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WO2025099127A1 - Nouvelles synthèses télescopiques de 6-hydroxy-benzomorpholine (3,4-dihydro-2h-1,4-benzoxazin-6-ol) - Google Patents

Nouvelles synthèses télescopiques de 6-hydroxy-benzomorpholine (3,4-dihydro-2h-1,4-benzoxazin-6-ol) Download PDF

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Publication number
WO2025099127A1
WO2025099127A1 PCT/EP2024/081440 EP2024081440W WO2025099127A1 WO 2025099127 A1 WO2025099127 A1 WO 2025099127A1 EP 2024081440 W EP2024081440 W EP 2024081440W WO 2025099127 A1 WO2025099127 A1 WO 2025099127A1
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Prior art keywords
acid
benzoxazin
mixtures
xxii
ethyl acetate
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Pending
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PCT/EP2024/081440
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English (en)
Inventor
Markus Speckbacher
Armin Osan
Heike ABEL
Felix TETSCHNER
Andreas SCHRAN
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Wella Germany GmbH
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Wella Germany GmbH
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Publication of WO2025099127A1 publication Critical patent/WO2025099127A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings
    • C07D265/36—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings condensed with one six-membered ring

Definitions

  • the present invention relates to a new telescoping synthesis of 3,4-dihydro-2H-l,4-benzoxazin-6-ol according to formula (I) or salts thereof.
  • This compound is known to the industry as an important oxidative coupler compound used in oxidative hair dye compositions. It is also known as 6- hydroxybenzomorpholine (COLIPA n° A25).
  • 3,4-Dihydro-2H-l,4-benzoxazin-6-ol provides, together with oxidative primaries such as para-phenylendiamine derivatives and other well-known oxidative precursors, an important base coat to support grey coverage and lastingness of any oxidative hair coloration.
  • Synthesis routes for benzo-annealed morpholine-type rings start typically with the formation of the second annealed heterocyclic ring from substituted aromatic starting materials.
  • CN111170958 references the most known traditional synthesis routes for the formation of benzomorpholine derivatives as described above. Moreover, it discloses a process for the preparation of 3,4-dihydro-2H-l,4-benzoxazin-6-ol (I) involving a solid acid catalyst, using 2-((2,5- dimethoxyphenyl)amino)ethane-l-ol as a starting raw material.
  • the above-mentioned solid acid is used as a catalyst and water is used as a solvent to carry out the demethylation ring-closure reaction.
  • the starting material is not very common and during the course of the reaction, some obstacles occur which may have a negative impact on the environment (waste water treatment, unwanted by-products etc.).
  • the biggest roadblock remains the high cost structure following this synthesis pathway which is truly an enormous burden for the hair color industry in comparison to cheap and readily available resorcinol derivatives or resorcinol itself.
  • the process should also reduce the risk of non- controllable side reactions, involve inexpensive starting materials, and use more standardized chemical reactions versus known processes which are regarded state of the art.
  • manufacturers should be able to conduct the process under mild reaction conditions, involving moderate temperatures, using ecologically acceptable solvents, and producing a minimum of non-recyclable waste solutions.
  • Subject matter of the present invention is a method for preparing 3,4-dihydro-2H-l,4-benzoxazin-6- ol (I), or a salt thereof, or mixture thereof, as defined in claim 1.
  • the dependent claims relate to particular embodiments thereof.
  • the method according to the present invention for preparing 3,4-dihydro-2H-l,4-benzoxazin-6-ol (I) or a salt thereof, or mixture thereof comprises the following steps: providing a benzoxazin compound selected from (XXI) and (XXII) , and
  • the method further comprises reducing the carbonyl group.
  • the order of steps is not critical, so that reducing may be carried out prior to reacting with [bis(trifluoroacetoxy)iodo]benzene, or vice versa.
  • Suitable acids for the reaction in step (b) are, for example, trifluoro acetid acid, acetic acid, propionic acid, oxalic acid, malonic acid, sulfuric acid, phosphoric acid, hydrogen chloride, mixtures thereof, and aqueous mixtures thereof. If the acid or acid mixture used in step (b) is in the form of an aqueous mixture, the concentration of water may be up to 50 wt%, for example up to 30 wt%. In a preferred embodiment, the acid or acid mixture in step (b) is used in concentrated form.
  • the acid used in step (b) is trifluoro acetid acid.
  • the inventive method further comprises separating the reaction product of step (b).
  • separating the reaction product may comprise recrystallization.
  • Suitable recrystallization solvents comprise 1,2-dimethoxyethane, ethyl acetate, 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, iso-pentanol, t-butanol, isopropanol, n-propanol, ethanol, methanol, glycols, hydrogen chloride, mixtures thereof, and aqueous solutions thereof.
  • the recrystallization solvent is selected from ethyl acetate, toluene, acetic acid, propionic acid, oxalic acid, malonic acid, sulfuric acid, phosphoric acid, hydrogen chloride, n- butanol, isopropanol, n-propanol, ethanol, methanol, mixtures thereof, and aqueous solutions thereof.
  • the recrystallization solvent may be selected from ethyl acetate, toluene, acetic acid, n-propanol, ethanol, methanol, mixtures thereof, and aqueous solutions thereof. If the solvent or solvent mixture used in the recrystallization is an aqueous mixture, the concentration of water may be up to 50 wt%, for example up to 30 wt% .
  • step (a) When the benzoxazin compound provided in step (a) is (XXII), i.e. if the starting material comprises the carbonyl group, reducing the said carbonyl group is carried out, according to a particular embodiment, in THF in the presence of a boron-THF complex.
  • a particularly suitable boron-THF complex is boron dimethylsulfide-THF complex.
  • the reaction product After reduction of the carbonyl group in THF, in the presence of a boron-THF complex, the reaction product typically is extracted from THF.
  • Suitable solvents for extracting the reaction product from THF comprise chloroform, methylenchloride, tert-butyl-methyl-ether, diethyl ether, ethyl acetate, 1,2-dimethoxyethane, pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, 1,4- dioxane, tetrahydrofuran, methyl-tetrahydrofuran, methanol, ethanol, and mixtures thereof.
  • reducing the carbonyl group, and optionally extracting the reaction product is carried out after the reaction with [bis(trifluoroacetoxy)iodo]benzene in the acidic environment, and prior to separating the reaction product from the acidic environment.
  • the starting material method 4H-l,4-benzoxazin-3-one (XXII) may be obtained by reacting o-amino- phenol (XXIII)
  • the reaction of o-amino-phenol (XXIII) with chloroacetyl chloride may be carried out in a solvent selected from chloroform, methylenchloride, dimethylformamide, dimethylacetamide, NMP (N- methylpyrrolidone), acetonitrile, 1,2-dimethoxyethane, ethyl acetate, pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, 1,4-dioxane, diethyl ether, tetrahydrofuran, methyltetrahydrofuran, and mixtures thereof.
  • the reaction product 4H-l,4-benzoxazin-3-one (XXII) conveniently may be separated via trituration in water, methanol, ethanol, and mixtures thereof.
  • the method according to the present invention comprises the direct introduction of an hydroxygroup to Benzomorpholine (XXI) (3,4-dihydro-2H-l,4-benzoxazine) or 4H-l,4-benzoxazin-3-one (XXII), respectively, yielding the intermediate 6-hydroxy-4H-l,4-benzoxazin-3-one (XV) or directly the desired 3,4-dihydro-2H-l,4-benzoxazin-6-ol (I), respectively.
  • XXI Benzomorpholine
  • XXII Benzomorpholine
  • Benzomorpholine (XXI) (3,4-dihydro-2H-l,4-benzoxazine), for example the commercially available compound, is reacted with [bis(trifluoracetoxy)iodo]benzene (PIFA).
  • PIFA as well is commercially available, or can be prepared according to known literature procedures (e.g. Page, T. Keri; et al, Synthesis (2006), (18), 3153-3155).
  • the reaction is carried out in an acidic environment, for example in TFA (trifluoroacetic acid) to yield the desired 3,4-dihydro-2H-l,4- benzoxazin-6-ol (I) in one step.
  • TFA trifluoroacetic acid
  • o-amino-phenol for example the commercially available compound, is reacted with chloroacetyl chloride to yield the intermediate 4H-l,4-benzoxazin-3-one (XXII).
  • This intermediate analogously is reacted with [bis(trifluoracetoxy)iodo]benzene.
  • the reaction is carried out in an acidic environment, for example in TFA (trifluoroacetic acid) to yield the next intermediate 6- hydroxy-4H-l,4-benzoxazin-3-one (XV) according to a known procedure (e.g. W02008150848, Itoh, Naoki; et al, Journal of Organic Chemistry (2002), 67(21), 7424-7428).
  • Final reduction of the carbonyl group yields the desired 3,4-dihydro-2H-l,4-benzoxazin-6-ol (I).
  • Benzomorpholine (XXI) (3,4-dihydro-2H-l,4-benzoxazine) is treated with [bis(trifluoracetoxy)iodo]benzene (PIFA) in strong acid medium, preferable in trifluoro acetid acid (TFA).
  • PIFA [bis(trifluoracetoxy)iodo]benzene
  • TFA trifluoro acetid acid
  • This reaction will lead to introduction of an hydroxy group in one step.
  • the insertion of the hydroxy group is not regioselective.
  • the desired 3,4-dihydro-2H-l,4-benzoxazin-6-ol (I) is obtained via recrystallization processes in moderate yields.
  • Reaction Scheme (B) o-Amino-phenol (XXIII) is reacted with chloroacetyl chloride for example in DMF to perform the ring closure condensation to yield the intermediate 4H-l,4-benzoxazin-3-one (XXII). After reducing the solvent under vacuum, the product is isolated via trituration with water and/or lower alcohol(s). Compound (XXII) is then treated under strong acidic conditions, for example in TFA (trifluoroacetic acid) with [bis(trifluoracetoxy)iodo]benzene (PIFA), to yield the next intermediate 6-hydroxy-4H-l,4- benzoxazin-3-one (XV) according to a known procedure.
  • TFA trifluoroacetic acid
  • PIFA [bis(trifluoracetoxy)iodo]benzene
  • the introduction of the hydroxy group is very clean and highly regio selective as the donor direction of the oxygen atom in para position is dominant versus the lactam nitrogen in 4H-l,4-benzoxazin-3-one (XXII).
  • the following reduction of the carbonyl group may then be carried out via a process described herein, using for example a commercially available solution containing the boron dimethylsulfide-THF complex in THF which acts as a very selective and clean reagent to yield the desired compound 3,4-dihydro-2H-l,4-benzoxazin- 6-ol (I).
  • cosmetically acceptable salts are preferred.
  • Preferred cosmetically acceptable salts are the lithium, sodium, potassium, ammonium, magnesium and calcium salts of 3,4- dihydro-2H-l,4-benzoxazin-6-ol (I), or of intermediates discussed herein, respectively.
  • the term salt, as used herein, comprises salts in the classical meaning, as well as addition salts. Addition salts encompass addition complexes with acid, base and/or solvent(s).
  • addition salts with an acid include complexes of the target compound or of intermediates disclosed herein, with hydrogen chloride, hydrogen bromide, sulfuric acid, phosphoric acid, acetic acid, citric acid, succinic acid, tartaric acid, lactic acid, tosylic acid, benzenesulfonic acid.
  • 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.
  • steps described to prepare 3,4-dihydro-2H-l,4-benzoxazin-6-ol according to formula (I) may be performed in a sequential one-pot synthesis, with reagents added to a reactor one at a time and without work-up in between.
  • the reaction steps require suitable solvents, as indicated below. Sequential one-pot synthesis without work-up in between is preferred, unless it is preferred to avoid by-products from a preceding step in a subsequent step.
  • Benzomorpholine (XXI) (3,4-dihydro-2H-l,4-benzoxazine) is treated with [bis(trifluoracetoxy)iodo]benzene (PIFA) in strong acid medium.
  • the acid may be selected from the group of trifluoro acetid acid, acetic acid, propionic acid, oxalic acid, malonic acid, sulfuric acid, phosphoric acid, hydrogen chloride, aqueous solutions thereof, and mixtures thereof.
  • the acid may be selected from the group consisting of trifluoro acetic acid (TFA), acetic acid, hydrogen chloride, sulfuric acid, and mixtures thereof.
  • the acid is trifluoro acetic acid (TFA).
  • TFA trifluoro acetic acid
  • PIFA may be prepared according to known literature procedures as described herein, or as well is commercially readily available. This reaction will lead to introduction of an hydroxy group in one step. However, due to the comparable electron donor strengths of the nitrogen and the vicinal hydroxy group, the insertion of the hydroxy group is not regioselective. The desired 3,4-dihydro-2H-l,4-benzoxazin-6-ol (I) is obtained via recrystallization processes in moderate yields.
  • Solvents for the recrystallization may be selected from the group of 1,2-dimethoxyethane, ethyl acetate, 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, iso-pentanol, t-butanol, isopropanol, n-propanol, ethanol, methanol, glycols, hydrogen chloride, aqueous solutions thereof, and mixtures thereof.
  • the solvent for the recrystallization may be selected from the group consisting of ethyl acetate, toluene, n-butanol, isopropanol, n-propanol, ethanol, methanol, acetic acid, propionic acid, oxalic acid, malonic acid, hydrogen chloride, sulfuric acid, phosphoric acid and mixtures thereof.
  • the solvent for the recrystallization may be selected from the group consisting of n-propanol, acetic acid, toluene, ethyl acetate and mixtures thereof.
  • Solvents for the condensation reaction may be selected from the group of chloroform, methylenchloride, dimethylformamide, dimethylacetamide, NMP (N-methylpyrrolidone), acetonitrile, 1,2-dimethoxyethane, ethyl acetate, pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, 1,4-dioxane, diethyl ether, tetrahydrofuran, methyl-tetrahydrofuran, and mixtures thereof.
  • the solvent for the condensation reaction may be selected from the group consisting of chloroform, methylenchloride, dimethylformamide, dimethylacetamide, ethyl acetate, acetonitrile, toluene and mixtures thereof.
  • the solvent for the condensation reaction may be selected from the group consisting of chloroform, methylenchloride, dimethylformamide, dimethylacetamide and mixtures thereof.
  • Compound (XXII) is then treated under strong acidic conditions with [bis(trifluoracetoxy)iodo]benzene (PIFA) to introduce the desired hydroxy group in para position to the ring oxygen atom yielding the intermediate 6-hydroxy-4H-l,4-benzoxazin-3-one (XV).
  • the acid may be selected from the group of trifluoro acetid acid, acetic acid, propionic acid, oxalic acid, malonic acid, sulfuric acid, phosphoric acid, hydrogen chloride, aqueous solutions thereof, and mixtures thereof.
  • the acid may be selected from the group consisting of trifluoro acetic acid (TFA), acetic acid, hydrogen chloride, sulfuric acid, and mixtures thereof.
  • the acid is trifluoro acetic acid (TFA).
  • PIFA may be prepared according to known literature procedures as described herein, or as well is commercially readily available.
  • the introduction of the hydroxy group is very clean and highly regio selective as the donor direction of the oxygen atom in para position is dominant versus the lactam nitrogen in 4H-l,4-benzoxazin-3- one (XXII).
  • the following reduction of the carbonyl group is then carried out via a process described herein, for example using a commercially available solution containing the boron dimethylsulfide-THF complex in THF which acts as a very selective and clean reagent to yield the desired compound 3,4- dihydro-2H-l,4-benzoxazin-6-ol (I).
  • the selective carbonyl reduction is carried out carefully in THF as solvent using commercially available solution containing the boron dimethylsulfide-THF complex which acts as a very selective and clean reagent, to yield the desired product 3,4-dihydro-2H-l,4- benzoxazin-6-ol (I).
  • the reaction solvent according to a preferred embodiment is exclusively THF.
  • other commercially available boron complexes such as boron-THF complex solution in THF can be used as reductive medium.
  • the desired product 3,4- dihydro-2H-l,4-benzoxazin-6-ol (I) may be extracted.
  • Suitable solvents for the extraction comprise chloroform, methylenchloride, tert-butyl-methyl-ether, diethyl ether, ethyl acetate, 1,2- dimethoxyethane, pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, 1,4-dioxane, tetrahydrofuran, methyl-tetrahydrofuran, and mixtures thereof.
  • the solvent for the extraction may be selected from the group consisting of chloroform, methylenchloride, tert-butyl-methyl-ether, diethyl ether, ethyl acetate, 1,2- dimethoxyethane, and mixtures thereof.
  • the solvent for the extraction may be selected from the group consisting of chloroform, methylenchloride, tert-butyl-methyl-ether, diethyl ether, ethyl acetate and mixtures thereof.
  • the isolated product obtained after removal of the extraction solvent may be recrystallized to obtain 3,4-dihydro-2H-l,4-benzoxazin-6-ol (I) as pure compound.
  • Solvents for the recrystallization may be selected from the group consisting of 1,2-dimethoxyethane, ethyl acetate, 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, iso-pentanol, t-butanol, isopropanol, n- propanol, ethanol, methanol, glycols
  • the solvent for the recrystallization may be selected from the group consisting of ethyl acetate, toluene, n-butanol, isopropanol, n-propanol, ethanol, methanol, acetic acid, propionic acid, oxalic acid, malonic acid, hydrogen chloride, sulfuric acid, phosphoric acid and mixtures thereof.
  • the solvent for the recrystallization may be selected from the group consisting of n-propanol, acetic acid, toluene, ethyl acetate and mixtures thereof.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

L'invention concerne un procédé de préparation de 3,4-dihydro-2H-1,4-benzoxazin-6-ol à partir du composé (XXI) ou (XXII) et par introduction du groupe hydroxyle à l'aide de [bis(trifluoroacétoxy)iodo]benzène.
PCT/EP2024/081440 2023-11-10 2024-11-07 Nouvelles synthèses télescopiques de 6-hydroxy-benzomorpholine (3,4-dihydro-2h-1,4-benzoxazin-6-ol) Pending WO2025099127A1 (fr)

Applications Claiming Priority (2)

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EP23209034 2023-11-10
EP23209034.0 2023-11-10

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WO2025099127A1 true WO2025099127A1 (fr) 2025-05-15

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008150848A1 (fr) 2007-05-30 2008-12-11 Wyeth Dérivés d'hétéro-aryle antidépresseurs de benzodioxanes condensés avec un hétérocycle
WO2009036351A2 (fr) * 2007-09-13 2009-03-19 University Of Massachusetts Colorants activables
CN111170958A (zh) 2019-12-25 2020-05-19 浙江鼎龙科技有限公司 一种羟苯并吗啉的制备方法

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008150848A1 (fr) 2007-05-30 2008-12-11 Wyeth Dérivés d'hétéro-aryle antidépresseurs de benzodioxanes condensés avec un hétérocycle
WO2009036351A2 (fr) * 2007-09-13 2009-03-19 University Of Massachusetts Colorants activables
CN111170958A (zh) 2019-12-25 2020-05-19 浙江鼎龙科技有限公司 一种羟苯并吗啉的制备方法

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
ITOH, NAOKI ET AL., JOURNAL OF ORGANIC CHEMISTRY, vol. 67, no. 21, 2002, pages 7424 - 7428
PAGE, T. KERI ET AL., SYNTHESIS, no. 18, 2006, pages 3153 - 3155
XIAN HUANG: "Synthesis of 3-Oxo-3,4-dihydro-2H-1,4-benzoxazines and -1,4-benzothiazines under Phase Transfer Catalysis", SYNTHESIS COMMUNICATIONS, 1 October 1984 (1984-10-01), pages 851 - 852, XP055592861, DOI: 10.1055/s-1984-30993 *
ZHANG HUIJUN ET AL: "Design, synthesis and characterization of potent microtubule inhibitors with dual anti-proliferative and anti-angiogenic activities", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, ELSEVIER, AMSTERDAM, NL, vol. 157, 20 July 2018 (2018-07-20), pages 380 - 396, XP085491705, ISSN: 0223-5234, DOI: 10.1016/J.EJMECH.2018.07.043 *

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