EP4291169A1

EP4291169A1 - Novel method for manufacturing tomato leafminer pheromone components

Info

Publication number: EP4291169A1
Application number: EP22708978.6A
Authority: EP
Inventors: Eric Gayon; Loic GUILLONNEAU; Olivier Guerret
Original assignee: Melchior Material and Life Science France SAS
Current assignee: Melchior Material and Life Science France SAS
Priority date: 2021-02-11
Filing date: 2022-02-11
Publication date: 2023-12-20
Also published as: WO2022171965A1; FR3119621A1; US20240140902A1; CN116916898A; FR3119621B1

Abstract

The present invention relates to a method for synthesising a pheromone of general formula selected from the group comprising compounds (I) and (I'), alone or in admixture: (I) (I') comprising reacting (2E)-pentene-1,5-diyl diacetate with at least one Grignard reagent in the presence of a copper-based catalyst. The method according to the invention is particularly applicable to the selective synthesis of tomato leafminer (Tuta absoluta) pheromone comprising: (3E,8Z,11Z)-tetradecatrien-1-yl acetate and (3E,8Z)-tetradecadien-1-yl acetate.

Description

NEW METHOD FOR MAKING THE COMPONENTS OF THE TOMATO MINER PHEROMONE

DESCRIPTION

For reasons of public health and management of the agricultural potential of the soil, crop treatment technologies against pests are evolving towards more targeted and more environmentally friendly modes of action. As such, the use of sex pheromones to modify the behavior of insects has advantages since these pheromones are specific to each species of pest and are effective, at very low doses, in various types of strategy (trapping, sexual confusion by example).

However, an obstacle to the development of these technologies lies in the cost of access to active molecules. Indeed these molecules often have many possible isomers and selective synthesis technologies are generally expensive.

The tomato leaf miner, Tuta absoluta, a tomato pest present on all continents, is a good example of the problems encountered by those skilled in the art in developing pheromone-based control solutions. Indeed, the main components of the Tuta absoluta pheromone are:

Table 1: main components of the Tuta absoluta pheromone

These molecular structures have many positional and configurational isomers. For triene, no less than 8 configurations are possible, but only the 3E,8Z,11Z configuration is active on the insect's olfactory receptors. May that some isomers even have an antagonistic function. It is therefore not only necessary to produce these compounds more economically but also with the highest possible purity. These two requirements are often contradictory and the person skilled in the art has rarely succeeded in reconciling them.

The first known synthesis of the components of the Tuta absoluta pheromone is reported in the publications: AB Attygalle & al. Tetrahedron Letters, Vol. 36, No. 31 , p. 5471-5474, 1995 and AB Attygalle & al. Bioorganic & Medicinal Chemistry, Vol. 4, No. 3, p. 305-314, 1996. This academic work describes an interesting synthetic route because it makes it possible to answer the problem of selectivity of the synthesis via the reduction of triple bonds into double bonds Z or E. The structure construction reaction at 14 carbon atoms consists of the reaction of a lithium alkynide with the intermediate IVa: IVa which requires very dilute conditions and therefore high fixed costs. In total it is a return of 7% which also implies high variable costs. Furthermore, the lithiated derivative must be protected by a tetrahydropyran group, which requires an additional deprotection and acetylation step.

On the other hand, the teaching of EP 2639217 consists of a synthetic route similar to the previous one but which differs because the compound: in the presence of a catalyst composed of CuCl and triethylphosphite. The product of coupling is then converted into alcohol and then acetylated to yield the desired compound. In this patent, the principle therefore consists in coupling a chain with 9 carbon atoms and 2 unsaturations Z, with a synthon with 5 carbon atoms carrying an unsaturation E. The interest of compound V for the inventors of EP 2639217 consisted to protect one end of the chain with the methoxymethyl ether function to avoid side reactions during the reaction with the Grignard compound.

However, after the coupling, there are still 2 steps to obtain the target molecule, which greatly reduces the overall yield.

There thus remains a need to develop a selective process for obtaining isomerically pure pheromone involving a limited number of reactions and allowing a good yield.

Surprisingly, the Applicant has discovered that it was possible to produce a magnesian coupling, in the presence of a catalyst, of compound II, perfectly selective with a substitution of the acetate function in position 1 (allylic position) and no reactivity of the acetate function in position 5 (homoallylic position). Indeed, the coupling between an organomagnesium derivative and a homoallylic acetate derivative {ie (3Z-octen-1-yl acetate) catalyzed by a copper(II) complex has been described by Hu et al. Molecules (2012), vol. 17, p. 12140-12150 and led to the corresponding coupling product with a yield of 87% and a purity of 97%. It was therefore not obvious to those skilled in the art that the substitution reaction forming the subject of this patent is specific for position 1 (allylic position). The inventors have also observed that the level of substitution products in position 3 is much lower according to the method of the invention than according to the known methods mentioned above. Since the acetate function in position 5 is desired for the structure of the targeted pheromone, the fact that it is not at all affected by the reaction under the conditions of the invention is an advantage of the invention because this makes it possible to avoid protection, deprotection and acetylation reactions which, if they have good yields, do not require less working time important and generate aqueous effluents in large quantities which is detrimental from the point of view of sustainable industrial development.

Another advantage noted by the inventors lies in the fact that, when two magnesia R-MgX and R′-MgX are used simultaneously in a given ratio, their reaction products with compound II are then themselves in the same ratio. This makes it possible to prepare pheromone mixtures without having to prepare each component of the mixture individually.

Thus, the present invention relates to a process for synthesizing a pheromone of general formula chosen from the group comprising the compounds (I) and ( ), alone or as a mixture: where R is a linear hydrocarbon chain with molecular formula CnH2n-2 _P +i ,

R’ is a linear hydrocarbon chain of molecular formula Cn'H2n -2p +i with:

- n and n’, identical or different, are integers between 5 and 17 and

- p and p' corresponding to the number of unsaturations of the hydrocarbon chain, identical or different, are integers between 1 and 3,

Ac is an Acetyl radical, comprising the reaction of (2E)-pentene-1,5-diyl diacetate of formula (II): with at least one Grignard reagent chosen from the group comprising compounds (III) and (III'), alone or as a mixture:

R-MgX (III), R'-MgX (III') where X is a chlorine or bromine atom; R and R' are as defined previously for the compounds of formulas (I) and (G) in the presence of a catalyst based on copper.

Advantageously n and n′, identical or different, are between 7 and 15, particularly between 9 and 13.

Also advantageously, p and p', identical or different, are integers comprised between 1 and 3, more particularly between 1 and 2. p and p' represent, as indicated, the total number of unsaturations of the chain R or of the chain R'. It is understood that one double bond counts as one unsaturation and one triple bond counts as two unsaturations. The R or R' chain may thus comprise one or more double bonds, but also a triple bond associated with a double bond.

In one embodiment, the process is characterized in that the copper-based catalyst further comprises, i.e. is supplemented with, at least one copper ligand chosen from the group comprising trialkylphosphine, trialkylphosphite, an amine, as well as their mixtures.

The term “alkyl” in the expression trialkylphosphite or trialkylphosphine corresponds to a C1-C6 alkyl group, in particular methyl, ethyl or propyl.

In one embodiment, the method is characterized in that the ligand is a trialkylphosphite selected from the group comprising triethylphosphite, trimethylphosphite and mixtures thereof.

In one embodiment, the process is characterized in that the reaction is carried out in an aprotic solvent, in particular of the ether type, linear or cyclic, in particular chosen from the group comprising diethyl ether, methyl tert-butyl ether, tetrahydrofuran, methyltetrahydrofuran, tetrahydropyran, methyltetrahydropyran, dioxane and glycol dimethyl ether, as well as mixtures thereof.

In one embodiment, the process is characterized in that the copper-based catalyst is a copper II salt. More particularly, the catalyst based on copper II can be chosen from the group comprising copper II halides and copper II carboxylates.

In one embodiment, the method is characterized in that the copper II halide is chosen from CuCl2 and CuBr2; the copper II carboxylate is advantageously chosen from copper acetate Cu(OAc)2 and copper II acetyl acetonate, Cu(Acac)2.

In the present description, and unless otherwise indicated, when reference is made to equivalent, it is a question of molar equivalent expressed with respect to compound (II) at 1 molar eq.

The invention also relates to a method comprising the following steps: a. Preparation in an aprotic solvent of a solution comprising 1 equivalent of (2E)-pentene-1,5-diyl diacetate of formula (II); b. addition, to the preparation obtained in step a), of the catalyst based on copper II in an amount of 0.001 to 0.02 equivalent of copper, the copper possibly being able to be bound optionally to a ligand chosen from the group comprising a trialkylphosphine, a trialkylphosphite, an amine, as well as their mixtures; vs. preparation in an aprotic solvent identical to or different from the solvent of step a), of a solution comprising between 0.95 and 1.25 equivalents of a Grignard reagent chosen from the group comprising compounds (III) and (III '), alone or as a mixture; d. adding the solution obtained in step c) to the solution prepared in step b) with stirring and at a reaction temperature below 25° C.; e. stopping the reaction, in particular by adding 0.1 to 1 equivalent of acetic anhydride to the reaction medium obtained following step d); f. neutralization of the reaction medium obtained following step e) and extraction of the pheromone of formula (I) or (G) or of the mixture of pheromones of formulas (I) and (G).

According to one embodiment, the process according to the invention is characterized in that the compound (III): compound (IIG) molar ratio is between 0:1 and 1:0. Advantageously, the compound (III): compound (IIG) molar ratio is between 0.01:0.99 and 0.99:0.01, particularly between 0.05:0.95 and 0.95:0, 0.5, or even between 0.1:0.9 and 0.9:0.1, or even between 0.2:0.8 and 0.8:0.2, or between 0.3:0.7 and 0.7:0.3, and again between 0.6:0.4 and 0.4:0.6, or even around 0.5:0.5.

Advantageously, step a) is carried out under an inert atmosphere, for example under nitrogen or argon. This step a) is preferably carried out at a temperature between -20°C and +60°C, particularly between -10°C and +10°C.

The amount of copper-based catalyst may advantageously be between 0.005 and 0.03 equivalents of Copper II, or even between 0.01 and 0.02 equivalents.

The amount of Grignard reagent (compound III or compound IIG or compound III+IIG) may advantageously be between 1 and 1.2 equivalents, or even between 1 and 1.15 equivalents.

Step c) is also advantageously carried out under an inert atmosphere, for example under nitrogen or argon, preferably at a temperature between -15°C and 50°C. More preferably, step c) advantageously carried out under an inert atmosphere, for example under nitrogen or argon, is carried out at a temperature between -10°C and 10°C.

Step d) is carried out with stirring and advantageously at a reaction temperature below 25°C, preferably below 15°C, even more preferably between 8°C and 12°C. At the end of the addition, the temperature of the medium can advantageously be lowered to 0° C. and stirring maintained until one of the reagents has disappeared. The disappearance of one of the reagents can be followed by GC (gas phase chromatography) and/or TLC (thin layer chromatography).

Stage e) of stopping the reaction, in particular by adding 0.1 to 1.5 equivalents of acetic anhydride, is advantageously carried out at a temperature maintained below 30° C., preferably at a temperature maintained below or equal to 25°C. Indeed the addition of acetic anhydride is exothermic and it is preferable to maintain the temperature below 30°C. The neutralization step f) is advantageously carried out using an ammonium chloride solution at a concentration and in an amount suitable for adjusting the pH to a value of the order of 7 to 8, and this without excessively diluting the middle. The ammonium chloride solution can be a solution at a concentration of 10 to 20% w/w, or even about 16% w/w. The pH will advantageously be adjusted to a value between 7 and 8, particularly between 6.5 and 8.

The invention also relates to a composition comprising a pheromone of general formula chosen from the group comprising the compounds (I) and (), alone or as a mixture: where :

R is a linear hydrocarbon chain with the molecular formula CnH2n-2 _P +i ,

R′ is a linear hydrocarbon chain of molecular formula Cn′H2n −2p _+i with: n and n′, which are identical or different, are integers between 5 and 17; p and p' corresponding to the number of unsaturations in the hydrocarbon chain, which are identical or different, are integers between 1 and 3;

Ac is an acetyl radical, and containing, in% by weight of the composition, less than 2%, preferably less than 1.9%, of a compound chosen from the group comprising compounds (VI) and (VI ') , alone or in combination: Advantageously, the amount of compound chosen from the group comprising compounds (VI) and (VI'), alone or as a mixture, is less than 1.8%, or even less than 1.7%, less than 1.6 %, less than 1.5%, in % by weight of the composition.

In particular R and R′ are chosen from the (3Z,6Z)-nonadien-1-yl group and the (3Z)-nonen-1-yl group.

In particular, the method applies to the selective synthesis of the tomato leafminer pheromone (Tuta absoluta) comprising; (3E,8Z,11Z)-tetradecadien-1-yl acetate on the one hand and (3E,8Z)-tetradecadien-1-yl acetate, alone or in mixtures.

Thus an advantage of the process according to the invention lies in the selectivity of the reaction with respect to substitutions in position 3. Indeed, the coupling reaction between the compound (II) and the Grignard reagent(s) (III or IIG or a III/IIG mixture) in the presence of a catalyst based on copper II, in particular a copper II salt, makes it possible to favor the products (I) and/or (G): corresponding to an allylic substitution in position 1 while limiting the products (VI) and (VI'): corresponding to an allylic substitution at position 3.

The products (VI) and/or (VI′) represent particularly troublesome impurities because they are not part of the family of pheromones with fatty chains of Lepidoptera, which induces problems of toxicity and eco-toxicity. Reducing such impurities obviously has an economic advantage but above all, it makes it possible to obtain a more effective pheromone because the impurities can have anti-synergistic roles with the pheromones, the insect being able to be repelled by an impurity even in small quantities as is reported in the publication Kawazu & al. Journal of Chemical Ecology (2007), vol. 33 p. 1978-1985.

The inventors have found that the rate of substitution products in position 3 is much lower according to the method of the invention than according to the known methods mentioned above and that this contributes to a greater effectiveness of the products for the control of insects. .

The process according to the invention is particularly advantageous because the products (VI) and/or (VI') corresponding to an allylic substitution at position 3 are particularly difficult to separate from the product(s) corresponding to an allylic substitution at position 1 , and this by methods known to those skilled in the art because their boiling points are very close. It was therefore essential to minimize the content of substitution product(s) in position 3 before starting the purification steps. This is what the method according to the invention allows.

Another advantage of the present process compared to the process taught by document EP 2639217 is also that the use of compound (II) makes it possible to obtain the molecules sought without the need for subsequent protection, deprotection and acetylation reactions taught by EP2639217. This allows a real gain in the number of reactions involved and therefore in yield; which makes it a much more economically advantageous process.

The process according to the invention is detailed below.

It begins with a first step in which one prepares on the one hand, in particular under an atmosphere of an inert gas such as nitrogen or argon, for example at a temperature between -15°C and 50°C, preferably between -10° and 10°C, a solution of one equivalent of (2 ^E )-pentene-1,5-diyl II diacetate: in an aprotic solvent, in particular of the ether type, more particularly the diethyl ether, methyl tert-butyl ether, tetrahydrofuran, methyltetrahydrofuran, tetrahydropyran, methyltetrahydropyran, dioxane or else glycol dimethyl ether, then the catalyst based on copper II is introduced into this mixture, optionally in the presence of a ligand, characterized in which it comprises between 0.001 and 0.02 equivalents of copper II salt such as a copper II halide (such as CuCl2, CuBr2) or a copper carboxylate (such as copper acetate Cu(OAc)2 or copper II acetyl acetonate Cu(Acac)2).

- In a second step, always advantageously under an inert atmosphere of nitrogen or argon, a solution is prepared separately in an aprotic solvent of the ether type, particularly diethyl ether, methyltertbutylether, tetrahydrofuran, methyltetrahydrofuran, tetrahydropyran, methyltetrahydropyran , dioxane or else glycol dimethyl ether, which may be identical to or different from the solvent chosen in the first stage, containing between 0.95 and 1.25 equivalents of a Grignard reagent chosen from the group comprising the compounds (III ) and (IIG), alone or as a mixture:

R-MgX (III), R'-MgX (III') where X is a chlorine or bromine atom,

R is a linear hydrocarbon chain of molecular formula C _n H2n-2 _P +i ,

R' is a linear hydrocarbon chain of molecular formula Cn'H2n -2'p _+i with: n and n', identical or different, are integers between 5 and 17 and p and p' corresponding to the number of unsaturations of the hydrocarbon chain, identical or different, are integers between 1 and 3:

Ac is an acetyl radical.

Preferably, the quantity of Grignard reagent (compound III or compound IIG or mixture of compound III+IIG) is between 1.05 and 1.15 equivalents. This solution is brought to a temperature between -15°C and 50°C, preferably between -10°C and 10°C.

- In a third stage, the solution obtained in the second stage is added to the solution prepared in stage 1 while maintaining vigorous stirring and a reaction temperature below 25° C., preferably below 15° C., even more preferentially included between 8 and 12°C. At the end of the addition, the medium temperature is lowered to 0 ° C and stirring is maintained until disappearance of one of the reagents.

- In a fourth step, the reaction is stopped by adding between 0.1 and 1.5 equivalents of acetic anhydride while maintaining a temperature below 30°C, preferably at a temperature below or equal to 25°C.

- In a fifth step, the medium is neutralized by means of an ammonium chloride solution, taking care preferentially not to lower the pH below 7, or even not below 6.5. Then the product is extracted several times using an organic solvent chosen by a person skilled in the art. The organic phases are then dried, concentrated and then distilled to isolate the final product of general formula chosen from the group comprising the compounds (I) and (G), alone or as a mixture:

The Applicant has thus further found that it was possible to use, as a reagent prepared in step 2, a Grignard reagent comprising a single product such as the product (III) or the product (IIG) but also a mixture of products (III + IIG), in a chosen ratio. The end product is thus a product (I) or a product (G), or a mixture of the two products: in a ratio equivalent to that of their Grignard reactive precursor products. Thus if the only product (III) is used, the only product (I) will be obtained; if we use the only product (IIG) we will obtain the only product ( ) and if we use a mixture (III+II ) in a given molar ratio III:IIG, we will obtain a mixture of products (I + G) in a molar ratio 1:1 equivalent. This discovery makes it possible to simplify the routes of synthesis of pheromonal mixtures, particularly at the industrial level since it there is no longer any need to mobilize reaction capacities for one of the components, then for the second and finally for the mixture: the mixture is obtained directly in the desired proportions at the end of the synthesis.

Another object of the invention is to obtain a composition comprising the product of formula characterized in that the content of impurity of formula does not exceed 2%, in% by weight, and preferably less than 1.9%, or even less than or equal to 1.6% and this in particular when the compound R is the group (3Z,6Z)-nonadien- 1-yl or the (3Z)-nonen-1-yl group.

The present invention finally relates to the use of a composition according to the invention, comprising a pheromone of general formula chosen from the group comprising the compounds (I) and (G), alone or as a mixture as explained further for the crop protection against the Tuta absoluta pest.

Finally, the invention also relates to a method for protecting an agricultural plot against the pest Tuta absoluta comprising the application, within said plot, of a composition according to the invention comprising a pheromone of general formula chosen from the group comprising compounds (I) and (G), alone or as a mixture as described above.

Examples:

Raw materials and solvents are commercially available from Sigma Aldrich.

Compound II is either purchased from a supplier or manufactured according to the publication S. Olsen & al. Acta Chimica Scandinavica 6 (1952) pp 641-645.

Compound IVb is prepared according to patent EP 2639217.

The analytical method consists of an analysis by gas phase chromatography (GC) on an HP 5890 Series II device equipped with an FID detector. The column chromatography is an Innowax 30m, 0.25 mm, 0.25 μm column, the carrier gas being helium.

The oven follows the following temperature profile: T0=150°C, Initial time 10 min. Gradient 20 min; Final temperature: 200°C. Duration 7 mins.

The injector is at 250°C, the detector at 300°C.

The injected volume is 1 µl. The sample concentration is 4 mg/l in ethyl acetate (AcOEt).

Example outside the invention: synthesis of the pheromone mixture (3E,8Z,11Z)- tetradecatrien-1-yl acetate - (3E,8Z)-tetradecadien-1-yl acetate according to the conditions reported in patent application EP 2639217 A1

A. Synthesis of (3E,8Z,11Z)-tetradecatrien-1-yl methoxymethyl ether Magnesium (3.43 g, 141 mmol) and THF (59 mL, 52 g) are successively introduced into a reactor, then the medium is stirred at 62°C ± 2°C for 30 min. The (3Z,6Z)-nonadien-1-yl chloride (2.13 g, 134 mmol) is then added dropwise, ensuring that the temperature of the reaction medium is between 60°C and 65°C. The reaction medium is then stirred at 72° C. ± 2° C. for 2 hours in order to generate (3Z,6Z)-nonadien-1-yl-magnesium chloride.

In another reactor, copper (II) chloride (0.074 g, 0.548 mmol), triethylphosphite (0.79 mL, 4.62 mmol) and THF (92 mL, 82 g) are successively introduced. 5-acetoxy-(E3)-3-pentenylmethoxymethyl ether (22.91 g, 122 mmol) in solution in THF (92 mL, 82 g) is then added between 5°C and 10°C then the reaction medium is then stirred between 0°C and 5°C for 30 min. Next, the previously prepared solution of (3Z,6Z)-nonadien-1-yl-magnesium chloride is introduced drop by drop, ensuring that the temperature of the reaction medium is between 0 and 5°C. At the end of the introduction, the reaction medium is stirred between 5° C. and 10° C. for 40 min and then neutralized with ammonium chloride (1.46 g) then with a 20% w hydrochloric acid solution. /p (38g). The aqueous phase is discarded, the organic phase is concentrated under reduced pressure then the residue obtained is distilled under reduced pressure to give (3E,8Z,11Z)-tetradecatrien-1-yl methoxymethyl ether (24.2 g; yield = 78%) which contains 2.7% impurity resulting from the substitution in position 3.

B. Synthesis of (3E,8Z,11 Z)-tetradecatrien-1-yl acetate The (3E,8Z,11Z)-tetradecatrien-1-yl methoxymethyl ether (24.2 g, 95.8 mmol) and methanol (61.8 g) are placed in a reactor equipped with a distillation column and the reaction medium is stirred at 45°C ±2°C. A 20% w/w hydrochloric acid solution (35.8 g) is then added drop by drop over 1 hour, ensuring that the temperature is between 45°C and 50°C. At the end of the introduction, the reaction medium is then heated to 55° C. and stirred for 1 hour. The reaction by-products (dimethoxymethane, methanol) are then eliminated by distillation while placing themselves under a vacuum of 450 mmHg then the residue obtained is stirred for 9 hours. After stirring, the medium is cooled to 25° C. and extracted with hexane (60 g). The organic phase is washed with brine and then with an aqueous solution of sodium bicarbonate. The organic phase is then concentrated under reduced pressure and then the residue obtained is distilled under reduced pressure to give (3E,8Z,11Z)-tetradecatrien-1-ol (18 g; yield=90%).

The (3E,8Z,11Z)-tetradecatrien-1-ol obtained (18 g, 69.2 mmol), toluene (41.2 g), acetic anhydride (1.76 g, 17.2 mmol) and dimethylaminopyridine (0.176 g) are successively introduced into a reactor and then the mixture is heated to around 55°C. Acetic anhydride (7.07 g, 69.2 mmol) is once again introduced dropwise between 65° C. and 70° C. over 30 minutes then the reaction medium is stirred at 70° C. for 1 hour. The reaction medium is then cooled to 30° C. and then the reaction is quenched by adding water (27.5 g). The two phases obtained are decanted then the organic phase is washed with brine then with an aqueous solution of sodium bicarbonate. The organic phase is then concentrated under reduced pressure then the residue obtained is distilled under reduced pressure to give (3E,8Z,11Z)-tetradecatrien-1-yl acetate (17 g; yield = 98%) which contains 2.7% impurity resulting from the substitution in position 3.

C. Synthesis of (3E,8Z)-tetradecadien-1-yl methoxymethyl ether Magnesium (1.56 g, 64.0 mmol) and THF (6.7 mL, 6 g) are successively introduced into a reactor, then the medium is stirred at 62 °C ± 2°C for 30 min. The (3Z)-nonen-1-yl chloride (8.87 g, 55.2 mmol) is then added dropwise, ensuring that the temperature of the reaction medium is between 60°C and 65°C. The reaction medium is then stirred at 72° C. ± 2° C. for 2 hours in order to generate (3Z)-nonen-1-yl-magnesium chloride. In another reactor, copper chloride (II) (0.033 g, 0.248 mmol), triethylphosphite (0.36 ml_, 2.1 mmol) and THF (4 ml_, 3.7 g) are successively introduced. 5-acetoxy-(E3)-3-pentenylmethoxymethyl ether (10.40 g, 55.2 mmol) in solution in THF (4 mL, 3.7 g) is then added between 5°C and 10°C then the reaction medium is then stirred between 0°C and 5°C for 30 min. Then, the previously prepared solution of (3Z)-nonen-1-yl-magnesium chloride is introduced drop by drop, ensuring that the temperature of the reaction medium is between 0 and 5°C. At the end of the introduction, the reaction medium is stirred between 5°C and 10°C for 40 min then quenched with ammonium chloride (0.66 g) then with a 20% w/w hydrochloric acid solution (17g). The aqueous phase is discarded, the organic phase is concentrated under reduced pressure then the residue obtained is distilled under reduced pressure to give (3E,8Z)-tetradecadien-1-yl methoxymethyl ether (25 g; yield = 80%) which contains 2.5% impurity resulting from substitution at position 3.

D. Synthesis of (3E,8Z)-tetradecadien-1-yl acetate

The (3E,8Z)-tetradecadien-1-yl methoxymethyl ether (25 g, 98.3 mmol) and the methanol (63.4 g) are placed in a reactor equipped with a distillation column and the reaction medium is stirred at 45° C. ±2°C. A 20% w/w hydrochloric acid solution (36.7 g) is then added dropwise over 1 hour, ensuring that the temperature is between 45°C and 50°C. At the end of the introduction, the reaction medium is then heated to 55° C. and stirred for 1 hour. The reaction by-products (dimethoxymethane, methanol) are then eliminated by distillation while placing themselves under a vacuum of 450 mmHg then the residue obtained is stirred for 9 hours. After stirring, the medium is cooled to 25°C and extracted with hexane (62 g). The organic phase is washed with brine and then with an aqueous solution of sodium bicarbonate. The organic phase is then concentrated under reduced pressure and then the residue obtained is distilled under reduced pressure to give (3E,8Z)-tetradecadien-1-ol (17 g; yield=82%).

The (3E,8Z)-tetradecadien-1-ol obtained (16 g, 76 mmol), toluene (45 g), acetic anhydride (1.93 g, 18.9 mmol) and dimethylaminopyridine (0.193 g) are successively introduced into a reactor then the mixture is heated to around 55°C. Acetic anhydride (7.77 g, 76 mmol) is once again introduced drop by drop between 65° C. and 70° C. over 30 minutes then the reaction medium is stirred at 70°C for 1 hour. The reaction medium is then cooled to 30° C. then the reaction is quenched by adding water (30 g). The two phases obtained are decanted then the organic phase is washed with brine then with an aqueous solution of sodium bicarbonate. The organic phase is then concentrated under reduced pressure then the residue obtained is distilled under reduced pressure to give (3E,8Z)-tetradecadien-1-yl acetate (18 g; yield = 94%) which contains 2.5% of impurity resulting from substitution in position 3.

E. Preparation of the pheromone mixture (3E,8Z,11Z)-tetradecatrien-1-yl-acetate - (3E,8Z)-tetradecadien-1-yl acetate from pheromones previously synthesized according to the conditions reported in the patent application EP 2 639 217 A1

17.0 g of (3E,8Z,11Z)-tetradecadien-1-yl acetate obtained in example B and 2.32 g of (3E,8Z)-tetradecadien-1-yl acetate obtained in example D are mixed then the pheromone obtained is analyzed by GC.

GPC analysis: tr = 20.4 min ((3E,8Z)-tetradecadien-1-yl acetate, 9.5%), tr = 20.8min ((3E,8Z,11Z)-tetradecadien-1-yl acetate, 76.2%) i.e. at a total content of 85.7% of the pheromone mixture. Content of substitution impurities in position 3: 2.5%.

Example 1: Synthesis of (3£,8Z,11Z)-tetradecatrien-1-yl acetate

In a 50 mL three-necked flask, under an inert atmosphere and magnetic stirring, is introduced the tetrahydrofuran (9.5 mL) then the magnesium (0.47 g; 18.79 mmol). Dibromoethane (0.1 mL; 1.25 mmol) is added and the reaction medium is brought to a temperature of 65°C. After holding for 45 minutes at this same temperature, (3Z,6Z)-nonadien-1-yl chloride (2.84 g; 1.34 mmol) is added dropwise. The mixture thus obtained is stirred at reflux for 2 hours to generate (3Z,6Z)-nonadien-1-yl magnesium chloride.

In a second 50 mL three-necked flask, under inert atmosphere and magnetic stirring, a solution of copper (II) chloride (9.6 mg; 0.0715 mmol; 0.004 eq.) and triethylphosphite (101 mg; 0.0462 mol; 0.034 eq) in tetrahydrofuran (1.3 mL) is prepared and then cooled to 0°C. A solution of (2E)-pentene-1,5-diyl diacetate (2.8 g; 15.04 mmol) in tetrahydrofuran (1.3 mL) is then introduced.

After stirring for 30 minutes at 0° C., the previously prepared (3Z,6Z)-nonadien-1-yl magnesium chloride solution is added drop by drop to the mixture. previous. At the end of the introduction, the reaction medium is maintained for one hour at 0° C. then for 16 hours at ambient temperature.

The reaction medium is neutralized by adding a saturated aqueous solution of ammonium chloride (20 mL). The aqueous phase is then extracted with methyl tert-butyl ether (3 x 20 mL), dried over MgSC, filtered and concentrated under reduced pressure to yield a crude (m = 3.6 g) which is purified by gel chromatography column of silica (Eluent: Heptane/AcOEt: 90/10) to give (3£,8Z,11Z)-tetradecatrien-1-yl acetate (2.0 g; 53%).

GPC analysis: tr = 20.8 min Purity: 94% - content of substitution impurity in position 3: 0.93%.

¹ H NMR analysis (CDCI3): compliant.

No impurity corresponding to a substitution in position 5 of the diacetate of (2 £)-pentene-1,5-diyl is detected which highlights the advantage of the invention which avoids a protection step, another of deprotection then another one of acetylation which, even if they can have high yields, consume other raw materials (here methanol, dimethylaminopyridine, toluene, acetic acid and sodium chloride) generate significant quantities aqueous effluents and mobilize resources over longer periods of time.

Example 2: Synthesis of (3£,8Z)-tetradecadien-1-yl acetate

In a 50 mL three-necked flask, under an inert atmosphere and magnetic stirring, is introduced the tetrahydrofuran (9.5 mL) then the magnesium (0.45 g; 18.79 mmol). Dibromoethane (0.1 mL); 1.25 mmol) is added and the reaction medium is brought to a temperature of 65°C. After holding for 45 minutes at this same temperature, (3 Z)-1-chlorononene (2.84 g; 1.34 mmol) is added dropwise. The resulting mixture is stirred at reflux for 2 hours to generate (3Z)-nonen-1-yl magnesium chloride.

In a second 50 mL three-necked flask, under inert atmosphere and magnetic stirring, a solution of copper (II) chloride (9.6 mg; 0.0715 mmol; 0.004 eq.) and triethylphosphite (101 mg; 0.0462 mol; 0.034 mmol) in tetrahydrofuran (1.3 mL) is prepared and then cooled to 0°C. A solution of (2£)-pentene-1,5-diyl diacetate (2.8 g; 15.04 mmol) in tetrahydrofuran (1.5 mL) is then introduced. After 30 minutes of stirring at 0°C, the previously prepared Grignard solution is added drop by drop over 35 minutes. At the end of the introduction, the reaction medium is maintained for 1 hour at 0° C. then for 16 hours at room temperature.

The reaction medium is neutralized by adding a saturated aqueous solution of ammonium chloride (25 mL). The aqueous phase is then extracted with methyl tert-butyl ether (3 x 20 mL), dried over MgS04, filtered and concentrated under reduced pressure to yield a crude (m = 3.7 g) which is purified by chromatography on silica gel (Eluant: Heptane/AcOEt: 90/10) to give (3£,8Z)-tetradecadien-1-yl acetate (2.5 g; 69%).

GPC analysis: tr = 20.4 min Purity: 97.7% - content of substitution impurity in position 3: not detected.

¹ H NMR analysis (CDCI3): compliant.

No impurity corresponding to a substitution in position 5 of the diacetate of (2 £)-pentene-1,5-diyl is detected in this example which highlights the advantage of the invention which avoids a protection step, another for deprotection and then another for acetylation which, even if they can have high yields, consume other raw materials, generate large quantities of aqueous effluents and mobilize resources over longer periods of time.

Example 3: Preparation of the pheromone mixture from examples 1 and 2

0.95 g of the compound obtained in example 1 and 0.1 g of the compound obtained in example 2 are mixed in a flask under nitrogen.

GPC analysis: tr = 20.4 min ((3E,8Z)-tetradecadien-1-yl acetate, 8.1%), tr = 20.8 min ((3E,8Z,11Z)-tetradecadien-1-yl acetate, 86%). Content of substitution impurities in position 3: 0.85%.

If we compare these examples with example E outside the invention, we find that the content of substitution impurities in position 3 is much lower and that the purity of the pheromone mixture is 86%+8.1%=94.1% against only 85% in Example E excluding the invention.

Example 4: Synthesis of the pheromone mixture (3£,8Z,11Z)-tetradecatrien-1-yl- acetate - (3£,8Z)-tetradecadien-1-yl acetate

Into a 250 mL three-necked flask, under an inert atmosphere and magnetic stirring, is introduced the tetrahydrofuran (94 mL) then the magnesium (4.57 g; 188 mmol). Dibromoethane (1.1 mL; 12.5 mmol) is added then the reaction medium is brought to a temperature of 65°C. After maintaining 30 minutes at this same temperature, a mixture of (3Z,6Z)-nonadien-1-yl chloride (25.5 g; 160.7 mmol) and (3Z)-1-chlorononene (2.9 g; 18.0 mmol) is added drip. The solution thus obtained is stirred under reflux for 2 hours to generate the Grignard reagent. In a second 250 mL three-necked flask, under an inert atmosphere and magnetic stirring, a solution of copper (II) chloride (94 mg; 0.72 mmol; 0.004 eq.) and triethylphosphite (1.01 g; 6.08 mmol; 0.034 eq ) in tetrahydrofuran (13 mL) is prepared and then cooled to 0°C. A solution of (2E)-pentene-1,5-diyl diacetate (25.0 g; 134 mmol) in tetrahydrofuran (1.3 mL) is then introduced.

After 30 minutes of stirring at 0°C, the previously prepared Grignard solution is added drop by drop to the previous mixture over 90 minutes. At the end of the introduction, the reaction medium is maintained for one hour at 0° C. then for 16 hours at room temperature.

The reaction medium is neutralized by adding a saturated aqueous solution of ammonium chloride (150 mL). The aqueous phase is then extracted with methyl tert-butyl ether (2 x 100 mL), dried over MgS04, filtered and concentrated under reduced pressure to yield a crude (m = 38.2 g) which is purified by distillation under reduced pressure ( 1.1 mmHg; Bath temp = 150 to 160°C; Head temp = 110 to 120°C). Two fractions of the mixture (3E,8Z,11Z)-tetradecatrien-1-yl acetate / (3E,8Z)-tetradecadien-1-yl acetate were obtained and combined after NMR analysis.

GPC analysis: tr = 20.4 min (((3E,8Z)-tetradecadien-1-yl acetate, 10.8%) tr=20.8min ((3E,8Z,11Z)-tetradecadien-1-yl acetate 80.5%) i.e. in total a content of 91% of the pheromone mixture Content of substitution impurities in position 3: 1.12%.

Example 5: Synthesis of the pheromone mixture (3£,8Z,11Z)-tetradecatrien-1-yl acetate - (3E,8Z)-tetradecadien-1-yl acetate on a scale of 1 kg with stopping of the reaction with anhydride acetic

Into a 5L reactor, under an inert atmosphere and mechanical stirring, is introduced the tetrahydrofuran (3.36 kg) then the magnesium (150 g; 6.25 mol). Dibromoethane (41 g; 0.39 mol) is added then the reaction medium is brought to a temperature of 65°C. After maintaining 30 minutes at this same temperature, a mixture of (3Z,6Z)-nonadien-1-yl chloride (825 g; 5.2 mol) and (3Z)-1-chlorononene (116 g; 0.7 mol) is added slowly. The solution thus obtained is stirred at reflux for 2 hours to generate the Grignard reagent and then brought back to 10°C. In a second 20L reactor, under an inert atmosphere and mechanical stirring, a solution of copper (II) chloride (2.9g; 0.022mol; 0.004 eq.) and triethylphosphite (30.6 g; 0.184 mol; 0.034 eq) in tetrahydrofuran (0.409 kg) is prepared and then cooled to 0°C. A solution of (2E)-pentene-1,5-diyl diacetate (1 kg; 5.3 mol) in tetrahydrofuran (0.478 kg) is then introduced.

After 30 minutes of stirring at 0°C, the previously prepared Grignard solution is added to the previous mixture over 70 minutes. At the end of the introduction, the reaction medium is maintained for one hour at 0° C. then for 16 hours at room temperature. After verification by chromatography of the disappearance of the reagents, 82.2 g of acetic anhydride are added without exceeding 25°C.

The reaction medium is neutralized by adding an aqueous solution of ammonium chloride (3.8 kg at 16% by weight). The aqueous phase is then extracted with methyl tert-butyl ether (0.8 kg), dried over MgSC, filtered and concentrated under reduced pressure to yield a crude (m = 38.2 g) which is purified by distillation under reduced pressure (1. 1 mmHg; Bath temp = 150 to 160°C; Head temp = 110 to 120°C). Two fractions of the mixture (3E,8Z,11Z)-tetradecatrien-1-yl acetate / (3E,8Z)-tetradecadien-1-yl acetate were obtained and combined after NMR analysis (1,049 kg).

GPC analysis: tr=20.4 min (11.7%), tr=20.8min (81.96%) i.e. a total content of 93.5% of the pheromonal mixture. Content of substitution impurities in position 3: 1.58%.

This example illustrates the interest of the invention which makes it possible to directly synthesize the pheromonal mixture with the correct proportions of the two components by reacting the diacetate of (2E)-pentene-1,5-diyl directly on the mixture of the two magnesium precursors in the proportions of the final mixture. This avoids having to synthesize 2 compounds and then having to mix them. In industrial terms, this reduces the downtime of resources, which illustrates the industrial interest of the process according to the invention.

Example 6: Comparative trapping test with a pheromone according to the invention and outside the invention

Preparation of plastic diffusers:

0.1 g of pheromonal mixture obtained according to Example 3 (Solution S1) or according to Example E outside the invention (Solution S0) is diluted in 10 ml of pentane. 3 ml of solution S0 or S1 are placed in the flask of a 200 ml rotary evaporator in the presence of 15 septa of the Precision Seal® rubber septa 7 mm type, rotated at room temperature and atmospheric pressure for one hour at the speed of 120 rpm. 15 diffusers each loaded on average with 2 mg of pheromone mixture according to the invention or outside the invention are thus obtained.

Setting up a comparison test:

In a greenhouse of 1 ha, 10 pheromone traps of the red Delta type are placed, each equipped with a sticky plate. On 5 of them, a septum loaded with pheromone according to the invention is placed (population of traps P1) and on the 5 others, the same is done with the septa loaded with pheromone outside the invention (population of traps PO). The traps are checked every week, i.e. the Tuta absoluta butterflies trapped on the sticky plate are counted and the sticky plate is replaced with a new one. The septa are renewed after 4 weeks. In addition, in order to limit the effects of local insect concentration, the traps are rotated every week.

Results :

Table 1: number of moths trapped per family of 5 traps (cumulative) per week

A better capture of the butterflies is thus observed with the pheromone containing the least impurities resulting from the substitution in position 3, namely the pheromone synthesized according to the method according to the invention. This demonstrates the negative role of these impurities on the attractiveness of pheromonal mixtures used as bait.

Example 7: comparative tests in greenhouses for the treatment of tomatoes using the pheromone mixture (3E,8Z,11Z)-tetradecatrien-1-yl-acetate - (3E,8Z)-tetradecadien-1-yl acetate according to the invention and outside the invention

Principle: 3 treatment methods for tomatoes in greenhouses are studied in parallel: - Modality 1 (comparative): Normal chemical treatment by the farmer (depends on the country). - Modality 2 (comparative): Mating disruption treatment using isonet® T ³ dosed at 60 g of pheromonal mixture per ha. Analysis of the pheromone mixture indicates a pheromone content of 85% and an impurity level resulting from a substitution in position 3 of 2.4%, which corresponds to a pheromone mixture outside the invention.

- Modality 3 (invention): Treatment in sexual confusion with the pheromonal mixture of example 5, formulated by microencapsulation according to patent EP3258780A1 and dosed at 46.5 g/ha. The product containing the mixture of active ingredients is applied in the form of 1.1 g dots at the rate of 700 dots per ha.

The treatments according to the 3 methods were set up in a greenhouse on the same farm, all constituting a trial. These trials were repeated in different locations in Europe to obtain a statistical picture of the comparative performance of the 3 treatment modalities. Each trial was carried out over a period of 3 months and the trials took place between November 2019 and November 2020. The effectiveness of the mating disruption products of modalities 2 and 3 ultimately depends on the pheromonal bouquet perceived by the insects in the ambiant air. The effectiveness of this pheromone bouquet depends on the purity and impurity profile of the active ingredients used, as well as the dose emitted. All the tests were carried out over the same duration and it was found at the end of each test that the residual level of active ingredient in the diffusers was zero. The trials according to modality 3 therefore always emitted less pheromone per day than the trials according to modality 2 (46.5 g/ha v. 60 g/ha) and despite this, the superiority of the composition of pheromones according to the invention has demonstrated its superiority compared to market references outside the invention as illustrated by the results below, demonstrating the importance of a low impurity content resulting from a substitution in position 3.

Trials are tracked in 3 different ways:

A) Weekly trapping records: for each treatment modality, between 3 and 5 pheromone traps are randomly placed and the number of moths trapped is recorded each week. If mating confusion works, the level of trapping must be much lower in modalities 2 and 3 than in modality 1. Trapping has no protective function by mating confusion but only a function of measuring the intensity of the presence of Tuta absoluta in crops. B) Records at the end of the trial (3 months) of damage to stems and leaves: for each treatment method, the number of traces of Tuta absoluta in a space of 2 m of row and the average percentage of leaves or stems damaged by the insect is reported.

C) Readings at the end of the trial (3 months) of damaged fruits: for each method of treatment, the number of fruits damaged by the insect is evaluated on 50 fruits randomly sampled from 5 different places in the greenhouse.

The test results are then analyzed to assess whether these results are statistically equivalent. The tests are grouped by type of insect pressure. Number of tests carried out: 15 (Italy, France, Spain).

Surface of the greenhouses for the trials: between 0.5 ha and 1 ha per treatment modality (each trial presenting equivalent surfaces for each different treatment modality).

The results of the statistical analysis of the trials are presented below.

Cumulative trapping per trap over 3 months:

On 7 high pressure tests, the following results were obtained:

- Modality 1: average 1256 (max. >1800) moths trapped

- Modality 2: 248 (max. 568) butterflies trapped

- Modality 3: 266 (max. 521) butterflies trapped

These results indicate a strong reduction in trapping for modalities 2 and 3 and validate the principle that treatments according to modalities 2 and 3 reduce the pressure of the Tuta absoluta in an equivalent manner.

Over 8 tests at low or medium pressure:

- Modality 1: 153 (max. 280) butterflies trapped

- Modality 2: average 13.25 (max. 24) butterflies trapped

- Modality 3: 22.5 (max. 43) moths trapped

Similar to the results obtained for high insect pressure, treatments according to modalities 2 and 3 reduce the pressure of Tuta absoluta.

Percentage of damage on leaves and stems: average percentage max percentage

The results presented above show that the treatment according to modality 3 (invention) makes it possible to reduce the damage to the leaves and stems whether this is compared to an ordinary chemical treatment (modality 1) or by another treatment in sexual confusion (modality 2).

Percentage of fruit damage:

The treatment according to modality 3 reduces the damage of Tuta absoluta on the fruits compared to a conventional chemical treatment (Modality 1) or another treatment in mating disruption (Modality 3).

Conclusion :

This example illustrates that the pheromone mixture according to the invention makes it possible to have equivalent or even superior results for the protection of tomatoes in greenhouses compared to the other examples, whereas the dose used is significantly lower (46.5 g/ha against 60 g/ha, i.e. 23% less between modalities 2 and 3). The difference in purity (approximately +10% in favor of the pheromone mixture according to the invention) and the much lower level of impurities resulting from the substitutions in position 3 in the pheromone according to the invention (-45%) largely explain this difference in efficiency.

Claims

1 . Process for the synthesis of pheromone of general formula chosen from the group comprising compounds (I) and (G), alone or as a mixture: where R is a linear hydrocarbon chain of molecular formula C _n H2n-2 _{P+i ,}

R' is a linear hydrocarbon chain of molecular formula Cn'H2n -2p _+i with:

- n and n’, identical or different, are integers between 5 and 17 and

- Ac is an acetyl radical; comprising the reaction of (2E)-pentene-1,5-diyl diacetate of formula (II): with at least one Grignard reagent chosen from the group comprising compounds (III) and (II), alone or as a mixture:

R-MgX (III), R'-MgX (III')

R and R' are as defined previously for the compounds of formula (I) and

(I') where X is a chlorine or bromine atom; in the presence of a copper catalyst.

2. Method according to claim 1, characterized in that the copper-based catalyst further comprises at least one copper ligand selected from the group comprising a trialkylphosphine, a trialkylphosphite, an amine, and mixtures thereof.

3. Method according to claim 2, characterized in that the ligand is a trialkylphosphite chosen from the group comprising triethylphosphite, trimethylphosphite and mixtures thereof.

4. Method according to one of the preceding claims, characterized in that the reaction is carried out in an aprotic solvent, in particular of the ether type, in particular chosen from the group comprising diethyl ether, methyl tert-butyl ether, tetrahydrofuran, methyltetrahydrofuran, tetrahydropyran, methyltetrahydropyran, dioxane, glycol dimethyl ether, and mixtures thereof.

5. Method according to one of the preceding claims, characterized in that the copper-based catalyst is a copper II salt, and advantageously chosen from the group comprising copper II halides and copper II carboxylates.

6. Method according to claim 5, characterized in that the copper halide is chosen from CuC and CuBr2; the copper carboxylate is chosen from copper acetate Cu(OAc)2 and copper II acetyl acetonate Cu(Acac)2

7. Method according to one of the preceding claims, comprising the following steps: a. preparation in an aprotic solvent of a solution comprising 1 equivalent of (2E)-pentene-1,5-diyl diacetate of formula (II): b. addition to the preparation obtained following step a) of the catalyst based on copper in an amount of 0.001 to 0.02 equivalent of copper, the copper possibly being bound optionally to a ligand chosen from the group comprising a trialkylphosphine, a trialkylphosphite, an amine, and mixtures thereof; vs. preparation in an aprotic solvent identical to or different from the solvent of step a) of a solution comprising between 0.95 and 1.25 equivalents of a Grignard reagent chosen from the group comprising compounds (III) and (IIG) , alone or as a mixture; d. adding the solution obtained in step c) to the solution prepared in step b) with stirring and at a reaction temperature below 25° C.; e. stopping the reaction, in particular by adding 0.1 to 1.5 equivalents of acetic anhydride to the reaction medium obtained following step d); f. neutralization of the reaction medium obtained following step e) and extraction of the pheromone of formula (I) or ( ) or of the mixture of pheromones of formulas (I) and ( ).

8. Method according to one of the preceding claims, characterized in that the compound (III): compound (IIG) molar ratio is between 0:1 and 1:0.

9. Composition comprising a pheromone of general formula chosen from the group comprising compounds (I) and (G), alone or as a mixture: Where :

R is a linear hydrocarbon chain with the molecular formula CnH2n-2 _P +i ,

Ac is an acetyl radical, and containing less than 2%, by weight % of the composition, preferably less than 1.6%, of a compound chosen from the group comprising compounds (VI) and (VI'), alone or in combination:

10. Use of a composition according to claim 9 for the protection of crops against the Tuta absoluta pest.

11. Method for protecting an agricultural plot against the pest Tuta absoluta comprising the application within said plot of a composition according to claim 9.