EP3233815A2

EP3233815A2 - Polyaromatic dimers, method for preparing same and use of same

Info

Publication number: EP3233815A2
Application number: EP15823691.9A
Authority: EP
Inventors: Chahinez AOUF; Erika ZAGO; Jérôme LECOMTE; Pierre Villeneuve; Hélène FULCRAND; Frédéric FINE; Jean-François ROUS
Original assignee: Terres Inovia; Institut National de la Recherche Agronomique INRA; Centre de Cooperation Internationalel en Recherche Agronomique pour le Development CIRAD; Avril SARL
Current assignee: Terres Inovia; Institut National de la Recherche Agronomique INRA; Centre de Cooperation Internationalel en Recherche Agronomique pour le Development CIRAD; Avril SARL
Priority date: 2014-12-18
Filing date: 2015-12-18
Publication date: 2017-10-25
Also published as: FR3030514A1; WO2016097657A3; WO2016097657A2

Abstract

The invention relates to a compound having the following Formula (I), wherein n and m are whole numbers from 0 to 6, selected independently from each other, and R1, R2, R3, R4, R5, R6, R7, R8, R9, and R10, selected independently from each other, and are each a hydrogen atom, an -OH group, or a group selected among: - straight, branched, or cyclic C1-C6 alkyl radicals; - straight, branched, or cyclic C2-C6 alkenyl radicals, optionally interrupted by one or more heteroatoms such as O or N and/or substituted by one or more -OH groups; and - ether oxide radicals having 0 to 6 saturated or unsaturated, straight, branched, or cyclic carbon atoms, optionally interrupted by one or more heteroatoms such as O, Si, or N and/or substituted by one or more -OH groups. In Formula (I), at least one R1 through R5 group is an O-methyl oxirane, at least one R6 through R10 group is an O-methyl oxirane, and at least one of the radicals R2, R4, R7, and R9 is an O-methyl. The invention also relates to a preparation method and to uses of the Formula (I) compound.

Description

Polvaromatic dimers, their method of preparation and use

The present invention relates to the field of polyaromatic ethers of glycidyl, as well as their applications in particular as precursors of polymers such as resins. The invention also relates to a process for the improved preparation of phenolic dimeric compounds from renewable resources and compositions containing such compounds.

The development of compounds derived from renewable resources responds to regulatory, social and environmental concerns by protecting public health throughout their lifetime. However, the cost of such compounds is sometimes an obstacle to their implementation.

Bisphenol A is a chemical compound widely used for its thermal, optical or electrical properties, and in the synthesis of polymeric derivatives, such as epoxy resins or polycarbonates. It thus enters the composition of many consumer products.

However, bisphenol A has been recognized as an endocrine disruptor, which can lead to serious health problems, such as cancers and fetal malformations, and its use must be restricted or even abandoned. It is also a product of fossil origin that does not meet the requirements of sustainable development. There is therefore a need for new compounds, having properties similar to those of bisphenol A, but derived from biological products and lacking the harmful side effects of this product. There is also a need for biodegradable compounds, which can be prepared by a simple process with a good yield. These and other objects are achieved by compounds obtained by transformation of molecules derived from vegetable raw materials, which have outstanding qualities and can serve as starting materials for polymerization reactions leading to biodegradable materials.

For this purpose, the invention relates to compounds of formula (A)

in which,

Y represents a saturated or unsaturated carbon chain comprising from 1 to 30 carbon atoms,

- R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, chosen independently of each other, may represent each

a hydrogen atom,

a group -OH, or

a group selected from linear, branched or cyclic C1-C6 alkyl radicals, linear, branched or cyclic C2-C6 alkenyl radicals, optionally interrupted by one or more heteroatoms such as O or N and / or substituted with one or more heteroatoms; a plurality of -OH groups, and linear, branched or cyclic, saturated or unsaturated, linear or branched or cyclic ether groups having 1 to 6 carbon atoms, optionally interrupted by one or more heteroatoms such as O, Si or N and / or substituted with one or more several -OH groups,

wherein at least one R1, R2, R3, R4, R5, R6, R7, R8, R9, or R10 is O-methyl oxirane.

The subject of the invention is thus a compound of formula (I) below:

in which,

n and m, are integers ranging from 0 to 6, chosen independently of one another, - R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, chosen independently of each other, may each represent:

a hydrogen atom,

a group -OH, or

a group chosen from linear, branched or cyclic C1-C6 alkyl radicals, linear, branched or cyclic C2-C6 alkenyl radicals, optionally interrupted by one or more heteroatoms such as O or N and / or substituted with one or more heteroatoms; a plurality of -OH groups, and linear, branched or cyclic, saturated or unsaturated, linear or branched or cyclic ether groups having 1 to 6 carbon atoms, optionally interrupted by one or more heteroatoms such as O, Si or N and / or substituted with one or more several -OH groups,

wherein at least one group R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 9, or R 10 represents an O-methyl oxirane, with at least one of R 1 to R 5 being an O-methyl oxirane group and at least one of the groups R6 to R10 representing an O-methyloxirane radical.

Preferably at least one of R2, R4, R7 and R9 is O-methyl.

The invention also relates to a process for preparing compounds of formula (I) from molecules present in raw materials of plant origin.

According to one of the embodiments of the invention, the method thus implements the one-step preparation of a glycidyl derivative which may, during a further step, be subjected to a metathesis reaction to give a dimer. homo and / or heterodimer - of formula (I).

The invention also relates to compositions containing compounds of formula (I), optionally in polymerized form, and the applications of the compounds or compositions. The compounds of formula (I) according to the invention are dimers whose two aromatic units may be identical or different, and linked by an unsaturated or saturated hydrocarbon chain whose length may vary. Thus n and m, identical or different, may be 0, 1, 2, 3 or 4. According to particular embodiments of the invention, at least n or m is 0. Advantageously, n and m identical or different, are worth 0, 1 or 2, especially 0 or 1

The radicals R1 to R10 may represent a hydrogen atom. R1 to R10 identical or different, may also each denote a hydrocarbon chain, saturated or unsaturated, linear, branched or cyclic, optionally interrupted by a heteroatom such as O, Si or N and may have up to 6 atoms of O, Si or N, preferably 1 or 2 atoms of O or N. These chains generally comprise from 1 to 6 carbon atoms, in particular they are chains C1-C4, advantageously C1-C2.

R1 to R10 may also represent sugars comprising one or more C5-C6 subunits, in particular monosaccharides or disaccharides. Such sugars are in particular sugars resulting from the metabolism of carbohydrates, such as for example glucose, fructose, xylose or arabinose.

R1 to R10 may also represent various protective groups such as esters comprising a linear, branched or cyclic C1-C6 carbon chain, optionally interrupted by a heteroatom, in particular O, Si or N, which may comprise up to 6 carbon atoms. O, Si or N, preferably 1 or 2 O or N.

R1 to R10 may also represent various protective groups, such as ether-oxides, comprising a linear, branched or cyclic C1-C12 carbon chain, optionally interrupted by a heteroatom, in particular O, Si or N, and may contain up to 6 O, Si or N atoms, preferably 1 or 2 atoms of O or N. For example -OSiR ', with R' in C1-C6, it is then a silyl ether. Mention may in particular be made of trimethylsilyl, triethylsilyl, tributylsilyl or dimethylterbutyl silyl ethers.

The compounds of formula (I) can also comprise several -OH groups, among the groups R1 to R10 or as a substitute for hydrocarbon chains as defined above.

Preferably, the compounds of formula (I) comprise a single free -OH group per aromatic ring, or no free -OH group.

The compounds of interest of formula (I) can comprise at least one O-methyl oxirane group among R1, R2, R3, R4, R5, R6, R7, R8, R9, R10; advantageously, the compounds comprise at least one O-methyl oxirane group on each aromatic ring, preferably in the meta or para position with respect to the intercycle chain.

According to one embodiment of the invention, R3 and R8 each represent an O-methyloxirane radical.

Advantageously, the compound of formula (I) has only two O-methyl oxirane radicals, in particular in the para position. Compounds of formula (I) particularly meeting the objectives of the invention have at least one O-methyl group in the meta or para position on each aromatic ring. Such compounds preferably have at least one of R2, R4, R7 and R9 representing O-methyl.

R 1, R 5, R 6 and R 10 denote in particular methyl, methoxy groups or a hydrogen atom, preferably a methyl or a hydrogen atom.

In particular, in the formula (I), R 1, R 5, R 6 and R 10 each represent a hydrogen atom and at least one of the radicals R 2, R 4, R 7 and R 9 represents an O-methyl. Compounds have in particular at least one of the radicals R1 or R2 which represents an O-methyl, and at least one of the radicals R7 or R9 which represents an O-methyl. Compounds of interest according to the invention thus have 2, 3 or 4 O-methyl groups.

It is understood that the compound of formula (I) does not correspond to a resveratrol molecule comprising -OH groups in R2, R4 and R8 or R3, R7 and R9 and with n and m each being 0.

The compounds of formula (I) according to the invention may have an unsaturated carbon chain connecting two aromatic rings, having an unsaturation in a cis or trans configuration. It is possible to obtain via the same process molecules having a Trans configuration, Cis or a mixture of molecules in Trans and Cis configuration, in variable proportions.

The subject of the invention is therefore compounds corresponding to the general formula (I) and having one of the following specific formulas:

Each of these compounds can be obtained in a cis or trans configuration, or in the form of a mixture of cis and trans configuration.

The compounds of formula (I) according to the invention are particularly those obtained by functionalization of natural phenolic compounds, obtained from plant extracts, in particular from eugenol, canolol (4-vinyl syringol) and from -vinyl guaiacol; these molecules can be obtained respectively from clove, rapeseed and agricultural co-products such as wheat straw.

The invention also relates to precursor compounds in the preparation of compounds of formula (I). These precursor compounds have in particular the following formula (VIII):

in which

R1, R2, R3, R4, R5, independently selected from each other, each represents a linear C1-C6 alkyl or C1-C6 alkenyl radical, a hydrogen atom or an ether ether radical having from 1 to 6 carbon atoms; carbon, saturated or unsaturated, linear, branched or cyclic, optionally interrupted by one or more heteroatoms such as O, Si or N and / or substituted by one or more - OH groups.

The precursors may have the following formula (IX)

in which

R3 represents a C2-C6 alkenyl radical and R1 represents a hydrogen atom or an O-methyl radical.

In particular, R3 represents a hydrocarbon chain having at least one unsaturated, linear or branched, C2-C4. Advantageously, the unsaturation is between the last and the penultimate free carbon.

As indicated above, the compounds of formula (I) are particularly interesting because it has been found in the context of the present invention that it is possible to prepare them from biosourced compounds, by simple reactions to be carried out. work and showing a good performance. They are generally easily biodegradable, thus meeting the standards of sustainable development. The invention therefore also relates to a method for preparing a compound of formula (I) below:

in which,

n and m, are integers ranging from 0 to 6, chosen independently of one another,

- R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, chosen independently of each other, each represent a hydrogen atom, a group -OH, a group selected from C1 alkyl radicals; -C6, linear, branched or cyclic, linear, branched or cyclic C 2 -C 6 alkenyl radicals, optionally interrupted by one or more heteroatoms such as O or N and / or substituted by one or more -OH groups, and ether radicals; an oxide having 1 to 6 carbon atoms, saturated or unsaturated, linear, branched or cyclic, optionally interrupted by one or more heteroatoms such as O, Si or N and / or substituted with one or more -OH groups, and

in which at least one group R1, R2, R3, R4, R5, R6, R7, R8, R9, R10 represents an ether ether, a silyl ether or an ester,

comprising the following steps:

a) etherification, silylation or esterification reaction of a compound comprising a phenolic group to obtain a compound of formula (X):

in which,

R 'represents H or a radical - [CH2] _m -CH3 n and m, are integers ranging from 0 to 6, chosen independently of one another

in which,

n and m, are integers ranging from 0 to 6, chosen independently of one another,

- R1, R2, R3, R4, and R5 chosen independently of each other, each represent a hydrogen atom, a group -OH, a group selected from linear, branched or cyclic C 1 -C 6 alkyl radicals, linear, branched or cyclic C2-C6 alkenyl radicals, optionally interrupted by one or more heteroatoms such as O or N and / or substituted with one or more -OH groups, and ether ether radicals having from 1 to 6 carbon atoms, saturated or unsaturated, linear, branched or cyclic, optionally interrupted by one or more heteroatoms such as O, Si or N and / or substituted with one or more -OH groups, and

at least one of the groups R1 to R5 represents an ether ether oxide, silyl ether or ester radical; and b) a metathesis reaction of at least two compounds of formula (X), which are identical or different, in the presence of a catalyst to obtain at least one compound of formula (I).

The compound of formula (X) may in particular correspond to the following formula

wherein all the substituents have the previously given meanings.

The process makes it possible to prepare the compounds of formula I as defined in all of the above, in all their variants. The compounds are obtained with a yield greater than 50%, especially greater than 90%. Indeed, the implementation of the process leads to compounds of formula I, single or in mixture, in particular to mixtures of homo or hetero dimers, without significant presence of compounds not corresponding to formula I, or without any presence of compound not corresponding to formula I among the reaction products.

For example, the esterification reaction is an acetylation reaction in which the phenolic compound reacts with excess acetic anhydride in the presence of pyridine at room temperature.

The at least partial protection of the free -OH groups of the phenolic compound by protective groups such as ether-oxide, silyl ether or ester radicals makes it possible to inactivate the free -OH groups and thus to improve the reactivity of the reaction of metathesis taking place in step b).

Advantageously, during step a), the phenolic compound is reacted with epichlorohydrin in order to obtain a compound of formula (X) in which at least one of the groups R 1 to R 5 represents an O-methyl oxirane radical. This O-glycidylation reaction of the starting phenolic compounds makes it possible to obtain compounds (X) with improved reactivity. Advantageously, this makes it possible to avoid carrying out two additional protection steps before the implementation of step b) and then deprotection after step b). Indeed, step a) makes it possible both to introduce the methyloxirane group and to inactivate the phenolic hydroxyl responsible for the deactivation of the catalyst during the metathesis step.

Advantageously, the phenolic compound has the following formula (Χ '):

in which,

R 'represents H or a radical - [CH2] _m -CH3,

n and m, are integers ranging from 0 to 6, chosen independently of one another,

- R'1, R'2, R'3, R'4, R'5, chosen independently of each other, each represent a hydrogen atom, a group -OH, a group selected from the alkyl radicals in C1 -C6, linear, branched or cyclic, the alkenyl radicals in C2-C6 linear, branched or cyclic, optionally interrupted by one or more heteroatoms such as O or N and / or substituted with one or more -OH groups, and ether ether radicals having from 1 to 6 carbon atoms, saturated or unsaturated , linear, branched or cyclic, optionally interrupted by one or more heteroatoms such as O, Si or N and / or substituted by one or more -OH groups, and in which at least one of the groups R'1 to R'5 represents a group -OH.

Particularly advantageously, the phenolic compound is eugenol, 4-vinyl guaiacol or canolol.

Preferably, step a) is carried out by the action of a phase transfer catalyst in an alkaline medium. It is understood that the meaning of radicals R 1 to R 10 may be as defined in all of the above.

In particular, the compound of formula (X) obtained at the end of step a) may be a glycidyl derivative of eugenol, 4-vinyl guaiacol or canolol.

Advantageously, the catalyst used in step b) is a Grubbs catalyst.

By Grubbs catalyst is meant complex transition metal-carbene, in particular ruthenium complex; it can be Grubbs catalyst of first or second generation, in particular of second generation. In particular, benzylidene [1,3-bis (2,4,6-trimethylphenyl) -2-imidazolidinylidene] dichloro (tricyclohexylphosphine) ruthenium is used.

This a) etherification, silylation or esterification step, preferably glycidylation, of the phenolic compound may be partial, in which case all the -OH groups of the phenolic compound will not react during this reaction, or on the contrary total, in which case all the -OH groups of the phenolic compound will react during this reaction. The -OH groups of the phenolic compound will be found either partially substituted with an ether ether, silyl ether or ester radical, preferably with an O-methyl oxirane group, or totally substituted by an ether ether, silyl ether or ester radical. preferably by an O-methyl oxirane group. The free hydroxyl compounds of formula (I) among R1, R2, R3, R4, R5, R6, R7, R8, R9, R10 may result from a partial reaction of etherification, silylation or esterification, preferably glycidylation, in which all the free - OH groups of the phenolic compound do not react in step a) of the process. They can also be regenerated by a subsequent deprotection step of at least one ether ether oxide, silyl ether or ester, preferably an O-methyl oxirane group of the compound of formula (I). Such a deprotection of at least one O-methyl oxirane group of the compound of formula (I) may for example be carried out by hydrogenation in the presence of palladium on carbon (Pd / C).

In step b), the dimerization reaction can be carried out in the presence of several types of compounds of formula (X), in which the radicals R1 to R5 have different meanings.

Thus, a compound of formula (I) or a mixture of compounds of formula (I) will be obtained, in variable proportions, by varying the reaction conditions. Advantageously, a mixture of 2, 3 or 4 compounds of formula (I) will be obtained. It will generally be a mixture of homodimers and heterodimers.

According to the embodiments of the invention, the compounds of formulas (II) to (VII) as defined in the foregoing are obtained.

Obtainable these compounds (II) to (VII) trans configurations or c / ^'s, or a mixture of compounds in these two configurations.

In particular, the following compounds are obtained:

According to one of the embodiments of the invention, step b) of the process will be followed by a step of hydrogenation of the double bond of the compound of formula (I) in order to obtain a compound of formula (A) wherein Y represents a saturated carbon chain comprising from 1 to 30 carbon atoms.

The compounds of formula (I) and (A) according to the invention may be useful for example as anti-oxidants, or as precursors of substitute polymers of bisphenol A and its derivatives.

The invention therefore also relates to a composition for cosmetic, pharmaceutical use, comprising at least one compound of general formula (I) and a physiologically acceptable excipient.

It also relates to the use of compounds of formula (I) to (VIII) as defined in the foregoing, as a drug, precursor of a polymer or antioxidant agent. Another subject of the invention is a thermosetting or thermoplastic polymer which comprises subunits of formula (I) or (A) as defined above or derived from such subunits, and a process for preparing a polymer from said compounds of formula (I) to (VII ). The polymers are capable of being obtained by polymerization of compounds corresponding to formula I according to one of the preceding definitions. It can be homopolymer prepared from a single type of compound of formula I, or heteropolymers or copolymers prepared from a mixture of at least two types of compounds of formula I for which at least one of the substituents has a different meaning.

The copolymer can be obtained solely by polymerization of compounds corresponding to formula I as defined above. It may also be a copolymer obtained by polymerizing at least one compound of formula I with one or more compounds not corresponding to formula I.

The compounds of formula I according to the invention or the polymers obtained from subunits of formula I are particularly interesting because it has been found that the compounds of formula (I) do not exhibit endocrine receptor agonist activity as the alpha receptor for human estrogen.

This lack of interaction with the endocrine receptors is also observed for the form obtained after hydrolysis of the O-methyl oxirane function to give a compound having two alcohol functions; this reaction is likely to occur after absorption by the body of a mammal, in particular human.

These are in particular the following compounds

The products according to the invention will therefore be very useful as substitutes in all applications of bisphenol A.

Other advantages and characteristics of the invention will appear on reading the following illustrative examples.

Example 1 Preparation of Glycidylated Aromatic Monomers

R ¹ - H ₂ CC = CH R ² = H 7, 84%

H

R - C = CH ₂ R ² = H 8 80% H

R ¹ - C = CH ₂ R ² = OCH ₃ 9, 90% H Scheme: Synthesis of glycidylated aromatic monomers (7), (8) and (9) derived respectively from eugenol (1), 4-vinyl quaiacol (2) and canolol (3).

The O-glycidylation reaction of compounds 1, 2 and 3 is conducted in the presence of epichlorohydrin in an alkaline medium.

The epichlorohydrin used is marketed by Sigma-Aldrich (product reference: 45340-1 L). It is a racemic mixture of the two enantiomeric forms.

In a 250 ml two-necked flask equipped with a condenser, a septum cap and a magnetic stirring bar, 1 g of the compounds 1, 2 or 3 were added in 4 molar equivalents. epichlorohydrin. The suspension is heated to 100 ° C and 0.05 molar equivalents of benzyltriethylammonium chloride (BnEtaNCl) are added.

After 90 min, the resulting solution is cooled to 30 ° C and 2 molar equivalents of 20% by weight aqueous NaOH solution are added with an identical amount of phase transfer catalyst (BnEt ₃ NCI).

The mixture is stirred vigorously for 90 minutes. The organic phase is separated, dried over MgSO ₄ and concentrated in vacuo.

The crude product is purified by silica gel chromatography using a mixture of petroleum ether / ethyl acetate (70:30, v / v) to obtain products 7, 8 and 9.

The epichlorohydrin is therefore placed in an alkaline excess in the presence of a catalytic amount of BnEt ₃ NCI in order to react with the compounds 1, 2 and 3 to give the glycidyl compounds 7, 8 and 9, respectively, according to scheme 1 above. During this reaction, the proton of the hydroxy phenol is substituted by the methyl oxirane group. The proton and carbon NMR spectra below of the glycidyl compounds 7, 8 and 9 make it possible to demonstrate this substitution.

¹ H NMR spectrum of the glycidyl eugenol derivative

2 - ((4-Allyl-2-methoxyphenoxy) methyl) oxirane 7: Colorless oil, 84% yield (5.12 mmol).

H NMR (500 MHz, DMSO-d ₆ ) δ = 2.67 (dd, J = 5.1, 2.7 Hz, 1H, Ηγ ¹ ), 2.82 (m, 1H, Ηγ), 3 , 29-3.30 (m, 2H, H7 and Ηβ), 3.75 (s, 3H, Me), 3.77 (m, 1H, Hoc '), 4.24 (dd, J = 11, 3. 2.7 Hz, 1H, Ha), 5.04 (dd, J = 12.5, 8.0 Hz, 2H, H9), 5.93 (tdd, J = 16.8, 10.0 , 6.8 Hz, 1H, H8), 6.68 (d, J = 8.1Hz, 1H, H5), 6.80 (s, 1H, H3), 6.87 (d, J) = 8.1 Hz, 1H, H6) ppm, 3C NMR (125 MHz, DMSO-d ₆ ) δ = 39.3 (C7), 44.0 (C-γ), 50.0 (Οβ), 55 , 6 (Me), 70.2 (Ca), 112.7 (C3), 113.9 (C6), 115.7 (C9), 120.3 (C5), 133.1 (C4), 138.0 (C8), 146.2 (C1), 149 , 1 (C2) ppm. C ₁₃ H ₁₆ O ₃ calcd. C 70.89, H 7.32; found. C 70.57, H 7.21.

¹ H and ³ C NMR spectra of the glycidyl derivative of 4-vinyl guaiacol

2 - ((2-methoxy-4-vinylphenoxy) methyl) oxirane 8: light yellow solid, 80% yield (5.32 mmol).

H NMR (500 MHz, DMSO-d ₆ ) δ = 2.68 (dd, J = 5.0, 2.6 Hz, 1H, Ηγ ¹ ), 2.83 (m, 1H, Ηγ), 3.32 (qd, J = 6.8, 3.1 Hz, 1 Η, Ηβ), 3.78-3.82 (m, 1H, Hoc '), 3.71 (s, 3H, Me), 4.27 (dd, J = 11.3, 2.7 Hz, 1H, Ha), 5.13. (d, J = 11.0 Hz, 1H, H8), 5.74 (d, J = 17.6 Hz, 1H, H8), 6.65 (dd, J = 17.6, 11.0 Hz, 1H, H7), 6.92 (d, J = 8.3Hz, 1H, H5), 6.94 (d, J = 8.3Hz, 1H, H6), 7.11 (s, 1H, H3) ppm. ³ C NMR (125 MHz, DMSO-d ₆ ) δ = 43.8 (Ογ), 49.7 (Οβ), 55.4 (Me), 69.8 (Ca), 109.3 (C3), 112.2 (C8), 113.1 (C6), 119.1 (C5), 130.7 (C4), 136.4 (C7), 147.7 (C1), 149.0 (C2) ppm. C ₁₂ H ₁₄ 0 ₃ calcd. C 69.88, H 6.84; found. C 69.98, H 6.96.

NMR spectrum ¹ H glycidyl derivative of canolol

2 - ((2,6-dimethoxy-4-vinylphenoxy) methyl) oxirane 9: light green solid, 90% yield (5.0 mmol).

H NMR (500 MHz, DMSO-d ₆ ) δ = 2.56 (dd, J = 5.1, 2.7 Hz, 1H, Ηγ ¹ ), 2.73 (m, 1H, Ηγ), 3.24 (dt, J = 6.8, 2.9 Hz, 1 Η, Ηβ), 3.74 (dd, J = 11.5, 6.5 Hz, 1H, Hoc '), 3.80 (s, 6H, Me), 4.07 (dd, J = 11.5, 3.0 Hz, 1H, Ha), 5.21 (d, J = 11.0 Hz, 1H, H8), 5.80 (d, J = 17.6 Hz, 1H, H8), 6.66 (dd, J = 17.6, 11.0 Hz). , 1H, H7), 6.79 (s, 2H, H5 and H3) ppm. ³ C NMR (125 MHz, DMSO-ds) δ = 43.3 (Ογ), 50.3 (Οβ), 56.0 (Me), 63.9 (Ca), 103.5 (2C, C3 and C5), 113.7 (C8), 133.0 (C4) ), 136.3 (C7), 136.7 (C1), 153.0 (2C, C2 and C6) ppm. C ₁₃ H ₁₆ O ₄ calcd. C 66.09, H 6.83; found. C 65.88, H 6.62.

EXAMPLE 2 Preparation of Compounds by Metathesis a) Cross Metathesis in the Presence of Several Monomers

Dimerization of the glycidyl compounds obtained in Example 1 by cross-metathesis, by reacting two compounds selected from 7, 8 and 9.

The dimerization of two glycidyl compounds makes it possible to obtain a mixture of homodimer and heterodimer, as well as other dimeric compounds and / or monomeric. The catalyst used in the examples is of the following chemical formula:

This is the 2nd generation Grubbs catalyst.

The metathesis reactions of compounds 7-8, 8-9 and 7-9 are carried out under identical reaction conditions detailed below.

Mix in a balloon:

- 0.5 mmol of compound 7 with 0.5 mmol of compound 8; or

0.5 mmol of compound 8 with 0.5 mmol of compound 9; or - 0.5 mmol of compound 7 with 0.5 mmol of compound 9; with 0.025 mmol of Grubbs 2nd Generation Catalyst (Formula XII) at 5 mol% in 1 ml of dichloromethane (CH 2 Cl 2).

This mixture is heated at 42 ° C. in an argon atmosphere for 48 hours. The solvent is then evaporated under vacuum. The crude product is purified by silica gel chromatography using a mixture of petroleum ether / ethyl acetate (50:50, v / v) to give the following products:

By metathesis of compounds 7 and 8, the following compounds are obtained:

a compound IV, in an amount of 0.09 mmol, ie a yield of 36%, corresponding to 2,2 '- (4,4' - (prop-1-en-1, 3-diyl) bis (2- Methoxy-4,1-phenylene)) bis (oxy) bis (methylene) dioxirane H NMR spectrum:

HNMR (500 MHz, DMSO-d ₆ ) δ = 2.67 (m, 2H, Ηγ ¹ ), 2.83 (m, 1H, Ηγ), 3.32 (m, 2Η, Ηβ), 3.43 (d, J = 6.4 Hz, 2H, H9), 3.75 (m, 2H, Hoc ^' ), 3.77 (s, 3H, Me), 3.78 (s, 3H, Me), 4.26 (dd, J = 11.0, 2.7 Hz, 1H, Ha). ), 6.31 (m, 1H, H8), 6.37 (d, J = 15.8 Hz, 1H, H7), 6.74 (d, J = 8.0 Hz, 1H, H5 _B), 6.87-6.91 (m, 4H , H5 _A , H6 _A , H6 _B and H3 _B ), 7.05 (s, 1 H, H3 _A ) ppm. ³ C NMR (125 MHz, DMSO-d ₆ ) δ = 38.0 (C9), 43.5 (2C, Cy), 49.5 (2C, Οβ), 55.2 (2C, Me), 69.5 (2C, Ca), 108.9 (C3) _A ), 112.2 (C3 _B ), 113.0 (C6 _A ), 113.4 (C6 _B ), 118.6 (C5 _A ), 120.0 (C5 _B ), 127.5 (C8), 129.5 (C7), 133.2 (2C, C4 _A and C4 _B ), 145.8 (C1 _B ), 146.8 (C1 _A ), 148.7 (C2 _B ), 148.8 (C2 _A ) ppm. C23H26O6 calculated. C 69.33, H 6.58; determined. C 69.08, H 6.13.

a compound II, in an amount of 0.025 mmol, ie a yield of 10%, corresponding to 4,4 '- (but-2-ene-1,4-diyl) bis (2-methoxyphenol), of an H NMR spectrum: H NMR (500 MHz, DMSO-d ₆ ) δ = 2.67 (dd, J = 5.1, 2.7 Hz, 1H, Ηγ ¹ ), 2.82 (m, 1H, Ηγ), 3.26 (d, J = 4.8 Hz, 2H, H7), 3.30 (td, J = 9.4, 4.8 Hz, 1H, Ηβ), 3.73 (s, 3H, Me), 3.76 (dd, J = 11.0, 6.4 Hz, 1H, Ha ^'). ), 4.23 (dd, J = 1.14, 2.7 Hz, 1H, Ha), 5.63 (t, J = 3.8 Hz, 1H, H8), 6.66 (d, J = 8.2 Hz, 1H, H5); ), 6.79 (s, 1H, H3), 6.86 (d, J = 8.2 Hz, 1H, H6) ppm. ³ C NMR (125 MHz, DMSO-d ₆ ) δ = 37.8 (C7), 43.9 (Cy), 50.0 (Οβ), 55.5 (Me), 70.2 (Ca), 1 12.6 (C3), 1 14.0 (C6) , 120.2 (C5), 130.4 (C8), 133.9 (C4), 146.1 (C1), 149.1 (C2) ppm. C24H28O6 calculated. C 69.88, H 6.84; determined. C 69.12, H 6.32. and

a compound III, in an amount of 0.1 mmol, ie a yield of 44%, corresponding to 4,4 '- (ethene-1,2-diyl) bis (2-methoxyphenol), light yellow solid of NMR spectrum Ή:

HNMR (500 MHz, DMSO-d ₆ ) δ = 2.70 (dd, J = 5.0, 2.6 Hz, 1H, Ηγ ¹ ), 2.85 (m, 1H, Ηγ), 3.34 (m, 1Η, Ηβ), 3.82 (dd, J = 10.0, 5.1Hz, 1H, Ηα ^' ), 3.84 (s, 3H, Me), 4.30 (dd, J = 1.14, 2.7Hz, 1H, Ha), , J = 8.3 Hz, 1H, H6), 7.05 (d, J = 8.3Hz, 1H, H5), 7.08 (s, 1H, H7), 7.23 (s, 1H, H3) ppm. ³ C NMR (125 MHz, DMSO-d ₆ ) δ = 43.0 (Cy), 49.3 (Οβ), 54.9 (Me), 69.3 (Ca), 109.0 (C3), 1 12.7 (C6), 1 18.8 (C5) , 125.8 (C7), 130.3 (C4), 146.7 (C1), 148.6 (C2) ppm. C22H24O6 calculated. C 68.74, H 6.29; determined. C 67.98, H 5.88.

By metathesis of compounds 8 and 9, the following compounds are obtained:

a compound VII, in an amount of 0.075 mmol, a yield of 30%,

a compound V, in an amount of 0.082 mmol, that is a yield of 33%, corresponding to 4,4 '- (ethene-1,2-diyl) bis (2,6-dimethoxyphenol), a light yellow solid of 1 H NMR spectrum; :

HNMR (500 MHz, DMSO-d ₆ ) δ = 2.58 (dd, J = 5.0, 2.7 Hz, 1H, Ηγ ¹ ), 2.75 (m, 1H, Ηγ), 3.25 (dt, J = 6.8, 2.9 Hz , 1 Η, Ηβ), 3.76 (dd, J = 1.15, 6.5 Hz, 1H, Ηα ^' ), 3.84 (s, 6H, Me), 4.10 (dd, J = 1.15, 2.9 Hz, 1H, Ηα), 6.92 (s, 2H, H3 and H5), 7.18 (s, 1H, H7) ppm. ³ C NMR (125 MHz, DMSO-d ₆ ) δ = 43.3 (C-gamma), 50.3 (ββ), 55.9 (Me), 74.0 (CO), 103.6 (2C, C3 and C5), 127.9 (C7), 133.0 (C4) 136.0 (C1) 153.0 (C2) ppm. C ₂ 4H ₂ 80 ₈ calculated. C 64.85, H 6.35; determined. C 65.06, H 6.19.

and

a compound III, in an amount of 0.06 mmol, in the evening a yield of 24%.

By metathesis of compounds 7 and 9, a mixture of the following compounds is obtained:

a compound II: in an amount of 0.04 mmol, ie a yield of 16%,

a compound V: in an amount of 0.04 mmol, ie a yield of 16%,

a compound IV: in an amount of 0.12 mmol, a yield of 48%, a light yellow solid corresponding to ((2,6-dimethoxy-4- (3- (3-methoxy-4- (oxiran-2- Ylmethoxy) phenyl) prop-1-enyl) phenoxy) methyl) oxirane H NMR spectrum:

HNMR (500 MHz, DMSO-d ₆ ) δ = 2.55 (dd, J = 5.2, 2.7 Hz, 1H, Ηγ ¹ ), 2.67 (dd, J = 5.0, 2.6Hz, 1H, Ηγ ^' ), 2.72 ( m, 1 Η, Ηγ), 2.82 (m, 1H, Ηγ), 3.23 (m, 1H, Ηβ), 3.30 (m, 1H, Ηβ), 3.44 (d, J = 5.1Hz, 2H, H9 ), 3.71 (dd, 2H, Hoc ^' ), 3.76 (s, 3H, Me), 3.77 (s, 6H, Me), 4.05 (dd, J = 1.14, 3.0 Hz, 1H, Ha), 4.24 (dd, J = 1 1 .3, 2.5 Hz, 1H, Ha), 6.38 (s, 2H, H7 and H8), 6.71 (s, 2H, H3 and H _A 5A), 6.73 (d, J = 8.2 Hz, 1H, H5 _B ), 6.86 (s, 1H, H3 _B ), 6.90 (d, J = 8.2 Hz, 1H, H6 _B ) ppm. ³ C NMR (125 MHz, DMSO-d ₆₎ δ = 37.8 (C9), 42.8 (Cy _A), 43.2 (Cy _B), 49.4 _(Οβ Α), 49.7 _(Οβ Β), 55.3 (Me _B), 69.5 (Ca _B), 73.4 (Ca _A), 55.3 (2C, Mr. _A), 103.0 (2C, C 3 _A and C 5 _A) 1 12.4 (C3 _B) 1 13.2 (C6 _B) 120.0 (C5 _B) 128.7 (C8), 129.8 (C7), 132.7 _(C4), 132.8 (C4 _B), 145.2 (C1 _A), 145.7 (C1 _B), 148.5 (C2 _B), 152.4 (2C, C 2 _A and C 6 _A) ppm. C24H28O7 calculated. C 67.28, H 6.59; determined. C 66.90, H 6.28. and,

a compound VII: in an amount of 0.012 mmol, ie a yield of 5%, light yellow solid, corresponding to 2 - ((2,6-dimethoxy-4- (3-methoxy-4- (oxiran-2-ylmethoxy) styryl) phenoxy) methyl) oxirane, H NMR spectrum:

HNMR (500 MHz, DMSO-d ₆₎ δ = 2.57 (dd, J = 5.0, 2.6 Hz, 1H, ΗγΆ), 2.70 (dd, J = 5.0, 2.6 Hz, 1H, Ηγ ^'B), 2.74 ( m, 1 Η, Ηγ _Α ), 2.84 (m, 1H, Ηγ _Β ), 3.25 (m, 1H, Ηβ _Α ), 3.34 (m, 1H, Ηβ _Β ), 3.75 (dd, J = 1 1 5.5 Hz, 1H, Ha ^' _A ), 3.82 (m, 1H, Ha ^' _B ), 3.83 (s, 6H, Me _A ), 3.85 (s, 3H, Me _B ), 4.10 (dd, J = 1 1 .6, 3.0 Hz, 1H, _Ha), 4.30 (dd, J = 1 1 .4, 2.7 Hz, 1H, Ha _B), 6.90 (s, 2H, H3 and H5 _A _A) , 6.96 (d, J = 8.3 Hz, 1H, H6 _B ), 7.07 (d, J = 8.7 Hz, 1H, H5 _B ), 7.10 (d, J = 16.3Hz, 2H, H7 and H8), 7.24 (s, 1H, H3 _A) ppm. ³ C NMR (125 MHz, DMSO-ds) δ = 43.0 (Ογ _Α ), 43.5 (Ογ _Β ), 49.3 (Οβ _Β ), 50.0 (Οβ _Α ), 55.1 (Me _B ), 55.5 (2C, ΜΘΑ), 69.6 (Ca _B), 73.6 (Ca _B) 103.1 (2C, C 3 _A and C 5 _A), 108.9 (C3 _B) 1 12.9 (C6 _B) 1 19.2 (C5 _B) 126.1 (C7), 127.5 ( C8), 130.3 (C4 _B), 132.8 _(C4), 135.4 (C1 _A), 147.1 (C1 _B), 148.3 (C2 _B), 152.6 (2C, _C2-C6 and _A) ppm. C23H26O7 calculated. C 66.65, H 6.32; determined. C 67.02, H 6.63. products

Entrance Monomers _u ... ^,,. ,,. , Yield ^a (%)

Homodimeres Heterodimeres

III 44 iv 7 + 8 II 10

IV 36

II 16

V 16 v 7 + 9

IV 48

VII 5

V 33 vi 8 + 9 III 24

VII 30 ^a Isolated yield

Table 1: Cross Metathesis of derivatives 7, 8 and 9.

In general, the cross metathesis of two different compounds leads to the production of three products, two homodimers and one heterodimer.

In the case of compounds 7-8 and 8-9, the three expected reaction products 11-III-IV and III-VII are obtained in an overall yield of the order of 90%.

The metathesis of the mixture 7-9 leads to four products 11-V-VI-VII with an overall yield of 85%.

However, it is noted that in the presence of transition metals, the allyl group (propenyl-2,3) is isomerized to 1,2-propenyl group. The existence of the two isomers of compound 7 in the reaction medium leads to the formation of three compounds: homodimer of the first isomer of 7, homodimer of the second isomer of 7 and the heterodimer of the two isomers of 7 (b) Cross metathesis in the presence of a single monomer During this reaction, mixed in a ball ^"I mmol of 7, 8 or 9 and catalyst 0,05mmol Grubbs II (5 mol%, of formula XII) in 1 ml of CH2Cl2, which was heated to 42 ⁰ C, under argon atmosphere, for 48 h.

The mixture is concentrated under vacuum. The residue is then purified by silica gel chromatography using a mixture of petroleum ether / ethyl acetate (50:50, v / v) to give the following products:

From 7:

0.28 mmol of a compound II is obtained, ie a yield of 56%,

0.05 mmol of a compound III is obtained, ie a yield of 10%, and

0.07 mmol of a compound IV is obtained, ie a yield of 14%. From 8:

0.38 mmol of a compound III is obtained, ie a yield of 76%.

From 9:

0.39 mmol of a compound V is obtained, ie a yield of 78%.

The identification of compounds II, III, IV and V is as enumerated above in the example.

In the case of non-glycidylated substrates, that is to say comprising their free -OH groups, no reaction product is observed except in the case of eugenol where a maximum yield of 15% is obtained. dimerization product.

products

Monomer input Yield ^a (%)

Homodimers heterodimers

II 56 i 7 III 10

IV 14 ii 8 III 76 iii 9 IV 78 ^a Isolated yield

Example 3 Preparation of an Epoxy Resin from a Compound of Formula (I) According to the Invention For the production of an epoxy resin, 1 mmol of compound of formula (V) is mechanically mixed at room temperature with 1 mmol of isophorone diamine (IPD).

The mixture is then placed in a silicone mold and cross-linked at 100 ° C. for 12 hours, followed by 2 hours at 250 ° C.

Example 4 Evaluation of the Affinity of Glycidylated Dimers and Their Intermediates for Era Estrogen Receptors

The affinity of the synthesized molecules and their derivatives for the ER alpha human endocrine receptor (hER alpha) was evaluated according to the method described in Trott O, Oison AJ (2010) AutoDock Vina: improving the speed and accuracy of docking with a new scoring funct ion, efficient optimization, and multithreading. J Comput Chem. 31: 455-461.

For this, we downloaded the structure of the hER alpha receptor protein representing the ligand binding domain which is linked to the agonist ligand diethylstilbestrol and a peptide derived from the NR box II region of the co-activator GRIP1.

The ligand structure has been converted to 3D with Marvin Sketch software 15.4.6.0 [ChemAxon (2015).

The agonist activity of the compounds was estimated from the affinity constants, expressed in μΜ, calculated by docking.

The affinity constant expresses the concentration at which the ligand occupies 50% of the active site of the receptor. The affinities of structures hydrolysed with the alpha receptor have also been estimated. These structures are likely to be generated by metabolizing the compounds in the body, which will cause the epoxy rings to break down.

The values of the reference compounds 4,4 '- (propane-2,2-diyl) diphenol (BPA or Bis-phenol A) and 2,2-bis (4-glycidyloxyphenyl) propane (BADGE) were also estimated .

The results are reported in the following table: Number of positions in the

Compound Affinity constant Kd (μΜ) active site (out of a total of 10 positions)

BPA 2.0 10

Resveratrol 3.8 1

BADGE 50.0 0 ^*

EG-EG II 40.0 2

VG-VG III DD DD

VG-EG IV DD DD

CN-CN V DD DD

CN-EG VI 20.0 0 ^*

CN-VG VII DD DD

BADGE-diol 40.0 0 ^*

EG-EG-11-diol DD DD

VG-VG-III-Diol DD DD

VG-EG-IV-DD DD diol

CN-CN-V-Diol DD DD

CN-EG-VI-diol 100.0 0 ^*

CN-VG-VII-DD DD diol

DD: these compounds are completely outside the receptor binding domain (ligand binding domain).

^* : These compounds do not position themselves in the active site of the receptor but may have potential interferences with the helix of the hormone and thus hinder the action of the hormone.

The glycidyl dimers according to the invention and their hydrolysed derivatives have, for the most part, no agonist activity. Only the compound II (EG-EG II) has a slight activity, which remains negligible compared to that of the reference compound, BPA.

This compound II loses its initial agonist activity after hydrolysis.

Claims

1. Compound of formula (I) below:

in which,

n and m, are integers ranging from 0 to 6, chosen independently of one another,

in which at least one R1 to R5 group represents an O-methyl oxirane and at least one group R6 to R10 represents an O-methyl oxirane,

and at least one of R2, R4, R7 and R9 is O-methyl.

2. The compound of claim 1, wherein

at most one of the groups R1 to R5 represents a free -OH group, and at most one of the groups R6 to R10 represents a free -OH group 3. A compound according to at least one of claims 1 or 2, in which R3 and R8 each represents an O-methyl oxirane radical.

4. Compound according to at least one of claims 1 to 3, wherein R1, R5, R6 and R10 each represent a hydrogen atom and at least one of R2, R4, R7 and R9 is O-methyl.

The compound according to at least one of claims 1 to 4, wherein n and m, independently, are each 0 or 1.

6. A compound according to any one of the preceding claims, of the following formulas:

7. Composition for cosmetic, pharmaceutical or food use, comprising at least one compound of general formula (I) according to one of the preceding claims, and a physiologically acceptable excipient.

8. Process for preparing a compound of formula (I) below:

in which, n and m, are integers ranging from 0 to 6, chosen independently of one another,

comprising the following steps:

(X) wherein,

R 'represents H or a radical - [CH2] _m -CH3,

n and m, are integers ranging from 0 to 6, chosen independently of one another,

- R1, R2, R3, R4, R5, chosen independently of each other, each represent a hydrogen atom, a group -OH, a group selected from the linear, branched or cyclic alkyl radicals 01 -06, the linear, branched or cyclic C2-C6 alkenyl radicals, optionally interrupted by one or more heteroatoms such as O or N and / or substituted with one or more -OH groups, and ether ether radicals having from 1 to 6 carbon atoms, saturated or unsaturated, linear, branched or cyclic, optionally interrupted by one or more heteroatoms such as O, Si or N and / or substituted by one or more OH groups, and at least one of the groups R1 to R5 represents an ether ether oxide, silyl ether or ester radical; and b) a metathesis reaction of at least two compounds of formula (X), which are identical or different, in the presence of a catalyst to obtain at least one compound of formula (I).

The process according to claim 8, wherein the phenolic compound of step a) is reacted with epichlorohydrin to obtain a compound of formula (X) wherein at least one of R1 to R5 represents a radical O-methyl oxirane.

The process according to claim 8 or 9, wherein the compound obtained in step a) is a glycidyl derivative of eugenol, 4-vinyl guaiacol or canolol.

11. The process according to at least one of claims 8 to 10, further comprising a subsequent step of regenerating the hydroxyl group of the compound of formula (I) by deprotecting at least one ether ether, silyl ether or ester radical.

12. Use of compounds according to any one of claims 1 to 6, or a composition according to claim 7, as a precursor of a polymer or antioxidant.

13. A compound according to any one of claims 1 to 6 or a composition according to claim 7 for use as a medicament.

14. Thermosetting or thermoplastic polymer characterized in that it is obtainable by polymerization of the subunits of formula (I) according to any one of claims 1 to 6.