WO2021156406A1

WO2021156406A1 - Process for preparing 8-hydroxy-9,10-dioxo-anthracene-1-carboxylic acid

Info

Publication number: WO2021156406A1
Application number: PCT/EP2021/052744
Authority: WO
Inventors: Guillaume BOISSONNAT; Kevin COTTET; Vincent Blanchard; Filipe GOMEZ
Original assignee: Pili
Priority date: 2020-02-07
Filing date: 2021-02-05
Publication date: 2021-08-12
Also published as: TW202146366A

Abstract

The present invention relates to a process for preparing 8-hydroxy-9,10-dioxo-anthracene-1- carboxylic acid. It also relates to a method for preparing an anthraquinone derivative comprising a step for preparing 8-hydroxy-9,10-dioxo-anthracene-1-carboxylic acid according to such process.

Description

PROCESS FOR PREPARING 8-HYDROXY-9,10-DIOXO-ANTHRACENE-l-

CARBOXYLIC ACID

TECHNICAL FIELD

The present invention relates to the field of synthesis in organic chemistry. More particularly, the present invention provides an improved process for preparing a particular anthraquinone derivative, namely 8-hydroxy-9,10-dioxo-anthracene-l-carboxylic acid.

BACKGROUND OF THE INVENTION

Anthraquinone and derivatives thereof have been developed during decades and are still of interest in view of their different applications. For instance, anthraquinone is a building block of many dyes. It can also be used in bleaching pulp for papermaking, in the production of hydrogen peroxide. Anthraquinone derivatives are also used as drugs, such as laxatives, antimalarials, and antineoplastics in the treatment of cancer. Further niches are the use of anthraquinone and derivatives thereof as a bird repellent on seeds, gas generator in satellite balloons, and as material in batteries.

Three main processes are used to produce anthraquinone. The most ancient one relies on the Friedel Crafts addition of benzene on phthalic anhydride, using two molar equivalents of liquid Aluminum chloride followed by the second ring closure using 3 volumes of sulfuric acid at 115 - 140 °C. Other processes have been developed and require the use of oxidation reactions of anthracene in the gas phase (350 °C, using a solid vanadium oxide catalyst), or the oxidation of naphthalene into naphthoquinone in the presence of another vanadium catalyst (reaction carried out in the gas phase at 385 °C), followed by a Diels Alder reaction with butadiene and oxidation with air. However, such processes require the use of petroleum or coal tar derived compounds, extracted with polluting processes and reactions at high temperature using toxic chemicals as activators in large quantities.

Methods to functionalize anthraquinones are usually based on chlorination, sulfonation, and nitration of the anthraquinone core. Among those, anthraquinone nitration is the most used methodology. It requires the reaction of anthraquinone with a nitration mixture composed of nitric acid and sulfuric acid in at least 5 volumes of 20% oleum as a solvent. The reaction is carried out at 100 °C and produces complex mixtures of mono-, di- and tri-nitrated compounds. For instance, production of 1,8-dinitroanthraquinone yields 28% of the desired compound isolated after several steps of crystallization to get rid of 1,5-dinitroanthraquinone contamination. Although these processes are used for a long time, there is still some issues or drawbacks when they are implemented in industrial scale. Indeed, vast amounts of concentrated sulfuric acid are generated by the reaction and must be eliminated. Also, the complex separation of isomers usually leads to a strong increase of production costs to obtain anthraquinone derivatives with acceptable levels of purity.

Among anthraquinone derivatives, 8-hydroxy-9,10-dioxo-anthracene-l-carboxylic acid presents a particular interest since it has two functionals groups on the anthraquinone core, more particularly, a hydroxy at position 8 and a carboxyl at position 1 of the anthraquinone core.

Golden et al. (J. Am. Chem. Soc., 1972, 94, 3080) have disclosed one of the first synthesis of 8-hydroxy-9,10-dioxo-anthracene-l-carboxylic acid from anthracene as starting material. Such a synthesis requires the implementation of 7 chemical steps. More particularly, anthracene (extracted from coal tar or naphtha fractions of petroleum) was first oxidized in gas phase to produce anthraquinone, which was then nitrated in concentrated oleum with nitric acid and sulfuric acid. The mixture of di-nitroanthraquinones was then hot filtered and recrystallization allowed to isolate 28% of 1,8-dinitroanthraquinone. Chlorination occurred in a mixture of melted dinitroanthraquinone with addition of 2.3 volumes of dichloroanthraquinones and with gas phase chlorine flowing through the mixture to yield a final liquid containing 83% of dichloroanthraquinone. The latter compound was converted to its chloro-cyano derivative by action of copper cyanide and hydrolysis of the resulting copper salt with nitric acid, and the cyano- anthraquinone was immediately converted into its carboxylic acid derivative, which was purified through conversion to the potassium carboxylate and reacidification with 36% HC1. The last step consisted in hydrolysis of the chlorine atom with potassium hydroxide in 25 volumes of aqueous alkali during two days in reflux water affording the title compound. However, the method of Golden et al. has several drawbacks such as the liberation of CO2 using a fossil-derived carbon source to provide anthracene, originating in heavy fractions of petroleum or coal tar, the use of very corrosive reactants (nitric acid, chlorine potassium hydroxide) and solvents (oleum, sulfuric acid), and implementation of most reactions at high temperatures. In addition, the major issue relies on the difficulty to selectively 1,8-functionalize the anthraquinone at positions 1 and 8 of the anthraquinone core.

Therefore, it remains a need to provide improved and environmentally friendly processes for the synthesis of 8-hydroxy-9,10-dioxo-anthracene-l-carboxylic that are also easier and less dangerous to implement.

In this context, biological approaches using microorganisms providing functionalized anthraquinone derivatives have been developed. More particularly, it has been reported to use the ability of host cells and genetic sequences thereof to synthesize the substituted anthraquinones 3,8-dihydroxy- l-methyl-2-anthraquinone-carboxy lie acid (also called DMAC) and its decarboxylate analog 3,8-dihydroxy-l-methylanthracene-9,10-dione (also called Aloesaponarin II) having the following formulae:

, (Aloesaponarin II).

Such biological processes afford large quantities of Aloesaponarin II and DMAC from sugar or other biomass -derived carbon sources using low energy industrial fermentation in high quantities.

The chemical synthesis of 8-hydroxy-9,10-dioxo-anthracene-l-carboxylic acid from Aloesaponarin II mainly consists to remove the hydroxy group at position 3 of the anthraquinone core and replace the methyl group at position 1 of the anthraquinone core by a carboxyl group, which is more reactive, offering thereby a large panel of functional substituents. However, such a synthesis remains unexplored at this date.

SUMMARY OF THE INVENTION

In this context, the inventors have developed and provided a novel method or process for preparing 8-hydroxy-9,10-dioxo-anthracene-l -carboxylic acid in large quantities starting from Aloesaponarin II, with good yields. Such a process, environmentally friendly, is based on two main catalytic reactions under mild conditions using easy to handle and non-corrosive compounds.

The present invention as defined herein relates to a process for preparing 8-hydroxy-9,10- dioxo-anthracene- 1 -carboxylic acid comprising the steps of: a) reacting Aloesaponarin II under palladium catalyzed hydrogenation; b) reacting the mixture obtained at step a) under photocatalyzed oxidation; and c) recovering 8-hydroxy-9,10-dioxo-anthracene-l-carboxylic acid.

A preferred embodiment of the invention relates to a process for preparing 8-hydroxy-9,10- dioxo-anthracene- 1 -carboxylic acid comprising the steps of: aO) forming a reaction mixture by contacting Aloesaponarin II with tosyl chloride and triethylamine in acetonitrile, said reaction mixture is stirred to reflux for about 16 hours; al) forming a reaction mixture by mixing the mixture obtained at step aO), Palladium acetate, triethylamine and formic acid in methanol, said reaction mixture is stirred at about 50 °C for about 16 hours; bO) forming a reaction mixture by contacting the mixture obtained at step al) with acetic anhydride and sodium acetate, said reaction mixture is stirred at about 100 °C for about 16 hours; bl) forming a reaction mixture by contacting the mixture obtained at step bO) with lithium bromide in a polar solvent, preferably ethyl acetate, under oxygen atmosphere and LED irradiation, said reaction mixture is stirred at room temperature for about 16 hours; and cl) recovering 8-hydroxy-9,10-dioxo-anthracene-l -carboxylic acid.

A further preferred embodiment of the invention relates to a process for preparing 8-hydroxy- 9,10-dioxo-anthracene-l-carboxylic acid comprising the steps of: aO) forming a reaction mixture by contacting Aloesaponarin II with triflic anhydride and a base, preferably triethylamine or pyridine, in dichloromethane, said reaction mixture is stirred at room temperature for about 16 hours; al) forming a reaction mixture by mixing the mixture obtained at step aO), Palladium acetate, triethylamine and formic acid in dimethylsulfoxide, said reaction mixture is stirred at room temperature for about 16 hours; bO) forming a reaction mixture by contacting the mixture obtained at step al) with acetic anhydride and sodium acetate, said reaction mixture is stirred at about 100 °C for about 16 hours; bl) forming a reaction mixture by contacting the mixture obtained at step bO) with lithium bromide in a polar solvent, preferably ethyl acetate, under oxygen atmosphere and LED irradiation, said reaction mixture is stirred at room temperature for about 16 hours; and cl) recovering 8-hydroxy-9,10-dioxo-anthracene-l -carboxylic acid.

A further preferred embodiment of the invention relates to a process for preparing 8-hydroxy- 9,10-dioxo-anthracene-l-carboxylic acid comprising the steps of: aO) forming a reaction mixture by contacting Aloesaponarin II with triflic anhydride and a base, preferably triethylamine or pyridine, in dichloromethane, said reaction mixture is stirred at room temperature for about 16 hours; al) forming a reaction mixture by mixing the mixture obtained at step aO), Palladium acetate, in dimethylsulfoxide under hydrogen atmosphere, preferably using hydrogen bubbling, said reaction mixture is stirred at room temperature for about 16 hours; bO) forming a reaction mixture by contacting the mixture obtained at step al) with acetic anhydride and sodium acetate, said reaction mixture is stirred at about 100 °C for about 16 hours; bl) forming a reaction mixture by contacting the mixture obtained at step bO) with lithium bromide in a polar solvent, preferably ethyl acetate, under oxygen atmosphere and LED irradiation, said reaction mixture is stirred at room temperature for about 16 hours; and cl) recovering 8-hydroxy-9,10-dioxo-anthracene-l -carboxylic acid.

In a particular embodiment, Aloesaponarin II is obtained from a recombinant host cell, preferably a recombinant microbial host cell.

A further object of the invention is a method for preparing an anthraquinone derivative comprising a step for preparing 8 -hydroxy-9, 10-dioxo-anthracene-l -carboxylic acid as defined herein. LEGENDS OF THE FIGURES

Figure 1: Process for preparing 8-hydroxy-9,10-dioxo-anthracene-l-carboxylic acid disclosed by Golden et al.

Figure 2: Process for preparing 8-hydroxy-9,10-dioxo-anthracene-l-carboxylic acid according to the invention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a simple and environmentally friendly two-step process for preparing 8-hydroxy-9,10-dioxo-anthracene-l-carboxylic acid starting from Aloesaponarin II using mild conditions with good yields (global yields around 10%).

8-hydroxy-9,10-dioxo-anthracene-l-carboxylic acid (CAS Registry Number 38366-35-7) has the following formula:

and is also called 8 -hydroxyanthraquinone-1 -carboxylic acid or 9,10-dihydro-8-hydroxy-9,10- dioxo-anthracenecarboxylic acid. 8-hydroxy-9,10-dioxo-anthracene-l-carboxylic acid is also referred herein as compound#6.

The present invention relates to a process for preparing 8-hydroxy-9,10-dioxo-anthracene-l- carboxylic acid comprising the steps of: a) reacting Aloesaponarin II under palladium catalyzed hydrogenation; b) reacting the mixture obtained at step a) under photocatalyzed oxidation; and c) recovering 8-hydroxy-9,10-dioxo-anthracene-l-carboxylic acid. As used herein, the term “about” will be understood by those skilled in the art and can vary to a certain extent according to the context in which it is used. If some uses of this term are not clear for those skilled in the art depending on the context, “about” means plus or minus 30%, 20%, preferably plus or minus 10% of the specific term.

The first step a) of the process corresponds to a palladium catalyzed hydrogenation of Aloesaponarin II (IUPAC Name: 3,8-dihydroxy- l-methylanthracene-9,10-dione) to obtain 8- hydroxy-l-methylanthracene-9,10-dione. Thus, the step a) allows to remove the hydroxy group at position 3 of the anthraquinone core. More particularly, Aloesaponarin II is added in a polar solvent with a catalytic amount of Palladium to implement the palladium catalyzed hydrogenation.

In a particular embodiment, the step a) comprises forming a reaction mixture by adding Aloesaponarin II, Palladium acetate, triethylamine and formic acid in a polar solvent. The solvent may be chosen among any solvent currently used in the implementation of a palladium-catalyzed hydrogenation, such as methanol, ethanol, and dimethylsulfoxide (DMSO). In a preferred embodiment, the reaction mixture of step a) is stirred in dimethylsulfoxide at room temperature for about 16 hours. In a further preferred embodiment, the reaction mixture of step a) is stirred in methanol at about 50 °C for about 16 hours.

In a further particular embodiment, the step a) comprises forming a reaction mixture by adding Aloesaponarin II, Palladium acetate, in a polar solvent under hydrogen atmosphere, preferably using hydrogen bubbling, said reaction mixture is preferably stirred at room temperature for about 16 hours. Preferably, the solvent is DMSO.

Aloesaponarin II may also be added in a polar solvent, preferably ethanol with a catalytic amount of Palladium on carbon (Pd/c) and placed under hydrogen atmosphere at room temperature for 16 hours.

In a preferred embodiment, the process of the invention comprises a protecting step aO) of the hydroxy group at position 3 of Aloesaponarin II before the implementation of step a). Any protecting group of a hydroxy can be used. In a preferred embodiment, the protecting group is a tosyl or a triflate (trifluoromethylsulfonate). In a particular embodiment, the protection step aO) comprises forming a reaction mixture by contacting Aloesaponarin II with tosyl chloride. Preferably, triethylamine as a base and acetonitrile as a solvent is used for the implementation of this protecting step aO). More preferably, the reaction mixture is stirred at reflux for about 16 hours.

In a further particular embodiment, the protection step aO) comprises forming a reaction mixture by contacting Aloesaponarin II with triflic anhydride. Preferably, triethylamine or pyridine as a base, and dichloromethane as a solvent are used for the implementation of this protecting step aO). More preferably, the reaction mixture is stirred at room temperature for about 16 hours.

In the particular embodiment when Aloesaponarin II is protected by a tosyl as a protecting group, then the palladium catalyzed hydrogenation is preferably implemented using the following conditions: palladium acetate, triethylamine and formic acid, in methanol at about 50 °C for about 16 hours.

In the particular embodiment when Aloesaponarin II is protected by a triflate as a protecting group, then the palladium catalyzed hydrogenation is preferably implemented using the following conditions: palladium acetate, triethylamine and formic acid, in DMSO at room temperature for about 16 hours; or palladium acetate, hydrogen atmosphere, preferably hydrogen bubbling, in DMSO at room temperature for about 16 hours.

Aloesaponarin II, used as a starting material in the process of the invention, can be provided by any biological route or any synthesis chemical route. Preferably, Aloesaponarin II is provided by a biological route, more particularly using host cells and genetic sequences thereof.

In a preferred embodiment Aloesaponarin II is obtained from a recombinant host cell, preferably from a recombinant microbial host cell. The use of a recombinant microbial host cell allows to provide Aloesaponarin II as starting material of the process of the invention in large quantities and mild conditions by simple fermentation. As used herein, the term “recombinant host cell” designates a cell that is not found in nature and which contains a modified genome as a result of either a deletion, insertion or modification of one or several 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 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, even more preferably a bacteria of the genus Escherichia , such as Escherichia coli or Streptomyces, such as Streptomyces coelicolor. The biological processes to obtain Aloesaponarin II from a recombinant microbial host cell have been made the subject-matter of the patent application EP No. 19305157.0, and a person skilled in the art can readily refer to such disclosure. It may also be referred to the Article of Khosla et al. (J. Am. Chem. Soc., 1996, 118, 5158-5189) disclosing an efficient synthesis of aromatic polyketides in Vitro by the actinorhodin polyketide synthase, and more particularly synthesis of DMAC.

The second step b) of the process corresponds to a photocatalyzed oxidation of the mixture obtained after step a). Thus, the step b) allows to replace the methyl group at position 1 of the anthraquinone core by a carboxyl group (-COOH). More particularly, the mixture obtained at step a) is contacted with lithium bromide, in a polar solvent, under oxygen atmosphere and LED irradiation at room temperature. The solvent may be chosen among any solvent currently used in the implementation of a photocatalyzed oxidation. In a preferred embodiment, the solvent is ethyl acetate. In a further preferred embodiment, LED irradiation is white LED 6200 K irradiation.

In a particular embodiment, the step b) thus comprises forming a reaction mixture by contacting the mixture obtained at step a) with lithium bromide, in a polar solvent, preferably ethyl acetate, under oxygen atmosphere and LED irradiation, said reaction mixture is preferably stirred at room temperature for about 16 hours.

In a preferred embodiment, the process of the invention comprises a protecting step bO) of the hydroxyl group at position 8 of the anthraquinone core before the implementation of step b). Any protecting group of a hydroxyl can be used. In a preferred embodiment, the protecting group is an acetate. Accordingly, in a preferred embodiment, the protecting step bO) comprises forming a reaction mixture by contacting the mixture obtained at step a) with acetic anhydride and sodium acetate. More preferably, the reaction mixture is stirred at about 100 °C for about 16 hours.

The last step c) of the process corresponds to recovering the final product recovering 8- hydroxy-9,10-dioxo-anthracene-l-carboxylic acid. Such recovering step (c) may comprise a deprotecting step cO) of the optional protecting group of the hydroxyl at position 8 of the anthraquinone core. In a preferred embodiment, the deprotecting step cO) comprising forming a reaction mixture by contacting the mixture obtained at step b) with potassium carbonate in a polar solvent, preferably a mixture of methanol and water.

In a preferred embodiment, the process of the invention comprises: aO) a protecting step of Aloesaponarin II; al) a palladium catalyzed hydrogenation; bO) a protecting step of the compound obtained after step al); bl) a photocatalyzed oxidation; cO) an optional deprotecting step of the compound obtained after step bl); and cl) recovering 8-hydroxy-9,10-dioxo-anthracene-l -carboxylic acid.

In a more preferred embodiment, the process according to the invention comprises the steps of: aO) forming a reaction mixture by contacting Aloesaponarin II with tosyl chloride; al) reacting the mixture obtained at step aO) under palladium catalyzed hydrogenation; bO) forming a reaction mixture by contacting the mixture obtained at step al) with acetic anhydride and sodium acetate. bl) reacting the mixture obtained at step bO) under photocatalyzed oxidation; cO) optionally forming a reaction mixture by contacting the mixture obtained at step b) with potassium carbonate in a polar solvent, preferably a mixture of methanol and water; and cl) recovering 8-hydroxy-9,10-dioxo-anthracene-l -carboxylic acid.

In an even more preferred embodiment, the process according to the invention comprises the steps of: aO) forming a reaction mixture by contacting Aloesaponarin II with tosyl chloride and triethylamine in acetonitrile, said reaction mixture is stirred to reflux for about 16 hours; al) forming a reaction mixture by mixing the mixture obtained at step aO), Palladium acetate, triethylamine and formic acid in methanol, said reaction mixture is stirred at about 50 °C for about 16 hours; bO) forming a reaction mixture by contacting the mixture obtained at step al) with acetic anhydride and sodium acetate, said reaction mixture is stirred at about 100 °C for about 16 hours; bl) forming a reaction mixture by contacting the mixture obtained at step bO) with lithium bromide in a polar solvent, preferably ethyl acetate, under oxygen atmosphere and LED irradiation, said reaction mixture is stirred at room temperature for about 16 hours; and cl) recovering 8-hydroxy-9,10-dioxo-anthracene-l -carboxylic acid.

A further preferred process according to the invention comprises the steps of: aO) forming a reaction mixture by contacting Aloesaponarin II with tosyl chloride to provide (5-hydroxy-4-methyl-9,10-dioxo-2-anthryl)-4-methylbenzenesulfonate; al) reacting (5-hydroxy-4-methyl-9, 10-dioxo-2-anthryl)-4-methylbenzenesulfonate obtained at step aO) under palladium catalyzed hydrogenation to provide 8-hydroxy- 1- methylanthracene-9, 10-dione; bO) forming a reaction mixture by contacting 8-hydroxy- l-methylanthracene-9, 10- dione obtained at step al) with acetic anhydride and sodium acetate to provide 8-acetoxy-l- methylanthracene-9, 10-dione; bl) reacting 8-acetoxy- l-methylanthracene-9, 10-dione obtained at step bO) under photocatalyzed oxidation to provide 8-hydroxy-9,10-dioxo-anthracene-l-carboxylic acid; and c) recovering 8-hydroxy-9,10-dioxo-anthracene-l-carboxylic acid.

In a further more preferred embodiment, the process according to the invention comprises the steps of: aO) forming a reaction mixture by contacting Aloesaponarin II with triflic anhydride; al) reacting the mixture obtained at step aO) under palladium catalyzed hydrogenation; bO) forming a reaction mixture by contacting the mixture obtained at step al) with acetic anhydride and sodium acetate. bl) reacting the mixture obtained at step bO) under photocatalyzed oxidation; cO) optionally forming a reaction mixture by contacting the mixture obtained at step b) with potassium carbonate in a polar solvent, preferably a mixture of methanol and water; and cl) recovering 8-hydroxy-9,10-dioxo-anthracene-l -carboxylic acid. In an even more preferred embodiment, the process according to the invention comprises the steps of: aO) forming a reaction mixture by contacting Aloesaponarin II with triflic anhydride and a base, preferably triethylamine or pyridine, in dichloromethane, said reaction mixture is stirred at room temperature for about 16 hours; al) forming a reaction mixture by mixing the mixture obtained at step aO), Palladium acetate, triethylamine and formic acid in dimethylsulfoxide, said reaction mixture is stirred at room temperature for about 16 hours; bO) forming a reaction mixture by contacting the mixture obtained at step al) with acetic anhydride and sodium acetate, said reaction mixture is stirred at about 100 °C for about 16 hours; bl) forming a reaction mixture by contacting the mixture obtained at step bO) with lithium bromide in a polar solvent, preferably ethyl acetate, under oxygen atmosphere and LED irradiation, said reaction mixture is stirred at room temperature for about 16 hours; and cl) recovering 8-hydroxy-9,10-dioxo-anthracene-l -carboxylic acid.

In a further even more preferred embodiment, the process according to the invention comprises the steps of: aO) forming a reaction mixture by contacting Aloesaponarin II with triflic anhydride and a base, preferably triethylamine or pyridine, in dichloromethane, said reaction mixture is stirred at room temperature for about 16 hours; al) forming a reaction mixture by mixing the mixture obtained at step aO), Palladium acetate, in dimethylsulfoxide under hydrogen atmosphere, preferably using hydrogen bubbling, said reaction mixture is stirred at room temperature for about 16 hours; bO) forming a reaction mixture by contacting the mixture obtained at step al) with acetic anhydride and sodium acetate, said reaction mixture is stirred at about 100 °C for about 16 hours; bl) forming a reaction mixture by contacting the mixture obtained at step bO) with lithium bromide in a polar solvent, preferably ethyl acetate, under oxygen atmosphere and LED irradiation, said reaction mixture is stirred at room temperature for about 16 hours; and cl) recovering 8-hydroxy-9,10-dioxo-anthracene-l -carboxylic acid.

A further preferred process according to the invention comprises the steps of: aO) forming a reaction mixture by contacting Aloesaponarin II with triflic anhydride to provide (5-hydroxy-4-methyl-9,10-dioxo-2-anthryl)-4-trifluoromethanesulfonate; al) reacting (5-hydroxy-4-methyl-9, 10-dioxo-2-anthryl)-4-methylbenzenesulfonate obtained at step aO) under palladium catalyzed hydrogenation to provide 8-hydroxy- 1- methylanthracene-9, 10-dione; bO) forming a reaction mixture by contacting 8-hydroxy- l-methylanthracene-9, 10- dione obtained at step al) with acetic anhydride and sodium acetate to provide 8-acetoxy-l- methylanthracene-9, 10-dione; bl) reacting 8-acetoxy- l-methylanthracene-9, 10-dione obtained at step bO) under photocatalyzed oxidation to provide 8-hydroxy-9,10-dioxo-anthracene-l-carboxylic acid; and c) recovering 8-hydroxy-9,10-dioxo-anthracene-l-carboxylic acid.

A further object of the invention is 8-hydroxy-9,10-dioxo-anthracene-l-carboxylic acid obtained by the process of the invention as defined herein.

The product obtained by the process of the invention, namely 8-hydroxy-9,10-dioxo- anthracene-1 -carboxylic acid (Cas No.: 3866-35-7), is a useful anthraquinone derivative, in which the orthogonal 1,8 substitution offers access to a wide variety of functionalized compounds that can be used as dyes and pigments, pharmaceutical ingredients, or active photosensitizers for solar cells. Accordingly, 8-hydroxy-9,10-dioxo-anthracene-l-carboxylic acid can be considered as a main intermediate or a main precursor of synthesis to provide libraries of functionalized anthraquinone derivatives. As used herein the term “anthraquinone derivative” encompasses any compounds having a substituted anthraquinone core that are obtained via more or less short synthesis chemical routes starting from 8-hydroxy-9,10-dioxo- anthracene-1 -carboxylic acid.

A further object of the present invention thus concerns a use of 8-hydroxy-9,10-dioxo- anthracene-1 -carboxylic acid as a precursor of synthesis for the preparation of an anthraquinone derivative.

Another object of the present invention further relates to a method for preparing an anthraquinone derivative comprising a step for preparing 8-hydroxy-9,10-dioxo-anthracene-l- carboxylic acid as defined herein. Other features and advantages of the invention will appear more clearly on reading the following examples given by way of non-limiting illustration.

EXAMPLES

1. Synthesis of compound #2: (5-hydroxy-4-methyl-9,10-dioxo-2-anthryl)- trifluoromethanesulfonate

Method 1:

0.1 g of aloesaponarin II (4.0 x 10-4 mol, 1 eq) were partially dissolved into 15 mL of dry dichloromethane under inert atmosphere at 0°C. Then, triethylamine (56 microliters, 1 eq) was added, followed by triflic anhydride (65 microliters, 1.1 eq) and the reaction was left to heat up to room temperature and stirring during 16 hours. The crude was concentrated under vacuum and treated two times with ethyl acetate and a IN HC1 aqueous solution. Organic phases were pooled, dried over magnesium sulphate and evaporated. Purification on flash chromatography (9/0.5 cyclohexane: ethyl acetate) yields to 55 mg (35 %) desired product.

1H NMR (400 MHz, DMSO-d6): 8.36 (dd, J1 = 4.5 Hz, J2 = lHz), 8.06 (d, J= 3.0 Hz, 1H) ), 7.98 (t, J= 8.5 Hz, 1H), 7.81 (d, J= 8.5 Hz, 1H ), 7.64 ( d, J= 3.0 Hz, 1H), 2.85 (s, 3H)

13C NMR (400 MHz, DMSO-d6): 190.2, 180.9, 162.33, 152.12, 146.63, 137.44, 136.33, 132.54, 130.60, 129.93, 124.49, 118.75 117.65,116.71 22.52.

MS: [M-H]- m/z= 385.31

Method 2:

1 g of aloesaponarin II (4.0 x 10-3 mol, 1 eq) were partially dissolved into 15 mL of dry dichloromethane under inert atmosphere at 0°C. Then at 0°C, 1.3 mL of dry pyridine (4 eq) was added, followed by l.lg of triflic anhydride (1.0 eq) and the reaction was left to heat up to room temperature and stirring during 16 hours. The crude was concentrated under vacuum and treated two times with ethyl acetate and a IN HC1 aqueous solution. Organic phases were pooled, dried over magnesium sulphate and evaporated. Purification on flash chromatography (9/0.5 cyclohexane: ethyl acetate) yields to 55 mg (71 %) desired product. 2. Synthesis of compound #3: (5-hydroxy-4-methyl-9,10-dioxo-2-anthryl)-4- methylbenzenesulfonate

0.1 g of aloesaponarin II (4.0 x 10-4 mol, 1 eq) and 0.074 g of tosyl chloride (1 eq) are dissolved in 15 mL of dry acetonitrile under inert atmosphere. Then, 56 microliters of triethylamine (1 eq) are added and the reaction mixture was heated to reflux during 16 hours. When complete conversion was observed by TLC, the crude was concentrated under vacuum and treated two times with ethyl acetate and a IN HC1 aqueous solution. Organic phases were pooled, dried over magnesium sulphate and evaporated. Purification on flash chromatography (9/1 cyclohexane: ethyl acetate) yields to 85 % desired product.

1H NMR (400 MHz, DMSO-d6): 7.68 (d, J = 8.5 Hz, 2H), 2.66-2.61 (m, 3H), 7.36 (d, J = 8.5 Hz, 2H), 7.26-7.21 (m, 2H), 2.71 (s, 3H), 2.37 (s, 3H)

MS: [M-H]- m/z= 407.41

3. Synthesis of compound #4: 8-hydroxy-l-methylanthracene-9,10-dione

Method 1:

17mg of triflated aloesaponarin (compound #2) (4.8 xl0-5mol) and a catalytic amount of palladium acetate (~ 1 mg) were dissolved into 2 mL of dry DMSO under inert atmosphere. Then, 25 pL of triethylamine (4eq) and 15 pL of formic acid (8eq) were slowly added. The crude was vigorously stirred during 16 hours and the reaction quenched by addition of aqueous HC1 solution. H product was extracted by 3x30 mL of ethyl acetate, organic phases were pooled dried and evaporated under reduced pressure. The crude was purified by flash chromatography using a 9/1 mix of cyclohexane: dichloromethane to afford 8 mg of compound (73 % yield) 1H NMR (400 MHz, DMSO-d6): 12.6 (s, 1H), 8.12 (dd, Jl= 8Hz J2= lHz, 1H), 7.8 (t, J = 8 Hz, 1H), 7.76 (t, J = 8Hz, 1H), 7.68 (dd, J = 8Hz, J = lHz), 7.37 (dd, J = 8HzJ = lHz, 1H), 2.8 (s, 3H).

13C NMR (400 MHz, DMSO-d6): 191.2, 182.2, 161.9, 142.5, 139.1, 137.1, 134.9, 134.6, 133.1, 130.8, 126.2, 124.7, 118.9, 117.3, 23.9 MS: [M-H]- m/z= 237.32

Method 2:

Same protocol than method 1, using hydrogen bubbling instead of triethylamine/formic acid couple. Isolated Yield = 55 %

Method 3:

A similar protocol than method 1 was performed with tosylated product (compound #3), using dry methanol at 50°C instead of DMSO. Isolated yield 53 %

4. Synthesis of compound #5: 8-acetoxy-l-methylanthracene-9,10-dione

8-hydroxy-l-methylanthracene-9,10-dione (compound #4) (25 mg, 0.11 mmol) was magnetically stirred in a solution of acetic anhydride (149 pL, 1.58 mmol, 15 eq) and sodium acetate (1 mg, 0.01 mmol, 0.1 eq) at 100_°C overnight. The reaction was checked by TLC (CyHex/EtOAc 1/1) after a mini workup (HC1 lM/EtOAc). The reaction was diluted with water and extracted with ethyl acetate. The organic phase was dried with MgS04 and the solvent evaporated under vacuum. The crude was purified by flash column chromatography (80/20 to 50/50 Cyclohexane/Ethyl acetate) F2: 22 mg Yield 76%

1H NMR (400 MHz, CDC13) d: 8.20 (dd, J = 7.8, 1.2 Hz, 1H), 8.16 (dd, J = 7.4, 1.2 Hz, 1H), 7.73 (t, J = 7.9 Hz, 1H), 7.59 (t, J = 7.6 Hz, 1H), 7.55 (dd, J = 7.5, 0.7 Hz, 1H), 7.39 (dd, J = 8.0, 1.2 Hz, 1H), 2.76 (s, 3H), 2.49 (s, 3H). 5. Synthesis of compound #6: 8-hydroxy-9,10-dioxo-anthracene-l-carboxylic acid

In a microwave vessel were introduced 8-acetoxy-l-methylanthracene-9,10-dione (compound #5) (50 mg, 0.22 mmol) and lithium bromide (9.4 mg, 0.11 mmol, 0.5 eq) in dry ethyl acetate (5.5 mL). The vessel was sealed and equipped with an oxygen balloon. It was stirred overnight at room temperature under LED irradiation (white LED 6200 K). The reaction was homogeneous. After 16h a light-yellow precipitate appeared. The reaction was checked by TLC (CyHex/EtOAc 1/1) after a mini workup (water/HCl 1M and EtOAc). The reaction was quenched with water and extracted with dichloromethane. The organic phase was dried with MgS04 and the solvent was evaporated under vacuum giving 48 mg of light-yellow crude solid. Purification by flash column chromatography (50/50 Cyclohexane/ Ethyl acetate to 0/100):

F2: 17 mg of light yellow solid (the product was still on the silica after the column washings with ethyl acetate, it was recovered by flushing with 80/20 dichloromethane/methanol). Yield 22%

Claims

1. A process for preparing 8-hydroxy-9,10-dioxo-anthracene-l-carboxylic acid comprising the steps of: a) reacting Aloesaponarin II under palladium catalyzed hydrogenation; b) reacting the mixture obtained at step a) under photocatalyzed oxidation; and c) recovering 8-hydroxy-9,10-dioxo-anthracene-l-carboxylic acid.

2. The process according to claim 1, wherein the step a) comprises forming a reaction mixture by adding Aloesaponarin II, Palladium acetate, triethylamine and formic acid in a polar solvent.

3. The process according to claim 1 or 2, wherein the reaction mixture of step a) is stirred in dimethylsulfoxide at room temperature for about 16 hours.

4. The process according to claim 1 or 2, wherein the reaction mixture of step a) is stirred in methanol at about 50 °C for about 16 hours.

5. The process according to claim 1, wherein the step a) comprises forming a reaction mixture by adding Aloesaponarin II, Palladium acetate, in a polar solvent under hydrogen atmosphere, preferably using hydrogen bubbling, said reaction mixture is preferably stirred at room temperature for about 16 hours.

6. The process according to any one of claims 1 to 5, wherein the step b) comprises forming a reaction mixture by contacting the mixture obtained at step a) with lithium bromide, in a polar solvent, preferably ethyl acetate, under oxygen atmosphere and LED irradiation, said reaction mixture is preferably stirred at room temperature for about 16 hours.

7. The process according to any one of claims 1 to 6, further comprising a protecting step aO) comprising forming a reaction mixture by contacting Aloesaponarin II with tosyl chloride.

8. The process according to any one of claims 1 to 6, further comprising a protecting step aO) comprising forming a reaction mixture by contacting Aloesaponarin II with triflic anhydride.

9. The process according to any one of claims 1 to 8, further comprising a protecting step bO) comprising forming a reaction mixture by contacting the mixture obtained at step a) with acetic anhydride and sodium acetate.

10. The process according to any one of claims 1, 2, 4, 6, 7, and 9, comprising the steps of: aO) forming a reaction mixture by contacting Aloesaponarin II with tosyl chloride and triethylamine in acetonitrile, said reaction mixture is stirred to reflux for about 16 hours; al) forming a reaction mixture by mixing the mixture obtained at step aO), Palladium acetate, triethylamine and formic acid in methanol, said reaction mixture is stirred at about 50 °C for about 16 hours; bO) forming a reaction mixture by contacting the mixture obtained at step al) with acetic anhydride and sodium acetate, said reaction mixture is stirred at about 100 °C for about 16 hours; bl) forming a reaction mixture by contacting the mixture obtained at step bO) with lithium bromide in a polar solvent, preferably ethyl acetate, under oxygen atmosphere and LED irradiation, said reaction mixture is stirred at room temperature for about 16 hours; and cl) recovering 8-hydroxy-9,10-dioxo-anthracene-l -carboxylic acid.

11. The process according to any one of claims 1, 2, 3, 5, 6, 8, and 9 comprising the steps of: aO) forming a reaction mixture by contacting Aloesaponarin II with triflic anhydride and a base, preferably triethylamine or pyridine, in dichloromethane, said reaction mixture is stirred at room temperature for about 16 hours; al) forming a reaction mixture by mixing the mixture obtained at step aO), Palladium acetate, triethylamine and formic acid in dimethylsulfoxide, said reaction mixture is stirred at room temperature for about 16 hours; bO) forming a reaction mixture by contacting the mixture obtained at step al) with acetic anhydride and sodium acetate, said reaction mixture is stirred at about 100 °C for about 16 hours; bl) forming a reaction mixture by contacting the mixture obtained at step bO) with lithium bromide in a polar solvent, preferably ethyl acetate, under oxygen atmosphere and LED irradiation, said reaction mixture is stirred at room temperature for about 16 hours; and cl) recovering 8-hydroxy-9,10-dioxo-anthracene-l -carboxylic acid.

12. The process according to any one of claims 1, 2, 3, 5, 6, 8, and 9 comprising the steps of: aO) forming a reaction mixture by contacting Aloesaponarin II with triflic anhydride and a base, preferably triethylamine or pyridine, in dichloromethane, said reaction mixture is stirred at room temperature for about 16 hours; al) forming a reaction mixture by mixing the mixture obtained at step aO), Palladium acetate, in dimethylsulfoxide under hydrogen atmosphere, preferably using hydrogen bubbling, said reaction mixture is stirred at room temperature for about 16 hours; bO) forming a reaction mixture by contacting the mixture obtained at step al) with acetic anhydride and sodium acetate, said reaction mixture is stirred at about 100 °C for about 16 hours; bl) forming a reaction mixture by contacting the mixture obtained at step bO) with lithium bromide in a polar solvent, preferably ethyl acetate, under oxygen atmosphere and LED irradiation, said reaction mixture is stirred at room temperature for about 16 hours; and cl) recovering 8-hydroxy-9,10-dioxo-anthracene-l -carboxylic acid.

13. The process according to any one of claims 1 to 12, wherein Aloesaponarin II is obtained from a recombinant host cell, preferably a recombinant microbial host cell.

14. A method for preparing an anthraquinone derivative comprising a step for preparing 8- hydroxy-9,10-dioxo-anthracene-l-carboxylic acid as defined in any one of claims 1 to 13.