Method for preparing o-toluidine-free toluene-2,5-diamine and salt thereof

Abstract

The present invention relates to a method for preparing toluene-2,5-diamine or a salt thereof. The present invention further relates to a method for preparing a toluene-2,5-diamine sulfate. The method avoids the use of carcinogenic and allergenic raw materials (such as o-toluidine), utilizes a brand-new synthesis route, and has the advantages whereby starting raw materials are easily available, the reaction environment is safe, the operation is simple, the intermediate is stable and the separation is simple, prohibited components (such as o-toluidine) are not used nor generated, etc.

Description

A method for preparing toluene-2,5-diamine and salts thereof free of o-toluidine TECHNICAL FIELD

[0001] The present invention is in the field of synthetic organic chemistry, and in particular to a synthetic route and method for the synthesis of toluene-2,5-diamine and salts thereof, such as the sulfate salt. BACKGROUND

[0002] Toluene-2,5-diamine, also known as 2,5-diaminotoluene, CAS Registry Number 95-70-5, has the chemical structure:

[0003] Toluene-2,5-diamine and toluene-2,5-diamine sulfate (CAS Registry Number 615-50-9) are both listed as a hair dye for cosmetic use in the "Cosmetic Safety Technical Specifications", and can also be used in the synthesis of monomers for polymers and pharmaceutical intermediates, among many other fields.

[0004] Current synthesis methods generally use the following production process route: (1) o-toluidine and sodium nitrite to form a diazonium salt; (2) condensation of the diazonium salt with o-toluidine to obtain dye 2-aminoazotoluene (also known as o-aminoazotoluene, solvent yellow 3, C.I. 11160, etc., CAS Registry Number 97-56-3); (3) reduction of 2-aminoazotoluene to obtain toluene-2,5-diamine and the starting material o-toluidine; (4) removal of the generated and excess o-toluidine by steam distillation, with o-toluidine being recycled after distillation, and toluene-2,5-diamine remaining in the mother liquor; (5) decolorization with activated carbon, and then salification to obtain the product.

[0005] The disadvantages of this route are: (1) the starting material o-toluidine is carcinogenic and causes allergies, according to the preliminary sorting reference of the carcinogenic list published by the International Agency for Research on Cancer of the World Health Organization, o-toluidine is in the Class 1 carcinogenic list. O-toluidine is one of 24 aromatic amine compounds that are definitely carcinogenic, and is a dye intermediate that is prohibited; (2) the intermediates generated in the production process are also carcinogenic, according to the preliminary sorting reference of the carcinogenic list published by the International Agency for Research on Cancer of the World Health Organization, 2-aminoazotoluene is in the Class 2B carcinogenic list; (3) o-toluidine is continuously recycled in the process, which requires large equipment investment and high energy consumption; (4) the intermediate 2-aminoazotoluene is a dye, which makes it difficult to remove color from the final product; (5) the process route is long and costly, and it is difficult to treat the three wastes; (6) the final product inevitably contains the carcinogen o-toluidine. The product grade is generally determined according to the residual amount of o-toluidine in the product, for example, 10 ppm is first grade, 25 ppm is superior grade, and 50 ppm is qualified grade.

[0006] A method for synthesizing toluene-2,5-diamine and its sulfate salt from methyl-p-nitroaniline has also been reported, but it is not possible for commercial production because of the high price of the raw material.

[0007] Therefore, there is a need in the art for a commercial production method of toluene-2,5-diamine and its salts. SUMMARY

[0008] The object of the present application is to provide a new method for preparing toluene-2,5-diamine and its salts (e.g. sulfate salt), which avoids the use of carcinogenic and allergenic raw materials (e.g. o-toluidine), adopts a completely new synthetic route, has the advantages of easy availability of starting materials, safe reaction environment, simple operation, stable intermediates and simple separation, and does not use or produce prohibited ingredients.

[0009] In one aspect, the present application provides a method for preparing toluene-2,5-diamine and its salts, which comprises the following steps:

[0010] ii) reacting compound (I) with a hydroxylamine salt to obtain compound (II):

[0011] In another aspect, the present application also provides a method for preparing toluene-2,5-diamine and its salts, which comprises the following steps:

[0012] ii) reacting compound (V) with a hydroxylamine salt to obtain compound (II):

[0013] In another aspect, the present application also provides a method for preparing toluene-2,5-diamine and its salts, which comprises the following steps:

[0014] ii) reacting methyl-p-benzoquinone with a hydroxylamine salt to obtain compound (II):

[0015] The above method also optionally comprises the step of reacting toluene-2,5-diamine of compound (III) with an acid (preferably sulfuric acid) to obtain toluene-2,5-diamine salt (preferably toluene-2,5-diamine sulfate salt).

[0016] The method has the advantages that: (1) the starting material is easy to obtain, such as 2-methylphenol, which is a monomer of engineering plastic PPO, obtained by methylating phenol, and has a million-ton device for production, and other raw and auxiliary materials are bulk basic chemicals; (2) each reaction can be completed in water, which is intrinsically safe; (3) standard equipment is used in the whole production process, and the operation is simple; (4) the intermediates are stable, and the separation is simple, without the need for purification and drying; (4) the reduction of oxime is much milder than the reduction of nitro; (6) the waste water can be reused and easily treated to meet the requirements; (7) the product does not use or produce the prohibited component o-toluidine, and has excellent quality.

[0017] Unless otherwise indicated in the present application or clearly contradicted by context, all methods described herein can be performed in any suitable order according to the understanding of those skilled in the art.

[0018] All patents, patent applications and references cited herein are incorporated by reference in their entirety for all purposes to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference. In the event of a conflict between the present application and the literature incorporated by reference, the present application controls. BRIEF DESCRIPTION OF DRAWINGS

[0019] Figure 1 is the HNMR spectrum of toluene-2,5-diamine sulfate. 1 HNMR spectrum. DETAILED DESCRIPTION

[0020] In order to facilitate the understanding of the present application, the present application will be described more fully below. However, the present application can be realized in different forms and is not limited to the embodiments described herein. The purpose of providing these embodiments is to make the disclosure of the present application more thorough and comprehensive.

[0021] DEFINITIONS

[0022] Unless otherwise indicated, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the present application pertains, but in case of conflict, the definitions provided in this specification prevail. The terminology used in the specification of the present application is only for the purpose of describing the specific embodiments and is not intended to limit the present application.

[0023] All ranges of values involving the same component or property are inclusive of the endpoints, which can be combined independently. Since these ranges are continuous, they include every value between the minimum and maximum values. It should also be understood that any numerical range recited in the present application is intended to include all sub-ranges of the range.

[0024] When the application is defined to encompass a range of physical properties, e.g., molecular weight, or of chemical properties, all combinations and subcombinations of ranges, as well as specific embodiments therein, are intended to be included. The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "including") is intended to include embodiments of, e.g., a composition, method or process, etc., that "consist of or "consist essentially of, the described features.

[0025] As used in the specification and claims, "and / or" means "one or the other or both" as is conventional in the art. Thus, the phrase "A and / or B" is understood to mean "A alone, B alone, or A and B together." Other components can optionally be present in addition to those specifically identified, whether or not associated with the specifically identified components. Thus, as a non-limiting example, a reference to "A and / or B" when used in the context of a "comprising" or "including" clause, can refer to A alone (optionally including other components or steps not specifically identified as B), B alone (optionally including other components or steps not specifically identified as A), or A and B together (optionally including other components or steps not specifically identified as A or B), etc.

[0026] As used herein, the term "acid" includes inorganic acids and organic acids. The inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like, as well as other inorganic acids known in the art. The organic acids include, but are not limited to, acetic acid, hydroxyacetic acid, propionic acid, lactic acid, pyruvic acid, malonic acid, fumaric acid, maleic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, formic acid, and the like, as well as other organic acids known in the art (e.g., the acids described in Handbook of Pharmaceutical Salts, P. Heinrich Stahl & Camille G. Wermuth (eds.), Verlag Helvetica Chimica Acta-Zurich, 2002, 329-345).

[0027] The term "salt" as used herein refers to ionic compounds resulting from the neutralization reaction of an acid and a base. Salts consist of one or more cations (positively charged ions) and one or more anions (negative ions), and thus the salt is electrically neutral (no net charge). Salts of the compounds of the present application, especially toluene-2,5-diamine, include those derived from inorganic and organic acids and bases. Examples of acid addition salts are salts of an amino group with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by using other methods known in the art, for example ion exchange. Other salts of the compounds of the present application, especially toluene-2,5-diamine, include sulfate, adipate, alginate, ascorbate, aspartate, besylate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N + (C 1-4 alkyl)4 - Salts. Representative alkali or alkaline earth metal salts include the sodium, lithium, potassium, calcium, magnesium salts and the like. Further salts include ammonium, quaternary ammonium, and amine cations, such as benzathine, choline, diethanolamine, diethylamine, dicyclohexylamine, and other salts known to those skilled in the art.

[0028] The term "reduction" as used herein refers to the conversion of a functional group in a molecule from a higher oxidation state to a lower oxidation state by reaction with a reducing agent. The term "reducing agent" refers to any compound or complex known in the art to have the effect of converting a functional group in a molecule from a higher oxidation state to a lower oxidation state. Reduction can be achieved via direct electron, hydride, or hydrogen atom transfer. Reducing agents useful in the methods of the present application include metal hydrides (e.g., lithium aluminum hydride, sodium borohydride, sodium cyanoborohydride), hydrazine hydrate, and hydrogen in the presence of a catalyst (e.g., Raney nickel, palladium on carbon, nickel boride, platinum metal or its oxides, rhodium, ruthenium and zinc oxides, pentacyanocobaltate(II) Co(CN)5 3- ) salts, and the like.

[0029] Process for the preparation of toluene-2,5-diamine

[0030] Scheme 1

[0031] In one aspect of the present application, the present application relates to a process for the preparation of toluene-2,5-diamine and salts thereof.

[0032] In one embodiment, the present application relates to a process for the preparation of toluene-2,5-diamine. In one embodiment, the process comprises the following steps:

[0033] ii) reacting compound (I) with a salt of hydroxylamine to obtain compound (II):

[0034] In a further embodiment, the process further comprises the following step before step ii):

[0035] i) reacting 2-methylphenol with a nitrite salt to obtain compound (I):

[0036] In a further embodiment, the process further comprises the following step after step ii):

[0037] iii) reducing compound (II) to obtain toluene-2,5-diamine of compound (III):

[0038] In a more specific embodiment, the present application relates to a process for the preparation of toluene-2,5-diamine, said process comprising the following steps:

[0039] i) reacting 2-methylphenol with a nitrite salt to obtain compound (I):

[0040] ii) reacting compound (I) with a salt of hydroxylamine to obtain compound (II):

[0041] and

[0042] iii) reducing compound (II) to obtain toluene-2,5-diamine of compound (III):

[0043] Step i) above relates to the synthesis of compound (I) using 2-methylphenol. In some embodiments, step i) is preferably reacted in the presence of an acid. In some embodiments, step i) further comprises mixing 2-methylphenol and the acid, and adding dropwise to an aqueous solution of the nitrite salt under stirring.

[0044] In some embodiments, the acid in step i) is an organic acid. In further embodiments, the organic acid is selected from acetic acid, hydroxyacetic acid, propionic acid, lactic acid, pyruvic acid, malonic acid, fumaric acid, maleic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, citric acid, methylsulfonic acid, ethanesulfonic acid, benzenesulfonic acid, or formic acid. In preferred embodiments, the organic acid is acetic acid.

[0045] In some embodiments, the nitrite salt in step i) is a metal nitrite salt. In some embodiments, the nitrite salt is an alkali metal nitrite salt. In some embodiments, the nitrite salt is an alkaline earth metal nitrite salt. In some embodiments, the nitrite salt is selected from one or more of sodium nitrite, potassium nitrite, calcium nitrite, or magnesium nitrite. In further embodiments, the nitrite salt is sodium nitrite. In further embodiments, the nitrite salt is potassium nitrite. In further embodiments, the nitrite salt is calcium nitrite. In further embodiments, the nitrite salt is magnesium nitrite.

[0046] In some embodiments, step i) is reacted at 0-95 °C. In some embodiments, step i) is reacted at 0-25 °C, 10-35 °C, 20-30 °C, 50-95 °C, 55-95 °C, 60-95 °C, 65-95 °C, 70-95 °C, 75-95 °C, 80-95 °C, 85-95 °C, or 90-95 °C.

[0047] In some specific embodiments, step i) comprises: mixing 2-methylphenol and acetic acid, and adding dropwise to an aqueous solution of sodium nitrite under stirring, and reacting at 55-95 °C. The reaction is judged by HPLC to determine the end point of the reaction, and after the reaction is completed, the temperature is lowered to 0-10 °C. The solid is separated by filtration, and the solid is both compound (I), which is washed with water and used in the next step. Those skilled in the art will recognize that other reagents and / or conditions can be used to perform step i).

[0048] In some embodiments, step ii) involves the synthesis of compound (II) using compound (I). In some embodiments, compound (I) in step ii) is reacted with a hydroxylamine salt in water or a mixture of water and an organic acid.

[0049] In some embodiments, the organic acid is selected from acetic acid, hydroxyacetic acid, propionic acid, lactic acid, pyruvic acid, malonic acid, fumaric acid, maleic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, citric acid, methylsulfonic acid, ethanesulfonic acid, benzenesulfonic acid, or formic acid. In preferred embodiments, the organic acid is acetic acid.

[0050] In some embodiments, the hydroxylamine salt is an inorganic acid salt of hydroxylamine. In some embodiments, the hydroxylamine salt is selected from one or more of hydroxylamine hydrochloride, hydroxylamine sulfate, hydroxylamine nitrate, or hydroxylamine phosphate. In some embodiments, the hydroxylamine salt is hydroxylamine hydrochloride. In some embodiments, the hydroxylamine salt is hydroxylamine sulfate. In some embodiments, the hydroxylamine salt is hydroxylamine nitrate. In some embodiments, the hydroxylamine salt is hydroxylamine phosphate.

[0051] In some embodiments, step ii) is carried out at 50-100 °C, preferably 45-75 °C.

[0052] In some specific embodiments, step ii) comprises: mixing compound (I) and a hydrochloride, sulfate and / or phosphate salt of hydroxylamine in a mixed solvent of water and acetic acid, warming to 50-100 °C, and determining the end point of the reaction by HPLC. After the reaction is completed, the temperature is lowered to 0-10 °C. The solid is separated by filtration. The solid is compound (II) and is used in the next step after being washed with water. Those skilled in the art will recognize that other reagents and / or conditions can be used to carry out the reaction of step ii).

[0053] In some embodiments, step iii) involves the synthesis of compound (III) using compound (II). In some embodiments, the reduction in step iii) comprises: adding a catalyst to a solution of compound (II), and then adding hydrazine hydrate, formic acid, sulfur dioxide, sodium metabisulfite, iron powder, or sodium sulfite.

[0054] In some embodiments, the catalyst is selected from one or more of palladium on carbon, nickel, and iron trichloride. In some embodiments, the catalyst is palladium on carbon. In some embodiments, the catalyst is nickel. In some embodiments, the catalyst is iron trichloride. In some embodiments, the solution of compound (II) is a solution of compound (II) in methanol, tetrahydrofuran, n-butanol, or ethanol, preferably ethanol.

[0055] In some embodiments, step iii) is carried out at 0 to the boiling point of the solvent, preferably at 0-80 °C, 0-50 °C, or 50-80 °C.

[0056] In other embodiments, the reduction in step iii) comprises: adding a catalyst to a solution of compound (II), and then bubbling hydrogen gas, preferably at 25-120 °C and 1-50 atm.

[0057] In some embodiments, the catalyst is selected from one or more of palladium on carbon and Raney nickel. In some embodiments, the catalyst is palladium on carbon. In some embodiments, the catalyst is Raney nickel.

[0058] In some embodiments, step iii) comprises dissolving compound (II) in ethanol, adding a catalyst, which can be one or more of palladium on carbon, nickel, iron trichloride, and adding hydrazine hydrate dropwise at 50-80 °C. The reaction is monitored by HPLC and upon completion, the catalyst is filtered off and the ethanol and volatiles are evaporated. Toluene-2,5-diamine (III) is obtained by distillation. Those skilled in the art will recognize that other reagents and / or conditions can be used to perform step iii).

[0059] In other embodiments, step iii) comprises dissolving compound (II) in ethanol, adding a catalyst, which can be one or more of palladium on carbon, Raney nickel, and bubbling hydrogen gas through the reaction. The reaction is monitored by HPLC and upon completion, the catalyst is filtered off and the ethanol and volatiles are evaporated. Toluene-2,5-diamine (III) is obtained by distillation. Those skilled in the art will recognize that other reagents and / or conditions can be used to perform step iii).

[0060] In some embodiments, the method further involves synthesizing a salt of toluene-2,5-diamine. In some embodiments, an acid is added to the solution of compound (III) after step iii) and the reaction is allowed to proceed to obtain the salt of toluene-2,5-diamine.

[0061] In some embodiments, the acid is an inorganic acid. In further embodiments, the inorganic acid is selected from one or more of hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid. In further embodiments, the inorganic acid is hydrochloric acid. In further embodiments, the inorganic acid is hydrobromic acid. In further embodiments, the inorganic acid is phosphoric acid. In further embodiments, the inorganic acid is sulfuric acid. In further embodiments, the inorganic acid is perchloric acid.

[0062] In some embodiments, the method further involves synthesizing toluene-2,5-diamine sulfate. The method comprises filtering off the catalyst after the reaction of step iii) and adding sulfuric acid dropwise directly to the ethanol solution of toluene-2,5-diamine, and the solid that precipitates is toluene-2,5-diamine sulfate (IV). Those skilled in the art will recognize that other reagents and / or conditions can be used to perform this reaction.

[0063] In some embodiments, the method further involves purification of toluene-2,5- diamine sulfate (IV), which comprises dissolving solid toluene-2,5-diamine sulfate (IV) in water, adjusting pH to 8 with aqueous sodium hydroxide or ammonia, adding activated carbon, stirring, warming to 50-100 °C, filtering off the activated carbon, and adding the filtered mother liquor dropwise to dilute sulfuric acid, and isolating the solid, which is toluene-2,5-diamine sulfate (IV). Those skilled in the art will recognize that other reagents and / or conditions can be used to purify toluene-2,5-diamine sulfate (IV).

[0064] In some embodiments, the method is characterized in that the toluene-2,5-diamine or toluene-2,5-diamine salt obtained by the method contains substantially no or no detectable amount of o-toluidine. In some preferred embodiments, the toluene-2,5-diamine or toluene-2,5-diamine salt obtained by the method contains less than 50 ppm of o-toluidine. In some preferred embodiments, the toluene-2,5-diamine or toluene-2,5-diamine salt obtained by the method contains less than 25 ppm of o-toluidine. In some preferred embodiments, the toluene-2,5-diamine or toluene-2,5-diamine salt obtained by the method contains less than 10 ppm of o-toluidine. In some preferred embodiments, the toluene-2,5-diamine or toluene-2,5-diamine salt obtained by the method contains less than 1 ppm of o-toluidine. In some preferred embodiments, the toluene-2,5-diamine or toluene-2,5-diamine salt obtained by the method contains less than 0.1 ppm of o-toluidine. In some preferred embodiments, the toluene-2,5-diamine or toluene-2,5-diamine salt obtained by the method contains less than 0.01 ppm of o-toluidine. In some preferred embodiments, the toluene-2,5-diamine or toluene-2,5-diamine salt obtained by the method contains no o-toluidine.

[0065] Scheme 2

[0066] In another aspect of the application, the application relates to a method for preparing toluene-2,5-diamine and salts thereof, starting from m-cresol.

[0067] In one embodiment, the method comprises the following steps:

[0068] ii) reacting compound (V) with a salt of hydroxylamine to obtain compound (II):

[0069] In a further embodiment, the method further comprises the following step before step ii):

[0070] i) reacting m-cresol with a nitrite salt to obtain compound (V):

[0071] In further embodiments, the method further comprises the following step after step ii):

[0072] iii) reducing compound (II) to obtain toluene-2,5-diamine of compound (III):

[0073] In more specific embodiments, the method comprises the following steps:

[0074] i) reacting m-cresol with a nitrite salt to obtain compound (V):

[0075] ii) reacting compound (V) with a hydroxylamine salt to obtain compound (II):

[0076] and

[0077] iii) reducing compound (II) to obtain toluene-2,5-diamine of compound (III):

[0078] Step i) above involves the synthesis of compound (I) using 3-methylphenol. In some embodiments, step i) is preferably reacted in the presence of an acid. In some embodiments, step i) further comprises mixing 3-methylphenol and the acid, and adding dropwise to an aqueous solution of a nitrite salt under stirring.

[0079] In some embodiments, the acid in step i) is an organic acid. In further embodiments, the organic acid is selected from acetic acid, hydroxyacetic acid, propionic acid, lactic acid, pyruvic acid, malonic acid, fumaric acid, maleic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, citric acid, methylsulfonic acid, ethanesulfonic acid, benzenesulfonic acid, or formic acid. In preferred embodiments, the organic acid is acetic acid.

[0080] In some embodiments, the nitrite salt in step i) is a metal nitrite salt. In some embodiments, the nitrite salt is an alkali metal nitrite salt. In some embodiments, the nitrite salt is an alkaline earth metal nitrite salt. In some embodiments, the nitrite salt is selected from one or more of sodium nitrite, potassium nitrite, calcium nitrite, or magnesium nitrite. In further embodiments, the nitrite salt is sodium nitrite. In further embodiments, the nitrite salt is potassium nitrite. In further embodiments, the nitrite salt is calcium nitrite. In further embodiments, the nitrite salt is magnesium nitrite.

[0081] In some embodiments, step i) is reacted at 0-95 °C. In some embodiments, step i) is reacted at 0-25 °C, 10-35 °C, 20-30 °C, 50-95 °C, 55-95 °C, 60-95 °C, 65-95 °C, 70-95 °C, 75-95 °C, 80-95 °C, 85-95 °C, or 90-95 °C.

[0082] In some specific embodiments, step i) comprises: mixing 3-methylphenol and acetic acid, adding dropwise to an aqueous solution of sodium nitrite under stirring, and reacting at 55-95 °C. The reaction is judged by HPLC to determine the end point of the reaction, and after the reaction is completed, the temperature is lowered to 0-10 °C. The solid is separated by filtration, and the solid is both compound (I) which is washed with water and used in the next step. Those skilled in the art will recognize that other reagents and / or conditions can be used to perform step i).

[0083] In some embodiments, step ii) involves the synthesis of compound (II) using compound (V). In some embodiments, compound (V) in step ii) is reacted with a hydroxylamine salt in water or a mixed solvent of water and an organic acid.

[0084] In some embodiments, the organic acid is selected from acetic acid, hydroxyacetic acid, propionic acid, lactic acid, pyruvic acid, malonic acid, fumaric acid, maleic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, or formic acid. In preferred embodiments, the organic acid is acetic acid.

[0085] In some embodiments, the hydroxylamine salt is an inorganic acid salt of hydroxylamine. In some embodiments, the hydroxylamine salt is selected from one or more of hydroxylamine hydrochloride, hydroxylamine sulfate, hydroxylamine nitrate, or hydroxylamine phosphate. In some embodiments, the hydroxylamine salt is hydroxylamine hydrochloride. In some embodiments, the hydroxylamine salt is hydroxylamine sulfate. In some embodiments, the hydroxylamine salt is hydroxylamine nitrate. In some embodiments, the hydroxylamine salt is hydroxylamine phosphate.

[0086] In some embodiments, step ii) is reacted at 50-100 °C, preferably 45-75 °C.

[0087] In some specific embodiments, step ii) comprises: mixing compound (V) and a hydrochloride, sulfate, and / or phosphate salt of hydroxylamine in a mixed solvent of water and acetic acid, and heating to 50-100 °C. The reaction is judged by HPLC to determine the end point of the reaction, and after the reaction is completed, the temperature is lowered to 0-10 °C. The solid is separated by filtration, and the solid is both compound (II) which is washed with water and used in the next step. Those skilled in the art will recognize that other reagents and / or conditions can be used to perform step ii).

[0088] In some embodiments, step iii) involves the synthesis of compound (III) using compound (II). In some embodiments, the reduction in step iii) comprises: adding a catalyst to a solution of compound (II), and then adding hydrazine hydrate, formic acid, sulfur dioxide, sodium metabisulfite, iron powder, or sodium sulfite, etc.

[0089] In some embodiments, the catalyst is selected from one or more of: palladium on carbon, nickel, iron trichloride. In some embodiments, the catalyst is palladium on carbon. In some embodiments, the catalyst is nickel. In some embodiments, the catalyst is iron trichloride. In some embodiments, the solution of compound (II) is a solution of compound (II) in methanol, tetrahydrofuran, n-butanol, or ethanol, etc., preferably ethanol.

[0090] In some embodiments, step iii) comprises reacting at 0 to the boiling point of the solvent, preferably at 0-80 °C, 0-50 °C, 50-80 °C.

[0091] In other embodiments, the reduction in step iii) comprises: adding a catalyst to a solution of compound (II), and then bubbling hydrogen gas, preferably at 25-120 °C, 1-50 atm.

[0092] In some embodiments, the catalyst is selected from one or more of: palladium on carbon, Raney nickel. In some embodiments, the catalyst is palladium on carbon. In some embodiments, the catalyst is Raney nickel.

[0093] In some specific embodiments, step iii) comprises: dissolving compound (II) in ethanol, adding a catalyst, which can be one or more of palladium on carbon, nickel, iron trichloride. Adding hydrazine hydrate dropwise at 50-80 °C, controlling the end point of the reaction by HPLC, after the reaction is complete, filtering off the catalyst, evaporating the ethanol and volatiles, and distilling toluene-2,5-diamine (III). Those skilled in the art will recognize that other reagents and / or conditions can be used to perform step iii).

[0094] In other specific embodiments, step iii) comprises: dissolving compound (II) in ethanol, adding a catalyst, which can be one or more of palladium on carbon, Raney nickel. Bubbling hydrogen gas to react, controlling the end point of the reaction by HPLC, after the reaction is complete, filtering off the catalyst, evaporating the ethanol and volatiles, and distilling toluene-2,5-diamine (III). Those skilled in the art will recognize that other reagents and / or conditions can be used to perform step iii).

[0095] In some embodiments, the method further involves synthesizing toluene-2,5-diamine salt. In some embodiments, the reaction is carried out by adding an acid to the solution of compound (III) after step iii).

[0096] In some embodiments, the acid is an inorganic acid. In further embodiments, the inorganic acid is selected from one or more of hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid. In further embodiments, the inorganic acid is hydrochloric acid. In further embodiments, the inorganic acid is hydrobromic acid. In further embodiments, the inorganic acid is phosphoric acid. In further embodiments, the inorganic acid is sulfuric acid. In further embodiments, the inorganic acid is perchloric acid.

[0097] In some specific embodiments, the method further involves synthesizing toluene-2,5-diamine sulfate salt. The method involves filtering off the catalyst after the reaction of step iii), and directly adding sulfuric acid dropwise into the toluene-2,5-diamine solution in ethanol, and the solid precipitates, which is toluene-2,5-diamine sulfate salt (IV). Those skilled in the art will recognize that other reagents and / or conditions can be used to carry out this reaction.

[0098] In some specific embodiments, the method further involves purifying toluene-2,5-diamine sulfate salt (IV), which involves dissolving the solid toluene-2,5-diamine sulfate salt (IV) in water, adjusting the pH to 8 with aqueous sodium hydroxide or ammonia, adding activated carbon, stirring, warming to 50-100 °C, filtering off the activated carbon, and adding the filtered mother liquor dropwise into dilute sulfuric acid, and the solid precipitates, which is filtered off to obtain the qualified toluene-2,5-diamine sulfate salt (IV). Those skilled in the art will recognize that other reagents and / or conditions can be used to purify toluene-2,5-diamine sulfate salt (IV).

[0099] In some embodiments, the method is characterized in that the toluene-2,5-diamine or toluene-2,5-diamine salt obtained by the method is substantially free of or does not detectable amounts of o-toluidine. In some preferred embodiments, the toluene-2,5-diamine or toluene-2,5-diamine salt obtained by the method has a content of o-toluidine of less than 50 ppm. In some preferred embodiments, the toluene-2,5-diamine or toluene-2,5-diamine salt obtained by the method has a content of o-toluidine of less than 25 ppm. In some preferred embodiments, the toluene-2,5-diamine or toluene-2,5-diamine salt obtained by the method has a content of o-toluidine of less than 10 ppm. In some preferred embodiments, the toluene-2,5-diamine or toluene-2,5-diamine salt obtained by the method has a content of o-toluidine of less than 1 ppm. In some preferred embodiments, the toluene-2,5-diamine or toluene-2,5-diamine salt obtained by the method has a content of o-toluidine of less than 0.1 ppm. In some preferred embodiments, the toluene-2,5-diamine or toluene-2,5-diamine salt obtained by the method has a content of o-toluidine of less than 0.01 ppm. In some preferred embodiments, the toluene-2,5-diamine or toluene-2,5-diamine salt obtained by the method is free of o-toluidine.

[0100] Scheme 3

[0101] In another aspect of the application, the present application relates to a process for the preparation of toluene-2,5-diamine and salts thereof starting from methyl-p-benzoquinone.

[0102] In one embodiment, the process comprises the following steps:

[0103] ii) reacting methyl-p-benzoquinone with a hydroxylamine salt to obtain compound (II):

[0104] In a further embodiment, the process further comprises the following steps after step ii):

[0105] iii) reducing compound (II) to obtain toluene-2,5-diamine of compound (III):

[0106] In a more particular embodiment, the process comprises the following steps:

[0107] ii) reacting methyl-p-benzoquinone with a hydroxylamine salt to obtain compound (II):

[0108] and

[0109] iii) reducing compound (II) to obtain toluene-2,5-diamine of compound (III):

[0110] In some embodiments, step ii) involves synthesizing compound (II) using methyl-p-benzoquinone. In some embodiments, the methyl-p-benzoquinone in step ii) is reacted with a hydroxylamine salt in water or a mixed solvent of water and an organic acid.

[0111] In some embodiments, the organic acid is selected from acetic acid, hydroxyacetic acid, propionic acid, lactic acid, pyruvic acid, malonic acid, fumaric acid, maleic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, citric acid, methylsulfonic acid, ethanesulfonic acid, benzenesulfonic acid, or formic acid. In preferred embodiments, the organic acid is acetic acid.

[0112] In some embodiments, the hydroxylamine salt is an inorganic acid salt of hydroxylamine. In some embodiments, the hydroxylamine salt is selected from one or more of hydroxylamine hydrochloride, hydroxylamine sulfate, hydroxylamine nitrate, or hydroxylamine phosphate. In some embodiments, the hydroxylamine salt is hydroxylamine hydrochloride. In some embodiments, the hydroxylamine salt is hydroxylamine sulfate. In some embodiments, the hydroxylamine salt is hydroxylamine nitrate. In some embodiments, the hydroxylamine salt is hydroxylamine phosphate.

[0113] In some embodiments, step ii) is reacted at 50-100°C, preferably 45-75°C.

[0114] In some specific embodiments, step ii) comprises: mixing methyl-p-benzoquinone and a hydrochloride, sulfate, and / or phosphate salt of hydroxylamine in a mixed solvent of water and acetic acid, warming to 50-100°C, reacting to determine the reaction endpoint by HPLC, after the reaction is complete, cooling to 0-10°C. Separating the solid by filtration to obtain compound (II), which is washed with water and used in the next step. Those skilled in the art will recognize that other reagents and / or conditions can be used to perform step ii).

[0115] In some embodiments, step iii) involves synthesizing compound (III) using compound (II). In some embodiments, the reduction in step iii) comprises: adding a catalyst to a solution of compound (II), and then adding hydrazine hydrate, formic acid, sulfur dioxide, sodium metabisulfite, sodium hyposulfite, or the like.

[0116] In some embodiments, the catalyst is selected from one or more of palladium on carbon, nickel, iron trichloride. In some embodiments, the catalyst is palladium on carbon. In some embodiments, the catalyst is nickel. In some embodiments, the catalyst is iron trichloride. In some embodiments, the solution of compound (II) is a solution of compound (II) in methanol, tetrahydrofuran, n-butanol, or ethanol, and the like, preferably ethanol.

[0117] In some embodiments, step iii) comprises reacting at 0 to the boiling point of the solvent, preferably at 0-80 °C, 0-50 °C, 50-80 °C.

[0118] In other embodiments, the reduction in step iii) comprises adding a catalyst to the solution of compound (II) and then bubbling in hydrogen gas, preferably at 25-120 °C, 1-50 atmospheres of pressure.

[0119] In some embodiments, the catalyst is selected from one or more of palladium on carbon, Raney nickel. In some embodiments, the catalyst is palladium on carbon. In some embodiments, the catalyst is Raney nickel.

[0120] In some specific embodiments, step iii) comprises dissolving compound (II) in ethanol, adding a catalyst, which can be one or more of palladium on carbon, nickel, iron trichloride. Adding hydrazine hydrate drop-wise at 50-80 °C, controlling the end point by HPLC, after the reaction is complete, filtering off the catalyst, evaporating the ethanol and volatiles, and distilling to obtain toluene-2,5-diamine (III). Those skilled in the art will recognize that other reagents and / or conditions can be used to perform step iii).

[0121] In other specific embodiments, step iii) comprises dissolving compound (II) in ethanol, adding a catalyst, which can be one or more of palladium on carbon, Raney nickel. Bubbling in hydrogen gas, controlling the end point by HPLC, after the reaction is complete, filtering off the catalyst, evaporating the ethanol and volatiles, and distilling to obtain toluene-2,5-diamine (III). Those skilled in the art will recognize that other reagents and / or conditions can be used to perform step iii).

[0122] In some embodiments, the method further involves synthesizing a salt of toluene-2,5-diamine. In some embodiments, after step iii) an acid is added to the solution of compound (III) and reacted to obtain a salt of toluene-2,5-diamine.

[0123] In some embodiments, the acid is an inorganic acid. In further embodiments, the inorganic acid is selected from one or more of hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid. In further embodiments, the inorganic acid is hydrochloric acid. In further embodiments, the inorganic acid is hydrobromic acid. In further embodiments, the inorganic acid is phosphoric acid. In further embodiments, the inorganic acid is sulfuric acid. In further embodiments, the inorganic acid is perchloric acid.

[0124] In some specific embodiments, the method further involves synthesizing toluene-2,5- diamine sulfate salt. The method comprises, after the reaction of step iii) is complete, filtering off the catalyst, and directly adding sulfuric acid dropwise into an ethanol solution of toluene-2,5-diamine, and the solid that precipitates is toluene-2,5-diamine sulfate salt (IV). Those skilled in the art will recognize that other reagents and / or conditions can be used to perform this reaction.

[0125] In some specific embodiments, the method further involves purifying toluene-2,5-diamine sulfate salt (IV), comprising dissolving the solid toluene-2,5-diamine sulfate salt (IV) in water, adjusting the pH to 8 with aqueous sodium hydroxide or ammonia, adding activated carbon, stirring, warming to 50-100 °C, filtering off the activated carbon, and adding the filtered mother liquor dropwise to dilute sulfuric acid, and the solid that precipitates is the purified toluene-2,5-diamine sulfate salt (IV). Those skilled in the art will recognize that other reagents and / or conditions can be used to purify toluene-2,5-diamine sulfate salt (IV).

[0126] In some embodiments, the method is characterized in that the toluene-2,5-diamine or toluene-2,5-diamine salt obtained by the method contains substantially no or no detectable amount of o-toluidine. In some preferred embodiments, the toluene-2,5-diamine or toluene-2,5-diamine salt obtained by the method contains less than 50 ppm of o-toluidine. In some preferred embodiments, the toluene-2,5-diamine or toluene-2,5-diamine salt obtained by the method contains less than 25 ppm of o-toluidine. In some preferred embodiments, the toluene-2,5-diamine or toluene-2,5-diamine salt obtained by the method contains less than 10 ppm of o-toluidine. In some preferred embodiments, the toluene-2,5-diamine or toluene-2,5-diamine salt obtained by the method contains less than 1 ppm of o-toluidine. In some preferred embodiments, the toluene-2,5-diamine or toluene-2,5-diamine salt obtained by the method contains less than 0.1 ppm of o-toluidine. In some preferred embodiments, the toluene-2,5-diamine or toluene-2,5-diamine salt obtained by the method contains less than 0.01 ppm of o-toluidine. In some preferred embodiments, the toluene-2,5-diamine or toluene-2,5-diamine salt obtained by the method contains no o-toluidine.

[0127] Exemplary schemes

[0128] The compound 2-methylphenol is used as the raw material and reacts with sodium nitrite in the presence of acetic acid to obtain nitroso compound (I). The nitroso compound (I) reacts with a salt of hydroxylamine to obtain bisoxime compound (II). The bisoxime compound (II) is reduced to obtain the target product toluene-2,5-diamine (III). The toluene-2,5-diamine is salted with sulfuric acid to obtain toluene-2,5-diamine sulfate (IV).

[0129] The bisoxime compound (II) can also be obtained using m-cresol or methyl-p-benzoquinone as the raw material. The synthetic method using m-cresol as the raw material is similar to the route using 2-methylphenol. The m-cresol reacts with a salt of nitrite under acidic conditions to obtain the corresponding nitroso compound (V). The nitroso compound (V) reacts with a salt of hydroxylamine to obtain the bisoxime (II). When methyl-p-benzoquinone is used as the raw material, the bisoxime compound (II) is directly obtained by reacting the methyl-p-benzoquinone with a salt of hydroxylamine hydrochloride. The chemical reaction formula is as follows:

[0130] A typical synthetic method is as follows:

[0131] The synthesis of compound (I) is carried out by mixing 2-methylphenol and acetic acid, and then adding dropwise to an aqueous solution of sodium nitrite under stirring at 0-95°C. The reaction is judged by HPLC to determine the end point of the reaction. After the reaction is completed, the temperature is lowered to 0-10°C. The solid is separated by filtration. The solid is compound (I), which is washed with water and used in the next step. Instead of sodium nitrite, other metal salts such as potassium nitrite can also be used.

[0132] The synthesis of compound (II) is carried out by mixing compound (I) and hydroxylamine hydrochloride, sulfate or phosphate in a mixed solvent of water and acetic acid, and then heating to 50-100°C. The reaction is judged by HPLC to determine the end point of the reaction. After the reaction is completed, the temperature is lowered to 0-10°C. The solid is separated by filtration. The solid is compound (II), which is washed with water and used in the next step.

[0133] The synthesis of compound (III) is carried out by dissolving compound (II) in ethanol, and then adding a catalyst, which can be one or a combination of palladium / carbon, nickel, and ferric trichloride. Hydrazine hydrate is added dropwise at 50-80°C. The end point of the reaction is controlled by HPLC. After the reaction is completed, the catalyst is filtered off, and ethanol and volatile substances are distilled off. Toluene-2,5-diamine (III) is obtained by distillation.

[0134] The synthesis of compound (III) can also be carried out by catalytic hydrogenation. Compound (II) is dissolved in ethanol, and then a catalyst, which can be one or a combination of palladium / carbon and Raney nickel, is added. Hydrogen is introduced for the reaction. The end point of the reaction is controlled by HPLC. After the reaction is completed, the catalyst is filtered off, and ethanol and volatile substances are distilled off. Toluene-2,5-diamine (III) is obtained by distillation.

[0135] The synthesis of compound (IV) is carried out by dissolving compound (II) in ethanol, and then adding a catalyst, which can be one or a combination of palladium / carbon, nickel, and ferric trichloride. Hydrazine hydrate is added dropwise at 50-80°C. The end point of the reaction is controlled by HPLC. After the reaction is completed, the catalyst is filtered off, and sulfuric acid is added dropwise in the ethanol solution. The solid obtained is toluene-2,5-diamine sulfate (IV).

[0136] The purification of compound (IV) is carried out by dissolving the solid toluene-2,5-diamine sulfate (IV) in water, adjusting the pH to 8 with sodium hydroxide aqueous solution or ammonia water, adding activated carbon, stirring, and heating to 50-100°C. The activated carbon is filtered off, and the filtrate is added dropwise to dilute sulfuric acid. The solid obtained is filtered off to obtain qualified toluene-2,5-diamine sulfate (IV).

[0137] The advantages of this route are as follows: (1) the starting material is easy to obtain, such as 2-methylphenol which is a monomer of engineering plastic PPO and is obtained by methylating phenol, and there is a million-ton device for producing the same, and other raw and auxiliary materials are bulk basic chemicals; (2) each reaction can be completed in water, which is intrinsically safe; (3) standard equipment is used in the whole production process, and the operation is simple; (4) the intermediates are stable, and separation is simple without the need for purification and drying; (5) the reduction of oxime is much milder than the reduction of nitro; (6) the wastewater can be reused and is easy to treat to meet the requirements; and (7) the product does not use or produce the prohibited ingredient o-toluidine, and the quality is excellent.

[0138] Embodiment

[0139] The preferred embodiments are described in the present application, and those skilled in the art can make appropriate changes to the embodiments and examples described in the present application on the basis of the present application. Therefore, the content claimed in the present application includes all equivalent modifications and changes to the subject matter of the claims of the present application within the scope permitted by law.

[0140] Embodiment 1

[0141] Synthesis of compound (I): 2-methyl-4-nitrosophenol (monoximation)

[0142] Prepare a sodium nitrite aqueous solution: add 147.36 g of sodium nitrite and 1000 g of water into a 2 L three-necked flask, and stir until dissolved.

[0143] Prepare an acetic acid / 2-methylphenol mixture: add 144.72 g of glacial acetic acid and 200 g of 2-methylphenol into a 500 ml beaker, stir until uniform, and transfer into a 500 ml dropping funnel, and wait for use.

[0144] Cool the sodium nitrite aqueous solution to 0-5℃, and drop the prepared acetic acid / 2-methylphenol mixture, drop completely in about 4 h, continue to react for 3 h, turn off the ice machine, and naturally warm to room temperature, stir overnight, about 16 h, take a sample for detection, and the reaction is complete. Perform suction filtration, add 500 ml of pure water to the filter cake for washing once, perform suction filtration, and the pH is 6-7 to obtain compound (I), the wet weight of the filter cake is 508 g (moisture: 50.93%), and the yield is 98.26%.

[0145] LR-MS ESI [M-H] = 136.2.

[0146] Embodiment 2

[0147] Synthesis of compound (I): 2-methyl-4-nitrosophenol (monoximation)

[0148] Preparation of potassium nitrite aqueous solution: 182.46 g of potassium nitrite was added into a 2 L three-necked flask, 1000 g of water was added, and stirred until dissolved.

[0149] Preparation of acetic acid / 2-methyl phenol mixture: 144.72 g of glacial acetic acid and 200 g of 2-methyl phenol were added into a 500 ml beaker, stirred until dissolved, and transferred into a 500 ml dropping funnel, and used after cooling.

[0150] The potassium nitrite aqueous solution was cooled to 0-5°C, and the prepared acetic acid / 2-methyl phenol mixture was added dropwise. The dropwise addition was completed in about 4 h, and the reaction was continued for 3 h. The ice machine was turned off, and the temperature was naturally increased to room temperature. The stirring was continued overnight, about 16 h. The reaction was completed after sampling and testing. Filtration was performed, the filter cake was washed once with 500 ml of pure water, and filtration was performed again. The pH was 6-7, and 242 g of compound (I) was obtained after drying, with a yield of 95.38%.

[0151] LR-MS ESI [M-H] = 136.2.

[0152] Example 3

[0153] Synthesis of compound (II) (bisoxime):

[0154] Preparation of hydroxylamine hydrochloride aqueous solution: 193.05 g of hydroxylamine hydrochloride was added into 386.1 g of water, and stirred until dissolved, and used after cooling.

[0155] The above 508 g of compound (I) was added into a 5 L three-necked flask, 623.32 g of pure water and 814 g of glacial acetic acid were added, and stirred until dissolved. The prepared hydroxylamine hydrochloride aqueous solution was added dropwise, and the dropwise addition was completed in about 4 h. The reaction was continued for 24 h, and sampling and testing were performed. The HPLC peak area of compound (I) was less than 2%. The temperature was decreased to 0-10°C. Filtration was performed, and the filter cake was washed twice with water. Compound (II) was obtained, with a wet weight of 329.3 g (moisture content 28.5%) and a yield of 85.10%.

[0156] LR-MS ESI [M-H] = 151.05.

[0157] Example 4

[0158] Synthesis of compound (II) (bisoxime):

[0159] Preparation of hydroxylamine sulfate aqueous solution: 200 g of hydroxylamine sulfate was added into 390 g of water, and stirred until dissolved, and used after cooling.

[0160] Into a 5L three neck flask, add 250g of the same batch of compound (I) from Example 1 above, add 600g of purified water, 800g of glacial acetic acid, stir well, and heat to 67°C. Add dropwise the prepared aqueous hydroxylamine sulfate solution, dropwise for about 4h, and keep the reaction temperature constant (24h). Take a sample for analysis, and HPLC analysis shows that the peak area of compound (I) is <2%. Cool to 0-10°C. Filter, and wash the filter cake twice with water to obtain compound (II) with a yield of 86.33%.

[0161] LR-MS ESI [M-H] = 151.05.

[0162] Example 5

[0163] Synthesis of toluene-2,5-diamine (III) and toluene-2,5-diamine sulfate (IV):

[0164] 1. Ethanol solution preparation: Into a 5L three neck flask, add 1175.1g of ethanol, 2.35g of ferric chloride, and 23.5g of activated carbon, and stir for 30min.

[0165] 2. Add the above 329.3g of compound (II) to the ethanol solution prepared in step 1, and stir while heating to 80°C to reflux. Add dropwise 174g of 80% hydrazine hydrate, and react until the remaining 8% of the intermediate is consumed. Cool to 0-5°C to obtain compound (III) toluene-2,5-diamine.

[0166] 3. Add dropwise 1 eq of 30% dilute sulfuric acid to the solution in step 2 to precipitate, and filter to obtain the filter cake, which is toluene-2,5-diamine sulfate (IV). Dry the filter cake, and the weight is 298g, which is a yield of 86.9%.

[0167] Toluene-2,5-diamine sulfate: 1 H NMR (400MHz, D2O) δ 7.42 (d, J = 8.4 Hz, 1H), 7.34 (1H), 7.26-7.29 (m, 1H), 2.352 (s, 3H).

[0168] The detection of o-toluidine was performed using an external standard method (HPLC-ES) using a Hypersil ODS 5um C18 (4.6x250mm) column, a detection wavelength of 228nm, and a mobile phase of 35% methanol-65% 0.02M phosphate buffer at a flow rate of 1mL / min. The detection result for this sample was that o-toluidine was not detected.

[0169] Example 6

[0170] Synthesis of toluene-2,5-diamine (III) and toluene-2,5-diamine sulfate (IV):

[0171] 1. Ethanol solution preparation: To a 5L three neck flask was added 1000g ethanol, 5g palladium on carbon (5%, 54% moisture), and stirred for 30 minutes.

[0172] 2. To the solution was added 300g of oven dried compound (II) and heated to 80°C with stirring. 174g of 80% hydrazine hydrate was added dropwise and the reaction was continued until 3% of the intermediate remained. The reaction was cooled to 0-5°C to give compound (III) toluene-2,5-diamine.

[0173] 3. The reaction was acidified with 1 eq of 30% sulfuric acid and filtered to give compound (IV) toluene-2,5-diamine sulfate. The solid was oven dried to give 401g of product in 92.2% yield. This sample was tested and found to be free of o-toluidine.

[0174] Example 7

[0175] Synthesis of toluene-2,5-diamine (III) and toluene-2,5-diamine sulfate (IV):

[0176] 1. To a 5L three neck flask was added 1000g ethanol, 5g palladium on carbon (5%, 54% moisture), and stirred for 30 minutes. Sulfur dioxide was carefully bubbled into the solution and the reaction was heated to 40°C and stirred for 24 hours. The reaction was cooled to 0-5°C to give compound (III) toluene-2,5-diamine.

[0177] 2. The reaction was acidified with 1 eq of 30% sulfuric acid and filtered to give compound (IV) toluene-2,5-diamine sulfate. The solid was oven dried to give 401g of product in 92.2% yield. This sample was tested and found to be free of o-toluidine.

[0178] Example 8

[0179] Synthesis of toluene-2,5-diamine (III) and toluene-2,5-diamine sulfate (IV):

[0180] 1. To a 5L three neck flask was added 1000g ethanol, 5g palladium on carbon (5%, 54% moisture), and stirred for 30 minutes. Sulfur dioxide was carefully bubbled into the solution and the reaction was heated to 40°C and stirred for 24 hours. The reaction was cooled to 0-5°C to give compound (III) toluene-2,5-diamine.

[0181] 2. The reaction was acidified with 1 eq of 30% sulfuric acid and filtered to give compound (IV) toluene-2,5-diamine sulfate. The solid was oven dried to give 401g of product in 92.2% yield. This sample was tested and found to be free of o-toluidine.

[0182] Example 9

[0183] Synthesis of compound (V) (monoximation) of 3-methyl-4-nitrosophenol

[0184] Prepare sodium nitrite aqueous solution: add 147.36 g of sodium nitrite into a 2 L three-necked flask, add 1000 g of water, and stir until dissolved.

[0185] Prepare acetic acid / 3-methylphenol mixture: add 144.72 g of glacial acetic acid and 200 g of m-methylphenol into a 500 ml beaker, stir until dissolved, and transfer into a 500 ml dropping funnel, and wait for use.

[0186] Cool the sodium nitrite aqueous solution to 0-5°C, and add the prepared acetic acid / 3-methylphenol mixture dropwise, which takes about 4 h, continue to react for 3 h, turn off the ice machine, and naturally warm to room temperature, stir overnight, about 16 h, and sample for detection, which shows that the reaction is complete. Filter, add 500 ml of pure water to the filter cake for washing once, filter, and obtain compound V with pH = 6-7, filter cake wet weight 499 g (moisture: 50.93%), and yield 96.33%.

[0187] LR-MS ESI [M-H] = 136.2.

[0188] Example 10

[0189] Synthesis of compound (II) (dioximation):

[0190] Prepare hydroxylamine hydrochloride aqueous solution: add 200 g of hydroxylamine hydrochloride into 400 g of water, and stir until dissolved, and wait for use.

[0191] Add 250 g of dried compound (V) into a 5 L three-necked flask, add 800 g of pure water and 800 g of glacial acetic acid, stir until dissolved, and warm to 75°C. Add the prepared hydroxylamine hydrochloride aqueous solution dropwise, which takes about 4 h, and keep the temperature for reaction (24 h), sample for detection, and HPLC detection reaction, which shows that when the peak area of (V) is less than 3%, cool to 0-10°C. Filter, wash the filter cake with water twice, and obtain compound (II), which is dried under reduced pressure to obtain a solid 223.3 g, and yield 79.92%.

[0192] LR-MS ESI [M-H] = 151.05.

[0193] Example 11

[0194] Synthesis of compound (II) (dioximation) using methyl-p-benzoquinone as raw material

[0195] Prepare hydroxylamine sulfate aqueous solution: add 200 g of hydroxylamine sulfate into 390 g of water, and stir until dissolved, and wait for use.

[0196] Add 200 g of methyl-p-benzoquinone, 300 g of pure water, and 800 g of glacial acetic acid to a 5 L three-necked flask, stir well, and heat to 67 °C. Add the prepared hydroxylamine sulfate aqueous solution dropwise over approximately 4 hours, maintain the reaction temperature for 24 hours, and take a sample for analysis. HPLC analysis showed that the peak area of ​​compound (I) was <2%. Cool to 0-10 °C. Filter, wash the filter cake twice with water to obtain compound (II), yield: 90.26%.

[0197] LR-MS ESI[MH] = 151.05.

[0198] Example 12

[0199] Purification of toluene-2,5-diamine sulfate:

[0200] 200g of crude toluene-2,5-diamine sulfate (IV) solid was added to a 5L three-necked flask, followed by 850g of pure water and 1 eq of 10% sodium hydroxide (pH≈8) to dissolve it. The mixture was heated to 70℃, and 34g of activated carbon was added and stirred for adsorption for 20min. The mixture was then cooled to 0-5℃ and filtered. 15g of activated carbon was added to the filtrate for a second adsorption and filtration. 1.1 eq of 50% sulfuric acid was added to the filtrate and acidified at 0-5℃ to precipitate the solid. The filtrate was filtered and dried to obtain 171g of white solid. The yield was 85.5%. The filtrate can be reused.

Claims

1. A process for the preparation of toluene-2,5-diamine or a salt thereof comprising the steps of: ii) reacting compound (I) with a salt of hydroxylamine to obtain compound (II):

2. The process of claim 1 further comprising the step of: i) reacting 2-methylphenol with a nitrite salt to obtain compound (I):

3. The process of claim 1 or 2 further comprising the step of: iii) reducing compound (II) to obtain compound (III) toluene-2,5-diamine:

4. A process for the preparation of toluene-2,5-diamine or a salt thereof comprising the steps of: ii) reacting compound (V) with a salt of hydroxylamine to obtain compound (II):

5. The process of claim 4 further comprising the step of: i) reacting m-cresol with a nitrite salt to obtain compound (V):

6. The process of claim 4 or 5 further comprising the step of: iii) reducing compound (II) to obtain compound (III) toluene-2,5-diamine:

7. A process for the preparation of toluene-2,5-diamine or a salt thereof comprising the steps of: ii) reacting methyl-p-benzoquinone with a hydroxylamine salt to obtain compound (II):

8. The process of claim 7 further comprising the step of: iii) reducing compound (II) to obtain compound (III) toluene-2,5-diamine:

9. The process of claim 2 or 5 wherein step i) is reacted in the presence of an acid.

10. The process of claim 9 wherein the acid of step i) is an organic acid.

11. The process of claim 10 wherein the organic acid is acetic acid, formic acid, propionic acid, oxalic acid or malonic acid, preferably acetic acid.

12. The process of any one of claims 2, 5, 10 and 11 wherein the nitrite salt is selected from one or more of sodium nitrite, potassium nitrite, calcium nitrite or magnesium nitrite.

13. The process of claim 12 wherein the nitrite salt is sodium nitrite.

14. The process of any one of claims 1-13 wherein step ii) further comprises: mixing compound (I), compound (V) or methyl-p-benzoquinone with a hydroxylamine salt in water or a mixture of water and an organic acid, heating to obtain compound (II).

15. The process of claim 14 wherein the organic acid is acetic acid, formic acid, propionic acid, oxalic acid or malonic acid, preferably acetic acid.

16. The process of any one of claims 1-15 wherein the hydroxylamine salt is selected from one or more of hydroxylamine hydrochloride, hydroxylamine sulfate, hydroxylamine nitrate or hydroxylamine phosphate.

17. The process of claim 16 wherein the hydroxylamine salt is hydroxylamine hydrochloride.

18. The process of any one of claims 3, 6 and 8 wherein the reduction comprises: a. adding a catalyst to a solution of compound (II); and b. adding hydrazine hydrate, formic acid, ammonium formate, sodium sulfite, sulfur dioxide, iron powder or sodium metabisulfite.

19. The process of claim 18 wherein the catalyst is selected from one or more of palladium on carbon, nickel, iron trichloride.

20. The process of claim 19 wherein the catalyst is iron trichloride.

21. The process of any one of claims 3, 6 and 8 wherein the reduction comprises: a. adding a catalyst to a solution of compound (II); and b. bubbling hydrogen gas.

22. The process of claim 21 wherein the catalyst is selected from one or more of palladium on carbon, Raney nickel.

23. The process of any one of claims 18-22 wherein the solution of compound (II) is a solution of compound (II) in methanol, tetrahydrofuran, n-butanol or ethanol, preferably ethanol.

24. The process of any one of claims 1-23, further comprising reacting the toluene- 2,5-diamine of compound (III) with an acid to obtain a toluene-2,5-diamine salt.

25. The process of claim 24, wherein the toluene-2,5-diamine of compound (III) is reacted with sulfuric acid to obtain a toluene-2,5-diamine sulfate salt.

26. Toluene-2,5-diamine or a salt thereof prepared according to the method of any one of claims 1-25, characterized by the toluene-2,5-diamine or salt thereof contains no or no detectable o-toluidine.

27. The toluene-2,5-diamine or salt thereof of claim 26, wherein the no or no detectable o-toluidine means that the o-toluidine content is less than 50 ppm.

28. The toluene-2,5-diamine or salt thereof of claim 26, wherein the no or no detectable o-toluidine means that the o-toluidine content is less than 25 ppm.

29. The toluene-2,5-diamine or salt thereof of claim 26, wherein the no or no detectable o-toluidine means that the o-toluidine content is less than 10 ppm.

30. The toluene-2,5-diamine or salt thereof of claim 26, wherein the no or no detectable o-toluidine means that the o-toluidine content is less than 1 ppm.

31. The toluene-2,5-diamine or salt thereof of claim 26, wherein the no or no detectable o-toluidine means that the o-toluidine content is less than 0.1 ppm.

32. The toluene-2,5-diamine or salt thereof of claim 26, wherein the no or no detectable o-toluidine means that the o-toluidine content is less than 0.01 ppm.

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