Process for synthesising lipophilic derivatives of sinapoyl malate and analogues thereof, and uses thereof

Abstract

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 synthesising lipophilic derivatives of sinapoyl malate and analogues thereof, and also new lipophilic analogues of sinapoyl malate as such, and uses thereof.

Description

PROCESS FOR THE SYNTHESIS OF LIPOPHILIC 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 method for synthesizing 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 in plants for its anti-UV properties. Sinapoyl malate and its derivatives are considered an alternative to chemical filters in sunscreens.

[0003] So far, three methodologies have been described in the literature for obtaining sinapoyl malate and its derivatives ().

[0004] The first methods described are tedious, requiring numerous protection, deprotection, and activation steps using a large amount of coupling agent and toxic solvents. The analysis of the publication by Allaiset al. (Synthesis2009, (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. The significant reaction time is mainly due to a relatively long first protection step (22 days) of the two acids from malic acid (: 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 (: 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 amount 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) ( : Sinapic acid to 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 (). These reagents are non-reusable, toxic, often put in large excess and also generate the formation of a stoichiometric amount of urea. It is then necessary to deprotect molecule 4 at the level of the ester-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 ( : Molecule 4 towards 5). Then the acetate (OAc) is deprotected in the presence of HCl in acetone ( : 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 by 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) with the protection of malic acid by desiso-propanol and not desert-butanol (, 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% (: 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 the esterification, the protecting groups (iso-propanol & acetate) are removed in the presence of sulfuric acid which is absolutely not selective for one or the other 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 synthetic 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. 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. Under optimized conditions, the yield of this reaction can reach 66% but requires the use of pyridine (harmful, ecotoxic) as a solvent and aniline (very toxic, ecotoxic, carcinogenic) as a catalyst.Thus, despite the significant reduction in the number of stages (2 compared to 6 previously), the impact on the environment is harmful. 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.

[0008] In terms of yield, particularly when applying the process described in patent WO2021 / 156578 and in the article by Peyrotet al. cited above, the Knoevenagel-Doebner step gives a very low yield (16%) when carried out using green solvents and catalysts. Optimizing the process using this approach therefore requires the use of environmentally harmful solvents and catalysts.

[0009] None of the methods described above allows the production of lipophilic derivatives of sinapoyl malate in a completely sustainable manner and with high yield.

[0010] The invention provides a new three-step process for the sustainable synthesis of lipophilic sinapoyl malate derivatives 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.

[0011] The present invention thus relates to a new process for the synthesis of lipophilic derivatives of sinapoyl malate of formula (I)

[0012] (I)

[0013] in which:

[0014] R1 is an alkane or alkene or alkyne ranging from C2 to C 30 linear, cyclic or branched

[0015] R2 is an H, an alkane or alkene or alkyne ranging from C2 to C 30linear, cyclic, or branched

[0016] R1 and R2 can be chosen independently of each other

[0017] X1 and X2 are an O, an NH or an NR8 group

[0018] X1 and X2 can be independently chosen with respect to each other

[0019] R3, R4, R5, R6 and R7 are independently selected from H, OH, NH2, SH, O-SiH3, halogen, C1 to C alkyl group 20 linear, cyclic or branched, saturated or unsaturated, a C1 to C O-alkyl group 20 linear, cyclic or branched, saturated or unsaturated, a C1 to C NH-alkyl group 20 linear, cyclic or branched, saturated or unsaturated, an N-(alkyl)2 group in C1 to C 20 linear, cyclic or branched, saturated or unsaturated, an O-Si-C1 to C alkyl group 20 linear, cyclic or branched, saturated or unsaturated, an O-(C=O)-C1 to C alkyl group 20linear, cyclic or branched, saturated or unsaturated, a NH-(C=O)-C1 to C alkyl group 20 linear, cyclic or branched, saturated or unsaturated

[0020] R8 is an alkane or alkene or alkyne ranging from C2 to C 30 linear, cyclic or branched

[0021] including the following steps:

[0022] Step 1: Reaction of a Meldrum acid of formula (II)

[0023] (II)

[0024] and an ester of malic acid of formula (III)

[0025] (III)

[0026] in which:

[0027] R10 and R11 are C1 to C10 alkyl groups. 30 , linear, cyclic or branched, saturated or unsaturated, which can be chosen independently of each other,

[0028] in the presence of 2-MeTHF at a temperature between 60 and 80°C, for a period between 12 and 24 h;

[0029] 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;

[0030] 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,

[0031] 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.

[0032] The invention also relates to an intermediate compound of formula (IV):

[0033] (IV).

[0034] in which:

[0035] R10 and R11 are C1 to C10 alkyl groups. 30 , linear, cyclic or branched, saturated or unsaturated, which can be chosen independently of each other.

[0036] Finally, the invention relates to the use of lipophilic derivatives of sinapoyl malate of formula (IV) as an anti-UV agent, but also an anti-microbial and / or anti-oxidant in cosmetic and / or therapeutic compositions as well as other non-therapeutic applications. Advantages of the invention

[0037] The inventors have developed an optimized process for the synthesis of lipophilic sinapoyl malate derivatives 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 sinapoyl malate derivatives. 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.).

[0038] This process allows the production of lipophilic derivatives of sinapoyl malate with an overall yield of up to 69%.

[0039] This process differs from those of the prior art by the order of the steps, in particular because the Knoevenagel-Doebner coupling reaction occurs before the incorporation of the fatty part of the molecule.

[0040] Due to this particularity, the Knoevenagel-Doebner reaction can be carried out in ethanol, without the significant loss of yield observed in the process described in patent WO2021 / 156578. Indeed, when the fatty part is present at the Knoevenagel-Doebner reaction stage, a secondary transesterification reaction occurs on the 3 ester functions present on the molecule.

[0041] Another advantage is that the by-product formed by transesterification of ethyl esters is ethanol, a molecule that is easily evaporated (more so than water).

[0042] This process involves solvents (2-MeTHF, ethanol) and catalysts (Proline, Cal-B) offering green reaction conditions, in addition to very good yields at each step (>80%). Thus, this synthetic route demonstrates a very low influence of the fatty chain on the efficiency of the reaction, which allows to obtain a high overall yield on the three steps described ranging from 61% to 69%.

[0043] The change in order of the synthesis steps compared to the prior art processes therefore makes it possible to remove the technological barrier of the Knoevenagel-Doebner reaction.

[0044] Concerning the lipophilization step, it is carried out in a regioselective manner 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 bio-sourced enzyme, is in accordance with the principles of green chemistry. Thus, enzymatic transesterification makes it possible to obtain sinapoyl malate derivatives - and particularly its fatty esters - in a totally eco-responsible manner, only by using bio-sourced and / or natural solvents and catalysts, which has never been described before.

[0045] Remarkably, the process according to the invention does not involve a coupling agent or activator and does not require protection / deprotection steps. The only co-products generated are acetone, ethanol and CO2, all of which are easy to process. It can operate using only natural and / or bio-sourced solvents and catalysts. In addition, the reaction can be carried out in a single step (“one pot”). It is also possible to recover sinapic acid, a reaction co-product.

[0046] When the Knoevenagel-Doebner step produces sinapoyl diethyl malate, the simultaneous production of sinapic acid is not a problem, since the latter also has comparable physical / biological properties. It is therefore quite feasible to use the mixture as is, without the need for purification, which further simplifies the process and reduces its cost.

[0047] This process allows the unprecedented 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.

[0048] This process is faster than those of the state of the art and economically viable by controlling costs linked to the choice of solvents. It provides access to new molecules of interest in quantities high enough to meet market needs, in particular as anti-UV and / or anti-oxidant agents in the field of agriculture, phytosanitary and in additives in polymers and as anti-UV and / or anti-oxidant agents. DETAILED DESCRIPTION OF THE INVENTION

[0049] A first subject of the invention relates to a process for the synthesis of lipophilic derivatives of sinapoyl malate of formula (I)

[0050] (I)

[0051] in which:

[0052] R1 is an alkane or alkene or alkyne ranging from C2 to C 30 linear, cyclic or branched

[0053] R2 is an H, an alkane or alkene or alkyne ranging from C2 to C 30 linear, cyclic, or branched

[0054] R1 and R2 can be chosen independently of each other

[0055] X1 and X2 are an O, an NH or an NR8 group

[0056] X1 and X2 can be independently chosen with respect to each other

[0057] R3, R4, R5, R6 and R7 are independently selected from H, OH, NH2, SH, O-SiH3, halogen, C1 to C alkyl group 20 linear, cyclic or branched, saturated or unsaturated, a C1 to C O-alkyl group 20 linear, cyclic or branched, saturated or unsaturated, a C1 to C NH-alkyl group 20linear, cyclic or branched, saturated or unsaturated, an N-(alkyl)2 group in C1 to C 20 linear, cyclic or branched, saturated or unsaturated, an O-Si-C1 to C alkyl group 20 linear, cyclic or branched, saturated or unsaturated, an O-(C=O)-C1 to C alkyl group 20 linear, cyclic or branched, saturated or unsaturated, a NH-(C=O)-C1 to C alkyl group 20 linear, cyclic or branched, saturated or unsaturated.

[0058] R8 is an alkane or alkene or alkyne ranging from C2 to C 30 linear, cyclic or branched

[0059] including the following steps:

[0060] Step 1: Reaction of a Meldrum acid of formula (II)

[0061] (II)

[0062] and an ester of malic acid of formula (III)

[0063] (III)

[0064] in which:

[0065] R10 and R11 are C1 to C10 alkyl groups. 30, linear, cyclic or branched, saturated or unsaturated, which can be chosen independently of each other.

[0066] in the presence of 2-MeTHF at a temperature between 60 and 80 °C, for a period between 12 and 24 h.

[0067] 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.

[0068] 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,

[0069] 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.

[0070] 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.

[0071] 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.

[0072] 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 C alcohol. 30, saturated or unsaturated, linear or branched. When the reaction is carried out in the presence of a diol, it is preferably a C2 to C diol 30 , saturated or unsaturated, linear or branched. When the reaction is carried out in the presence of a monoamine, it is preferably a C7 to C amine 30 , saturated or unsaturated, linear or branched. When the reaction is carried out in the presence of a diamine, it is preferably a C6 to C diamine 30 , 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.

[0073] An example of the implementation of the process for the synthesis of lipophilic derivatives of sinapoyl malate is presented in ; 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 ().

[0074] 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. A particular embodiment of this step is illustrated with sinapoyl diethyl malate.

[0075] 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.

[0076] A second subject of the invention relates to the compound of formula (IV)

[0077] (IV)

[0078] in which:

[0079] R10 and R11 are C1 to C10 alkyl groups. 30 , linear, cyclic or branched, saturated or unsaturated, which can be chosen independently of each other.

[0080] This new compound is an intermediate in the reaction of step 1 of the process according to the invention.

[0081] A third subject of the invention relates to the use of lipophilic derivatives of sinapoyl malate of formula (IV) as an anti-UV and anti-oxidant agent.

[0082] These derivatives can be used in cosmetic or therapeutic compositions, whether for preventive or curative purposes. These compounds are found as UV filters in sunscreens and as antioxidant agents (anti-aging, preservatives) in cosmetic compositions.

[0083] These derivatives can also be used in non-therapeutic compositions. They can be used in the field of agriculture as an anti-UV agent, antioxidant, anti-microbial, heating molecule, herbicide, in the field of agri-food (antioxidant agent as preservative) and phytosanitary and as additives in polymers (additive, monomer, crosslinking agent).

[0084] The present invention will be better understood from 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

[0085] :Sinapoylmalate and its analogues

[0086] : Synthetic route described Allaiset al. (Synthesis2009,(21), 3571-3578).

[0087] : Synthetic route described in WO2018 / 165189.

[0088] : Synthetic route described in WO2021 / 156578 and the publication by Peyrot et al. (Green Chem.2020, 22, 6210-6518).

[0089] : Synthesis route of sinapoyl dioctyl malate via the process of the invention.

[0090] : 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.

[0091] : Particular embodiment of the process allowing the production of molecules in an asymmetric version. Example of sinapoyl ethyleoctyl malate.

[0092] : UV spectra of different lipophilic molecules in dioctyl malate series

[0093] : UV spectra of the different molecules in the malate series

[0094] : UV spectrum of coumaroyl ethyloctyl malate EXAMPLES

[0095] EXAMPLE 1: Anti-UV properties of lipophilic derivatives of sinapoylmalate

[0096] The new molecules are analyzed in solution in ethanol at a concentration of 10 -6 mol / L before and after UV irradiation (λ = 300 nm) in a closed chamber for 60 minutes. Absorbance loss is defined as the difference in absorbance maximum before and after irradiation.

[0097] 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.

[0098] In addition, the stability of these molecules with respect to UV is presented in Table 1.

[0099] MoleculeAbsorbance loss (%)Octinoxate (reference)27Sinapoyl diethyl malate26Sinapoyl dioctyl malate27Sinapoyl dioleyl malate15Sinapoyl dicitronellyl malate18Sinapoyl digeranyl malate17Sinapoyl dilauryl malate23Sinapoyl difarnesyl malate16Feruloyl dioctyl malate18Caffeoyl dioctyl malate18Coumaroyl dioctyl malate23Coumaroyl ethyloctyl malate22

[0100] Table 1: Photodegradation of lipophilic sinapoyl malate analogues after UV irradiation for 1 h

[0101] These results show stability at least equivalent to that of octinoxate and much higher for a number of analogues.

[0102] EXAMPLE 2: Antioxidant properties of lipophilic derivatives of sinapoylmalate

[0103] The antioxidant properties of the new molecules are studied using the DPPH (2,2-diphenyl-1-picrylhydrazyl) method. To do this, a solution of DPPH is prepared in ethanol (4.2 μmol). The molecules to be tested are also dissolved in ethanol to obtain different solutions (from 80 to 2.5 nmol), 10 μL of which are placed in a 96-well microplate. The EC 50 is determined by adding 190 μL of the DPPH solution (40 nmol) to the test molecules by following the absorbance at λ = 520 nm (DPPH absorbance) for 7 h with analysis every 5 minutes. The EC 50 corresponds to the amount of antioxidant needed to reduce 50% of DPPH.

[0104] The antioxidant power of certain molecules is presented in Table 2.

[0105] MoleculeEC 50 (nmol)BHA (reference)4.31BHT (reference)7.60Sinapoyl diethyl malate18.34Sinapoyl dioctyl malate15.65Sinapoyl dioleyl malate14.27Sinapoyl dicitronellyl malate11.20Sinapoyl digeranyl malate13.42Sinapoyl dilauryl malate13.07Sinapoyl difarnesyl malate13.34

[0106] Table 2: Antioxidant power of lipophilic analogues of sinapoyl malate and its derivatives

[0107] 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

Process for the synthesis of lipophilic sinapoyl malate derivatives of formula (I) (I) in which: R1 is an alkane or alkene or alkyne ranging from C2 to C 30 linear, cyclic or branched. R2 is an H, an alkane or alkene or alkyne ranging from C2 to C 30 linear, cyclic, or branched.R1and R2may be independently selected from one another.X1and X2are O, NH, or NR8.X1and X2may be independently selected from one another.R3, R4, R5, R6and R7are independently selected from H, OH, NH2, SH, O-SiH3, halogen, C1-C alkyl 20 linear, cyclic or branched, saturated or unsaturated, a C1 to C O-alkyl group 20 linear, cyclic or branched, saturated or unsaturated, a C1 to C NH-alkyl group 20 linear, cyclic or branched, saturated or unsaturated, an N-(alkyl)2 group in C1 to C 20linear, cyclic or branched, saturated or unsaturated, an O-Si-C1 to C alkyl group 20 linear, cyclic or branched, saturated or unsaturated, an O-(C=O)-C1 to C alkyl group 20 linear, cyclic or branched, saturated or unsaturated, a NH-(C=O)-C1 to C alkyl group 20 linear, cyclic or branched, saturated or unsaturated. R8 is an alkane or alkene or alkyne ranging from C2 to C 30 linear, cyclic or branched.comprising the following steps:Step 1: Reaction of a Meldrum acid of formula (II) (II) and an ester of malic acid of formula (III) (III) in which: R10 and R11 is a C1 to C alkyl group 30, 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 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, either (iv) a diamine or (v) an aqueous solvent, 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. 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. Process according to one of the preceding claims, characterized in that said substituted benzaldehyde is vanillin or syringaldehyde. Method according to one of the preceding claims, characterized in that said lipase is lipase N435. Process according to one of the preceding claims, characterized in that the reaction of step 3 is carried out for a period of 16 hours, at a temperature of 80°C and under a reduced pressure of 30 mbar. 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. Compound of formula (IV) (IV) in which: R10 and R11 is a C1 to C alkyl group 30 , linear, cyclic or branched, saturated or unsaturated, which can be chosen independently of each other. Use of lipophilic derivatives of sinapoyl malate of formula (IV) as defined in claim 7 in non-therapeutic compositions as anti-UV and / or anti-oxidant agent, heating molecule and / or herbicide in the field of agriculture, in the field of phytosanitary products and as additives in polymers. Lipophilic derivative of sinapoyl malate of formula (IV) as defined in claim 7 for its use in cosmetic or therapeutic compositions as an anti-UV and / or anti-oxidant agent.

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