Process for preparation of indigo or substituted derivatives thereof

Abstract

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

Description

Technical Field

[0001] The present invention relates to the synthesis of dyes. More specifically, the present invention relates to a process for the preparation of optionally substituted indigo starting from optionally substituted aminobenzoic acids. Background Art

[0002] Indigo has a history of thousands of years and is famous for its strong dark blue color, especially in denim and Tuareg scarves. Historically, indigo was mainly obtained by extracting and then oxidizing indigo glycosides contained in plants of the Indigofera family, especially indigo plants. In the 17th and 18th centuries, indigo plant plantations were established in North America, the French Antilles and India to meet the strong demand for indigo in the West. However, the production of natural indigo has gradually been replaced by chemical synthesis. Today, 50,000 tons of synthetic indigo are produced each year, and most of them are intended to be used for dyeing 4 billion pieces of denim garments produced each year.

[0003] Several methods for preparing indigo have been proposed since the late 19th century, when chemist Adolf von Baeyer first synthesized it from 2-nitrobenzaldehyde and acetone.

[0004] Karl Heumann (Chem. Ber, 1890, 3431) proposed two strategies for synthesizing indigo. In the first strategy, aniline reacts with chloroacetic acid to form N-phenylglycine, which is then converted to indoxyl in an alkaline medium. Indoxyl is then oxidized to form indigo. However, the yields obtained with this first strategy are low. The second strategy uses o-aminobenzoic acid instead of aniline: it reacts with chloroacetic acid to form 2-(carboxymethylamino)benzoic acid. The latter is then contacted with a base to form 2-indoxylcarboxylic acid. Finally, indigo is produced by heating and oxidizing the acid. However, the yields obtained are still moderate, and the method is very energy-intensive, not environmentally friendly, and uses toxic reactants, especially chloroacetic acid.

[0005] The formation of 2-(carboxymethylamino)benzoic acid from o-aminobenzoic acid and chloroacetic acid is a key step in indigo synthesis. Various reaction conditions have been described, but the yield obtained is still not high enough for industrial processes. For example, the reaction described in patent application US2008 / 051426 is carried out in the presence of sodium bicarbonate at 40-45°C, and the yield is only 80%. Lai et al. (Helvetica Chimica Acta 2008, 91, 1975-1983) describe the same reaction with the reflux of water in the presence of a mixture of sodium bicarbonate and sodium hydroxide. 90% of the 2-(carboxymethylamino)benzoic acid yield was obtained. Except for the insufficient yield, the chloroacetic acid used in these methods is a poisonous reactant.

[0006] Koeppe et al. (ChemPhotoChem 2019, 3, 613-618) describe the formation of 2-(carboxymethylamino)benzoic acid from o-aminobenzoic acid and ethyl glyoxylate by reductive amination in the presence of sodium cyanoborohydride. However, the reaction produces a large amount of waste, especially because the amount of sodium cyanoborohydride used is large and non-recyclable. In addition, the use of glyoxylate requires an additional saponification step with sodium hydroxide to obtain the acid.

[0007] Therefore, there is still a real need for an improved indigo preparation process that is simple, efficient and environmentally friendly. Summary of the invention

[0008] Against this background, the inventors have developed a process for preparing optionally substituted indigo starting from optionally substituted anthranilic acid and glyoxylic acid in three steps, which is simple and suitable for industrial-scale application. The key step of the process is to use a metal catalyst, especially a palladium catalyst (advantageously heterogeneous), to produce optionally substituted 2-(carboxymethylamino)benzoic acid in excellent yield under a hydrogen atmosphere. The acid can then be effectively converted to optionally substituted indigo, especially by a cyclization reaction in the presence of acetic anhydride and a dimerization reaction in an alkaline medium. The process is very environmentally friendly because it produces little waste and uses recyclable solvents and catalysts. In addition, the process uses glyoxylic acid, which is non-toxic and can be obtained from ethanol or bio-sourced glycolic acid (glycolic acid).

[0009] Therefore, the present invention relates to a process for preparing compounds of formula (III):

[0010]

[0011] Wherein, R1, R2, R3 and R4 are each independently hydrogen, halogen, -CN, -NO2, -C(O)H, -SO3H, -CO2H, -SO3 - M1+ 、-CO2 - M2 + , -SO3R5, -CO2R6, -C(O)R7 or -OR8,

[0012] M1 + and M2 + are each independently a cation,

[0013] R5, R6, R7 and R8 are each independently a C1-C6 aliphatic group or an aromatic group;

[0014] The method comprises the following steps:

[0015] a) making a compound of formula (I):

[0016]

[0017] wherein R1, R2, R3 and R4 are each as defined above,

[0018] With glyoxylic acid in a solvent in the presence of a metal catalyst under hydrogenation to obtain a compound of formula (II):

[0019]

[0020] Wherein, R1, R2, R3 and R4 are as defined above;

[0021] b) converting the compound of formula (II) into the compound of formula (III);

[0022] c) recovering the compound of formula (III).

[0023] In a preferred embodiment, R1, R2, R3 and R4 are hydrogen.

[0024] Preferably, the metal catalyst is a palladium, nickel or platinum catalyst. More preferably, the metal catalyst is palladium on carbon, palladium on alumina, nickel on aluminum oxide, nickel on alumina and silicon dioxide, or platinum on carbon. Even more preferably, the metal catalyst is palladium on carbon.

[0025] 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.

[0026] In another particular embodiment, the process according to the invention further comprises a step of recovering the solvent from step a) after step a), preferably by evaporation or distillation under reduced pressure.

[0027] Preferably, the solvent from step a) is a polar solvent, such as THF or a THF / water mixture.

[0028] According to another particular embodiment, the glyoxylic acid is obtained from ethanol or glycolic acid of biological origin.

[0029] 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 time between 30 seconds and 8 hours.

[0030] 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 bar, preferably between 5 and 20 bar.

[0031] In particular, step b) comprises:

[0032] b1) reacting a compound of formula (II) as defined in the present application with acetic anhydride to obtain a compound of formula (II'):

[0033]

[0034] wherein R1, R2, R3 and R4 are each independently hydrogen, halogen, -CN, -NO2, -C(O)H, -SO3H, -CO2H, -SO3 - M1 + 、-CO2 - M2 + , -SO3R5, -CO2R6, -C(O)R7 or OR8,

[0035] M1 + and M2 + are each independently a cation,

[0036] R5, R6, R7 and R8 are each independently a C1-C6 aliphatic group or an aryl group; and

[0037] b2) reacting said compound of formula (II') with a base to obtain a compound of formula (III) as defined in the present application.

[0038] According to a preferred embodiment, the method according to the present invention comprises the following steps:

[0039] a) reacting a compound of formula (I) as defined herein with glyoxylic acid in the presence of palladium on carbon and under a hydrogen atmosphere in a polar solvent at a temperature of 35°C to 120°C, preferably for a time between 30 seconds and 8 hours, to obtain a compound of formula (II) as defined herein.

[0040] 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 carried out sequentially as follows:

[0041] At a temperature between 10°C and 40°C, preferably for a time between 15 minutes and 3 hours, and thereafter

[0042] at a temperature between 70°C and 110°C, preferably for a time between 15 minutes and 3 hours, to obtain the compound of formula (II') as defined in the present application;

[0043] 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 time between 1 hour and 5 hours, to obtain a compound of formula (III) as defined in the application; and

[0044] c) recovering the compound of formula (III).

[0045] In a particular embodiment, the compound of formula (I), especially anthranilic acid, is of biological origin. In a more particular embodiment, the compound of formula (I), especially anthranilic acid, is produced by a recombinant host cell, preferably a microorganism. Preferably, the recombinant microbial host cell is selected from the genus Escherichia (Escherichia coli coli), Streptomyces, Bacillus, Cupridavidus, Corynebacterium, Mycobacterium, Kitasatospora, Luteipulveratus, Thermobifida, Thermomonospora, Frankia, Pseudonocardia, Saccharothrix, Kutzneria, Lentzea, Prauserella, Salinispora, Micromonospora, Actinoplastis, lanes, Catenulispora, Mycolicibacterium, Dietzia, Aeromicrobium, Nonomuraea, Blastococcus, Modestobacter, Saccharopolyspora, Amycolatopsis, Actinopolyspora, Acidimicrobium, Photorhabdus, Hoeflea, Azospirillum, Crinalium and Cylindrospermum, preferably selected from the genus Escherichia coli), Streptomyces, Corynebacterium and Bacillus, and even more preferably, the recombinant microbial host cell is Escherichia coli. DETAILED DESCRIPTION

[0046] definition

[0047] Expressions related to chemical groups "C x -C y ” (wherein x and y are integers) means that the chemical group comprises x to y carbon atoms. For example, if the expression C1-C6 is associated with a chemical group, it means that the chemical group contains 1 to 6 carbon atoms, in particular 1, 2, 3, 4, 5 or 6 carbon atoms.

[0048] "Aliphatic group" means a straight or branched, saturated or unsaturated, cyclic or acyclic, preferably acyclic hydrocarbon group. In a specific embodiment, the C1-C6 aliphatic group is a C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl.

[0049] "Alkyl" means a saturated, non-cyclic, linear or branched hydrocarbon group. Examples of alkyl (or C1-C6 alkyl) include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl or hexyl.

[0050] "Alkenyl" means an unsaturated, linear or branched, non-cyclic hydrocarbon group comprising at least one carbon-carbon double bond. Examples of alkenyl (or C2-C6 alkenyl) include vinyl, propenyl, isopropenyl, butenyl, isobutenyl, pentenyl or hexenyl.

[0051] "Alkynyl" means an unsaturated, linear or branched non-cyclic hydrocarbon group including at least one carbon-carbon triple bond. Examples of alkynyl (or C2-C6 alkynyl) include ethynyl, propynyl, butynyl, pentynyl or hexynyl.

[0052] "Aryl" means a monocyclic or polycyclic aromatic hydrocarbon group, preferably having 6 to 20 ring members. Examples of aryl include phenyl, biphenyl and naphthyl, preferably phenyl.

[0053] "Halogen" means fluorine, chlorine, bromine or iodine, preferably bromine.

[0054] "Cation" means an atom or group of atoms with a positive charge (e.g., +1, +2, +3 or +4 charge). The cation may be an organic or inorganic cation, preferably an inorganic cation. Examples of organic cations include tetra(C1-C6 alkyl)ammonium cations, pyridinium cations, Cation or tetra(C1-C6 alkyl) Examples of inorganic cations are, inter alia, alkali metal (e.g. sodium, lithium, potassium or cesium) cations, alkaline earth metal (e.g. magnesium or calcium) cations, aluminum cations or ammonium cations (NH4 + ). The preferred cation is the sodium cation.

[0055] In this application, the abbreviation "Ac" means "acetyl" (ie, -C(O)-CH3).

[0056] In this application, the term "about" associated with a value is a term familiar to those skilled in the art, and means that the value may vary to a certain extent depending on the context in which the term is used. If certain uses of the term are unclear to those skilled in the art based on the context, "about" means greater than or less than 30% of the associated value, greater than or less than 20% of the associated value, preferably greater than or less than 10% of the associated value.

[0057] Unless otherwise stated, when a range is expressed by the expression "between", the limit values ​​are included in the range.

[0058] The present invention provides a method for obtaining indigo-type optionally substituted compounds in a simple, efficient and environmentally friendly manner.

[0059] The process according to the present invention is a process for preparing a compound of formula (III):

[0060]

[0061] The method comprises the following steps:

[0062] a) making a compound of formula (I):

[0063]

[0064] With glyoxylic acid in a solvent in the presence of a metal catalyst under hydrogenation to obtain a compound of formula (II):

[0065]

[0066] b) converting the compound of formula (II) into a compound of formula (III) as defined above;

[0067] c) recovering the compound of formula (III).

[0068] In these formulas, R1, R2, R3 and R4 are each independently hydrogen, halogen, -CN, -NO2, -C(O)H, -SO3H, -CO2H, -SO3 - M1 + 、-CO2 - M2 + , -SO3R5, -CO2R6, -C(O)R7 or -OR8,

[0069] M1 + and M2 + are each independently a cation (preferably an alkali metal (eg sodium) cation),

[0070] R5, R6, R7 and R8 are each independently a C1-C6 aliphatic group (eg, a C1-C6 alkyl group) or an aryl group (eg, a phenyl group).

[0071] In certain embodiments, the compounds of formula (I), (II) and (III) are such that at least two (preferably at least three) of R1, R2, R3 and R4 are hydrogen.

[0072] In certain embodiments, the compounds of formula (I), (II) and (III) are such that R1, R3 and R4 are hydrogen, and R2 is -SO3 - Na + .

[0073] In another specific embodiment, the compounds of formula (I), (II) and (III) are such that R1, R2, R3 and R4 are each independently hydrogen or bromine, provided that at least one of R1, R2, R3 and R4 is hydrogen and at least another one of R1, R2, R3 and R4 is bromine.

[0074] In a preferred embodiment, the compounds of formula (I), (II) and (III) are such that R1, R2, R3 and R4 are hydrogen. In the 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 known as indigotin and is represented by the following formula:

[0075]

[0076] According to the method of the present invention, step a) comprises: reacting a compound of formula (I) as defined in the present application with glyoxylic acid in a solvent in the presence of a metal catalyst under hydrogenation (or equivalently "under metal-catalyzed hydrogenation"). The metal-catalyzed hydrogenation in step a) reduces the imine to form a compound of formula (II) as defined in the present application, the imine being formed by coupling between the amine functional group of the compound of formula (I) and the aldehyde functional group of glyoxylic acid.

[0077] The metal-catalyzed hydrogenation is carried out using 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, more preferably about 10 bar.

[0078] The metal catalyst is preferably heterogeneous. The term "heterogeneous" defining the catalyst is familiar to those skilled in the art and means 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.

[0079] The metal catalyst is preferably a transition metal catalyst. Examples of transition metals are especially nickel, palladium, platinum, rhodium or a combination 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 and silicon dioxide, or platinum on carbon. As an example of nickel on aluminum oxide and silicon dioxide, the NiSat® series can be mentioned, including Ni / Al2O3-SiO2 54%Ni – 310RS sold by Clariant. As an example of nickel on aluminum oxide, Ni / Al2O3 21%Ni (HTC 500Ni – Johnson-Matthey) can be mentioned.

[0080] Even more preferably, the metal catalyst is palladium on carbon.

[0081] 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, more preferably between 5% and 15% by weight, for example about 10% by weight, relative to the weight of the compound of formula (I).

[0082] The reaction in step a) can be carried out at a temperature between 35°C and 120°C, in particular between 35°C and 90°C, even between 35°C and 65°C, for example at about 50°C.

[0083] The reaction in step a) can 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 about 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 may also be used, in particular those conventionally used in metal-catalyzed hydrogenation reactions.

[0084] In a specific embodiment, step a) comprises:

[0085] i) forming a mixture by adding a compound of formula (I) as defined herein and a metal catalyst, preferably palladium on carbon, to a polar solvent such as THF or a THF / water mixture under stirring;

[0086] ii) placing the mixture from step i) under hydrogen pressure, preferably between 1 and 30 bar (more preferably between 5 and 20 bar);

[0087] iii) heating the mixture from step ii) at a temperature between 35°C and 120°C, in particular between 35°C and 65°C; and

[0088] iv) adding glyoxylic acid to the mixture from step iii).

[0089] Preferably, the reaction in step a) is carried out for a time 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 about 4 hours.

[0090] The glyoxylic acid used as raw material in the process of the invention may be produced by any type of chemical synthesis process.Preferably, the glyoxylic acid is obtained from bioderived ethanol (also called "bioethanol") or bioderived glycolic acid.

[0091] The compound of formula (I) used as raw material in the method of the present invention can be produced by chemical synthesis or biological method. Preferably, the compound of formula (I) (preferably anthranilic acid) is obtained by biological method, for example, by host cells or their gene sequences.

[0092] In a preferred embodiment, the compound of formula (I) (preferably anthranilic acid) is produced by a recombinant host cell, and the cell is preferably a microorganism. The use of the recombinant host cell enables the compound of formula (I) (preferably anthranilic acid) to be supplied in large quantities under mild conditions by simple fermentation. The term "recombinant host cell" refers to a cell that does not exist in nature, and it comprises a modified genome caused by the deletion, insertion or modification of one or more genetic components (genetic elements). The term "host cell" also includes the offspring of any parent host cell different from the parent host cell due to the mutation occurring during the replication process. The host cell can 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 a bacterium, a filamentous fungus or a yeast, preferably a bacterium or a yeast, more preferably a bacterium.

[0093] 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 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.

[0094] Preferably, the host cell is a bacterium of the genus Escherichia, such as Escherichia coli, or Streptomyces, such as Streptomyces coelicolor. A biological method for producing anthranilic acid from a recombinant microbial host cell has formed the subject of International Patent Application No. PCT / EP2021 / 079927, to which a person skilled in the art will be able to readily refer.

[0095] The metal catalyst, in particular a heterogeneous metal catalyst, provides the advantage of being able to be more easily separated from the reaction mixture in step a), so that it can be recovered and reused, i.e. recycled. In a particular embodiment, the method according to the invention further comprises a step of recovering the metal catalyst, in particular a heterogeneous metal catalyst, after step a). The step of recovering the catalyst is preferably carried out by filtering, for example by filtering on diatomaceous earth.

[0096] 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 a step of recovering the solvent after step a). The solvent recovery step is preferably carried out by distillation or evaporation under reduced pressure.

[0097] Step b) of the process of the present invention comprises converting a compound of formula (II) as defined herein into a compound of formula (III) as defined herein.

[0098] Preferably, step b) comprises:

[0099] b1) reacting a compound of formula (II) as defined in the present application with acetic anhydride to obtain a compound of formula (II'):

[0100]

[0101] wherein R1, R2, R3 and R4 are each independently hydrogen, halogen, -CN, -NO2, -C(O)H, -SO3H, -CO2H, -SO3 - M1 + 、-CO2 - M2 + , -SO3R5, -CO2R6, -C(O)R7 or -OR8,

[0102] M1 + and M2 + are each independently a cation (preferably an alkali metal (such as sodium) cation),

[0103] R5, R6, R7 and R8 are each independently a C1-C6 aliphatic group (eg, a C1-C6 alkyl group) or an aryl group (eg, a phenyl group); and

[0104] b2) reacting said compound of formula (II') with a base to obtain a compound of formula (III) as defined in the present application.

[0105] In a particular embodiment, the compound of formula (II') is such that at least two (preferably at least three) of the groups R1, R2, R3 and R4 are hydrogen atoms.

[0106] In a particular embodiment, the compound of formula (II') is such that R1, R3 and R4 are hydrogen atoms, and R2 is -SO3 - Na + .

[0107] In another specific embodiment, the compound of formula (II') is such that R1, R2, R3 and R4 are each independently hydrogen or bromine, provided that at least one of R1, R2, R3 and R4 is hydrogen and at least another of R1, R2, R3 and R4 is bromine.

[0108] In a preferred embodiment, the compound of formula (II') is such that R1, R2, R3 and R4 are hydrogen. In said preferred embodiment, the compound of formula (II') is 1-acetylindol-3-yl acetate.

[0109] Preferably, the reaction in step b1) is carried out in the presence of a base. When the base is present, it is preferably an amine base. Examples of amine bases include in particular triethylamine, diisopropylethylamine, dimethylaniline or piperidine.

[0110] Preferably, the amine base is triethylamine.

[0111] In a particular embodiment, step b1) comprises forming a mixture comprising or consisting of a compound of formula (II), acetic anhydride and optionally a base, preferably triethylamine, and stirring the resulting reaction mixture.

[0112] The reaction in step b1) is preferably carried out sequentially as follows:

[0113] At a temperature between 10°C and 40°C, preferably for a time between 15 minutes and 3 hours (e.g. about 30 minutes), then

[0114] At a temperature between 70°C and 110°C, it is preferably carried out for a time between 15 minutes and 3 hours, for example about 30 minutes.

[0115] 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) (when present) may be between 3 and 10 equivalents relative to the molar amount of the compound of formula (II).

[0116] The base in step b1) (when present) may optionally be recovered and reused, ie recycled. In a particular embodiment, the process according to the invention further comprises a step of recovering the base from step b1) after step b1), preferably by distillation or evaporation under reduced pressure.

[0117] Step b2) allows the compound of formula (II') obtained in step b1) to be converted into the compound of formula (III). Step b2) is carried out in the presence of a base. The base may be an oxygenated base, such as a hydroxide (such as sodium hydroxide or potassium hydroxide), an alkoxide (such as sodium ethoxide or sodium isopropoxide) or a carbonate (such as sodium carbonate).

[0118] Preferably, the base in step b2) is a hydroxide, especially sodium hydroxide.

[0119] 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').

[0120] In a specific embodiment, the reaction in step b2) is carried out in water or in a water / alcohol mixture. Examples of alcohols include ethanol, propanol or butanol, preferably ethanol. Water may optionally include one or more additives, which may be selected from glycol derivatives (e.g., ethylene glycol, diethylene glycol or propylene glycol) and surfactants.

[0121] 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.

[0122] In a particular embodiment, step b2) comprises forming a mixture by adding a compound of formula (II') as defined above to a solution of a base in water 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.

[0123] The compound of formula (III) obtained in step b) of the process of the present invention, especially in step b2), is usually obtained in the form of a precipitate. Step c) of the process of the present invention comprises recovering the compound of formula (III) obtained in step b). The compound of formula (III) can be separated in step c) by any technique known to those skilled in the art, for example by filtration.

[0124] The purity of the compound of formula (III) obtained by the process of the present invention is preferably greater than or equal to 90%, more preferably greater than or equal to 95%, or even greater than or equal to 98%.

[0125] In a specific embodiment, the method comprises the following steps:

[0126] 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 (e.g. a THF / water mixture) 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 a compound of formula (II) as defined above;

[0127] 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 carried out sequentially as follows:

[0128] At a temperature between 10°C and 40°C, preferably for a time between 15 minutes and 3 hours, and thereafter

[0129] at a temperature between 70°C and 110°C, preferably for a time between 15 minutes and 3 hours, to obtain a compound of formula (II') as defined above;

[0130] 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 1 hour and 5 hours, to obtain a compound of formula (III) as defined above; and

[0131] c) recovering the compound of formula (III).

[0132] In another specific embodiment, the method comprises the following steps:

[0133] 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 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 a compound of formula (II) as defined above;

[0134] a') recovering the palladium on carbon, preferably by filtration, and recovering the polar solvent, preferably by distillation or evaporation under reduced pressure;

[0135] 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 carried out sequentially as follows:

[0136] At a temperature between 10°C and 40°C, preferably for a time between 15 minutes and 3 hours, and thereafter

[0137] at a temperature between 70°C and 110°C, preferably for a time between 15 minutes and 3 hours, to obtain a compound of formula (II') as defined above;

[0138] b') recovering the amine base, preferably by distillation or evaporation under reduced pressure;

[0139] 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 1 hour and 5 hours, to obtain a compound of formula (III) as defined above; and

[0140] c) recovering the compound of the above formula (III).

[0141] In another specific embodiment, the method according to the present invention is essentially composed of steps a), b1), b2) and c) as described in the present application. "Method essentially composed of steps a), b1) and b2)" means a method consisting of reaction steps a), b1) and b2), step c) of collecting the compound of formula (III), and may further include one or more additional steps of conventional treatment, especially at the end of each step a), b1) and b2). These steps commonly used in organic synthesis are steps such as washing, liquid-liquid extraction, filtering, purification or drying.

[0142] In a specific embodiment, the method consists essentially of the following steps:

[0143] 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 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 a compound of formula (II) as defined above;

[0144] 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 carried out sequentially as follows:

[0145] At a temperature between 10°C and 40°C, preferably for a time between 15 minutes and 3 hours, and thereafter

[0146] at a temperature between 70°C and 110°C, preferably for a time between 15 minutes and 3 hours, to obtain the compound of formula (II') as defined above;

[0147] 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 1 hour and 5 hours, to obtain a compound of formula (III) as defined above; and

[0148] c) recovering the compound of formula (III).

[0149] A preferred object of the present invention is a method for preparing indigo, comprising the following steps:

[0150] 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;

[0151] b) converting 2-(carboxymethylamino)benzoic acid into indigo; and

[0152] c) Collecting indigo.

[0153] Preferably, the metal catalyst is a palladium catalyst, preferably palladium on carbon.

[0154] 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.

[0155] In another particular embodiment, the process according to the invention further comprises a step of recovering the solvent from step a) after step a), preferably by distillation or evaporation under reduced pressure.

[0156] Preferably, the solvent from step a) is a polar solvent, such as THF or a THF / water mixture.

[0157] According to another particular embodiment, the glyoxylic acid is obtained from ethanol or glycolic acid of biological origin.

[0158] 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 time between 30 seconds and 8 hours.

[0159] 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 amount of anthranilic acid, and the hydrogen pressure is between 1 and 30 bar, preferably between 5 and 20 bar.

[0160] In particular, step b) comprises:

[0161] b1) reacting 2-(carboxymethylamino)benzoic acid with acetic anhydride to obtain 1-acetylindol-3-yl acetate; and

[0162] b2) Reaction of 1-acetylindol-3-yl acetate with a base to obtain indigo.

[0163] According to a preferred embodiment, the method according to the present invention comprises the following steps:

[0164] 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 time between 30 seconds and 8 hours, to obtain 2-(carboxymethylamino)benzoic acid;

[0165] 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 carried out sequentially as follows:

[0166] At a temperature between 10°C and 40°C, preferably for a time between 15 minutes and 3 hours, and thereafter

[0167] at a temperature between 70°C and 110°C, preferably for a time between 15 minutes and 3 hours, to obtain 1-acetylindol-3-yl acetate;

[0168] b2) reacting 1-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 time between 1 hour and 5 hours, to obtain indigo; and

[0169] c) Collecting indigo.

[0170] In a particular embodiment, the compounds of formula (I), in particular anthranilic acid, are of biological origin. "Biogenic" products or compounds mean renewable organic matter obtained from microorganisms, plants, fungi or animals, and more precisely, microorganisms in the context of the present invention. As examples of bacteria producing anthranilic acid, mention may be made of, but is not limited to, Gram-positive or Gram-negative bacteria, such as Escherichia (Escherichia coli) and 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.

[0171] In a more specific embodiment, the compound of formula (I), especially anthranilic acid, is produced by a recombinant host cell, preferably a microorganism. Examples of recombinant microbial host cells are described in international application WO 2022 / 090363 (PCT / EP2021 / 079927). According to a preferred embodiment of the present invention, the recombinant microbial host cell is selected from the genus Escherichia (Escherichia coli (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 the group consisting of Escherichia, Streptomyces, Corynebacterium and Bacillus, and even more preferably, the recombinant microbial host cell is Escherichia coli.

[0172] Example

[0173] The present invention will be better understood by means of the following examples, which are purely illustrative and are not intended to limit the scope of the present invention, which is defined by the appended claims.

[0174] Example 1. Method for preparing the compound of formula (III): Indigo

[0175]

[0176] Before loading, 5 volumes / weight (also written as "v / w", where 1 v / w means 1 l / kg) of THF were introduced, 1 kg of anthranilic acid and 0.1 kg of palladium on carbon (10% by weight of palladium, 50% water) were added to the reactor while stirring at 90 rpm. The mixture was then pressurized to 10 bar of hydrogen and heated to 50° C., and then 1.3 v / w of a 50% aqueous solution of glyoxylic acid (1.2 molar equivalents) was introduced over 30 minutes.

[0177] The reaction mixture was then heated at 50° C. and stirred at 90 rpm for an additional 3.5 hours. If technical conditions allow for regular sampling, the progress of the reaction can be monitored by high performance liquid chromatography (HPLC).

[0178] When the conversion was sufficient (> 97%), the reaction was stopped and filtered on diatomaceous earth (1 v / w) to remove the palladium particles. The solvent was then evaporated to obtain 1.3 kg of 2-(carboxymethylamino)benzoic acid (2) with a purity of 85% as assessed by NMR. The 15% impurities present were mainly composed of minerals.

[0179] 1H NMR (400 MHz, DMSO): 7.78 (dd, = 8.1, 1.7 Hz, 1H), 7.29 (t, = 1.5 Hz, 1H), 6.54-6.51 (m, 2H), 3.75 (s, 2H)

[0180] 13C NMR: (101 MHz, DMSO) δ 172.6, 170.9, 149.8, 132.9, 131.8, 114.0,113.4, 111.0, 46.5

[0181] HPLC retention time: anthranilic acid (1): 9.4 minutes; 2-(carboxymethylamino)benzoic acid (2): 13.1 minutes; major impurity: 8.6 minutes

[0182] Indigo was also prepared under the same experimental conditions as described above, except that the palladium on carbon was replaced by 0.5% palladium on alumina, or nickel on alumina and silica (NiSat ®: Ni / Al2O3-SiO2 54%Ni), or alumina-supported nickel (Ni / Al2O3 21%Ni), or carbon-supported platinum.

[0183] Analytical data (HPLC):

[0184] Mobile phase: A: H2O + 0.1% formic acid / B: acetonitrile (HPLC purity)

[0185] Column: Kromasil KR5C18-25M (250 x 4.6 mm)

[0186] Gradient: t0: 90 / 10; t=15 min: 50 / 50; t=20 min: 50 / 50; t=30 min: 90 / 10

[0187] Comparison of step a) of the method of the present invention with the method of the prior art (Table 1)

[0188] [Table 1]

[0189]

[0190] Compared with the method of Lai et al. and the method described in US 2008 / 051426, step a) of the method of the present invention uses a non-toxic reactant (ie, glyoxylic acid) to obtain 2-(carboxymethylamino)benzoic acid in excellent yield.

[0191] Unlike the method of Koeppe et al., which used saponification after the coupling of anthranilic acid and ethyl glyoxylate, access to this key intermediate was achieved in a single step.

[0192] Finally, step a) generates minimal waste since it uses a recyclable catalyst. The used solvent can also be recycled, whereas the wastewater in prior art processes is contaminated with toxic reactants.

[0193]

[0194] 1-Acetyl indol-3-yl acetic acid (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 maintained at room temperature for 30 minutes to protect the amine. The reaction mixture is then heated at 90°C for 30 minutes to effect cyclization and protection of the hydroxyl group.

[0195] After HPLC analysis confirmed that the conversion rate was greater than 95%, a portion (about 25%) of the volatile products can be evaporated under reduced pressure (40°C, 150 mbar) to recover triethylamine. Then 10 liters of water are 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°C to obtain about 1.01 kg (91% of the expected weight) of powder. The purity of the product (3) is thus determined by NMR analysis or HPLC (83%) to adjust the ratio of the reactants used for the next reaction. (Measured yield: 75%).

[0196] 1H NMR (400 MHz, MeOD) 8.39 (d, = 8.3 Hz, 1H), 7.80 (s, 1H),7.57-7.48 (m, 1H), 7.36 (ddd, = 8.5, 7.2, 1.4 Hz, 1H),

[0197] 7.29 (td, = 7.5, 1.0 Hz, 1H), 2.61 (s, 3H), 2.37 (s, 3H)

[0198] HPLC retention time: impurity (monoacetylated product): 9.2 minutes; 1-acetylindol-3-yl acetic acid (3): 7.3 minutes

[0199] HPLC analysis data:

[0200] Mobile phase: A: H2O + 0.1% formic acid / B: acetonitrile (HPLC purity)

[0201] Column: Kromasil KR5C18-25M (250 x 4.6 mm)

[0202] Gradient: t0: 50 / 50; t=15 min: 5 / 95; t=23 min: 5 / 95; t=25 min: 90 / 10; t=30 min: 50 / 50

[0203]

[0204] The preparation of indigo (4) from 1-acetylindol-3-yl acetic acid (3) (1 kg) was carried out 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 was heated to reflux for two hours and then the mixture was stirred at room temperature for 5 hours. The blue precipitate thus formed was filtered (retention threshold 10 microns) and then washed with water (10 volumes) and ethanol (10 volumes). The product was then dried in an oven (80°C) to obtain 0.42 kg of indigo (yield: 69%).

[0205] The purity of the final product was determined by UV spectroscopy. The purity of the obtained indigo was greater than 95%.

[0206] 1H NMR (400 MHz, DMSO) 10.50 (s, 2H), 7.61 (d, = 7.7 Hz, 2H),7.51 (ddd, = 8.3, 7.1, 1.3 Hz, 2H), 7.33 (d, = 8.2 Hz, 2H), 6.95 (t, =7.3 Hz, 2H).

Claims

1. A method for preparing a compound of formula (III): (III), wherein R1, R2, R3 and R4 are each independently hydrogen, halogen, -CN, -NO2, -C(O)H, -SO3H, -CO2H, -SO3 - M1 + 、-CO2 - M2 + , -SO3R5, -CO2R6, -C(O)R7 or -OR8, M1 + and M2 + are each independently a cation, R5, R6, R7 and R8 are each independently a C1-C6 aliphatic group or an aromatic group; The method comprises the following steps: a) making a compound of formula (I): (I)， wherein R1, R2, R3 and R4 are each as defined above, With glyoxylic acid in a solvent in the presence of a metal catalyst under hydrogenation to obtain a compound of formula (II): (II), wherein R1, R2, R3 and R4 are each as defined above; b) converting the compound of formula (II) into the compound of formula (III); c) recovering the compound of formula (III).

2. The method according to claim 1, wherein R1, R2, R3 and R4 are hydrogen.

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

4. The method according to any one of claims 1 to 3, wherein the metal catalyst is palladium on carbon, palladium on alumina, nickel on alumina, nickel on alumina and silica, or platinum on carbon.

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): a step of recovering the metal catalyst, preferably by filtration; and / or The step of recovering the solvent from step a) is preferably by distillation or evaporation under reduced pressure.

7. The process 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 process according to any one of claims 1 to 7, wherein the glyoxylic acid is obtained from ethanol or glycolic acid of biological origin.

9. The process 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% and 40% by weight, preferably between 5% and 25% by weight, relative to the amount of compound of formula (I), and the hydrogen pressure is between 1 and 30 bar, preferably between 5 and 20 bar.

11. The method according to any one of claims 1 to 10, wherein step b) comprises: b1) reacting a compound of formula (II) as defined in claim 1 or 2 with acetic anhydride to obtain a compound of formula (II'): (II'), wherein R1, R2, R3 and R4 are each independently hydrogen, halogen, -CN, -NO2, -C(O)H, -SO3H, -CO2H, -SO3 - M1 + 、-CO2 - M2 + , -SO3R5, -CO2R6, -C(O)R7 or -OR8, M1 + and M2 + are each independently a cation, R5, R6, R7 and R8 are each independently a C1-C6 aliphatic group or an aromatic group; Preferably R1, R2, R3 and R4 are hydrogen; and b2) reacting the compound of formula (II′) with a base to obtain a compound of formula (III) as defined in claim 1 or 2.

12. The method 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 time between 30 seconds and 8 hours, to obtain a compound of formula (II) as defined in claim 1 or 2; 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 carried out sequentially as follows: At a temperature between 10°C and 40°C, preferably for a time between 15 minutes and 3 hours, and thereafter at a temperature between 70°C and 110°C, preferably for a time 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 time between 1 hour and 5 hours, to obtain a compound of formula (III) as defined in claim 1 or 2; and c) recovering the compound of formula (III).

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

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

15. The method according to claim 14, wherein the recombinant microbial host cell is selected from the group consisting of Escherichia (Escherichia coli coli), Streptomyces, Bacillus, Cupridavidus, Corynebacterium, Mycobacterium, Kitasatospora, Luteipulveratus, Thermobifida, Thermomonospora, Frankia, Pseudonocardia, Saccharothrix, Kutzneria, Lentzea, Prauserella, Salinispora, Micromonospora, Actinoplanes, Catenulispora, Mycolicibacter The recombinant microbial host cell is preferably selected from the genera Escherichia, Streptomyces, Corynebacterium and Bacillus, and even more preferably, the recombinant microbial host cell is Escherichia coli.

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