield of the collected colorless solid was calculated to be 92% (232.7 g).

[0084] Example 2: Synthesis of [5-ethyl-2-(methoxycarbonylamino)phenyl]methyl carbonate (VI)

[0085] 200.0g (0.79mol) carbonic acid (4-ethyl-N-methoxycarbonyl-anilino) methyl esters (V) are dissolved in 1.8L p-Xylol and are heated to reflux and reach 35 hours.Monitor reaction process by TLC.In case starting material is consumed fully (as determined by TLC), just reaction mixture is concentrated into approximately 250mL by vaporising in a vacuum, and it is cooled to envrionment temperature.Reaction mixture is handled with 250mL hexanaphthene, and is cooled to 0 ℃.Precipitated product carbonic acid [5-ethyl-2-(methoxycarbonyl amino) phenyl] methyl esters (VI) is collected by filtration and is dry in air.Calculating productive rate is 84% ​​(167.9g).

[0086] Example 3: Synthesis of 5-ethyl-2-aminophenol (I)

[0087] 150.0g (0.59mol) of [5-ethyl-2-(methoxycarbonylamino)phenyl]methyl carbonate (VI) is dissolved in 1.2L of methanol, and in the reaction solution, 99.1g (1.77mol) of solid potassium hydroxide are slowly added. Once sodium hydroxide is completely dissolved, the reaction mixture is heated to reflux and reaches another 6 hours. After being cooled to ambient temperature, the reaction mixture is carefully neutralized to pH 7 by adding 2N hydrochloric acid, and is cooled to 0 ℃. The precipitate is collected by filtration and recrystallized from methanol and ethyl acetate to obtain the required final product 5-ethyl-2-aminophenol (I) (94% yield (75.9g)).

Claims

1. A method for preparing 5-ethyl-2-aminophenol (I) or a salt thereof, The method comprises: (a) Providing 4-ethylnitrobenzene (II): (b) 4-Ethylnitrobenzene (II) is partially reduced and reacted with chloroformate ClC(O)-OR to form the diester intermediate (III): wherein R is selected from hydrogen, C1-C6 alkyl and C1-C6 hydroxyalkyl, (c) The diester intermediate (III) undergoes a sigma shift rearrangement to form the amide ester intermediate (IV): and (d) hydrolyzing the amide ester intermediate (IV) under basic conditions to form 5-ethyl-2-aminophenol (I):

2. The process according to claim 1, wherein the alkyl chloroformate is methyl chloroformate or ethyl chloroformate.

3. The process according to claim 1 or 2, wherein the partial reduction of 4-ethylnitrobenzene (II) is performed electrochemically or in the presence of a reducing agent.

4. The process according to claim 1 , wherein the partial reduction of 4-ethylnitrobenzene (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.

5. A process according to any one of the preceding claims, wherein step (b) is carried out in an aqueous solution of an organic solvent in the presence of a water-soluble acid.

6. The process according to claim 5, wherein the water-soluble acid is selected from ammonium chloride, acetic acid and hydrogen halide, in particular wherein the acid is aqueous hydrochloric acid or ammonium chloride.

7. The process according to any one of the preceding claims, wherein step (b) is carried out in a solvent selected from the group consisting of 1,2-dimethoxyethane, 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, methyltetrahydrofuran, preferably in a solvent selected from the group consisting of tetrahydrofuran, methyl tert-butyl ether, methyltetrahydrofuran, aqueous solutions thereof and mixtures thereof.

8. The method of claim 7, wherein step (b) further comprises extracting the diester intermediate (III) into a solvent selected from the group consisting of methyl tert-butyl ether, 1,2-dimethoxyethane, methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, 1,4-dioxane, diethyl ether, tetrahydrofuran, methyltetrahydrofuran, pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, methyl propionate, ethyl propionate, n-propyl propionate, isopropyl propionate, n-butyl propionate, n-butanol, isopropanol, n-propanol, ethanol, methanol, aqueous solutions thereof, and mixtures thereof.

9. The method according to claim 8, further comprising precipitating the diester intermediate (III) by adding a hydrophobic organic solvent, in particular a solvent selected from pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, 1,2-dichlorobenzene, 1,4-dichlorobenzene, DMSO, DMAcA, NMP, 1,4-dioxane and diethyl ether.

10. The process according to any one of the preceding claims, wherein the sigma shift rearrangement reaction is carried out in the presence of an aprotic solvent at a temperature in the range of 100-200°C, in particular in the range of 120-180°C.

11. The method according to claim 10, wherein the sigma shift rearrangement reaction is carried out at normal pressure in an inert atmosphere for a reaction time of 10 to 55 hours, particularly 42 to 48 hours, and preferably in a solvent selected from the group consisting of toluene, o-xylene, m-xylene, p-xylene, nitrobenzene, mesitylene, anisole, 1,2-dichlorobenzene, 1,4-dichlorobenzene, diphenyl ether, naphthalene, DMF, DMAcA, NMP, DMSO, quinoline, 1,2-dimethoxyethane, ethylene glycol, diol, polyethylene glycol, or a mixture thereof.

12. The method according to claim 10 or 11, further comprising precipitating the amide ester intermediate (IV) by adding an aprotic organic solvent, in particular an aprotic organic solvent selected from the group consisting of pentane, cyclopentane, hexane, cyclohexane, methyl tert-butyl ether, 1,2-dimethoxyethane, methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, 1,4-dioxane, diethyl ether and mixtures thereof.

13. The process according to any one of the preceding claims, wherein the conversion of the amide ester intermediate (IV) to 5-ethyl-2-aminophenol (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.

14. The method of claim 13, wherein the nucleophilic base is selected from the group consisting of sodium hydroxide, potassium hydroxide, calcium carbonate, sodium carbonate, potassium carbonate, sodium acetate, DBU, DBN, Huenig's base, DABCO, ammonium sulfate, sodium bicarbonate, and potassium bicarbonate, and / or wherein the solvent is 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, methyltetrahydrofuran, n-butanol, isopropanol, n-propanol, ethanol, methanol, aqueous solutions thereof, and mixtures thereof.

15. The process according to any one of the preceding claims, further comprising recrystallizing 5-ethyl-2-aminophenol (I) from methanol, ethyl acetate or a mixture thereof.

Images