WO2025099125A1

WO2025099125A1 - New telescoping syntheses of 6-hydroxy-benzomorpholine (3,4-dihydro-2h-1,4-benzoxazin-6-ol)

Info

Publication number: WO2025099125A1
Application number: PCT/EP2024/081434
Authority: WO
Inventors: Markus Speckbacher; Armin Osan; Heike ABEL; Felix TETSCHNER; Andreas SCHRAN
Original assignee: Wella Germany GmbH
Current assignee: Wella Germany GmbH
Priority date: 2023-11-10
Filing date: 2024-11-07
Publication date: 2025-05-15
Anticipated expiration: 2026-05-10

Abstract

The invention relates to a method for preparing 3,4-dihydro-2H-1,4-benzoxazin-6-ol.

Description

NEW TELESCOPING SYNTHESES OF 6-HYDROXY-BENZOMORPHOLINE

(3,4-DIHYDRO-2H-l,4-BENZOXAZIN-6-OL)

FIELD OF THE INVENTION

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 paraphenylendiamine derivatives and other well-known oxidative precursors, an important base coat to support grey coverage and lastingness of any oxidative hair coloration. Due to similar dyeing properies compared with resorcinol or methyl-resorcinol, it is therefore a suitable candidate for replacing resorcinol and resorcinol derivatives in oxidative hair color formulations. In light of the rapidly changing global regulatory environments, a suitable replacement for resorcinol and methyl-resorcinol will be needed in the near future. Hence, 3,4-dihydro-2H-l,4- benzoxazin-6-ol according to formula (I) represents an attractive candidate to achieve this aim.

O H

(I)

BACKGROUND OF THE INVENTION

3.4-dihydro-2H-l,4-benzoxazin-6-ol (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. 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 such as resorcinol or methyl-resorcinol, the focus is now on providing an advanced and improved synthesis to minimize the financial impact a potential ban of resorcinol derivatives may have to hair color companies.

In the past, the industry already published different synthetic routes to manufacture 3,4-dihydro-2H-

1.4-benzoxazin-6-ol (I) or salts thereof.

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.

For example, 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. However, 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 byproducts 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.

Therefore, there exists a massive need to provide a new process for preparing 3,4-dihydro-2H-l,4- benzoxazin-6-ol (I), or a salt thereof, or mixture thereof which offers an attractive and considerably improved cost structure, particularly in comparison with the current existing synthesis methods or other published and/or commercialized methods. In regard of an increasing global demand, an economical access to 3,4-dihydro-2H-l,4-benzoxazin-6-ol (I) would be appreciated. This manufacturing process should also be able to provide a material with a low impurity level in accordance with global regulations. Furthermore, 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. Finally, in view of increasing ecological demands, 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.

It has surprisingly now been found, that a new synthesis pathway starting with readily commercially available feedstock materials, will lead to the desired 3,4-dihydro-2H-l,4-benzoxazin-6-ol (I) with enhanced economics and significantly decreased use of organic solvents and/or harsh chemicals/process aids as compared to the current state of the art. The synthesis route presented herein may use water and aqueous, alhoholic solutions in one or more steps of the reaction course, and therefore may replace expensive and environmentally problematic organic solvents used in previously described synthesis methods for the preparation of 3,4-dihydro-2H-l,4-benzoxazin-6-ol (I).

SUMMARY OF THE INVENTION

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:

(a) protecting one hydroxyl group of hydroquinone (II) to form (4-hydroxyphenyl)-Pr (III), wherein

Pr is a protecting moiety

(b) nitrating (4-hydroxyphenyl)-Pr (III) to form (4-hydroxy-3-nitro-phenyl)-Pr (IV)

(c) reacting (4-hydroxy-3-nitro-phenyl)-Pr (IV) in the presence of a hydrogen source and in the presence of a metal catalyst to form (3-amino-4-hydroxy-phenyl)-Pr (V)

(d) condensing (3-amino-4-hydroxy-phenyl)-Pr ) with 2-chloroacetyl chloride to form 3-oxo-4H- l,4-benzoxazin-6-yl)-Pr (VI)

(e) deprotecting 3-oxo-4H-l,4-benzoxazin-6-yl)-Pr (VI) to form 6-hydroxy-4H-l,4-benzoxazin-3- one (VII)

(f) reducing 6-hydroxy-4H-l,4-benzoxazin-3-one (VII) to form 3,4-dihydro-2H-l,4-benzoxazin-6-ol

(I).

According to an embodiment, the protecting moiety Pr in step (a) of the inventive method is acyl or benzyl. For example, using acyl as the protecting moiety Pr, good results have been obtained.

According to an embodiment, the 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.

According to an embodiment, the reaction product of step step (b), i.e. (4-hydroxy-3-nitro-phenyl)-Pr (IV), may be separated. Conveniently, separating (4-hydroxy-3-nitro-phenyl)-Pr (IV) may comprise recrystallizing.

According to an embodiment, the hydrogen source used in step (c) may be selected from ammonium formate, hydrazine hydrate and/or H2. According to a particular embodiment, hydrogen gas may be used as the hydrogen source, and Pd/C as the metal catalyst.

The condensation reaction of step (d) conveniently may be carried out in a two-phase system. When using a two-phase system, the reaction suitably may be carried out in the presence of at least one phase-transfer catalyst. Suitable phase transfer catalysts include benzyl trialkyl ammonium salts. Particular examples of such 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.

The method according to any of the preceding claims, wherein step (d) further comprises separating 3-oxo-4H-l,4-benzoxazin-6-yl)-Pr (VI). Subsequent deprotection of 3-oxo-4H-l,4-benzoxazin-6-yl)-Pr (VI), to obtain 6-hydroxy-4H-l,4-benzoxazin-3-one (VII) usually is carried out in the presence of at least one mineral or organic base.

According to an embodiment, deprotected 6-hydroxy-4H-l,4-benzoxazin-3-one (VII) may be separated. Typically, 6-hydroxy-4H-l,4-benzoxazin-3-one (VII) 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). According to an embodiment, 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.

After reduction of the carbonyl group in THF, in the presence of a boron-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.

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. The following further describes the method according to the present invention. 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.

The method starts with hydrochinone (ll)₇ which is commercially available. Key steps of the method according to the present invention may be summarized as follows:

• Providing (4-hydroxyphenyl) acetate (III) via controlled half side acetylation

• Nitration of (4-hydroxyphenyl) acetate (III) to yield (4-hydroxy-3-nitro-phenyl) acetate (IV)

• Transforming (4-hydroxy-3-nitro-phenyl) acetate (IV) via hydrogenation into the related amino compound (3-amino-4-hydroxy-phenyl) acetate (V)

• Approaching the ring closure to obtain 3-oxo-4H-l,4-benzoxazin-6-yl) acetate (VI)

• Cleavage of the acetyl protection group to give 6-hydroxy-4H-l,4-benzoxazin-3-one (VII)

• Final carbonyl reduction of 6-hydroxy-4H-l,4-benzoxazin-3-one (VII) to obtain the desired target compound 3,4-dihydro-2H-l,4-benzoxazin-6-ol (I)

Reaction Scheme (A)

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.

Reaction Scheme (B)

The following nitration in ortho-position to the hydroxy group is carried out via standard conditions for nitrations at activated aromatic rings. Concentrated nitric acid (67%) is used to nitrate the substrate (4-hydroxyphenyl) acetate (III) under mild conditions at temperatures below 0°C to allow a selective nitration without the formation of unwanted byproducts yielding the desired (4-hydroxy-3- nitro-phenyl) acetate (IV). Reaction Scheme (C)

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.

Reaction Scheme (D)

The next step involves the ring closure using 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 in Chloroform as solvent using a phase transfer catalyst in the presence of a weak base to neutralize the formed acid as byproduct. The chloroform can be completely recycled as there is no other solvent used, hence no solvent mixtures required, and therefore promotes the environmentally friendly concept with dramatically reduced organic waste.

Reaction Scheme (E)

Once the ring closure reaction has been completed, the resulting crystallized precipitate of 3-oxo-4H- l,4-benzoxazin-6-yl) acetate (VI) is directly used for the next step which is the cleavage of the acetyl protecting group to obtain the next intermediate 6-hydroxy-4H-l,4-benzoxazin-3-one (VII). Reaction Scheme (F)

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).

As far as the present invention relates to salts of 3,4-dihydro-2H-l,4-benzoxazin-6-ol (I), or of intermediates disclosed herein, 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). Examples of 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. Examples of 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. Examples of 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.

DETAILED DESCRIPTION OF THE INVENTION

The sequence of steps, including all identified intermediates, involved in the telescoping synthesis and large scale process, is described in detail in the following. It is to be understood that when the present disclosure refers to a particular structure, all of the reasonable additional tautomeric structures are included. In the art tautomeric structures are frequently represented by one single structure and the present disclosure follows this general practice. It is to be understood that the 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.

The detailed description that follows exemplifies the method according to the present invention by referring to, for example, particular reactants and/or reaction conditions. This is done for the sake of exemplification, and the present invention is not limited thereby. For example, reference to chlorine is to be understood as a reference to a suitable halogen, or the reference to a particular solvent is to be understood as a reference to solvents being generally suitable for the respective reaction, and the respective solubilisation intended. Analogously, the reference to a particular acid or base is to be understood as a general reference to a suitable acid or base, respectively.

Synthesis of 3,4-dihydro-2H-l,4-benzoxazin-6-ol (I) using hydrochinone (II) as starting material

Reaction Scheme (A)

In the solution of of hydroquinone (II) in excess of acetic acid, one half equivalent of acetic anhydride was added dropwise for one hour while agitating the solution at 110°C. The mixture was maintained at 110°C for two hours, and acetic acid was distilled under vacuum. The double amount of toluene in relation to acetic acid was added to the reaction mixture and the unreacted excess hydroquinone was filtered and collected (recycled without any purification process). The desired (4-hydroxyphenyl) acetate (III) was obtained by evaporating the residue under vacuum.

Reaction Scheme (B)

(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. Preferably, 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. In particular, the solvent for the recrystallization may be selected from the group consisting of n-propanol, acetic acid, toluene, ethyl acetate and mixtures thereof.

Reaction Scheme (C)

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 H₂ with a metal catalyst selected from the group consisting of Fe, Pd/C, Pd/(OH)₂, Raney-Ni, Pt/C, PtO₂ and mixtures thereof. In particular, the hydrogen source may be H₂, and 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. Preferably, 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. Reaction Scheme (D)

(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. Preferably, 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. Preferably, 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. In particular, the solvent for the condensation reaction may be selected from the group consisting of chloroform, methylenchloride, dimethylformamide, dimethylacetamide and mixtures thereof. Reaction Scheme (E)

Once the ring closure reaction has been completed, the resulting crystallized precipitate of 3-oxo-4H- l,4-benzoxazin-6-yl) acetate (VI) is directly used for the next step which is the cleavage of the acetyl protecting group to obtain the next intermediate 6-hydroxy-4H-l,4-benzoxazin-3-one (VII).

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. According to an embodiment, 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. Preferably, the solvent for the hydrolysis may be selected from the group consisting of ethanol, methanol, glycols, water and mixtures thereof. In particular, the solvent for the hydrolysis may be selected from the group consisting of n-propanol, ethanol and methanol and mixtures thereof.

Reaction Scheme (F)

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. Alternatively, 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 (followed and controlled by TLC analysis) 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. Preferably, 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. In particular, 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. Preferably, 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. In particular, the solvent for the recrystallization may be selected from the group consisting of n-propanol, acetic acid, toluene, ethyl acetate and mixtures thereof.

EXAMPLES

The following non-limiting examples further illustrate the present invention. The examples are given solely for the purpose of illustration and are not to be construed as limitations of the present invention, as many variations thereof are possible without departing from the spirit and scope of the invention, which would be recognized by one of ordinary skill in the art. All concentrations are listed as weight percent, unless otherwise specified.

Example 1: Synthesis of (4-hydroxyphenyl) acetate (III)

A three necked flask was fitted with a reflux condenser and a thermometer. Hydrochinone (II) (2 eq., 50.00 g, 454 mmol) is suspended in acetic acid (100 ml) under stirring and the mixture heated to 120°C. Acetic anhydride (leq. 23.18g, 21.46 ml, H mmol) is added within 1 h to the reaction mixture and stirred for 1 further h. After cooling to RT, the solvent is evaporated under reduced pressure. The resulting residue is treated with 200 ml toluene and cooled to -20°C. The colorless residue comprising of hydrochinone (II) is filtered off and can be recycled. The filtrate is further evaporated under reduced pressure to obtain the desired (4-hydroxyphenyl) acetate (III) in 90% yield (31.34g). Example 2: Synthesis of (4-hydroxy-3-nitro-phenyl) acetate (IV)

1 eq. (4-hydroxyphenyl) acetate (III) (10.00 g, 66 mmol) is suspended in a mixture of acetic anhydride and acetic acid (20 ml each) and cooled to 0°C. Concentrated nitric acid (1.05 eq., 65%, 3.66g, 2.47 ml, 38 mmol) is slowly added within 1 h. The reaction mixture is heated to RT and stirred for 1 further hour. A solution of 8 ml concentrated nitric acid (65%) in 100 ml water is then slowly added. The resulting precipitate is filtered off and washed with ice cold methanol and water. The residue is recrystallized in methanol and the desired product (4-hydroxy-3-nitro-phenyl) acetate (IV) isolated in 83% yield (10.80 g) as yellow needles.

Example 3: Synthesis of (3-amino-4-hydroxy-phenyl) acetate (V)

1 eq. (4-hydroxy-3-nitro-phenyl) acetate (IV) (25.00g, 127 mmol) is suspended in 500 ml ethanol and 5 wt% Pd/C (1.25 g, 10 wt% Pd, 50 wt% H2O) catalyst is carefully added. The reaction mixture is then hydrogenated with a hydrogen stream under a pressure of 3 bar. After complete absorption of the calculated hydrogen, the reaction mixture is filtrated and the filtrate is evaporated under reduced pressure to yield the desired compound (3-amino-4-hydroxy-phenyl) acetate (V) in 94% yield (19.87 g) as colorless solid. Is is important to work strictly under nitrogen as compound (V) is very sensitive to oxygen.

Example 4: Synthesis of 3-oxo-4H-l,4-benzoxazin-6-yl) acetate (VI)

A solution of (3-amino-4-hydroxy-phenyl) acetate (V) (leq., 5.00g, 30 mmol) in 50 ml chloroform is prepared. 3.5 eq. sodium bicarbonate (5.00g, 90 mmol) and 0.05 eq. benzyl tributyl ammonium chloride (0.34 g, 1.5 mmol) are carefully added to this solution and cooled down to 0°C. Within 30 min, 1.75 eq. chloro acetyl chloride (6.20 g, 4.4 ml, 55 mmol) are slowly added dropwise. Once the addition is complete, the reaction mixture is heated to RT and stirred for 1 further h. The 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.

Example 5: Synthesis of 6-hydroxy-4H-l,4-benzoxazin-3-one (VII)

A solution of 2.35 g (11.3 mmol) of 3-oxo-4H-l,4-benzoxazin-6-yl) acetate (VI) is dissolved in 50 ml of methanol. An aqueous solution of sodium hydroxide (IN, 15 mL) is then added and the reaction mixture heated at reflux for lh. The solvent is removed by concentration in vacuum, and the residue subsequently redissolved in 150 mL of water, which is acidified with IN hydrochloric acid to pH 2. The resulting precipitate is collected and dried under vacuum to obtain 6-hydroxy-4H-l,4- benzoxazin-3-one (VII) in 80% yield (1.5 g).

Example 6: Synthesis of 3,4-dihydro-2H-l,4-benzoxazin-6-ol (I)

1 eq. 6-hydroxy-4H-l,4-benzoxazin-3-one (VII) (0.5 g, 2.4 mmol) is dissolved in 15 ml dry THF, followed by slow addition of 3.5 eq. 2 molar boron dimethylsulfide-THF complex (14.8 ml, 6.3 mmol) solution under a steady stream of nitrogen. The reaction mixture is then heated to reflux for 2 h. Excess of boron dimethylsulfide-THF complex solution is decomposed by the addition of slow portions of methanol. The solvent is evaporated under reduced pressure to obtain the desired product 3,4-dihydro-2H-l,4-benzoxazin-6-ol (I) as colorless solid in quantitative yield (0.44 g).

The following embodiments further describe the present invention.

1 Method for preparing 3,4-dihydro-2H-l,4-benzoxazin-6-ol (I)

or a salt thereof, or mixture thereof, the method comprising:

(a) protecting one hydroxyl group of hydroquinone (II) to form (4-hydroxyphenyl)-Pr (III), wherein Pr is a protecting moiety

(d) condensing (3-amino-4-hydroxy-phenyl)-Pr (V) with 2-chloroacetyl chloride to form 3- oxo-4H-l,4-benzoxazin-6-yl)-Pr (VI)

(e) deprotecting 3-oxo-4H-l,4-benzoxazin-6-yl)-Pr (VI) to form 6-hydroxy-4H-l,4- benzoxazin-3-one (VII)

l

I

(f) reducing 6-hydroxy-4H-l,4-benzoxazin-3-one (VII) to form 3,4-dihydro-2H-l,4- benzoxazin-6-ol (I). The method according to embodiment 1, wherein the protecting moiety Pr is acyl or benzyl. The method according to embodiment 1 or 1, wherein step (a) further comprises separating

(4-hydroxyphenyl)-Pr (III). The method according to any of the preceding embodiments, wherein step (b) further comprises separating (4-hydroxy-3-nitro-phenyl)-Pr (IV). The method according to embodiment 4, wherein separating comprises recrystallizing (4- hydroxy-3-nitro-phenyl)-Pr (IV). The method according to any of the preceding embodiments, wherein the hydrogen source used in step (c) is selected from ammonium formate, hydrazine hydrate and/or H2. The method according to embodiment 6, wherein the hydrogen source is H2 and the metal catalyst is Pd/C. The method according to any of the preceding embodiments, wherein step (d) is carried out in a two-phase system, in the presence of at least one phase-transfer catalyst. The method according to embodiment 8, wherein 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. The method according to any of the preceding embodiments, wherein step (d) further comprises separating 3-oxo-4H-l,4-benzoxazin-6-yl)-Pr (VI). The method according to any of the preceding embodiments, wherein step (e) is carried out in the presence of a base. The method according to any of the preceding embodiments, wherein step (e) further comprises separating 6-hydroxy-4H-l,4-benzoxazin-3-one (VII). The method according to any of the preceding embodiments, wherein step (f) is carried out in THF, in the presence of a boron-THF complex. The method according to embodiment 13, wherein the boron-THF complex is boron dimethylsulfide-THF complex. The method according to any of the preceding embodiments, further comprising separating

3.4-dihydro-2H-l,4-benzoxazin-6-ol (I). The method according to embodiment 15, wherein separating comprises 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. The method according to embodiment 16, further comprising recrystallizing 3,4-dihydro-2H-

1.4-benzoxazin-6-ol (I) from the extraction solvent. The method according to embodiment 17, wherein 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 method according to embodiment 18, wherein 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 method according to embodiment 19, wherein the recrystallization solvent is selected from ethyl acetate, toluene, acetic acid, n-propanol, and mixtures thereof.

Claims

WHAT IS CLAIMED IS:

1 Method for preparing 3,4-dihydro-2H-l,4-benzoxazin-6-ol (I)

or a salt thereof, or mixture thereof, the method comprising:

Ml r

(f) reducing 6-hydroxy-4H-l,4-benzoxazin-3-one (VII) to form 3,4-dihydro-2H-l,4- benzoxazin-6-ol (I). The method according to claim 1, wherein the protecting moiety Pr is acyl or benzyl. The method according to claim 1 or 1, wherein step (a) further comprises separating (4- hydroxyphenyl)-Pr (III). The method according to any of the preceding claims, wherein step (b) further comprises separating (4-hydroxy-3-nitro-phenyl)-Pr (IV), optionally wherein separating comprises recrystallizing (4-hydroxy-3-nitro-phenyl)-Pr (IV). The method according to any of the preceding claims, wherein the hydrogen source used in step (c) is selected from ammonium formate, hydrazine hydrate and/or H2. The method according to any of the preceding claims, wherein step (d) is carried out in a two- phase system, in the presence of at least one phase-transfer catalyst. The method according to claim 6, wherein 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. The method according to any of the preceding claims, wherein step (d) further comprises separating 3-oxo-4H-l,4-benzoxazin-6-yl)-Pr (VI). The method according to any of the preceding claims, wherein step (e) is carried out in the presence of a base. The method according to any of the preceding claims, wherein step (e) further comprises separating 6-hydroxy-4H-l,4-benzoxazin-3-one (VII). The method according to any of the preceding claims, wherein step (f) is carried out in THF, in the presence of a boron-THF complex, in particular wherein the boron-THF complex is boron dimethylsulfide-THF complex. The method according to any of the preceding claims, further comprising separating 3,4- dihydro-2H-l,4-benzoxazin-6-ol (I). The method according to claim 12, wherein separating comprises 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, methyltetrahydrofuran, and mixtures thereof. The method according to claim 13, further comprising recrystallizing 3,4-dihydro-2H-l,4- benzoxazin-6-ol (I) from the extraction solvent. The method according to claim 14, wherein 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, isopentanol, t-butanol, isopropanol, n-propanol, ethanol, methanol, glycols, hydrogen chloride, aqueous solutions thereof, and mixtures thereof.