Novel and cost-effective stackable synthesis of 2-methoxymethyl-p-phenylenediamine

Abstract

The present invention relates to a process for the preparation of 2-methoxymethyl-p-phenylenediamine.

Description

Technical Field

[0001] This invention relates to a novel, cost-effective, and environmentally friendly telescoping synthesis of 2-methoxymethyl-p-phenylenediamine or a salt thereof (also known as the abbreviation MBB (COLIPA n° A160)) according to formula (I). This compound is known in the industry as a low-allergenic primary dye precursor for use in oxidative hair dyeing compositions (as an alternative to conventional p-phenylenediamine or p-toluenediamine dye precursors).

[0002] Background Technology

[0003] p-Phenylenediamine derivatives are key precursors for oxidative hair dyeing. They are commonly used to produce darker shades. p-Phenylenediamine derivatives have been used in hair dyeing for decades. Among p-Phenylenediamine derivatives, a particularly advantageous candidate has been identified: 2-methoxymethyl-p-phenylenediamine. This dye precursor is particularly advantageous because it is typically characterized by a lower sensitizing potential than conventional p-phenylenediamine or p-toluenediamine dye precursors.

[0004] In the past, the industry has disclosed different synthetic routes for the production of 2-methoxymethyl-p-phenylenediamine (I) or its salts.

[0005] For example, US2003 / 0041392A1 discloses a method for preparing 2-methoxymethyl-p-phenylenediamine (I) via a Smiles rearrangement in one of the intermediate steps. Disadvantages of this method include harsh reaction conditions and the use of reactants such as trioxane (formaldehyde trimer), which may pose health hazards to workers on the production line. Furthermore, this method generates large quantities of waste solvent solutions containing sulfuric acid or toluene. These solutions cannot be recycled for use in this method and must be discarded. The yield according to the method in US2003 / 0041392A1 is approximately 50% of the theoretical yield.

[0006] Another possible synthetic route has been disclosed in WO2012 / 044758A1. This route involves a multi-step combination that begins with 2-chlorobenzyl chloride and methanol to form a methoxymethyl intermediate. Nitration occurs at the 4-position and activates the chloride as a leaving group. Substitution of the chloride with an amino donor (preferably benzylamine) requires a phase-transfer catalyst to obtain the aniline intermediate. Finally, hydrogenation leads to the desired 2-methoxymethyl-p-phenylenediamine. Disadvantages of this method include harsh nitrosation conditions (using a mixture of sulfuric acid and fuming nitric acid) and potentially relatively low overall yields. Furthermore, the carbon balance is insufficient because the reactant benzylamine contributes only nitrogen atoms, while the rest of the molecule is discarded as a toluene-containing mixture. A particular drawback of this method is that the resulting product contains amorphous material, which can lead to undesirable side effects such as surface oxidation. Surface oxidation, in turn, can negatively affect the appearance of powder materials, which can be a success criterion for cosmetic applications / formulations.

[0007] Another method described in patent document (EP4013739) utilizes the radical alkylation of p-benzoquinone, followed by conversion to the corresponding bisoxime and final hydrogenation. The challenge in this method lies in the complete separation of p-phenylenediamine from the desired 2-methoxymethyl-p-phenylenediamine (which is obtained as a byproduct).

[0008] Other synthetic methods (EP3215483, EP3215484, EP3215482, CN104744272A) describe the use of azo intermediates to introduce a second nitrogen atom into the methoxy-methyl-aniline precursor. However, the methods described therein suffer from the formation of numerous byproducts during azo coupling and the observed difficulty in easily separating the azo cleavage products after the reduction of the azo compound, making the isolation of pure cosmetic-grade 2-methoxymethyl-p-phenylenediamine challenging. Particularly in CN104744272A, the disadvantage of using a 2-methoxy-methylaniline intermediate derivative without protecting the free amino group for diazotization with a suitable reaction partner to introduce a second nitrogen atom at the para position is the generation of multiple byproducts, as the unprotected amino group remains active and is a competing element during the diazotization reaction conditions, significantly negatively impacting the purity of the para-coupling. Removing these byproducts is extremely challenging because they also tend to rearrange in the case of triazines (or alternatively, diazoamines). Furthermore, the described method of separating the thermosensitive 2-methoxymethyl-p-phenylenediamine (I) via steam distillation after the azo cleavage of the azo dye intermediate is energy-intensive and carries the risk of generating sensitive byproducts. PTC application WO2022 / 090235 discusses in detail the challenges of separating 2-methoxymethyl-p-phenylenediamine (I) from any final step of any possible and published preparation method while obtaining a pure, cosmetic-grade compound.

[0009] Therefore, there remains a need for a method for preparing 2-methoxymethyl-2-phenylenediamine (I), its salts, or mixtures thereof that is particularly cost-effective compared to other published and commercialized methods. Given the growing global demand, the cost-effective production of 2-methoxymethyl-2-phenylenediamine (I) will be highly desirable. Such a manufacturing method should also be able to 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 utilize chemical reactions that are more standardized than those considered state-of-the-art known methods. Finally, considering the growing global ecological demands and ongoing efforts to advance green chemistry (e.g., ESG projects launched by the United Nations), manufacturers should be able to produce specialty chemicals under mild reaction conditions, involving moderate temperatures, and with limited use of process aids and heavy metal catalysts. This may involve preparation methods such as electrolysis for reduction / hydrogenation reactions, the use of eco-acceptable solvents (water, alcohols, etc.), preferably operating the reaction at ambient temperatures, and generating minimal non-recyclable waste solvents. Therefore, green chemistry is becoming increasingly important, especially in an era where carbon footprint monitoring has become a measurable data point and the use of energy from fossil fuels should be minimized. Such approaches may represent a significant competitive advantage over other synthetic manufacturing routes.

[0010] It has now been surprisingly discovered that 2-methoxymethyl-2-phenylenediamine (I) can be prepared via an readily available and commercially attractive four-step synthesis involving the careful selection of a novel azo intermediate previously unknown in the literature, followed by a low-cost and environmentally friendly method of cleaving this azo intermediate. This can involve formate, metal catalysts, typical hydrogen sources such as hydrogen or hydrazine, or an electrochemical hydrogenation method via electrolysis, yielding a 1:1 mixture of cleavage products, one of which is the desired 2-methoxymethyl-2-phenylenediamine (I). These cleavage products are readily separated using standard methods such as liquid-phase extraction due to the difference in polarity between the two cleavage products. The key elements of this preparation strategy (also characterized by the formation of an azo intermediate equivalent to CN104744272A) are the novel aniline and the diazo intermediate (with a sulfomethyl protecting group as described herein). The strategy described herein ultimately solves all the problems associated with the concept outlined in CN104744272A as described above. Summary of the Invention

[0011] The subject of this invention is a method for preparing 2-methoxymethyl-p-phenylenediamine (I), or a salt thereof, or a mixture thereof, as defined in claim 1. The dependent claims relate to particular embodiments thereof. Another subject of this invention is a novel intermediate as defined in claim 15.

[0012] The method for preparing 2-methoxymethyl-p-phenylenediamine (I), its salts, or mixtures thereof according to the present invention

[0013]

[0014] The method includes the following steps:

[0015] (a) Provides 2-(methoxymethyl)aniline (IV),

[0016]

[0017] (b) Protecting the free amino group of 2-(methoxymethyl)aniline (IV) by reacting with hydroxymethanesulfonic acid or a salt thereof to form [2-methoxymethyl-aniline]methanesulfonate (V), wherein M + It is a monovalent ion.

[0018]

[0019] (c) In the presence of a nitrosating agent, a primary aromatic amine (VI) having the formula H2N-R1 (where R1 is the aromatic moiety) is diazotized, and the reaction product is coupled with [2-methoxymethyl-aniline]methanesulfonate (V) to form 4-azo-2-methoxymethyl-(sulfomethyl)aniline (VII), wherein M + It is a monovalent ion.

[0020]

[0021] (d) Deprotecting 4-azo-2-methoxymethyl-(sulfonyl)aniline (VII) to form 4-azo-2-(methoxymethyl)aniline (VIII),

[0022]

[0023] (e) 4-Azo-2-(methoxymethyl)aniline (VIII) is cleaved under reducing conditions to give 2-methoxymethyl-p-phenylenediamine (I) and aromatic amine (VI).

[0024] The method according to the present invention is illustrated by the following reaction scheme:

[0025] 2-(methoxymethyl)aniline (IV) is provided, and the free amino group of 2-(methoxymethyl)aniline (IV) is protected with hydroxymethanesulfonic acid or a salt thereof to form the corresponding [2-methoxymethyl-aniline]methanesulfonate (V):

[0026]

[0027] [2-Methoxymethyl-aniline]methanesulfonate (V) is azo coupled with a suitable aromatic amine of general formula (VI) (as a nitrogen donor) to form the azo intermediate 4-azo-2-methoxymethyl-(sulfomethyl)aniline (VII), which is separated by precipitation:

[0028]

[0029] The sulfonyl protecting group of the azo intermediate 4-azo-2-methoxymethyl-(sulfonylmethyl)aniline (VII) was cleaved in an alkaline medium to give the key azo intermediate 4-azo-2-(methoxymethyl)aniline (VIII) as the free acid:

[0030]

[0031] The azo free acid intermediate (VIII) is reductively cleaved by standard hydrogenation to yield 2-methoxymethyl-p-phenylenediamine (I), which can be readily separated from the aromatic nitrogen support compound of general formula (VI):

[0032]

[0033] The aromatic amine (VI) can then be reused, and for example, recycled for the diazotization process.

[0034] The exact properties of the aromatic amine (VI) are not particularly critical, and a wide variety of compounds can be used as the aromatic amine (VI). However, it is preferred that the polarity of 2-methoxymethyl-p-phenylenediamine (I) is significantly different from that of the aromatic amine (VI), because such a polarity difference is beneficial for separating 2-methoxymethyl-p-phenylenediamine (I) and the aromatic amine (VI) in the final step of the method according to the invention. The polarity of 2-methoxymethyl-p-phenylenediamine (I), expressed as a partition coefficient LogPow, is -0.49 (determined at pH 7 according to EU method A.8). The partition coefficient LogPow of the aromatic amine (VI) (as determined by EU method A.8) is less than -1.5 according to a preferred embodiment, for example less than -2, such as less than -3.

[0035] According to a particular embodiment, the aromatic moiety of an aromatic amine (VI) having the formula H2N-R1 can, for example, be selected from aromatic moieties R2 to R15:

[0036]

[0037] .

[0038] Preferred aromatic amines (VI) include aromatic amines having acidic groups, such as R2-NH2, R3-NH2, R10-NH2, R14-NH2, and R15-NH2. Another preferred aromatic amine (VI) contains phthalic acid as the aromatic moiety. Furthermore, preferred, but less preferred, are aromatic amines (VI) having nitro groups, such as R11-NH2.

[0039] A particularly preferred aromatic amine (VI) having the formula NH2-R1 is p-aminobenzenesulfonic acid (IX).

[0040] According to step (a) of the method of the present invention, there are several ways to provide 2-(methoxymethyl)aniline (IV).

[0041] For example, according to one embodiment, 2-(methoxymethyl)aniline (IV) can be provided in the following manner:

[0042] Methylation of o-nitrobenzyl alcohol (II)

[0043]

[0044] To form 2-methoxymethyl-nitrobenzene(III)

[0045] ,and

[0046] 2-Methoxymethyl-nitrobenzene (III) is reduced to form 2-(methoxymethyl)aniline (IV).

[0047] According to another embodiment, 2-(methoxymethyl)aniline (IV) can be provided in the following manner:

[0048] o-Toluidine(II)*

[0049]

[0050] It reacts with chlorine gas to form o-amino-benzyl chloride (II)**

[0051] ,and

[0052] The o-amino-benzyl chloride (II)** is reacted with a methanol salt to form 2-(methoxymethyl)aniline (IV).

[0053] According to yet another embodiment, 2-(methoxymethyl)aniline (IV) can be provided in the following manner:

[0054] o-Nitrobenzyl alcohol (II) is reduced to form 2-aminobenzyl alcohol (II)***

[0055] ,and

[0056] The o-aminobenzyl alcohol (II) is methylated to form 2-(methoxymethyl)aniline (IV). For example, methylation can be carried out using methanol in sulfuric acid.

[0057] The following reaction scheme illustrates the options for obtaining 2-(methoxymethyl)aniline (IV):

[0058] 2-Methoxymethylnitrobenzene (III) is provided by methylation of o-nitrobenzyl alcohol (II) as a commercially available starting material according to a known procedure:

[0059]

[0060] Next, 2-methoxymethyl-nitrobenzene (III) was hydrogenated to obtain 2-methoxymethyl-aniline (IV) (not separated):

[0061] .

[0062] o-amino-benzyl chloride (II)** is obtained by direct chlorination of o-toluidine (II)* as a starting material with chlorine gas, followed by methylation using, for example, sodium methoxide, to provide 2-methoxy-methyl-aniline (IV):

[0063]

[0064] 2-Methoxy-methyl-aniline (IV) is provided by hydrogenation of o-nitrobenzyl alcohol (II) followed by methylation in sulfuric acid, for example, using methanol:

[0065] .

[0066] According to a particular embodiment, step (b) of the method according to the invention comprises adding an aqueous solution of hydroxymethanesulfonate to a solution of 2-(methoxymethyl)aniline (IV) in methanol, ethanol, isopropanol, n-propanol, or a mixture thereof, or to a solution of 2-(methoxymethyl)aniline (IV) in an aqueous solution containing at least 50% by weight of methanol, ethanol, isopropanol, n-propanol, or a mixture thereof, particularly to a solution of 2-(methoxymethyl)aniline (IV) in methanol. According to an embodiment, such an aqueous solution contains at least 80% by weight of methanol, ethanol, isopropanol, n-propanol, or a mixture thereof, for example, at least 90% by weight of methanol, ethanol, isopropanol, n-propanol, or a mixture thereof.

[0067] According to one embodiment, the method further includes cooling the reaction mixture to precipitate [2-methoxymethyl-aniline]methanesulfonate (V).

[0068] According to one embodiment, step (b) further includes separating the precipitated [2-methoxymethyl-aniline]methanesulfonate (V).

[0069] According to a particular embodiment, step (c) includes diazotizing the aromatic amine (VI) in an aqueous solution under acidic conditions in the presence of a nitrosating agent. The nitrosating agent may be, for example, selected from sodium nitrite, potassium nitrite, nitrogen pentoxide, nitrososulfuric acid, and mixtures thereof.

[0070] According to one embodiment, the method further includes adding the diazonium salt solution to (V) of methanol, ethanol, isopropanol, n-propanol, or a mixture thereof, or to (V) of an aqueous solution containing at least 50% by weight of methanol, ethanol, isopropanol, n-propanol, or a mixture thereof. According to another embodiment, such an aqueous solution contains at least 80% by weight of methanol, ethanol, isopropanol, n-propanol, or a mixture thereof, for example, at least 90% by weight of methanol, ethanol, isopropanol, n-propanol, or a mixture thereof.

[0071] According to one embodiment, the method further includes precipitating (VII) by salting out. Optionally, step (c) further includes separating 4-azo-2-methoxymethyl-(sulfonyl)aniline (VII).

[0072] According to one embodiment, step (d) is carried out in an alkaline medium. Step (d) may further include adding an alkaline aqueous solution to a suspension of 4-azo-2-methoxymethyl-(sulfonyl)aniline (VII) in methanol, ethanol, isopropanol, n-propanol, or a mixture thereof, or to a suspension of 4-azo-2-methoxymethyl-(sulfonyl)aniline (VII) in an aqueous solution containing at least 50% by weight of methanol, ethanol, isopropanol, n-propanol, or a mixture thereof. According to an embodiment, such an aqueous solution contains at least 80% by weight of methanol, ethanol, isopropanol, n-propanol, or a mixture thereof, for example, at least 90% by weight of methanol, ethanol, isopropanol, n-propanol, or a mixture thereof.

[0073] The method may further include acidifying the reaction mixture with at least one inorganic or organic acid to precipitate 4-azo-2-(methoxymethyl)aniline (VIII). Optionally, the method may further include filtering out 4-azo-2-(methoxymethyl)aniline (VIII).

[0074] In step (e) of the method according to the invention, 4-azo-2-(methoxymethyl)aniline (VIII) is cleaved under reducing conditions to yield 2-methoxymethyl-p-phenylenediamine (I) and an aromatic amine (VI). Typically, this step is carried out using a hydrogen source in the presence of a metal catalyst, particularly ammonium formate, hydrazine hydrate, and / or H2. According to a particular embodiment, the hydrogen source is ammonium formate and the metal catalyst is Pd / C. Alternatively, step (e) can be carried out using an electrochemical method.

[0075] According to one embodiment, the solvent used in step (e) is methanol, ethanol, isopropanol, methyl acetate, ethyl acetate, toluene, or a mixture thereof.

[0076] Conveniently, the method may further include: cooling the reaction mixture and filtering the reaction mixture to obtain a solution of 2-methoxymethyl-p-phenylenediamine (I). Typically, the precipitate from the filter is collected to recover the metal catalyst and the aromatic amine (VI). In particular, the aromatic amine (VI) can be recycled to step (c).

[0077] 2-Methoxymethyl-p-phenylenediamine (I) is readily recovered from the solution obtained above. Separation of 2-methoxymethyl-p-phenylenediamine (I) typically includes concentrating the solution by removing the solvent through distillation and adding a nonpolar organic solvent to precipitate 2-methoxymethyl-p-phenylenediamine (I). According to a particular embodiment, the nonpolar organic solvent is toluene. The solvent removed by distillation in the concentration step can be readily recycled.

[0078] The method according to the invention provides a simple synthetic concept that meets the requirements of green synthesis, primarily using aqueous reaction solutions and avoiding unnecessary heating steps as much as possible. According to one embodiment, the temperature used in each method step does not exceed 85°C. Furthermore, when using organic solvents, the recycling rate is at least 70% and up to 80%. The solvents used can be recovered at analytical purity. The nitrogen-introducing aromatic amines used during the diazotization step can be recovered at a rate of up to 90%.

[0079] Other subjects of the present invention are the following novel intermediates:

[0080] [2-Methoxymethyl-aniline]methanesulfonic acid (V) or its salt.

[0081] 4-Azo-2-methoxymethyl-(sulfomethyl)aniline (VII) or its salt.

[0082] 4-Azo-2-(methoxymethyl)aniline (VIII) or its salt.

[0083] [4-[(E)-[3-(methoxymethyl)-4-(sulfonic acid methyl amino)phenyl]azo]benzenesulfonic acid] (X) or its salts.

[0084] 4-[(E)-[4-amino-3-(methoxymethyl)phenyl]azo]benzenesulfonic acid (XI) or its salt.

[0085] With respect to the salts of 2-methoxymethyl-p-phenylenediamine (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 2-methoxymethyl-p-phenylenediamine (I) or the intermediates discussed herein. As used herein, the term "salt" includes salts in the classical 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 hydrochloric acid, hydrobromic acid, 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) formed 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.

[0086] The key steps of this invention can be summarized as follows:

[0087] • Introduce a sulfonyl protecting group at the amino position of (IV) to obtain [2-methoxymethyl-aniline]methanesulfonate (V).

[0088] • Couple (V) to a diazotized aromatic amine support of general formula (VI) (e.g., p-aminobenzenesulfonic acid) to insert a nitrogen atom at the para position of (V).

[0089] • Cleavage of the sulfonyl protecting group under alkaline conditions and acid treatment of (VII) yields (VIII) as a free acid derivative.

[0090] • The desired 2-methoxymethyl-p-phenylenediamine (I) is isolated by cleaving the azo group of (VIII) as a free acid derivative through reduction and separation of the azo cleavage compound of general formula (VI).

[0091] • Optionally, 2-(methoxymethyl)aniline (IV) is provided by methylating the hydroxyl group of 2-nitrobenzyl alcohol (II) to obtain 2-methoxymethyl-nitrobenzene (III), followed by hydrogenating the nitro group in (III) to form (IV).

[0092] • Optionally, 2-(methoxymethyl)aniline (IV) is provided by halogenation (e.g., chlorination) of o-toluidine (II)* followed by methylation.

[0093] • Optionally, 2-amino-benzyl alcohol (II) is obtained by hydrogenation of 2-nitrobenzyl alcohol (II), followed by methylation, to provide 2-(methoxymethyl)aniline (IV). Detailed Implementation

[0094] 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.

[0095] It should be understood that the steps described for preparing 2-methoxymethyl-p-phenylenediamine 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.

[0096] The present invention relates to a condensation process for preparing 2-methoxymethyl-p-phenylenediamine (I), its salts (e.g., cosmetically acceptable salts) or mixtures thereof, comprising the steps described below.

[0097] 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 specific solvent should be understood as a solvent generally applicable to the corresponding reaction and the intended corresponding dissolution. Similarly, a reference to a specific acid or base should be understood as a reference to a suitable acid or base, respectively.

[0098] 1) Synthesis of 2-methoxymethylaniline (IV)

[0099] Reaction Scheme 1

[0100]

[0101] Commercially available 2-nitrobenzyl alcohol (II) and benzyltributylammonium chloride (as a phase transfer catalyst) were suspended in toluene to form a homogeneous brown suspension. Sodium hydroxide and a further amount of toluene were added, followed by dimethyl sulfate to initiate the methylation reaction. After stirring at 20°C for 4 hours, the reaction was complete and quenched accordingly with a 25% ammonia solution, then allowed to stand overnight to completely decompose any trace amounts of dimethyl sulfate. The desired 2-methoxymethyl-nitrobenzene (III) was separated from the toluene fraction by brine extraction as a low-viscosity brown oil in 95% yield. The separated toluene was recovered by gentle vacuum distillation and could be recycled at a rate of up to 80%.

[0102] Dissolve oily 2-methoxymethylnitrobenzene(III) in excess methanol, while adding Pd / C (wetted with 50% water) to the mixture, and purge the container with nitrogen before adding hydrogen.

[0103]

[0104] The hydrogenation step is carried out primarily in the presence of a hydrogen source. The hydrogen source can be selected from ammonium formate, hydrazine, or H2, and the metal catalyst is selected from the group consisting of: Fe, Pd / C, Pd / (OH)2, Raney-Ni, Pt / C, PtO2, and mixtures thereof. Specifically, the hydrogen source can be H2, and the metal catalyst can be a Pd / C catalyst. One or more solvents used in this step can 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 can be selected from the group consisting of methanol, ethanol, ethyl acetate, toluene, and mixtures thereof. From an ecological perspective, the solvent can preferably be selected from methanol, ethanol, and / or ethyl acetate, or an aqueous solution of methanol and / or ethanol. The reaction proceeds rapidly and is maintained at a mild cooling temperature of 20°C. After 1.5 hours, the reaction is complete, and the consumption of hydrogen automatically ceases. The catalyst is filtered off, and the filtrate (a methanol solution containing 2-methoxy-methyl-aniline (IV)) is used directly in the next step without separation.

[0105] Alternative Option A:

[0106] It is also advantageous to begin with the very inexpensive commercial o-toluidine (II)*. Chlorination can be carried out according to known industrial procedures (e.g., CN 111808075), while simultaneously reacting o-toluidine (II)* and chlorine in dichloroethane in the presence of a radical initiator such as AIBN. Alternatively, other common radical initiators such as benzoyl peroxide can also be used. The intermediate 2-aminobenzyl chloride (II)** is separated in yield >90%. Subsequent methylation in methanol using sodium methoxide proceeds smoothly, yielding the desired 2-methoxymethylaniline (IV) in good to excellent yields.

[0107]

[0108] Alternative Option B:

[0109] It has been shown that it is advantageous to begin with commercially available 2-nitrobenzyl alcohol (II) as a first step for hydrogenation, because hydrogenation is very clean and produces an acceptable amount of o-toluidine, which can be removed during a subsequent methylation step, which is advantageously carried out in sulfuric acid using methanol.

[0110] The hydrogenation step is carried out primarily in the presence of a hydrogen source. The hydrogen source can be selected from ammonium formate, hydrazine, or H2, and the metal catalyst can be selected from the group consisting of: Fe, Pd / C, Pd / (OH)2, Rannae-Ni, Pt / C, PtO2, and mixtures thereof. Specifically, the hydrogen source can be H2, and the metal catalyst can be a Pd / C catalyst. One or more solvents used in this step can 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 can be selected from the group consisting of: methanol, ethanol, ethyl acetate, toluene, and mixtures thereof. From an ecological perspective, the solvent can preferably be selected from methanol, ethanol, and / or ethyl acetate, or an aqueous solution of methanol and / or ethanol. The reaction proceeds rapidly and is maintained at a mild cooling of 20°C. After 1.5 hours, the reaction is complete, and the consumption of hydrogen stops automatically. The catalyst is filtered off, and the filtrate (a methanol solution containing 2-aminobenzyl alcohol (II)) is prepared for subsequent methylation steps.

[0111] One or more solvents used for methylation may be selected from the group consisting of: methanol, ethanol, isopropanol, sulfuric acid, DMF, chloroform, 1,2-dimethoxyethane, pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, 1,4-dioxane, diethyl ether, tetrahydrofuran, methyltetrahydrofuran, and mixtures thereof. Preferably, one or more solvents are selected from methanol and sulfuric acid, mixtures thereof, and aqueous solutions thereof.

[0112] Following methylation in toluene, related treatments (such as recrystallization) remove the o-toluidine content to cosmetically acceptable limits. The thus isolated 2-methoxy-methyl-aniline (IV) can be distilled under vacuum to improve purity distribution.

[0113]

[0114] 2) Synthesis of [2(methoxymethyl)-aniline]methanesulfonate (V) (as sodium salt)

[0115] Reaction Scheme 2

[0116]

[0117] A solution of sodium hydroxymethanesulfonate in water was slowly added to a methanol solution containing 2-(methoxymethyl)aniline (IV), and the mixture was heated to reflux for 2 hours (approximately 74°C). After cooling to 0–5°C, a white crystalline precipitate formed, which was washed with a small amount of ethyl acetate and dried in air. The product [2-(methoxy-methyl)aniline-]methanesulfonate (V), which is unknown in the literature, appeared to be stable, thus eliminating the need for nitrogen-supported drying. Precipitation from the aqueous solution was also a purification step to obtain the key intermediate [2-methoxymethyl-aniline-]methanesulfonate (V) in cosmetically acceptable quality, ready for use in subsequent synthetic steps.

[0118] 3) Synthesis of 4-[(E)-[4-amino-3-(methoxymethyl)phenyl]azo]benzenesulfonic acid (XI)

[0119] Reaction scheme 3a

[0120]

[0121] A commercially available p-aminobenzenesulfonic acid (IX), as an example of an aromatic amine (VI), was suspended in water, followed by the addition of a 32% sodium hydroxide solution to obtain a clear solution of the corresponding sodium salt. This solution was then diazotized with sodium nitrite and hydrochloric acid under standard conditions at 0°C, which produced a colorless and low-viscosity suspension after 60 minutes. In parallel, a solution of [2-methoxymethyl-aniline]methanesulfonate (V) was prepared in water. The diazotized suspension was then added to this clear aqueous solution over 30 minutes at a cooling temperature of 0–5°C. After stirring at a maximum of 7–8°C for 3 hours, the formation of the diazo compound 4-[(E)-[3-(methoxymethyl)-4-(sulfonylmethylamino)phenyl]azo]-benzenesulfonate disodium (X) was completed by TLC. The product was then gently precipitated by adding excess sodium chloride. The sulfonyl-protected diazo compound (X) was collected by filtration in 96% yield, washed with a small amount of ethyl acetate, and dried in air. Furthermore, this intermediate (X) appears to be stable, thus eliminating the need for nitrogen-supported drying.

[0122] The diazotization step is carried out in the presence of at least one nitrosating agent. One or more nitrosating agents may be selected from the group consisting of: sodium nitrite, potassium nitrite, nitrogen pentoxide, nitrososulfuric acid, and mixtures thereof.

[0123] 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: hydrochloric acid, trifluoroacetic acid, sulfuric acid, sulfurous acid, carbonic acid, nitric acid, acetic acid, propionic acid, phosphoric acid, and mixtures thereof. According to one embodiment, the inorganic or organic acid may be selected from the group consisting of: hydrochloric acid, sulfuric acid, sulfurous acid, acetic acid, and mixtures thereof. For example, the inorganic or organic acid may be sulfuric acid.

[0124] 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, 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, hydrochloric acid, water, and mixtures thereof. According to one embodiment, the one or more solvents may be selected from the group consisting of: n-butanol, isopropanol, n-propanol, ethanol, methanol, acetic acid, propionic acid, oxalic acid, malonic acid, hydrochloric acid, sulfuric acid, phosphoric acid, and mixtures thereof. For example, the one or more solvents may be selected from the group consisting of: n-propanol, acetic acid, propionic acid, oxalic acid, malonic acid, hydrochloric acid, sulfuric acid, phosphoric acid, water, and mixtures thereof.

[0125] Reaction scheme 3b

[0126]

[0127] Disodium 4-[(E)-[3-(methoxymethyl)-4-(sulfonylmethylamino)phenyl]azo]-benzenesulfonate (X) was suspended in isopropanol to form a homogeneous suspension, followed by the addition of excess 32% sodium hydroxide solution as a strong base. This mixture was then heated to reflux at 80°C for 2 hours. After 1.5 hours, a red precipitate began to form, and heating was stopped after 2 hours. The reaction mixture was then slowly treated with 25% hydrochloric acid solution to adjust the pH to 1-1.5 to neutralize the alkaline medium and obtain the protonated target compound 4-[(E)-[4-amino-3-(methoxymethyl)phenyl]azo]-benzenesulfonic acid (XI), as a free acid, which was collected by filtration (93% yield), washed with a small fraction of isopropanol, and dried in air.

[0128] The base may be selected from sodium hydroxide, potassium hydroxide, calcium carbonate, sodium carbonate, potassium carbonate, sodium acetate, DBU, DBN, Huenig base, ammonium sulfate, sodium bicarbonate, and potassium bicarbonate. According to one embodiment, sodium hydroxide and potassium hydroxide are used as the base.

[0129] The acid used in the neutralization step as described herein may be selected from at least one inorganic acid or organic acid. The inorganic acid or organic acid may be selected from the group consisting of: hydrochloric acid, trifluoroacetic acid, sulfuric acid, sulfurous acid, carbonic acid, nitric acid, acetic acid, propionic acid, phosphoric acid, and mixtures thereof. Preferred inorganic acids or organic acids are hydrochloric acid, sulfuric acid, sulfurous acid, acetic acid, and mixtures thereof. In particular, the inorganic acid or organic acid may be hydrochloric acid or sulfuric acid.

[0130] 4) Synthesis of 2-methoxymethyl-p-phenylenediamine (I)

[0131] Reaction scheme 4

[0132]

[0133] 4-[(E)-[4-amino-3-(methoxymethyl)phenyl]azo]benzenesulfonic acid (XI) was suspended in methyl acetate and stirred to form a homogeneous orange suspension. An excess of ammonium formate was added to this suspension, followed by the addition of Pd / C (wetted with 50% water). The black suspension was heated to a maximum of 50°C for 1 hour, while a colorless suspension formed. The mixture was then cooled to ambient temperature, and the residue containing palladium particles, carbon, and p-aminobenzenesulfonic acid (IX) was filtered off and washed with a small amount of methyl acetate. p-Aminobenzenesulfonic acid (IX) was separated from the carbon and palladium catalyst by pH adjustment. In this study, the filtered mixture was treated with a 32% aqueous solution of sodium hydroxide. The sulfonic acid-containing material (e.g., p-aminobenzenesulfonic acid (IX)) was converted to the corresponding sodium salt and readily dissolved in the aqueous phase, allowing the carbon and palladium catalyst to be filtered off, separated, and reused in other chemical operations. The catalyst can be reused in at least 10 consecutive chemical operations, such as hydrogenation, as described herein. The aqueous phase was then acidified with hydrochloric acid. After cooling to 0–5 °C, p-aminobenzenesulfonic acid (IX) was precipitated and could be easily collected by filtration. The maximum observed recovery was approximately 80%. The separated p-aminobenzenesulfonic acid (IX) can be reused in chemical operations such as diazotization as described herein, thus enhancing the economy of the chemical method described herein.

[0134] Then, approximately 70% by volume of the filtrate (containing 2-methoxymethyl-p-phenylenediamine (I) in methyl acetate) was slowly evaporated under reduced pressure at a moderate temperature (approximately 40°C), followed by the addition of a moderate excess of toluene. The remaining 30% by volume of methyl acetate was evaporated under reduced pressure at a moderate temperature (approximately 40°C). Thus, the entire amount of methyl acetate was recovered at this stage, with no trace amounts of toluene, as methyl acetate does not form an azeotropic mixture with toluene. The toluene solution was then slowly cooled to 0–5°C, while crystallization of 2-methoxymethyl-p-phenylenediamine (I) began at 30°C. After 30 minutes, precipitation was complete, and the crystals were collected by filtration with a yield of 90%, washed with a small amount of toluene, and air-dried under vacuum at 60°C for 3–5 hours. Furthermore, the toluene filtrate could be successfully recovered by evaporation under vacuum with a recovery rate of up to 95%. 2-methoxymethyl-p-phenylenediamine (I) conforming to global regulatory requirements was obtained at this stage with cosmetic-acceptable purity.

[0135] The azo bond cleavage step is carried out primarily in the presence of a hydrogen source. The hydrogen source can be selected from ammonium formate, hydrazine, or H2, and the metal catalyst is selected from Fe, Pd / C, Pd / (OH)2, Rannae-Ni, Pt / C, PtO2, and mixtures thereof. Specifically, the hydrogen source can be H2, and a Pd / C catalyst is used. One or more solvents used in this step can 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 can be selected from the group consisting of: methanol, ethanol, water, ethyl acetate, toluene, and mixtures thereof. From an ecological perspective, the solvent can preferably be selected from methyl acetate, methanol, ethanol and / or ethyl acetate, or aqueous solutions thereof.

[0136] Further details regarding the solvents, process aids, and other reagents used:

[0137] The amine source of compounds of the general formula NH2-R1 (VI) comprises a primary amine group. According to the embodiments, moiety R1 may be selected from:

[0138] • R2 represents a phenyl group with a sulfonic acid group chosen at any position on the benzene ring.

[0139] • R3 represents a naphthyl group, which carries a sulfonic acid group selected at any position in the naphthalene ring system.

[0140] • R4 represents a pyridinyl group, where the linkage with the amino group in NH2-R1 (VI) can occur at any position on the free carbon of the pyridinyl ring.

[0141] • R5 represents a pyrimidine group, where the linkage with the amino group in NH2-R1 (VI) can occur at any position on the free carbon of the pyrimidine ring.

[0142] • R6 represents 1,3,5-triazine, wherein the linkage with the amino group in NH2-R1 (VI) can occur at any position on the free carbon of the 1,3,5-triazine ring.

[0143] • R7 represents chlorophenyl, where the chlorine atom can be placed anywhere on the benzene ring.

[0144] • R8 represents bromophenyl, where the bromine atom can be placed anywhere on the benzene ring.

[0145] • R9 represents fluorophenyl, where the fluorine atom can be placed at any position on the benzene ring.

[0146] • R10 represents a phenyl group, which carries one or more carboxylic acid groups, specifically one or two carboxylic acid groups chosen at any position on the benzene ring.

[0147] • R11 represents a phenyl group with a nitro group chosen at any position on the benzene ring.

[0148] • R12 represents a 1-methyl-imidazolium group, wherein the linkage with the amino group in NH2-R1 (VI) can occur at any position on the free carbon of the 1-methyl-imidazolium ring.

[0149] • R13 represents a thiazolyl group, where the linkage with the amino group in NH2-R1 (VI) can occur at any position on the free carbon of the thiazolyl ring.

[0150] • R14 represents a naphthyl group, which carries two sulfonic acid groups chosen at any position in the naphthalene ring system.

[0151] • R15 represents a naphthyl group, which carries two sulfonic acid mixed metal (sodium and potassium) salt groups selected at any position in the naphthalene ring system.

[0152] The phase transfer catalyst can be selected from quaternary nitrogen compounds, including alkyltrimethylammonium salts, quaternized esters, dialkyldimethylammonium salts, benzylalkylammonium salts, crown ether derivatives (such as 18-crown-6, 15-crown-5, and 12-crown-4), imidazolium salts, and pyridinium salts. A preferred compound is benzyltributylammonium chloride.

[0153] The base described in the method may be selected from sodium hydroxide, potassium hydroxide, calcium carbonate, sodium carbonate, potassium carbonate, sodium acetate, DBU, DBN, Huenig base, ammonium sulfate, sodium bicarbonate, and potassium bicarbonate. According to one embodiment, sodium hydroxide is a preferred base.

[0154] Solvents used in any of the preparation and crystallization methods described herein are generally selected from the following: water, 1,2-dimethoxyethane, ethyl acetate, methyl 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, hydrochloric acid, water, and mixtures thereof. Preferably, the solvent used for crystallization is selected from the group consisting of: water, toluene, ethyl acetate, methyl acetate, isopropanol, n-propanol, ethanol, methanol, and mixtures thereof.

[0155] The hydrogenation step is primarily carried out in the presence of a hydrogen source. The hydrogen source can be selected from electrochemical methods, such as reduction electrolysis in an aqueous / alcoholic solution, ammonium formate, hydrazine, or hydrogen gas. The metal catalyst is selected from the group consisting of: Fe, Pd / C, Pd / (OH)₂, Ramane-Ni, Pt / C, PtO₂, and mixtures thereof. Specifically, the hydrogen source can be electricity (current), hydrogen gas, or ammonium formate, and the metal catalyst can be a Pd / C catalyst. One or more solvents used in this step can 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, methyl acetate, ethyl acetate, toluene, and mixtures thereof. From an ecological perspective, the solvent may preferably be selected from methanol, ethanol, and / or methyl acetate and / or ethyl acetate, or an aqueous solution of methanol and / or ethanol.

[0156] The hydrogen source can be selected from electricity (current), ammonium formate, hydrazine, or hydrogen gas, wherein the metal catalyst is selected from the group consisting of: Fe, Pd / C, Pd / (OH)2, Rannae-Ni, Pt / C, PtO2, and mixtures thereof. Specifically, the hydrogen source can be ammonium formate and hydrogen gas, using a Pd / C catalyst. One or more solvents used in this step can 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 can be selected from the group consisting of: methanol, ethanol, water, methyl acetate, ethyl acetate, toluene, and mixtures thereof. From an ecological perspective, the solvent can preferably be selected from methanol, ethanol and / or ethyl acetate, and / or methyl acetate or aqueous solutions thereof.

[0157] The dimensions and values ​​disclosed herein should not be construed as strictly limited to the precise numerical values ​​listed. Rather, unless otherwise stated, each dimension is intended to refer to the listed value and the functionally equivalent range around that value. For example, a concentration disclosed as “1%” is intended to mean “about 1%”. The term “about” is intended to cover the listed value plus / minus 10%, and in particular plus / minus 5% or plus / minus 1%.

[0158] Every reference cited herein, including any cross-references or related patents or applications, is incorporated herein in its entirety by reference unless expressly excluded or otherwise limited. The citation of any reference is not an admission that it is prior art to any invention disclosed or claimed herein, or that it, alone or in combination with any other one or more references, teaches, implies, or discloses any such invention. Furthermore, in the event of any conflict between any meaning or definition of a term herein and any meaning or definition of the same term in references incorporated herein, the meaning or definition assigned to that term herein shall prevail.

[0159] While particular embodiments of the invention have been illustrated and described, it will be apparent to those skilled in the art that various other changes and modifications can be made without departing from the spirit and scope of the invention. Therefore, it is intended that all such changes and modifications falling within the scope of the invention be covered by the appended claims.

[0160] Example

[0161] 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.

[0162] Example 1: [2(methoxy-methyl)aniline-]methanesulfonate (V) (sodium salt)

[0163] (1) 2-Methoxymethyl-nitrobenzene(III)

[0164] 1000 g of commercially available o-nitrobenzyl alcohol (II) was suspended in 5 parts toluene along with 2.5 mol% benzylbutylammonium chloride (phase transfer catalyst) and stirred at RT for 5 minutes until a brown homogeneous suspension was formed. Then, 3 equivalents of sodium hydroxide solution (32%) were added over 5 minutes, and stirring was continued for another 10 minutes. The suspension was cooled to 10–15 °C. Over 1 hour, 1 part by volume of a mixture of toluene and 1.3 equivalents of dimethyl sulfate was added to maintain the temperature at 10–15 °C. The 2-phase reaction mixture was then gently heated to 20 °C and stirred for another 4 hours. Then, over 30 minutes, 2.6 equivalents of ammonia solution (25%) and 2 parts by volume of water were added. The solution was allowed to stand overnight to ensure that any excess dimethyl sulfate decomposed at an alkaline pH (12.4–13.2). These layers were extracted twice with 1 part by volume of toluene each time, washed with 1 part by volume of brine, and the combined toluene phases were dried over sodium sulfate. The solvent was evaporated under vacuum to obtain 1092 g of 2-methoxymethyl-nitrobenzene(III) as a brown, low-viscosity oil (yield: 95%, by titration).

[0165] (2) 2-Methoxy-methyl-aniline (IV)

[0166] 1037 g (1 equivalent) of 2-methoxymethyl-nitrobenzene (III) was dissolved in 2.5 parts by volume of methanol (2730 l) to form a homogeneous solution. 5.0 wt% palladium / activated carbon (10%, wetted with 50% water) was added to the solution. The reaction solution was placed in a hydrogenation reactor and rinsed with nitrogen and hydrogen, and maintained at 17–22 °C. Hydrogen absorption began immediately and ended after 90 minutes. The catalyst was filtered off, and the residue was washed three times each with 300 ml of methanol. After evaporation of the solvent, 851 g of 2-methoxymethyl-aniline (IV) was separated (yield: 95%).

[0167] (3) 2-Amino-benzyl alcohol (II)***

[0168] 1 g of palladium / activated carbon (10%) was suspended in 20 ml of ammonia water and stirred for 30 minutes. The catalyst was then separated, washed with methanol, and prepared for the hydrogenation step. A mixture containing 20 g of commercially available o-nitrobenzyl alcohol (II), 100 ml of methanol, and 1 g of Pd / C (10%, pretreated as described above) was poured into a hydrogenation reactor and immediately purged with nitrogen and hydrogen at a stirring rate of 600 rpm and a pressure of 3.0 bar. Hydrogen absorption began rapidly, and the reaction mixture was cooled to maintain the temperature at 22–25 °C. After 50 minutes, the reaction was complete, and the temperature dropped to 17 °C. The mixture was stirred for another 20 minutes, the pressure was released, and the mixture was purged with nitrogen and filtered. The pale yellow filtrate was evaporated under reduced pressure. Upon further cooling, the product 2-aminobenzyl alcohol (II)*** crystallized and recrystallized from toluene to eliminate any byproducts (e.g., o-toluidine (II)*), yielding 13.32 g (88.8% yield).

[0169] (4) 2-Methoxy-methyl-aniline (IV)

[0170] Prepare 500 mL of methanol in a three-necked glass flask and slowly add 2 equivalents of concentrated sulfuric acid, heating to 50 °C. Dissolve 50 g (1 equivalent) of 2-aminobenzyl alcohol (II)*** in 500 mL of methanol and add this solution over 30 minutes while maintaining the temperature at 50 °C. Stir the reaction mixture for another 5 hours and cool to RT. Then, add a small amount of water and sodium hydroxide solution to maintain pH > 8. After evaporating the solvent, extract the two resulting phases three times with ethyl acetate and evaporate the combined organic phases again to give 2-methoxy-methyl-aniline (IV) in 89% yield as a brown oil (24.8 g). The obtained oil was then distilled using a short-path distillation process at 120 °C and 1 mbar to achieve 99.3% HPLC purity in 91.81% yield.

[0171] (5) [2(methoxy-methyl)aniline-]methanesulfonate (V) (sodium salt)

[0172] 851 g of 2-methoxy-methyl-aniline (IV) was dissolved in 2868 g of methanol. Separately, a solution of 1.3 equivalents of commercially available sodium hydroxymethanesulfonate in parts by volume of water was prepared to form a clear solution. This solution was added over 15 minutes to a methanol solution containing 2-methoxy-methyl-aniline (IV) to form an opaque, colorless solution. The reaction mixture was heated to a maximum of 75°C and stirred under reflux for 2 hours. After the reaction was complete, the reaction mixture was cooled to 50°C. It was then further cooled. At 38°C, large colorless crystals began to precipitate. The mixture was cooled to 0–5°C with continued stirring for another 30 minutes, and the suspension was filtered off. The colorless crystals were washed three times with 0.5 equivalents of ethyl acetate to give 1570 g of the desired product, sodium [2-(methoxy-methyl)aniline-]methanesulfonate (V), in 99.9% yield.

[0173] Example 2: 4-[(E)-[4-amino-3-(methoxymethyl)phenyl]azo]-benzenesulfonic acid (XI)

[0174] (1) 4-[(E)-[3-(methoxymethyl)-4-(sulfonate methylamino)phenyl]azo]-benzenesulfonate (X) (disodium salt)

[0175] 969 g of commercially available p-aminobenzenesulfonic acid (IX) was suspended in 4 parts by volume of water, while 1.25 equivalents of sodium hydroxide (32%) solution was added to form a clear solution. Then, 1.25 equivalents (386 g) of sodium nitrite was added over 5 minutes to form a slightly gray solution. The reaction mixture was cooled to 0–5 °C. 4 equivalents (2322 ml) of hydrochloric acid (25%) was slowly added, and the reaction mixture was diluted with 4 equivalents of water. After 45 minutes, a clear, low-viscosity diazonium salt solution was formed.

[0176] One equivalent (1334 g) of [2-methoxymethyl-aniline]methanesulfonate (V) was dissolved in seven equivalents of water, and four equivalents of sodium acetate were added to maintain the pH at 8.5. A colorless suspension was formed. A cold diazonium salt solution was added to the aqueous solution containing [2-methoxymethyl-aniline]methanesulfonate (V) over 30 minutes at 0–5 °C. The pH dropped to 4.9 during the azo coupling process. The reaction mixture was stirred for another 3 hours at 0–5 °C. The yellow to orange solution was slowly heated to 10 °C, at which point the solution turned deep red. Then, 1.5 parts by weight of sodium chloride were added over 1 minute at 10 °C. Stirring was continued for another 30 minutes, at which point a fine orange precipitate formed. The reaction mixture was filtered, the residue was collected, washed three times with ethyl acetate, and dried in air to give 1862 g of 4-[(E)-[3-(methoxymethyl)-4-(sulfonic acid methyl amino)phenyl]azo]-benzenesulfonate (X) (disodium salt), with a yield of 95.1%.

[0177] (2) 4-[(E)-[4-amino-3-(methoxymethyl)phenyl]azo]-benzenesulfonic acid (XI)

[0178] One equivalent (1862 g) of 4-[(E)-[3-(methoxymethyl)-4-(sulfonylamino)phenyl]azo]-benzenesulfonate (X) (disodium salt) was suspended in two parts by volume (7448 ml) of isopropanol. A deep orange suspension was formed, which became a homogeneous suspension after stirring for 10 minutes. Then, two equivalents (788 ml) of sodium hydroxide (32%) solution were added to form a viscous suspension, which was heated to 80°C under reflux for 2 hours. Crystals began to precipitate during the reaction process after 90 minutes. The reaction mixture was cooled to 70°C and filtered. The precipitate was washed with 0.5 parts by volume of isopropanol. The collected solid was suspended in 1.0 equivalent of isopropanol to form a deep red solution. To this solution, 2.1 equivalents of hydrochloric acid (25%) solution were added over 15 minutes, while a deep red precipitate formed. After stirring for another 30 minutes, the reaction mixture was filtered, and the precipitate was washed three times with 1 equivalent of isopropanol. The product 4-[(E)-[4-amino-3-(methoxymethyl)-phenyl]azo]-benzenesulfonic acid (XI) was dried and given in 93% yield (1231 g).

[0179] Example 3: 2-Methoxymethyl-p-phenylenediamine (I)

[0180] One equivalent (1231 g) of 4-[(E)-[4-amino-3-(methoxymethyl)-phenyl]azo]-benzenesulfonic acid (XI) was treated with 10 parts by volume (12310 ml) of methyl acetate to form an orange suspension after stirring for 10 minutes. Then, 8 equivalents (1932 g) of ammonium formate were added to the reaction mixture, and stirring was continued for another 10 minutes, while 5 equivalents of wetted Pd / C (10%, containing 50% water) catalyst were added. The black suspension formed during this process was heated to 50°C for 1 hour. The reaction mixture was cooled to RT and stirred for another 30 minutes. The reaction mixture was filtered, and the residue containing the catalyst and p-aminobenzenesulfonic acid (IX) was washed three times with 1 equivalent of methyl acetate each time. The clarified filtrate was evaporated under reduced pressure (40°C / 200 mbar) to reduce the volume by 70%. Add 4 equivalents (4924 ml) of toluene to the methyl acetate solution, and then evaporate the remaining 30% (v / v) of methyl acetate again under vacuum (40 °C / 100 mbar). Slowly cool the remaining toluene solution to 0–5 °C, while crystal formation has already begun at 30 °C. Stir the reaction mixture for another 30 minutes. Filter the mixture, and wash the colorless residue three times with 1 equivalent of toluene each time and dry it under nitrogen to give the desired product 2-methoxymethyl-p-phenylenediamine (I) in 90% (525 g).

[0181] The invention is further described below with reference to the following embodiments.

[0182] 1. A method for preparing 2-methoxymethyl-p-phenylenediamine (I), or a salt thereof, or a mixture thereof,

[0183]

[0184] The method includes the following steps:

[0185] (a) Provides 2-(methoxymethyl)aniline (IV),

[0186]

[0187] (b) Protecting the free amino group of 2-(methoxymethyl)aniline (IV) by reacting with hydroxymethanesulfonic acid or a salt thereof to form [2-methoxymethyl-aniline]methanesulfonate (V), wherein M + It is a monovalent ion.

[0188]

[0189] (c) In the presence of a nitrosating agent, a primary aromatic amine (VI) having the formula H2N-R1 (where R1 is the aromatic moiety) is diazotized, and the reaction product is coupled with [2-methoxymethyl-aniline]methanesulfonate (V) to form 4-azo-2-methoxymethyl-(sulfomethyl)aniline (VII), wherein M + It is a monovalent ion.

[0190]

[0191] (d) Deprotecting 4-azo-2-methoxymethyl-(sulfonyl)aniline (VII) to form 4-azo-2-(methoxymethyl)aniline (VIII),

[0192]

[0193] (e) 4-Azo-2-(methoxymethyl)aniline (VIII) is cleaved under reducing conditions to obtain 2-methoxymethyl-p-phenylenediamine (I) and aromatic amine (VI).

[0194] 2. The method according to embodiment 1, wherein the partition coefficient logPow of the aromatic amine (VI) (as determined by EU method A.8) is less than -1.5.

[0195] 3. The method according to embodiment 1 or 2, wherein the R1 portion of the aromatic amine (VI) is selected from R2 to R15:

[0196]

[0197] .

[0198] 4. The method according to embodiment 3, wherein the aromatic amine (VI) portion R1 is selected from R2, R3, R10, R14, and R15.

[0199] 5. The method according to any of the foregoing embodiments, wherein NH2-R1 is p-aminobenzenesulfonic acid (IX).

[0200] 6. The method according to any of the foregoing embodiments, wherein step (a) comprises:

[0201] (a1) Methylation of o-nitrobenzyl alcohol (II)

[0202]

[0203] To form 2-methoxymethyl-nitrobenzene(III)

[0204] ,and

[0205] (a2) Reduce 2-methoxymethyl-nitrobenzene (III) to form 2-(methoxymethyl)aniline (IV).

[0206] 7. The method according to any one of embodiments 1 to 5, wherein step (a) includes:

[0207] (a3) to make o-toluidine(II)*

[0208]

[0209] It reacts with chlorine gas to form o-amino-benzyl chloride (II)**

[0210] ,and

[0211] (a4) React o-amino-benzyl chloride (II)** with a methanol salt to form 2-(methoxymethyl)aniline (IV).

[0212] 8. The method according to any one of embodiments 1 to 5, wherein step (a) comprises:

[0213] (a5) Reduction of o-nitrobenzyl alcohol (II) to form 2-aminobenzyl alcohol (II)***

[0214] ,and

[0215] (a6) Methylation of o-aminobenzyl alcohol (II) to form 2-(methoxymethyl)aniline (IV).

[0216] 9. The method according to embodiment 8, wherein methylation is carried out in sulfuric acid using methanol.

[0217] 10. The method according to any of the foregoing embodiments, wherein step (b) comprises adding an aqueous solution of hydroxymethanesulfonate to a solution of 2-(methoxymethyl)aniline (IV) in methanol, ethanol, isopropanol, n-propanol or a mixture thereof, or to a solution of 2-(methoxymethyl)aniline (IV) in an aqueous solution containing at least 50% by weight of methanol, ethanol, isopropanol, n-propanol or a mixture thereof, particularly to a solution of 2-(methoxymethyl)aniline (IV) in methanol.

[0218] 11. The method according to embodiment 10, the method further comprising cooling the reaction mixture to precipitate [2-methoxymethyl-aniline]methanesulfonate (V).

[0219] 12. The method according to any of the foregoing embodiments, wherein step (b) further comprises isolating [2-methoxymethyl-aniline]methanesulfonate (V).

[0220] 13. The method according to any of the foregoing embodiments, wherein step (c) comprises: diazotizing the aromatic amine (VI) in an aqueous solution under acidic conditions in the presence of a nitrosating agent.

[0221] 14. The method according to embodiment 13, wherein the nitrosating agent is selected from sodium nitrite, potassium nitrite, nitrogen pentoxide, nitrososulfuric acid and mixtures thereof.

[0222] 15. The method according to embodiment 13 or 14, the method further comprising adding the diazonium salt solution to (V) in methanol, ethanol, isopropanol, n-propanol or a mixture thereof, or to (V) in an aqueous solution containing at least 50% by weight of methanol, ethanol, isopropanol, n-propanol or a mixture thereof.

[0223] 16. The method according to any one of embodiments 13 to 15, the method further comprising precipitating (VII) by salting out.

[0224] 17. The method according to any of the foregoing embodiments, wherein step (c) further comprises separating 4-azo-2-methoxymethyl-(sulfomethyl)aniline (VII).

[0225] 18. The method according to any of the foregoing embodiments, wherein step (d) is carried out in an alkaline medium.

[0226] 19. The method according to any of the foregoing embodiments, wherein step (d) comprises adding an alkaline aqueous solution to a suspension of 4-azo-2-methoxymethyl-(sulfomethyl)aniline (VII) in methanol, ethanol, isopropanol, n-propanol or a mixture thereof, or to a suspension of 4-azo-2-methoxymethyl-(sulfomethyl)aniline (VII) in an aqueous solution comprising at least 50% by weight of methanol, ethanol, isopropanol, n-propanol or a mixture thereof.

[0227] 20. The method according to embodiment 19, the method further comprising acidifying the reaction mixture with at least one inorganic or organic acid to precipitate 4-azo-2-(methoxymethyl)aniline (VIII).

[0228] 21. The method according to any of the foregoing embodiments, wherein step (d) further comprises filtering out 4-azo-2-(methoxymethyl)aniline (VIII).

[0229] 22. The method according to any of the foregoing embodiments, wherein step (e) is carried out using a hydrogen source in the presence of a metal catalyst, particularly using ammonium formate, hydrazine hydrate and / or H2 as the hydrogen source.

[0230] 23. The method according to embodiment 22, wherein the hydrogen source is ammonium formate and the metal catalyst is Pd / C.

[0231] 24. The method according to any one of embodiments 1 to 21, wherein step (e) is carried out using an electrochemical method.

[0232] 25. The method according to any one of embodiments 22 to 24, wherein the solvent used in step (e) is methanol, ethanol, isopropanol, methyl acetate, ethyl acetate, toluene, or a mixture thereof.

[0233] 26. The method according to any one of embodiments 22 to 25, the method further comprising cooling the reaction mixture and filtering the reaction mixture to obtain a solution of 2-methoxymethyl-p-phenylenediamine (I).

[0234] 27. The method according to embodiment 26, the method further comprising collecting the precipitate from the filter and recovering the metal catalyst and aromatic amine (VI).

[0235] 28. The method according to embodiment 27, the method further comprising recycling the aromatic amine (VI) to step (c).

[0236] 29. The method according to any of the foregoing embodiments, further comprising the following steps:

[0237] (f) Separation of 2-methoxymethyl-p-phenylenediamine (I).

[0238] 30. The method according to embodiment 29, wherein step (f) includes concentrating the solution by removing the solvent by distillation and adding a nonpolar organic solvent to precipitate 2-methoxymethyl-p-phenylenediamine (I).

[0239] 31. The method according to embodiment 30, wherein the nonpolar organic solvent is toluene.

[0240] 32. The method according to embodiment 30 or 31, the method further comprising recovering the solvent removed by distillation.

[0241] 33. The method according to any of the foregoing embodiments, wherein the temperature used in each method step does not exceed 85°C.

[0242] 34. The method according to any of the foregoing embodiments, the method further comprising recovering each solvent of analytical mass, wherein each solvent is recovered in an amount of at least 70%.

[0243] 35. [2-Methoxymethyl-aniline]methanesulfonic acid (V) or a salt thereof.

[0244] 36. 4-Azo-2-methoxymethyl-(sulfomethyl)aniline (VII) or a salt thereof.

[0245] 37. 4-Azo-2-(methoxymethyl)aniline (VIII) or its salt.

[0246] 38. [4-[(E)-[3-(methoxymethyl)-4-(sulfonic acid methyl amino)phenyl]azo]benzenesulfonic acid] (X) or a salt thereof.

[0247] 39. 4-[(E)-[4-amino-3-(methoxymethyl)phenyl]azo]benzenesulfonic acid (XI) or its salt.

Claims

1. A method for preparing 2-methoxymethyl-p-phenylenediamine (I), or a salt thereof, or a mixture thereof, The method includes the following steps: (a) Provides 2-(methoxymethyl)aniline (IV), (b) Protecting the free amino group of 2-(methoxymethyl)aniline (IV) by reacting with hydroxymethanesulfonic acid or a salt thereof to form [2-methoxymethyl-aniline]methanesulfonate (V), wherein M + It is a monovalent ion. (c) A primary aromatic amine (VI) having the formula H2N-R1 is diazotized in the presence of a nitrosating agent, wherein R1 is the aromatic moiety, and the reaction product is coupled with [2-methoxymethyl-aniline]methanesulfonate (V) to form 4-azo-2-methoxymethyl-(sulfonyl)aniline (VII), wherein M + It is a monovalent ion. (d) Deprotecting 4-azo-2-methoxymethyl-(sulfonyl)aniline (VII) to form 4-azo-2-(methoxymethyl)aniline (VIII), (e) 4-Azo-2-(methoxymethyl)aniline (VIII) is cleaved under reducing conditions to give 2-methoxymethyl-p-phenylenediamine (I) and aromatic amine (VI).

2. The method of claim 1, wherein the aromatic amine (VI) fraction R1 is selected from R2 to R15: 。 3. The method according to claim 2, wherein the aromatic amine (VI) portion R1 is selected from R2, R3, R10, R14, R15, and particularly wherein NH2-R1 is p-aminobenzenesulfonic acid (IX).

4. The method according to any one of the preceding claims, wherein step (a) comprises: (a1) Methylation of o-nitrobenzyl alcohol (II) To form 2-methoxymethyl-nitrobenzene(III) ,and (a2) Reduce 2-methoxymethyl-nitrobenzene (III) to form 2-(methoxymethyl)aniline (IV).

5. The method according to any one of claims 1 to 3, wherein step (a) comprises: (a3) to make o-toluidine(II)* It reacts with chlorine gas to form o-amino-benzyl chloride (II)** ,and (a4) React o-amino-benzyl chloride (II)** with methanol salt to form 2-(methoxymethyl)aniline (IV).

6. The method according to any one of claims 1 to 3, wherein step (a) comprises: (a5) Reduction of o-nitrobenzyl alcohol (II) to form 2-aminobenzyl alcohol (II)*** ,and (a6) Methylation of amino-benzyl alcohol (II) to form 2-(methoxymethyl)aniline (IV).

7. The method according to any one of the preceding claims, wherein step (b) comprises: An aqueous solution of hydroxymethanesulfonate is added to a solution of 2-(methoxymethyl)aniline (IV) in methanol, ethanol, isopropanol, n-propanol or a mixture thereof, or to a solution of 2-(methoxymethyl)aniline (IV) in an aqueous solution containing at least 50% by weight of methanol, ethanol, isopropanol, n-propanol or a mixture thereof, particularly to a solution of 2-(methoxymethyl)aniline (IV) in methanol.

8. The method according to any one of the preceding claims, wherein step (c) comprises: Aromatic amines (VI) are diazotized in aqueous solution under acidic conditions in the presence of a nitrosating agent.

9. The method according to claim 8, wherein the nitrosating agent is selected from sodium nitrite, potassium nitrite, nitrogen pentoxide, nitrososulfuric acid, and mixtures thereof.

10. The method according to claim 8 or 9, further comprising: The diazonium salt solution is added to (V) of methanol, ethanol, isopropanol, n-propanol or a mixture thereof, or to (V) of an aqueous solution containing at least 50% by weight of methanol, ethanol, isopropanol, n-propanol or a mixture thereof.

11. The method according to any one of the preceding claims, wherein step (d) comprises: An alkaline aqueous solution is added to a suspension of 4-azo-2-methoxymethyl-(sulfomethyl)aniline (VII) in methanol, ethanol, isopropanol, n-propanol or a mixture thereof, or to a suspension of 4-azo-2-methoxymethyl-(sulfomethyl)aniline (VII) in an aqueous solution containing at least 50% by weight of methanol, ethanol, isopropanol, n-propanol or a mixture thereof.

12. The method according to any one of the preceding claims, further comprising the following steps: (f) Separation of 2-methoxymethyl-p-phenylenediamine (I).

13. The method of claim 12, wherein step (f) comprises concentrating the solution by removing the solvent by distillation and adding a nonpolar organic solvent to precipitate 2-methoxymethyl-p-phenylenediamine (I).

14. The method according to any one of the preceding claims, further comprising recovering each solvent of analytical mass, wherein each solvent is recovered in an amount of at least 70%.

15. A compound selected from: • [2-Methoxymethyl-aniline]methanesulfonic acid (V) or a salt thereof, • 4-Azo-2-methoxymethyl-(sulfonyl)aniline (VII) or its salt, • 4-Azo-2-(methoxymethyl)aniline (VIII) or its salts, • [4-[(E)-[3-(methoxymethyl)-4-(sulfonic acid methylamino)phenyl]azo]benzenesulfonic acid](X) or its salt, • 4-[(E)-[4-amino-3-(methoxymethyl)phenyl]azo]benzenesulfonic acid (XI).

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