Method for preparing indigo or a substituted derivative thereof

Abstract

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

Description

[0001] Process for the preparation of indigo or a substituted derivative thereof

[0002] SUBJECT OF THE INVENTION

[0003] The present invention relates to the synthesis of dyes. More particularly, the present invention relates to a process for the preparation of optionally substituted indigo from an optionally substituted anthranilic acid.

[0004] BACKGROUND OF THE INVENTION

[0005] With its powerful and deep blue color, found in particular in jeans and the Tuareg scarf, indigo has been known to all for several millennia. Historically, indigo was mainly obtained by extraction and oxidation of the indican contained in plants of the Indigofera family, in particular the indigo tree. In the 17 eme and 18 emeOver the centuries, to meet the strong Western demand for indigo, indigo crops were established in North America, the French West Indies, and India. However, natural indigo production was gradually replaced by chemical synthesis. Today, 50,000 tons of synthetic indigo are produced annually, and most of this production is used to dye the 4 billion denim garments produced each year.

[0006] Since the first synthesis carried out at the end of the 19th eme century by the chemist Adolf von Baeyer, from 2-nitrobenzaldehyde and acetone, several processes for the preparation of indigo were proposed.

[0007] Karl Heumann (Chem. Ber, 1890, 3431) proposed two strategies for the synthesis of indigo. The first involves aniline and chloroacetic acid reacting to form N-phenylglycine, which in turn is converted to indoxyl in a basic medium. The indoxyl is then oxidized to form indigo. However, low yields are obtained with this first strategy. The second strategy uses anthranilic acid instead of aniline: this is reacted with chloroacetic acid to produce 2-(carboxymethylamino)benzoic acid. This is then combined with a base to form 2-indoxylcarboxylic acid. Indigo is finally produced by heating and oxidizing the acid. However, the yields obtained remain modest, and the process is very energy-intensive, environmentally unfriendly, and uses toxic reagents, particularly chloroacetic acid.

[0008] The formation of 2-(carboxymethylamino)benzoic acid from anthranilic acid and chloroacetic acid is a key step in the synthesis of indigo. Various reaction conditions have been described, but the yields obtained are not high enough for an industrial process. For example, the reaction described in patent application US2008 / 051426 is carried out in the presence of sodium bicarbonate at 40-45°C and achieves a yield of only 80%. Lai et al. (Helvetica Chimica Acta 2008, 91, 1975-1983) describe the same reaction in the presence of a mixture of sodium bicarbonate and sodium hydroxide, carried out at refluxing water. A yield of 90% of 2-(carboxymethylamino)benzoic acid is obtained. Besides the insufficient yields, the chloroacetic acid used in these processes is a toxic reagent.

[0009] 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 generates a lot of waste, particularly because sodium cyanoborohydride is used in large quantities and is not recyclable. In addition, the use of a glyoxylate requires an additional saponification step with sodium hydroxide to obtain the acid.

[0010] Thus, there remains a real need to provide an improved process for preparing indigo that is simple, efficient and ecological.

[0011] SUMMARY OF THE INVENTION

[0012] In this context, the inventors have developed a three-step process for the preparation of optionally substituted indigo, simple and suitable for industrial scale, carried out from optionally substituted anthranilic acid and glyoxylic acid. The key step of this process uses a metal catalyst, in particular palladium, advantageously heterogeneous, under a hydrogen atmosphere, making it possible to obtain an optionally substituted 2-(carboxymethylamino)benzoic acid with excellent yields. This acid can then be efficiently converted into optionally substituted indigo, in particular via cyclization in the presence of acetic anhydride and dimerization in a basic medium. The process is very environmentally friendly, as it generates little waste and uses solvents and a catalyst that can be recycled.Additionally, the process uses glyoxylic acid, which is non-toxic and can be obtained from ethanol or bio-based glycolic acid.

[0013] Thus, the subject of the present invention is a process for preparing a compound of formula (III): wherein each of Ri, R2, R3 and R4 is independently hydrogen, halogen, -CN, -NO2, -C(O)H, -SO3H, -CO2H, -SO3 Mi + , -CO2 M2 + , -SO3R5, -CO2R6, -C(O)R7OR -OR8, each of Mi + and M2 + being independently a cation, each of R5, R6, R7, and Rs being independently a C1-C6 aliphatic group or an aryl; said process comprising the following steps: a) reacting a compound of formula (I): wherein each of R1, R2, R3 and R4 is as defined above, with glyoxylic acid under hydrogenation in the presence of a metal catalyst in a solvent, to obtain a compound of formula (II): wherein each of R1, R2, R3 and R4 is as defined above; b) converting said compound of formula (II) into said compound of formula (III); c) recovering said compound of formula (III). In a preferred embodiment, R1, R2, R3, and R4 are hydrogen.

[0014] 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 and silicon oxide, or platinum on carbon. Even more preferably, the metal catalyst is palladium on carbon.

[0015] In a particular embodiment, the method according to the invention further comprises a step of recovering the metal catalyst, after step a), preferably by filtration.

[0016] In another particular embodiment, the process according to the invention further comprises, after step a), a step of recovering the solvent from step a), preferably by distillation or evaporation under reduced pressure.

[0017] Preferably, the solvent of step a) is a polar solvent, such as THF or a THF / water mixture.

[0018] According to another particular embodiment, the glyoxylic acid is obtained from ethanol or bio-sourced glycolic acid.

[0019] According to another particular embodiment, the reaction in step a) is carried out at a temperature between 35°C and 120°C, preferably for a duration between 30 seconds and 8 hours.

[0020] In particular, the amount of metal catalyst in step a) is between 0.0001% and 40% by weight, preferably between 5% and 25% by weight, relative to the weight of the compound of formula (I), and the hydrogen pressure is between 1 and 30 bars, preferably between 5 and 20 bars.

[0021] In particular, step b) comprises: bl) reacting a compound of formula (II) as defined in the present application with acetic anhydride, to obtain a compound of formula (IF): wherein each of Ri, R2, R3 and R4 is independently hydrogen, halogen, -CN, -NO2, -C(O)H, -SO3H, -CO2H, -SO3 Mi + , -CO2 M2 + , -SO3R5, -CO2R6, -C(O)R7OR -OR8, each of Mi + and M2 +being independently a cation, each of R5, R6, R7, and Rs being independently a C1-C6 aliphatic group or an aryl; and b2) reacting said compound of formula (II') with a base, to obtain a compound of formula (III) as defined in the present application.

[0022] According to a preferred embodiment, the process 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 the presence of palladium on carbon and under a hydrogen atmosphere, in a polar solvent, at a temperature of between 35°C and 120°C, preferably for a period of between 30 seconds and 8 hours, to obtain a compound of formula (II) as defined in the present application; b1) reacting said compound of formula (II) with acetic anhydride, in the presence of a base, preferably an amine base, such as triethylamine, said reaction being carried out successively:

[0023] - at a temperature between 10°C and 40°C, preferably for a period of between 15 minutes and 3 hours, then

[0024] - at a temperature between 70°C and 110°C, preferably for a period between 15 minutes and 3 hours, to obtain a compound of formula (II') as defined in the present application; b2) reacting said 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 period between 1h and 5h, to obtain a compound of formula (III) as defined in the present application; and c) recovering said compound of formula (III). In a particular embodiment, the compound of formula (I), in particular anthranilic acid, is biosourced. In a more particular embodiment, the compound of formula (I), in particular anthranilic acid, is produced by a recombinant host cell, said cell preferably being microbial.Preferably, the recombinant microbial host cell is selected from 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 Escherichia, Streptomyces, Corynebacterium and Bacillus, and even more preferably, the recombinant microbial host cell is Escherichia coli.

[0025] DETAILED DESCRIPTION

[0026] Definitions

[0027] The expression “C x -C y” associated with a chemical group, in which x and y are integers, means that said chemical group comprises from x to y carbon atoms. For example, if the expression Ci-Cô is associated with a chemical group, this means that said chemical group comprises from 1 to 6 carbon atoms, in particular 1, 2, 3, 4, 5, or 6 carbon atoms.

[0028] By "aliphatic group" is meant a hydrocarbon group, saturated or unsaturated, cyclic or acyclic (preferably acyclic), linear or branched. In a particular embodiment, said C1-C6 aliphatic group is C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl.

[0029] The term "alkyl" means a saturated, acyclic, straight or branched hydrocarbon group. Examples of alkyl (or C1-C6 alkyl) include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, or hexyl.

[0030] The term "alkenyl" means an acyclic, unsaturated, linear or branched hydrocarbon group comprising at least one carbon-carbon double bond. Examples of alkenyl (or C2-C6 alkenyl) include ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, pentenyl, or hexenyl. The term "alkynyl" means an acyclic, unsaturated, linear or branched hydrocarbon group comprising at least one carbon-carbon triple bond. Examples of alkynyl (or C2-C6 alkynyl) include ethynyl, propynyl, butynyl, pentynyl, or hexynyl.

[0031] By "aryl" is meant a mono- or polycyclic aromatic hydrocarbon group, preferably having from 6 to 20 members. Examples of aryl groups are phenyl, biphenyl, and naphthyl, preferably phenyl.

[0032] By "halogen" is meant fluorine, chlorine, bromine or iodine, preferably bromine.

[0033] The term "cation" means an atom or group of atoms having a positive charge (e.g., a +1, +2, +3, or +4 charge). Said cation may be an organic or inorganic cation, preferably an inorganic cation. Examples of organic cations include a tetra(C1-C6 alkyl)ammonium cation, a pyridinium cation, or a tetra(C1-C6 alkyl)phosphonium cation. Examples of inorganic cations include an alkali cation (such as sodium, lithium, potassium, or cesium), an alkaline earth cation (such as magnesium or calcium), an aluminum cation, or an ammonium cation (NÜ4 + ). A preferred cation is a sodium cation.

[0034] In the present application, the abbreviation “Ac” means “acetyl” (i.e. -C(O)-CÜ3).

[0035] In the present application, the term "about" associated with a value is a term well known to those skilled in the art and means that said value may vary to some 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, then "about" means plus or minus 30%, plus or minus 20%, preferably plus or minus 10% of said associated value.

[0036] Unless otherwise stated, where a range is expressed using the term "between", the limiting values ​​are included within the range described.

[0037] The present invention provides a method for accessing an optionally substituted indigo-type compound in a simple, efficient and environmentally friendly manner.

[0038] The process according to the invention is a process for preparing a compound of formula (III): said process comprising the following steps: a) reacting a compound of formula (I): with glyoxylic acid under hydrogenation in the presence of a metal catalyst in a solvent, to obtain a compound of formula (II): b) converting said compound of formula (II) into a compound of formula (III) as defined above; c) recovering said compound of formula (III); wherein each of R1, R2, R3 and R4 is independently hydrogen, halogen, -CN, -NO2, -C(O)H, -SO3H, -CO2H, -SO3 Mi + , -CO2M2 + , -SO3R5, -CO2R6, -C(O)R7or -ORs, each of Mi + and M2 + independently being a cation (preferably an alkali cation such as sodium), each of R5, R6, R7, and Rs independently being a C1-C6 aliphatic group (such as C1-C6 alkyl) or an aryl (such as phenyl).

[0039] In a particular embodiment, the compounds of formula (I), (II), and (III) are such that at least two groups (preferably, at least three) among R 1 , R 2 , R 3 , and R 4 are hydrogens. In a particular embodiment, the compounds of formula (I), (II), and (III) are such that R 1 , R 3 , and R 4 are hydrogens, and R 2 is -SO 3 ' Na + .

[0040] In another particular embodiment, the compounds of formula (I), (II), and (III) are such that each of R1, R2, R3, and R4is independently hydrogen or bromine, provided that at least one of R1, R2, R3, and R4 is hydrogen and at least one other of R1, R2, R3, and R4 is bromine.

[0041] In a preferred embodiment, the compounds of formula (I), (II), and (III) are such that R 1 , R 2 , R 3 , and R 4 are hydrogen. In such a 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 No. 482-89-3) is also called indigotin and is represented by the following formula:

[0042] Step a) of the process 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) allows a reduction of F imine formed by the coupling between the amine function of said compound of formula (I) and the aldehyde function of glyoxylic acid, to thus form a compound of formula (II) as defined in the present application.

[0043] Metal-catalyzed hydrogenation uses a metal catalyst, under a hydrogen atmosphere. The hydrogen pressure in step a) may in particular be between 1 and 30 bars, preferably between 5 and 20 bars, better still around 10 bars.

[0044] The metal catalyst is advantageously heterogeneous. The term "heterogeneous" describing a catalyst is well known to those skilled in the art and means that the catalyst is not in the same phase as the reaction medium in which it is used. Typically, a heterogeneous metal catalyst used in step a) is solid and the reaction medium is liquid and / or gaseous. The metal catalyst is advantageously a transition metal catalyst. Examples of transition metals include nickel, palladium, platinum, rhodium, or a combination thereof. In a particular embodiment, the metal catalyst is a nickel palladium or platinum catalyst. Preferably, the metal catalyst is palladium on carbon, palladium on aluminum oxide, nickel on aluminum oxide, nickel on aluminum oxide and silica oxide, or platinum on carbon.An example of nickel on aluminum oxide and silicon oxide is the NiSat® range, including Ni / AhCh-SiCh 54%Ni - 310RS, marketed by Clariant. An example of nickel on aluminum oxide is Ni / AhCh 21%Ni (HTC 500Ni-Johnson-Matthey).

[0045] Even more preferably, the metal catalyst is palladium on carbon.

[0046] The amount of metal catalyst used in step a) may be between 0.0001% and 40% by weight, in particular between 1% and 30% by weight, preferably between 5% and 25% by weight, better still between 5% and 15% by weight, for example approximately 10% by weight, relative to the weight of said compound of formula (I).

[0047] The reaction in step a) may be carried out at a temperature of between 35°C and 120°C, in particular between 35°C and 90°C, or even between 35°C and 65°C, for example approximately 50°C. The reaction in step a) may be carried out for a period of between 30 seconds and 15 hours, in particular between 15 minutes and 8 hours, or even between 2 hours and 8 hours, for example approximately 4 hours. The solvent in step a) is in particular a polar solvent, for example 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, including those conventionally used in metal-catalyzed hydrogenation reactions, can also be used.

[0048] In a particular embodiment, step a) comprises: i) forming a mixture by adding a compound of formula (I) as defined in the present application and the metal catalyst, preferably palladium on carbon, in a polar solvent, such as THF or a THF / water mixture, with stirring; ii) placing the mixture of step i) under hydrogen pressure, said pressure preferably being between 1 and 30 bars (better between 5 and 20 bars); iii) heating the mixture of step ii) to a temperature between 35°C and 120°C (in particular, between 35°C and 65°C); and iv) adding glyoxylic acid to the mixture of step iii).

[0049] Preferably, the reaction in step a) is carried out for a period of between 30 seconds and 8 hours, better still between 15 minutes and 8 hours, or even between 2 hours and 8 hours, for example approximately 4 hours.

[0050] The glyoxylic acid used as a raw material in the process of the invention can be produced by any type of chemical synthesis process. Preferably, the glyoxylic acid is obtained from bio-sourced ethanol (also called "bioethanol") or bio-sourced glycolic acid.

[0051] The compound of formula (I), used as a starting material in the process of the invention, can be produced by a chemical synthesis process or a biological process. Preferably, the compound of formula (I) (preferably anthranilic acid) is obtained by a biological process, for example by means of a host cell or a genetic sequence thereof.

[0052] In a preferred embodiment, the compound of formula (I) (preferably anthranilic acid) is produced by a recombinant host cell, said cell preferably being microbial. The use of such a recombinant host cell makes it possible to provide the compound of formula (I) (preferably anthranilic acid) in large quantities and under mild conditions by simple fermentation. The term "recombinant host cell" means a cell that does not occur in nature and that contains an altered genome resulting from either a deletion, an insertion, or a modification of one or more genetic elements. The term "host cell" also encompasses any progeny of a parent host cell that is not identical to the parent host cell due to mutations that occur during replication. The host cell may be a microbial or a plant host cell. Preferably, the host cell is a microbial host cell.As used herein, the term "microbial host cell" means a bacterium, a filamentous fungus or a yeast, preferably a bacterium or a yeast, more preferably a bacterium.

[0053] In particular, the host cell may be a bacterium of the genus Escherichia, Streptomyces, Corynebacterium, Bacillus, Achromobacter, Brevibacterium, Arthrobacter, Flavobacterium, or Pseudomonas. More particularly, the host cell may be a bacterium Escherichia coli, Streptomyces coelicolor, Bacillus subtilis, Bacillus megaterium, Achromobacter-polymorph, Achromobacter xerosis, Brevibacterium protoformiae, Arthrobacter oxydans, Flavobacterium esteraromaticum, Pseudomonas fluorescens, Pseudomonas diminuta, or Pseudomonas eruginosa.

[0054] Preferably, the host cell is a bacterium of the genus Escherichia, such as Escherichia coli or Streptomyces, such as Streptomyces coelicolor. The biological methods for obtaining anthranilic acid from a recombinant microbial host cell have been the subject of international patent application No. PCT / EP2021 / 079927, and those skilled in the art will be able to readily refer to it.

[0055] A metal catalyst, in particular a heterogeneous one, has the advantage of being able to be separated more easily from the reaction medium of step a), so that it can then be recovered and reused, i.e. recycled. In a particular embodiment, the process according to the invention further comprises, after step a), a step of recovering the metal catalyst, in particular a heterogeneous one. This step of recovering the catalyst is preferably carried out by filtration, for example by filtration on celite.

[0056] The solvent used in step a) can also be recovered and reused, i.e. recycled. In a particular embodiment, the method according to the invention further comprises, after step a), a step of recovering said solvent. This step of recovering the solvent is preferably carried out by distillation or evaporation under reduced pressure.

[0057] Step b) of the process of the invention comprises converting a compound of formula (II) as defined in the present application into a compound of formula (III) as defined in the present application.

[0058] Preferably, step b) comprises: bl) reacting a compound of formula (II) as defined in the present application with acetic anhydride, to obtain a compound of formula (II'): wherein each of Ri, R2, R3 and R4 is independently hydrogen, halogen, -CN, -NO2, -C(O)H, -SO3H, -CO2H, -SO3 Mi + , -CO2 M2 +, -SO3R5, -CO2R6, -C(O)R7OR -OR8, each of Mi + and M2 + being independently a cation (preferably an alkali cation such as sodium), each of R5, R6, R7, and Rs being independently a C1-C6 aliphatic group (such as C1-C6 alkyl) or an aryl (such as phenyl); and b2) reacting said compound of formula (II') with a base, to obtain a compound of formula (III) as defined in the present application.

[0059] In a particular embodiment, the compound of formula (II') is such that at least two groups (preferably, at least three) among R1, R2, R3, and R4 are hydrogen.

[0060] In a particular embodiment, the compound of formula (II') is such that R1, R3, and R4 are hydrogens, and R2 is -SO3' Na + .

[0061] In another particular embodiment, the compound of formula (II') is such that each of R1, R2, R3 and R4is independently hydrogen or bromine, provided that at least one of R1, R2, R3, and R4 is hydrogen and at least one other of R1, R2, R3, and R4 is bromine.

[0062] In a preferred embodiment, the compound of formula (II') is such that R1, R2, R3, and R4 are hydrogen. In such a preferred embodiment, the compound of formula (II') is 1-acetylindol-3-yl acetate.

[0063] Preferably, the reaction in step b1) is carried out in the presence of a base. When present, such a base is advantageously an amine base. Examples of amine bases include triethylamine, diisopropylethylamine, dimethylphenylamine, or piperidine.

[0064] Preferably, said amine base is triethylamine.

[0065] In a particular embodiment, step b1) comprises the formation of a mixture comprising (preferably consisting of) a compound of formula (II), acetic anhydride and the optional base (preferably triethylamine), and stirring the resulting reaction mixture.

[0066] The reaction in step b1) is advantageously carried out successively:

[0067] - at a temperature between 10°C and 40°C, preferably for a period between 15 minutes and 3 hours (for example, approximately 30 minutes), then - at a temperature between 70°C and 110°C, preferably for a period between 15 minutes and 3 hours (for example, approximately 30 minutes).

[0068] 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 base in step b1), when present, may be between 3 and 10 equivalents relative to the molar amount of the compound of formula (II).

[0069] The base in step b1), when present, can optionally be recovered and reused, i.e. recycled. In a particular embodiment, the process according to the invention further comprises, after step b1), a step of recovering the base from step b1), preferably by distillation or evaporation under reduced pressure.

[0070] Step b2) makes it possible to convert said compound of formula (II') obtained in step b1) into said compound of formula (III). Step b2) is carried out in the presence of a base. This base may be an oxygenated base such as a hydroxide (for example, sodium or potassium hydroxide), an alcoholate (for example, sodium ethylate or sodium isopropoxide) or a carbonate (for example, sodium carbonate).

[0071] Preferably, the base of step b2) is a hydroxide, in particular sodium hydroxide. The molar quantity of base in step b2) may be between 4 and 25 equivalents relative to the molar quantity of said compound of formula (II').

[0072] In a particular embodiment, the reaction in step b2) is carried out in water or in a water / alcohol mixture. Examples of alcohol include ethanol, propanol or butanol, preferably ethanol. The water may optionally contain one or more additives, which may for example be chosen from glycol derivatives (for example ethylene glycol, diethylene glycol, or propylene glycol) and surfactants.

[0073] In one embodiment, the reaction in step b2) is carried out at a temperature of between 80°C and 110°C, preferably for a period of between 1 h and 5 h.

[0074] In a particular embodiment, step b2) comprises the formation of a mixture by adding a compound of formula (II') as defined above to a solution of the base in water, then stirring the resulting mixture at a temperature of between 80°C and 110°C, preferably for a period of between 1 h and 5 h. The compound of formula (III) obtained in step b) of the process of the invention, and in particular in step b2), is typically obtained in the form of a precipitate. Step c) of the process of the invention comprises the recovery of the compound of formula (III) obtained in step b). The compound of formula (III) may be isolated in step c) by any technique known to those skilled in the art, for example by filtration.

[0075] The purity of the compound of formula (III) obtained by the process of the invention is advantageously greater than or equal to 90%, preferably greater than or equal to 95%, or even greater than or equal to 98%.

[0076] In a particular embodiment, the method comprises the following steps: a) reacting a compound of formula (I) as defined above with glyoxylic acid in the presence of palladium on carbon and under a hydrogen atmosphere, in a polar solvent (such as a THF / water mixture), at a temperature of between 35°C and 120°C (for example, between 35°C and 65°C), preferably for a period of between 30 seconds and 8 hours, to obtain a compound of formula (II) as defined above; b1) reacting said compound of formula (II) with acetic anhydride, in the presence of a base, preferably an amine base, such as triethylamine, said reaction being carried out successively:

[0077] - at a temperature between 10°C and 40°C, preferably for a period of between 15 minutes and 3 hours, then

[0078] - at a temperature between 70°C and 110°C, preferably for a period between 15 minutes and 3 hours, to obtain a compound of formula (II') as defined above; b2) reacting said 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 period between 1h and 5h, to obtain a compound of formula (III) as defined above; and c) recovering said compound of formula (III).

[0079] In another particular embodiment, the method comprises the following steps: a) reacting a compound of formula (I) as defined above with glyoxylic acid in the presence of palladium on carbon and under a hydrogen atmosphere, in a polar solvent (preferably a THF / water mixture), at a temperature of between 35°C and 120°C (for example, between 35°C and 65°C), preferably for a period of between 30 seconds and 8 hours, to obtain a compound of formula (II) as defined above; a') recovering the palladium on carbon, preferably by filtration, and recovering the polar solvent, preferably by distillation or evaporation under reduced pressure; bl) reacting said compound of formula (II) with acetic anhydride, in the presence of a base, preferably an amine base, such as triethylamine, said reaction being carried out successively:

[0080] - at a temperature between 10°C and 40°C, preferably for a period of between 15 minutes and 3 hours, then

[0081] - at a temperature between 70°C and 110°C, preferably for a period between 15 minutes and 3 hours, to obtain a compound of formula (II') as defined above; b') recovering the amine base, preferably by distillation or evaporation under reduced pressure; b2) reacting said 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 period between 1 h and 5 h, to obtain a compound of formula (III) as defined above; and c) recovering said compound of formula (III).

[0082] In another particular embodiment, the process according to the invention essentially consists of steps a), b1), b2) and c) as described in the present application. By "process essentially consisting of steps a), b1) and b2)" is meant a process consisting of the reaction steps a), b1) and b2), of step c) of recovery of the compound of formula (III), and which may further comprise one or more additional conventional treatment steps, in particular at the end of each of steps a), b1) and b2). These steps commonly used in organic synthesis are, for example, washing, liquid-liquid extraction, filtration, purification or drying steps.

[0083] In a particular embodiment, the process essentially consists of the following steps: a) reacting a compound of formula (I) as defined above with glyoxylic acid in the presence of palladium on carbon and under a hydrogen atmosphere, in a polar solvent such as a THF / water mixture, at a temperature of between 35°C and 120°C (for example, between 35°C and 65°C), preferably for a period of between 30 seconds and 8 hours, to obtain a compound of formula (II) as defined above; b1) reacting said compound of formula (II) with acetic anhydride, in the presence of a base, preferably an amine base, such as triethylamine, said reaction being carried out successively:

[0084] - at a temperature between 10°C and 40°C, preferably for a period of between 15 minutes and 3 hours, then

[0085] - at a temperature between 70°C and 110°C, preferably for a period between 15 minutes and 3 hours, to obtain a compound of formula (II') as defined above; b2) reacting said 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 period between 1 h and 5 h, to obtain a compound of formula (III) as defined above; and c) recovering said compound of formula (III).

[0086] A preferred subject matter of the present invention is a process for preparing indigo comprising the following steps: a) reacting anthranilic acid with glyoxylic acid under hydrogenation in the presence of a metal catalyst in a solvent, to obtain 2-(carboxymethylamino)benzoic acid; b) converting 2-(carboxymethylamino)benzoic acid into indigo; and c) recovering indigo.

[0087] Preferably, the metal catalyst is a palladium catalyst, preferably palladium on carbon.

[0088] In a particular embodiment, the method according to the invention further comprises a step of recovering the metal catalyst, after step a), preferably by filtration.

[0089] In another particular embodiment, the process according to the invention further comprises, after step a), a step of recovering the solvent from step a), preferably by distillation or evaporation under reduced pressure.

[0090] Preferably, the solvent of step a) is a polar solvent, such as THF or a THF / water mixture.

[0091] According to another particular embodiment, the glyoxylic acid is obtained from ethanol or bio-sourced glycolic acid.

[0092] According to another particular embodiment, the reaction in step a) is carried out at a temperature of between 35°C and 120°C, preferably for a duration of between 30 seconds and 8 hours. In particular, the quantity of metal catalyst in step a) is between 0.0001% and 40% by weight, preferably between 5% and 25% by weight, relative to the weight of anthranilic acid, and the hydrogen pressure is between 1 and 30 bars, preferably between 5 and 20 bars.

[0093] In particular, step b) comprises: bl) reacting 2-(carboxymethylamino)benzoic acid with acetic anhydride, to obtain l-acetylindol-3-yl acetate; and b2) reacting l-acetylindol-3-yl acetate with a base, to obtain indigo. According to a preferred embodiment, the process according to the invention comprises the following steps: a) reacting anthranilic acid with glyoxylic acid in the presence of palladium on carbon and under a hydrogen atmosphere, in a polar solvent, at a temperature between 35°C and 120°C, preferably for a period between 30 seconds and 8 hours, to obtain 2-(carboxymethylamino)benzoic acid; bl) the reaction of 2-(carboxymethylamino)benzoic acid with acetic anhydride, in the presence of a base, preferably an amine base, such as triethylamine, said reaction being carried out successively:

[0094] - at a temperature between 10°C and 40°C, preferably for a period of between 15 minutes and 3 hours, then

[0095] - at a temperature between 70°C and 110°C, preferably for a period between 15 minutes and 3 hours, to obtain l-acetylindol-3-yl acetate; b2) reacting l-acetylindol-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 period between 1h and 5h, to obtain indigo; and c) recovering the indigo.

[0096] In a particular embodiment, the compound of formula (I), in particular anthranilic acid, is biosourced. By "biosourced" product or compound, is meant a product or compound derived from renewable organic matter of microbial, plant, fungal or animal origin, and more precisely microbial in the context of the present invention. As an example of bacteria producing anthranilic acid, Gram+ or Gram- bacteria may be cited, in a non-exhaustive manner, such as bacteria of the genus Escherichia (Escherichia coli), Streptomyces, Bacillus, Cupridavidus, Corynebacterium Mycobacterium, Kitasatospora, Luteipulveratus, Thermobifida, Thermomonospora, Frankia, Pseudonocardia, Saccharothrix, Kulz.neria, Lentzea, Prauserella, Salinispora, Micromonospora, Actinoplanes, Catenulispora, Mycolicibacterium, Dietzia, Aeromicrobium, Nonomuraea, Blastococcus, Modestobacter, Saccharopolyspora, Amycolatopsis, Actinopolyspora, Acidimicrobium, Photorhabdus, Hoeflea, Azospirillum, Crinalium, and Cylindrospermum.

[0097] In a more particular embodiment, the compound of formula (I), in particular anthranilic acid, is produced by a recombinant host cell, said cell preferably being microbial. Examples of microbial recombinant host cells are described in international application WO 2022 / 090363 (PCT / EP2021 / 079927). According to a preferred embodiment of the invention, the microbial recombinant host cell is chosen from 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.According to an even more preferred embodiment, the recombinant microbial host cell is selected from Escherichia, Streptomyces, Corynebacterium and Bacillus, and even more preferably, the recombinant microbial host cell is Escherichia coli.

[0098] EXAMPLES

[0099] The invention will be better understood in light of the following examples, which are given purely for illustrative purposes and are not intended to limit the scope of the invention, defined by the appended claims.

[0100] Example 1. Process for the preparation of a compound of formula (III): indigo

[0101] 5 volumes / weight (also noted "V / P", where 1 V / P is 1 liter per kg) of THF are introduced prior to loading, under 90 rpm of stirring, 1 kg of anthranilic acid and 0.1 kg of palladium on carbon (10% by weight of palladium, 50% wet) into the reactor. The mixture is then pressurized under 10 bars of hydrogen and brought to 50 °C before the introduction in 30 min of 1.3 V / P of a 50% aqueous solution of glyoxylic acid (1.2 molar equivalents).

[0102] The reaction medium is then kept heated at 50°C and stirred at 90 rpm for a further 3.5 hours. If the technical conditions allow regular sampling, the progress of the reaction can be monitored by HPLC.

[0103] When the conversion is sufficient > 97%, the reaction is stopped and filtered through celite (1 V / P) to remove the palladium particles. The solvent is then evaporated to obtain 1.3 kg of 2-(carboxymethylamino)benzoic acid (2) whose purity is evaluated at 85% by NMR. The 15% of impurities present are essentially made up of minerals.

[0104] 1H NMR (400 MHz, DMSO): ô 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)

[0105] 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 min; 2-(carboxymethylamino)benzoic acid (2): 13.1 min; main impurity: 8.6 min

[0106] Indigo was also prepared under the same experimental conditions as described above except that palladium on carbon was replaced either by palladium on aluminum oxide 0.5%, or nickel on aluminum oxide and silica oxide (NiSat®: Ni / AliO SiOi 54%Ni), or nickel on aluminum oxide (Ni / AhOs 21%Ni), or platinum on carbon.

[0107] HPLC analytical data:

[0108] - Mobile phase: A: H2O + 0.1% formic acid / B: Acetonitrile (HPLC purity)

[0109] - Column: Kromasil KR5C18-25M (250 x 4.6 mm)

[0110] - Gradient: to: 90 / 10; t= 15 min.: 50 / 50; t=20 min.: 50 / 50; t=30 min.: 90 / 10 Comparison of step a) of the method of the invention with the methods of the prior art (Table 1)

[0111] Table 1: 1 Helvetica Chimica Acta 2008, 91, 1975-1983

[0112] 2 ChemPhotoChem 2019, 3, 613-618

[0113] Unlike the method of Lai et al. and that described in US 2008 / 051426, step a) of the process of the invention makes it possible to access 2-(carboxy methylamino)benzoic acid with an excellent yield, using a non-toxic reagent, namely glyoxylic acid.

[0114] Access to this key intermediate is achieved in a single step, unlike the method of Koeppe et al. which involves saponification after coupling anthranilic acid and ethyl glyoxylate. Finally, step a) generates a minimal amount of waste, as it uses a catalyst that can be recycled. It is also possible to recycle the solvent used, whereas the waters in the prior art methods are contaminated by toxic reagents.

[0115] (2) (3)

[0116] l-Acetylindol-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 first held at room temperature for 30 minutes to protect the amine. The reaction is then heated to 90 °C for 30 minutes to complete cyclization and hydroxyl protection.

[0117] After an HPLC analysis confirming a conversion greater than 95%, a portion (approximately 25%) of the volatile products can be evaporated under reduced pressure (40 °C, 150 mBars) to recycle the triethylamine. 10 liters of water are then added to precipitate the product. The product is then filtered (25 microns), washed with 10 liters of water and then dried in an oven at 80 0C to obtain approximately 1.01 kg (91% of the expected mass) of powder. The purity of the product (3) thus obtained is determined by NMR or HPLC analysis (83%) in order to adjust the proportions of reagents for the following reactions. (Dosed yield: 75%).

[0118] 1H NMR (400 MHz, MeOD) ô 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).

[0119] HPLC retention time: Impurity (Mono-acetylated product): 9.2 min; 1-acetylindol-3-yl acetate (3): 7.3 min

[0120] HPLC analytical data:

[0121] - Mobile phase: A: H2O + 0.1% formic acid / B: Acetonitrile (HPLC grade)

[0122] - Column: Kromasil KR5C18-25M (250 x 4.6 mm)

[0123] - Gradient: to: 50 / 50; t= 15 min. : 5 / 95; t=23 min. : 5 / 95; t=25 min. : 90 / 10; t=30 min. : 50 / 50

[0124] (3) (4)

[0125] The preparation of indigo (4) from l-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, i.e. 16 equivalents). First, the reaction mixture is heated to reflux for two hours, then this mixture is left at room temperature with stirring for 5 hours. The blue precipitate thus formed is filtered (cutoff threshold 10 microns), then washed with water (10 volumes) and ethanol (10 volumes). The product is then dried in an oven (80 °C) to obtain 0.42 kg of indigo (Yield: 69%). The purity of the final product is determined by UV spectroscopy. The purity of the indigo obtained is greater than 95%.

[0126] 1H NMR (400 MHz, DMSO) ô 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

DEMANDS 1. Process for preparing a compound of formula (III): in which each of Ri, R2, R3 and R4 is independently a hydrogen, a halogen, -CN, -NO2, -C(O)H, -SO3H, -CO2H, -SO3 Mi + -CO2 M2 + , -SO3R5, -CO2R6, -C(O)R7OU -OR8, each of Mi + and M2 + being independently a cation, each of R5, RÔ, R7, and Rs being independently an aliphatic group in C1-CÔ or an aryl; said process comprising the following steps: a) reacting a compound of formula (I): in which each of Ri, R2, R3 and R4 is as defined above, with glyoxylic acid under hydrogenation in the presence of a metal catalyst in a solvent, to obtain a compound of formula (II): in which each of Ri, R2, R3 and R4 is as defined above; b) the conversion of said compound of formula (II) into said compound of formula (III); c) the recovery of said compound of formula (III).

2. A method according to claim 1, wherein Ri, R2, R3, and R4 are hydrogens.

3. A method according to claim 1 or 2, wherein the metallic catalyst is a palladium, nickel, or platinum catalyst.

4. A process according to any one of claims 1 to 3, wherein the metallic catalyst is palladium on carbon, palladium on aluminum oxide, nickel on aluminum oxide, nickel on aluminum oxide and silica oxide, or platinum on carbon.

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

6. A method according to any one of claims 1 to 5, which method further comprises, after step a): - a step for recovering the metallic catalyst, preferably by filtration; and / or - a step for recovering the solvent from step a), preferably by distillation or evaporation under reduced pressure.

7. A 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. A process according to any one of claims 1 to 7, wherein glyoxylic acid is obtained from bio-based ethanol or glycolic acid.

9. A 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 duration between 30 seconds and 8 hours.

10. A process according to any one of claims 1 to 9, wherein, in step a), the amount of metallic catalyst is between 0.0001% and 40% by weight, preferably between 5% and 25% by weight, relative to 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. A process according to any one of claims 1 to 10, wherein step b) comprises: bl) reacting a compound of formula (II) as defined in claim 1 or 2, with acetic anhydride, to obtain a compound of formula (IF): in which each of Ri, R2, R3 and R4 is independently a hydrogen, a halogen, -CN, -NO2, -C(O)H, -SO3H, -CO2H, -SO3 Mi + -CO2 M2 + , -SO3R5, -CO2R6, -C(O)R7OU -OR8, each of Mi + and M2 +being independently a cation, each of R5, R2, R7, and Rs being independently an aliphatic group in CI-CO or an aryl, preferably Ri, R2, R3 and R4 are hydrogens; and b2) reacting said compound of formula (II') with a base, to obtain a compound of formula (III) as defined in claim 1 or 2.

12. A process according to any one of claims 1 to 5 or 11, comprising the following steps: a) reacting a compound of formula (I) as defined in claim 1 or 2 with glyoxylic acid in the presence of palladium on carbon and under a hydrogen atmosphere, in a polar solvent, at a temperature between 35 °C and 120 °C, preferably for a duration between 30 seconds and 8 hours, to obtain a compound of formula (II) as defined in claim 1 or 2; b) reacting said compound of formula (II) with acetic anhydride, in the presence of a base, preferably an amino base such as triethylamine, said reaction being carried out successively: - at a temperature between 10°C and 40°C, preferably for a period of between 15 minutes and 3 hours, then - at a temperature between 70°C and 110°C, preferably for a period of between 15 minutes and 3 hours, to obtain a compound of formula (II') as defined in claim 9; b2) reacting said 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 period of between 1h and 5h, to obtain a compound of formula (III) as defined in claim 1 or 2; and c) recovering said compound of formula (III).

13. A process according to any one of claims 1 to 12, wherein said compound of formula (I), in particular anthranilic acid, is bio-based.

14. A method according to any one of claims 1 to 13, wherein said compound of formula (I), in particular anthranilic acid, is produced by a recombinant host cell, preferably microbial.

15. A method according to claim 14, wherein the recombinant microbial host cell is selected from 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 Escherichia, Streptomyces, Corynebacterium and Bacillus, and even more preferably, the recombinant microbial host cell is Escherichia coli.

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