WO2021156578A1

WO2021156578A1 - New pathway for the synthesis of sinapoyl malate, of sinapine and of analogues thereof, and use thereof as antimicrobial molecules

Info

Publication number: WO2021156578A1
Application number: PCT/FR2021/050215
Authority: WO
Inventors: Florent ALLAIS; Cédric PEYROT; Louis MOUTERDE; Matthieu MENTION; Robin FOURNIER
Original assignee: Institut Des Sciences Et Industries Du Vivant Et De L'environnement - Agroparistech
Priority date: 2020-02-07
Filing date: 2021-02-05
Publication date: 2021-08-12
Also published as: EP4100388A1; FR3107058B1; FR3107058A1

Abstract

The invention relates to anti-UV molecules of natural origin, and to the process for the synthesis thereof and also the process for the synthesis of analogues thereof. More particularly, it relates to a two-step process for the synthesis of sinapoyl malate, of sinapine and of analogues and derivatives thereof; this process is faster and more ecological than the prior art processes. The molecules obtained by means of this process are water-soluble.

Description

NEW ROUTE OF SYNTHESIS OF SINAPOYL MALATE, SINAPINE AND THEIR ANALOGUES, AND THEIR USE AS ANTI-MICROBIAL MOLECULES

The invention relates to antimicrobial molecules of natural origin, their method of synthesis and that of their analogues. More particularly, it relates to a two-step process for the synthesis of sinapoyl malate, sinapine and their analogs and derivatives; this process is faster and more environmentally friendly than the processes of the prior art. The molecules obtained by the process are soluble in water.

Technical area

Sinapoyl malate is an essential UV-B filter in plants; it is generating a lot of interest as an anti-UV molecule in many applications.

Until now, two processes for obtaining sinapoyl malate and its derivatives have been described in the literature (F. Allais et al., 2009, Synthesis; N. Pernodet et al. WO2018 / 165189). These methods are comparable. They have in particular the common point of being tedious: they require numerous steps of protection, deprotection, activation and use a large amount of coupling agent and toxic solvents.

The process for preparing sinapoyl malate described in the publication by Allais et al. is shown in Figure 1. It comprises 6 steps and requires a minimum of 26 days of reaction (excluding reaction processing time). The consequent duration of the reaction is mainly due to a first relatively long protection step (22 days) of the two acids of the malic acid (Figure 1: N, N-diisopropylcarbodiimide (INN) towards compound 2). The coupling agent (DCI: corrosive, petro-sourced, non-reusable) is activated in the presence of a copper catalyst (CuCI: toxic, causes problems in cosmetics in trace amounts) in the presence of a large excess of tert-butanol (flammable, but reusable) to form compound 1. This product is then used for the protection of malic acid (Figure 1: Molecule 2). The reaction requires a large excess of activated coupling agent (Molecule 1; 6.7 eq whereas in theory only 2 eq would be needed), the whole dissolved in dichloromethane (carcinogenic, toxic). This reaction produces a stoichiometric amount of urea which is not reusable and must be disposed of. Before performing esterification, sinapic acid is acetylated to protect the free phenol

(acetic anhydride: explosive; pyridine: toxic, carcinogenic, non-renewable) (Figure 1: Sinapic acid towards molecule 3). Molecule 3 can then be esterified in the presence of compound 2. The formation of compound 4 requires the use of an activator and a coupling agent (DCI, dimethylaminopyridine (DMAP)) in dichloromethane (Figure 1). These reagents are non-reusable, toxic, often put in large excess and also generate the formation of a stoichiometric quantity of urea. Molecule 4 must then be deprotected at the level of tert-butanols (Ot-Bu) but also at the level of acetate. For this the first deprotection requires the use of trifluoroacetic acid (TFA) in large excess (20 eq) (TFA: corrosive, toxic) still in dichloromethane (Figure 1: Molecule 4 to 5). Then the acetate (OAc) is deprotected in the presence of HCl in acetone (Figure 1: Molecule 5 towards sinapoyl malate).

During this process, several liters of solvents are necessary (eg cyclohexane, ethyl acetate, dichloromethane, hexane, pyridine, water) in particular for the 5 column purifications essential to carry out the synthesis. After these 6 tedious steps requiring the use of extremely toxic compounds and solvents, the final yield of the molecule is 30%.

WO2018 / 165189 describes a comparable approach shown in Figure 2. This comprises the protection of malic acid by / so-propanol and not tert-butanol (Figure 2, compound 6), although the method protection is not described in itself. This process for the synthesis of sinapic acid induces the in situ protection of the free phenol, which reduces the synthesis route by one step but leads to a very average yield: 35% (FIG. 2: Syringaldehyde towards compound 3). The esterification of sinapic acid is carried out in the presence of a coupling agent and an activator (Dicyclohexylcarbodiimide (DCC), DMAP: toxic, petro-sourced, non-reusable) which leads to the formation of urea, such as in the method described above. Following esterification, the protective groups (/ so-propanol and acetate) are removed in the presence of sulfuric acid, which is not selective for one or the other of the protective groups. This can also induce the hydrolysis of sinapoyl malate to release sinapic acid and malonic acid. This can certainly partly explain the very low yield obtained over 5 steps in this patent (7%).

Despite the presence of a single purification on a column, the two processes described above require the use of large amounts of solvents for the various stages of crystallization or extraction (methanol, water, toluene, acetone, ethyl acetate, methyl-tert-butyl ether, etc.).

Sinapine is another natural anti-UV molecule, present in co-products of mustard, rapeseed and other plants of the Brassicaea family. Only one process for synthesizing this molecule has been described to date. However, the literature reports several methods of synthesizing sinapine derivatives.

The only synthetic route of sinapine described to date is shown in Figure 3. This process consists in halogenating choline to form chlorocholine (a commercially available compound). This halogenation requires the use of an excess of toxic reagents such as thionyl chloride. Sinapic acid is then brought into contact with chlorocholine in methanol to form sinapine as shown in FIG. 3. Starting from commercial chlorocholine, the yield of synthesis of sinapine reaches 50%, however this compound is not commercially available only in small quantities.

For sinapine derivatives, the literature reports several different processes. All of these processes use toxic compounds that generate a lot of by-products. They require the use of halogenated alkyls (Mel, MeBr) generating the formation of salt, but also the use of toxic solvents. These techniques generally lead to low yields, in particular due to the etherification of the unprotected phenol (parasitic side reaction).

Sinapine being structurally close to sinapoyl malate, the synthetic methods envisaged for the latter could be easily applied to sinapine and its analogues.

There is a need for new methods of synthesizing sinapoyl malate, sinapine and their analogs and derivatives which can be industrialized and which are more ecological.

Disclosure of the invention

The inventors have developed a two-step process for the synthesis of sinapoyl malate, sinapine and their analogues which is both faster and more environmentally friendly, respecting the principles of green chemistry. The molecules obtained by this process are soluble in water. The inventors have also shown that these molecules exhibit anti-microbial, anti-UV, anti-tyrosinase and / or antioxidant properties. Sinapoyl malate, sinapine and their analogs obtained by the process according to the invention are included in the general formula (I) below:

in which

R ₁ is a (CH ₂ ) _n COOH or (CH ₂ ) _n N (R ₄ ) ₃ ⁺ X ₂ - group

R ₂ is a group H, (CH ₂ ) _n COOH, (CH ₂ ) _n CH ₃ , (CH ₂ ) _n (CHOH) _n COOH, (CH ₂ ) _n (CHOR ₃ ) _n COOH,

(CH2) nN (R ₄ ) ₃ ⁺ X ₂ -, (CH2) n (CHOH) nN (R ₄ ) ₃ ⁺ X ₂ - or (CH ₂ ) _n (CHOR ₃ ) N (R ₄ ) ₃ ⁺ X ₂ -

R ₃ corresponds to group A

R ₄ is chosen from H or a group C _n H _{2n + 1}

X ₁ is an O or NH group

X ₂ ^" is a negative counterion (anion) chosen from halides, acetates, nitrates, oxides, phosphates, sulphates, bisulphites, carboxylates, citrates n being an integer between 0 and 5

R ₅ , R ₆ , R ₇ , R ₈ and Rg are independently selected from, an H, an OH, an NH ₂ , an SH, a halogen, a linear, cyclic or branched _{C 1} to C _{20 alkyl group, saturated} or unsaturated, a linear, cyclic or branched, saturated or unsaturated _{C 1} to C ₂₀ O-alkyl group, a _{linear, cyclic or branched NH-C 1} to C ₈ alkyl group, saturated or unsaturated; a linear, cyclic or branched, saturated or unsaturated N- (alkyl) _{2 group} in C ₁ to C _20. Thus, the process for the synthesis of the compounds of formula (I) consists in contacting an acid of

Meldrum of formula (II)

with a nucleophilic compound of formula (III)

in which

R ₁ is a (CH ₂ ) _n COOH or (CH ₂ ) _n N (R ₄ ) ₃ ⁺ X ₂ - group

R ₂ is a group H, (CH ₂ ) _n COOH, (CH ₂ ) _n CH ₃ , (CH ₂ ) _n (CHOH) _n COOH, (CH ₂ ) _n N (R ₄ ) ₃ ⁺ X ₂ - or ( CH2) n (CHOH) nN (R ₄ ) ₃ ⁺ X ₂ - R ₄ is chosen from H or a group C _n H _{2n + 1} X ₁ is an OH or NH2 group

X2- is a negative counterion (anion) chosen from halides, acetates, nitrates, oxides, phosphates, sulphates, bisulphites, carboxylates, citrates n being an integer between 0 and 5 n 'being a number integer between 0 and 5 and incubating the mixture either without solvent or in a polar aprotic solvent, then adding a benzaldehyde of formula (IV)

in which R ₅ , R ₆ , R ₇ , R ₈ and R ₉ are independently selected from, an H, an OH, an NH ₂ , an SH, a halogen, a linear, cyclic or branched _{C 1} to C _{20 alkyl group,} saturated or unsaturated, a linear, cyclic or branched, saturated or unsaturated _{C 1} to C ₂₀ O-alkyl group, a _{linear, cyclic or branched NH-C 1} to C ₈ alkyl group, saturated or unsaturated; _{a linear, cyclic or branched, saturated or unsaturated C 1} to C ₂₀ N- (alkyl) 2 group to the mixture obtained and to incubate this mixture in the presence of a catalyst and a solvent.

Figure 4 shows such a process applied to the synthesis of sinapoyl malate.

Advantages of the invention

The proposed method is particularly advantageous compared to the methods available in the prior art.

Indeed, it makes it possible to produce natural molecules with a broad application spectrum (antimicrobial, anti-UV, anti-aging, etc.) under conditions of sustainable synthesis. In addition, this process is much faster than those described previously.

This process remarkably makes it possible to obtain molecules of sinapoyl malate, of sinapin and their analogues which are soluble in water, which the processes of the prior art do not produce. Thus, the process and the uses that are the subject of this invention are intrinsically linked: the innovative character of the process lies in the fact that it makes it possible to prepare molecules soluble in water and this result makes it possible to envisage new applications in which this property is essential. Remarkably, the anti-microbial activity of the molecules prepared could be tested due to their water-soluble nature (this was not possible with the molecules prepared via the methods of the prior art); the results show very interesting antimicrobial activity. Thus, the molecules obtained can now be used in cosmetics, as a preservative, as a phytosanitary agent because they are not toxic, are biodegradable and can be easily formulated in aqueous compositions.

The major advances in this development compared to currently available technologies can be summarized as follows: The synthetic route is more durable offering a very greatly improved economy of atoms compared to the methods published in the literature. This process is characterized by 4 major points:

Lack of coupling agent and activator

No need for protection / deprotection of the acids of the molecule (II)

The only co-products generated are acetone and CO ₂ , which are easy to process and / or recycle Substantial time saving (a few hours vs. several days)

In addition, the reaction can be carried out in a “one pot”.

The use of toxic and petroleum-based compounds is limited.

The co-products of the reaction can be upgraded (for example sinapic acid as a co-product of the synthesis of sinapoyl malate).

DETAILED DESCRIPTION OF THE INVENTION

A first subject of the invention relates to a process for the synthesis of compounds of formula (I):

in which

R ₁ is a (CH2) _n COOH or (CH2) _n N (R ₄ ) ₃ ⁺ X ₂ - group

R ₂ is a group H, (CH ₂ ) _n COOH, (CH ₂ ) _n CH ₃ , (CH ₂ ) _n (CHOH) _n COOH, (CH2) n (CHOR ₃ ) nCOOH, (CH2) nN (R ₄ ) ₃ ⁺ X ₂ -, (CH2) n (CHOH) nN (R ₄ ) ₃ ⁺ X ₂ - or

(CH ₂ ) _n (CHOR ₃ ) N (R ₄ ) ₃ ⁺ X ₂ - R ₃ corresponds to the group AR ₄ is chosen from H or a group C _n H _{2n + 1} X ₁ is an O or NH group

X ₂ - is a negative counterion (anion) chosen from halides, acetates, nitrates, oxides, phosphates, sulphates, bisulphites, carboxylates, citrates n being an integer between 0 and 5

R5, R ₆ , R7, Rs and Rg are independently selected from, an H, an OH, an NH ₂ , an SH, a halogen, a linear, cyclic or branched, saturated or unsaturated _{C 1} to C _{20 alkyl group,} _{a linear, cyclic or branched, saturated or unsaturated C 1} to C ₂₀ O-alkyl group, a linear, cyclic or branched, saturated or unsaturated NH-C ₁ to C ₈ alkyl group; a linear, cyclic or branched, saturated or unsaturated N- (alkyl) _{2 group} in C ₁ to C _20. comprising the steps of:

A) contacting a Meldrum acid of formula (II)

and a nucleophilic compound of formula (III)

in which

R ₁ is a (CH2) _n COOH or (CH2) _n N (R ₄ ) 3 ⁺ X ₂ - group

R ₂ is a group H, (CH ₂ ) _n COOH, (CH ₂ ) _n CH ₃ , (CH ₂ ) _n (CHOH) _n COOH, (CH ₂ ) _n N (R ₄ ) ₃ ⁺ X ₂ - or ( CH ₂ ) n (CHOH) nN (R ₄ ) 3 ⁺ X ₂ - R ₄ is chosen from H or a group C _n H _{2n + 1} X ₁ is an OH or NH _{2 group}

B) Incubation of the mixture without solvent or in a polar aprotic solvent,

C) Addition of a hydroxybenzaldehyde of formula (IV) to the mixture obtained in step B)

in which

R ₅ , R ₆ , R ₇ , R ₈ and R ₉ are independently selected from, an H, an OH, an NH ₂ , an SH, a halogen, a linear, cyclic or branched _{C 1} to C _{20 alkyl group,} saturated or unsaturated, a linear, cyclic or branched, saturated or unsaturated _{C 1} to C ₂₀ O-alkyl group, a _{linear, cyclic or branched NH-C 1} to C ₈ alkyl group, saturated or unsaturated; a linear, cyclic or branched, saturated or unsaturated N- (alkyl) _{2 group} in C ₁ to C _20.

D) Incubation of the mixture obtained in step C) in the presence of a catalyst and a solvent.

In a particular embodiment of the invention, the radicals R ₅ , R ₆ , R ₇ , R ₈ and R ₉ of the compounds of formula (I) and (IV) are independently chosen from, an H, an OH, an NH ₂ , an SH, a halogen, a linear, cyclic or branched, saturated or unsaturated _{C 1} to C _{8 alkyl group, a group} _{Linear, cyclic or branched, saturated or unsaturated C 1} to C ₈ O-alkyl, a linear, cyclic or branched, saturated or unsaturated NH-C ₁ to C ₈ alkyl group; a linear, cyclic or branched, saturated or unsaturated N- (alkyl) 2 group in C ₁ to C _8.

In a preferred embodiment, the compound of formula (I) is sinapoyl malate or sinapine.

In a preferred embodiment of the invention, the nucleophilic compound of formula (III) is hydrophilic.

Preferably, in step B), the mixture is incubated at a temperature at which at least one of the reagents (compound (II) or (III)) is in the liquid state; this temperature can be around 80 ° C, 90 ° C, 94 ° C depending on the reagents. The incubation time is also suitable, but as an indication, an interesting yield was obtained around an incubation time of 20 min for a reaction without solvent and around 2 h at reflux for a reaction in the presence of polar solvents. aprotic. Those skilled in the art will know how to adapt these parameters to optimize the reactions.

Preferably in step D), the incubation is carried out for several hours, for example overnight, ie approximately 16 hours. The incubation temperature is chosen depending on the solvent used. It will for example be 60 ° C. with the pyridine / aniline mixture and 90 ° C. with the proline / ethanol mixture. Those skilled in the art will know how to adapt these parameters to optimize the reactions.

By "analogs" is meant analogs of sinapoyl malate and sinapine.

Examples of analogs of sinapoyl malate are feruloyl malate, caffeoyl malate, coumaroyl malate. Analogs of sinapoyl malate are shown in Figure 5.

This process is also applicable for the synthesis of other analogs of sinapoyl malate, such as compounds derived from sinapoyl lactate such as feruloyl lactate, caffeoyl lactate and coumaroyl lactate shown in Figure 6, and derivatives of sinapoyl tartrate such as feruloyl tartrate, caffeoyl tartrate, coumaroyl tartrate, disinapoyl tartrate, diferuloyl tartrate, dicaffeoyl tartrate and dicoumaroyl tartrate shown in Figure 7.

Examples of sinapine analogues are feruloyl choline, caffeoyl choline and coumaroyl choline. They are shown in Figure 8.

Preferably, the compound of formula (III) is chosen from malic acid, lactic acid, tartaric acid or choline. Malic acid provides access to sinapoyl malate and its derivatives, lactic acid to sinapoyl lactate and its derivatives, tartaric acid to sinapoyl tartrate and its derivatives and choline to sinapine and its derivatives.

For all the compounds envisaged, step A) can be carried out in the absence of solvent, which makes the process more economical and more ecological.

The catalyst and the solvent used in step D) are either proline and ethanol, or piperidine and DMF or pyridine and aniline. The reaction will preferably be carried out in the presence of proline and ethanol so as to make the process more environmentally friendly.

In a particular embodiment, the invention relates to a process for the synthesis of sinapoyl malate from a Meldrum acid and malic acid comprising the steps of:

Synthesis of a mixture comprising a compound of formula 9 and malonic acid by reacting a Meldrum acid of formula (II) with malic acid for at least 20 min at at least 94 ° C; this step is preferably carried out “without solvent” (that is to say without organic solvent, or even water) or in the presence of aprotic polar solvent for at least 2 h at reflux. Addition of a benzaldehyde of formula (IV) to the mixture comprising a compound of formula 9 and malonic acid obtained in step a)

Synthesis of sinapoyl malate and sinapic acid by reacting the mixture obtained in step b) overnight at 60 ° C. in the presence of proline and ethanol or of piperidine and DMF or of pyridine and aniline. Such an embodiment is shown in Figure 9.

The method according to the invention may further comprise a step of purifying sinapoyl malate, sinapine and their analogues; this purification can be carried out by liquid / liquid extraction followed by passage through a normal or reverse phase chromatography column. This step is not essential in the case where sinapoyl malate, tartrate and lactate are synthesized. Indeed, the simultaneous production of sinapic acid does not pose a problem since the latter also has comparable physical / biological properties. It is therefore entirely conceivable to use the mixture as it is, without having to carry out purification, which makes it possible to further simplify the process while reducing its cost.

A second subject of the invention relates to the use of sinapoyl malate and its analogs and derivatives as an anti-microbial molecule, an anti-UV molecule and / or an anti-oxidant molecule. Indeed, the inventors have demonstrated that the compounds exhibit such properties. In addition, these compounds being obtained by an ecological process, they can be used in new applications, hitherto excluded due to the presence of unacceptable co-products in fields such as cosmetics, agrifood, phytosanitary, see in the medical field. Additionally, the molecules synthesized using the method described above are water-soluble. This property allows their use in new applications where this property is required.

As regards ditartrates, however, solubility in water will only be possible at low concentration, which may limit their use to applications in which they are active at low concentration.

Due to their solubility in water, the anti-microbial properties of the compounds obtained by the process according to the invention could be tested and confirmed for the first time. Thus, the invention relates to the use of a water-soluble compound chosen from sinapoyl malate, feruloyl malate, caffeoyl malate, coumaroyl malate, sinapoyl mono-tartrate, feruloyl mono-tartrate, caffeoyl mono-tartrate, coumaroyl mono-tartrate, sinapoyl lactate, feruloyl lactate, caffeoyl lactate, coumaroyl lactate, disinapoyl tartrate, diferuloyl tartrate, dicaffeoyl tartrate, dicoumaroyl tartrate, sinapine, feruloyl choline, caffeoyl choline, coumaroyl choline as an anti-microbial agent. These compounds can thus be used as a preservative.

By “antimicrobial molecule” is meant a molecule exhibiting antibacterial and / or antiviral and / or antifungal properties.

Preferably, the anti-microbial compounds are chosen from coumaric derivatives (coumaroyl malate, coumaroyl mono-tartrate, coumaroyl lactate, dicoumaroyl tartrate, coumaroyl choline) or caffeic derivatives (caffeoyl malate, caffeoyl lactate, caffeoyl mono-tartrate, dicaffeoylaffeoyl mono-tartrate, dicaffeoylaffeoyl , caffeoyl choline) or ferulic derivatives (feruloyl malate, feruloyl lactate, feruloyl monotartrate, diferuloyl tartrate, feruloyl choline) or sinapic derivatives (sinapoyl malate, sinapoyl lactate, sinapoyl mono-tartrate, disinapoyl tartrate), sinlapoyl tartrate (disinapoyl tartrate).

In addition to the anti-microbial activities, the compounds presented above exhibit anti-UV and / or anti-oxidant activities. It also relates to the use of a water-soluble compound chosen from sinapoyl malate, caffeoyl malate, ferruloyl malate, coumaroyl malate, sinapoyl mono-tartrate, caffeoyl mono-tartrate, feruloyl mono-tartrate, coumaroyl mono -tartrate, sinapoyl lactate, feruloyl lactate, caffeoyl lactate, coumaroyl lactate, disinapoyl tartrate, diferuloyl tartrate, dicaffeoyl tartrate, dicoumaroyl tartrate, sinapin, feruloyl choline, coumaroyl choline, caffeoyl choline as an anti-UV molecule, for example as a sun filter in cosmetic compositions.

It also relates to the use of a water-soluble compound chosen from sinapoyl malate, feruloyl malate, caffeoyl malate, sinapoyl mono-tartrate, feruloyl mono-tartrate, caffeoyl mono-tartrate, sinapoyl lactate, feruloyl lactate. , caffeoyl lactate, disinapoyl tartrate, diferuloyl tartrate, dicaffeoyl tartrate, sinapine, feruloyl choline, caffeoyl choline, as an antioxidant molecule, for example as an anti-aging active in cosmetic compositions .

In a preferred embodiment, the uses described above are carried out in aqueous compositions. Interestingly, they can be used for the preparation of aqueous compositions without the addition of solubilizing additives.

Given their properties, these compounds can be used in the food industry and in cosmetics, for example as preservatives, in the field of biocontrol, in plant protection products and as additives for polymers, in particular as additive, monomer or crosslinking agent.

These compounds can also be used as surfactants. In a particular embodiment of the invention, the radicals Rs, R6, R ₇ , R ₈ and R ₉ of the compounds of formula (I) and (IV) are independently chosen from, an H, an OH, an NH ₂ , SH, halogen, alkyl C ₁ -C ₂₀ linear, cyclic or branched, saturated or unsaturated, O-alkyl C ₁ -C ₂₀ linear, cyclic or branched, saturated or unsaturated, a group NH linear, cyclic or branched, saturated or unsaturated C ₁ to C _{8 alkyl;} N- group (a lkyle) ₂ C ₁ -C ₂₀ linear, cyclic or branched, saturated or unsaturated.

A third subject of the invention relates to an aqueous anti-microbial and / or anti-UV and / or anti-oxidant composition comprising at least two compounds chosen from sinapoyl malate, feruloyl malate, caffeoyl malate, coumaroyl malate, sinapoyl mono-tartrate, feruloyl mono-tartrate, caffeoyl mono-tartrate, coumaroyl mono-tartrate, sinapoyl lactate, feruloyl lactate, caffeoyl lactate, coumaroyl lactate, disinapoyl tartrate, diferuloyl tartrate, dicoumaroyl tartrate, tartricoumaroylaffe , feruloyl choline, caffeoyl choline, coumaroyl choline.

BRIEF DESCRIPTION OF THE FIGURES

Figure 1: Synthesis route of sinapoyl malate described by Allais et al. Synthesis

Figure 2: Synthesis route of sinapoyl malate described in WO2018 / 165189

Figure 3: Synthetic route of sinapine published in the literature Figure 4: General synthetic route of sinapoyl malate, sinapine and their analogs according to the invention

Figure 5: Sinapoyl malate derivatives Figure 6: Sinapoyl lactate derivatives

Figure 7: Sinapoyl tartrate derivatives

Figure 8: Sinapine derivatives

Figure 9: Process for the synthesis of sinapoyl malate according to the process of the invention

Figure 10: UV spectra of the different molecules in the malate series Figure 11: UV spectra of the different molecules in the mono tartrate series

Figure 12: UV spectra of the different molecules in the choline series Figure 13: Bacterial growth (E.Coli) in the presence of a variable percentage of feruloyl malate over 24 hours

EXAMPLES

EXAMPLE 1 Process for the synthesis of the compounds sinalpoyl malate, sinapine and their analogs

Synthesis of sinapoyl malate

The objective was to optimize the synthetic route of sinapoyl malate. For this, it was chosen to limit the quantities of solvents and the quantities of coupling agent and catalyst in order to best apply an atom-saving policy respecting the principles of green chemistry. The developed process is shown in Figure 4 and described below.

The first step of synthesis takes place without solvent, at 95 ° C for only 2 hours. It makes it possible to obtain the synthetic intermediate 9 at around 80%, and the 20% of co-products (malonic acid) are subsequently upgraded.

The reaction of the second step is launched on the reaction crude without a treatment or purification step. The classic Knoevenagel-Doebner reaction is carried out without the need to protect the phenol (here syringaldehyde to obtain sinapoyl malate), in the presence of pyridine and a catalytic amount of aniline. Under these conditions, no coupling agent is necessary. The atomic economy achieved on this synthesis is remarkable compared to the two methods of the prior art. After 16 hours of reaction, all of the starting syringaldehyde is consumed for the benefit of the formation of sinapic acid and sinapoyl malate. Liquid / liquid extraction is necessary before column purification. At the end of these two stages, the amount of sinapoyl malate obtained corresponds to a yield of 48%. The synthesis process also gives access to a valuable reaction co-product: sinapic acid (sold at a price> 1000 € / kg; constitutes 20% of the products obtained).

Alternatively, the synthetic route can be made more eco-responsible in the presence of proline in ethanol by replacing pyridine and aniline.

Synthesis of phenol derivatives of sinapoyl malate The compounds feruloyl malate, caffeoyl malate and coumaroyl malate are obtained by replacing syringaldehyde during the Knoevenagel-Doebner reaction with vanillin, 3,4-hydroxybenzaldehyde or 4-hydroxybenzaldehyde, respectively.

Synthesis of the lactate derivatives of sinapoyl malate

The process according to the invention is carried out by reacting a lactic acid with a Meldrum acid.

Synthesis of sinapoyl malate tartrate derivatives

The process according to the invention is carried out by reacting a tartaric acid with a Meldrum acid.

Synthesis of sinapine and its analogues

The process according to the invention is carried out by reacting a choline with a Meldrum acid.

EXAMPLE 2: Properties of the compounds

Anti-UV activities

The anti-UV profiles of the compounds as well as their UV stability were studied and the results are presented in Figures 10 to 12.

Figure 10 shows equivalent properties for sinapoyl malate and other compounds of the malate series namely feruloyl malate, caffeoyl malate and coumaroyl malate.

Figure 11 shows the anti-UV activities of 3 compounds of the mono-tartrate series; coumaroyl mono-tartrate being more protective than sinapoyl monotartrate, itself more protective than feruloyl mono-tartrate. Figure 12 shows the anti-UV activities of 4 compounds of the choline series; coumaroyl choline being more protective than feruloyl choline, itself more protective than sinapine and caffeoyl choline.

The antioxidant power of certain molecules has been evaluated and agrees with the values described in the literature, which confirms the results obtained.

Anti-microbial activities

The antimicrobial activities of the serial compounds malate, mono tartrate, sinapine and its analogues were evaluated and all the compounds show a very interesting antibacterial activity on E.Coli, which has never been described before.

The results obtained with feruloyl malate are illustrated in FIG. 13. The curves representing the growth of E. coli over 24 h in the presence of different percentages of feruloyl malate in the culture medium. It is observed that from 0.31% bacterial growth is slowed down with a latency time to start more substantial growth. From 0.63% of product in the culture medium, growth is completely inhibited over 24 h. The antimicrobial activity of the other compounds in the malate series is comparable to that shown above.

In addition, the anti-microbial activity of the compounds in the malate, mono tartrate and choline series was also observed on the strains Pseudomonas aeruginosa, Staphylococcus aureus, Escherichia coli, Candida albicans, Aspergillus brasiliensis and Bacillius subtilis.

BIBLIOGRAPHY

Allais, F .; Martinet, S .; Ducrot, P. -H., Straightforward total synthesis of 2-O-feruloyl-L-malate, 2-0- sinapoyl-L-malate and 2-0-5-hydroxyferuloyl-L-malate, Synthesis 2009, 21, 3571 -3578: DOI 10.1055 / S-0029-1216983; (b) Pernodet, N .; Chen, C.-W .; Dong, K .; Huang, J .; Koch, O .; Bugdahn, N. Topical compositions containing synthetic esters of sinapinic acid and methods for treating keratin surfaces. WO2018165189A1, 2018.

Menezes, JCJMDS; Kamat, SP; Cavaleiro, JAS; Gaspar, A .; Garrido, J .; Borges, F., Synthesis and antioxidant activity of long chain alkyl hydroxycinnamates. Eur. J. Med. Chem. 2011, 46 (2), 773- 777: DOI: 10.1016 / j.ejmech.2010.12.016; (b) Padilha, G .; Birmann, PT; Domingues, M .; Kaufman, TS; Savegnago, L .; Silveira, CC, Convenient Michael addition / β-elimination approach to the synthesis of 4-benzyl- and 4-aryl-selenyl coumarins using diselenides as selenium sources. Tetrahedron Lett. 2017, 58 (10), 985-990: DOI: 10.1016 / j.tetlet.2017.01.084.

Claims

1. Process for the synthesis of a compound of formula (I)

in which

R ₁ is a (CH2) _n COOH or (CH2) _n N (R ₄ ) ₃ ⁺ X ₂ - group

R ₂ is a group H, (CH ₂ ) _n COOH, (CH ₂ ) _n CH ₃ , (CH ₂ ) _n (CHOH) _n COOH, (CH ₂ ) n (CHOR ₃ ) _n COOH, (CH2) nN ( R ₄ ) ₃ ⁺ X ₂ -, (CH2) n (CHOH) _n N (R ₄ ) ₃ ⁺ X ₂ - or

X2 ^" is a negative counterion (anion) chosen from halides, acetates, nitrates, oxides, phosphates, sulphates, bisulphites, carboxylates, citrates n being an integer between 0 and 5

R ₅ , R 6, R ₇ , Rs and Rg are independently selected from, an H, an OH, an NH2, an SH, a halogen, a linear, cyclic or branched, saturated or unsaturated _{C 1} to C _{20 alkyl group} , a linear, cyclic or branched, saturated or unsaturated _{C 1} to C ₂₀ O-alkyl group, a _{linear, cyclic or branched, saturated or C 1} to C _{8 NH-alkyl group} unsaturated; a linear, cyclic or branched, saturated or unsaturated N- (alkyl) 2 C ₁ to C _{20 group comprising the steps of:}

A) contacting a Meldrum acid of formula (II)

and a nucleophilic compound of formula (III)

in which

R ₁ is a (CH2) _n COOH or (CH2) _n N (R ₄ ) 3 ⁺ X ₂ - group

R ₂ is a group H, (CH ₂ ) _n COOH, (CH ₂ ) _n CH ₃ , (CH ₂ ) _n (CHOH) _n COOH, (CH ₂ ) _n N (R ₄ ) ₃ ⁺ X ₂ - or ( CH2) n (CHOH) _n N (R ₄ ) 3 ⁺ X ₂ - R ₄ is chosen from H or a group C _n H _{2n + 1} X ₁ is an OH or NH2 group

B) Incubation without solvent or in a polar aprotic solvent,

C) Addition of a hydroxybenzaldehyde of formula (IV) to the mixture obtained in step B) and

in which

R ₅ , R ₆ , R7, R ₈ and R ₉ are independently selected from, an H, an OH, an NH2, an SH, a halogen, a linear, cyclic or branched _{C 1} to C _{20 alkyl group, saturated or} _{unsaturated, a linear, cyclic or branched, saturated or unsaturated C 1} to C ₂₀ O-alkyl group, a linear, cyclic or branched, saturated or unsaturated NH-C ₁ to C ₈ alkyl group; a linear, cyclic or branched, saturated or unsaturated N- (alkyl) 2 group in C ₁ to C _20.

D) Incubation in the presence of a catalyst and a solvent.

2. The method of claim 1 wherein said nucleophilic compound of formula (III) is hydrophilic.

3. Method according to one of claims 1 or 2 wherein said compound of formula (III) is chosen from malic acid, lactic acid, tartaric acid or choline.

4. Method according to one of the preceding claims, in which step A) is carried out in the absence of any solvent.

5. Method according to one of the preceding claims wherein said catalyst and said solvent used in step B) are either pyridine and aniline, or proline and ethanol.

6. Method according to one of the preceding claims further comprising a step of purifying sinapoyl malate, sinapine and their analogues by liquid / liquid extraction followed by passage through a normal or reverse phase chromatography column.

7. Use of a water-soluble compound chosen from sinapoyl malate, feruloyl malate, caffeoyl malate, coumaroyl malate, sinapoyl mono-tartrate, feruloyl mono-tartrate, caffeoyl mono-tartrate, coumaroyl mono-tartrate, sinapoyl lactate, feruloyl lactate, caffeoyl lactate, coumaroyl lactate, disinapoyl tartrate, diferuloyl tartrate, dicaffeoyl tartrate, dicoumaroyl tartrate, iron sinuloyl tartrate, caffeoyl choline, coumaroyl choline as an antimicrobial agent.

8. Use according to claim 7 as an anti-UV molecule.

9. Use according to claim 7 of a compound selected from sinapoyl malate, feruloyl malate, caffeoyl malate, sinapoyl mono-tartrate, feruloyl mono-tartrate, caffeoyl mono-tartrate, sinapoyl lactate, feruloyl lactate. , caffeoyl lactate, disinapoyl tartrate, diferuloyl tartrate, dicaffeoyl tartrate, sinapine, feruloyl choline, caffeoyl choline as an anti-antioxidant molecule.

10. Use according to one of claims 7, 8 or 9 as an active ingredient or formulation adjuvant for biocontrol.

11. Use according to one of claims 7, 8 or 9 as a phytosanitary agent.

12. Use according to one of claims 7, 8 or 9 as a preservative.

13. Use according to claim 7 as a surfactant.

14. Anti-microbial and anti-UV and / or anti-oxidant aqueous composition comprising at least two water-soluble compounds chosen from sinapoyl malate, feruloyl malate, caffeoyl malate, coumaroyl malate, sinapoyl mono-tartrate, feruloyl mono -tartrate, caffeoyl mono- tartrate, coumaroyl mono-tartrate, sinapoyl lactate, feruloyl lactate, caffeoyl lactate, coumaroyl lactate, disinapoyl tartrate, diferuloyl tartrate, dicoumaroyl tartrate, dicoumaroylapaffe tartrate, feruloyl choline, caffeoyl choline, coumaroyl choline.