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WO2025099125A1 - Nouvelles synthèses télescopiques de 6-hydroxy-benzomorpholine (3,4-dihydro-2 h-1,4-benzoxazin-6-ol) - Google Patents

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

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Publication number
WO2025099125A1
WO2025099125A1 PCT/EP2024/081434 EP2024081434W WO2025099125A1 WO 2025099125 A1 WO2025099125 A1 WO 2025099125A1 EP 2024081434 W EP2024081434 W EP 2024081434W WO 2025099125 A1 WO2025099125 A1 WO 2025099125A1
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Prior art keywords
benzoxazin
hydroxy
dihydro
acid
phenyl
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PCT/EP2024/081434
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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 WO2025099125A1 publication Critical patent/WO2025099125A1/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 current commercialized synthesis routes use 1,4-di-methoxy-substituted starting materials, having both of the two required oxygen atoms already in the structural pattern of the starting materials.
  • the downside is the carbonyl reduction, the subsequent ring closure condensation, followed by deprotection of the two ether groups while cleaving the ether structure, which requires harsh conditions using hydrobromic acid followed by an intense neutralization step, which requires significant volumes of ammonia.
  • the byproducts formed are significant and of questionable from an environmental point of view.
  • 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 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:
  • Pr is a protecting moiety
  • the protecting moiety Pr in step (a) of the inventive method is acyl or benzyl.
  • acyl as the protecting moiety Pr, good results have been obtained.
  • reaction product of step (a), i.e. (4-hydroxyphenyl)-Pr (III), may be separated.
  • Separating (4-hydroxyphenyl)-Pr (III) may comprise filtering off unreacted hydroquinone (II), and solvent evaporation.
  • reaction product of step step (b), i.e. (4-hydroxy-3-nitro-phenyl)-Pr (IV) may be separated.
  • separating (4-hydroxy-3-nitro-phenyl)-Pr (IV) may comprise recrystallizing.
  • the hydrogen source used in step (c) may be selected from ammonium formate, hydrazine hydrate and/or H2.
  • hydrogen gas may be used as the hydrogen source, and Pd/C as the metal catalyst.
  • phase transfer catalysts include benzyl trialkyl ammonium salts.
  • phase-transfer catalyst include the chloride, bromide or sulfate salts of benzyl trimethyl ammonium, benzyl triethyl ammonium, benzyl tripropyl ammonium, benzyl tributyl ammonium. Mixtures of phase-transfer catalysts suitably may be used.
  • step (d) further comprises separating 3-oxo-4H-l,4-benzoxazin-6-yl)-Pr (VI).
  • step (d) further comprises separating 3-oxo-4H-l,4-benzoxazin-6-yl)-Pr (VI).
  • step (VI) further comprises separating 3-oxo-4H-l,4-benzoxazin-6-yl)-Pr (VI).
  • step (d) further comprises separating 3-oxo-4H-l,4-benzoxazin-6-yl)-Pr (VI).
  • step (VI) further comprises separating 3-oxo-4H-l,4-benzoxazin-6-yl)-Pr (VI).
  • deprotected 6-hydroxy-4H-l,4-benzoxazin-3-one may be separated.
  • 6-hydroxy-4H-l,4-benzoxazin-3-one precipitates, and may be collected by filtration.
  • the final step of the method according to the present invention concerns the reduction of the carbonyl group, to yield the desired target compound 3,4-dihydro-2H-l,4-benzoxazin-6-ol (I).
  • the reduction is carried out in THF, in the presence of a boron-THF complex.
  • a particularly suitable boron-THF complex is boron dimethylsulfide-THF complex.
  • 3,4-dihydro- 2H-l,4-benzoxazin-6-ol (I) is typically separated. Separating may comprise extracting 3,4-dihydro-2H- l,4-benzoxazin-6-ol (I) from THF using a solvent selected from 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.
  • a solvent selected from chloroform, methylenchloride, tert- butyl-methyl-ether, diethyl ether, ethyl acetate, 1,2-dimethoxyethane, pentane
  • the method may further comprise recrystallizing 3,4-dihydro-2H-l,4-benzoxazin-6-ol (I) from the extraction solvent.
  • 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, aqueous solutions thereof, and mixtures thereof.
  • Preferred recrystallization solvents include ethyl acetate, toluene, acetic acid, propionic acid, oxalic acid, malonic acid, sulfuric acid, phosphoric acid, hydrogen chloride, n-butanol, isopropanol, n- propanol, ethanol, methanol, aqueous solutions thereof, and mixtures thereof.
  • Particularly preferred recrystallization solvents are ethyl acetate, toluene, acetic acid, n-propanol, and mixtures thereof.
  • Reaction schemes (A) to (F) below exemplify the method according to the present invention using the acetyl group as an example of a protection group.
  • hydrochinone (ll) 7 which is commercially available. Key steps of the method according to the present invention may be summarized as follows:
  • the first step involves the addition of a protection group at the commodity hydrochinone (II) which can be easily removed during the course of the reaction once needed.
  • the acetyl group is a very suitable group as it can be added via standard methods and can be easily removed without using complex process aids.
  • the conversion is carried out via standard methods for acetylation using equimolar acetic anhydride in acetic acid as co-colvent.
  • the (4-hydroxy-3-nitro-phenyl) acetate (IV) intermediate is then converted to (3-amino-4-hydroxy- phenyl) acetate (V) via a standardized hydrogenation using palladium on charcoal as catalyst and hydrogen in ethanol as an environmentally friendly solvent.
  • the last step represents the final carbonyl reduction of the heterocycle ring of 6-hydroxy-4H-l,4- benzoxazin-3-one (VII).
  • 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 final target 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.
  • (4-hydroxyphenyl) acetate (III) is added along standard nitration protocols in small portions to a mixture comprising acetic acid and acetic anhydride, preferably in a ratio of 1:1 by volume, while cooling and an stirring. A solution of concentrated nitric acid is added carefully so that the temperature is kept between -5-0°C. The action is slowly allowed to warm up to ambient temperature for further 2 h. Standard workup while diluting the reaction mixture with ice water and extracting the latter with ethyl acetate followed by recrystallization yields the desired intermediate 4-hydroxy-3-nitrophenyl acetate (IV).
  • 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, sulphuric acid, phosphoric acid, iso-pentanol, t-butanol, isopropanol, n-propanol, ethanol, methanol, glycols, hydrogen chloride, water 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, sulphuric 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.
  • the hydrogenation step of 4-hydroxy-3-nitrophenyl acetate (IV) is principally carried out in the presence of a hydrogen source to yield (3-amino-4-hydroxy-phenyl) acetate (V).
  • the hydrogen source may be selected from ammonium formate, hydrazine or H 2 with a metal catalyst selected from the group consisting of Fe, Pd/C, Pd/(OH) 2 , Raney-Ni, Pt/C, PtO 2 and mixtures thereof.
  • the hydrogen source may be H 2
  • the metal catalyst may be a Pd/C catalyst.
  • the solvent(s) used in this step may be selected from the group consisting of 1,2-dimethoxyethane, pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, methylacetate, ethylacetate, n-propylacetate, isopropylacetate, n-butylacetate, methylpropionate, ethylpropionate, n-propylpropionate, isopropylpropionate, n-butylpropionate, 1,4-dioxane, diethyl ether, tetrahydrofuran, methyl- tetrahydrofuran, n-butanol, isopropanol, n-propanol, ethanol, methanol, water and mixtures thereof.
  • the solvent may be selected from the group consisting of 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.
  • (3-amino-4-hydroxy-phenyl) acetate (V) is treated in a solution of chloroform with 2-chloro acetyl chloride as a highly reactive but very selective reagent to condense a morpholine type ring on the (3- amino-4-hydroxy-phenyl) acetate (V) to form the desired 3-oxo-4H-l,4-benzoxazin-6-yl) acetate (VI).
  • the condensation reaction can be done at 0°C using a phase transfer catalyst in the presence of a weak base to neutralize the formed acid as byproduct.
  • the ring closure reaction may be carried out using at least one phase transfer catalyst.
  • the phase transfer catalyst(s) may be selected from the group consisting of benzyl trialkyl ammonium salts, alternatively from the group consisting of chloride, bromide or sulfate salts of benzyl trimethyl ammonium, benzyl triethyl ammonium, benzyl tripropyl ammonium, benzyl tributyl ammonium and mixtures thereof.
  • the phase transfer catalyst is benzyl tributyl ammonium chloride.
  • the base may be selected from sodium hydrogen carbonate, calcium carbonate, sodium carbonate, potassium carbonate, sodium acetate, DBU, DBN, Huenig Base, ammonium sulphate, sodium hydrogencarbonate and potassium hydrogencarbonate. According to an embodiment, potassium carbonate, sodium hydrogen carbonate, sodium carbonate, are used as the base.
  • 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.
  • the alkaline hydrolysis is carried out in the presence of bases such as sodium hydroxide, potassium hydroxide, calcium carbonate, sodium carbonate, potassium carbonate and sodium acetate.
  • bases such as sodium hydroxide, potassium hydroxide, calcium carbonate, sodium carbonate, potassium carbonate and sodium acetate.
  • sodium hydroxide and potassium hydroxide are used as the base.
  • Solvents for the hydrolysis may be selected from the group of t-butanol, isopropanol, n-propanol, ethanol, methanol, glycols, water and mixtures thereof.
  • the solvent for the hydrolysis may be selected from the group consisting of ethanol, methanol, glycols, water and mixtures thereof.
  • the solvent for the hydrolysis may be selected from the group consisting of n-propanol, ethanol and methanol and mixtures thereof.
  • the last step represents the final carbonyl reduction of the heterocycle ring of 6-hydroxy-4H-l,4- benzoxazin-3-one (VII) to yield the desired target 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.
  • the reaction solvent is exclusively THF.
  • other commercially available boron complexes such as boron-THF complex solution in THF can be used as reductive medium.
  • Solvents for the extraction after the reduction is completed are selected from the group of 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 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 reoval of the extraction solvent is 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 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, sulphuric acid, phosphoric acid, iso-pentanol, t-butanol, isopropanol, n-propanol, ethanol, methanol, glycols, hydrogen chloride, water 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, sulphuric 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.
  • reaction mixture is then diluted with 200 ml water and extracted 3 times with chloroform (100 ml each).
  • the combined organic phases are washed with 100 ml brine and dried over sodium sulfate.
  • the solvent is evaporated under reduced pressure and the resulting residue is treated with water and toluene and the desired product 3-oxo-4H-l,4-benzoxazin-6-yl) acetate (VI) collected by filtration as colorless solid in 75% yield.
  • the used solvent chloroform can be exchanged as well with DMF following the same experimental procedure.
  • step (f) reducing 6-hydroxy-4H-l,4-benzoxazin-3-one (VII) to form 3,4-dihydro-2H-l,4- benzoxazin-6-ol (I).
  • the protecting moiety Pr is acyl or benzyl.
  • step (a) further comprises separating
  • step (b) further comprises separating (4-hydroxy-3-nitro-phenyl)-Pr (IV).
  • step (c) wherein separating comprises recrystallizing (4- hydroxy-3-nitro-phenyl)-Pr (IV).
  • the hydrogen source used in step (c) is selected from ammonium formate, hydrazine hydrate and/or H2.
  • the hydrogen source is H2 and the metal catalyst is Pd/C.
  • step (d) is carried out in a two-phase system, in the presence of at least one phase-transfer catalyst.
  • the at least one phase transfer catalyst is selected from benzyl trialkyl ammonium salts, in particular from chloride, bromide or sulfate salts of benzyl trimethyl ammonium, benzyl triethyl ammonium, benzyl tripropyl ammonium, benzyl tributyl ammonium, and mixtures thereof.
  • step (d) further comprises separating 3-oxo-4H-l,4-benzoxazin-6-yl)-Pr (VI).
  • step (e) is carried out in the presence of a base.
  • step (e) further comprises separating 6-hydroxy-4H-l,4-benzoxazin-3-one (VII).
  • step (f) is carried out in THF, in the presence of a boron-THF complex.
  • boron-THF complex is boron dimethylsulfide-THF complex.
  • the recrystallization solvent is selected from 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 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, aqueous solutions thereof, and mixtures thereof.
  • the recrystallization solvent is selected from ethyl acetate, toluene, acetic acid, n-propanol, and mixtures thereof.

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  • 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.
PCT/EP2024/081434 2023-11-10 2024-11-07 Nouvelles synthèses télescopiques de 6-hydroxy-benzomorpholine (3,4-dihydro-2 h-1,4-benzoxazin-6-ol) Pending WO2025099125A1 (fr)

Applications Claiming Priority (2)

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EP23209031 2023-11-10

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4672013A (en) * 1984-07-20 1987-06-09 Minnesota Mining And Manufacturing Company Cyan dye-forming couplers and photographic elements and processes
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
WO2021150979A1 (fr) * 2020-01-24 2021-07-29 Oregon Health & Science University Composés fluorophores à base d'oxazine d'imagerie spécifique du nerf

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4672013A (en) * 1984-07-20 1987-06-09 Minnesota Mining And Manufacturing Company Cyan dye-forming couplers and photographic elements and processes
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
WO2021150979A1 (fr) * 2020-01-24 2021-07-29 Oregon Health & Science University Composés fluorophores à base d'oxazine d'imagerie spécifique du nerf

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
SMITH GERRY A. ET AL: "The design and properties of a series of calcium indicators which shift from rhodamine-like to fluorescein-like fluorescence on binding calcium", no. 6, 1 January 1993 (1993-01-01), GB, pages 1195, XP093146303, ISSN: 0300-9580, Retrieved from the Internet <URL:https://pubs.rsc.org/en/content/articlepdf/1993/p2/p29930001195> DOI: 10.1039/p29930001195 *
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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