Novel condensation synthesis of 6-hydroxy-benzomorpholine (3,4-dihydro-2H-1,4-benzoxazine-6-ol)

Abstract

This invention relates to a method for preparing 3,4-dihydro-2H-1,4-benzoxazine-6-ol (I) from compound (XXIV) or (XXV), wherein Ra is selected from halogen, amino, nitro or sulfonic acid groups, and wherein Ra is converted to a hydroxyl group.

Description

Technical Field

[0001] This invention relates to a novel telescoping synthesis of 3,4-dihydro-2H-1,4-benzoxazine-6-ol or a salt thereof according to formula (I). This compound is known in the industry as an important oxidative colorant compound used in oxidative hair dye compositions. It is also known as 6-hydroxybenzomorpholine (COLIPA n° A25). 3,4-dihydro-2H-1,4-benzoxazine-6-ol, together with oxidative primary intermediates (oxidative dye primaries) such as p-phenylenediamine derivatives and other known oxidative precursors, provides an important base coat to support gray hair coverage and durability in any oxidative hair coloring. Due to its similar coloring properties compared to resorcinol or methyl-resorcinol, it is therefore a suitable candidate for replacing resorcinol and resorcinol derivatives in oxidative hair dye formulations. Given the rapidly changing global regulatory environment, suitable alternatives to resorcinol and methyl-resorcinol will be needed in the near future. Therefore, 3,4-dihydro-2H-1,4-benzoxazine-6-ol according to formula (I) represents a very attractive candidate for achieving this goal.

[0002] Background Technology

[0003] 3,4-Dihydro-2H-1,4-benzoxazine-6-ol (I) has been identified as an ideal candidate for achieving the goal of providing a robust color framework in oxidative hair shade palettes. It has been rarely used in commercial formulations in the past. A major obstacle is the high cost of synthesizing this compound. As the hair coloring industry moves away from traditional and inexpensive resorcinol derivatives such as resorcinol or methyl-resorcinol, the focus is now on providing an advanced and improved synthesis to minimize the economic impact on hair coloring businesses from the potential ban on resorcinol derivatives.

[0004] In the past, the industry has published different synthetic routes for the production of 3,4-dihydro-2H-1,4-benzoxazine-6-ol (I) or its salts.

[0005] Current commercial synthetic routes use 1,4-di-methoxy-substituted starting materials, where the two required oxygen atoms are already included in the structural framework of the starting material. The drawbacks include carbonyl reduction, subsequent cyclization condensation, and then deprotection of the two ether groups during the cleavage of the ether structure, requiring harsh conditions with hydrobromic acid, followed by a strong neutralization step that demands large amounts of ammonia. Furthermore, the resulting byproducts are substantial and environmentally problematic.

[0006] Synthetic routes for annealed morpholine rings typically begin with the formation of a second annealed heterocycle from a substituted aromatic starting material.

[0007] For example, CN111170958 mentions the most well-known conventional synthetic route for forming benzomorpholine derivatives, as described above. Furthermore, it discloses a method for preparing 3,4-dihydro-2H-1,4-benzoxazine-6-ol (I), which involves a solid acid catalyst and the use of 2-((2,5-dimethoxyphenyl)amino)ethane-1-ol as the starting material. The aforementioned solid acid is used as the catalyst, and water is used as the solvent to carry out the demethylation and cyclization reaction. However, this starting material is not very common, and several obstacles arise during the reaction, which may have negative environmental impacts (wastewater treatment, unwanted byproducts, etc.). The biggest obstacle remains the high cost of following this synthetic route, which is undoubtedly a huge burden for the hair dyeing industry compared to the inexpensive and readily available resorcinol derivatives or resorcinol itself.

[0008] Therefore, there is an urgent need for a novel method for the preparation of 3,4-dihydro-2H-1,4-benzoxazine-6-ol (I), or its salts or mixtures thereof, offering a highly attractive and significantly improved cost structure, particularly compared to current existing synthetic methods or other disclosed and / or commercialized methods. Given the growing global demand, an economical route to obtain 3,4-dihydro-2H-1,4-benzoxazine-6-ol (I) would be extremely valuable. This manufacturing method should also provide materials with low impurity levels that comply with global regulatory requirements. Furthermore, the method should reduce the risk of uncontrollable side reactions, involve inexpensive starting materials, and use more standardized chemical reactions compared to known methods considered to be in the state of the art. Finally, given increasingly stringent ecological requirements, manufacturers should be able to carry out the method under mild reaction conditions, involving moderate temperatures, the use of ecologically acceptable solvents, and minimal generation of non-recyclable waste liquid.

[0009] It has now been surprisingly discovered that a novel synthetic route starting with readily available commercial starting materials yields the desired 3,4-dihydro-2H-1,4-benzoxazine-6-ol (I), which offers enhanced economic benefits and significantly reduces the use of organic solvents and / or caustic chemicals / process aids compared to the current state of the art. The synthetic route proposed herein can utilize water and aqueous or alcoholic solutions in one or more steps of the reaction process, and thus can replace the expensive and environmentally problematic organic solvents used in the previously described synthetic methods for preparing 3,4-dihydro-2H-1,4-benzoxazine-6-ol (I). Summary of the Invention

[0010] The subject of this invention is a method for preparing 3,4-dihydro-2H-1,4-benzoxazine-6-ol (I), or a salt thereof, or a mixture thereof, as defined in claim 1. The dependent claims relate to particular embodiments thereof.

[0011] The method according to the present invention for preparing 3,4-dihydro-2H-1,4-benzoxazine-6-ol (I), or a salt thereof or a mixture thereof.

[0012] ,

[0013] The method includes the following steps:

[0014] (a) Provide a benzoxazine according to formula (XXIV) or a benzoxazine-3-one according to formula (XXV):

[0015] ,

[0016] Ra is selected from halogen, amino, nitro, or sulfonate groups, and

[0017] (b) Convert Ra to hydroxyl groups.

[0018] If the method according to the invention begins with a benzoxazine compound (XXV) (i.e., a benzoxazine compound with a carbonyl group), the method further includes reducing the carbonyl group to obtain the target compound 3,4-dihydro-2H-1,4-benzoxazine-6-ol (I). The reduction of the carbonyl group can be carried out before or after the conversion of Ra to a hydroxyl group.

[0019] The present invention envisions different methods for synthesizing the starting material provided in step (a) of the method of the present invention. According to one embodiment of the cyclization synthesis according to the present invention, step (a) may include reacting 2-aminophenol (XXVI) (wherein Rb is a halogen, nitro, or sulfonic acid group) with dibromoethane in a solvent to form 3,4-dihydro-2H-1,4-benzoxazine (XXIVb) (wherein Rb is a halogen, nitro, or sulfonic acid group).

[0020] .

[0021] The above cyclization reaction can be carried out in the presence of a base at a temperature of at least 120°C.

[0022] Typical solvents used in this reaction include chloroform, dichloromethane, dimethylformamide, dimethylacetamide, NMP (N-methylpyrrolidone), acetonitrile, 1,2-dimethoxyethane, ethyl acetate, pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, 1,4-dioxane, diethyl ether, tetrahydrofuran, methyltetrahydrofuran, or mixtures thereof. According to a particular embodiment, the solvent may be selected from chloroform, dichloromethane, acetonitrile, dimethylformamide, dimethylacetamide, ethyl acetate, toluene, or mixtures thereof. For example, the solvent used may be acetonitrile, dimethylformamide, dimethylacetamide, or mixtures thereof.

[0023] The base can be selected, for example, from calcium carbonate, sodium carbonate, potassium carbonate, sodium acetate, DBU, DBN, Huenig base, ammonium sulfate, sodium bicarbonate, and potassium bicarbonate. According to a particular embodiment, potassium carbonate is used as the base.

[0024] The ring-forming reaction may also include separating the precipitate (XXIVb) by filtration. Furthermore, the separated (XXIVb) can be conveniently purified by recrystallization. Suitable solvents for recrystallization include 1,2-dimethoxyethane, ethyl acetate, pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, 1,4-dioxane, diethyl ether, tetrahydrofuran, methyltetrahydrofuran, n-pentanol, n-butanol, acetic acid, propionic acid, oxalic acid, malonic acid, sulfuric acid, phosphoric acid, isoamyl alcohol, tert-butanol, isopropanol, n-propanol, ethanol, methanol, glycol, hydrogen chloride, mixtures thereof, and aqueous solutions thereof. According to a particular embodiment, the solvent may be selected from ethyl acetate, toluene, n-butanol, isopropanol, n-propanol, ethanol, methanol, acetic acid, propionic acid, oxalic acid, malonic acid, hydrogen chloride, sulfuric acid, phosphoric acid, mixtures thereof, or aqueous solutions thereof. For example, n-propanol, acetic acid, toluene, ethyl acetate, or mixtures thereof may be used as solvents.

[0025] The solvent used in the ring-forming reaction can be recovered by distillation and can be easily recycled if needed. The recrystallization solvent can also be recovered and recycled if required.

[0026] According to another cyclization synthesis embodiment of the present invention, step (a) may include reacting 2-aminophenol (XXVI) (wherein Rb is a halogen, nitro or sulfonic acid group) with 2-chloroacetyl chloride to form 3,4-dihydro-2H-1,4-benzoxazin-3-one (XXVb) (wherein Rb is a halogen, nitro or sulfonic acid group).

[0027] .

[0028] This ring-forming reaction can be carried out in a two-phase system at a temperature in the range of 0-15°C (e.g., 0-10°C). The organic phase can be selected from chloroform, dichloromethane, dimethylformamide, dimethylacetamide, NMP (N-methylpyrrolidone), acetonitrile, 1,2-dimethoxyethane, ethyl acetate, pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, 1,4-dioxane, diethyl ether, tetrahydrofuran, methyltetrahydrofuran, or mixtures thereof. According to a particular embodiment, the organic phase can be selected from chloroform, dichloromethane, dimethylformamide, dimethylacetamide, ethyl acetate, acetonitrile, toluene, or mixtures thereof. For example, the organic phase can be selected from chloroform, dichloromethane, dimethylformamide, dimethylacetamide, or mixtures thereof.

[0029] The aqueous phase contains a base, such as a base selected from sodium bicarbonate, calcium carbonate, sodium carbonate, potassium carbonate, sodium acetate, DBU, DBN, Huenig base, ammonium sulfate, sodium bicarbonate, and potassium bicarbonate. According to a particular embodiment, potassium carbonate, sodium bicarbonate, or sodium carbonate may be used as the base.

[0030] Furthermore, this reaction in a two-phase system can be conveniently carried out using a phase transfer catalyst or a mixture of phase transfer catalysts. A particularly suitable class of phase transfer catalysts is benzyltrialkylammonium salt. According to a particular embodiment, the phase transfer catalyst can be selected from the chloride, bromide, or sulfate of benzyltrimethylammonium, benzyltriethylammonium, benzyltripropylammonium, benzyltributylammonium, or mixtures thereof. Benzyltributylammonium chloride is a particularly suitable phase transfer catalyst.

[0031] The ring-forming reaction may also include separating the precipitated (XXVb) by filtration. Furthermore, the separated (XXVb) can be conveniently purified by recrystallization. Suitable solvents for recrystallization include 1,2-dimethoxyethane, ethyl acetate, pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, 1,4-dioxane, diethyl ether, tetrahydrofuran, methyltetrahydrofuran, n-pentanol, n-butanol, acetic acid, propionic acid, oxalic acid, malonic acid, sulfuric acid, phosphoric acid, isoamyl alcohol, tert-butanol, isopropanol, n-propanol, ethanol, methanol, glycol, hydrogen chloride, mixtures thereof, and aqueous solutions thereof. According to a particular embodiment, the solvent may be selected from ethyl acetate, toluene, n-butanol, isopropanol, n-propanol, ethanol, methanol, acetic acid, propionic acid, oxalic acid, malonic acid, hydrogen chloride, sulfuric acid, phosphoric acid, mixtures thereof, and aqueous solutions thereof. For example, n-propanol, acetic acid, toluene, ethyl acetate, or mixtures thereof may be used as solvents.

[0032] The solvent used in the ring-forming reaction can be recovered by distillation and can be easily recycled if needed. The recrystallization solvent can also be recovered and recycled if required.

[0033] According to a first specific embodiment of the method of the present invention for preparing the target compound 3,4-dihydro-2H-1,4-benzoxazine-6-ol (I), the starting compound provided in step (a) has a carbonyl group in the morpholine ring structure and includes a nitro group as a substituent at the 6-position of the aromatic ring. According to this first specific embodiment, the method of the present invention includes: reducing the carbonyl group of the starting compound 6-nitro-4H-1,4-benzoxazin-3-one (XI) in THF in the presence of a boron-THF complex to form 6-nitro-3,4-dihydro-2H-1,4-benzoxazine (IX); reducing 6-nitro-3,4-dihydro-2H-1,4-benzoxazine (IX) in the presence of a hydrogen source and a metal catalyst to form 3,4-dihydro-2H-1,4-benzoxazine-6-amine (X); and converting the primary amino group in 3,4-dihydro-2H-1,4-benzoxazine-6-amine (X) to a hydroxyl group to form 3,4-dihydro-2H-1,4-benzoxazine-6-ol (I).

[0034]

[0035] A particularly suitable boron-THF complex for use in reducing the carbonyl group of the starting compound (XI) is the dimethyl boron sulfide-THF complex. The method may also include extraction of 6-nitro-3,4-dihydro-2H-1,4-benzoxazine (IX) from THF. Suitable solvents for extraction from THF (IX) include chloroform, dichloromethane, tert-butyl methyl ether, diethyl ether, ethyl acetate, 1,2-dimethoxyethane, pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, 1,4-dioxane, tetrahydrofuran, methyltetrahydrofuran, methanol, ethanol, and mixtures thereof.

[0036] The hydrogen source used in the reduction of 6-nitro-3,4-dihydro-2H-1,4-benzoxazine (IX) can be selected from ammonium formate, hydrazine, or H2, wherein the metal catalyst is 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 can be H2, and the metal catalyst can be a Pd / C catalyst.

[0037] In a particular embodiment of this first specific embodiment of the method according to the invention, the conversion of a primary amino group to a hydroxyl group can be carried out by diazotizing 3,4-dihydro-2H-1,4-benzoxazine-6-amine (X) under acidic conditions in the presence of at least one nitrosating agent to form a diazo compound (XXVII).

[0038] ,

[0039] Where X - It is a monovalent counterion and causes the diazo compound to decompose to form 3,4-dihydro-2H-1,4-benzoxazine-6-ol (I).

[0040] Suitable nitrosating agents include sodium nitrite, potassium nitrite, dinitrogen pentoxide, nitrososulfuric acid, and mixtures thereof.

[0041] The diazotization step is carried out in the presence of at least one inorganic or organic acid. The inorganic or organic acid may be selected from hydrogen chloride, trifluoroacetic acid, sulfuric acid, sulfurous acid, carbonic acid, nitric acid, acetic acid, propionic acid, phosphoric acid, or mixtures thereof. According to one embodiment, the inorganic or organic acid may be selected from hydrogen chloride, sulfuric acid, sulfurous acid, acetic acid, or mixtures thereof. For example, the inorganic or organic acid may be sulfuric acid.

[0042] One or more solvents used in this step may be selected from 1,2-dimethoxyethane, pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, 1,4-dioxane, diethyl ether, tetrahydrofuran, methyltetrahydrofuran, n-pentanol, n-butanol, acetic acid, propionic acid, oxalic acid, malonic acid, sulfuric acid, phosphoric acid, isoamyl alcohol, tert-butanol, isopropanol, n-propanol, ethanol, methanol, glycol, hydrogen chloride, mixtures thereof, or aqueous solutions thereof.

[0043] According to one embodiment, the diazotization step is carried out in the presence of hydrogen chloride, sulfuric acid, sulfurous acid, acetic acid, or mixtures thereof, in a solvent selected from n-butanol, isopropanol, ethanol, methanol, acetic acid, propionic acid, oxalic acid, malonic acid, hydrogen chloride, sulfuric acid, phosphoric acid, mixtures thereof, or aqueous solutions thereof.

[0044] In another particular embodiment of this first specific embodiment of the method according to the invention, the conversion of a primary amine to a hydroxyl group can be carried out by hydrolyzing 3,4-dihydro-2H-1,4-benzoxazine-6-amine (X) in a tubular reactor under acidic conditions. Suitable reaction conditions for the hydrolysis reaction include a temperature of 220°C or lower and a pressure of 2-20 bar.

[0045] According to one embodiment, hydrolysis can be carried out in the presence of a catalyst (e.g., a catalyst selected from zirconium, cerium, phosphotungstic acid, phosphotomolybdic acid, silicotungstic acid, silicotomolybdic acid, or mixtures thereof). According to a particularly preferred embodiment, the material of the tubular reactor in contact with the reaction includes cerium, zirconium, or composites thereof.

[0046] According to a second specific embodiment of the method of the present invention for preparing the target compound 3,4-dihydro-2H-1,4-benzoxazine-6-ol (I), the starting compound provided in step (a) also has a carbonyl group in the morpholine ring structure and contains a nitro group as a substituent at the 6-position of the aromatic ring (as described above), but the order of the method steps is reversed. According to this second specific embodiment, the method of the present invention includes: reducing the nitro group of 6-nitro-4H-1,4-benzoxazin-3-one (XI) in the presence of a hydrogen source and a metal catalyst to form 6-amino-4H-1,4-benzoxazin-3-one (XIV); converting the primary amino group in 6-amino-4H-1,4-benzoxazin-3-one (XIV) to form 6-hydroxy-4H-1,4-benzoxazin-3-one (XV); and reducing the carbonyl group in THF in the presence of a boron-THF complex to form 3,4-dihydro-2H-1,4-benzoxazin-6-ol (I).

[0047]

[0048] The hydrogen source and metal catalyst used for the nitro reduction of 6-nitro-4H-1,4-benzoxazin-3-one (XI) to form 6-amino-4H-1,4-benzoxazin-3-one (XIV) are similar to those described above in the context of the first specific embodiment.

[0049] Similar to what is described above in the context of the first specific embodiment, in the second specific embodiment, the conversion of a primary amino group to a hydroxyl group can be carried out by diazotizing 6-amino-4H-1,4-benzoxazin-3-one (XIV) under acidic conditions in the presence of at least one nitrosating agent to form a diazo compound (XXVIII).

[0050] ,

[0051] Where X - It is a monovalent counterion and causes the diazo compound to decompose to form 6-hydroxy-4H-1,4-benzoxazin-3-one (XV).

[0052] Suitable nitrifying agents, acids, and solvents are similar to those described above in the context of the first specific embodiment.

[0053] Similar to what has been described above in the context of the first embodiment, in the second embodiment, the conversion of a primary amine to a hydroxyl group can be carried out by hydrolyzing 6-amino-4H-1,4-benzoxazin-3-one (XIV) under acidic conditions in a tubular reactor. Suitable reaction conditions, catalysts, and tubular reactor materials for the acidic hydrolysis are similar to those described above in the context of the first embodiment.

[0054] As described above, the carbonyl reduction in THF, specifically the reduction of the carbonyl group of 6-hydroxy-4H-1,4-benzoxazin-3-one (XV) in this embodiment, is similar to that described in the context of the first specific embodiment. In particular, the preferred boron-THF complex, the extraction of 3,4-dihydro-2H-1,4-benzoxazin-6-ol (I) from THF, and the extraction solvent are all similar to those described in the context of the first specific embodiment.

[0055] According to a third embodiment of the method of the present invention for preparing the target compound 3,4-dihydro-2H-1,4-benzoxazine-6-ol (I), the starting compound provided in step (a) has a carbonyl group in a morpholine ring structure and includes fluorine, chlorine, or bromine as a substituent at the 6-position of the aromatic ring. According to this third embodiment, the method of the present invention comprises: reducing the carbonyl group of 6-halo-4H-1,4-benzoxazine-3-one (XVIII) in THF in the presence of a boron-THF complex to form 6-halo-3,4-dihydro-2H-1,4-benzoxazine (XVII); and hydrolyzing 6-halo-3,4-dihydro-2H-1,4-benzoxazine (XVII) under alkaline conditions to form 3,4-dihydro-2H-1,4-benzoxazine-6-ol (I).

[0056]

[0057] In formulas XVIII and XVII above, X is fluorine, chlorine, or bromine. According to a particular embodiment, X is bromine.

[0058] As above, the carbonyl reduction in THF, specifically the reduction of the carbonyl group of 6-halo-4H-1,4-benzoxazin-3-one (XVIII) in this embodiment, is similar to that described above in the context of the first specific embodiment. In particular, the preferred boron-THF complex, the extraction of 3,4-dihydro-2H-1,4-benzoxazin-6-ol (I) from THF, and the extraction solvent are all similar to those described above in the context of the first specific embodiment.

[0059] According to this third specific embodiment, the conversion of fluorine, chlorine, or bromine in 6-halo-3,4-dihydro-2H-1,4-benzoxazine (XVII) to hydroxyl groups can be carried out in a tubular reactor at a temperature of 180°C or lower and a pressure of 2-20 bar, in a solvent selected from sodium hydroxide, potassium hydroxide, potassium tert-butyrate, mixtures thereof, or aqueous solutions thereof. Suitable reaction conditions, catalysts, and tubular reactor materials for alkaline hydrolysis are similar to those described above in the context of acidic hydrolysis in the first specific embodiment. According to a particular embodiment, alkaline hydrolysis in the tubular reactor can be carried out at higher temperatures in the range of 200-230°C and pressures of 2-20 bar.

[0060] According to a fourth embodiment of the method of the present invention for preparing the target compound 3,4-dihydro-2H-1,4-benzoxazine-6-ol (I), the starting compound provided in step (a) also has a carbonyl group in the morpholine ring structure and, as in the third embodiment, includes fluorine, chlorine, or bromine as a substituent at the 6-position of the aromatic ring, but the order of the method steps is reversed, as in the second embodiment. According to this fourth embodiment, the method of the present invention includes hydrolyzing 6-halo-4H-1,4-benzoxazine-3-one (XVIII) under alkaline conditions to form 6-hydroxy-4H-1,4-benzoxazine-3-one (XV), and reducing the carbonyl group of 6-hydroxy-4H-1,4-benzoxazine-3-one (XV) in THF in the presence of a boron-THF complex to form 3,4-dihydro-2H-1,4-benzoxazine-6-ol (I).

[0061]

[0062] In formula XVIII above, X is either fluorine, chlorine, or bromine. According to a particular embodiment, X is bromine.

[0063] The first step of the fourth specific embodiment, namely the conversion of fluorine, chlorine, or bromine to hydroxyl groups, can be carried out in a manner similar to that described for the third specific embodiment: alkaline hydrolysis in a tubular reactor at a temperature of 180°C or lower and a pressure of 2-20 bar, in a solvent selected from sodium hydroxide, potassium hydroxide, potassium tert-butyrate, mixtures thereof, or aqueous solutions thereof. Suitable reaction conditions, catalysts, and tubular reactor materials for alkaline hydrolysis are similar to those described above in the context of acidic hydrolysis in the first specific embodiment. According to a particular embodiment, alkaline hydrolysis in the tubular reactor can be carried out at higher temperatures in the range of 200-230°C and pressures of 2-20 bar.

[0064] As above, the carbonyl group is reduced in THF, specifically the carbonyl group of 6-hydroxy-4H-1,4-benzoxazin-3-one (XV) in this embodiment, similar to that described above in the context of the first specific embodiment. In particular, the preferred boron-THF complex, the extraction of 6-hydroxy-4H-1,4-benzoxazin-3-one (XV) from THF, and the extraction solvent are all similar to those described above in the context of the first specific embodiment.

[0065] According to a fifth embodiment of the method of the present invention for preparing the target compound 3,4-dihydro-2H-1,4-benzoxazine-6-ol (I), the starting compound provided in step (a) also has a carbonyl group in the morpholine ring structure, but includes a sulfonyl group as a substituent at the 6-position of the aromatic ring. According to this fifth embodiment, the method of the present invention comprises: reducing the carbonyl group of 3-oxo-4H-1,4-benzoxazine-6-sulfonic acid (XXI) in THF in the presence of a boron-THF complex to form 3,4-dihydro-2H-1,4-benzoxazine-6-sulfonic acid (XX); and hydrolyzing 3,4-dihydro-2H-1,4-benzoxazine-6-sulfonic acid (XX) under alkaline conditions to form 3,4-dihydro-2H-1,4-benzoxazine-6-ol (I).

[0066]

[0067] The carbonyl group is reduced in THF, which in this scheme is the reduction of the carbonyl group of 3-oxo-4H-1,4-benzoxazine-6-sulfonic acid (XXI), a preferred boron-THF complex, extraction of the reduced compound (in this scheme, 3,4-dihydro-2H-1,4-benzoxazine-6-sulfonic acid (XX)) from THF, and the extraction solvent is similar to that described above.

[0068] According to this fifth specific implementation scheme, the conversion of the sulfonyl group of 3,4-dihydro-2H-1,4-benzoxazine-6-sulfonic acid (XX) to a hydroxyl group can be carried out by alkaline fusion at a temperature of 300°C or higher.

[0069] According to a sixth embodiment of the method of the present invention for preparing the target compound 3,4-dihydro-2H-1,4-benzoxazine-6-ol (I), the starting compound provided in step (a) also has a carbonyl group in the morpholine ring structure and, as in the fifth embodiment, includes a sulfonyl group as a substituent at the 6-position of the aromatic ring, but the order of the method steps is reversed, as in the second embodiment. According to this sixth embodiment, the method of the present invention includes hydrolyzing 3-oxo-4H-1,4-benzoxazine-6-sulfonic acid (XXI) under alkaline conditions to form 6-hydroxy-4H-1,4-benzoxazine-3-one (XV), and reducing the carbonyl group of 6-hydroxy-4H-1,4-benzoxazine-3-one (XV) in THF in the presence of a boron-THF complex to form 3,4-dihydro-2H-1,4-benzoxazine-6-ol (I).

[0070]

[0071] According to this sixth embodiment, the hydrolysis step to convert sulfonyl groups to hydroxyl groups under alkaline conditions can be carried out by alkaline melting at a temperature of 300°C or higher, as described above in the fifth embodiment.

[0072] The carbonyl reduction in THF, preferably the boron-THF complex, the extraction of the reduced compound from THF, and the extraction solvent are all similar to those described above.

[0073] According to a seventh embodiment of the method of the present invention for preparing the target compound 3,4-dihydro-2H-1,4-benzoxazine-6-ol (I), the starting compound provided in step (a) does not contain a carbonyl group in the morpholine ring structure and contains a nitro group as a substituent at the 6-position of the aromatic ring. According to this seventh embodiment, the method of the present invention comprises: reducing 6-nitro-3,4-dihydro-2H-1,4-benzoxazine (IX) in the presence of a hydrogen source and a metal catalyst to form 3,4-dihydro-2H-1,4-benzoxazine-6-amine (X); and converting the primary amino group in 3,4-dihydro-2H-1,4-benzoxazine-6-amine (X) to a hydroxyl group, thereby forming 3,4-dihydro-2H-1,4-benzoxazine-6-ol (I).

[0074]

[0075] The two method steps in this seventh specific embodiment correspond to the second and third steps of the first specific embodiment. The reagents, reaction conditions, and preferred embodiments are similar to those described above.

[0076] According to an eighth specific embodiment of the method of the present invention for preparing the target compound 3,4-dihydro-2H-1,4-benzoxazine-6-ol (I), the starting compound provided in step (a) does not contain a carbonyl group in the morpholine ring structure and contains a nitro group as a substituent at the 6-position of the aromatic ring. According to this eighth specific embodiment, the method of the present invention includes: protecting 6-nitro-3,4-dihydro-2H-1,4-benzoxazine (IX) with hydroxymethanesulfonate to form sulfomethyl-protected (6-nitro-2,3-dihydro-1,4-benzoxazine-4-yl)methanesulfonate (XII); reducing (6-nitro-2,3-dihydro-1,4-benzoxazine-4-yl)methanesulfonate (XII) in the presence of a hydrogen source and a metal catalyst to form sulfomethyl-protected (6-amino-2,3-dihydro-1,4-benzoxazine-4-yl)methanesulfonate (XIII); converting the primary amino group in (6-amino-2,3-dihydro-1,4-benzoxazine-4-yl)methanesulfonate (XIII) to a hydroxyl group; and deprotecting by removing the sulfomethyl group to form 3,4-dihydro-2H-1,4-benzoxazine-6-ol (I).

[0077]

[0078] In equations XII and XIII above, where M + It is a monovalent ion.

[0079] Except for the presence of a protecting group on the nitrogen atom in the morpholine ring structure, the eighth specific embodiment corresponds completely to the seventh specific embodiment (or to steps two and three of the first specific embodiment, respectively). The reagents, reaction conditions, and preferred embodiments are similar to those described above for steps two and three of the first specific embodiment.

[0080] According to a ninth embodiment of the method of the present invention for preparing the target compound 3,4-dihydro-2H-1,4-benzoxazine-6-ol (I), the starting compound provided in step (a) does not contain a carbonyl group in the morpholine ring structure and contains fluorine, chlorine, or bromine as a substituent at the 6-position of the aromatic ring. According to this ninth embodiment, the method of the present invention includes hydrolyzing 6-halo-3,4-dihydro-2H-1,4-benzoxazine (XVII) under alkaline conditions to form 3,4-dihydro-2H-1,4-benzoxazine-6-ol (I).

[0081]

[0082] In formula XVII above, X is fluorine, chlorine, or bromine. According to a particular embodiment, X is bromine.

[0083] This ninth specific embodiment corresponds to the final step of the third specific embodiment. The reagents, reaction conditions, and preferred embodiments are similar to those described above.

[0084] According to a tenth embodiment of the method of the present invention for preparing the target compound 3,4-dihydro-2H-1,4-benzoxazine-6-ol (I), the starting compound provided in step (a) does not contain a carbonyl group in the morpholine ring structure and contains a sulfonyl group as a substituent at the 6-position of the aromatic ring. According to this tenth embodiment, the method of the present invention includes hydrolyzing 3,4-dihydro-2H-1,4-benzoxazine-6-sulfonic acid (XX) under alkaline conditions to form 3,4-dihydro-2H-1,4-benzoxazine-6-ol (I).

[0085]

[0086] This tenth specific embodiment corresponds to the final step of the fifth specific embodiment. The reagents, reaction conditions, and preferred embodiments are similar to those described above.

[0087] According to an eleventh embodiment of the method of the present invention for preparing the target compound 3,4-dihydro-2H-1,4-benzoxazine-6-ol (I), the starting compound provided in step (a) contains a carbonyl group in a morpholine ring structure and contains an amino group as a substituent at the 6-position of the aromatic ring. According to this eleventh embodiment, the method of the present invention comprises: converting the primary amino group of the starting compound 6-amino-4H-1,4-benzoxazine-3-one (XIV) to form 6-hydroxy-4H-1,4-benzoxazine-3-one (XV); and reducing the carbonyl group in THF in the presence of a boron-THF complex to form 3,4-dihydro-2H-1,4-benzoxazine-6-ol (I). This eleventh embodiment corresponds to steps two and three of the second embodiment. The reagents, reaction conditions, and preferred embodiments are similar to those described above.

[0088]

[0089] According to a twelfth embodiment of the method of the present invention for preparing the target compound 3,4-dihydro-2H-1,4-benzoxazine-6-ol (I), the starting compound provided in step (a) contains a carbonyl group in a morpholine ring structure and contains an amino group as a substituent at the 6-position of the aromatic ring. According to this twelfth embodiment, the method of the present invention comprises: reducing the carbonyl group of the starting compound 6-amino-4H-1,4-benzoxazine-3-one (XIV) in THF in the presence of a boron-THF complex to form 3,4-dihydro-2H-1,4-benzoxazine-6-amine (X); and subsequently converting the primary amino group to form 3,4-dihydro-2H-1,4-benzoxazine-6-ol (I). This twelfth embodiment is the reverse of the steps in the eleventh embodiment. The reagents, reaction conditions, and preferred embodiments are similar to those described above.

[0090]

[0091] According to the cyclization synthesis embodiments of the eleventh and twelfth specific embodiments for synthesizing the starting compound 6-amino-4H-1,4-benzoxazin-3-one (XIV), the method may further include providing 6-amino-4H-1,4-benzoxazin-3-one (XIV) by reacting 2,4-dichloroaniline (XXIX) with 2-hydroxyacetamide.

[0092] .

[0093] The reaction of 2,4-dichloroaniline (XXIX) with 2-hydroxyacetamide can be carried out in the same manner as the reaction of 2-chloroacetyl chloride with 2-aminophenol (XXVI) as described above, wherein Rb is a halogen, nitro, or sulfonic acid group. In particular, the reaction can be carried out in a two-phase system as described above. The reagents, reaction conditions, and preferred embodiments are similar to those described above.

[0094] According to a thirteenth embodiment of the method of the present invention for preparing the target compound 3,4-dihydro-2H-1,4-benzoxazine-6-ol (I), the starting compound provided in step (a) does not contain a carbonyl group in the morpholine ring structure and contains an amino group as a substituent at the 6-position of the aromatic ring. According to this thirteenth embodiment, the method of the present invention includes converting the primary amino group of the starting compound 3,4-dihydro-2H-1,4-benzoxazine-6-amine (X) to a hydroxyl group to form 3,4-dihydro-2H-1,4-benzoxazine-6-ol (I). This thirteenth embodiment corresponds to the final step of the first embodiment. The reagents, reaction conditions, and preferred embodiments are similar to those described above.

[0095] In the thirteenth embodiment of the method for preparing the target compound 3,4-dihydro-2H-1,4-benzoxazine-6-ol (I) according to the present invention, those embodiments in which the benzoxazine provided in step (a) conforms to formula (XXV) (i.e., the benzoxazine provided in step (a) contains a carbonyl group) are preferred. These are the first, second, third, fourth, fifth, sixth, eleventh, and twelfth embodiments. Particularly preferred are embodiments in which the carbonyl group is reduced after the substituent Ra of formula (XXV) is converted to a hydroxyl group. These are the second, fourth, sixth, and eleventh embodiments.

[0096] The subject of this invention is a novel method for preparing 3,4-dihydro-2H-1,4-benzoxazine-6-ol (I), its salts, or mixtures thereof. The method according to the invention is further described below.

[0097] Both different cyclization synthetic embodiments of the present invention for forming the starting compound provided in step (a) begin with 2-aminophenol (XXVI), and are further described below. 2-Amino-4-nitrophenol (VIII) is well known and commercially available. It is also used as a direct dye (nitro dye) in non-oxidative hair dye formulations, and as a common intermediate for the production of other commercial dyes (e.g., mordant dyes).

[0098] Reaction Scheme 1

[0099]

[0100] To carry out the cyclization reaction, 2-amino-4-nitrophenol (VIII) is reacted with dibromoethane in DMF (dimethylformamide) or dimethylacetamide in the presence of a base such as potassium carbonate to give 6-nitro-3,4-dihydro-2H-1,4-benzoxazine (IX) in one step. This reaction requires relatively high temperatures (>120°C) to obtain yields up to 90%. The separated solids require some form of purification via recrystallization. Condensation can be carried out according to literature procedures (e.g., EP 2486039, US 8,222,417).

[0101] Reaction Scheme 2

[0102]

[0103] To proceed with cyclization, 2-amino-4-nitrophenol (VIII) is reacted with 2-chloroacetyl chloride (as a highly reactive but extremely selective reagent) to form the desired intermediate 6-nitro-4H-1,4-benzoxazin-3-one (XI). The condensation reaction can be carried out at 0°C in chloroform as a solvent, using a phase-transfer catalyst in the presence of a weak base to neutralize the acid that forms as a byproduct. Chloroform can be completely recycled, thus eliminating the need for other solvents and solvent mixtures, and therefore promoting an environmentally friendly approach with a significant reduction in organic waste. The condensation reaction can be carried out according to literature procedures (e.g., WO2008100463, US7985748).

[0104] The third cyclization synthesis embodiment according to the present invention for obtaining the starting compound that can be provided in step (a) begins with 2,4-dichloroaniline (XXIX), and is further described below. 2,4-Dichloroaniline (XXIX) is well known and commercially available.

[0105] Reaction scheme 3

[0106]

[0107] To achieve cyclization, 2,4-dichloroaniline (XXIX) is reacted with 2-hydroxyacetamide (as a highly reactive but extremely selective reagent) to form the desired intermediate 6-amino-4H-1,4-benzoxazin-3-one (XIV). The condensation reaction can be carried out in DMF as a solvent, using a phase-transfer catalyst in the presence of a weak base to neutralize the acid that forms as a byproduct. Since no other solvent is used, the DMF can be completely recycled, eliminating the need for solvent mixtures and thus promoting an environmentally friendly approach with a significant reduction in organic waste. The condensation reaction can be carried out according to literature procedures (e.g., WO2008100463, US7985748).

[0108] One specific embodiment of the method according to the invention (shown in reaction schemes 4A and 4B below) begins with 6-nitro-3,4-dihydro-2H-1,4-benzoxazine (IX), which is converted to the corresponding amino compound 3,4-dihydro-2H-1,4-benzoxazine-6-amine (X) via a standardized hydrogenation procedure in ethanol as an environmentally friendly solvent, using, for example, carbon-supported palladium as a catalyst and hydrogen. Subsequently, 3,4-dihydro-2H-1,4-benzoxazine-6-amine (X) is diazotized, followed by heating of the aqueous solution under strongly acidic conditions to obtain the target compound 3,4-dihydro-2H-1,4-benzoxazine-6-ol (I).

[0109] Reaction scheme 4A

[0110]

[0111] Reaction scheme 4B

[0112]

[0113] The steps of reaction scheme 4B begin with the formation of an intermediate diazonium salt derived from 3,4-dihydro-2H-1,4-benzoxazine-6-amine (X), obtained at 0°C using a standardized procedure with sodium nitrite and sulfuric acid. Once the corresponding diazonium salt is formed, the temperature is raised to 80-100°C to induce its decomposition, thereby releasing nitrogen and immediately generating the corresponding phenolic derivative, which is the desired product 3,4-dihydro-2H-1,4-benzoxazine-6-ol (I).

[0114] In another specific embodiment of the method according to the invention (shown in reaction schemes 5A to 5C below), 6-nitro-4H-1,4-benzoxazine-3-one (XI) is converted via carbonyl reduction to the corresponding intermediate 6-nitro-3,4-dihydro-2H-1,4-benzoxazine (IX). The intermediate 6-nitro-3,4-dihydro-2H-1,4-benzoxazine (IX) is converted via hydrogenation to the corresponding amino compound 3,4-dihydro-2H-1,4-benzoxazine-6-amine (X). Subsequently, diazotization of 3,4-dihydro-2H-1,4-benzoxazine-6-amine (X), followed by heating of an aqueous solution under strongly acidic conditions, yields the target compound 3,4-dihydro-2H-1,4-benzoxazine-6-ol (I).

[0115] Reaction scheme 5A

[0116]

[0117] The starting compound 6-nitro-4H-1,4-benzoxazin-3-one (XI) can be obtained according to reaction scheme 1 above, and if so, the compound can be used without further purification. 6-nitro-4H-1,4-benzoxazin-3-one (XI) undergoes carbonyl reduction of the heterocycle of 6-nitro-4H-1,4-benzoxazin-3-one (XI). Selective carbonyl reduction is carried out in THF as a solvent using a commercially available solution containing a dimethylboron sulfide-THF complex (which acts as a highly selective and clean reagent) to give the intermediate compound 6-nitro-3,4-dihydro-2H-1,4-benzoxazine (IX).

[0118] Reaction scheme 5B

[0119]

[0120] Then, in ethanol, an environmentally friendly solvent, 6-nitro-3,4-dihydro-2H-1,4-benzoxazine (IX) is converted via a standardized hydrogenation process using carbon-supported palladium as a catalyst and hydrogen to obtain 3,4-dihydro-2H-1,4-benzoxazine-6-amine (X).

[0121] Reaction scheme 5C

[0122]

[0123] The reaction scheme 5C begins with the formation of an intermediate diazonium salt derived from 3,4-dihydro-2H-1,4-benzoxazine-6-amine (X), obtained at 0°C using a standardized procedure with sodium nitrite and sulfuric acid. Once the corresponding diazonium salt is formed, the temperature is raised to 80-100°C to induce its decomposition, thereby releasing nitrogen and immediately forming the corresponding phenolic derivative, which is the desired product 3,4-dihydro-2H-1,4-benzoxazine-6-ol (I).

[0124] The target compound, 3,4-dihydro-2H-1,4-benzoxazine-6-ol (I), is strictly controlled in terms of its nitrosamine content. During the diazotization step used in the two embodiments described above, nitrosation at the heterocyclic nitrogen atom was observed to some extent as a side reaction. This N-nitroso group can be removed by thermal decomposition during the final step, simultaneously undergoing a diazotization to hydroxyl conversion. To completely eliminate this unwanted side reaction, a protecting group can be introduced into the sensitive heterocyclic nitrogen atom prior to the hydrogenation and subsequent diazotization steps as described above. A sulfonylmethyl group has been found to be suitable as a protecting group for secondary heterocyclic nitrogen atoms.

[0125] A specific embodiment of the method according to the invention involving the protection of heterocyclic nitrogen is shown in the following reaction schemes 6A to 6C.

[0126] Commercially available potassium hydroxymethanesulfonate was reacted with 6-nitro-3,4-dihydro-2H-1,4-benzoxazine (IX) in an aqueous medium to precipitate the corresponding sulfomethyl-protected potassium (6-nitro-2,3-dihydro-1,4-benzoxazine-4-yl)methanesulfonate (XII).

[0127] Reaction scheme 6A

[0128]

[0129] This intermediate can be further used for the following hydrogenation to obtain the corresponding amino compound (6-amino-2,3-dihydro-1,4-benzoxazine-4-yl) potassium methanesulfonate (XIII).

[0130] Reaction scheme 6B

[0131]

[0132] In the final step, while diazotization is performed and followed by thermal conversion to hydroxyl and cleaved nitrogen, the pH-sensitive sulfomethyl protecting group is also quantitatively cleaved and removed, thereby yielding the desired product 3,4-dihydro-2H-1,4-benzoxazine-6-ol (I).

[0133] Reaction scheme 6C

[0134]

[0135] In another specific embodiment of the method according to the invention, starting with 6-nitro-4H-1,4-benzoxazin-3-one (XI), the order of the method steps can be reversed, as described below. To avoid any possibility of unwanted side reactions (nitrosation of the cyclic nitrogen), the reaction can also advantageously proceed via a cascade reaction as described in reaction schemes 7A to 7C below. The formal lactam functional group within the heterocycle effectively prevents the cyclic nitrogen from being nitrosated by nitrite. 6-nitro-4H-1,4-benzoxazin-3-one (XI) can be hydrogenated without touching the carbonyl group in the heterocycle, and the nitro group will be converted to the corresponding amino group, thereby obtaining 6-amino-4H-1,4-benzoxazin-3-one (XIV).

[0136] Reaction scheme 7A

[0137]

[0138] 6-Amino-4H-1,4-benzoxazin-3-one (XIV) is then converted into the corresponding intermediate diazonium salt, which is obtained at 0 °C using sodium nitrite and hydrochloric acid or sulfuric acid, or a mixture thereof, via a standardized procedure. Once the corresponding diazonium salt is formed, the temperature is raised to 80-100 °C to induce its decomposition, thereby releasing nitrogen and immediately forming the corresponding phenolic derivative 6-hydroxy-4H-1,4-benzoxazin-3-one (XV).

[0139] Reaction scheme 7B

[0140]

[0141] The final step then involves selective carbonyl reduction, which is carefully carried out in THF as a solvent using a commercially available solution containing a dimethyl boron sulfide-THF complex (which acts as a highly selective and clean reagent) to give the desired compound 3,4-dihydro-2H-1,4-benzoxazine-6-ol (I).

[0142] Reaction scheme 7C

[0143]

[0144] Alternatively, as described in reaction schemes 8A and 8B, the carbonyl reduction can be carried out prior to the diazotization step described herein, thereby yielding 3,4-dihydro-2H-1,4-benzoxazine-3-one (XIV) to 3,4-dihydro-2H-1,4-benzoxazine-6-amine (X).

[0145] Reaction scheme 8A

[0146]

[0147] The diazotization of 3,4-dihydro-2H-1,4-benzoxazine-6-amine (X) is carried out at 0 °C using sodium nitrite and hydrochloric acid or sulfuric acid, or mixtures thereof, following a standardized protocol. Once the corresponding diazonium salt is formed, the temperature is raised to 80-100 °C to induce its decomposition, thereby releasing nitrogen and immediately forming the desired compound, 3,4-dihydro-2H-1,4-benzoxazine-6-ol (I).

[0148] Reaction scheme 8B

[0149]

[0150] Another specific embodiment of the method according to the invention (shown in reaction scheme 9 below) begins with 3,4-dihydro-2H-1,4-benzoxazine-6-amine (X), which is prepared according to the method described herein. The conversion of aromatic amino groups to the corresponding hydroxyl groups is part of a variety of well-known, large-scale, and industrially mature processes (e.g., patent number CN105693522). These processes primarily focus on the hydrolysis step of the amino group, using a large tubular reactor in the presence of a selective metal catalyst, to generate the hydroxyl group at high temperatures (up to 180°C) and high pressures.

[0151] Reaction Scheme 9

[0152]

[0153] The process for obtaining 3,4-dihydro-2H-1,4-benzoxazine-6-ol (I) is typically efficient and cost-effective, and will significantly reduce the number of steps.

[0154] Another specific embodiment of the method according to the invention (shown in reaction scheme 10 below) follows a well-known, mature, highly optimized, and well-established large-scale process. Reaction scheme 10 illustrates the complete pathway starting from an aminophenol starting compound. This embodiment includes the following steps:

[0155] • 6-Chloro-3,4-dihydro-2H-1,4-benzoxazine (XVII) is provided using 2-amino-4-chlorophenol (XVI) as an readily available and commercially available starting material. Compound (XVII) can be synthesized according to two different routes generally described herein. Cycloforming to obtain 6-chloro-3,4-dihydro-2H-1,4-benzoxazine (XVII) can be completed in a one-step process: under basic conditions, in a polar aprotic solvent, by condensing dibromoethane with 2-amino-4-chlorophenol (XVI); or in a two-step process: first, condensing 2-chloroacetyl chloride with 2-amino-4-chlorophenol (XVI) to obtain 6-chloro-4H-1,4-benzoxazine-3-one (XVIII), followed by carbonyl reduction to obtain 6-chloro-3,4-dihydro-2H-1,4-benzoxazine (XVII).

[0156] • In a one-pot reaction, 6-chloro-3,4-dihydro-2H-1,4-benzoxazine (XVII) was subjected to alkaline hydrolysis using caustic soda to give the desired product 3,4-dihydro-2H-1,4-benzoxazine-6-ol (I).

[0157] Reaction Scheme 10

[0158]

[0159] Commercially available 2-amino-4-chlorophenol (XVI) is cyclized in one step by reacting it with dibromoethane in DMF (dimethylformamide) or dimethylacetamide in the presence of potassium carbonate as a base, to give 6-chloro-3,4-dihydro-2H-1,4-benzoxazine (XVII). This reaction requires relatively high temperatures (>120°C) to obtain moderate to good yields (up to 90%). The resulting solid requires some form of purification via recrystallization.

[0160] The second option represents a two-step synthesis, beginning with the condensation of 2-chloroacetyl chloride to obtain 6-chloro-4H-1,4-benzoxazin-3-one (XVIII). This reaction is carried out under mild conditions at 0°C in chloroform, using up to 2% of a phase-transfer catalyst in the presence of a base such as potassium bicarbonate. Because no other solvents are used, and therefore no solvent mixture is required, chloroform can be completely recycled during the aqueous post-treatment, thus promoting an environmentally friendly approach with a significant reduction in organic waste. The compound (XVIII) from the first step can be used without further purification, undergoing carbonyl reduction of the heterocycle of 6-chloro-4H-1,4-benzoxazin-3-one (XVIII). Selective carbonyl reduction is carried out in THF as a solvent using a commercially available solution containing a dimethyl boron sulfide-THF complex (which acts as a highly selective and clean reagent) to obtain the intermediate compound 6-chloro-3,4-dihydro-2H-1,4-benzoxazine (XVII).

[0161] Finally, as shown in reaction scheme 11, 6-chloro-3,4-dihydro-2H-1,4-benzoxazine (XVII) is converted into the target compound 3,4-dihydro-2H-1,4-benzoxazine-6-ol (I).

[0162] Reaction Scheme 11

[0163]

[0164] The conversion of 6-chloro-3,4-dihydro-2H-1,4-benzoxazine (XVII) to the desired target compound 3,4-dihydro-2H-1,4-benzoxazine-6-ol (I) is achieved via alkaline hydrolysis of chlorine to generate the corresponding hydroxyl group. The conversion of aromatic chlorine atoms to the corresponding hydroxyl groups is part of many well-known, large-scale, and industrially mature processes (e.g., Lujian Gongye, Volume: 48, Issue: 10, Pages: 29-31, 2012, CN 114591175, etc.). It primarily involves the formal hydrolysis of chlorine atoms using large tubular reactors at high temperatures (up to 180°C) and high pressures, optionally in the presence of a selective metal catalyst, to generate the hydroxyl group.

[0165] The corresponding conversion of 6-bromo-3,4-dihydro-2H-1,4-benzoxazine (XVII) to the desired target compound 3,4-dihydro-2H-1,4-benzoxazine-6-ol (I) is similarly achieved via alkaline hydrolysis of the bromine atom to generate the corresponding hydroxyl group. For example, the conversion of aromatic bromine atoms to the corresponding hydroxyl groups can be carried out, for example, using an autoclave, at high temperatures (@200-230°C, e.g. @215-225°C) and high pressures (2-20 bar), optionally in the presence of a selective metal catalyst.

[0166] The inventors have discovered that the conversion of the bromine derivative 6-bromo-3,4-dihydro-2H-1,4-benzoxazine (XVII) to the desired target compound 3,4-dihydro-2H-1,4-benzoxazine-6-ol (I) unexpectedly leads to a significantly improved yield compared to the use of the corresponding chlorine derivative 6-chloro-3,4-dihydro-2H-1,4-benzoxazine (XVII).

[0167] This method for obtaining 3,4-dihydro-2H-1,4-benzoxazine-6-ol (I) is typically efficient and cost-effective, and will significantly reduce the number of steps.

[0168] Another specific embodiment of the method according to the invention (shown in reaction schemes 12 and 13 below) is also based on a well-known and mature large-scale process. This embodiment includes the following steps:

[0169] • 3,4-Dihydro-2H-1,4-benzoxazine-6-sulfonic acid (XX) is provided using 3-amino-4-hydroxy-benzenesulfonic acid (XIX), which is readily available and commercially available. Cycloforming can be achieved in one step by condensing dibromoethane with 3-amino-4-hydroxy-benzenesulfonic acid (XIX) under basic conditions in a dipolar aprotic solvent to generate 3,4-dihydro-2H-1,4-benzoxazine-6-sulfonic acid (XX).

[0170] • The alkaline fusion of 3,4-dihydro-2H-1,4-benzoxazine-6-sulfonic acid (XX) is carried out in a one-pot reaction using caustic soda / potassium hydroxide to obtain the desired product 3,4-dihydro-2H-1,4-benzoxazine-6-ol (I).

[0171] Reaction Scheme 12

[0172]

[0173] Commercially available 3-amino-4-hydroxy-benzenesulfonic acid (XIX) is reacted with dibromoethane in DMF (dimethylformamide) or dimethylacetamide in the presence of potassium carbonate as a base to perform cyclization in one step, thereby yielding 3,4-dihydro-2H-1,4-benzoxazine-6-sulfonic acid (XX). Dimethylacetamide is the preferred solvent for this step because it avoids any unwanted side reactions during the formation of the formylated compound, which can be detected when using DMF as a dipolar aprotic solvent. The reaction requires relatively high temperatures (>120°C) to obtain moderate to good yields (up to 90%). The organic solubility remains sufficient if any formation of alkali metal salts of the sulfonic acid group can be excluded. The resulting solid requires some form of purification via recrystallization. The alkali melting described below as in Scheme 13 is carried out under standard conditions at temperatures >300°C, see patent publications CN114835612, CN113929561, etc.

[0174] Reaction Scheme 13

[0175]

[0176] With respect to the salts of 3,4-dihydro-2H-1,4-benzoxazine-6-ol (I) or the intermediates disclosed herein, cosmetically acceptable salts are preferred. Preferred cosmetically acceptable salts are lithium, sodium, potassium, ammonium, magnesium, and calcium salts of 3,4-dihydro-2H-1,4-benzoxazine-6-ol (I) or the intermediates discussed herein, respectively. As used herein, the term salt includes salts in the conventional sense as well as addition salts. Addition salts encompass addition complexes with acids, bases, and / or one or more solvents. Examples of addition salts with acids include complexes of the target compound or the intermediates disclosed herein with hydrogen chloride, hydrogen bromide, sulfuric acid, phosphoric acid, acetic acid, citric acid, succinic acid, tartaric acid, lactic acid, p-toluenesulfonic acid, and benzenesulfonic acid. Examples of addition salts with bases include complexes of the target compound or the intermediates disclosed herein with bases (such as sodium hydroxide, potassium hydroxide, ammonia, amines, or alkanolamines). Examples of addition salts (solvents) with one or more solvents include complexes of the target compound or intermediates disclosed herein with water (hydrates) or lower alcohols (i.e., methanol, ethanol, isopropanol, n-propanol, isobutanol, n-butanol). A preferred solvate is a hydrate. Detailed Implementation

[0177] The sequence of steps involved in the condensation synthesis and large-scale processing will be described in detail below, including all identified intermediates. It should be understood that when this disclosure refers to a particular structure, all reasonable additional tautomers are included. In the art, tautomers are typically represented by a single structure, and this disclosure follows this convention.

[0178] It should be understood that the steps described for preparing 3,4-dihydro-2H-1,4-benzoxazine-6-ol according to formula (I) can be carried out in a continuous one-pot synthesis, wherein reagents are added to the reactor one at a time without post-treatment. As indicated below, the reaction steps require suitable solvents. Continuous one-pot synthesis without post-treatment is preferred unless preferred for avoiding byproducts from the preceding step in a later step.

[0179] The following detailed description illustrates the method according to the invention (by reference, for example, specific reactants and / or reaction conditions). This is done by way of example only, and the invention is not limited thereto. For example, a reference to chlorine should be understood as a reference to a suitable halogen, or a reference to a particular solvent should be understood as a reference to a solvent generally applicable to the corresponding reaction and the intended corresponding dissolution. Similarly, a reference to a particular acid or base should be understood as a general reference to a suitable acid or base, respectively.

[0180] 1. Synthesis of 3,4-dihydro-2H-1,4-benzoxazine-6-ol (I) using 2-amino-4-nitrophenol (VIII) as the starting material.

[0181] Reaction Scheme 1

[0182]

[0183] Commercially available 2-amino-4-nitrophenol (VIII) is reacted with dibromoethane in DMF (dimethylformamide) or dimethylacetamide in the presence of potassium carbonate as a base to undergo cyclization in one step, yielding 6-nitro-3,4-dihydro-2H-1,4-benzoxazine (IX). This reaction requires relatively high temperatures (>120°C) to obtain yields up to 90%. The solvent used for the condensation reaction can be selected from the group consisting of: chloroform, dichloromethane, 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. Preferably, the solvent used for the condensation reaction can be selected from the group consisting of: chloroform, dichloromethane, acetonitrile, dimethylformamide, dimethylacetamide, ethyl acetate, toluene, and mixtures thereof. Specifically, the solvent used for the condensation reaction can be selected from the group consisting of: acetonitrile, dimethylformamide, dimethylacetamide, and mixtures thereof. The base can be selected from calcium carbonate, sodium carbonate, potassium carbonate, sodium acetate, DBU, DBN, Huenig base, ammonium sulfate, sodium bicarbonate, and potassium bicarbonate. According to one embodiment, potassium carbonate is used as the base. The separated solid requires some purification via a recrystallization process. The solvent used for 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, methyltetrahydrofuran, n-pentanol, n-butanol, acetic acid, propionic acid, oxalic acid, malonic acid, sulfuric acid, phosphoric acid, isoamyl alcohol, tert-butanol, isopropanol, n-propanol, ethanol, methanol, glycol, hydrogen chloride, water, and mixtures thereof. Preferably, the solvent used for 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. In particular, the solvent used for recrystallization may be selected from the group consisting of: n-propanol, acetic acid, toluene, ethyl acetate, and mixtures thereof.

[0184] Reaction scheme 4A

[0185]

[0186] Then, in ethanol, an environmentally friendly solvent, 6-nitro-3,4-dihydro-2H-1,4-benzoxazine (IX) is converted to 3,4-dihydro-2H-1,4-benzoxazine-6-amine (X) via a standardized hydrogenation procedure using carbon-supported palladium as a catalyst and hydrogen. This hydrogenation step is carried out primarily in the presence of a hydrogen source. The hydrogen source can be selected from hydrazine or H2, and the metal catalyst is selected from the group consisting of: Fe, Pd / C, Pd / (OH)2, Rune-Ni, Pt / C, PtO2, and mixtures thereof. Specifically, the hydrogen source can be H2, and the metal catalyst can be a Pd / C catalyst. The one or more solvents used in this step may be selected from the group consisting of: 1,2-dimethoxyethane, pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, methyl propionate, ethyl propionate, n-propyl propionate, isopropyl propionate, n-butyl propionate, 1,4-dioxane, diethyl ether, tetrahydrofuran, methyltetrahydrofuran, n-butanol, isopropanol, n-propanol, ethanol, methanol, water, and mixtures thereof. Preferably, the solvent may be selected from the group consisting of: methanol, ethanol, ethyl acetate, toluene, and mixtures thereof. From an ecological perspective, the solvent may preferably be selected from methanol, ethanol, and / or ethyl acetate, or an aqueous solution of methanol and / or ethanol.

[0187] Reaction scheme 4B

[0188]

[0189] This step then begins with the formation of an intermediate diazonium salt derived from 3,4-dihydro-2H-1,4-benzoxazine-6-amine (X), obtained at 0°C using sodium nitrite and sulfuric acid via a standardized procedure. Once the corresponding diazonium salt is formed, the temperature is raised to 80-100°C to induce its decomposition, releasing nitrogen and immediately generating the corresponding phenolic derivative, which is the desired product 3,4-dihydro-2H-1,4-benzoxazine-6-ol (I). This diazotization step is carried out in the presence of at least one nitrosating agent to convert 3,4-dihydro-2H-1,4-benzoxazine-6-amine (X) into the desired compound 3,4-dihydro-2H-1,4-benzoxazine-6-ol (I). One or more nitrosating agents may be selected from the group consisting of sodium nitrite, potassium nitrite, nitrous oxide, nitrososulfuric acid, and mixtures thereof.

[0190] This step is carried out in the presence of at least one inorganic or organic acid. The inorganic or organic acid may be selected from the group consisting of: hydrogen chloride, trifluoroacetic acid, sulfuric acid, sulfurous acid, carbonic acid, nitric acid, acetic acid, propionic acid, phosphoric acid, and mixtures thereof. Alternatively, the inorganic or organic acid may be selected from the group consisting of: hydrogen chloride, sulfuric acid, sulfurous acid, acetic acid, and mixtures thereof. Alternatively, the inorganic or organic acid may be sulfuric acid.

[0191] The solvent used in this step of converting the diazonium salt into the final phenol derivative may be selected from the group consisting of: 1,2-dimethoxyethane, pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, 1,4-dioxane, diethyl ether, tetrahydrofuran, methyltetrahydrofuran, n-pentanol, n-butanol, acetic acid, propionic acid, oxalic acid, malonic acid, sulfuric acid, phosphoric acid, isoamyl alcohol, tert-butanol, isopropanol, n-propanol, ethanol, methanol, glycol, hydrogen chloride, water, and mixtures thereof; alternatively, it may be selected from the group consisting of: n-butanol, isopropanol, n-propanol, ethanol, methanol, acetic acid, propionic acid, oxalic acid, malonic acid, hydrogen chloride, sulfuric acid, phosphoric acid, and mixtures thereof; preferably, it may be selected from the group consisting of: n-propanol, acetic acid, propionic acid, oxalic acid, malonic acid, hydrogen chloride, sulfuric acid, phosphoric acid, water, and mixtures thereof.

[0192] 2. Synthesis of 3,4-dihydro-2H-1,4-benzoxazine-6-ol (I) using 2-amino-4-nitrophenol (VIII) as the starting material.

[0193] Reaction Scheme 2

[0194]

[0195] This synthetic concept begins with an initial cyclization operation, which uses 2-chloroacetyl chloride, a highly reactive but extremely selective reagent, to condense a morpholine ring onto 2-amino-4-nitrophenol (VIII) to form the desired intermediate 6-nitro-4H-1,4-benzoxazin-3-one (XI). This condensation reaction can be carried out using a phase-transfer catalyst in the presence of a weak base to neutralize the acid that forms a byproduct, in chloroform as a solvent, at 0°C.

[0196] The cyclization reaction can be carried out using at least one phase transfer catalyst. One or more phase transfer catalysts may be selected from the group consisting of benzyltrialkylammonium salts, and alternatively from the group consisting of: benzyltrimethylammonium, benzyltriethylammonium, benzyltripropylammonium, chlorides, bromides, or sulfates of benzyltributylammonium, and mixtures thereof. Preferably, the phase transfer catalyst is benzyltributylammonium chloride. The base may be selected from sodium bicarbonate, calcium carbonate, sodium carbonate, potassium carbonate, sodium acetate, DBU, DBN, Huenig base, ammonium sulfate, sodium bicarbonate, and potassium bicarbonate. According to one embodiment, potassium carbonate, sodium bicarbonate, and sodium carbonate are used as the base.

[0197] The solvent used for the condensation reaction can be selected from the group consisting of: chloroform, dichloromethane, 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. Preferably, the solvent used for the condensation reaction can be selected from the group consisting of: chloroform, dichloromethane, dimethylformamide, dimethylacetamide, ethyl acetate, acetonitrile, toluene, and mixtures thereof. In particular, the solvent used for the condensation reaction can be selected from the group consisting of: chloroform, dichloromethane, dimethylformamide, dimethylacetamide, and mixtures thereof.

[0198] Reaction scheme 5A

[0199]

[0200] In the next step, the 6-nitro-4H-1,4-benzoxazin-3-one (XI) obtained from the first step is used without further purification to reduce the carbonyl group of the heterocycle of 6-nitro-4H-1,4-benzoxazin-3-one (XI). The selective carbonyl reduction is carried out in THF as a solvent using a commercially available solution containing a dimethylboron sulfide-THF complex (which acts as a highly selective and clean reagent), yielding the intermediate compound 6-nitro-3,4-dihydro-2H-1,4-benzoxazine (IX).

[0201] The reaction solvent is only THF. Alternatively, other commercially available boron complexes, such as boron-THF complex solutions in THF, can be used as the reduction medium. The solvent used for extraction after reduction (tracked and controlled by TLC analysis) is selected from the group consisting of: chloroform, dichloroform, 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. Preferably, the solvent used for extraction can be selected from the group consisting of: chloroform, dichloroform, tert-butyl methyl ether, diethyl ether, ethyl acetate, 1,2-dimethoxyethane, and mixtures thereof. In particular, the solvent used for extraction can be selected from the group consisting of: chloroform, dichloroform, tert-butyl methyl ether, diethyl ether, ethyl acetate, and mixtures thereof. The separated product obtained after removing the extraction solvent is recrystallized to obtain 3,4-dihydro-2H-1,4-benzoxazine-6-ol (I) as a pure compound. The solvent used for recrystallization may be selected from the following: 1,2-dimethoxyethane, ethyl acetate, pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, 1,4-dioxane, diethyl ether, tetrahydrofuran, methyltetrahydrofuran, n-pentanol, n-butanol, acetic acid, propionic acid, oxalic acid, malonic acid, sulfuric acid, phosphoric acid, isoamyl alcohol, tert-butanol, isopropanol, n-propanol, ethanol, methanol, glycol, hydrogen chloride, water, and mixtures thereof. Preferably, the solvent used for 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. In particular, the solvent used for recrystallization can be selected from the group consisting of: n-propanol, acetic acid, toluene, ethyl acetate, and mixtures thereof.

[0202] Reaction scheme 5B

[0203]

[0204] Then, in methanol, an environmentally friendly solvent, 6-nitro-3,4-dihydro-2H-1,4-benzoxazine (IX) is converted to 3,4-dihydro-2H-1,4-benzoxazine-6-amine (X) via a standardized hydrogenation process using carbon-supported palladium as a catalyst. The hydrogenation step is carried out primarily in the presence of a hydrogen source. The hydrogen source can be selected from hydrazine or H2, and the metal catalyst is selected from the group consisting of: Fe, Pd / C, Pd / (OH)2, Rune-Ni, Pt / C, PtO2, and mixtures thereof. In particular, the hydrogen source can be H2, and the metal catalyst can be a Pd / C catalyst. The one or more solvents used in this step may be selected from the group consisting of: 1,2-dimethoxyethane, pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, methyl propionate, ethyl propionate, n-propyl propionate, isopropyl propionate, n-butyl propionate, 1,4-dioxane, diethyl ether, tetrahydrofuran, methyltetrahydrofuran, n-butanol, isopropanol, n-propanol, ethanol, methanol, water, and mixtures thereof. Preferably, the solvent may be selected from the group consisting of: methanol, ethanol, ethyl acetate, toluene, and mixtures thereof. From an ecological perspective, the solvent may preferably be selected from methanol, ethanol, and / or ethyl acetate, or an aqueous solution of methanol and / or ethanol.

[0205] Reaction scheme 5C

[0206]

[0207] The final step in this synthetic process then begins with the formation of an intermediate diazonium salt. This intermediate diazonium salt is derived from 3,4-dihydro-2H-1,4-benzoxazine-6-amine (X), obtained at 0°C using sodium nitrite and sulfuric acid via a standardized procedure. Once the corresponding diazonium salt is formed, the temperature is raised to 80-100°C to induce its decomposition, releasing nitrogen and immediately generating the corresponding phenolic derivative, which is the desired product 3,4-dihydro-2H-1,4-benzoxazine-6-ol (I). This diazotization step is carried out in the presence of at least one nitrosating agent to convert 3,4-dihydro-2H-1,4-benzoxazine-6-ol (I) into the desired compound 3,4-dihydro-2H-1,4-benzoxazine-6-ol (I). One or more nitrosating agents may be selected from the group consisting of sodium nitrite, potassium nitrite, nitrous oxide, nitrososulfuric acid, and mixtures thereof.

[0208] This step is carried out in the presence of at least one inorganic or organic acid. The inorganic or organic acid may be selected from the group consisting of: hydrogen chloride, trifluoroacetic acid, sulfuric acid, sulfurous acid, carbonic acid, nitric acid, acetic acid, propionic acid, phosphoric acid, and mixtures thereof. Alternatively, the inorganic or organic acid may be selected from the group consisting of: hydrogen chloride, sulfuric acid, sulfurous acid, acetic acid, and mixtures thereof. Alternatively, the inorganic or organic acid may be sulfuric acid.

[0209] One or more solvents used in this step of converting the diazonium salt into the final phenol derivative may be selected from the group consisting of: 1,2-dimethoxyethane, pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, 1,4-dioxane, diethyl ether, tetrahydrofuran, methyltetrahydrofuran, n-pentanol, n-butanol, acetic acid, propionic acid, oxalic acid, malonic acid, sulfuric acid, phosphoric acid, isoamyl alcohol, tert-butanol, isopropanol, n-propanol, ethanol, methanol, glycol, hydrogen chloride, water, and mixtures thereof; alternatively selected from the group consisting of: n-butanol, isopropanol, n-propanol, ethanol, methanol, acetic acid, propionic acid, oxalic acid, malonic acid, hydrogen chloride, sulfuric acid, phosphoric acid, and mixtures thereof; preferably selected from the group consisting of: n-propanol, acetic acid, propionic acid, oxalic acid, malonic acid, hydrogen chloride, sulfuric acid, phosphoric acid, water, and mixtures thereof.

[0210] Alternatively, the carbonyl reduction can be carried out prior to the diazotization step described herein to yield 3,4-dihydro-2H-1,4-benzoxazine-3-one (XIV) to 3,4-dihydro-2H-1,4-benzoxazine-6-amine (X).

[0211] Reaction scheme 8A

[0212]

[0213] Selective carbonyl reduction was carried out in THF using a commercially available solution containing a boron dimethyl sulfide-THF complex (which acts as a highly selective and clean reagent) as the solvent, to give the intermediate compound 3,4-dihydro-2H-1,4-benzoxazine-6-amine (X). The reaction solvent was THF only. Alternatively, other commercially available boron complexes, such as boron-THF complex solutions in THF, could be used as the reducing medium. After reduction (monitored and controlled by TLC analysis), the solvent used for extraction could be selected from the following: chloroform, dichloromethane, 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. Preferably, the solvent used for extraction can be selected from the group consisting of: chloroform, dichloromethane, tert-butyl methyl ether, diethyl ether, ethyl acetate, 1,2-dimethoxyethane, and mixtures thereof. Specifically, the solvent used for extraction can be selected from the group consisting of: chloroform, dichloromethane, tert-butyl methyl ether, diethyl ether, ethyl acetate, and mixtures thereof. The product obtained after removing the extraction solvent is recrystallized to obtain 3,4-dihydro-2H-1,4-benzoxazine-6-amine (X) as a pure compound. The solvent used for recrystallization may be selected from the following: 1,2-dimethoxyethane, ethyl acetate, pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, 1,4-dioxane, diethyl ether, tetrahydrofuran, methyltetrahydrofuran, n-pentanol, n-butanol, acetic acid, propionic acid, oxalic acid, malonic acid, sulfuric acid, phosphoric acid, isoamyl alcohol, tert-butanol, isopropanol, n-propanol, ethanol, methanol, glycol, hydrogen chloride, water, and mixtures thereof. Preferably, the solvent used for 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. In particular, the solvent used for recrystallization may be selected from the group consisting of: n-propanol, acetic acid, toluene, ethyl acetate, and mixtures thereof.

[0214] The diazotization of 3,4-dihydro-2H-1,4-benzoxazine-6-amine (X) follows a standardized protocol, carried out at 0°C using sodium nitrite and hydrochloric acid or sulfuric acid, or mixtures thereof. Once the corresponding diazonium salt is formed, the temperature is raised to 80-100°C to promote its decomposition, thereby releasing nitrogen and immediately forming the desired compound 3,4-dihydro-2H-1,4-benzoxazine-6-ol (I).

[0215] Reaction scheme 8B

[0216]

[0217] This diazotization step is carried out in the presence of at least one nitrosating agent to convert 3,4-dihydro-2H-1,4-benzoxazine-6-amine (X) into the desired compound 3,4-dihydro-2H-1,4-benzoxazine-6-ol (I). One or more nitrosating agents may be selected from the group consisting of sodium nitrite, potassium nitrite, nitrous oxide, nitrososulfuric acid, and mixtures thereof.

[0218] This step is carried out in the presence of at least one inorganic or organic acid. The inorganic or organic acid may be selected from the group consisting of: hydrogen chloride, trifluoroacetic acid, sulfuric acid, sulfurous acid, carbonic acid, nitric acid, acetic acid, propionic acid, phosphoric acid, and mixtures thereof. Alternatively, the inorganic or organic acid may be selected from the group consisting of: hydrogen chloride, sulfuric acid, sulfurous acid, acetic acid, and mixtures thereof. Alternatively, the inorganic or organic acid may be sulfuric acid.

[0219] One or more solvents used in this step of converting the diazonium salt into the final phenol derivative may be selected from the group consisting of: 1,2-dimethoxyethane, pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, 1,4-dioxane, diethyl ether, tetrahydrofuran, methyltetrahydrofuran, n-pentanol, n-butanol, acetic acid, propionic acid, oxalic acid, malonic acid, sulfuric acid, phosphoric acid, isoamyl alcohol, tert-butanol, isopropanol, n-propanol, ethanol, methanol, glycol, hydrogen chloride, water, and mixtures thereof; alternatively selected from the group consisting of: n-butanol, isopropanol, n-propanol, ethanol, methanol, acetic acid, propionic acid, oxalic acid, malonic acid, hydrogen chloride, sulfuric acid, phosphoric acid, and mixtures thereof; preferably selected from the group consisting of: n-propanol, acetic acid, propionic acid, oxalic acid, malonic acid, hydrogen chloride, sulfuric acid, phosphoric acid, water, and mixtures thereof.

[0220] 3. Using 3,4-dihydro-2H-1,4-benzoxazine-6-amine (X) as the starting material, 3,4-dihydro-2H-1,4-benzoxazine-6-ol (I) was synthesized.

[0221] Reaction Scheme 9

[0222]

[0223] 3,4-Dihydro-2H-1,4-benzoxazine-6-amine (X) is prepared by the method described herein. This method for obtaining 3,4-dihydro-2H-1,4-benzoxazine-6-ol (I) via acidic or alkaline hydrolysis is typically efficient and cost-effective, and significantly reduces the number of steps. Typical solvents used for this hydrolytic conversion are selected from acetic acid, propionic acid, oxalic acid, malonic acid, sulfuric acid, phosphoric acid, hydrogen chloride, sodium hydroxide, potassium hydroxide, potassium tert-butyrate, water, and mixtures thereof. Preferably, the solvent used for hydrolysis can be selected from the group consisting of acetic acid, propionic acid, hydrogen chloride, sulfuric acid, phosphoric acid, sodium hydroxide, potassium hydroxide, and mixtures thereof. Metal catalysts include zirconium, cerium, and acid catalysts such as phosphotungstic acid, phosphomolybdic acid, silicotungstic acid, and silicotomolybdic acid. The material used for the tubular autoclave in contact with the materials in the reaction system includes one of cerium, zirconium, or composites thereof.

[0224] 4. Synthesis of 3,4-dihydro-2H-1,4-benzoxazine-6-ol (I) using 2-amino-4-chlorophenol (XVI) as the starting material.

[0225] Reaction Scheme 10

[0226]

[0227] Commercially available 2-amino-4-chlorophenol (XVI) is reacted with dibromoethane in DMF (dimethylformamide) or dimethylacetamide in the presence of potassium carbonate as a base to undergo cyclization in one step, yielding 6-chloro-3,4-dihydro-2H-1,4-benzoxazine (XVII). Alternatively, 2-amino-4-bromophenol (XVI) can be reacted as a starting material via a similar cyclization reaction to give the corresponding 6-bromo-3,4-dihydro-2H-1,4-benzoxazine (XVII). This reaction requires relatively high temperatures (>120°C) to obtain moderate to good yields (up to 90%). The resulting solid requires some form of purification via recrystallization.

[0228] The solvent used for the condensation reaction can be selected from the following: chloroform, dichloromethane, 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. Preferably, the solvent used for the condensation reaction can be selected from the group consisting of: chloroform, dichloromethane, acetonitrile, dimethylformamide, dimethylacetamide, ethyl acetate, toluene, and mixtures thereof. In particular, the solvent used for the condensation reaction can be selected from the group consisting of: acetonitrile, dimethylformamide, dimethylacetamide, and mixtures thereof. The base can be selected from calcium carbonate, sodium carbonate, potassium carbonate, sodium acetate, DBU, DBN, Huenig base, ammonium sulfate, sodium bicarbonate, and potassium bicarbonate. According to one embodiment, potassium carbonate is used as the base. The separated solid requires some purification via a recrystallization process. The solvent used for recrystallization may be selected from the following: 1,2-dimethoxyethane, ethyl acetate, pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, 1,4-dioxane, diethyl ether, tetrahydrofuran, methyltetrahydrofuran, n-pentanol, n-butanol, acetic acid, propionic acid, oxalic acid, malonic acid, sulfuric acid, phosphoric acid, isoamyl alcohol, tert-butanol, isopropanol, n-propanol, ethanol, methanol, glycol, hydrogen chloride, water, and mixtures thereof. Preferably, the solvent used for 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. In particular, the solvent used for recrystallization may be selected from the group consisting of: n-propanol, acetic acid, toluene, ethyl acetate, and mixtures thereof.

[0229] The second option represents a two-step synthesis, beginning with the condensation of 2-amino-4-chlorophenol (XVI) with 2-chloroacetyl chloride to yield 6-chloro-4H-1,4-benzoxazin-3-one (XVIII). Alternatively, this second option uses 2-amino-4-bromophenol (XVI) as the starting material to yield the corresponding 6-bromo-4H-1,4-benzoxazin-3-one (XVIII). The reaction is carried out under mild conditions at 0°C in chloroform, using a maximum of 2% of a phase-transfer catalyst in the presence of a base such as potassium bicarbonate.

[0230] The cyclization reaction can be carried out using at least one phase transfer catalyst. One or more phase transfer catalysts may be selected from the group consisting of benzyltrialkylammonium salts, and alternatively from the group consisting of: benzyltrimethylammonium, benzyltriethylammonium, benzyltripropylammonium, chlorides, bromides, or sulfates of benzyltributylammonium, and mixtures thereof. Preferably, the phase transfer catalyst is benzyltributylammonium chloride. The base may be selected from sodium bicarbonate, calcium carbonate, sodium carbonate, potassium carbonate, sodium acetate, DBU, DBN, Huenig base, ammonium sulfate, sodium bicarbonate, and potassium bicarbonate. According to one embodiment, potassium carbonate, sodium bicarbonate, and sodium carbonate are used as the base.

[0231] The solvent used for the condensation reaction may be selected from the following: chloroform, dichloromethane, 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. Preferably, the solvent used for the condensation reaction may be selected from the group consisting of: chloroform, dichloromethane, dimethylformamide, dimethylacetamide, ethyl acetate, acetonitrile, toluene, and mixtures thereof. In particular, the solvent used for the condensation reaction may be selected from the group consisting of: chloroform, dichloromethane, dimethylformamide, dimethylacetamide, and mixtures thereof.

[0232] The compound (XVIII) from the first step can be used without further purification to reduce the carbonyl group of the heterocycle undergoing 6-chloro-4H-1,4-benzoxazin-3-one (XVIII). Similarly, the corresponding bromine-compound (XVIII) from the first step can be used without further purification to reduce the carbonyl group of the heterocycle undergoing 6-bromo-4H-1,4-benzoxazin-3-one (XVIII).

[0233] The selective carbonyl reduction reaction was carefully carried out in THF as a solvent using a commercially available solution containing a dimethylboron sulfide-THF complex (which acts as a highly selective and clean reagent) to produce the intermediate compound 6-chloro-3,4-dihydro-2H-1,4-benzoxazine (XVII) or 6-bromo-3,4-dihydro-2H-1,4-benzoxazine (XVII). THF was the only solvent used in the reaction. Alternatively, other commercially available boron complexes, such as boron-THF complex solutions in THF, could be used as the reducing medium. After reduction (monitored and controlled by TLC analysis), the solvent used for extraction was selected from the following: chloroform, dichloromethane, 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. Preferably, the solvent used for extraction can be selected from the group consisting of: chloroform, dichloromethane, tert-butyl methyl ether, diethyl ether, ethyl acetate, 1,2-dimethoxyethane, and mixtures thereof. Specifically, the solvent used for extraction can be selected from the group consisting of: chloroform, dichloromethane, tert-butyl methyl ether, diethyl ether, ethyl acetate, and mixtures thereof. The separated product obtained after removing the extraction solvent is recrystallized to obtain 3,4-dihydro-2H-1,4-benzoxazine-6-ol (I) as a pure compound. The solvent used for recrystallization may be selected from the following: 1,2-dimethoxyethane, ethyl acetate, pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, 1,4-dioxane, diethyl ether, tetrahydrofuran, methyltetrahydrofuran, n-pentanol, n-butanol, acetic acid, propionic acid, oxalic acid, malonic acid, sulfuric acid, phosphoric acid, isoamyl alcohol, tert-butanol, isopropanol, n-propanol, ethanol, methanol, glycol, hydrogen chloride, water, and mixtures thereof. Preferably, the solvent used for 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. In particular, the solvent used for recrystallization may be selected from the group consisting of: n-propanol, acetic acid, toluene, ethyl acetate, and mixtures thereof.

[0234] Reaction Scheme 11

[0235]

[0236] Then, 6-chloro-3,4-dihydro-2H-1,4-benzoxazine (XVII) is converted to the desired target compound 3,4-dihydro-2H-1,4-benzoxazine-6-ol (I) via alkaline hydrolysis of chlorine to generate the corresponding hydroxyl group. The conversion of aromatic chlorine to the corresponding hydroxyl group is part of many well-known, large-scale, and industrially sophisticated processes (e.g., Lujian Gongye, Volume: 48, Issue: 10, Pages: 29-31, 2012, CN 114591175, etc.). These processes primarily focus on the formal hydrolysis of chlorine atoms using large tubular reactors at high temperatures (up to 180°C) and high pressures, optionally in the presence of a selective metal catalyst, to generate hydroxyl groups.

[0237] The corresponding conversion of 6-bromo-3,4-dihydro-2H-1,4-benzoxazine (XVII) to the desired target compound 3,4-dihydro-2H-1,4-benzoxazine-6-ol (I) is similarly achieved via alkaline hydrolysis of the bromine atom to generate the corresponding hydroxyl group. For example, the conversion of aromatic bromine atoms to the corresponding hydroxyl groups can be carried out, for example, in an autoclave at high temperatures (@200-230°C, e.g. @215-225°C) and high pressures (2-20 bar), optionally in the presence of a selective metal catalyst.

[0238] The inventors have discovered that the conversion of the bromine-derived 6-bromo-3,4-dihydro-2H-1,4-benzoxazine (XVII) to the desired target compound 3,4-dihydro-2H-1,4-benzoxazine-6-ol (I) unexpectedly leads to a significantly improved yield compared to the conversion using the corresponding chlorine-derived 6-chloro-3,4-dihydro-2H-1,4-benzoxazine-6-ol.

[0239] This method for obtaining 3,4-dihydro-2H-1,4-benzoxazine-6-ol (I) is typically efficient and cost-effective, and will significantly reduce the number of steps.

[0240] Typical solvents used for this hydrolytic conversion are selected from sodium hydroxide, potassium hydroxide, potassium tert-butyrate, water, and mixtures thereof. Preferably, the solvent used for hydrolysis can be selected from the group consisting of sodium hydroxide, potassium hydroxide, and mixtures thereof. Metal catalysts include zirconium and cerium, and acid catalysts such as phosphotungstic acid, phosphomolybdic acid, silicotungstic acid, and silicotomolybdic acid. The material used for the tubular autoclave in contact with the materials in the reaction system includes one of cerium, zirconium, or composites thereof.

[0241] 5. Synthesizing 3,4-dihydro-2H-1,4-benzoxazine-6-ol (I) using 3-amino-4-hydroxybenzenesulfonic acid (XIX) as the starting material.

[0242] Reaction Scheme 12

[0243]

[0244] Commercially available 3-amino-4-hydroxy-benzenesulfonic acid (XIX) is reacted with dibromoethane in DMF (dimethylformamide) or dimethylacetamide in the presence of a base to undergo cyclization in one step, thereby yielding 3,4-dihydro-2H-1,4-benzoxazine-6-sulfonic acid (XX). The solvent is selected from the following: chloroform, dichloromethane, 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. Preferably, the solvent used for the condensation reaction may be selected from the group consisting of: chloroform, dichloromethane, dimethylformamide, dimethylacetamide, ethyl acetate, acetonitrile, toluene, and mixtures thereof. Specifically, the solvent used for the condensation reaction can be selected from the group consisting of dimethylformamide, dimethylacetamide, and mixtures thereof. The reaction requires relatively high temperatures (>120°C) to obtain moderate to good yields (up to 90%). Organic solubility remains sufficient if any formation of alkali metal salts with sulfonic acid groups can be excluded. The base can be selected from calcium carbonate, sodium carbonate, potassium carbonate, sodium acetate, DBU, DBN, Huenig base, ammonium sulfate, sodium bicarbonate, and potassium bicarbonate. According to one embodiment, potassium carbonate is used as the base. The separated solid requires some form of purification via recrystallization. The base melting described below as in Scheme 13 is carried out under standard conditions at temperatures >300°C, see patent publications CN114835612, CN113929561, etc.

[0245] Reaction Scheme 13

[0246]

[0247] Following alkali melting, the product is separated under strongly acidic conditions during a neutralization step to obtain the desired compound 3,4-dihydro-2H-1,4-benzoxazine-6-ol (I). Typical solvents are selected from acetic acid, propionic acid, oxalic acid, malonic acid, sulfuric acid, phosphoric acid, hydrogen chloride, water, and mixtures thereof. Preferably, the solvent used for neutralization can be selected from the group consisting of sulfuric acid, hydrogen chloride, water, and mixtures thereof.

[0248] Example

[0249] The following non-limiting embodiments further illustrate the invention. These embodiments are given for illustrative purposes only and should not be construed as limiting the invention, as many modifications are possible without departing from the spirit and scope of the invention, as will be recognized by those skilled in the art. Unless otherwise stated, all concentrations are listed as weight percentages.

[0250] Example 1: Synthesis of 6-nitro-4H-1,4-benzoxazin-3-one (XI) using 2-amino-4-nitrophenol (VIII) as the starting material.

[0251] A solution of 2-amino-4-nitrophenol (VIII) (1 equivalent, 10.00 g, 65.00 mmol) in DMF (50 ml) containing 15.69 g potassium carbonate (1.75 equivalent, 15.69 g, 114 mmol) was treated at 0 °C with 1.75 equivalent of 2-chloroacetyl chloride (12.82 g, 9.0 ml, 114.00 mmol) for 1 h. The reaction mixture was then heated to reflux for an additional 1 h. After cooling to room temperature (RT), the reaction mixture was diluted with 200 ml of water. The precipitate formed was filtered and washed with ice-cold methanol. The desired compound, 6-nitro-4H-1,4-benzoxazin-3-one (XI), was given as a light brown solid in 85% (10.5 g) yield.

[0252] Example 2: Reduction of (XI) to produce 6-amino-4H-1,4-benzoxazin-3-one (XIV)

[0253] 5.00 g of 6-nitro-4H-1,4-benzoxazin-3-one (XI) (26.00 mmol) was suspended in 100 mL of ethanol, and Pd / C (10 wt% Pd, 5 mol%) was added in fractions. The solution was hydrogenated under nitrogen with a regular stream of hydrogen at 3 bar. After hydrogen absorption, the reaction mixture was cooled to 0 °C, and the catalyst was filtered off. The solution was evaporated under reduced pressure to give 6-amino-4H-1,4-benzoxazin-3-one (XIV) as a colorless solid in a yield of 64% (2.7 g).

[0254] Example 3: Hydrolysis of (XIV) to generate 6-hydroxy-4H-1,4-benzoxazin-3-one (XV)

[0255] One equivalent of 6-amino-4H-1,4-benzoxazin-3-one (XIV) (1.0 g, 6.00 mmol) was dissolved in a mixture containing sulfuric acid and water (1:4, 12.5 ml) and cooled to 0 °C. 1.2 equivalents of sodium nitrite (0.5 g, 7.00 mmol) was dissolved in 2 ml of water and slowly added to the reaction mixture over 20 minutes. The reaction mixture was stirred at 0 °C for another 30 minutes. The cooled solution was then slowly added to refluxed aqueous sulfuric acid solution (ratio = 1:1, 8 ml) and stirred under reflux for another hour. The reaction mixture was cooled to room temperature and diluted with 10 ml of water. The precipitate was filtered and washed with ice water to give the product 6-hydroxy-4H-1,4-benzoxazin-3-one (XV) as a colorless solid.

[0256] Example 4: Reduction of (XV) to produce 3,4-dihydro-2H-1,4-benzoxazine-6-ol (I)

[0257] One equivalent of 6-hydroxy-4H-1,4-benzoxazin-3-one (XV) (5.00 g, 30.30 mmol) was dissolved in 85 mL of anhydrous THF. Under nitrogen purging, 3.75 equivalents of dimethylboron sulfide-THF complex (10 mol / L, 11.3 mL, 113.00 mmol) was slowly added. The reaction mixture was then heated to reflux for 2 hours. Excess dimethylboron sulfide-THF complex solution was decomposed by slow addition of fractions of methanol, and diluted with 170 mL of water. The reaction mixture was extracted three times with chloroform and finally washed with 100 mL of brine. The combined organic phases were dried over sodium sulfate. The solvent was evaporated under reduced pressure to give the desired product, 3,4-dihydro-2H-1,4-benzoxazin-6-ol (I), in 75% yield as a colorless solid (3.43 g).

[0258] Example 5: Hydrolysis of 6-chloro-3,4-dihydro-2H-1,4-benzoxazine (XVII) to produce 3,4-dihydro-2H-1,4-benzoxazine-6-ol (I).

[0259] 1.0 g of 6-chloro-3,4-dihydro-2H-1,4-benzoxazine, 1.3 g of KOH, 0.1 g of CuCl, 1.5 g of ethylene glycol, and 6.0 g of water were added to a steel autoclave. The mixture was heated to 200-230 °C and reacted for 4 hours. The autoclave was then cooled to 20-25 °C, and 15% HCl solution was added to adjust the pH to 6-7. The lower layer was separated, and the organic layer was extracted three times (3 x 5 g) with deionized water. After removing the solvent, the desired 6-hydroxy-benzomorpholine was obtained in a yield of 3%.

[0260] Example 6: Hydrolysis of 6-bromo-3,4-dihydro-2H-1,4-benzoxazine (XVII) to produce 3,4-dihydro-2H-1,4-benzoxazine-6-ol (I).

[0261] In a steel autoclave, 0.52 g of 95% KOH, 4 g of water, 0.05 g of CuI, and 2.0 g of diethylene glycol dimethyl ether were charged, followed by the addition of 0.5 g of 6-bromo-3,4-dihydro-2H-1,4-benzoxazine. The reaction mixture was heated to 215 °C over approximately 1.5 hours, then maintained at 215 °C and stirred between 215 and 225 °C for approximately 8 hours. After the autoclave cooled to room temperature, the reaction mixture was neutralized with 15% HCl solution to adjust the pH to 6–7. The lower layer was separated, and the organic layer was extracted three times with deionized water. After solvent removal, the desired 6-hydroxybenzomorpholine was obtained in 60% yield (confirmed by HPLC area %).

[0262] Example 7: Synthesis of 2-amino-4-bromophenol (XVI)

[0263] 2-Amino-4-chlorophenol (XVI), a chlorine-derived compound used as a starting material for, for example, the cyclization reaction described in reaction scheme 10 above, is commercially available. The corresponding bromine-derived compound, 2-amino-4-bromophenol (XVI), is less readily available commercially. The following examples describe the synthesis of 2-amino-4-bromophenol (XVI) in good yield from the inexpensive and commercially available chemical 4-bromophenol.

[0264] Step 1: Synthesis of 4-bromo-2-nitrophenol

[0265]

[0266] 4-Bromophenol (5.0 g, 29 mmol) was suspended in acetic acid (15 ml, 3 parts by volume) and heated to 110 °C. 65% nitric acid (1.1 equivalent, 32 mmol, 2.2 ml) was added over 30 minutes with vigorous stirring. After the addition, the reaction mixture was stirred for 15 minutes without further heating. Water (30 ml, 6 VT) was then slowly added to the reaction mixture, and the mixture was cooled to 0 °C. The resulting suspension was filtered, and the residue was washed with a small amount of ice water and recrystallized in methanol to give the product (4.0 g, 64%) as yellow needle-like crystals.

[0267] Step 2: Synthesis of 2-amino-4-bromo-phenol

[0268]

[0269] 4-Bromo-2-nitrophenol (5.0 g, 23 mmol) was dissolved in ethanol (50 ml) with Pd / C (0.1 w%, 0.5 g, 10 w% Pd, 50 w% H2O) and heated to 30 °C. Hydrogen was catalytically hydrogenated with 3 bar of hydrogen gas at a temperature not exceeding 45 °C. The reaction was considered complete when the reaction mixture no longer absorbed any hydrogen gas. The reaction mixture was filtered under nitrogen. The solvent was removed under reduced pressure, allowing the product to crystallize as a colorless solid (3.8 g, 90%).

[0270] Step 3: Synthesis of 6-bromo-4H-1,4-benzoxazin-3-one:

[0271]

[0272] 2-Amino-4-bromophenol (5.0 g, 27 mmol) and sodium bicarbonate (1.25 equivalents, 5.58 g, 67 mmol) were suspended in THF (25 ml, 5 VT) and cooled to 0 °C. 2-Chloroacetyl chloride (1.25 equivalents, 3.8 g, 2.6 ml, 33 mmol) was added over half an hour. The reaction mixture was then heated to room temperature and stirred for 3 hours. The suspension was filtered, and the filtrate was concentrated under reduced pressure. The residue was absorbed in water, and the remaining solid was filtered off and washed with water, so that the product remained as a gray solid (4.97 g, 82%).

[0273] The invention is further described below with reference to the following embodiments.

[0274] 1. A method for preparing 3,4-dihydro-2H-1,4-benzoxazine-6-ol (I), its salts, and mixtures thereof.

[0275] ,

[0276] The method includes:

[0277] (a) Provide a benzoxazine according to formula (XXIV) or a benzoxazine-3-one according to formula (XXV):

[0278] ,

[0279] Ra is selected from halogen, amino, nitro or sulfonic acid groups, and

[0280] (b) Convert Ra to hydroxyl groups.

[0281] If the benzoxazine compound provided in step (a) is (XXV), the method further includes reducing the carbonyl group, wherein the reduction is performed before or after converting Ra to a hydroxyl group.

[0282] 2. The method according to embodiment 1, wherein step (a) comprises reacting 2-aminophenol (XXVI) (wherein Rb is a halogen, nitro, or sulfonic acid group) with dibromoethane in a solvent to form 3,4-dihydro-2H-1,4-benzoxazine (XXIVb) (wherein Rb is a halogen, nitro, or sulfonic acid group).

[0283] .

[0284] 3. The method according to embodiment 2, wherein the reaction is carried out in the presence of a base at a temperature of at least 120°C, and wherein the solvent is selected from chloroform, dichloromethane, dimethylformamide, dimethylacetamide, NMP (N-methylpyrrolidone), acetonitrile, 1,2-dimethoxyethane, ethyl acetate, pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, 1,4-dioxane, diethyl ether, tetrahydrofuran, methyltetrahydrofuran, or mixtures thereof.

[0285] 4. The method according to embodiment 3, wherein the solvent is selected from chloroform, dichloromethane, acetonitrile, dimethylformamide, dimethylacetamide, ethyl acetate, toluene, or mixtures thereof.

[0286] 5. The method according to embodiment 4, wherein the solvent is selected from acetonitrile, dimethylformamide, dimethylacetamide, or mixtures thereof.

[0287] 6. The method according to any one of embodiments 2 to 5, wherein the base is selected from calcium carbonate, sodium carbonate, potassium carbonate, sodium acetate, DBU, DBN, Huenig base, ammonium sulfate, sodium bicarbonate and potassium bicarbonate, and particularly wherein the base is potassium carbonate.

[0288] 7. The method according to any one of embodiments 2 to 6, wherein the method further comprises separating the precipitated (XXIVb) by filtration.

[0289] 8. The method according to embodiment 7, further comprising purifying the separated (XXIVb) by recrystallization from a solvent selected from 1,2-dimethoxyethane, ethyl acetate, pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, 1,4-dioxane, diethyl ether, tetrahydrofuran, methyltetrahydrofuran, n-pentanol, n-butanol, acetic acid, propionic acid, oxalic acid, malonic acid, sulfuric acid, phosphoric acid, isoamyl alcohol, tert-butanol, isopropanol, n-propanol, ethanol, methanol, glycol, hydrogen chloride, or mixtures thereof, or aqueous solutions thereof.

[0290] 9. The method according to embodiment 8, wherein the solvent is selected from ethyl acetate, toluene, n-butanol, isopropanol, ethanol, methanol, acetic acid, propionic acid, oxalic acid, malonic acid, hydrogen chloride, sulfuric acid, phosphoric acid, or mixtures thereof, or aqueous solutions thereof.

[0291] 10. The method according to embodiment 9, wherein the solvent is selected from n-propanol, acetic acid, toluene, ethyl acetate, or mixtures thereof.

[0292] 11. The method according to any one of embodiments 2 to 10, wherein the method further comprises recovering the solvent by distillation.

[0293] 12. The method according to embodiment 1, wherein step (a) comprises reacting 2-aminophenol (XXVI) (wherein Rb is a halogen, nitro, or sulfonic acid group) with 2-chloroacetyl chloride to form 3,4-dihydro-2H-1,4-benzoxazin-3-one (XXVb) (wherein Rb is a halogen, nitro, or sulfonic acid group).

[0294] .

[0295] 13. The method according to embodiment 12, wherein the reaction is carried out in a two-phase system at a temperature in the range of 0-15°C, wherein the organic phase is selected from chloroform, dichloromethane, dimethylformamide, dimethylacetamide, NMP (N-methylpyrrolidone), acetonitrile, 1,2-dimethoxyethane, ethyl acetate, pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, 1,4-dioxane, diethyl ether, tetrahydrofuran, methyltetrahydrofuran, or mixtures thereof, and the aqueous phase contains a base.

[0296] 14. The method according to embodiment 13, wherein the organic phase is selected from chloroform, dichloromethane, dimethylformamide, dimethylacetamide, ethyl acetate, acetonitrile, toluene, or mixtures thereof.

[0297] 15. The method according to embodiment 14, wherein the organic phase is selected from chloroform, dichloromethane, dimethylformamide, dimethylacetamide, or mixtures thereof.

[0298] 16. The method according to any one of embodiments 13 to 15, wherein the base is selected from sodium bicarbonate, calcium carbonate, sodium carbonate, potassium carbonate, sodium acetate, DBU, DBN, Huenig base, ammonium sulfate, sodium bicarbonate and potassium bicarbonate.

[0299] 17. The method according to embodiment 16, wherein the base is selected from potassium carbonate, sodium bicarbonate and sodium carbonate.

[0300] 18. The method according to any one of embodiments 13 to 17, wherein the reaction is carried out using at least one phase transfer catalyst.

[0301] 19. According to the method of embodiment 18, wherein the at least one phase transfer catalyst is at least one benzyltrialkylammonium salt.

[0302] 20. The method according to embodiment 19, wherein the at least one phase transfer catalyst is selected from the chloride, bromide or sulfate of benzyltrimethylammonium, benzyltriethylammonium, benzyltripropylammonium, benzyltributylammonium, or a mixture thereof, particularly wherein the phase transfer catalyst is benzyltributylammonium chloride.

[0303] 21. The method according to any one of embodiments 13 to 20, wherein the method further comprises separating (XXVb) by filtration.

[0304] 22. The method according to embodiment 21, further comprising purifying the separated (XXIVb) by recrystallization from a solvent selected from 1,2-dimethoxyethane, ethyl acetate, pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, 1,4-dioxane, diethyl ether, tetrahydrofuran, methyltetrahydrofuran, n-pentanol, n-butanol, acetic acid, propionic acid, oxalic acid, malonic acid, sulfuric acid, phosphoric acid, isoamyl alcohol, tert-butanol, isopropanol, n-propanol, ethanol, methanol, glycol, hydrogen chloride, or mixtures thereof, or aqueous solutions thereof.

[0305] 23. The method according to embodiment 22, wherein the solvent is selected from ethyl acetate, toluene, n-butanol, isopropanol, n-propanol, ethanol, methanol, acetic acid, propionic acid, oxalic acid, malonic acid, hydrogen chloride, sulfuric acid, phosphoric acid, or mixtures thereof, or aqueous solutions thereof.

[0306] 24. The method according to embodiment 23, wherein the solvent is selected from n-propanol, acetic acid, toluene, ethyl acetate, or mixtures thereof.

[0307] 25. The method according to any one of embodiments 13 to 24, wherein the method further comprises recovering the organic phase by distillation.

[0308] 26. The method according to any one of embodiments 1 and 12 to 25, wherein the method comprises:

[0309] The carbonyl group of 6-nitro-4H-1,4-benzoxazin-3-one (XI)

[0310]

[0311] Reduction in THF in the presence of a boron-THF complex to form 6-nitro-3,4-dihydro-2H-1,4-benzoxazine (IX).

[0312] ,

[0313] In the presence of a hydrogen source and a metal catalyst, 6-nitro-3,4-dihydro-2H-1,4-benzoxazine (IX) is reduced to form 3,4-dihydro-2H-1,4-benzoxazine-6-amine (X).

[0314] ,and

[0315] The primary amino group in 3,4-dihydro-2H-1,4-benzoxazine-6-amine (X) is converted to a hydroxyl group to form 3,4-dihydro-2H-1,4-benzoxazine-6-ol (I).

[0316] 27. The method according to embodiment 26, wherein the boron-THF complex is a dimethyl boron sulfide-THF complex.

[0317] 28. The method according to embodiment 26 or 27, further comprising extracting 6-nitro-3,4-dihydro-2H-1,4-benzoxazine (IX) from THF using a solvent selected from chloroform, dichloromethane, tert-butylmethyl ether, diethyl ether, ethyl acetate, 1,2-dimethoxyethane, pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, 1,4-dioxane, tetrahydrofuran, methyltetrahydrofuran, methanol, ethanol, or mixtures thereof.

[0318] 29. The method according to any one of embodiments 26 to 28, wherein the hydrogen source is selected from ammonium formate, hydrazine hydrate and / or H2.

[0319] 30. The method according to any one of embodiments 26 to 29, wherein the hydrogen source is H2 and the metal catalyst is Pd / C.

[0320] 31. The method according to any one of embodiments 26 to 30, wherein the conversion of the primary amino group to the hydroxyl group is carried out by diazotizing 3,4-dihydro-2H-1,4-benzoxazine-6-amine (X) under acidic conditions in the presence of at least one nitrosating agent to form a diazo compound (XXVII).

[0321] ,

[0322] Where X - It is a monovalent counterion and causes the diazo compound to decompose to form 3,4-dihydro-2H-1,4-benzoxazine-6-ol (I).

[0323] 32. The method according to embodiment 31, wherein the nitrosating agent is selected from sodium nitrite, potassium nitrite, nitrogen pentoxide, nitrososulfuric acid or a mixture thereof.

[0324] 33. The method according to embodiment 31 or 32, wherein the diazotization step is carried out in the presence of at least one inorganic or organic acid selected from hydrogen chloride, trifluoroacetic acid, sulfuric acid, sulfurous acid, carbonic acid, nitric acid, acetic acid, propionic acid, phosphoric acid, or mixtures thereof, in a solvent selected from 1,2-dimethoxyethane, pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, 1,4-dioxane, diethyl ether, tetrahydrofuran, methyltetrahydrofuran, n-pentanol, n-butanol, acetic acid, propionic acid, oxalic acid, malonic acid, sulfuric acid, phosphoric acid, isoamyl alcohol, tert-butanol, isopropanol, n-propanol, ethanol, methanol, glycol, hydrogen chloride, or mixtures thereof, or aqueous solutions thereof.

[0325] 34. The method according to any one of embodiments 31 to 33, wherein the diazotization step is carried out in the presence of hydrogen chloride, sulfuric acid, sulfurous acid, acetic acid or a mixture thereof, in a solvent selected from n-butanol, isopropanol, ethanol, methanol, acetic acid, propionic acid, oxalic acid, malonic acid, hydrogen chloride, sulfuric acid, phosphoric acid, or a mixture thereof, or an aqueous solution thereof.

[0326] 35. The method according to any one of embodiments 26 to 30, wherein the conversion of the primary amino group to the hydroxyl group is carried out by hydrolyzing 3,4-dihydro-2H-1,4-benzoxazine-6-amine (X) in a tubular reactor under acidic conditions.

[0327] 36. The method according to embodiment 35, wherein hydrolysis is carried out at a temperature of 220°C or lower and a pressure of 2-20 bar.

[0328] 37. The method according to embodiment 35 or 36, wherein the hydrolysis reaction is carried out in the presence of at least one catalyst selected from zirconium, cerium, phosphotungstic acid, phosphotomolybdic acid, silicotungstic acid, and silicotomolybdic acid.

[0329] 38. The method according to any one of embodiments 35 to 37, wherein the material of the tubular reactor in contact with the reaction includes cerium, zirconium, or a composite thereof.

[0330] 39. The method according to any one of embodiments 1 and 12 to 25, the method comprising:

[0331] The nitro group of 6-nitro-4H-1,4-benzoxazin-3-one (XI)

[0332]

[0333] Reduction is carried out in the presence of a hydrogen source and a metal catalyst to form 6-amino-4H-1,4-benzoxazin-3-one (XIV).

[0334] ,

[0335] The primary amino group in 6-amino-4H-1,4-benzoxazin-3-one (XIV) is converted to form 6-hydroxy-4H-1,4-benzoxazin-3-one (XV).

[0336] ,

[0337] The carbonyl group is reduced in THF in the presence of a boron-THF complex to form 3,4-dihydro-2H-1,4-benzoxazine-6-ol (I).

[0338] 40. The method according to embodiment 39, wherein the hydrogen source is selected from ammonium formate, hydrazine hydrate and / or H2.

[0339] 41. The method according to embodiment 39 or 40, wherein the hydrogen source is H2 and the metal catalyst is Pd / C.

[0340] 42. The method according to any one of embodiments 39 to 41, wherein the conversion of the primary amino group to the hydroxyl group is carried out by diazotizing 6-amino-4H-1,4-benzoxazin-3-one (XIV) under acidic conditions in the presence of at least one nitrosating agent to form a diazo compound (XXVIII).

[0341] ,

[0342] Where X - It is a monovalent counterion and causes the diazo compound to decompose to form 6-hydroxy-4H-1,4-benzoxazine-3-one (XV).

[0343] 43. The method according to embodiment 42, wherein the nitrosating agent is selected from sodium nitrite, potassium nitrite, nitrogen pentoxide, nitrososulfuric acid or a mixture thereof.

[0344] 44. The method according to embodiment 42 or 43, wherein the diazotization step is carried out in the presence of at least one inorganic or organic acid selected from hydrogen chloride, trifluoroacetic acid, sulfuric acid, sulfurous acid, carbonic acid, nitric acid, acetic acid, propionic acid, phosphoric acid, or mixtures thereof, in a solvent selected from 1,2-dimethoxyethane, pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, 1,4-dioxane, diethyl ether, tetrahydrofuran, methyltetrahydrofuran, n-pentanol, n-butanol, acetic acid, propionic acid, oxalic acid, malonic acid, sulfuric acid, phosphoric acid, isoamyl alcohol, tert-butanol, isopropanol, n-propanol, ethanol, methanol, glycol, hydrogen chloride, or mixtures thereof, or aqueous solutions thereof.

[0345] 45. The method according to any one of embodiments 42 to 44, wherein the diazotization step is carried out in the presence of hydrogen chloride, sulfuric acid, sulfurous acid, acetic acid or a mixture thereof, in a solvent selected from n-butanol, isopropanol, ethanol, methanol, acetic acid, propionic acid, oxalic acid, malonic acid, hydrogen chloride, sulfuric acid, phosphoric acid, or a mixture thereof, or an aqueous solution thereof.

[0346] 46. ​​The method according to any one of embodiments 39 to 41, wherein the conversion of the primary amino group to the hydroxyl group is carried out by hydrolyzing 6-amino-4H-1,4-benzoxazin-3-one (XIV) in a tubular reactor under acidic conditions.

[0347] 47. The method according to embodiment 46, wherein hydrolysis is carried out at a temperature of 220°C or lower and a pressure of 2-20 bar.

[0348] 48. The method according to embodiment 46 or 47, wherein the hydrolysis is carried out in the presence of at least one catalyst selected from zirconium, cerium, phosphotungstic acid, phosphotomolybdic acid, silicotungstic acid, and silicotomolybdic acid.

[0349] 49. The method according to any one of embodiments 46 to 48, wherein the material of the tubular reactor in contact with the reaction comprises cerium, zirconium, or a composite thereof.

[0350] 50. The method according to any one of embodiments 39 to 49, wherein the boron-THF complex is a dimethyl boron sulfide-THF complex.

[0351] 51. The method according to any one of embodiments 39 to 50, the method further comprising extracting 3,4-dihydro-2H-1,4-benzoxazine-6-ol (I) from THF using a solvent selected from chloroform, dichloromethane, tert-butyl methyl ether, diethyl ether, ethyl acetate, 1,2-dimethoxyethane, pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, 1,4-dioxane, tetrahydrofuran, methyltetrahydrofuran, methanol, ethanol, or mixtures thereof.

[0352] 52. The method according to any one of embodiments 1 and 12 to 25, wherein the method comprises:

[0353] The carbonyl group of 6-halo-4H-1,4-benzoxazin-3-one (XVIII)

[0354] Where X is fluorine, chlorine, or bromine.

[0355] Reduction in THF in the presence of a boron-THF complex is carried out to form 6-halo-3,4-dihydro-2H-1,4-benzoxazine (XVII).

[0356] Where X is fluorine, chlorine, or bromine, and

[0357] 6-Halo-3,4-dihydro-2H-1,4-benzoxazine (XVII) was hydrolyzed under alkaline conditions to form 3,4-dihydro-2H-1,4-benzoxazine-6-ol (I).

[0358] 53. The method according to embodiment 52, wherein the boron-THF complex is a dimethyl boron sulfide-THF complex.

[0359] 54. The method according to embodiment 52 or 53, the method further comprising extracting 6-halo-3,4-dihydro-2H-1,4-benzoxazine (XVII) from THF using a solvent selected from chloroform, dichloromethane, tert-butylmethyl ether, diethyl ether, ethyl acetate, 1,2-dimethoxyethane, pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, 1,4-dioxane, tetrahydrofuran, methyltetrahydrofuran, methanol, ethanol, or mixtures thereof.

[0360] 55. The method according to any one of embodiments 52 to 54, wherein hydrolysis is carried out in a tubular reactor at a temperature of 180°C or lower and a pressure of 2-20 bar in a solvent selected from sodium hydroxide, potassium hydroxide, potassium tert-butyrate, mixtures thereof, or aqueous solutions thereof.

[0361] 56. The method according to any one of embodiments 52 to 55, wherein the hydrolysis is carried out in the presence of at least one catalyst selected from zirconium, cerium, phosphotungstic acid, phosphomolybdic acid, silicotungstic acid, and silicotomolybdic acid.

[0362] 57. The method according to any one of embodiments 52 to 56, wherein the material of the tubular reactor in contact with the reaction comprises cerium, zirconium, or a composite thereof.

[0363] 58. The method according to any one of embodiments 1 and 12 to 25, the method comprising:

[0364] 6-Halo-4H-1,4-Benzoxazin-3-one (XVIII)

[0365] Where X is fluorine, chlorine, or bromine.

[0366] Hydrolysis is carried out under alkaline conditions to form 6-hydroxy-4H-1,4-benzoxazin-3-one (XV).

[0367] ,and

[0368] The carbonyl group of 6-hydroxy-4H-1,4-benzoxazine-3-one (XV) is reduced in THF in the presence of a boron-THF complex to form 3,4-dihydro-2H-1,4-benzoxazine-6-ol (I).

[0369] 59. The method according to embodiment 58, wherein hydrolysis is carried out in a tubular reactor at a temperature of 180°C or lower and a pressure of 2-20 bar in a solvent selected from sodium hydroxide, potassium hydroxide, potassium tert-butyrate, or mixtures thereof, or aqueous solutions thereof.

[0370] 60. The method according to embodiment 58 or 59, wherein the hydrolysis is carried out in the presence of at least one catalyst selected from zirconium, cerium, phosphotungstic acid, phosphotomolybdic acid, silicotungstic acid, and silicotomolybdic acid.

[0371] 61. The method according to any one of embodiments 58 to 60, wherein the material of the tubular reactor in contact with the reaction comprises cerium, zirconium, or a composite thereof.

[0372] 62. The method according to any one of embodiments 58 to 61, wherein the boron-THF complex is a dimethyl boron sulfide-THF complex.

[0373] 63. The method according to any one of embodiments 58 to 62, the method further comprising extracting 6-hydroxy-4H-1,4-benzoxazin-3-one (XV) from THF using a solvent selected from chloroform, dichloromethane, tert-butyl methyl ether, diethyl ether, ethyl acetate, 1,2-dimethoxyethane, pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, 1,4-dioxane, tetrahydrofuran, methyltetrahydrofuran, methanol, ethanol, or mixtures thereof.

[0374] 64. The method according to any one of embodiments 1 and 12-25, the method comprising:

[0375] The carbonyl group of 3-oxo-4H-1,4-benzoxazine-6-sulfonic acid (XXI)

[0376]

[0377] Reduction in THF in the presence of a boron-THF complex is carried out to form 3,4-dihydro-2H-1,4-benzoxazine-6-sulfonic acid (XX).

[0378] ,and

[0379] 3,4-Dihydro-2H-1,4-benzoxazine-6-sulfonic acid (XX) is hydrolyzed under alkaline conditions to form 3,4-dihydro-2H-1,4-benzoxazine-6-ol (I).

[0380] 65. The method according to embodiment 64, wherein the boron-THF complex is a dimethyl boron sulfide-THF complex.

[0381] 66. The method according to embodiment 64 or 65, the method further comprising extracting 3,4-dihydro-2H-1,4-benzoxazine-6-sulfonic acid (XX) from THF using a solvent selected from chloroform, dichloromethane, tert-butyl methyl ether, diethyl ether, ethyl acetate, 1,2-dimethoxyethane, pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, 1,4-dioxane, tetrahydrofuran, methyltetrahydrofuran, methanol, ethanol, or mixtures thereof.

[0382] 67. The method according to any one of embodiments 64 to 66, wherein hydrolysis under alkaline conditions is carried out by alkaline melting at a temperature of 300°C or higher.

[0383] 68. The method according to any one of embodiments 1 and 12-25, the method comprising:

[0384] 3-O-4H-1,4-Benzoxazine-6-sulfonic acid (XXI)

[0385]

[0386] Hydrolysis is carried out under alkaline conditions to form 6-hydroxy-4H-1,4-benzoxazin-3-one (XV).

[0387] ,and

[0388] The carbonyl group of 6-hydroxy-4H-1,4-benzoxazine-3-one (XV) is reduced in THF in the presence of a boron-THF complex to form 3,4-dihydro-2H-1,4-benzoxazine-6-ol (I).

[0389] 69. The method according to embodiment 68, wherein hydrolysis under alkaline conditions is carried out by alkaline melting at a temperature of 300°C or higher.

[0390] 70. The method according to embodiment 68 or 69, wherein the boron-THF complex is a dimethyl boron sulfide-THF complex.

[0391] 71. The method according to any one of embodiments 68 to 70, the method further comprising extracting 3,4-dihydro-2H-1,4-benzoxazine-6-amine (X) from THF using a solvent selected from chloroform, dichloromethane, tert-butyl methyl ether, diethyl ether, ethyl acetate, 1,2-dimethoxyethane, pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, 1,4-dioxane, tetrahydrofuran, methyltetrahydrofuran, methanol, ethanol, or mixtures thereof.

[0392] 72. The method according to any one of embodiments 1 to 11, wherein the method comprises:

[0393] 6-Nitro-3,4-dihydro-2H-1,4-benzoxazine (IX)

[0394] ,

[0395] Reduction was carried out in the presence of a hydrogen source and a metal catalyst to form 3,4-dihydro-2H-1,4-benzoxazine-6-amine (X).

[0396] ,and

[0397] The primary amino group in 3,4-dihydro-2H-1,4-benzoxazine-6-amine (X) is converted to a hydroxyl group to form 3,4-dihydro-2H-1,4-benzoxazine-6-ol (I).

[0398] 73. The method according to embodiment 72, wherein the hydrogen source is selected from ammonium formate, hydrazine hydrate and / or H2.

[0399] 74. The method according to embodiment 72 or 73, wherein the hydrogen source is H2 and the metal catalyst is Pd / C.

[0400] 75. The method according to any one of embodiments 72 to 74, wherein the conversion of the primary amino group to the hydroxyl group is carried out by diazotizing 3,4-dihydro-2H-1,4-benzoxazine-6-amine (X) under acidic conditions in the presence of at least one nitrosating agent to form a diazo compound (XXVII).

[0401] ,

[0402] Where X - It is a monovalent counterion and causes the diazo compound to decompose to form 3,4-dihydro-2H-1,4-benzoxazine-6-ol (I).

[0403] 76. The method according to embodiment 75, wherein the nitrosating agent is selected from sodium nitrite, potassium nitrite, nitrogen pentoxide, nitrososulfuric acid or a mixture thereof.

[0404] 77. The method according to embodiment 75 or 76, wherein the diazotization step is carried out in the presence of at least one inorganic or organic acid selected from hydrogen chloride, trifluoroacetic acid, sulfuric acid, sulfurous acid, carbonic acid, nitric acid, acetic acid, propionic acid, phosphoric acid, or mixtures thereof, in a solvent selected from 1,2-dimethoxyethane, pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, 1,4-dioxane, diethyl ether, tetrahydrofuran, methyltetrahydrofuran, n-pentanol, n-butanol, acetic acid, propionic acid, oxalic acid, malonic acid, sulfuric acid, phosphoric acid, isoamyl alcohol, tert-butanol, isopropanol, n-propanol, ethanol, methanol, glycol, hydrogen chloride, or mixtures thereof, or aqueous solutions thereof.

[0405] 78. The method according to any one of embodiments 75 to 77, wherein the diazotization step is carried out in the presence of hydrogen chloride, sulfuric acid, sulfurous acid, acetic acid or mixtures thereof, in a solvent selected from n-butanol, isopropanol, ethanol, methanol, acetic acid, propionic acid, oxalic acid, malonic acid, hydrogen chloride, sulfuric acid, phosphoric acid, mixtures thereof, or aqueous solutions thereof.

[0406] 79. The method according to any one of embodiments 72 to 74, wherein the conversion of the primary amino group to the hydroxyl group is carried out by hydrolyzing 3,4-dihydro-2H-1,4-benzoxazine-6-amine (X) in a tubular reactor under acidic conditions.

[0407] 80. The method according to embodiment 79, wherein hydrolysis is carried out at a temperature of 220°C or lower and a pressure of 2-20 bar.

[0408] 81. The method according to embodiment 79 or 80, wherein the hydrolysis is carried out in the presence of at least one catalyst selected from zirconium, cerium, phosphotungstic acid, phosphotomolybdic acid, silicotungstic acid, and silicotomolybdic acid.

[0409] 82. The method according to any one of embodiments 79 to 81, wherein the material of the tubular reactor in contact with the reaction comprises cerium, zirconium, or a composite thereof.

[0410] 83. The method according to any one of embodiments 1 to 11, the method further comprising using a hydroxymethanesulfonate to protect 6-nitro-3,4-dihydro-2H-1,4-benzoxazine (IX) to form a sulfomethyl-protected (6-nitro-2,3-dihydro-1,4-benzoxazine-4-yl)methanesulfonate (XII).

[0411] M + It is a monovalent ion.

[0412] (6-nitro-2,3-dihydro-1,4-benzoxazin-4-yl)methanesulfonate (XII) is reduced in the presence of a hydrogen source and a metal catalyst to form sulfomethyl-protected (6-amino-2,3-dihydro-1,4-benzoxazin-4-yl)methanesulfonate (XIII).

[0413] M + It is a monovalent ion, and

[0414] The primary amino group in (6-amino-2,3-dihydro-1,4-benzoxazine-4-yl)methanesulfonate (XIII) is converted to a hydroxyl group, and deprotection is achieved by removing the sulfomethyl group to form 3,4-dihydro-2H-1,4-benzoxazine-6-ol (I).

[0415] 84. The method according to embodiment 83, wherein the hydrogen source is selected from ammonium formate, hydrazine hydrate and / or H2.

[0416] 85. The method according to embodiment 83 or 84, wherein the hydrogen source is H2 and the metal catalyst is Pd / C.

[0417] 86. The method according to any one of embodiments 83 to 85, wherein the conversion of the primary amino group to a hydroxyl group and the deprotection are carried out by diazotizing (6-amino-2,3-dihydro-1,4-benzoxazin-4-yl)methanesulfonate (XIII) under acidic conditions in the presence of at least one nitrosating agent, and decomposing the diazo compound to form 3,4-dihydro-2H-1,4-benzoxazin-6-ol (I).

[0418] 87. The method according to embodiment 86, wherein the nitrosating agent is selected from sodium nitrite, potassium nitrite, nitrogen pentoxide, nitrososulfuric acid or a mixture thereof.

[0419] 88. The method according to embodiment 86 or 87, wherein the diazotization step is carried out in the presence of at least one inorganic or organic acid selected from hydrogen chloride, trifluoroacetic acid, sulfuric acid, sulfurous acid, carbonic acid, nitric acid, acetic acid, propionic acid, phosphoric acid, or mixtures thereof, in a solvent selected from 1,2-dimethoxyethane, pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, 1,4-dioxane, diethyl ether, tetrahydrofuran, methyltetrahydrofuran, n-pentanol, n-butanol, acetic acid, propionic acid, oxalic acid, malonic acid, sulfuric acid, phosphoric acid, isoamyl alcohol, tert-butanol, isopropanol, n-propanol, ethanol, methanol, glycol, hydrogen chloride, or mixtures thereof, or aqueous solutions thereof.

[0420] 89. The method according to any one of embodiments 86 to 88, wherein the diazotization step is carried out in the presence of hydrogen chloride, sulfuric acid, sulfurous acid, acetic acid or a mixture thereof, in a solvent selected from n-butanol, isopropanol, ethanol, methanol, acetic acid, propionic acid, oxalic acid, malonic acid, hydrogen chloride, sulfuric acid, phosphoric acid, or a mixture thereof, or an aqueous solution thereof.

[0421] 90. The method according to any one of embodiments 83 to 85, wherein the conversion of the primary amino group to a hydroxyl group and the deprotection by removing the sulfomethyl group are carried out by hydrolyzing (6-amino-2,3-dihydro-1,4-benzoxazine-4-yl)methanesulfonate (XIII) in a tubular reactor under acidic conditions.

[0422] 91. The method according to embodiment 90, wherein hydrolysis is carried out at a temperature of 220°C or lower and a pressure of 2-20 bar.

[0423] 92. The method according to embodiment 90 or 91, wherein the hydrolysis is carried out in the presence of at least one catalyst selected from zirconium, cerium, phosphotungstic acid, phosphotomolybdic acid, silicotungstic acid, and silicotomolybdic acid.

[0424] 93. The method according to any one of embodiments 90 to 92, wherein the material of the tubular reactor in contact with the reaction includes cerium, zirconium, or a composite thereof.

[0425] 94. The method according to any one of embodiments 1 to 11, wherein the method comprises:

[0426] 6-Halo-3,4-dihydro-2H-1,4-benzoxazine (XVII)

[0427] Where X is fluorine, chlorine, or bromine.

[0428] Hydrolysis is carried out under alkaline conditions to form 3,4-dihydro-2H-1,4-benzoxazine-6-ol (I).

[0429] 95. The method according to embodiment 94, wherein hydrolysis is carried out in a tubular reactor at a temperature of 180°C or lower and a pressure of 2-20 bar in a solvent selected from sodium hydroxide, potassium hydroxide, potassium tert-butyrate, or mixtures thereof, or aqueous solutions thereof.

[0430] 96. The method according to embodiment 94 or 95, wherein the hydrolysis is carried out in the presence of at least one catalyst selected from zirconium, cerium, phosphotungstic acid, phosphotomolybdic acid, silicotungstic acid, and silicotomolybdic acid.

[0431] 97. The method according to any one of embodiments 94 to 96, wherein the material of the tubular reactor in contact with the reaction comprises cerium, zirconium, or a composite thereof.

[0432] 98. The method according to any one of embodiments 1 to 11, wherein the method comprises:

[0433] 3,4-Dihydro-2H-1,4-benzoxazine-6-sulfonic acid (XX)

[0434]

[0435] Hydrolysis is carried out under alkaline conditions to form 3,4-dihydro-2H-1,4-benzoxazine-6-ol (I).

[0436] 99. The method according to embodiment 98, wherein hydrolysis under alkaline conditions is carried out by alkaline melting at a temperature of 300°C or above.

[0437] 100. The method according to implementation scheme 1, wherein the method comprises:

[0438] The primary amino group of 6-amino-4H-1,4-benzoxazin-3-one (XIV)

[0439]

[0440] The conversion was carried out to form 6-hydroxy-4H-1,4-benzoxazin-3-one (XV).

[0441] ,and

[0442] The carbonyl group is reduced in THF in the presence of a boron-THF complex to form 3,4-dihydro-2H-1,4-benzoxazine-6-ol (I).

[0443] 101. The method according to embodiment 100, wherein the conversion of a primary amino group to a hydroxyl group is carried out by diazotizing 6-amino-4H-1,4-benzoxazin-3-one (XIV) under acidic conditions in the presence of at least one nitrosating agent to form a diazo compound (XXVIII).

[0444] ,

[0445] Where X - It is a monovalent counterion and causes the diazo compound to decompose to form 6-hydroxy-4H-1,4-benzoxazine-3-one (XV).

[0446] 102. The method according to embodiment 101, wherein the nitrosating agent is selected from sodium nitrite, potassium nitrite, nitrogen pentoxide, nitrososulfuric acid or a mixture thereof.

[0447] 103. The method according to embodiment 101 or 102, wherein the diazotization step is carried out in the presence of at least one inorganic or organic acid selected from hydrogen chloride, trifluoroacetic acid, sulfuric acid, sulfurous acid, carbonic acid, nitric acid, acetic acid, propionic acid, phosphoric acid, or mixtures thereof, in a solvent selected from 1,2-dimethoxyethane, pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, 1,4-dioxane, diethyl ether, tetrahydrofuran, methyltetrahydrofuran, n-pentanol, n-butanol, acetic acid, propionic acid, oxalic acid, malonic acid, sulfuric acid, phosphoric acid, isoamyl alcohol, tert-butanol, isopropanol, n-propanol, ethanol, methanol, glycol, hydrogen chloride, or mixtures thereof, or aqueous solutions thereof.

[0448] 104. The method according to any one of embodiments 101 to 103, wherein the diazotization step is carried out in the presence of hydrogen chloride, sulfuric acid, sulfurous acid, acetic acid or a mixture thereof, in a solvent selected from n-butanol, isopropanol, ethanol, methanol, acetic acid, propionic acid, oxalic acid, malonic acid, hydrogen chloride, sulfuric acid, phosphoric acid, or a mixture thereof, or an aqueous solution thereof.

[0449] 105. The method according to embodiment 100, wherein the conversion of the primary amino group to the hydroxyl group is carried out by hydrolyzing 6-amino-4H-1,4-benzoxazin-3-one (XIV) in a tubular reactor under acidic conditions.

[0450] 106. The method according to implementation plan 105, wherein hydrolysis is carried out at a temperature of 220°C or lower and a pressure of 2-20 bar.

[0451] 107. The method according to embodiment 105 or 106, wherein the hydrolysis is carried out in the presence of at least one catalyst selected from zirconium, cerium, phosphotungstic acid, phosphomolybdic acid, silicotungstic acid, and silicotomolybdic acid.

[0452] 108. The method according to any one of embodiments 105 to 107, wherein the material of the tubular reactor in contact with the reaction comprises cerium, zirconium, or a composite thereof.

[0453] 109. The method according to any one of embodiments 100 to 108, wherein the boron-THF complex is a dimethyl boron sulfide-THF complex.

[0454] 110. The method according to any one of embodiments 100 to 109, the method further comprising extracting 3,4-dihydro-2H-1,4-benzoxazine-6-ol (I) from THF using a solvent selected from chloroform, dichloromethane, tert-butyl methyl ether, diethyl ether, ethyl acetate, 1,2-dimethoxyethane, pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, 1,4-dioxane, tetrahydrofuran, methyltetrahydrofuran, methanol, ethanol, or mixtures thereof.

[0455] 111. The method according to implementation scheme 1, wherein the method includes:

[0456] The carbonyl group of 6-amino-4H-1,4-benzoxazin-3-one (XIV)

[0457]

[0458] Reduction in THF in the presence of a boron-THF complex is carried out to form 3,4-dihydro-2H-1,4-benzoxazine-6-amine (X).

[0459] ,and

[0460] The primary amino group of 3,4-dihydro-2H-1,4-benzoxazine-6-amine (X) is converted to form 3,4-dihydro-2H-1,4-benzoxazine-6-ol (I).

[0461] 112. The method according to embodiment 111, wherein the boron-THF complex is a dimethyl boron sulfide-THF complex.

[0462] 113. The method according to embodiment 111 or 112, further comprising extracting 3,4-dihydro-2H-1,4-benzoxazine-6-ol (I) from THF using a solvent selected from chloroform, dichloromethane, tert-butyl methyl ether, diethyl ether, ethyl acetate, 1,2-dimethoxyethane, pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, 1,4-dioxane, tetrahydrofuran, methyltetrahydrofuran, methanol, ethanol, or mixtures thereof.

[0463] 114. The method according to any one of embodiments 111 to 113, wherein the conversion of the primary amino group to the hydroxyl group is carried out by diazotizing 3,4-dihydro-2H-1,4-benzoxazine-6-amine (X) under acidic conditions in the presence of at least one nitrosating agent to form a diazo compound (XXVII).

[0464] ,

[0465] Where X - It is a monovalent counterion and causes the diazo compound to decompose to form 3,4-dihydro-2H-1,4-benzoxazine-6-ol (I).

[0466] 115. The method according to embodiment 114, wherein the nitrosating agent is selected from sodium nitrite, potassium nitrite, nitrogen pentoxide, nitrososulfuric acid or a mixture thereof.

[0467] 116. The method according to embodiment 114 or 115, wherein the diazotization step is carried out in the presence of at least one inorganic or organic acid selected from hydrogen chloride, trifluoroacetic acid, sulfuric acid, sulfurous acid, carbonic acid, nitric acid, acetic acid, propionic acid, phosphoric acid, or mixtures thereof, in a solvent selected from 1,2-dimethoxyethane, pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, 1,4-dioxane, diethyl ether, tetrahydrofuran, methyltetrahydrofuran, n-pentanol, n-butanol, acetic acid, propionic acid, oxalic acid, malonic acid, sulfuric acid, phosphoric acid, isoamyl alcohol, tert-butanol, isopropanol, n-propanol, ethanol, methanol, glycol, hydrogen chloride, or mixtures thereof, or aqueous solutions thereof.

[0468] 117. The method according to any one of embodiments 114 to 116, wherein the diazotization step is carried out in the presence of hydrogen chloride, sulfuric acid, sulfurous acid, acetic acid or a mixture thereof, in a solvent selected from n-butanol, isopropanol, ethanol, methanol, acetic acid, propionic acid, oxalic acid, malonic acid, hydrogen chloride, sulfuric acid, phosphoric acid, or a mixture thereof, or an aqueous solution thereof.

[0469] 118. The method according to any one of embodiments 111 to 113, wherein the conversion of the primary amino group to the hydroxyl group is carried out by hydrolyzing 3,4-dihydro-2H-1,4-benzoxazine-6-amine (X) in a tubular reactor under acidic conditions.

[0470] 119. The method according to embodiment 118, wherein the hydrolysis reaction is carried out at a temperature of 220°C or lower and a pressure of 2-20 bar.

[0471] 120. The method according to embodiment 118 or 119, wherein the hydrolysis is carried out in the presence of at least one catalyst selected from zirconium, cerium, phosphotungstic acid, phosphomolybdic acid, silicotungstic acid, and silicotomolybdic acid.

[0472] 121. The method according to any one of embodiments 118 to 120, wherein the material of the tubular reactor in contact with the reaction comprises cerium, zirconium, or a composite thereof.

[0473] 122. The method according to any one of embodiments 100 to 121, the method further comprising providing 6-amino-4H-1,4-benzoxazin-3-one (XIV) by reacting 2,4-dichloroaniline (XXIX) with 2-hydroxyacetamide.

[0474] .

[0475] 123. The method according to embodiment 122, wherein the reaction is carried out in a two-phase system at a temperature in the range of 0-15°C, wherein the organic phase is selected from chloroform, dichloromethane, dimethylformamide, dimethylacetamide, NMP (N-methylpyrrolidone), acetonitrile, 1,2-dimethoxyethane, ethyl acetate, pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, 1,4-dioxane, diethyl ether, tetrahydrofuran, methyltetrahydrofuran, or mixtures thereof, and wherein the aqueous phase contains a base.

[0476] 124. The method according to embodiment 123, wherein the organic phase is selected from chloroform, dichloromethane, dimethylformamide, dimethylacetamide, ethyl acetate, acetonitrile, toluene, or mixtures thereof.

[0477] 125. The method according to embodiment 124, wherein the organic phase is selected from chloroform, dichloromethane, dimethylformamide, dimethylacetamide, or mixtures thereof.

[0478] 126. The method according to any one of embodiments 123 to 125, wherein the base is selected from sodium hydroxide, potassium hydroxide, sodium bicarbonate, calcium carbonate, sodium carbonate, potassium carbonate, sodium acetate, DBU, DBN, Huenig base, ammonium sulfate, sodium bicarbonate and potassium bicarbonate.

[0479] 127. According to the method of embodiment 126, the base is selected from sodium hydroxide, potassium hydroxide, potassium carbonate, sodium bicarbonate and sodium carbonate.

[0480] 128. The method according to any one of embodiments 123 to 127, wherein the reaction is carried out using at least one phase transfer catalyst.

[0481] 129. The method according to embodiment 128, wherein the at least one phase transfer catalyst is at least one benzyltrialkylammonium salt.

[0482] 130. The method according to embodiment 129, wherein the at least one phase transfer catalyst is selected from the chloride, bromide or sulfate of benzyltrimethylammonium, benzyltriethylammonium, benzyltripropylammonium, benzyltributylammonium, or a mixture thereof, particularly wherein the phase transfer catalyst is benzyltributylammonium chloride.

[0483] 131. The method according to implementation scheme 1, wherein the method comprises:

[0484] The primary amino group of 3,4-dihydro-2H-1,4-benzoxazine-6-amine (X)

[0485]

[0486] It is converted to a hydroxyl group to form 3,4-dihydro-2H-1,4-benzoxazine-6-ol (I).

[0487] 132. According to the method of embodiment 131, wherein the conversion of the primary amino group to the hydroxyl group is carried out by diazotizing 3,4-dihydro-2H-1,4-benzoxazine-6-amine (X) under acidic conditions in the presence of at least one nitrosating agent to form a diazo compound (XXVII).

[0488] ,

[0489] Where X - It is a monovalent counterion and causes the diazo compound to decompose to form 3,4-dihydro-2H-1,4-benzoxazine-6-ol (I).

[0490] 133. The method according to embodiment 132, wherein the nitrosating agent is selected from sodium nitrite, potassium nitrite, nitrogen pentoxide, nitrososulfuric acid or a mixture thereof.

[0491] 134. The method according to embodiment 132 or 133, wherein the diazotization step is carried out in the presence of at least one inorganic or organic acid selected from hydrogen chloride, trifluoroacetic acid, sulfuric acid, sulfurous acid, carbonic acid, nitric acid, acetic acid, propionic acid, phosphoric acid, or mixtures thereof, in a solvent selected from 1,2-dimethoxyethane, pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, 1,4-dioxane, diethyl ether, tetrahydrofuran, methyltetrahydrofuran, n-pentanol, n-butanol, acetic acid, propionic acid, oxalic acid, malonic acid, sulfuric acid, phosphoric acid, isoamyl alcohol, tert-butanol, isopropanol, n-propanol, ethanol, methanol, glycol, hydrogen chloride, or mixtures thereof, or aqueous solutions thereof.

[0492] 135. The method according to any one of embodiments 132 to 134, wherein the diazotization step is carried out in the presence of hydrogen chloride, sulfuric acid, sulfurous acid, acetic acid or a mixture thereof, in a solvent selected from n-butanol, isopropanol, ethanol, methanol, acetic acid, propionic acid, oxalic acid, malonic acid, hydrogen chloride, sulfuric acid, phosphoric acid, or a mixture thereof, or an aqueous solution thereof.

[0493] 136. The method according to embodiment 131, wherein the conversion of the primary amino group to the hydroxyl group is carried out by hydrolyzing 3,4-dihydro-2H-1,4-benzoxazine-6-amine (X) in a tubular reactor under acidic conditions.

[0494] 137. The method according to embodiment 136, wherein hydrolysis is carried out at a temperature of 220°C or lower and a pressure of 2-20 bar.

[0495] 138. The method according to embodiment 136 or 137, wherein the hydrolysis is carried out in the presence of at least one catalyst selected from zirconium, cerium, phosphotungstic acid, phosphomolybdic acid, silicotungstic acid, and silicotomolybdic acid.

[0496] 139. The method according to any one of embodiments 136 to 138, wherein the material of the tubular reactor in contact with the reaction comprises cerium, zirconium, or a composite thereof.

[0497] 140. The method according to any one of embodiments 1 to 25, wherein the halogen is bromine.

[0498] 141. The method according to any one of embodiments 52 to 63 and 94 to 97, wherein X is bromine.

[0499] 142. A method for preparing 2-amino-4-bromophenol, or a salt thereof, or a mixture thereof, said method comprising:

[0500] 4-Bromophenol reacts in the presence of nitric acid to form 2-nitro-4-bromophenol, and

[0501] The nitro group of 2-nitro-4-bromophenol is reduced in the presence of a hydrogen source and a metal catalyst to form 2-amino-4-bromophenol.

[0502] 143. The method according to embodiment 142, wherein the reaction of 4-bromophenol in the presence of nitric acid is carried out at a temperature in the range of 80-120°C.

[0503] 144. The method according to embodiment 142 or 143, the method further comprising separating 2-nitro-4-bromo-phenol.

[0504] 145. The method according to any one of embodiments 142 to 144, wherein separating 2-nitro-4-bromophenol comprises: recrystallizing 2-nitro-4-bromophenol from an alcohol or an aqueous solution of alcohol.

[0505] 146. The method according to embodiment 145, wherein 2-nitro-4-bromophenol is recrystallized from n-pentanol, isoamyl alcohol, tert-butanol, isopropanol, n-propanol, ethanol, methanol, mixtures thereof or aqueous solutions thereof.

[0506] 147. The method according to embodiment 146, wherein 2-nitro-4-bromo-phenol is recrystallized from methanol.

[0507] 148. The method according to any one of embodiments 142 to 147, wherein the hydrogen source is selected from ammonium formate, hydrazine hydrate and / or H2.

[0508] 149. The method according to any one of embodiments 142 to 148, wherein the hydrogen source is H2 and the metal catalyst is Pd / C.

[0509] 150. The method according to any one of embodiments 142 to 148, wherein the method further comprises:

[0510] (a) Reaction of 2-amino-4-bromophenol with 2-chloroacetyl chloride to form 6-bromo-3,4-dihydro-2H-1,4-benzoxazine-3-one

[0511] (b) Reduction of the carbonyl group of 6-bromo-4H-1,4-benzoxazine-3-one in THF in the presence of a boron-THF complex to form 6-bromo-3,4-dihydro-2H-1,4-benzoxazine, and

[0512] (c) Hydrolyze 6-bromo-3,4-dihydro-2H-1,4-benzoxazine under alkaline conditions to form 3,4-dihydro-2H-1,4-benzoxazine-6-ol (I).

[0513] 151. Use of 2-amino-4-bromo-phenol in the preparation of 3,4-dihydro-2H-1,4-benzoxazine-6-ol (I).

Claims

1. A method for preparing 3,4-dihydro-2H-1,4-benzoxazine-6-ol (I), or a salt thereof, or a mixture thereof, ， The method includes: (a) Provide a benzoxazine according to formula (XXIV) or a benzoxazine-3-one according to formula (XXV): Ra is selected from halogen, amino, nitro or sulfonic acid groups, and (b) Convert Ra to hydroxyl groups. The method further includes reducing the carbonyl group if the benzoxazine compound provided in step (a) is (XXV), and wherein the reduction is performed before or after the conversion of Ra to a hydroxyl group.

2. The method according to claim 1, wherein step (a) comprises: 2-Aminophenol (XXVI), in which Rb is a halogen, nitro, or sulfonic acid group, is reacted with dibromoethane in a solvent to form 3,4-dihydro-2H-1,4-benzoxazine (XXIVb), in which Rb is a halogen, nitro, or sulfonic acid group. 。 3. The method according to claim 1, wherein step (a) comprises: 2-Aminophenol (XXVI), in which Rb is a halogen, nitro, or sulfonic acid group, is reacted with 2-chloroacetyl chloride to form 3,4-dihydro-2H-1,4-benzoxazin-3-one (XXVb), in which Rb is a halogen, nitro, or sulfonic acid group. 。 4. The method according to claim 1 or 3, wherein the method comprises: In THF, the carbonyl group of 6-nitro-4H-1,4-benzoxazin-3-one (XI) is reduced in the presence of a boron-THF complex. ， To form 6-nitro-3,4-dihydro-2H-1,4-benzoxazine (IX). ， 6-nitro-3,4-dihydro-2H-1,4-benzoxazine (IX) was reduced in the presence of a hydrogen source and a metal catalyst to form 3,4-dihydro-2H-1,4-benzoxazine-6-amine (X). ,and The primary amino group in 3,4-dihydro-2H-1,4-benzoxazine-6-amine (X) is converted to a hydroxyl group to form 3,4-dihydro-2H-1,4-benzoxazine-6-ol (I).

5. The method according to claim 1 or 3, wherein the method comprises: The nitro group of 6-nitro-4H-1,4-benzoxazin-3-one (XI) is reduced in the presence of a hydrogen source and a metal catalyst. ， To form 6-amino-4H-1,4-benzoxazin-3-one (XIV) ， The primary amino group in 6-amino-4H-1,4-benzoxazin-3-one (XIV) is converted to form 6-hydroxy-4H-1,4-benzoxazin-3-one (XV). ， In THF, the carbonyl group is reduced in the presence of a boron-THF complex to form 3,4-dihydro-2H-1,4-benzoxazine-6-ol (I).

6. The method according to claim 1 or 3, wherein the method comprises: In THF, the carbonyl group of 6-halo-4H-1,4-benzoxazin-3-one (XVIII) is reduced in the presence of a boron-THF complex. Where X is fluorine, chlorine, or bromine. To form 6-halo-3,4-dihydro-2H-1,4-benzoxazine (XVII) Where X is fluorine, chlorine, or bromine, and 6-Halo-3,4-dihydro-2H-1,4-benzoxazine (XVII) is hydrolyzed under alkaline conditions to form 3,4-dihydro-2H-1,4-benzoxazine-6-ol (I).

7. The method according to claim 1 or 3, wherein the method comprises: Hydrolysis of 6-halo-4H-1,4-benzoxazin-3-one (XVIII) under alkaline conditions Where X is fluorine, chlorine, or bromine. To form 6-hydroxy-4H-1,4-benzoxazin-3-one (XV) ,and In THF, the carbonyl group of 6-hydroxy-4H-1,4-benzoxazin-3-one (XV) is reduced in the presence of a boron-THF complex to form 3,4-dihydro-2H-1,4-benzoxazin-6-ol (I).

8. The method according to claim 1 or 3, wherein the method comprises: In THF, the carbonyl group of 3-oxo-4H-1,4-benzoxazine-6-sulfonic acid (XXI) is reduced in the presence of a boron-THF complex. ， To form 3,4-dihydro-2H-1,4-benzoxazine-6-sulfonic acid (XX). ,and 3,4-Dihydro-2H-1,4-benzoxazine-6-sulfonic acid (XX) is hydrolyzed under alkaline conditions to form 3,4-dihydro-2H-1,4-benzoxazine-6-ol (I).

9. The method according to claim 1 or 3, wherein the method comprises: 3-oxo-4H-1,4-benzoxazine-6-sulfonic acid (XXI) is hydrolyzed under alkaline conditions. ， To form 6-hydroxy-4H-1,4-benzoxazin-3-one (XV) ,and In THF, the carbonyl group of 6-hydroxy-4H-1,4-benzoxazin-3-one (XV) is reduced in the presence of a boron-THF complex to form 3,4-dihydro-2H-1,4-benzoxazin-6-ol (I).

10. The method according to claim 1 or 2, wherein the method comprises: Reduction of 6-nitro-3,4-dihydro-2H-1,4-benzoxazine (IX) in the presence of a hydrogen source and a metal catalyst. ， To form 3,4-dihydro-2H-1,4-benzoxazine-6-amine (X) ,and The primary amino group in 3,4-dihydro-2H-1,4-benzoxazine-6-amine (X) is converted to a hydroxyl group to form 3,4-dihydro-2H-1,4-benzoxazine-6-ol (I).

11. The method according to claim 1 or 2, further comprising protecting 6-nitro-3,4-dihydro-2H-1,4-benzoxazine (IX) with hydroxymethanesulfonate to form sulfomethyl-protected (6-nitro-2,3-dihydro-1,4-benzoxazine-4-yl)methanesulfonate (XII). M + It is a monovalent ion. (6-nitro-2,3-dihydro-1,4-benzoxazin-4-yl)methanesulfonate (XII) is reduced in the presence of a hydrogen source and a metal catalyst to form sulfomethyl-protected (6-amino-2,3-dihydro-1,4-benzoxazin-4-yl)methanesulfonate (XIII). M + It is a monovalent ion, and The primary amino group in (6-amino-2,3-dihydro-1,4-benzoxazin-4-yl)methanesulfonate (XIII) is converted to a hydroxyl group, and deprotection is achieved by removing the sulfomethyl group to form 3,4-dihydro-2H-1,4-benzoxazin-6-ol (I).

12. The method according to claim 1 or 2, wherein the method comprises Hydrolysis of 6-halo-3,4-dihydro-2H-1,4-benzoxazine (XVII) under alkaline conditions Where X is fluorine, chlorine, or bromine. To form 3,4-dihydro-2H-1,4-benzoxazine-6-ol (I).

13. The method according to claim 1, wherein the method comprises: The primary amino group of 6-amino-4H-1,4-benzoxazin-3-one (XIV) was converted. To form 6-hydroxy-4H-1,4-benzoxazin-3-one (XV) ,and In THF, the carbonyl group is reduced in the presence of a boron-THF complex to form 3,4-dihydro-2H-1,4-benzoxazine-6-ol (I).

14. The method according to claim 1, wherein the method comprises: In THF, the carbonyl group of 6-amino-4H-1,4-benzoxazin-3-one (XIV) is reduced in the presence of a boron-THF complex. To form 3,4-dihydro-2H-1,4-benzoxazine-6-amine (X) ,and The primary amino group of 3,4-dihydro-2H-1,4-benzoxazine-6-amine (X) is converted to form 3,4-dihydro-2H-1,4-benzoxazine-6-ol (I).

15. The method according to claim 13 or 14, further comprising providing 6-amino-4H-1,4-benzoxazin-3-one (XIV) by reacting 2,4-dichloroaniline (XXIX) with 2-hydroxyacetamide. 。

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