Method for preparing indigo or its substituted derivatives

Abstract

The present invention relates to the synthesis of dyes. More specifically, the present invention is a method for preparing substituted or unsubstituted indigo, which comprises reacting a substituted or unsubstituted anthranilic acid with glyoxylic acid in a solvent in the presence of a metal catalyst under hydrogenation to obtain a substituted or unsubstituted 2-(carboxymethylamino)benzoic acid, and a step of converting the substituted or unsubstituted 2-(carboxymethylamino)benzoic acid into a substituted or unsubstituted indigo.

Description

Technical Field

[0001] The present invention relates to the synthesis of dyes. More particularly, the present invention relates to a method for preparing substituted or unsubstituted indigo starting from substituted or unsubstituted anthranilic acid.

Background Art

[0002] In particular, indigo has been known for millennia for its strong, deep blue color, as found in denim and Tuareg scarves. Historically, indigo was obtained mainly by the extraction of indican contained in plants of the Indigofera family, particularly the indigo plant, followed by oxidation. In the 17th and 18th centuries, indigo plantations were established in North America, French Antilles, and India to meet the strong demand for indigo in Western countries. However, the production of natural indigo has gradually been replaced by production by chemical synthesis. Currently, 50,000 tons of synthetic indigo are produced each year, and most of this production is for dyeing 4 billion products of denim clothing produced each year.

[0003] Since the first synthesis starting from 2-nitrobenzaldehyde and acetone was carried out by chemist Adolf von Baeyer at the end of the 19th century, several methods for preparing indigo have been proposed.

[0004] Karl Heumann (Chem. Ber., 1890, 3431) proposed two methods for the synthesis of indigo. The first method involves the reaction of aniline and chloroacetic acid to form N-phenylglycine, which is then converted to indoxyl in a basic medium. Indoxyl is then oxidized to form indigo. However, this first method gives a low yield. The second method uses anthranilic acid instead of aniline: anthranilic acid is reacted with chloroacetic acid to produce 2-(carboxymethylamino)benzoic acid. 2-(Carboxymethylamino)benzoic acid is then contacted with a base to form 2-indoxylcarboxylic acid. Finally, indigo is produced by heating and oxidizing the above acid. However, the yield obtained is still low, and the method is very energy-consuming, not environmentally friendly, and uses toxic reactants, especially chloroacetic acid.

[0005] The formation of 2-(carboxymethylamino)benzoic acid starting from anthranilic acid and chloroacetic acid is a major step in the synthesis of indigo. Although various reaction conditions are described, the yields obtained are not high enough for industrial processes. For example, the reaction described in patent application US Patent No. 2008 / 051426 was carried out at 40 - 45 °C in the presence of sodium bicarbonate, resulting in a yield of at most 80%. Lai et al. (Helvetica Chimica Acta 2008, 91, 1975 - 1983) describe the same reaction carried out using reflux of water in the presence of a mixture of sodium bicarbonate and sodium hydroxide. A yield of 90% of 2-(carboxymethylamino)benzoic acid is obtained. In addition to the insufficient yields, the chloroacetic acid used in these methods is a toxic reactant.

[0006] Koeppe et al. (ChemPhotoChem 2019, 3, 613 - 618) describe the formation of 2-(carboxymethylamino)benzoic acid by reductive amination from anthranilic acid and ethyl glyoxylate in the presence of sodium cyanoborohydride. However, this reaction produces a large amount of waste, especially due to the use of sodium cyanoborohydride, which is used in large quantities and cannot be recycled. Furthermore, the use of glyoxylate requires an additional step of saponification with sodium hydroxide to obtain the above acid.

Prior Art Documents

Patent Documents

[0007]

Patent Document 1

Patent Document 2

Non-Patent Documents

[0008]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

Summary of the Invention

Problems to be Solved by the Invention

[0009] Therefore, there still exists a practical need for a simple, efficient, environmentally friendly, and improved method for preparing indigo.

Means for Solving the Problems

[0010] In the context of the present invention, the inventors have developed a method for preparing substituted or unsubstituted indigo in three steps starting from substituted or unsubstituted anthranilic acid and glyoxylic acid, which is simple and suitable for industrial-scale applications. The main steps of this method involve using a heterogeneous metal catalyst, particularly a palladium catalyst, under a hydrogen atmosphere to afford substituted or unsubstituted 2-(carboxymethylamino)benzoic acid in excellent yields. This acid can then be efficiently converted to substituted or unsubstituted indigo, particularly by cyclization in the presence of acetic anhydride and dimerization in a basic medium. The method is extremely environmentally friendly as it produces little to no waste and uses recyclable solvents and catalysts. Furthermore, the method uses non-toxic glyoxylic acid that can be obtained from ethanol or bio-derived glycolic acid.

[0011] Accordingly, the present invention provides a method for preparing a compound of formula (III):

[0012]

Chemical formula

[0013] (wherein each of R1, R2, R3, and R4 is independently hydrogen, halogen, -CN, -NO2, -C(O)H, -SO3H, -CO2H, -SO3M1 + , -CO2 - M2 + , -SO3R5, -CO2R6, -C(O)R7, or -OR8, and M1 + and M2 + are each independently a cation, and R5, R6, R 7、 and R8 are each independently a C1-C6 aliphatic group or aryl) , comprising the following steps: a) In a solvent, in the presence of a metal catalyst, under hydrogenation, a compound of formula (I):

[0014]

Chemical formula

[0015] (wherein each of R1, R2, R3, and R4 is as defined above) Reacting the compound of formula (I):

[0016]

Chemical formula

[0017] (wherein each of R1, R2, R3, and R4 is as defined above) to obtain a compound of formula (II): b) converting the compound of formula (II) to a compound of formula (III); c) recovering the compound of formula (III); and a method comprising the steps of:

[0018] In a preferred embodiment, R1, R2, R3, and R4 are hydrogen.

[0019] Preferably, the metal catalyst is a palladium, nickel, or platinum catalyst. More preferably, the metal catalyst is palladium on carbon, palladium on aluminum oxide, nickel on aluminum oxide, nickel on aluminum oxide / silica, or platinum on carbon. Even more preferably, the metal catalyst is palladium on carbon.

[0020] In a particular embodiment, the method according to the invention further comprises, after step a), recovering the metal catalyst, preferably by filtration.

[0021] In another particular embodiment, the method according to the invention further comprises, after step a), recovering the solvent from step a), preferably by distillation or evaporation under reduced pressure.

[0022] Preferably, the solvent from step a) is a polar solvent such as THF or a THF / water mixture.

[0023] According to another specific embodiment, glyoxylic acid is obtained from ethanol or from bio-derived glycolic acid.

[0024] According to another specific embodiment, the reaction in step a) is carried out at a temperature between 35 °C and 120 °C, preferably for a time between 30 seconds and 8 hours.

[0025] In particular, in step a), the amount of the metal catalyst is between 0.0001% by mass and 40% by mass, preferably between 5% by mass and 25% by mass, based on the mass of the compound of formula (I), and the hydrogen pressure is between 1 and 30 bar, preferably between 5 and 20 bar.

[0026] In particular, step b) comprises b1) reacting the compound of formula (II) as defined in the present application with acetic anhydride to obtain a compound of formula (II'):

[0027]

Chemical formula

[0028] (wherein each of R1, R2, R3, and R4 is independently hydrogen, halogen, -CN, -NO2, -C(O)H, -SO3H, -CO2H, -SO3 - M1 + 、-CO2 - M2 + 、-SO3R5, -CO2R6, -C(O)R7, or -OR8, M1 + and M2 + each of which is independently a cation, R5, R6, R 7、 and R8 each independently is a C1-C6 aliphatic group or aryl) to obtain a compound of b2) reacting the compound of formula (II') with a base to obtain the compound of formula (III) as defined in the present application and comprises.

[0029] According to a preferred embodiment, the method according to the invention comprises the following steps: a) reacting a compound of formula (I) as defined in the present application with glyoxylic acid in a polar solvent, in the presence of hydrogen atmosphere and in the presence of palladium on carbon, at a temperature between 35 °C and 120 °C, preferably for a time between 30 seconds and 8 hours, to obtain a compound of formula (II) as defined in the present application; b1) reacting the compound of formula (II) with acetic anhydride in the presence of a base, preferably an amine base, such as triethylamine, the reaction being - at a temperature between -10 °C and 40 °C, preferably for a time between 15 minutes and 3 hours, and then - at a temperature between 70 °C and 110 °C, preferably for a time between 15 minutes and 3 hours, sequentially carried out to obtain a compound of formula (II') as defined in the present application; b2) reacting the compound of formula (II') with a base, preferably a hydroxide, such as sodium hydroxide, in water, at a temperature between 80 °C and 110 °C, preferably for a time between 1 hour and 5 hours, to obtain a compound of formula (III) as defined in the present application; c) recovering the compound of formula (III); and comprises.

[0030] In a particular embodiment, the compound of formula (I), particularly anthranilic acid, is of biological origin. In a more detailed embodiment, the compound of formula (I), particularly anthranilic acid, is produced by a recombinant host cell, which is preferably a microorganism.Preferably, the recombinant microbial host cell is selected from the genus Escherichia (Escherichia coli), Streptomyces, Bacillus, Cupridavidus, Corynebacterium, Mycobacterium, Kitasatospora, Luteipulveratus, Thermobifida, Thermomonospora, Frankia, Pseudonocardia, Saccharothrix, Kutzneria, Lentzea, Prauserella, Salinispora, Micromonospora, Actinoplanes, Catenulispora, Mycolicibacterium, Dietzia, Aeromicrobium, Nonomuraea, Blastococcus, Modestobacter, Saccharopolyspora, Amycolatopsis, Actinopolyspora, Acidimicrobium, Photorhabdus, Hoeflea, Azospirillum, Crinalium, and Cylindrospermum, preferably selected from the genus Escherichia, Streptomyces, Corynebacterium, and Bacillus, and even more preferably, the recombinant microbial host cell is Escherichia coli.

Modes for Carrying Out the Invention

[0031] Definition The expression "C x ~C y " related to a chemical group, where x and y are integers, represents that the chemical group contains x to y carbon atoms. For example, when the expression C1~C6 is related to a chemical group, this represents that the chemical group contains 1 to 6 carbon atoms, in particular, 1, 2, 3, 4, 5, or 6 carbon atoms.

[0032] "Aliphatic group" means a linear or branched, saturated or unsaturated, cyclic or acyclic (preferably acyclic) hydrocarbon group. In a specific embodiment, the C1~C6 aliphatic group is C1~C6 alkyl, C2~C6 alkenyl, or C2~C6 alkynyl.

[0033] "Alkyl" means a saturated, acyclic, linear or branched hydrocarbon group. Examples of alkyl (or C1~C6 alkyl) are in particular methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, or hexyl.

[0034] "Alkenyl" means an unsaturated, linear or branched acyclic hydrocarbon group containing at least one carbon-carbon double bond. Examples of alkenyl (or C2~C6 alkenyl) are in particular ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, pentenyl, or hexenyl.

[0035] "Alkynyl" means an unsaturated, linear or branched acyclic hydrocarbon group containing at least one carbon-carbon triple bond. Examples of alkynyl (or C2~C6 alkynyl) are in particular ethynyl, propynyl, butynyl, pentynyl, or hexynyl.

[0036] "Aryl" preferably means a monocyclic or polycyclic aromatic hydrocarbon group having 6 to 20 ring members. Examples of aryl groups are phenyl, biphenyl, and naphthyl, preferably phenyl.

[0037] "Halogen" means fluorine, chlorine, bromine, or iodine, preferably bromine.

[0038] "Cation" means an atom or group of atoms having a positive charge (e.g., a charge of +1, +2, +3, or +4). The cation may be an organic or inorganic cation, preferably an inorganic cation. Examples of organic cations are, in particular, tetra(C1-C6 alkyl)ammonium cations, pyridinium cations, or tetra(C1-C6 alkyl)phosphonium cations. Examples of inorganic cations are, in particular, alkali cations (e.g., sodium, lithium, potassium, or cesium), alkaline earth cations (e.g., magnesium or calcium), aluminum cations, or ammonium cations (NH4 + ). The preferred cation is the sodium cation.

[0039] In the present application, the abbreviation "Ac" represents "acetyl" (i.e., -C(O)-CH3).

[0040] In the present application, the term "about" in relation to a value is a term well known to those skilled in the art and indicates that the above value can vary to a certain extent depending on the context in which the term is used. If certain uses of this term are not clear to those skilled in the art depending on the context, "about" represents, more or less, 30%, more or less, 20%, preferably more or less, 10% of the related value above.

[0041] Unless otherwise indicated, when a range is represented by the expression "between", the limit values are included within the stated range.

[0042] The present invention provides a method that enables the obtaining of substituted or unsubstituted indigo compounds in a simple, efficient, and environmentally friendly manner.

[0043] The method according to the present invention is a method for preparing a compound of formula (III), wherein

[0044]

Chem.

[0045] The following steps: a) In a solvent, in the presence of a metal catalyst, under hydrogenation, a compound of formula (I):

[0046]

Chem.

[0047] is reacted with glyoxylic acid to obtain a compound of formula (II):

[0048]

Chem.

[0049] and a step of obtaining a compound of formula (III): b) A step of converting the compound of formula (II) into a compound of formula (III) as defined above; c) A step of recovering the compound of formula (III); and comprising In these formulas, each of R1, R2, R3, and R4 is independently hydrogen, halogen, -CN, -NO2, -C(O)H, -SO3H, -CO2H, -SO3 - M1 + 、-CO2 - M2 + 、-SO3R5, -CO2R6, -C(O)R7, or -OR8, M1 + and M2 + each of which is independently a cation (preferably an alkali cation, such as sodium), R5, R6, R 7、 and each of R8 is independently a C1-C6 aliphatic group (e.g., C1-C6 alkyl) or aryl (e.g., phenyl), is a method.

[0050] In a specific embodiment, the compounds of formula (I), the compounds of formula (II), and the compounds of formula (III) are such that at least two groups (preferably at least three) out of R1, R2, R3, and R4 are hydrogen.

[0051] In a specific embodiment, the compounds of formula (I), the compounds of formula (II), and the compounds of formula (III) are such that R1, R3, and R4 are hydrogen and R2 is -SO3 - Na + and is such.

[0052] In another specific embodiment, the compounds of formula (I), the compounds of formula (II), and the compounds of formula (III) are such that each of R1, R2, R3, and R4 is independently hydrogen or bromine, provided that at least one of R1, R2, R3, and R4 is hydrogen and at least one of the others of R1, R2, R3, and R4 is bromine.

[0053] In a preferred embodiment, the compounds of formula (I), the compounds of formula (II), and the compounds of formula (III) are such that R1, R2, R3, and R4 are hydrogen. In the above preferred embodiment, the compound of formula (I) is anthranilic acid, the compound of formula (II) is 2-(carboxymethylamino)benzoic acid, and the compound of formula (III) is indigo. Indigo (CAS number: 482-89-3) is also referred to as indigotin and is represented by the following formula:

[0054]

Chemical formula

[0055] Step a) of the method according to the invention comprises reacting a compound of formula (I) as defined in the present application with glyoxylic acid in a solvent under hydrogenation in the presence of a metal catalyst (or equivalently "under metal-catalyzed hydrogenation"). The metal-catalyzed hydrogenation in step a) enables the reduction of the imine formed by the coupling between the amine functional group of the compound of formula (I) and the aldehyde functional group of glyoxylic acid, thus forming a compound of formula (II) as defined in the present application.

[0056] Metal-catalyzed hydrogenation uses a metal catalyst in a hydrogen atmosphere. The hydrogen pressure in step a) may in particular be between 1 and 30 bar, preferably between 5 and 20 bar, and even more preferably about 10 bar.

[0057] The metal catalyst is advantageously heterogeneous. The term "heterogeneous" used to characterize the catalyst is well known to those skilled in the art and indicates that the catalyst is not in the same phase as the reaction mixture to which it is applied. Typically, the heterogeneous metal catalyst used in step a) is solid and the reaction mixture is liquid and / or gaseous.

[0058] The metal catalyst is preferably a transition metal catalyst. Examples of transition metals are in particular nickel, palladium, platinum, rhodium, or combinations thereof. In a particular embodiment, the metal catalyst is a palladium, nickel, or platinum catalyst. Preferably, the metal catalyst is palladium on carbon, palladium on aluminum oxide, nickel on aluminum oxide, nickel on aluminum oxide / silica, or platinum on carbon. As an example of nickel on aluminum oxide / silica, the NiSat® product group including Ni / Al2O3-SiO2 54% Ni - 310RS sold by Clariant may be mentioned. As an example of nickel on aluminum oxide, Ni / Al2O3 21% Ni (HTC 500Ni - Johnson - Matthey) may be mentioned.

[0059] Even more preferably, the metal catalyst is palladium on carbon.

[0060] The amount of the metal catalyst used in step a) is between 0.0001% by mass and 40% by mass, particularly between 1% by mass and 30% by mass, preferably between 5% by mass and 25% by mass, even more preferably between 5% by mass and 15% by mass, for example, about 10% by mass, based on the mass of the compound of formula (I).

[0061] The reaction in step a) can be carried out at a temperature between 35 °C and 120 °C, particularly between 35 °C and 90 °C, or further between 35 °C and 65 °C, for example, about 50 °C. The reaction in step a) can be carried out for a time between 30 seconds and 15 hours, particularly between 15 minutes and 8 hours, or further between 2 hours and 8 hours, for example, about 4 hours. The solvent in step a) is particularly a polar solvent, such as an ether, such as THF or diethyl ether, an alcohol, such as ethanol, propanol, or butanol, dimethyl sulfoxide, water, or a combination thereof, preferably tetrahydrofuran (THF) or a THF / water mixture. Other solvents, particularly those conventionally used in metal-catalyzed hydrogenation reactions, can also be used.

[0062] In a specific embodiment, step a) comprises i) forming a mixture by adding the compound of formula (I) and the metal catalyst, preferably palladium on carbon, defined in the present application, while stirring, to a polar solvent, such as THF or a THF / water mixture; ii) placing the mixture from step i) under a hydrogen pressure, wherein the pressure is preferably between 1 and 30 bar (even more preferably between 5 and 20 bar); iii) heating the mixture from step ii) at a temperature between 35 °C and 120 °C (particularly between 35 °C and 65 °C); iv) adding glyoxylic acid to the mixture from step iii). and includes.

[0063] Preferably, the reaction in step a) is carried out for a time between 30 seconds and 8 hours, even more preferably between 15 minutes and 8 hours, or further between 2 hours and 8 hours, for example, about 4 hours.

[0064] The glyoxylic acid used as a raw material in the method of the present invention can be produced by any kind of chemical synthesis method. Preferably, the glyoxylic acid is obtained from bio-derived ethanol (also referred to as "bioethanol") or from bio-derived glycolic acid.

[0065] The compound of formula (I) used as a raw material in the method of the present invention can be produced by a chemical synthesis method or a biological method. Preferably, the compound of formula (I) (preferably anthranilic acid) is obtained by a biological method, for example, using a host cell or its gene sequence.

[0066] In a preferred embodiment, the compound of formula (I) (preferably anthranilic acid) is produced by a recombinant host cell, and the above cells are preferably microorganisms. By using the above recombinant host cells, it becomes possible to supply a large amount of the compound of formula (I) (preferably anthranilic acid) under mild conditions by simple fermentation. The term "recombinant host cell" refers to a cell that does not exist in nature and contains a modified genome obtained from deletion, insertion, or modification of one or more genetic factors. The term "host cell" also includes any progeny of the parent host cell that is not identical to the parent host cell, taking into account mutations that occur during replication. The host cell may be a microorganism or a plant host cell. Preferably, the host cell is a microbial host cell. As used herein, the term "microbial host cell" refers to bacteria, filamentous fungi, or yeast, preferably bacteria or yeast, more preferably bacteria.

[0067] In particular, the host cell may be a bacterium of the genus Escherichia, Streptomyces, Corynebacterium, Bacillus, Achromobacter, Brevibacterium, Arthrobacter, Flavobacterium, or Pseudomonas. More specifically, the host cell may be a recent one, such as Escherichia coli, Streptomyces coelicolor, Bacillus subtilis, Bacillus megaterium, Achromobacter-polymorph, Achromobacter xerosis, Brevibacterium protoformiae, Arthrobacter oxydans, Flavobacterium esteraromaticum, Pseudomonas fluorescens, Pseudomonas diminuta, or Pseudomonas aeruginosa.

[0068] Preferably, the host cell is a bacterium of the genus Escherichia, such as Escherichia coli, or Streptomyces, such as Streptomyces coelicolor. The biological method for the production of anthranilic acid starting from a recombinant microbial host cell forms the subject matter of international patent application number PCT / EP2021 / 079927, which can be easily referred to by those skilled in the art.

[0069] Particularly heterogeneous metal catalysts can be more easily separated from the reaction mixture in step a), and then recovered and reused, i.e., recycled. In a specific embodiment, the method according to the invention further comprises a step of recovering the particularly heterogeneous metal catalyst after step a). This step of recovering the catalyst is preferably carried out by filtration, for example, filtration through celite.

[0070] The solvent used in step a) can also be recovered and reused, i.e., recycled. In a specific embodiment, the method according to the invention further comprises a step of recovering the above solvent after step a). This step of recovering the solvent is preferably carried out by distillation or evaporation under reduced pressure.

[0071] Step b) of the method of the present invention comprises the step of converting the compound of formula (II) as defined in this application into the compound of formula (III) as defined in this application.

[0072] Preferably, step b) b1) reacting the compound of formula (II) as defined in this application with acetic anhydride to give the formula (II'):

[0073]

Chemical formula

[0074] (wherein each of R1, R2, R3, and R4 is independently hydrogen, halogen, -CN, -NO2, -C(O)H, -SO3H, -CO2H, -SO3 - M1 + 、-CO2 - M2 + 、-SO3R5, -CO2R6, -C(O)R7, or -OR8, and M1 + and M2 + each of which is independently a cation (preferably an alkali cation, such as sodium), R5, R6, R 7、Each of and R8 is independently a C1-C6 aliphatic group (e.g., C1-C6 alkyl) or aryl (e.g., phenyl). a step of obtaining a compound of b2) a step of reacting the compound of formula (II') with a base to obtain a compound of formula (III) as defined in the present application and includes.

[0075] In a specific embodiment, the compound of formula (II') is such that at least two groups (preferably at least three) out of R1, R2, R3, and R4 are hydrogen.

[0076] In a specific embodiment, the compound of formula (II') is such that R1, R3, and R4 are hydrogen and R2 is -SO3 - Na + and is such that.

[0077] In another specific embodiment, the compound of formula (II') is such that each of R1, R2, R3, and R4 is independently hydrogen or bromine, provided that at least one of R1, R2, R3, and R4 is hydrogen and at least one of the others of R1, R2, R3, and R4 is bromine.

[0078] In a preferred embodiment, the compound of formula (II') is such that R1, R2, R3, and R4 are hydrogen. In the above preferred embodiment, the compound of formula (II') is 1-acetylindol-3-yl acetate.

[0079] Preferably, the reaction in step b1) is carried out in the presence of a base. When present, the base is advantageously an amine base. Examples of amine bases are, in particular, triethylamine, diisopropylethylamine, dimethylphenylamine, or piperidine.

[0080] Preferably, the amine base is triethylamine.

[0081] In a specific embodiment, step b1) comprises forming (preferably consisting of) a mixture comprising a compound of formula (II), acetic anhydride, and an optional base (preferably triethylamine), and stirring the resulting reaction mixture.

[0082] The reacting step in step b1) is advantageously - at a temperature between -10 °C and 40 °C, preferably for a time between 15 minutes and 3 hours (e.g., about 30 minutes), and then - at a temperature between -70 °C and 110 °C, preferably for a time between 15 minutes and 3 hours (e.g., about 30 minutes), executed sequentially.

[0083] The molar amount of acetic anhydride in step b1) may be between 3 and 10 equivalents relative to the molar amount of the compound of formula (II). The molar amount of the base in step b1), if present, may be between 3 and 10 equivalents relative to the molar amount of the compound of formula (II).

[0084] The base in step b1), if present, may optionally be recovered and reused, i.e., recycled. In a specific embodiment, the method according to the invention further comprises recovering the base from step b1), preferably by distillation or evaporation under reduced pressure, after step b1).

[0085] Step b2) enables the conversion of the compound of formula (II') obtained in step b1) into the compound of formula (III). Step b2) is carried out in the presence of a base. This base may be an oxygen-containing base, such as a hydroxide (e.g., sodium hydroxide or potassium hydroxide), an alcoholate (e.g., sodium ethoxide or sodium isopropylate), or a carbonate (e.g., sodium carbonate).

[0086] Preferably, the base in step b2) is a hydroxide, especially sodium hydroxide.

[0087] The molar amount of the base in step b2) may be between 4 and 25 equivalents relative to the molar amount of the compound of formula (II').

[0088] In a specific embodiment, the reaction in step b2) is carried out in water or in a water / alcohol mixture. Examples of the alcohol are, in particular, ethanol, propanol, or butanol, preferably ethanol. The water may optionally contain one or more additives, and the additives may be selected, for example, from glycol derivatives (such as ethylene glycol, diethylene glycol, or propylene glycol) and surfactants.

[0089] In one embodiment, the reaction in step b2) is carried out at a temperature between 80 °C and 110 °C, preferably for a time between 1 hour and 5 hours.

[0090] In a specific embodiment, step b2) includes the steps of adding the compound of formula (II') as defined above to an aqueous solution of a base, and then stirring the resulting mixture at a temperature between 80 °C and 110 °C, preferably for a time between 1 hour and 5 hours, to form a mixture.

[0091] The compound of formula (III) obtained in step b), particularly step b2), of the method of the present invention is typically obtained in the form of a precipitate. Step c) of the method of the present invention includes the step of recovering the compound of formula (III) obtained in step b). The compound of formula (III) can be isolated in step c) by any technique known to those skilled in the art, for example by filtration.

[0092] The purity of the compound of formula (III) obtained by the method of the present invention is advantageously 90% or more, preferably 95% or more, and more preferably 98% or more.

[0093] In a specific embodiment, the method comprises the following steps: a) In a polar solvent (e.g., THF / water mixture), under a hydrogen atmosphere, in the presence of palladium on carbon, react the compound of formula (I) as defined above with glyoxylic acid at a temperature between 35°C and 120°C (e.g., between 35°C and 65°C), preferably for a time between 30 seconds and 8 hours, to obtain the compound of formula (II) as defined above; b1) A step of reacting the compound of formula (II) with acetic anhydride in the presence of a base, preferably an amine base such as triethylamine, wherein the reaction is - at a temperature between -10°C and 40°C, preferably for a time between 15 minutes and 3 hours, and then - at a temperature between 70°C and 110°C, preferably for a time between 15 minutes and 3 hours, sequentially carried out to obtain the compound of formula (II') as defined above; b2) In water, react the compound of formula (II') with a base, preferably a hydroxide such as sodium hydroxide, at a temperature between 80°C and 110°C, preferably for a time between 1 hour and 5 hours, to obtain the compound of formula (III) as defined above; c) A step of recovering the compound of formula (III); and

[0094] In another specific embodiment, the method comprises the following steps: a) In a polar solvent (preferably a THF / water mixture), under a hydrogen atmosphere, in the presence of palladium on carbon, react the compound of formula (I) as defined above with glyoxylic acid at a temperature between 35°C and 120°C (e.g., between 35°C and 65°C), preferably for a time between 30 seconds and 8 hours, to obtain the compound of formula (II) as defined above; a') A step of recovering palladium on carbon, preferably by filtration, and recovering the polar solvent, preferably by distillation or evaporation under reduced pressure; b1) A step of reacting the compound of formula (II) with acetic anhydride in the presence of a base, preferably an amine base such as triethylamine, wherein the reaction is - at a temperature between -10°C and 40°C, preferably for a time between 15 minutes and 3 hours, and then - at a temperature between 70 °C and 110 °C, preferably for a time between 15 minutes and 3 hours, sequentially carried out to obtain the compound of formula (II') as defined above, and b') recovering the amine base, preferably by distillation or evaporation under reduced pressure, and b2) reacting the compound of formula (II') with a base, preferably a hydroxide such as sodium hydroxide, in water at a temperature between 80 °C and 110 °C, preferably for a time between 1 hour and 5 hours, to obtain the compound of formula (III) as defined above, and c) recovering the compound of formula (III) and comprising.

[0095] In another specific embodiment, the method according to the invention consists essentially of steps a), b1), b2), and c) as described in the present application. A "method consisting essentially of steps a), b1), and b2)" means a method composed of reaction step a), reaction step b1), and reaction step b2), and step c) of recovering the compound of formula (III), which may, in particular, further include one or more additional steps of conventional treatments at the end of each of steps a), b1), and b2). These steps, commonly used in organic synthesis, are, for example, washing steps, liquid-liquid extraction steps, filtration steps, purification steps, or drying steps.

[0096] In a specific embodiment, the method comprises the following steps: a) reacting the compound of formula (I) as defined above with glyoxylic acid in a polar solvent such as a THF / water mixture, in a hydrogen atmosphere, in the presence of palladium on carbon, at a temperature between 35 °C and 120 °C (e.g., between 35 °C and 65 °C), preferably for a time between 30 seconds and 8 hours, to obtain the compound of formula (II) as defined above, and b1) reacting the compound of formula (II) with acetic anhydride in the presence of a base, preferably an amine base such as triethylamine, wherein the reaction is - at a temperature between -10 °C and 40 °C, preferably for a time between 15 minutes and 3 hours, then - at a temperature between 70 °C and 110 °C, preferably for a time between 15 minutes and 3 hours, sequentially carried out to obtain the compound of formula (II') as defined above, and b2) in water, reacting the compound of formula (II') with a base, preferably a hydroxide, such as sodium hydroxide, at a temperature between 80 °C and 110 °C, preferably for a time between 1 hour and 5 hours, to obtain the compound of formula (III) as defined above, and c) recovering the compound of formula (III) and is essentially composed of.

[0097] A preferred object of the present invention is a method for preparing indigo, comprising the following steps: a) reacting anthranilic acid with glyoxylic acid in a solvent in the presence of a metal catalyst under hydrogenation to obtain 2-(carboxymethylamino)benzoic acid, and b) converting 2-(carboxymethylamino)benzoic acid to indigo, and c) recovering indigo and is a method comprising.

[0098] Preferably, the metal catalyst is a palladium catalyst, preferably palladium on carbon.

[0099] In a specific embodiment, the method according to the invention further comprises, after step a), recovering the metal catalyst, preferably by filtration.

[0100] In another specific embodiment, the method according to the invention further comprises, after step a), recovering the solvent from step a), preferably by distillation or evaporation under reduced pressure.

[0101] Preferably, the solvent from step a) is a polar solvent, such as THF or a THF / water mixture.

[0102] According to another specific embodiment, glyoxylic acid is obtained from ethanol or from bio-derived glycolic acid.

[0103] According to another specific embodiment, the reaction in step a) is carried out at a temperature between 35 °C and 120 °C, preferably for a time between 30 seconds and 8 hours.

[0104] In particular, in step a), the amount of the metal catalyst is between 0.0001% by mass and 40% by mass, preferably between 5% by mass and 25% by mass, based on the mass of anthranilic acid, and the hydrogen pressure is between 1 and 30 bar, preferably between 5 and 20 bar.

[0105] In particular, step b) b1) reacting 2-(carboxymethylamino)benzoic acid with acetic anhydride to obtain 1-acetylindole-3-yl acetate; b2) reacting 1-acetylindole-3-yl acetate with a base to obtain indigo and includes.

[0106] According to a preferred embodiment, the method according to the invention comprises the following steps: a) reacting anthranilic acid with glyoxylic acid in a polar solvent under a hydrogen atmosphere in the presence of palladium on carbon at a temperature between 35 °C and 120 °C, preferably for a time between 30 seconds and 8 hours, to obtain 2-(carboxymethylamino)benzoic acid; b1) reacting 2-(carboxymethylamino)benzoic acid with acetic anhydride in the presence of a base, preferably an amine base such as triethylamine, the reaction being: - at a temperature between 10 °C and 40 °C, preferably for a time between 15 minutes and 3 hours, and then - at a temperature between 70 °C and 110 °C, preferably for a time between 15 minutes and 3 hours, sequentially carried out to obtain 1-acetylindole-3-yl acetate; b2) reacting 1-acetylindole-3-yl acetate with a base, preferably a hydroxide such as sodium hydroxide, in water at a temperature between 80 °C and 110 °C, preferably for a time between 1 hour and 5 hours, to obtain indigo; c) a step of recovering indigo and including.

[0107] In a specific embodiment, the compound of formula (I), particularly anthranilic acid, is of biological origin. A "biologically derived" product or compound means a product or compound derived from renewable organic materials of microbial, plant, fungal, or animal origin, and more precisely, a product or compound derived from microorganisms in the context of the present invention. Examples of bacteria that produce anthranilic acid include, but are not limited to, Gram-positive or Gram-negative bacteria, such as Escherichia (E. coli), Streptomyces, Bacillus, Cupridavidus, Corynebacterium, Mycobacterium, Kitasatospora, Lutibacter, Thermobifida, Thermomonospora, Frankia, Pseudonocardia, Saccharothrix, Kutzneria, Lentzea, Prauserella, Salinispora, Micromonospora, Actinoplanes, Catellatospora, Mycolicibacterium, Dietzia, Aeromicrobium, Nonlabens, Blastococcus, Modestobacter, Saccharopolyspora, Amycolatopsis, Actinopolyspora, Acidimicrobium, Photorhabdus, Whewellia, Azospirillum, Kribbella, and Kineosporium bacteria.

[0108] In a more detailed embodiment, the compound of formula (I), in particular anthranilic acid, is produced from recombinant host cells, which are preferably microorganisms. Examples of recombinant microbial host cells are described in International Application Publication No. WO 2022 / 090363 (PCT / EP2021 / 079927). According to a preferred embodiment of the invention, the recombinant microbial host cell is selected from the genus Escherichia (E. coli), Streptomyces, Bacillus, Cupridavidus, Corynebacterium, Mycobacterium, Kitasatospora, Lutibacter, Thermobifida, Thermomonospora, Frankia, Pseudonocardia, Saccharothrix, Kutzneria, Lentzea, Prauserella, Salinispora, Micromonospora, Actinoplanes, Catenulispora, Mycolicibacterium, Dietzia, Aeromicrobium, Nonomuraea, Blastococcus, Modestobacter, Saccharopolyspora, Amycolatopsis, Actinopolyspora, Acidimicrobium, Photorhabdus, Whewellia, Azospirillum, Klingelhoferia, and Kinetosporium. According to an even more preferred embodiment, the recombinant microbial host cell is selected from the genus Escherichia, Streptomyces, Corynebacterium, and Bacillus, and even more preferably, the recombinant microbial host cell is E. coli.

Examples

[0109] The present invention will be more fully understood from the following examples, which are given purely for the purpose of illustration and are not intended to limit the scope of the invention as defined by the appended claims.

[0110] (Example 1) Method for preparing the compound of formula (III): indigo

[0111]

Chemical formula

[0112] Before charging 1 kg of anthranilic acid and 0.1 kg of palladium on carbon (10% by mass of palladium, 50% moisture) into the reactor while stirring at 90 rpm, 5 volumes / mass of THF (also denoted as "v / w", where 1 v / w has a value of 1 liter per kg) is introduced. Then, the mixture is pressurized to 10 bar with hydrogen and heated to 50 °C before introducing 1.3 v / w of an aqueous solution of 50% glyoxylic acid (1.2 molar equivalents) over 30 minutes.

[0113] The reaction mixture is then heated at 50 °C and stirred at 90 rpm for an additional 3.5 hours. If the technical conditions allow for regular sampling, the progress of the reaction can be monitored by HPLC.

[0114] If the conversion is sufficiently > 97%, the reaction is stopped and filtered through celite (1 v / w) to remove palladium particles. The solvent is then evaporated to obtain 1.3 kg of 2-(carboxymethylamino)benzoic acid (2), the purity of which is evaluated by NMR to be 85%. The 15% impurities present are essentially composed of minerals. 1H NMR (400 MHz, DMSO): δ 7.78 (dd, J = 8.1, 1.7 Hz, 1H), 7.29 (t, J = 1.5 Hz, 1H), 6.54 - 6.51 (m, 2H), 3.75 (s, 2H) 13C NMR: (101 MHz, DMSO) δ 172.6, 170.9, 149.8, 132.9, 131.8, 114.0, 113.4, 111.0, 46.5 HPLC retention time: anthranilic acid (1): 9.4 minutes; 2-(carboxymethylamino)benzoic acid (2): 13.1 minutes; main impurity: 8.6 minutes

[0115] Indigo was also prepared under the same experimental conditions as above, except that the carbon-supported palladium was replaced by any one of 0.5% palladium supported on aluminum oxide, nickel supported on aluminum oxide / silica (NiSat (registered trademark): Ni / Al2O3 - SiO2 54% Ni), nickel supported on aluminum oxide (Ni / Al2O3 21% Ni), or carbon-supported palladium.

[0116] HPLC analysis data: - Mobile phase: A: H2O + 0.1% formic acid / B: acetonitrile (HPLC purity) - Column: Kromasil KR5C18 - 25M (250×4.6 mm) - Gradient: t0: 90 / 10; t = 15 min: 50 / 50; t = 20 min: 50 / 50; t = 30 min: 90 / 10

[0117] Comparison between step a) of the method of the present invention and the prior art method (Table 1)

[0118]

Table 1

[0119] In contrast to the method of Lai et al. described in U.S. Patent No. 2008 / 051426, step a) of the method of the present invention uses a non-toxic reactant, namely glyoxylic acid, to provide 2-(carboxymethylamino)benzoic acid in excellent yield.

[0120] In contrast to the method of Koeppe et al., where saponification is carried out after the coupling of anthranilic acid and ethyl glyoxylate, the utilization of this main intermediate is achieved in a single step.

[0121] Finally, step a) uses a recyclable catalyst, thus generating minimal waste. It is also possible to recycle the solvents used, whereas the waste water in the prior art methods is contaminated with toxic reactants.

[0122]

Chem.

[0123] 1-Acetylindole-3-yl acetate (3) can be formed in a "one-pot" reaction in the presence of 2-(carboxymethylamino)benzoic acid (2) (1 kg), acetic anhydride (2.15 kg or 2.0 L, or 5 equivalents), and triethylamine (2.1 kg or 2.8 L, or 5 equivalents). The reaction is initially maintained at room temperature for 30 minutes to protect the amine. The reaction mixture is then heated at 90 °C for 30 minutes for the cyclization reaction and protection of the hydroxyl group.

[0124] After HPLC analysis confirmed a conversion higher than 95%, a portion (about 25%) of the volatile products was evaporated under reduced pressure (40 °C, 150 mbar) to allow for the recycling of triethylamine. Then, 10 liters of water is added to precipitate the product. The product is then filtered (25 microns), washed with 10 liters of water, and then dried in an 80 °C oven to obtain about 1.01 kg of powder (91% of the predicted mass). To adjust the proportion of reactants for the next reaction, the purity of the product (3) thus obtained is determined by NMR analysis or HPLC (83%) (measured yield: 75%). 1H NMR (400 MHz, MeOD) δ 8.39 (d, J = 8.3 Hz, 1H), 7.80 (s, 1H), 7.57 - 7.48 (m, 1H), 7.36 (ddd, J = 8.5, 7.2, 1.4 Hz, 1H), 7.29 (td, J = 7.5, 1.0 Hz, 1H), 2.61 (s, 3H), 2.37 (s, 3H). HPLC retention time: impurities (mono-acetylated product): 9.2 min; 1-acetylindole-3-yl acetate (3): 7.3 min

[0125] HPLC analysis data: - Mobile phase: A: H2O + 0.1% formic acid / B: acetonitrile (HPLC quality) - Column: Kromasil KR5C18-25M (250×4.6 mm) - Gradient: t0: 50 / 50; t = 15 min: 5 / 95; t = 23 min: 5 / 95; t = 25 min: 90 / 10; t = 30 min: 50 / 50

[0126]

Chem.

[0127] The preparation of indigo (4) starting from 1-acetylindol-3-yl acetate (3) (1 kg) takes place in an aqueous solution of sodium hydroxide (2.95 kg of sodium hydroxide in 23.6 L of solution, or 16 equivalents). First, the reaction mixture is heated under reflux for 2 hours, and then the mixture is left at room temperature with stirring for 5 hours. The blue precipitate thus formed is filtered off (cut-off threshold 10 microns) and then washed with water (10 volumes) and ethanol (10 volumes). The product is then dried on a stove (80 °C) to obtain 0.42 kg of indigo (yield: 69%).

[0128] The purity of the final product is determined by UV spectroscopy. The purity of the obtained indigo is higher than 95%. 1H NMR (400 MHz, DMSO) δ 10.50 (s, 2H), 7.61 (d, J = 7.7 Hz, 2H), 7.51 (ddd, J = 8.3, 7.1, 1.3 Hz, 2H), 7.33 (d, J = 8.2 Hz, 2H), 6.95 (t, J = 7.3 Hz, 2H).

Claims

1. A method for preparing a compound of formula (III), comprising the following steps: 【Chemical 1】 (wherein, R 1 , R 2 , R 3 , and R 4 each independently is hydrogen, halogen, -CN, -NO 2 , -C(O)H, -SO 3 H, -CO 2 H, -SO 3 - M 1 + , -CO 2 - M 2 + , -SO 3 R 5 , -CO 2 R 6 , -C(O)R 7 , or -OR 8 ; M 1 + and M 2 + each of which is, independently, a cation, R 5 、R 6 、R 7、 and R 8 each of which is, independently, C 1 ~C 6 an aliphatic group or an aryl) a) Reacting a compound of formula (I): in a solvent in the presence of a metal catalyst under hydrogenation with glyoxylic acid to obtain a compound of formula (II): b) Converting the compound of formula (II) into the compound of formula (III); and 【Chemical 2】 (wherein R 1 , R 2 , R 3 , and R 4 are each as defined above) c) Recovering the compound of formula (III). [Chemical Formula 3] (wherein R 1 , R 2 , R 3 , and R 4 are each as defined above)

2.

3. The method according to claim 1 or 2, wherein the metal catalyst is a catalyst of palladium, nickel or platinum.

4. The method according to any one of claims 1 to 3, wherein the metal catalyst is palladium on carbon, palladium on aluminum oxide, nickel on aluminum oxide, nickel on aluminum oxide / silica, or platinum on carbon. R 1 、R 2 、R 3 、and R 4 is hydrogen, the method according to claim 1.

5. The method according to any one of claims 1 to 4, wherein the metal catalyst is palladium on carbon.

6. The method according to any one of claims 1 to 5, further comprising, after step a): - recovering the metal catalyst, preferably by filtration, and / or - recovering the solvent from step a), preferably by distillation or evaporation under reduced pressure.

7. The method according to any one of claims 1 to 6, wherein the solvent in step a) is a polar solvent such as THF or a THF / water mixture.

8. The method according to any one of claims 1 to 7, wherein the glyoxylic acid is obtained from ethanol or from bio-derived glycolic acid.

9. The method according to any one of claims 1 to 8, wherein the reaction in step a) is carried out at a temperature between 35°C and 120°C, preferably for a time between 30 seconds and 8 hours.

10. The method according to any one of claims 1 to 9, wherein in step a), the amount of the metal catalyst is between 0.0001% by weight and 40% by weight, preferably between 5% by weight and 25% by weight, based on the weight of the compound of formula (I), and the hydrogen pressure is between 1 and 30 bar, preferably between 5 and 20 bar.

11. Step b) comprises: b1) Reacting the compound of formula (II) as defined in claim 1 or 2 with acetic anhydride to obtain a compound of formula (II'): b2) Reacting the compound of formula (II') with a base to obtain the compound of formula (III) as defined in claim 1 or 2.

12. The following steps: ​ ​ 【Chemical Formula 4】 (wherein each of R 1 , R 2 , R 3 , and R 4 is independently hydrogen, halogen, -CN, -NO 2 , -C(O)H, -SO 3 H, -CO 2 H, -SO 3 - M 1 + , -CO 2 - M 2 + , -SO 3 R 5 , -CO 2 R 6 , -C(O)R 7 , or -OR 8 ; and M 1 + and M 2 + each of which is, independently, a cation, R 5 、R 6 、R 7、 and R 8 each of which is, independently, C 1 to C 6 an aliphatic group or an aryl, Preferably R 1 , R 2 , R 3 , and R 4 is hydrogen) ​ ​ ​ ​ ​ a) In a polar solvent, under a hydrogen atmosphere, in the presence of palladium on carbon, reacting the compound of formula (I) as defined in claim 1 or 2 with glyoxylic acid at a temperature between 35°C and 120°C, preferably for a time between 30 seconds and 8 hours, to obtain the compound of formula (II) as defined in claim 1 or 2; b1) A step of reacting the compound of formula (II) with acetic anhydride in the presence of a base, preferably an amine base such as triethylamine, wherein the reaction is - at a temperature between -10°C and 40°C, preferably for a time between 15 minutes and 3 hours, and then - at a temperature between 70°C and 110°C, preferably for a time between 15 minutes and 3 hours, sequentially carried out to obtain the compound of formula (II') as defined in claim 9; b2) In water, reacting the compound of formula (II') with a base, preferably a hydroxide such as sodium hydroxide, at a temperature between 80°C and 110°C, preferably for a time between 1 hour and 5 hours, to obtain the compound of formula (III) as defined in claim 1 or 2; c) A step of recovering the compound of formula (III); The method according to any one of claims 1 to 5 and claim 11, comprising the above steps.

13. The method according to any one of claims 1 to 12, wherein the compound of formula (I), particularly anthranilic acid, is of biological origin.

14. The method according to any one of claims 1 to 13, wherein the compound of formula (I), particularly anthranilic acid, is produced by a recombinant host cell, preferably a microorganism.

15. The recombinant microbial host cell is selected from the genus Escherichia (E. coli), Streptomyces, Bacillus, Cupridavidus, Corynebacterium, Mycobacterium, Kitasatospora, Lutibacter, Thermobifida, Thermomonospora, Frankia, Pseudonocardia, Saccharothrix, Kutzneria, Lentzea, Prauserella, Salinispora, Micromonospora, Actinoplanes, Catellatospora, Mycolicibacterium, Dietzia, Aeromicrobium, Nonlabens, Blastococcus, Modestobacter, Saccharopolyspora, Amycolatopsis, Actinopolyspora, Acidimicrobium, Photorhabdus, Whewellia, Azospirillum, Kribbella, and Kineococcus, preferably selected from the genus Escherichia, Streptomyces, Corynebacterium, and Bacillus, and even more preferably, the recombinant microbial host cell is E. coli, the method according to claim 14.

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