New method for manufacturing a component of the tomato leafminer sex pheromone

Abstract

The present invention relates to a process for the synthesis of pheromones, the general formula of which is chosen from the compounds (I) and (I') alone or in mixture: said process comprising the reaction of (2E)-penten-1,5-diyl diacetate with at least one Grignard reagent in the presence of a copper-based catalyst. The process according to the invention is particularly suitable for the selective synthesis of the tomato leafminer (Tuta absoluta) pheromone, which comprises: acetic acid (3E,8Z,11Z)-tetradecatrien-1-yl ester and acetic acid (3E,8Z)-tetradecadien-1-yl ester.

Description

Background Technology

[0001] For public health and soil agriculture potential management reasons, crop treatment technologies for pests are evolving towards more targeted and environmentally friendly action models. Therefore, using sex pheromones to alter insect behavior is advantageous because these pheromones are specific to each pest and effective at very low doses for a variety of strategies, such as trapping and mating disruption.

[0002] However, the limiting factor for the development of these technologies is the cost of obtaining active molecules. In fact, these molecules often have many possible isomers, and selective synthesis techniques are usually expensive.

[0003] The tomato leafminer (Tomato leafminer moth), a tomato pest found on every continent, is a prime example of the problems encountered by those skilled in the art when developing pheromone-based control schemes. In fact, the main components of the tomato leafminer pheromone are:

[0004] Table 1: Main components of tomato leafminer pheromones

[0005]

[0006] These molecular structures have numerous positional and configurational isomers. For trienes, there may be no fewer than eight configurations, but only the 3E, 8Z, and 11Z configurations are active on insect olfactory receptors. Some isomers may even exhibit antagonistic effects. Therefore, not only is there a need to produce these compounds more economically, but also to achieve the highest possible purity. These two requirements are often contradictory, and those skilled in the art rarely succeed in reconciling them.

[0007] The first known synthesis of a tomato leafminer pheromone component was reported in publications such as *ABAttygalle & al. Tetrahedron Letters*, Vol. 36, No. 31, pp. 5471-5474, 1995, and *ABAttygalle & al. Bioorganic & Medicinal Chemistry*, Vol. 4, No. 3, pp. 305-314, 1996. This work describes an interesting synthetic route because it addresses the issue of synthetic selectivity by reducing the triple bond to a double bond (Z or E). The reactions that construct the 14-carbon structure include the reaction of lithium acetylation with the intermediate IVa:

[0008]

[0009] This requires very diluted conditions, resulting in high fixed costs. The total yield is 7%, which also implies high variable costs. Furthermore, the lithiated derivatives must be protected by a tetrahydropyran group, which requires additional deprotection and acetylation steps.

[0010] On the other hand, the teachings of EP 2639217 include a synthetic route similar to the former, but differ due to the following compounds:

[0011] It is first converted into a Grignard reagent, and then coupled with compound V in the presence of a catalyst composed of CuCl2 and triethyl phosphite:

[0012]

[0013] The coupling product is then converted to ethanol and acetylated to produce the desired compound. Therefore, the principle in this patent lies in coupling a chain with 9 carbon atoms and 2 degrees of unsaturation (Z) with a synthon having 5 carbon atoms and a degree of unsaturation (E). The inventors of EP 2639217 were interested in compound V by protecting one end of the chain with a methoxymethyl ether functional group to avoid side reactions during reaction with Grignard compounds.

[0014] However, after coupling, there are still two steps to obtain the target molecule, which greatly reduces the overall yield.

[0015] Therefore, there is still a need to develop a selective method for obtaining isomer-pure pheromones that involves a limited number of reactions and allows for good yields. Summary of the Invention

[0016] Surprisingly, the applicant discovered that magnesium coupling of compound II could be produced in the presence of a catalyst.

[0017]

[0018] The acetate functional group at position 1 (allyl position) is substituted, while the acetate functional group at position 5 (highly allyl position) is unreactive, thus exhibiting perfect selectivity. Indeed, Hu et al., Molecules (2012), Vol. 17, pp. 12140-12150, have described the coupling between an organomagnesium derivative and a highly allyl acetate derivative (i.e., (3Z-octen-1-yl acetate)) catalyzed by a copper(II) complex, yielding the corresponding coupling product in 87% yield and 97% purity. Therefore, the substitution reaction forming the subject matter of this patent is specific to position 1 (allyl position), which is not obvious to those skilled in the art. The inventors have also observed that, according to the method of the invention, the level of the product substituted at position 3 is much lower than according to the methods known above. Since the structure of the target pheromone requires an acetate functional group at position 5, it is completely unaffected by the reaction under the conditions of this invention. This is an advantage of this invention because it avoids protection, deprotection, and acetylation reactions, which, even with good yields, require a lot of working time and generate a lot of wastewater, which is harmful from the perspective of sustainable industrial development.

[0019] Another advantage noted by the inventors is that when the two magnesium oxides, R-MgX and R'-MgX, are used simultaneously in a certain proportion, their reaction products with compound II are also in the same proportion as themselves. This allows for the preparation of pheromone mixtures without having to prepare each component of the mixture separately.

[0020] Therefore, the present invention relates to a method for synthesizing pheromones, wherein the general formula of the pheromones is selected from compounds (I) and (I'), alone or in mixtures:

[0021]

[0022] Where R is a molecular formula C n H 2n-2p+1 Straight-chain hydrocarbon chains,

[0023] R' is a molecular formula C n’ H 2n’-2p’+1 Straight-chain hydrocarbon chains,

[0024] in:

[0025] -n and n', whether the two integers are the same or different, are integers between 5 and 17.

[0026] -p and p' correspond to the degree of unsaturation in the hydrocarbon chain, and can be the same or different, and are integers between 1 and 3.

[0027] Ac is an acetyl group.

[0028] The method comprises reacting the diacetic acid (2E)-penten-1,5-dimethyl ester of formula (II) with at least one Grignard reagent in the presence of a copper-based catalyst:

[0029]

[0030] The Grignard reagent is selected from compounds (III) and (III'), alone or in mixtures:

[0031] R-MgX(III), R'-MgX(III')

[0032] Where X is a chlorine atom or a bromine atom;

[0033] R and R' are as previously defined for compounds of formulas (I) and (I').

[0034] Advantageously, n and n', whether the same or different, are between 7 and 15, and especially between 9 and 13.

[0035] Furthermore, p and p', whether the same or different, are integers between 1 and 3, or more favorablely between 1 and 2.

[0036] As noted, p and p' represent the total number of unsaturations in chain R or chain R'. It can be understood that one double bond counts as one degree of unsaturation, and one triple bond counts as two degrees of unsaturation. Therefore, chain R or R' can include one or more double bonds, but also includes triple bonds associated with those double bonds.

[0037] In one embodiment, the method is characterized in that the copper-based catalyst further comprises (i.e. supplemented with) at least one copper ligand selected from trialkylphosphine, trialkyl phosphite, amine, and mixtures thereof.

[0038] The term "alkyl" in the description of trialkyl phosphite or trialkylphosphine corresponds to C1-C6 alkyl, particularly methyl, ethyl, or propyl.

[0039] In one embodiment, the method is characterized in that the ligand is a trialkyl phosphite selected from triethyl phosphite, trimethyl phosphite, and mixtures thereof.

[0040] In one embodiment, the method is characterized in that the reaction is carried out in an aprotic solvent, particularly a straight-chain or cyclic ether solvent, especially selected from diethyl ether, methyl tert-butyl ether, tetrahydrofuran, methyl tetrahydrofuran, tetrahydropyran, methyl tetrahydropyran, dioxane and ethylene glycol dimethyl ether and mixtures thereof.

[0041] In one embodiment, the method is characterized in that the copper-based catalyst is a copper II salt.

[0042] More specifically, the copper II-based catalyst can be selected from copper II halide and copper II carboxylate.

[0043] In one embodiment, the method is characterized in that copper halide II is selected from CuCl2 and CuBr2; copper carboxylate II is advantageously selected from copper acetate Cu(OAc)2 and copper acetylacetonate II, Cu(Acac)2.

[0044] In this specification, unless otherwise stated, when referring to equivalents, it means molar equivalents relative to 1 molar equivalent of compound (II).

[0045] The present invention also relates to a method comprising the following steps:

[0046] a. Prepare a solution containing 1 equivalent of diacetic acid (2E)-pentene-1,5-dimethyl ester of formula (II) in an aprotic solvent;

[0047] b. In the formulation obtained in step a), a copper II-based catalyst is added in a ratio of 0.001 to 0.02 equivalents of copper, wherein the copper is optionally capable of binding with a ligand selected from trialkylphosphine, trialkyl phosphite, amine, and mixtures thereof;

[0048] c. Prepare a solution containing between 0.95 and 1.25 equivalents of a Grignard reagent in an aprotic solvent that is the same as or different from the solvent used in step a), the Grignard reagent being selected from compounds (III) and (III'), alone or in mixtures.

[0049] d. Add the solution obtained in step c) to the solution prepared in step b) under stirring and at a reaction temperature below 25°C;

[0050] e. Stop the reaction, specifically by adding 0.1 to 1 equivalent of acetic anhydride to the reaction medium obtained after step d).

[0051] f. Neutralize the reaction medium obtained after step e) and extract the pheromone of formula (I) or (I') or a mixture of pheromones of formula (I) and (I').

[0052] According to one embodiment, the method according to the invention is characterized in that the molar ratio of compound (III):compound (III') is between 0:1 and 1:0.

[0053] Advantageously, the molar ratio of compound (III):compound (III') is between 0.01:0.99 and 0.99:0.01, particularly between 0.05:0.95 and 0.95:0.05, 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 still around 0.5:0.5.

[0054] Advantageously, step a) is carried out under an inert atmosphere, such as nitrogen or argon. Step a) is preferably carried out at a temperature between -20°C and +60°C, particularly between -10°C and +10°C.

[0055] 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.

[0056] The amount of Grignard reagent (compound III or compound III' or compound III+III') can advantageously be between 1 and 1.2 equivalents, or even between 1 and 1.15 equivalents.

[0057] Step c) is also advantageously carried out in an inert atmosphere, such as nitrogen or argon, preferably at a temperature between -15°C and 50°C. More preferably, step c) is advantageously carried out in an inert atmosphere, such as nitrogen or argon, at a temperature between -10°C and 10°C.

[0058] Step d) is carried out with stirring, advantageously at a reaction temperature below 25°C, preferably below 15°C, and even more preferably between 8°C and 12°C. At the end of the addition, the temperature of the medium can be advantageously lowered to 0°C, and stirring is maintained until one of the reagents disappears. The disappearance of one of the reagents can be tracked by GC (gas chromatography) and / or TLC (thin-layer chromatography).

[0059] In particular, step e) of stopping the reaction by adding 0.1 to 1.5 equivalents of acetic anhydride is advantageously carried out at a temperature kept below 30°C, preferably at a temperature kept below or equal to 25°C. In fact, the addition of acetic anhydride is exothermic, therefore it is preferable to keep the temperature below 30°C.

[0060] Neutralization step f) is advantageously carried out using an ammonium chloride solution, the concentration and amount of which are suitable for adjusting the pH to a value of approximately 7 to 8 without over-diluting the medium. The ammonium chloride solution may be a solution with a concentration of 10 to 20% w / w, or even about 16% w / w. The pH is advantageously adjusted to a value between 7 and 8, particularly between 6.5 and 8.

[0061] The present invention also relates to a composition comprising pheromones, said pheromones having a general formula selected from compounds (I) and (I'), alone or in mixtures:

[0062]

[0063] in:

[0064] R is a molecular formula C n H 2n-2p+1 Straight-chain hydrocarbon chains,

[0065] R' is a molecular formula C n’ H 2n’-2p’+1 Straight-chain hydrocarbon chains,

[0066] in:

[0067] n and n', whether the same or different, are integers between 5 and 17;

[0068] p and p' correspond to the number of unsaturations in the hydrocarbon chain, and can be the same or different, and are integers between 1 and 3.

[0069] Ac is an acetyl group.

[0070] The composition contains less than 2%, preferably less than 1.9%, of a compound selected from compounds (VI) and (VI'), alone or in mixtures, based on a weight percentage of the composition:

[0071]

[0072] Advantageously, the amount of the compound selected from compounds (VI) and (VI') (in the form of alone or in mixtures) is less than 1.8%, or even less than 1.7%, less than 1.6%, or less than 1.5% by weight of the composition.

[0073] Specifically, R and R' are selected from the groups (3Z,6Z)-nonadien-1-yl and (3Z)-nonene-1-yl.

[0074] In particular, the method is applicable to the selective synthesis of pheromones from the tomato leafminer moth, the pheromones comprising: (3E,8Z,11Z)-tetradecanetrien-1-yl acetate on one side and (3E,8Z)-tetradecanedien-1-yl acetate on the other side, either alone or in mixtures.

[0075] Therefore, the advantage of the method according to the invention lies in the selectivity of the reaction relative to the substitution at position 3. Indeed, in the presence of a copper II-based catalyst (particularly a copper II salt), the coupling reaction between compound (II) and one or more Grignard reagents (III or III' or a mixture of III / III') can promote the product (I) and / or (I') corresponding to the allyl substitution at position 1:

[0076]

[0077] Simultaneously restrict the products (VI) and (VI') corresponding to the allyl substitution at position 3:

[0078]

[0079] Products (VI) and / or (VI') represent particularly harmful impurities because they do not belong to the pheromone family with fatty chains in Lepidoptera, which raises concerns about toxicity and ecotoxicity.

[0080] Reducing these impurities obviously has economic advantages, but more importantly, it allows for the production of more effective pheromones because impurities can have an anti-synergistic effect with pheromones. Even small amounts of impurities can repel insects, as reported in the publication Kawazu & al. Journal of Chemical Ecology (2007), Vol. 33, pp. 1978-1985.

[0081] The inventors have discovered that, according to the method of the present invention, the proportion of the substituted product at position 3 is much lower than that according to the methods known above, which helps to improve the insect-resistant effect of the product.

[0082] The method according to the invention is particularly advantageous because the allyl-substituted products (VI) and / or (VI') corresponding to position 3 are particularly difficult to separate from the allyl-substituted products corresponding to position 1 by methods known to those skilled in the art, due to their very close boiling points. Therefore, the content of one or more substituted products at position 3 must be minimized before initiating the purification step. This is what the method according to the invention allows.

[0083] Another advantage of this method compared to the method taught in document EP 2639217 is that the desired molecule can be obtained using compound (II) without the subsequent protecting, deprotecting, and acetylation reactions taught in EP 2639217. This results in a real improvement in the number of reactions involved, thereby increasing the yield; making it a more economically advantageous method.

[0084] The method according to the present invention is detailed below.

[0085] - Starting from the first step, in which, on the one hand, particularly in 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°C and 10°C, a solution of 1 equivalent of diacetic acid (2E)-pentene-1,5-dimethyl ester II is prepared in an aprotic solvent, particularly an ether solvent, more particularly diethyl ether, methyl tert-butyl ether, tetrahydrofuran, methyltetrahydrofuran, tetrahydropyran, methyltetrahydropyran, dioxane or ethylene glycol dimethyl ether:

[0086]

[0087] The copper II-based catalyst is then introduced into the mixture, optionally in the presence of a ligand, characterized in that the copper II-based catalyst comprises a copper II salt, such as copper II halide (e.g., CuCl2, CuBr2) or copper carboxylate (e.g., copper acetate Cu(OAc)2 or copper acetylacetonate II, Cu(Acac)2), in amounts between 0.001 and 0.02 equivalents.

[0088] - In the second step, it is always advantageous to prepare a solution, under an inert atmosphere of nitrogen or argon, in an ether-based aprotic solvent, particularly diethyl ether, methyl tert-butyl ether, tetrahydrofuran, methyltetrahydrofuran, tetrahydropyran, methyltetrahydropyran, dioxane, or ethylene glycol dimethyl ether, which may be the same as or different from the solvent selected in the first step, containing 0.95 to 1.25 equivalents of a Grignard reagent selected from compounds (III) and (III'), alone or in mixtures:

[0089] R-MgX(III), R'-MgX(III'),

[0090] Where X is a chlorine atom or a bromine atom.

[0091] R is a molecular formula C n H 2n-2p+1 Straight-chain hydrocarbon chains,

[0092] R' is a molecular formula C n’ H 2n’-2’p+1 Straight-chain hydrocarbon chains,

[0093] in:

[0094] n and n', whether the two integers are the same or different, are integers between 5 and 17.

[0095] p and p' correspond to the degree of unsaturation in the hydrocarbon chain, and are either the same or different, and are integers between 1 and 3:

[0096] Ac is an acetyl group.

[0097] Preferably, the amount of Grignard reagent (compound III or a mixture of compound III' or compound III+III') is between 1.05 and 1.15 equivalents. The solution is brought to a temperature between -15°C and 50°C, preferably between -10°C and 10°C.

[0098] - In the third step, the solution obtained in the second step is added to the solution prepared in step 1 while maintaining vigorous stirring. The reaction temperature is below 25°C, preferably below 15°C, and even more preferably between 8°C and 12°C. At the end of the addition, the temperature of the medium is lowered to 0°C while stirring is maintained until one of the reagents disappears.

[0099] - In the fourth step, the reaction is stopped by adding 0.1 to 1.5 equivalents of acetic anhydride while maintaining a temperature below 30°C, preferably below or equal to 25°C.

[0100] - In the fifth step, the medium is neutralized with an ammonium chloride solution, preferably taking care not to lower the pH below 7, or even below 6.5. The product is then extracted multiple times using an organic solvent selected by those skilled in the art. The organic phase is then dried, concentrated, and distilled to separate the final product, which has the general formula selected from compounds (I) and (I'), alone or in mixtures:

[0101]

[0102] Therefore, the applicant further discovered that, as the reagent prepared in step 2, a Grignard reagent comprising a single product (such as product (III) or product (III')) or a mixture of products (III+III') in a selected proportion can be used. Thus, the final product is product (I) or product (I'), or a mixture of two products in proportions equivalent to their Grignard reactive precursor products:

[0103]

[0104] Therefore, if only product (III) is used, only product (I) will be obtained; if only product (III') is used, only product (I') will be obtained; and if a mixture (III+III') is used in a given molar ratio of III:III', a mixture of products (I+I') will be obtained in an equivalent molar ratio of I:I'. This discovery simplifies the synthetic route for pheromone mixtures, particularly at the industrial level, because it eliminates the need to mobilize reactivity for one component, then for the second component, and finally for the mixture: the desired proportions of the mixture are obtained directly at the end of the synthesis.

[0105] Another object of the present invention is to obtain a composition comprising the product of the following formula,

[0106]

[0107] Its characteristic is that the content of the following impurities is...

[0108]

[0109] Not exceeding 2% (by weight), preferably less than 1.9%, or even less than or equal to 1.6%, especially when compound R is a (3Z,6Z)-nonadien-1-yl or (3Z)-nonene-1-yl group.

[0110] Finally, this invention relates to the use of compositions according to the invention for protecting crops from the tomato leafminer pest, said compositions comprising pheromones of the general formula selected from compounds (I) and (I'), alone or in mixtures, as further explained.

[0111] Finally, the present invention also relates to a method for protecting farmland from tomato leafminer pests, the method comprising applying a composition according to the invention to the farmland, the composition comprising a pheromone selected from compounds (I) and (I') as described above, alone or in mixtures. Detailed Implementation

[0112] Example:

[0113] Raw materials and solvents are commercially available from Sigma Aldrich.

[0114] Compound II was purchased from the supplier or manufactured according to publication S. Olsen & al. Acta Chimica Scandinavica 6 (1952), pp. 641-645.

[0115] Compound IVb was prepared according to patent EP 2639217.

[0116] The analytical method involved gas chromatography (GC) analysis performed on an HP 5890 Series II instrument equipped with an FID detector. The chromatographic columns were Innowax 30m, 0.25mm, and 0.25μm columns, and the carrier gas was helium.

[0117] The oven follows the following temperature profile: T0 = 150℃, initial time 10 minutes, gradient 20° / min; final temperature: 200℃, duration 7 minutes.

[0118] The syringe was heated to 250°C, and the detector to 300°C.

[0119] The injection volume was 1 μl. The concentration of the sample in ethyl acetate (AcOEt) was 4 mg / L.

[0120] Examples not conforming to the present invention: A conditional synthesis of the pheromone mixture acetic acid (3E,8Z,11Z)-tetradecanetriene-1-yl ester-acetic acid (3E,8Z)-tetradecanediene-1-yl ester reported in patent application EP 2 639 217 A1.

[0121] Synthesis of (3E,8Z,11Z)-tetradecanetrien-1-ylmethoxymethyl ether

[0122] Magnesium (3.43 g, 141 mmol) and THF (59 mL, 52 g) were successively introduced into the reactor, and the medium was stirred at 62 °C ± 2 °C for 30 minutes. Then, (3Z,6Z)-nonadien-1-yl chloride (2.1 g, 134 mmol) was added dropwise, ensuring the temperature of the reaction medium was between 60 °C and 65 °C. The reaction medium was then stirred at 72 °C ± 2 °C for 2 hours to generate (3Z,6Z)-nonadien-1-yl magnesium chloride.

[0123] In another reactor, copper(II) chloride (0.074 g, 0.548 mmol), triethyl phosphite (0.79 mL, 4.62 mmol), and THF (92 mL, 82 g) were introduced sequentially. Then, a solution of 5-acetoxy-(E3)-3-pentenylmethoxymethyl ether (22.91 g, 122 mmol) in THF (92 mL, 82 g) was added between 5°C and 10°C, and the reaction medium was stirred between 0°C and 5°C for 30 minutes. Next, a previously prepared (3Z,6Z)-nonadien-1-yl-magnesium chloride solution was introduced dropwise, ensuring the temperature of the reaction medium remained between 0°C and 5°C. After the introduction was complete, the reaction medium was stirred between 5°C and 10°C for 40 minutes, then neutralized with ammonium chloride (1.46 g), followed by neutralization with 20% w / w hydrochloric acid solution (38 g). The aqueous phase was discarded, the organic phase was concentrated under reduced pressure, and the resulting residue was then distilled under reduced pressure to give (3E,8Z,11Z)-tetradecanetrien-1-ylmethoxymethyl ether (24.2 g; yield = 78%), which contained 2.7% impurities resulting from substitution at position 3.

[0124] B. Synthesis of (3E,8Z,11Z)-tetradecanetrien-1-yl ester of acetate

[0125] (3E,8Z,11Z)-tetradecanetrien-1-ylmethoxymethyl ether (24.2 g, 95.8 mmol) and methanol (61.8 g) were placed in a reactor equipped with a distillation column, and the reaction medium was stirred at 45 °C ± 2 °C. Then, a 20% w / w hydrochloric acid solution (35.8 g) was added dropwise over 1 hour, ensuring the temperature remained between 45 °C and 50 °C. After the addition was complete, the reaction medium was heated to 55 °C and stirred for 1 hour. The mixture was then placed under a vacuum of 450 mmHg mercury, and the reaction byproducts (dimethoxymethane, methanol) were eliminated by distillation. The resulting residue was then stirred for 9 hours. After stirring, the medium was cooled to 25 °C and extracted with hexane (60 g). The organic phase was washed with brine and then with an aqueous sodium bicarbonate solution. The organic phase was then concentrated under reduced pressure, and the resulting residue was distilled under reduced pressure to give (3E,8Z,11Z)-tetradecanetrien-1-ol (18 g; yield = 90%).

[0126] The obtained (3E,8Z,11Z)-tetradecanetrien-1-ol (18 g, 69.2 mmol), toluene (41.2 g), acetic anhydride (1.76 g, 17.2 mmol), and dimethylaminopyridine (0.176 g) were successively introduced into the reactor, and the mixture was then heated to approximately 55 °C. Acetic anhydride (7.07 g, 69.2 mmol) was again introduced dropwise between 65 °C and 70 °C over 30 minutes, and the reaction medium was then stirred at 70 °C for 1 hour. The reaction medium was then cooled to 30 °C, and the reaction was quenched by adding water (27.5 g). The resulting two phases were decanted, and the organic phase was washed with brine and then with an aqueous sodium bicarbonate solution. The organic phase was then concentrated under reduced pressure, and the resulting residue was distilled under reduced pressure to give (3E,8Z,11Z)-tetradecanetrien-1-yl ester of acetate (17 g; yield = 98%), which contained 2.7% impurities resulting from substitution at position 3.

[0127] Synthesis of C.(3E,8Z)-tetradecadien-1-ylmethoxymethyl ether

[0128] Magnesium (1.56 g, 64.0 mmol) and THF (6.7 mL, 6 g) were successively introduced into the reactor, and the medium was stirred at 62 °C ± 2 °C for 30 minutes. Then, (3Z)-nonen-1-yl chloride (8.87 g, 55.2 mmol) was added dropwise, ensuring the temperature of the reaction medium was between 60 °C and 65 °C. The reaction medium was then stirred at 72 °C ± 2 °C for 2 hours to generate (3Z)-nonen-1-yl magnesium chloride.

[0129] In another reactor, copper(II) chloride (0.033 g, 0.248 mmol), triethyl phosphite (0.36 mL, 2.1 mmol), and THF (4 mL, 3.7 g) were introduced sequentially. A solution of 5-acetoxy-(E3)-3-pentenylmethoxymethyl ether (10.40 g, 55.2 mmol) in THF (4 mL, 3.7 g) was then added between 5°C and 10°C, and the reaction medium was subsequently stirred between 0°C and 5°C for 30 minutes. Subsequently, a previously prepared (3Z)-nonen-1-yl-magnesium chloride solution was introduced dropwise, ensuring the temperature of the reaction medium remained between 0°C and 5°C. After the introduction was complete, the reaction medium was stirred between 5°C and 10°C for 40 minutes, and then quenched with ammonium chloride (0.66 g) followed by 20% w / w hydrochloric acid solution (17 g). The aqueous phase was discarded, the organic phase was concentrated under reduced pressure, and the resulting residue was then distilled under reduced pressure to give (3E,8Z)-tetradecadien-1-ylmethoxymethyl ether (25 g; yield = 80%), which contained 2.5% impurities resulting from substitution at position 3.

[0130] D. Synthesis of (3E,8Z)-tetradecadien-1-yl ester of acetate

[0131] (3E,8Z)-tetradecadien-1-ylmethoxymethyl ether (25 g, 98.3 mmol) and methanol (63.4 g) were placed in a reactor equipped with a distillation column, and the reaction medium was stirred at 45 °C ± 2 °C. Then, a 20% w / w hydrochloric acid solution (36.7 g) was added dropwise over 1 hour, ensuring the temperature remained between 45 °C and 50 °C. After the introduction was complete, the reaction medium was heated to 55 °C and stirred for 1 hour. The mixture was then placed under a vacuum of 450 mmHg mercury, and the reaction byproducts (dimethoxymethane, methanol) were eliminated by distillation. The resulting residue was then stirred for 9 hours. After stirring, the medium was cooled to 25 °C and extracted with hexane (62 g). The organic phase was washed with brine, followed by an aqueous sodium bicarbonate solution. The organic phase was then concentrated under reduced pressure, and the resulting residue was distilled under reduced pressure to give (3E,8Z)-tetradecadien-1-ol (17 g; yield = 82%).

[0132] The obtained (3E,8Z)-tetradecadien-1-ol (16 g, 76 mmol), toluene (45 g), acetic anhydride (1.93 g, 18.9 mmol), and dimethylaminopyridine (0.193 g) were successively introduced into the reactor, and the mixture was then heated to approximately 55 °C. Acetic anhydride (7.77 g, 76 mmol) was again introduced dropwise between 65 °C and 70 °C for 30 minutes, and the reaction medium was then stirred at 70 °C for 1 hour. The reaction medium was then cooled to 30 °C, and the reaction was quenched by adding water (30 g). The obtained two phases were decanted, and the organic phase was washed with brine and then with an aqueous sodium bicarbonate solution. The organic phase was then concentrated under reduced pressure, and the resulting residue was distilled under reduced pressure to give (3E,8Z)-tetradecadien-1-yl acetate (18 g; yield = 94%) containing 2.5% impurities resulting from position 3 substitution.

[0133] E. Preparation of a pheromone mixture from pheromones synthesized under the conditions previously reported in patent application EP 2 639 217 A1: Acetate (3E,8Z,11Z)-tetradecanetriene-1-yl ester-acetate (3E,8Z)-tetradecanediene-1-yl ester

[0134] 17.0 g of (3E,8Z,11Z)-tetradecanetrien-1-yl acetate obtained in Example B and 2.32 g of (3E,8Z)-tetradecanedien-1-yl acetate obtained in Example D were mixed, and the pheromones obtained were analyzed by CPG.

[0135] GC analysis: tr = 20.4 min (acetic acid (3E,8Z)-tetradecadien-1-yl ester, 9.5%), tr = 20.8 min (acetic acid (3E,8Z,11Z)-tetradecadien-1-yl ester, 76.2%), indicating a total pheromone mixture content of 85.7%. Content of position 3 substituted impurities: 2.5%.

[0136] Example 1: Synthesis of (3E,8Z,11Z)-tetradecanetrien-1-yl ester of acetate

[0137] Tetrahydrofuran (9.5 mL) followed by magnesium (0.47 g; 18.79 mmol) was introduced into a 50 mL three-necked flask under an inert atmosphere and with magnetic stirring. Dibromoethane (0.1 mL; 1.25 mmol) was added, and the reaction medium was brought to 65 °C. After maintaining this temperature for 45 minutes, (3Z,6Z)-nonadien-1-yl chloride (2.84 g; 1.34 mmol) was added dropwise. The resulting mixture was stirred under reflux for 2 hours to produce (3Z,6Z)-nonadien-1-yl magnesium chloride.

[0138] In a second 50 mL three-necked flask, a solution of copper(II) chloride (9.6 mg; 0.0715 mmol; 0.004 equivalents) and triethyl phosphite (101 mg; 0.0462 mol; 0.034 equivalents) in tetrahydrofuran (1.3 mL) was prepared under an inert atmosphere and with magnetic stirring, and then cooled to 0 °C. A solution of diacetic acid (2E)-penten-1,5-diyl diacetate (2.8 g; 15.04 mmol) in tetrahydrofuran (1.3 mL) was then introduced.

[0139] After stirring at 0°C for 30 minutes, the previously prepared (3Z,6Z)-nonadien-1-yl magnesium chloride solution was added dropwise to the above mixture. At the end of the introduction, the reaction medium was kept at 0°C for 1 hour, and then kept at room temperature for 16 hours.

[0140] The reaction medium was neutralized by adding a saturated aqueous solution of ammonium chloride (20 mL). The aqueous phase was then extracted with methyl tert-butyl ether (3 × 20 mL), dried over MgSO4, filtered, and concentrated under reduced pressure to obtain a crude product (m = 3.6 g). The crude product was purified by silica gel column chromatography (eluent: heptane / AcOEt: 90 / 10) to obtain (3E,8Z,11Z)-tetradecanetrien-1-yl acetic acid (2.0 g; 53%).

[0141] GC analysis: tr = 20.8 min; purity: 94%; content of position 3 substituted impurities: 0.93%.

[0142] 11H NMR analysis (CDCl3): Meets requirements.

[0143] No impurities corresponding to position 5 substitution of diacetic acid (2E)-penten-1,5-dimethyl ester were detected, which highlights the advantages of the present invention by avoiding the protection step, another deprotection step, and another acetylation step, even though they can be in high yield but consume other feedstocks (in this case, methanol, dimethylaminopyridine, toluene, acetic acid, and sodium chloride), generate large amounts of wastewater, and mobilize resources over a long period of time.

[0144] Example 2: Synthesis of (3E,8Z)-tetradecadien-1-yl ester of acetate

[0145] Tetrahydrofuran (9.5 mL) followed by magnesium (0.45 g; 18.79 mmol) was introduced into a 50 mL three-necked flask under an inert atmosphere and with magnetic stirring. Dibromoethane (0.1 mL; 1.25 mmol) was added, and the reaction medium was brought to 65 °C. After maintaining this temperature for 45 minutes, (3Z)-1-chlorononene (2.84 g; 1.34 mmol) was added dropwise. The resulting mixture was stirred under reflux for 2 hours to produce (3Z)-nonen-1-ylmagnesium chloride.

[0146] A solution of copper(II) chloride (9.6 mg; 0.0715 mmol; 0.004 equivalents) and triethyl phosphite (101 mg; 0.0462 mol; 0.034 mmol) in tetrahydrofuran (1.3 mL) was prepared and then cooled to 0 °C in a second 50 mL three-necked flask under an inert atmosphere and with magnetic stirring. A solution of (2E)-penten-1,5-diyl diacetate (2.8 g; 15.04 mmol) in tetrahydrofuran (1.5 mL) was then introduced. After stirring at 0 °C for 30 min, the previously prepared Grignard solution was added dropwise over 35 min. At the end of the introduction, the reaction medium was maintained at 0 °C for 1 h, and then at ambient temperature for 16 h.

[0147] The reaction medium was neutralized by adding a saturated aqueous solution of ammonium chloride (25 mL). The aqueous phase was then extracted with methyl tert-butyl ether (3 × 20 mL), dried over MgSO4, filtered, and concentrated under reduced pressure to obtain a crude product (m = 3.7 g). The crude product was purified by silica gel chromatography (eluent: heptane / AcOEt: 90 / 10) to obtain (3E,8Z)-tetradecadien-1-yl acetate (2.5 g; 69%).

[0148] GC analysis: tr = 20.4 min; purity: 97.7%; content of position 3 substituted impurities: not detected.

[0149] 11H NMR analysis (CDCl3): Meets requirements.

[0150] In this embodiment, no impurities corresponding to position 5 substitution of diacetic acid (2E)-pentene-1,5-dimethyl ester were detected, which highlights the advantages of the present invention by avoiding the protection step, another deprotection step and another acetylation step, which, even if they can have high yields, consume other raw materials, generate a large amount of wastewater and mobilize resources over a long period of time.

[0151] Example 3: Preparation of the pheromone mixture of Examples 1 and 2

[0152] 0.95 g of the compound obtained in Example 1 and 0.1 g of the compound obtained in Example 2 were mixed in a flask under nitrogen atmosphere.

[0153] GC analysis: tr = 20.4 min (acetic acid (3E,8Z)-tetradecadien-1-yl ester, 8.1%), tr = 20.8 min (acetic acid (3E,8Z,11Z)-tetradectrien-1-yl ester, 86%). Content of position 3 substituted impurities: 0.85%.

[0154] Comparing these examples with Example E, which does not conform to the present invention, it is found that the content of the substitution impurity at position 3 is much lower, and the purity of the pheromone mixture is 86% + 8.1% = 94.1%, while that of Example E, which does not conform to the present invention, is only 85%.

[0155] Example 4: Synthesis of a pheromone mixture, acetic acid (3E,8Z,11Z)-tetradecanetrien-1-yl ester-acetic acid (3E,8Z)-tetradecanedien-1-yl ester

[0156] Tetrahydrofuran (94 mL) followed by magnesium (4.57 g; 188 mmol) was introduced into a 250 mL three-necked flask under an inert atmosphere and with magnetic stirring. Dibromoethane (1.1 mL; 12.5 mmol) was added, and the reaction medium was brought to a temperature of 65 °C. After maintaining this temperature for 30 minutes, 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) was added dropwise. The resulting solution was stirred under reflux for 2 hours to generate the Grignard reagent.

[0157] A solution of copper(II) chloride (94 mg; 0.72 mmol; 0.004 equivalents) and triethyl phosphite (1.01 g; 6.08 mmol; 0.034 equivalents) in tetrahydrofuran (13 mL) was prepared and then cooled to 0 °C in a second 250 mL three-necked flask under an inert atmosphere and with magnetic stirring. A solution of (2E)-penten-1,5-diyl diacetate (25.0 g; 134 mmol) in tetrahydrofuran (1.3 mL) was then introduced.

[0158] After stirring at 0°C for 30 minutes, the previously prepared Grignard solution was added dropwise to the mixture over a period of 90 minutes. After the addition was complete, the reaction medium was kept at 0°C for 1 hour, and then at room temperature for 16 hours.

[0159] The reaction medium was neutralized by adding a saturated aqueous solution of ammonium chloride (150 mL). The aqueous phase was then extracted with methyl tert-butyl ether (2 × 100 mL), dried over MgSO4, filtered, and concentrated under reduced pressure to give a crude product (m = 38.2 g). The crude product was purified by distillation under reduced pressure (1.1 mmHg; bath temperature = 150 °C to 160 °C; top temperature = 110 °C to 120 °C). Two fractions of a mixture of (3E,8Z,11Z)-tetradecanetrien-1-yl ester and (3E,8Z)-tetradecanedien-1-yl ester were obtained and combined after NMR analysis.

[0160] GC analysis: tr = 20.4 min (acetic acid (3E,8Z)-tetradecadien-1-yl ester, 10.8%) tr = 20.8 min (acetic acid (3E,8Z,11Z)-tetradecadien-1-yl ester, 80.5%), indicating a total pheromone mixture content of 91%. Content of position 3 substituted impurities: 1.12%.

[0161] Example 5: Synthesis of a 1 kg-scale pheromone mixture, acetic acid (3E,8Z,11Z)-tetradecanetrien-1-yl ester-acetic acid (3E,8Z)-tetradecanedien-1-yl ester, with the reaction stopped by acetic anhydride.

[0162] Tetrahydrofuran (3.36 kg) and magnesium (150 g; 6.25 mol) were introduced into a 5 L reactor under an inert atmosphere and with mechanical stirring. Dibromoethane (41 g; 0.39 mol) was added, and the reaction medium was then brought to a temperature of 65 °C. After maintaining this temperature for 30 minutes, a mixture of (3Z,6Z)-nonadien-1-yl chloride (825 g; 5.2 mol) and (3Z)-1-chlorononene (116 g; 0.7 mol) was slowly added. The resulting solution was stirred under reflux for 2 hours to generate a Grignard reagent, and then brought back to 10 °C.

[0163] A solution of copper(II) chloride (2.9 g; 0.022 mol; 0.004 equivalents) and triethyl phosphite (30.6 g; 0.184 mol; 0.034 equivalents) in tetrahydrofuran (0.409 kg) was prepared and then cooled to 0 °C in a second 20 L reactor under an inert atmosphere and with mechanical stirring. A solution of diacetic acid (2E)-penten-1,5-diyl diacetate (1 kg; 5.3 mol) in tetrahydrofuran (0.478 kg) was then introduced.

[0164] After stirring at 0°C for 30 minutes, the previously prepared Grignard solution was added to the previous mixture and stirred for 70 minutes. After the introduction was complete, the reaction medium was kept at 0°C for 1 hour, and then at room temperature for 16 hours. After checking the disappearance of the reagent by chromatography, 82.2 g of acetic anhydride was added at a temperature not exceeding 25°C.

[0165] The reaction medium was neutralized by adding an aqueous solution of ammonium chloride (3.8 kg, 16 wt%). The aqueous phase was then extracted with methyl tert-butyl ether (0.8 kg), dried over MgSO4, filtered, and concentrated under reduced pressure to give a crude product (m = 38.2 g). The crude product was purified by distillation under reduced pressure (1.1 mmHg; bath temperature = 150 °C to 160 °C; top temperature = 110 °C to 120 °C). Two fractions (1.049 kg) of a mixture of acetic acid (3E,8Z,11Z)-tetradecanetrien-1-yl ester and acetic acid (3E,8Z)-tetradecanedien-1-yl ester were obtained and combined after NMR analysis.

[0166] Gc analysis: tr = 20.4 min (11.7%), tr = 20.8 min (81.96%), meaning the total content of the pheromone mixture is 93.5%. Content of position 3 substituted impurities: 1.58%.

[0167] This embodiment illustrates the significance of the invention, which directly synthesizes a pheromone mixture with the correct proportions of two components by reacting diacetate (2E)-penten-1,5-diyl ester directly on a mixture of two magnesium precursors in the proportions of the final mixture. This avoids the need to synthesize two compounds and then mix them. From an industrial perspective, this reduces resource downtime, demonstrating the industrial benefits of the method according to the invention.

[0168] Example 6: Comparative trapping experiment using pheromones according to the present invention and pheromones that do not conform to the present invention.

[0169] Preparation of plastic diffusers:

[0170] 0.1 g of the pheromone mixture (solution S1) obtained according to Example 3 or the pheromone mixture (solution S0) obtained according to Example E which does not conform to the present invention was diluted in 10 ml of pentane.

[0171] In 15 7mm type Precision In the presence of a rubber diaphragm, 3 ml of solution S0 or S1 was placed in a flask of a 200 ml rotary evaporator and rotated at 120 rpm for 1 hour at room temperature and atmospheric pressure. This yielded 15 diffusers, each loaded with an average of 2 mg of the pheromone mixture according to the invention or a pheromone mixture not conforming to the invention.

[0172] Conduct comparative tests:

[0173] Ten red Delta-type pheromone traps, each equipped with an adhesive plate, were placed in a 1-hectare greenhouse. Five of the red Delta-type pheromone traps were fitted with septa loaded with pheromones according to the invention (trap group P1), while the other five red Delta-type pheromone traps were fitted with septa loaded with pheromones not conforming to the invention (trap group P0).

[0174] The traps are inspected weekly, including counting the tomato leafminers trapped on the sticky boards and replacing the boards with new ones. The septum is replaced every four weeks. Furthermore, to limit the impact of local insect concentrations, the traps are rotated weekly.

[0175] result:

[0176] Table 1: Number of moths trapped weekly (cumulative) by 5 traps of each type.

[0177] P0 1 0 5 4 1 33 58 74 33 1 0 1 211 P1 0 3 12 8 0 40 72 81 45 8 0 0 269

[0178] Therefore, better trapping of moths can be observed using pheromones containing the fewest impurities generated by substitution at position 3 (i.e., pheromones synthesized according to the method of the present invention). This indicates that these impurities have a negative effect on the attractiveness of the pheromone mixture used as bait.

[0179] Example 7: Comparative test of tomatoes treated with a mixture of pheromones according to the present invention and those not conforming to the present invention in a greenhouse.

[0180] Principle: Three modes of tomato treatment in a greenhouse were studied simultaneously:

[0181] - Mode 1 (Comparison): Normal chemical treatment for farmers (depending on the country).

[0182] -Mode 2 (Comparison): Using T 3 A mating interference treatment was performed by adding 60g of a pheromone mixture per hectare. Analysis of the pheromone mixture showed a pheromone content of 85% and an impurity level of 2.4% due to position 3 substitution, which corresponds to a pheromone mixture that does not conform to the present invention.

[0183] - Mode 3 (Invention): Treatment with the pheromone mixture of Example 5 in mating disorder, formulated by microencapsulation according to patent EP3258780A1, at a dosage of 46.5 g / ha. The product containing the surfactant mixture was deposited at 1.1 g points at a rate of 700 points / ha.

[0184] The treatments according to the three models were conducted in a greenhouse on the same farm, and the entire process constituted an experiment. These experiments were repeated in different locations in Europe to obtain statistical graphs comparing the performance of the three treatment models. Each experiment was conducted over a three-month period, between November 2019 and November 2020. The effectiveness of the mating interference products of Models 2 and 3 ultimately depended on the pheromone scent perceived by insects in ambient air. The effect of this pheromone scent depended on the purity and impurity levels of the active ingredient used, as well as the dosage emitted. All experiments were conducted at the same time, and at the end of each experiment, the residual level of the active ingredient in the diffuser was found to be zero. Therefore, the daily pheromone emissions according to Model 3 were always less than those according to Model 2 (46.5 g / ha vs. 60 g / ha). Nevertheless, the pheromone composition according to the invention has shown its superiority compared to market references that do not conform to the invention, as illustrated by the results below, demonstrating the importance of the low impurity content resulting from position 3 substitution.

[0185] The experiment was tracked in three different ways:

[0186] A) Weekly trapping records: For each treatment mode, 3 to 5 pheromone traps were randomly placed, and the number of moths trapped was recorded weekly. If mating disorganization was effective, the trapping levels in modes 2 and 3 would be significantly lower than in mode 1. Trapping does not provide protection against mating disorganization; it only serves to measure the intensity of tomato leafminer presence in the culture.

[0187] B) Recording of stem and leaf damage at the end of the trial (3 months): For each treatment mode, five different locations were randomly selected in the greenhouse to assess the number of traces of tomato leafminer moths in a 2-meter row space and report the average percentage of leaves or stems damaged by the insect.

[0188] C) Record of damaged fruit at the end of the experiment (3 months): For each treatment mode, 50 fruits were randomly selected from 5 different locations in the greenhouse to assess the number of fruits damaged by insects.

[0189] The experimental results were then analyzed to assess whether they were statistically equivalent. The experiments were grouped according to the type of insect stress.

[0190] Number of trials conducted: 15 (Italy, France, Spain).

[0191] Greenhouse area used for the experiment: the area for each treatment mode is between 0.5 hectares and 1 hectare (each experiment has an equal area for each different treatment mode).

[0192] The following shows the statistical analysis results of the experiment.

[0193] Cumulative number of traps captured by each trap within 3 months:

[0194] The following results were obtained in 7 high-voltage tests:

[0195] -Mode 1: Average trapping of 1256 moths (maximum >1800)

[0196] -Mode 2: Traps 248 (maximum 568) moths

[0197] -Mode 3: Traps 266 (maximum 521) moths

[0198] These results demonstrate that the trapping volume was significantly reduced in both Mode 2 and Mode 3, and verify that the principles of treatment according to Mode 2 and Mode 3 can reduce the stress on tomato leafminers in the same way.

[0199] In 8 low- or medium-pressure tests:

[0200] -Mode 1: Traps 153 (maximum 280) moths

[0201] -Mode 2: Average trapping 13.25 (maximum 24) moths

[0202] -Mode 3: Traps 22.5 (maximum 43) moths

[0203] Similar to the results obtained under high insect stress, treatments according to Modes 2 and 3 reduced the stress on tomato leafminers.

[0204] Percentage of damage to leaves and stems:

[0205] Mode 1 19.1 54.2 Mode 2 8.1 15.1 Mode 3 5.3 7.5

[0206] The above results indicate that the treatment according to Mode 3 (the present invention) reduces damage to leaves and stems, both compared to ordinary chemical treatment (Mode 1) and another mating-disrupting treatment (Mode 2).

[0207] Percentage of fruit damaged:

[0208] Mode 1 24 54.2 Mode 2 13.9 24.0 Mode 3 9.5 16.2

[0209] Compared to traditional chemical treatment (Mode 1) or another mating-disrupting treatment (Mode 3), the treatment according to Mode 3 reduced the damage to the fruit caused by the tomato leafminer.

[0210] in conclusion:

[0211] This embodiment illustrates that, compared to other embodiments, the pheromone mixture according to the invention can have the same or even greater effect in protecting tomatoes in greenhouses, while using a significantly lower dosage (46.5 g / ha vs. 60 g / ha, i.e., a 23% reduction between Mode 2 and Mode 3). The difference in purity (approximately +10% in the pheromone mixture according to the invention) and the much lower level of impurities resulting from substitution at position 3 in the pheromone according to the invention (-45%) largely explain this difference in effectiveness.

Claims

1. A method for synthesizing a pheromone, wherein the pheromone is selected from compound (I), compound (I'), and a mixture of compound (I) and compound (I'): （I）， （I’）， in: - R is a molecular formula C n H 2n-2p+1 Straight-chain hydrocarbon chains, - R' is a molecular formula C n’ H 2n’-2p’+1 Straight-chain hydrocarbon chains, - n and n' may be the same or different, and are integers between 5 and 17. - p and p' correspond to the degree of unsaturation in the hydrocarbon chain, and can be the same or different; they are integers between 1 and 3. - Ac is an acetyl group. The method comprises reacting the diacetic acid (2E)-penten-1,5-dimethyl ester of formula (II) with at least one Grignard reagent in the presence of a copper-based catalyst: (II) The Grignard reagent is selected from compound (III), compound (III'), and mixtures of compound (III) and compound (III'): R-MgX(III), R'-MgX(III'), Where R and R' are as previously defined for compounds (I) and (I'), X is a chlorine atom or a bromine atom; The copper-based catalyst comprises at least one copper ligand selected from trialkylphosphine, trialkyl phosphite, amine, and mixtures thereof.

2. The method according to claim 1, characterized in that, The copper ligand is a trialkyl phosphite selected from triethyl phosphite, trimethyl phosphite, and mixtures thereof.

3. The method according to claim 1, characterized in that, The reaction takes place in an aprotic solvent.

4. The method according to claim 3, characterized in that, The aprotic solvent is an ether solvent.

5. The method according to claim 4, characterized in that, The ether solvent is selected from diethyl ether, methyl tert-butyl ether, tetrahydrofuran, methyl tetrahydrofuran, tetrahydropyran, methyl tetrahydropyran, dioxane, ethylene glycol dimethyl ether, and mixtures thereof.

6. The method according to claim 1, characterized in that, The copper-based catalyst is a copper II salt.

7. The method according to claim 6, characterized in that, The copper-based catalyst is selected from copper halide II and copper carboxylate II.

8. The method according to claim 7, characterized in that, Copper halides are selected from CuCl2 and CuBr2; copper carboxylate is selected from copper acetate Cu(OAc)2 and copper acetylacetonate II, Cu(Acac)2.

9. The method according to claim 1, comprising the following steps: a. Prepare a solution containing 1 equivalent of diacetic acid (2E)-pentene-1,5-dimethyl ester of formula (II) in an aprotic solvent; b. Add a copper-based catalyst to the solution obtained in step a) at a ratio of 0.001 to 0.02 equivalents of copper; c. Prepare a solution containing between 0.95 and 1.25 equivalents of Grignard reagent in an aprotic solvent that is the same as or different from the aprotic solvent in step a); d. Add the solution obtained in step c) to the solution obtained in step b) while stirring and at a reaction temperature below 25°C; e. Stop the reaction carried out in step d); f. Neutralize the reaction medium obtained in step e) and extract the pheromone.

10. The method according to claim 9, characterized in that, Copper binds to ligands selected from trialkylphosphine, trialkyl phosphite, amines, and mixtures thereof.

11. The method according to claim 9, wherein, The reaction is stopped by adding 0.1 to 1.5 equivalents of acetic anhydride to the reaction medium.

12. The method according to claim 1, characterized in that, Compound (III): The molar ratio of compound (III') is between 0:1 and 1:0.

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