PROCESS FOR THE SYNTHESIS OF LIPOPHILE DERIVATIVES OF SINAPOYL MALATE AND ITS ANALOGUES AND THEIR USES

Abstract

The invention relates to the field of lipophilic derivatives from green chemistry possessing anti-UV properties. More particularly, the invention concerns a process for the synthesis of lipophilic derivatives of sinapoyl malate and its analogues, as well as new lipophilic analogues of sinapoyl malate as such, and their uses.

Description

Title of the invention: PROCESS FOR THE SYNTHESIS OF LI-POPHILIC DERIVATIVES OF SINAPOYL MALATE AND ITS ANALOGUES AND THEIR USES

[0001] The invention relates to the field of lipophilic derivatives derived from green chemistry and having anti-UV properties. More particularly, the invention relates to a process for the synthesis of lipophilic derivatives of sinapoyl malate and its analogues as well as new lipophilic analogues of sinapoyl malate as such, and their uses. Field of invention

[0002] Sinapoyl malate is a natural molecule widely described for its anti-UV properties in plants. Sinapoyl malate and its derivatives are considered an alternative to chemical filters in sunscreens.

[0003] Until now, three methodologies have been described in the literature for obtaining sinapoyl malate and its derivatives ([Fig.l]).

[0004] The first methods described are tedious, requiring numerous protection, deprotection, and activation steps using a large quantity of coupling agent and toxic solvents. The analysis of the publication by Allais et al. (Synthesis 2009, (21), 3571-3578) describes obtaining the target molecule after 6 steps and requires at least 26 days of reaction (excluding reaction processing time). This process is presented in [Fig. 2]. The substantial duration of the reaction is mainly due to a relatively long first protection step (22 days) of the two acids of malic acid ([Fig. 2]: DCI to compound 2). The coupling agent (INN: corrosive, petroleum-sourced, non-reusable) is activated in the presence of a copper catalyst (CuCl: toxic, causes problems in cosmetics at trace levels) 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 ([Fig.2]: 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 required), all dissolved in dichloromethane (carcinogenic, toxic). This reaction produces a stoichiometric quantity of urea which is not reusable and must be eliminated. Before carrying out the esterification, sinapic acid is acetylated in order to protect the free phenol (Acetic anhydride: explosive; pyridine: toxic, carcinogenic, non-renewable) ([Fig.2]: 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 (INN, DMAP) in dichloromethane ([Fig.2]). These reagents are not reusable. readable, toxic, often put in large excess and also generate the formation of a stoichiometric quantity of urea. It is then necessary to deprotect molecule 4 at the level of the tert-butanols (Ot-Bu) but also at the level of the acetate. For this, the first deprotection requires the use of trifluoroacetic acid in large excess (20 eq) (TFA: corrosive, toxic) always in dichloromethane ([Fig.2]: Molecule 4 towards 5). Then the acetate (OAc) is deprotected in the presence of HCl in acetone ([Fig.2]: Molecule 5 towards sinapoyl malate). During this process, several liters of solvents are necessary (e.g. cyclohexane, ethyl acetate, dichloromethane, hexane, pyridine, water) in particular for the 5 purifications per column essential to complete the synthesis. After these 6 tedious steps requiring the use of extremely toxic compounds and solvents, the final yield of the molecule is 30%.

[0005] Patent WO2018 / 165189 describes a comparable approach (presented in [Fig.3]) with the protection of malic acid by Ao-propanol and not tert-butanol ([Fig.3], compound 6)2. The protocol 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.3]: Syringaldehyde to compound 3). The esterification of sinapic acid is carried out under comparable conditions in the presence of a coupling agent and an activator (DCC, DMAP: toxic, petroleum-sourced, non-reusable) which also leads to the formation of urea. Following esterification, the protecting groups (Ao-propanol & acetate) are removed in the presence of sulfuric acid, which is absolutely not selective for either of the protecting 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 column purification, the processes require the use of large quantities of solvents for different crystallization or extraction steps (methanol, water, toluene, acetone, ethyl acetate, methyl-tert-butyl ether, etc.).

[0006] The most recent synthesis route, described in patent WO2021 / 156578 and the publication by Peyrot et al. (Green Chem. 2020, 22, 6210-6518) corresponds to a more eco-responsible approach to the synthesis of sinapoyl malate in two steps without any protection / deprotection, thus limiting the use of toxic compounds; this process is presented in [Fig.4]. The first step consists of a transesterification of Meldrum acid by malic acid in tetrahydrofuran (THF) to obtain compound 9 as a reaction intermediate. This compound is then used in a second step to carry out a Knoevenagel-Doebner reaction to obtain sinapoyl malate with an overall yield of 48%. The conditions of this synthesis remain average regarding their impact on the environment with the use of THF (toxic, carcinogenic, petro-sourced), pyridine (harmful, ecotoxic) as a solvent, and aniline (very toxic, ecotoxic, carcinogenic) as a catalyst despite the significant reduction in the number of stages (2 compared to 6 previously). Disadvantages of the state of the art

[0007] All of these synthesis methodologies provide access to sinapoyl malate and its analogues, but are limited to obtaining these molecules by routes involving toxic substances and none of the target molecules obtained carry functionalization on the acid groups of the “malic” part in their final structure. In addition, none of these synthesis routes offer conditions that fully respect the principles of green and environmentally friendly synthesis.

[0008] None of the methods described above allows the production of lipophilic derivatives of sinapoyl malate in a completely sustainable manner. Statement of the invention

[0009] The invention provides a new three-step process for the sustainable synthesis of lipophilic derivatives of sinapoyl malate and its analogues. This process provides access to new lipophilic molecules derived or analogues of sinapoyl malate. These molecules have anti-UV, antioxidant and / or antimicrobial properties.

[0010] The present invention thus relates to a new process for the synthesis of lipophilic derivatives of sinapoyl malate of formula (I)

[0011] [Chem.l] AA A. .R? y ~ R g (I)

[0012] in which:

[0013] Ri is a linear, cyclic or branched alkane or alkene or alkyne ranging from C2 to C30

[0014] R2 is an H, a linear, cyclic alkane or alkene or alkyne ranging from C2 to C30, or branch

[0015] Ri and R2 can be independently chosen from each other.

[0016] Xi and X2 are an O, an NH or an NR8 group

[0017] Xi and X2 can be independently chosen with respect to each other

[0018] R3, R4, R5, R6 and R7 are independently selected from H, OH, NH2, SH, O-SiH3, halogen, linear, cyclic or branched, saturated or unsaturated C1-C20 alkyl group, linear, cyclic or branched, saturated or unsaturated O-C1-C20 alkyl group, linear, cyclic or branched, saturated or unsaturated NH-C1-C20 alkyl group, linear, cyclic or branched, saturated or unsaturated N-(alkyl)2 group, linear, cyclic or branched, saturated or unsaturated O-Si-C1-C20 alkyl group, linear, cyclic or branched, saturated or unsaturated O-(C=O)-C1-C20 alkyl group, linear, cyclic or branched, saturated or unsaturated NH-(C=O)-C1-C20 alkyl group

[0019] R8 is a linear, cyclic or branched alkane or alkene or alkyne ranging from C2 to C30

[0020] comprising the following steps:

[0021] Step 1: Reaction of a Meldrum acid of formula (II)

[0022] [Chem.2] (II)

[0023] and an ester of malic acid of formula (III)

[0024] [Chem.3] A HO'" (III)

[0025] in which:

[0026] R10 and Rn is a linear, cyclic or branched, saturated or unsaturated, C1 to C30 alkyl group, which can be chosen independently of one another,

[0027] in the presence of 2-MeTHF at a temperature between 60 and 80°C, for a period between 12 and 24 h;

[0028] Step 2: Knoevenagel-Doebner reaction by adding a substituted benzaldehyde to the crude reaction product from step 1 in the presence of pyridine and aniline, or ethanol and L-proline, respectively as solvent and catalyst, or ammonium bicarbonate without solvent, for a period of between 16 and 24 h;

[0029] Step 3: Regioselective enzymatic transesterification reaction of the substituted cinnamic acid ester obtained in step 2 in the presence of an esterase or lipase type enzyme and either (i) a monoalcohol, or (ii) a diol, or (iii) a monoamine, or (iv) a diamine or (v) an aqueous solvent,

[0030] for a period of between 16 h and 48 h, at a temperature of between 70 and 90°C, under reduced pressure of between 30 and 50 mbar.

[0031] The invention also relates to: - new lipophilic derivatives of sinapoyl malate of formula (I) as defined above with the exception of molecules having the following CAS numbers: 2244236-35-7, 1427306-89-5, 2561486-74-4, 514805-05-1, 2244569-55-7, 2078011-39-7, 2413462-74-3, 1204743-60-1, 1383141-56-7, 1019652-32-4, 1019652-33-5 and- - an intermediate compound of formula (IV):

[0032] [Chem.4] (IV).

[0033] in which:

[0034] Rio and Ru is a C1 to C30 alkyl group, linear, cyclic or branched, saturated or unsaturated, which can be chosen independently of one another.

[0035] Finally, the invention relates to the use of lipophilic derivatives of sinapoyl malate of formula (I) as an anti-UV agent, but also an anti-microbial and / or antioxidant. Advantages of the invention

[0036] The inventors have developed an optimized process for the synthesis of lipophilic derivatives of sinapoyl malate in order to limit the quantities of toxic and / or petroleum-sourced solvents, the quantities of coupling agent and catalyst while respecting the principles of green chemistry. This is the first entirely eco-responsible process for the synthesis of lipophilic derivatives of sinapoyl malate. This process allows rapid access, under sustainable synthesis conditions, to derivatives of a natural molecule with a broad spectrum of applications (anti-UV, anti-aging, antibacterial, etc.).

[0037] This process differs from those of the prior art by properties in line with the principles of green chemistry. In particular, and remarkably, it does not involve a coupling agent and activator and it does not require protection / deprotection steps. The only co-products generated are acetone, ethanol and CO2, all easy to treat. It can operate using only natural and / or bio-sourced solvents and catalysts. In addition, the reaction can take place in a single step (“one pot”). It is also possible to recover sinapic acid, a co-product of reaction.

[0038] This process allows in a novel manner the synthesis of sinapoyl malate functionalized with lipophilic groups at the level of the “malic” part, as well as its analogues. In particular, the mono-esters of malonic acid with a malic ester obtained by this process have never been described in the literature.

[0039] In the case of the Knoevenagel-Doebner step to obtain sinapoyl diethyl malate, the simultaneous production of sinapic acid does not pose a problem, since the latter also has comparable physical / biological properties. It is therefore entirely possible to use the mixture as is, without having to carry out purification, which makes it possible to further simplify the process while reducing its cost.

[0040] The lipophilization step is carried out regioselectively using a lipase, only at the level of the two acids of the “malic” part while the molecule used for this synthesis has three sites likely to be able to undergo transformation by the enzyme. In addition, the ester function of the substituted cinnamic skeleton is not modified. The use of a lipase, a natural and biosourced enzyme, is in accordance with the principles of green chemistry. Thus, enzymatic hydrolysis makes it possible to obtain sinapoyl malate and its derivatives in a completely eco-responsible manner, only by the use of biosourced and / or natural solvents and catalysts, which has never been described before. DETAILED DESCRIPTION OF THE INVENTION

[0041] A first subject of the invention relates to a process for the synthesis of lipophilic derivatives of sinapoyl malate of formula (I)

[0042] [Chem.l] (I)

[0043] in which:

[0044] Ri is a linear, cyclic or branched alkane or alkene or alkyne ranging from C2 to C30

[0045] R2 is H, a linear, cyclic C2 to C30 alkane or alkene or alkyne, or branch

[0046] Ri and R2 can be independently chosen from each other.

[0047] Xi and X2 are an O, an NH or an NR8 group

[0048] Xi and X2 can be independently chosen with respect to each other

[0049] R3, R4, R5, R6 and R7 are independently selected from H, OH, NH2, SH, an O-SiH3, a halogen, a linear, cyclic or branched, saturated or unsaturated C1-C20 alkyl group, a linear, cyclic or branched, saturated or unsaturated O-C1-C20 alkyl group, a linear, cyclic or branched, saturated or unsaturated NH-C1-C20 alkyl group, a linear, cyclic or branched, saturated or unsaturated N-(alkyl)2 group, a linear, cyclic or branched, saturated or unsaturated O-Si-C1-C20 alkyl group, a linear, cyclic or branched, saturated or unsaturated O-(C=O)-C1-C20 alkyl group, a linear, cyclic or branched, saturated or unsaturated NH-(C=O)-C1-C20 alkyl group.

[0050] R8 is a linear, cyclic or branched alkane or alkene or alkyne ranging from C2 to C30

[0051] comprising the following steps:

[0052] Step 1: Reaction of a Meldrum acid of formula (II)

[0053] [Chem.2] (II)

[0054] and an ester of malic acid of formula (III)

[0055] [Chem.3] T HO"" > (neither)

[0056] in which:

[0057] R10 and Rn is a linear, cyclic or branched, saturated or unsaturated, C1 to C30 alkyl group, which can be chosen independently of one another.

[0058] in the presence of 2-MeTHF at a temperature between 60 and 80°C, for a period between 12 and 24 h.

[0059] Step 2: Knoevenagel-Doebner reaction by adding a substituted benzaldehyde to the crude reaction product from step 1 in the presence of pyridine and aniline, or ethanol and L-proline, respectively as solvent and catalyst, or ammonium bicarbonate without solvent, for a period of between 16 and 24 h.

[0060] Step 3: Regioselective enzymatic transesterification reaction of the substituted cinnamic acid ester obtained in step 2 in the presence of an esterase or lipase type enzyme and either (i) a monoalcohol, or (ii) a diol, or (iii) a monoamine, or (iv) a diamine or (v) an aqueous solvent,

[0061] for a period of between 16 and 48 hours, at a temperature of between 70 and 90°C, under reduced pressure of between 30 and 50 mbar.

[0062] Concerning step 1, the reaction temperature is between 60 and 80°C, preferably 75°C, for a duration of between 12 and 24 h, preferably 16 h.

[0063] Regarding step 2, in a preferred embodiment, the substituted benzaldehyde is vanillin or syringaldehyde. Furthermore, preferably, for a more environmentally friendly reaction, the solvent and catalyst are ethanol and L-proline. Also preferably, the reaction is carried out for 16 h.

[0064] Regarding step 3, when the enzyme is a lipase, it is preferably lipase N435 (commercial). When the reaction is carried out in the presence of a monoalcohol, it is preferably a C7 to C30 alcohol, saturated or unsaturated, linear or branched. When the reaction is carried out in the presence of a diol, it is preferably a C2 to C30 diol, saturated or unsaturated, linear or branched. When the reaction is carried out in the presence of a monoamine, it is preferably a C7 to C30 amine, saturated or unsaturated, linear or branched. When the reaction is carried out in the presence of a diamine, it is preferably a C6 to C30 diamine, saturated or unsaturated, linear or branched. When the reaction is carried out in the presence of an aqueous solvent, it is preferably water. Preferably, the reaction is carried out for a period of 16 h, at a temperature of 80 °C and under a reduced pressure of 30 mbar.

[0065] An example of the implementation of the process for the synthesis of lipophilic derivatives of sinapoyl malate is presented in [Fig. 5]; it is the synthesis of sinapoyl dioctyl malate. This process can be applied in the same way to all substituted cinnamic acids using different fatty alcohols. This type of synthesis has never been described before. The molecules obtained are new: feruloyl dioctyl malate, caffeoyl dioctyl malate and coumaroyl dioctyl malate ([Fig. 6]).

[0066] In a particular embodiment of the invention, when the last step is carried out in the presence of a lipase (preferably lipase N35), it is possible to reduce the reaction time of this last step, over a period of 12 to 16 h, in order to obtain the molecules in an asymmetric version using a mono-transesterification. [Fig.7] illustrates a particular embodiment of this step with sinapoyl diethyl malate.

[0067] In another particular embodiment of the invention, the method comprises an additional step at the end of step 3, of evaporation of the solvent, said solvent then being an alcohol or an aqueous solvent.

[0068] A second subject of the invention relates to a lipophilic derivative of formula (I)

[0069] [Chem.l] (I)

[0070] in which:

[0071] Ri is a linear, cyclic or branched alkane or alkene or alkyne ranging from C2 to C30

[0072] R2 is an H, a linear, cyclic alkane or alkene or alkyne ranging from C2 to C30, or branch

[0073] Ri and R2 can be independently chosen from each other

[0074] Xi and X2 are an O, an NH or an NR8 group

[0075] Xi and X2 can be independently chosen with respect to each other

[0076] R3, R4, R5, R6 and R7 are independently selected from H, OH, NH2, SH, O-SiH3, halogen, linear, cyclic or branched, saturated or unsaturated C1-C20 alkyl group, linear, cyclic or branched, saturated or unsaturated O-C1-C20 alkyl group, linear, cyclic or branched, saturated or unsaturated NH-C1-C20 alkyl group, linear, cyclic or branched, saturated or unsaturated N-(alkyl)2 group, linear, cyclic or branched, saturated or unsaturated O-Si-C1-C20 alkyl group, linear, cyclic or branched, saturated or unsaturated O-(C=O)-C1-C20 alkyl group, linear, cyclic or branched, saturated or unsaturated NH-(C=O)-C1-C20 alkyl group

[0077] R8 is a linear, cyclic or branched alkane or alkene or alkyne ranging from C2 to C30

[0078] with the exception of molecules having the following CAS numbers: 2244236-35-7, 1427306-89-5, 2561486-74-4, 514805-05-1, 2244569-55-7, 2078011-39-7, 2413462-74-3, 1204743-60-1, 1383141-56-7, 1019652-32-4, 1019652-33-5.

[0079] A third subject of the invention relates to the compound of formula (IV)

[0080] [Chem.4] (IV)

[0081] in which:

[0082] Rio and Rn is a linear, cyclic or branched, saturated C1 to C30 alkyl group or unsaturated, which can be chosen independently of each other.

[0083] This new compound is an intermediate in the reaction of step 1 of the process according to the invention.

[0084] A fourth subject of the invention relates to the use of lipophilic derivatives of sinapoyl malate of formula (I) with the exception of molecules having the following CAS numbers: 2244236-35-7, 1427306-89-5, 2561486-74-4, 514805-05-1, 2244569-55-7, 2078011-39-7, 2413462-74-3, 1204743-60-1, 1383141-56-7, 1019652-32-4, 1019652-33-5, as an anti-UV and anti-oxidant agent.

[0085] These derivatives can be used in cosmetic and / or preventive / curative applications in the therapeutic field such as UV filters in sun creams, as an anti-oxidant (anti-aging, preservative) agent in cosmetic compositions.

[0086] These derivatives can also be used in non-therapeutic applications, in the field of agriculture, agri-food (antioxidant agent as preservative), phytosanitary, as additives in polymers (additive, monomer, crosslinking agent).

[0087] The present invention will be better understood upon reading the following examples, provided for illustration purposes and in no way to be considered as limiting the scope of the present invention. DESCRIPTION OF FIGURES

[0088] [Fig.l][Fig.l]: Sinapoyl malate and its analogues

[0089] [Fig.2] [Fig.2]: Synthetic route described Allais et al. (Synthesis 2009, (21), 3571-3578).

[0090] [Fig.3] [Fig.3]: Synthetic route described in WO2018 / 165189.

[0091] [Fig.4][Fig.4]: Synthetic route described in WO2021 / 156578 and the publication of Peyrot et al. (Green Chem. 2020, 22, 6210-6518).

[0092] [Fig.5] [Fig.5]: Synthesis route of sinapoyl dioctyl malate via the process of the invention.

[0093] [Fig.6] [Fig.6]: Representation of the molecules obtained via the synthesis process according to the invention using different fatty alcohols. Exemplification with p-hydroxycinnamic acids: feruloyl dioctyl malate, caffeoyl dioctyl malate and coumaroyl dioctyl malate.

[0094] [Fig.7][Fig.7]: Particular embodiment of the process allowing the production of molecules in an asymmetric version. Example of sinapoyl ethyleoctyl malate.

[0095] [Fig.8] [Fig.8]: UV spectra of the different lipophilic molecules in the dioctyl malate series

[0096] [Fig.9] [Fig.9]: UV spectra of the different molecules in the malate series

[0097] [Fig. 10] [Fig. 10]: UV spectrum of coumaroyl ethyloctyl malate EXAMPLES

[0098] EXAMPLE 1: Anti-UV properties of lipophilic derivatives of sinapoyl malate

[0099] The new molecules are analyzed in solution in ethanol at a concentration of 106 mol / L before and after UV irradiation (X = 300 nm) in a closed chamber for 60 minutes. The loss of absorbance is defined as the difference in the absorbance maximum before and after irradiation.

[0100] The UV spectra of new molecules synthesized via the process according to the invention are presented in figures 8 to 10 respectively for: different lipophilic molecules in dioctyl malate series, different molecules in malate series, coumaroyl ethyloctyl malate, coumaroyl monoethyl malonate.

[0101] In addition, the stability of these molecules with respect to UV is presented in Table 1.

[0102] [Tables 1] Molecule Absorbance loss (%) Octinoxate (reference) 27 Sinapoyl diethyl malate 26 Sinapoyl dioctyl malate 27 Sinapoyl dioleyl malate 15 Sinapoyl dicitronellyl malate 18 Sinapoyl digeranyl malate 17 Sinapoyl dilauryl malate 23 Sinapoyl difarnesyl malate 16 Feruloyl dioctyl malate 18 Caffeoyl dioctyl malate 18 Coumaroyl dioctyl malate 23 Coumaroyl ethyloctyl malate 22

[0103] Table 1: Photodegradation of lipophilic analogues of sinapoyl malate after UV irradiation for 1 h

[0104] These results show a stability at least equivalent to that of octinoxate and much superior for a certain number of analogues.

[0105] EXAMPLE 2: Antioxidant properties of lipophilic derivatives of sinapoyl malate

[0106] The antioxidant properties of the new molecules are studied using the DPPH (2,2-diphenyl-l-picrylhydrazyl) method. To do this, a solution of DPPH is prepared in ethanol (4.2 pmol). The test molecules are also dissolved in ethanol to obtain different solutions (from 80 to 2.5 nmol), of which 10 μL are placed in a 96-well microplate. The EC50 is determined by adding 190 qL of the DPPH solution (40 nmol) to the test molecules by monitoring the absorbance at X = 520 nm (DPPH absorbance) for 7 h with analysis every 5 minutes. The EC50 corresponds to the amount of antioxidant required to reduce 50% of DPPH.

[0107] The antioxidant power of certain molecules is presented in Table 2.

[0108] [Tables2] ECSo molecule (nmol) BHA (reference) 4.31 BHT (reference) 7.60 Sinapoyl diethyl malate 18.34 Sinapoyl dioctyl malate 15.65 Sinapoyl dioleyl malate 14.27 Sinapoyl dicitronellyl malate 11.20 Sinapoyl digeranyl malate 13.42 Sinapoyl dilauryl malate 13.07 Sinapoyl difarnesyl malate 13.34

[0109] Table 2: Antioxidant power of lipophilic analogues of sinapoyl malate and its derivatives

[0110] These results show that the lipophilic analogues of sinapoyl malate all exhibit an antioxidant power in an order of magnitude similar to that of the reference molecules.

Claims

1. Claims Process for the synthesis of lipophilic derivatives of sinapoyl malate of formula (I) [Chem.l] (I) in which: Ri is a linear, cyclic or branched alkane or alkene or alkyne from C2 to C30. R2 is an H, an alkane or alkene or alkyne ranging from C2 to C30 linear, cyclic, or branched. Ri and R2 can be independently chosen from each other. Xi and X2 are an O, an NH or an NR8 group. Xi and X2 can be independently chosen relative to each other. R3, R4, R5, R6 and R7 are independently selected from H, OH, NH2, SH, O-SiH3, halogen, a linear, cyclic or branched, saturated or unsaturated C1-C20 alkyl group, a linear, cyclic or branched, saturated or unsaturated O-C1-C20 alkyl group, a linear, cyclic or branched, saturated or unsaturated NH-C1-C20 alkyl group, a linear, cyclic or branched, saturated or unsaturated N-(alkyl)2 group, a linear, cyclic or branched, saturated or unsaturated O-Si-C1-C20 alkyl group, a linear, cyclic or branched, saturated or unsaturated O-(C=O)-C1-C20 alkyl group, a linear, cyclic or branched, saturated or unsaturated NH-(C=O)-C1-C20 alkyl group. R8 is a linear, cyclic or branched alkane or alkene or alkyne from C2 to C30. including the following steps: Step 1: Reaction of a Meldrum acid of formula (II) [Chem. 2] ¥ O" '0 (II) and an ester of malic acid of formula (III) [Chem. 3] (HD in which: Rio and Rn is a C1 to C30 alkyl group, linear, cyclic or branched, saturated or unsaturated, which can be chosen independently of each other. in the presence of 2-MeTHF at a temperature between 60 and 80 °C, for a period between 12 and 24 h. Step 2: Knoevenagel-Doebner reaction by adding a substituted benzaldehyde to the crude reaction product from step 1 in the presence of pyridine and aniline, or ethanol and L-proline, respectively as solvent and catalyst, or ammonium bicarbonate without solvent, or for a period of between 16 and 24 h. Step 3: Regioselective enzymatic transesterification reaction of the substituted cinnamic acid ester obtained in step 2 in the presence of an esterase or lipase enzyme and either (i) a monoalcohol, or (ii) a diol, or (iii) a monoamine, or (iv) a diamine or (v) an aqueous solvent, for a period of between 16 and 48 h, at a temperature of between 70 and 90 °C, under reduced pressure of between 30 and 50 mbar.

2. Process according to one of the preceding claims, characterized in that the reaction of step 2 is carried out in the presence of ethanol and L-proline as solvent and catalyst.

3. Method according to one of the preceding claims, characterized in that said substituted benzaldehyde is vanillin or syringaldehyde.

4. Method according to one of the preceding claims, characterized in that said lipase is lipase N435.

5. Process according to one of the preceding claims, characterized in that the reaction of step 3 is carried out for a period of 16 h, at a temperature of 80°C and under a reduced pressure of 30 mbar.

6. Method according to one of the preceding claims, characterized in that it comprises an additional step at the end of step 3, of evaporation of the solvent, said solvent then being an alcohol or an aqueous solvent.

7. Lipophilic derivative of formula (I) [Chem.l] . 0^ .,X< QY 'R? ..--¾ Rs" YR? Q" X, " (I) in which: Ri is a linear, cyclic or branched C2 to C30 alkane or alkene or alkyne R2 is H, a linear, cyclic or branched C2 to C30 alkane or alkene or alkyne Ri and R2 may be independently selected from each other Xi and X2 are O, NH or NR8 Xi and X2 may be independently selected from each other R3, R4, R5, R6 and R7 are independently selected from H, OH, NH2, SH, O-SiH3, halogen, a linear, cyclic or branched, saturated or unsaturated C1 to C20 alkyl group, a linear, cyclic or branched, saturated or unsaturated C1 to C20 0-alkyl group, a NH-alkyl group C1 to C20 linear, cyclic or branched, saturated or unsaturated, a C1 to C20 linear, cyclic or branched, saturated or unsaturated N-(alkyl)2 group, a C1 to C20 linear O-Si-alkyl group,cyclic or branched, saturated or unsaturated, a linear, cyclic or branched, saturated or unsaturated 0-(C=O)-C1-C20 alkyl group, a linear, cyclic or branched, saturated or unsaturated NH-(C=O)-C1-C20 alkyl group R8 is a linear, cyclic or branched C2-C30 alkane or alkene or alkyne. with the exception of molecules having the following CAS numbers: 2244236-35-7, 1427306-89-5, 2561486-74-4, 514805-05-1, 2244569-55-7, 2078011-39-7, 2413462-74-3, 1204743-60-1, 1383141-56-7, 1019652-32-4, 1019652-33-5. ^Claim 8] Compound of formula (IV) [Chem. 4] CX XX OO > H il l ho” xr (IV) in which: Rio and Rn is a C1 to C30 alkyl group, linear, cyclic or branched, saturated or unsaturated, which can be chosen independently of one another. ^Claim 9] Use of lipophilic sinapoyl malate derivatives of formula (I) with the exception of molecules having the following CAS numbers: 2244236-35-7, 1427306-89-5, 2561486-74-4, 514805-05-1,2244569-55-7, 2078011-39-7, 2413462-74-3, 1204743-60-1, 1383141-56-7, 1019652-32-4, 1019652-33-5, as an anti-UV and / or anti-oxidant agent in the field of agriculture, phytosanitary and in additives in polymers. ^Claim 10] Lipophilic derivative of sinapoyl malate of formula (I) with the exception of molecules having the following CAS numbers: 2244236-35-7, 1427306-89-5, 2561486-74-4, 514805-05-1, 2244569-55-7, 2078011-39-7,2413462-74-3, 1204743-60-1, 1383141-56-7, 1019652-32-4, 1019652-33-5, for its use as an anti-UV and / or anti-oxidant agent.,