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WO2025176676A1 - Procédé de synthèse de 5-éthyl-2-amino phénol - Google Patents

Procédé de synthèse de 5-éthyl-2-amino phénol

Info

Publication number
WO2025176676A1
WO2025176676A1 PCT/EP2025/054353 EP2025054353W WO2025176676A1 WO 2025176676 A1 WO2025176676 A1 WO 2025176676A1 EP 2025054353 W EP2025054353 W EP 2025054353W WO 2025176676 A1 WO2025176676 A1 WO 2025176676A1
Authority
WO
WIPO (PCT)
Prior art keywords
ethyl
methyl
tetrahydrofuran
benzene
solvent
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/EP2025/054353
Other languages
English (en)
Inventor
Markus Speckbacher
Heike ABEL
Armin Osan
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Wella Germany GmbH
Original Assignee
Wella Germany GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Wella Germany GmbH filed Critical Wella Germany GmbH
Publication of WO2025176676A1 publication Critical patent/WO2025176676A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C269/04—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups from amines with formation of carbamate groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C239/00—Compounds containing nitrogen-to-halogen bonds; Hydroxylamino compounds or ethers or esters thereof
    • C07C239/08—Hydroxylamino compounds or their ethers or esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups

Definitions

  • the present invention relates to a method for synthesizing 5-ethyl-2-amino phenol, or salts thereof.
  • This compound is also known under COLIPA n° A158.
  • 5-ethyl-2-amino phenol is known to the industry as an important oxidative coupler compound used in oxidative hair dye compositions. It provides with oxidative primaries such as paraphenylendiamine derivatives and other well-known oxidative precursors an important yellowish base coat to support grey coverage and lastingness of any oxidative hair coloration. Due to similar dyeing properies compared with resorcinol or methylresorcinol, it is therefore a suitable candidate for replacing resorcinol and resorcinol derivatives in oxidative hair color formulations.
  • 5-ethyl-2-amino phenol (I) has been found a suitable candidate to achieve the aim of providing a solid color backbone in the oxidative hair shade palette. It has been used in the past rarely in market formulations as the yellow color strike was only specifically needed in special light shades but not to address the grey coverage concerns. A big barrier was the cost intensive synthesis for this compound. As the hair color industry is moving out of traditional and cheap resorcinol derivatives compounds such as resorcinol or methyl-resorcinol, the focus is now on providing an advanced and improved synthesis to minimize the financial impact the exit of resorcinol derivatives may have to hair color companies.
  • the synthesis route currently used for preparing 5-ethyl-2-amino phenol (I) is the method going back to US5214194A by Eastman-Kodak. As depicted in reaction scheme 1 below, the method starts with commercially available 4-ethyl-nitrobenzene, which is condensed with benzaldehyde in the presence of zinc in acetic acid. This intermediate is reacted with trichloroacetyl chloride to form the desired compound 5-ethyl-2-amino phenol (I) after a rearrangement reaction.
  • Subject matter of the present invention is a method for preparing 5-ethyl-2-amino phenol (I):
  • the method according to the present invention comprises:
  • the step of providing 4-ethyl nitro benzene (II) may comprise reacting an appropriate precursor compound with one or more respective reactant(s), in one or more steps, and optionally separating or isolating 4-ethyl nitro benzene (II).
  • the partial reduction of 4-ethyl nitro benzene (II) may be carried out conveniently by electrochemical reduction, which is well-known to the person skilled in the art.
  • the partial reduction may be carried out in the presence of a reducing agent.
  • Suitable reducing agents are well-known to the person skilled in the art.
  • Organic reducing agents suitable for the partial reduction comprise, for example, and comprise for example hydrazine and hydrazine derivatives such as methylhydrazine.
  • Inorganic reducing agents suitable for the partial reduction comprise, for example, base metals, in particular base metals in a reactive form.
  • the solvent used for the reductive transformational step may be, for example, 1,2-dimethoxy- ethane, pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, 1,2-dichlorobenzene, 1,4- dichlorobenzene, DMSO, DMAcA, NMP, 1,4-dioxane, diethyl ether, methyl-tert-butyl-ether, tetrahydrofuran, methyl-tetrahydrofuran, n-pentanol, n-butanol, iso-pentanol, t-butanol, isopropanol, n-propanol, ethanol, methanol, glycols, an aqueous solution thereof, or a mixture thereof.
  • the diester intermediate (III) obtained conveniently may be separated from the reaction mixture, typically by extraction.
  • the extraction solvent for diester intermediate (III) may be selected from methyl-tert- butyl-ether, 1,2-dimethoxyethane, methylacetate, ethylacetate, n-propylacetate, iso-propylacetate, n-butylacetate, 1,4-dioxane, diethyl ether, tetrahydrofuran, methyl-tetrahydrofuran, pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, methylpropionate, ethylpropionate, n- propylpropionate, iso-propylpropionate, n-butylpropionate, n-butanol, isopropanol, n-propanol, ethanol,
  • the partial reduction of 4-ethyl nitro benzene (II) and subsequent reaction with chloroformate to form diester intermediate (III) is carried out in the presence of ammonium chloride and an excess of chloroformate at 0°C (preferably freshly prepared, i.e. non-hydrolyzed chloroformate), followed by the addition of organic solvents as denoted above to extract the organic layers.
  • diester intermediate (III) conveniently may be precipitated by addition of a hydrophobic organic solvent.
  • Suitable hydrophobic precipitation solvents comprise pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, 1,2- dichlorobenzene, 1,4-dichlorobenzene, DMSO, DMAcA, NMP, 1,4-dioxane, diethyl ether.
  • the hydrophobic solvent is hexane or cyclohexane.
  • diester intermediate (III) undergoes a sigmatropic rearrangement, to form amidoester intermediate (IV).
  • the sigmatropic rearrangement of diester intermediate (III) to yield amidoester intermediate (IV) is carried out via a thermal rearrangement in high boiling solvents.
  • a suitable temperature may be selected, for example within a temperature range from 100-180°C, in particular within a temperature range of 120-160°C.
  • the thermodynamic reaction requires reaction times of 24-48h to enable essentially complete conversion, or complete conversion of the diester intermediate (III).
  • Microwave-assisted energy supply may significantly reduce the reaction time to a range of 5-10h.
  • Suitable solvents used for the rearrangement of diester intermediate intermediate (III) to amidoester intermediate (IV) are high-boiling aprotic organic solvents.
  • the solvent may be selected, for example, from from toluene, o-xylene, m-xylene, p-xylene, nitro benzene, mesitylene, anisoles, 1,2- dichlorobenzene, 1,4-dichlorobenzene, diphenyl ethers, naphthalenes, DMF, DMAcA, NMP, DMSO, chinoline, 1,2-dimethoxyethane, ethylene glycol, glycols, polyethylenglycols, or a mixture thereof.
  • amidoester intermediate (IV) may be separated from the reaction mixture.
  • One route for separating amidoester intermediate (IV) comprises concentrating the reaction mixture obtained, cooling down to ambient temperature, and diluting the concenbtrated reaction mixture by addition of aprotic, organic solvents to cause precipitation of amidoester intermediate (IV).
  • the formate moieties are cleaved- off from amidoester intermediate (IV), to yield the desired compound 5-ethyl-2-amino phenol (I).
  • Cleaving-off the formate moieties may be carried out via alkaline hydrolysis, in the presence of a nucleophilic base.
  • a typical temperature range for the alkaline hydrolysis is 40-140°C, preferably between 50 and 90 °C.
  • the nucleophilic base may selected, for example, from calcium carbonate, sodium carbonate, potassium carbonate, sodium acetate, DBU, DBN, Huenig Base, DABCO, ammonium sulphate, sodium hydrogencarbonate and potassium hydrogencarbonate.
  • potassium hydroxide and/or sodium hydroxide are used as the base.
  • the solvent may be selected from methanol, ethanol, ethylacetate, toluene and mixtures thereof. From an ecological viewpoint, the solvent may preferably be selected from methanol, ethanol and/or ethylacetate, or an aqueous solution of methanol and/or ethanol.
  • Reaction scheme 2B illustrates sigmatropic rearrangement of (4-ethyl-N-methoxycarbonyl- anilino)methyl carbonate (V) to form the corresponding [5-ethyl-2- (methoxycarbonylamino)phenyl]methyl carbonate (VI).
  • the exemplified embodiment shows thermally driven sigmatropic rearrangement at high temperatures using xylene as the solvent for the rearragment step.
  • Reaction scheme 2C illustrates alkaline hydrolysis of the methylformate moieties to obtain the desired endproduct 5-ethyl-2-amino phenol (I).
  • the exemplified embodiment shows alkaline hydrolysis of (4- ethyl-N-methoxycarbonyl-anilino)methyl carbonate (V) in the presence of potassium hydroxide as the base, in methanol.
  • ambient temperature and “room temperature” are used herein interchangeably, and refer to a temperature in the range of 20-30°C, in particular to a temperature in the range of 22-27°C, for example about 25°C.
  • addition salts with a base include complexes of the target compound or of intermediates disclosed herein, with a base such as sodium hydroxide, potassium hydroxide, ammonia, amines or alkanolamines.
  • addition salts with solvent(s) (solvates) include complexes of the target compound or of intermediates disclosed herein with water (hydrates) or lower alcohols, i.e. methanol, ethanol, isopropanol, n-propanol, isobutanol, n-butanol.
  • Preferred solvates are hydrates.
  • cosmetically acceptable salt encompasses addition salts as exemplified above, and salts in the classical meaning comprising as counter ion a cation selected from lithium, sodium, potassium, beryllium, magnesium, calcium, boron, aluminium, iron, copper, zink, or ammonium, or respectively an anion selected from fluoride, chloride, bromide, jodide, hydroxide, sulfate, sulfonate, or phosphate.
  • a cation selected from lithium, sodium, potassium, beryllium, magnesium, calcium, boron, aluminium, iron, copper, zink, or ammonium, or respectively an anion selected from fluoride, chloride, bromide, jodide, hydroxide, sulfate, sulfonate, or phosphate.
  • the solvent may be selected from ethylacetate, toluene, methyl-tert-butyl-ether and mixtures thereof. After collecting all organic phases and evaporation of the solvent, the product will be precipitated as a white solid with strongly hydrophobic organic solvents.
  • the solvent may be selected from pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, 1,2-dichlorobenzene, 1,4-dichlorobenzene, DMSO, DMAcA, NMP, 1,4-dioxane and diethyl ether.
  • the solvent may be selected from hexane, cyclohexane, benzene and toluene.
  • the solvent in this step is selected from an aprotic solvent, preferably an aromatic aprotic solvent, selected from toluene, o-xylene, m-xylene, p-xylene, nitro benzene, mesitylene, anisoles, 1,2-dichlorobenzene, 1,4-dichlorobenzene, diphenyl ethers, naphthalenes, DMF, DMAcA, NMP, DMSO, chinoline, 1,2-dimethoxyethane, ethylene glycol, glycols, polyethylenglycols.
  • Preferred solvents are xylene derivatives, particularly preferred, according to an embodiment, is p-xylene.
  • the product [5-ethyl-2-(methoxycarbonylamino)phenyl]methyl carbonate (VI) is isolated via reducing the aromatic aprotic solvent down to 20-30% by volume, preferable down to 25% by volume and cooling down to ambient temperature, followed by dilution of the obtained reaction mixture with aprotic, organic solvents to cause precipitation of the intermediate [5-ethyl-2- (methoxycarbonylamino)phenyl]methyl carbonate (VI).
  • the conversion follows well know standard procedures for cleaving off ester-type and amido-type protection groups under alkaline conditions. This method typically is highly efficient and cost advantageous, as the alkaline hydrolysis can be carried out already under mild conditions. Hence, reaction conditions which require less harsh conditions in terms of temperature and pressure, can be applied advantageously for this particular case.
  • the conversion of [5-ethyl-2- (methoxycarbonylamino)phenyl]methyl carbonate (VI) to 5-ethyl-2-amino phenol (I) may be carried out under conditions applying atmospheric pressure, which allows skipping a sophisticated autoclave system in combination with moderate to slightly higher reaction temperatures.
  • the temperature range is 40-140°C, preferably between 50 and 90 °C.
  • the nucleophilic base may be selected from sodium hydroxide, potassium hydroxide, calcium carbonate, sodium carbonate, potassium carbonate, sodium acetate, DBU, DBN, Huenig Base, DABCO, ammonium sulphate, sodium hydrogencarbonate and potassium hydrogencarbonate.
  • potassium hydroxide and/or sodium hydroxide may be used as the base.
  • the solvents for the alkaline hydrolysis may be selected, for example, from 1,2-dimethoxyethane, pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, methylacetate, ethylacetate, n- propylacetate, iso-propylacetate, n-butylacetate, methylpropionate, ethylpropionate, n- propylpropionate, iso-propylpropionate, n-butylpropionate, 1,4-dioxane, diethyl ether, tetrahydrofuran, methyl-tetrahydrofuran, n-butanol, isopropanol, n-propanol, ethanol, methanol, aqueous solutions thereof, and mixtures thereof.
  • the solvent may be selected from methanol, ethanol, ethylacetate, toluene and mixtures thereof.
  • the solvent may preferably be selected from methanol, ethanol and/or ethylacetate, or an aqueous solution of methanol and/or ethanol.
  • the hydrolysis step is typically performed under reflux conditions.
  • the reaction time typically is selected to be in the range of 4-10 h, preferable 5-7 h to allow for essentially complete conversion and cleavage of the formate moieties.
  • the reaction mixture is allowed to cool to ambient temperature, followed by neutralization to pH 7 via addition of mineral acids to form the desired 5-ethyl-2-amino phenol (I) by protonation of the obtained phenolate derivative.
  • the acids conveniently may be selected from hydrochloric acid, acetic acid, sulfuric acid, phosphoric acid, nitric acid, and mixtures thereof. In a particular embodiment, hydrochloric acid may be used as the acid.
  • the precipitated 5-ethyl-2-amino phenol (I) is collected by filtration. Further recrystallization yields the pure 5-ethyl-2-amino phenol (I).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne un procédé de synthèse de 5-éthyl-2-amino phénol.
PCT/EP2025/054353 2024-02-22 2025-02-18 Procédé de synthèse de 5-éthyl-2-amino phénol Pending WO2025176676A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP24159196 2024-02-22
EP24159196.5 2024-02-22

Publications (1)

Publication Number Publication Date
WO2025176676A1 true WO2025176676A1 (fr) 2025-08-28

Family

ID=90053920

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2025/054353 Pending WO2025176676A1 (fr) 2024-02-22 2025-02-18 Procédé de synthèse de 5-éthyl-2-amino phénol

Country Status (2)

Country Link
CN (1) CN120554237A (fr)
WO (1) WO2025176676A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5214194A (en) 1991-09-24 1993-05-25 Eastman Kodak Company Coupler intermediates and their formation
US20020128321A1 (en) * 1998-08-14 2002-09-12 Smithkline Beecham Corporation IL-8 receptor antagonists

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5214194A (en) 1991-09-24 1993-05-25 Eastman Kodak Company Coupler intermediates and their formation
US20020128321A1 (en) * 1998-08-14 2002-09-12 Smithkline Beecham Corporation IL-8 receptor antagonists

Also Published As

Publication number Publication date
CN120554237A (zh) 2025-08-29

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