Process for the continuous flow preparation of a mixture of isomers of hexa-1,3-dien-1-yl-diethylphosphate

Abstract

The present invention relates to a process for the continuous flow preparation of a mixture of isomers of hexa-1,3-dien-1-yl-diethylphosphate mainly composed of the (E,Z) isomer and essentially free of the (E,E) isomer.

Description

[0001] Continuous flow process for preparing a mixture of isomers of hexa-1,3-dien-1-yl-diethylphosphate

[0002] FIELD OF INVENTION

[0003] The present invention relates to a continuous flow preparation process of a mixture of isomers of hexa-1,3-dien-1-yl-diethylphosphate mainly composed of the (7E,9Z) isomer and essentially devoid of the (7E,9E) isomer.

[0004] STATE OF THE ART

[0005] (E,Z)-7,9-dodecadienyl-1-acetate is the major component of the pheromone bouquet of Lobesia botrana (also known as the grapevine moth), a moth known for the damage it causes to grapevines. Indeed, the pheromone bouquet of this moth contains isomers of 7,9-dodecadienyl-1-acetate in the following proportions: (E,Z): 94.1%, (E,E): 3.0%, (Z,E): 2.7%, (Z,Z): 0.1% (Witzgall et al. 2005). This pheromone bouquet is used in dispensers placed in the vineyards to create mating confusion by drowning the signal emitted by females of the species in a cloud of pheromones.

[0006] The different isomers of (E,Z)-7,9-dodecadienyl-1-acetate are shown in Table 1.

[0007] Table 1

[0008] It is used in the form of a mixture of isomers composed primarily of the (7E,9Z) isomer and often of the (7E,9E) isomer, the ratio of which varies significantly from one commercial product to another. Thus, except in the products manufactured by the Applicant, the (7Z,9Z) and (7Z,9E) isomers are generally absent, which weakens the pheromone bouquet. In the remainder of this text, isomers will be designated solely by the numbers corresponding to the position of the unsaturations. For example, the (7E,9Z) isomer will be abbreviated as (E,Z) isomer.

[0009] Documents WO 2016 / 001383 A1 and WO 2018 / 162739 A1 relate to processes for the synthesis of (E,Z)-7,9-dodecadienyl-1-acetate, via the preparation of a mixture of hexa-1,3-dien-1-yl-diethylphosphate isomers as a synthetic intermediate. A distinctive feature of these syntheses lies in the highly specific mixture of isomers they produce. Indeed, the synthesis of a mixture of (E,Z) and (E,E) had already been described previously. However, the preparation of a mixture of isomers containing nearly 94% (E,Z) and a distribution of the different isomers close to the natural distribution of the pheromone was not known at the time. Access to a mixture whose isomeric composition is closer to that of the natural composition makes it possible to consider manufacturing more effective mating disruption products.

[0010] Furthermore, it is known that the excessive use of mating disruption products based on incomplete pheromone bouquets leads to the development of insects more sensitive to minor components and the risks of developing resistance to mating disruption treatments become real.

[0011] It is therefore clear that access to a pheromone bouquet with a composition closer to the natural pheromone bouquet under economical conditions is essential for the sustainable development of these alternative technologies to insecticides.

[0012] In documents WO 2016 / 001383 A1 and WO 2018 / 162739 A1, the processes for preparing the pheromonal bouquet of Lobesia botrana comprise 3 steps: a) Preparation of a mixture of dienol phosphate isomers comprising predominantly the (E,Z) isomer by reaction of trans-2-hexenal, a strong base and diethyl chlorophosphate; b) Reaction of the mixture of dienol phosphate isomers obtained in step a) with a hydrolyzable dienophile to form an adduct only with the (E,E) isomer which can then be removed from the reaction medium after its basic hydrolysis; c) Coupling of the mixture of dienol phosphate isomers obtained in step b) with the magnesium derivative of 6-chloro-1-hexanol in the presence of an iron-based catalyst followed by acetylation in the presence of acetic anhydride which generates the targeted mixture of 7,9-dodecadienyl-1-acetate isomers.

[0013] The natural content of the E,E) isomer in the pheromone is approximately 3%. However, step c) of the previously described process naturally induces partial isomerization of the other isomers to (E,E) because step c) involves heating the reaction medium in the presence of metals that facilitate this isomerization. Therefore, the dienolphosphate intermediate used for this step should be low in the (E,E) isomer.

[0014] The distribution of pheromone isomers is therefore determined in the first two steps a) and b), which are thus crucial. Step a) leads to a mixture of dienolphosphate isomers of formula 1, and step b) refines the isomer distribution by eliminating almost all of the (E,E) isomer.

[0015] Better technical and economic control of these steps has a direct impact on the industrial availability of a mixture of 7,9-dodecadienyl-1-acetate isomers with a composition close to the natural composition.

[0016] The criteria for the economic success of a process are numerous, but the main ones are: mass yield, isomeric selectivity, hourly productivity, and the investment cost required to implement the process. In this respect, a continuous process would likely have a significant advantage in terms of investment cost because reaction volumes are minimal, thus reducing the need for complex reactors. Furthermore, safety issues are more easily managed since simply stopping the process feed halts the reaction. However, for this continuous process to be economically efficient, it must be both productive and selective.

[0017] Thus, even though processes are known for preparing dienolphosphates, a need remains for a simple, efficient, and economical industrial-scale process to manufacture a mixture of formula 1 dienolphosphate isomers with control over the isomeric ratio. FIGURES

[0018] Figure 1A: Diagram of a process according to the invention comprising steps a1), a2), b1), b2), and b3), in which steps a1), a2), and b1) are carried out in continuous flow. Steps b1), b2), and b3) are shown in more detail in Figure 1B.

[0019] Figure 1B: Diagram of a process according to the invention comprising steps a1), a2), b1), b2), and b3), in which steps a1), a2), and b1) are carried out in continuous flow. Steps a1) and a2) are shown in more detail in Figure 1A.

[0020] SUMMARY OF THE INVENTION

[0021] The present invention therefore reveals an innovative way of accessing the pheromone qualities described in WO 2016 / 001383 A1 and WO 2018 / 162739 A1 by simplifying the manufacture of the dienolphosphate intermediates described in these patents.

[0022] Thus, a first object of the invention is a process for preparing a mixture M2 of enolphosphate isomers of the following formula 1: comprising less than 5%, preferably less than 2%, of (E,E) isomer and comprising at least 93% of (E,Z) isomer, at least 0.1% of (Z,Z) isomer and at least 0.1% of (Z,E) isomer, comprising the following steps: b1) contacting in a continuous flow reactor Rt>i a mixture M1 of enolphosphate isomers of formula 1 comprising at least 10% of (E,E) isomer, at least 60% of (E,Z) isomer, at least 0.1% of (Z,Z) isomer and at least 0.1% of (Z,E) isomer, with a hydrolyzable dienophile DH being maleic anhydride, to give a reaction medium comprising the mixture M2 of enolphosphate isomers and an adduct formed between the (E,E) isomer and the hydrolyzable dienophile DH, b2) the contacting of the reaction medium obtained in step b1) with a base to give a hydrolyzed medium comprising the mixture M2 of enolphosphate isomers and an adduct formed between the (E,E) isomer and the hydrolyzed dienophile DH,and b3) the removal of the hydrolyzed adduct from the hydrolyzed medium obtained in step b2) to obtain the M2 mixture of enolphosphate isomers.

[0023] Preferably, step b1) is carried out in an organic solvent St>i comprising an aromatic solvent, preferably toluene, at a temperature Tt>i ranging from 110 °C to 250 °C, preferably from 110 °C to 200 °C, and at a pressure Pt>i ranging from 2 bar to 50 bar. Preferably, the residence time tRbi in reactor Rbi is less than or equal to 15 min. Preferably, the process further comprises the following steps: a1) contacting trans-2-hexenal with potassium tert-butylate or sodium tert-butylate in a continuous flow reactor Rai to obtain an enolate of trans-2-hexenal, and a2) contacting the trans-2-hexenal enolate with diethyl chlorophosphate in a continuous flow reactor Ra2 to obtain mixture M1 as defined above.

[0024] A second object of the invention is a process for preparing a mixture M1 of enolphosphate isomers of the following formula 1: comprising at least 10% of (E,E) isomer, at least 60% of (E,Z) isomer, at least 0.1% of (Z,Z) isomer and at least 0.1% of (Z,E) isomer, comprising the following steps: a1) contacting trans-2-hexenal with potassium tert-butylate or sodium tert-butylate in a continuous flow Rai reactor, to obtain an enolate of trans-2-hexenal, and a2) contacting the trans-2-hexenal enolate with diethyl chlorophosphate in a continuous flow Ra2 reactor, to obtain mixture M1.

[0025] Preferably, step a1) is carried out in an organic solvent S ai comprising an aromatic solvent, preferably toluene, and at a temperature T ai ranging from -70 °C to -40 °C, and step a2) is carried out in an organic solvent S a2 comprising an aromatic solvent, preferably toluene, and at a temperature T a 2 ranging from -70 °C to 0 °C.

[0026] DETAILED DESCRIPTION OF THE INVENTION

[0027] The various embodiments presented throughout the description can be used alone or in combination with each other, without limitation of combination.

[0028] Definitions

[0029] Any range of values ​​designated by the expression "between a and b" as well as by the expression "from a to b" designates the range of values ​​from a to b (that is to say including the limits a and b). By "ambient temperature", for the purposes of the present invention, is understood to mean a temperature between 15 and 40°C, preferably between 15 and 30°C, in particular between 20 and 25°C.

[0030] In the context of the present invention, a "dienophile" is a molecule, in the sense of the Diels-Alder reaction, which has a double bond substituted by groups depleting said double bond of electrons by inductive or mesomeric effect.

[0031] By "hydrolyzable dienophile" is meant a dienophile whose product of the Diels-Alder reaction with the (E,E) isomer can be easily transformed into a water-soluble salt, for example at pH>8.

[0032] For the purposes of this invention, the term "alkyl (Ci-C0) group" refers to a monovalent, saturated, linear or branched hydrocarbon chain comprising 1 to 6 carbon atoms. Examples of alkyl (Ci-C0) groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl.

[0033] By "xylene" we mean 1,2-dimethylbenzene, 1,3-dimethylbenzene, 1,4-dimethylbenzene or mixtures thereof.

[0034] In this description, "approximately" means that the value in question may be 10% lower or higher, in particular 5%, and especially 1% higher, than the stated value.

[0035] In the following description, unless otherwise stated, flow rates refer to molar flow rates (in mol / h). They are obtained by multiplying the volumetric flow rate (L / h) by the molar concentration of the solution (mol / L).

[0036] Residence time is the time required for the reaction medium of a given reaction to pass through the reactor. Residence time is calculated by dividing the internal volume of the reactor by the volumetric flow rate of the incoming reaction medium. When the incoming reaction medium consists of several reactants introduced at different volumetric flow rates, the residence time is calculated by dividing the reactor volume by the sum of the volumetric flow rates.

[0037] Process for preparing a mixture M2 of enolphosphate isomers

[0038] The present invention relates to a process for preparing a mixture M2 of enolphosphate isomers of the following formula 1: comprising less than 5%, preferably less than 2%, of (E,E) isomer and comprising at least 93% of (E,Z) isomer, at least 0.1% of (Z,Z) isomer and at least 0.1% of (Z,E) isomer, comprising the following steps: b1) contacting in a continuous flow Rbi reactor a mixture M1 of enolphosphate isomers of formula 1 comprising at least 10% of (E,E) isomer, at least 60% of (E,Z) isomer, at least 0.1% of (Z,Z) isomer and at least 0.1% of (Z,E) isomer, with a hydrolyzable dienophile DH being maleic anhydride to give a reaction medium comprising the mixture M2 of enolphosphate isomers and an adduct formed between the (E,E) isomer and the hydrolyzable dienophile DH, b2) the contacting of the reaction medium obtained in step b1) with a base to give a hydrolyzed medium comprising the mixture M2 of enolphosphate isomers and an adduct formed between the (E, E) isomer and the hydrolyzed dienophile DH,and b3) the removal of the hydrolyzed adduct from the hydrolyzed medium obtained in step b2) to obtain the M2 mixture of enolphosphate isomers.

[0039] Step b1) is more particularly carried out in an organic solvent St>i comprising an aromatic solvent, at a temperature Tt>i ranging from 110 °C to 250 °C, preferably from 110 °C to 200 °C, and at a pressure Pt>i ranging from 2 bar to 50 bar. Preferably, the residence time tRbi in the reactor Rbi is less than or equal to 15 min.

[0040] This process efficiently obtains the M2 mixture of enolphosphate isomers. Indeed, raising the temperature promotes the isomerization of the different isomers into the (E,E) isomer, which is the most thermodynamically stable isomer. Thanks to the combined use of a temperature of at least 110 °C under pressure and a continuous flow reaction, the residence time of the isomer mixture in the Rbi reactor at high temperatures is limited, thus minimizing this undesirable isomerization.

[0041] The M2 mixture of enolphosphate isomers of formula 1 may comprise: less than 2% of (E,E) isomer, preferably less than 1%, or even less than 0.5%, typically less than 0.3% or less than 0.1% of (E,E) isomer; and / or at least 93% of (E,Z) isomer, preferably at least 94%, or even at least 95%, typically at least 96% of (E,Z) isomer; and / or at least 0.1% of (Z,Z) isomer, preferably at least 0.3%, or even at least 0.5%, at least 0.7%, typically at least 0.8% of (Z,Z) isomer; and / or at least 0.1% of (Z,E) isomer, preferably at least 0.3%, or even at least 0.5%, at least 0.7%, typically at least 0.9% of (Z,E) isomer.

[0042] Advantageously, the M2 mixture comprises less than 0.3% of (E,E) isomer and comprises at least 96% of (E,Z) isomer, at least 0.8% of (Z,Z) isomer and at least 0.9% of (Z,E) isomer.

[0043] The M2 mixture may comprise from 0.3% to 10%, preferably from 0.5% to 5%, of (Z,Z) isomer and / or from 0.3% to 10% of (Z,E) isomer, preferably from 0.5% to 5%.

[0044] Thus, the M2 mixture of enolphosphate isomers of formula 1 can be prepared in two successive steps from the M1 mixture of enolphosphate isomers of formula 1.

[0045] The M1 mixture of enolphosphate isomers of formula 1 comprises, on the one hand, a proportion of (E,E) isomer substantially greater than that of the M2 mixture of enolphosphate isomers, and on the other hand, a proportion of (E,Z) isomer less than that of the M2 mixture.

[0046] The M1 mixture of enolphosphate isomers of formula 1 may therefore comprise: at least 10% of the (E,E) isomer, preferably at least 12%, or at least 15%, typically about 20% of the (E,E) isomer; and / or at least 60% of the (E,Z) isomer, preferably at least 65%, or at least 70%, typically about 75% of the (E,Z) isomer; and / or at least 0.1% of the (Z,Z) isomer, preferably at least 0.3%, or at least 0.5%, at least 0.7%, typically at least 0.8% of the (Z,Z) isomer; and / or at least 0.1% of (Z,E) isomer, preferably at least 0.3%, or even at least 0.5%, at least 0.7%, typically at least 0.9% of (Z,E) isomer.

[0047] The mixture M1 may comprise from 0.3% to 10%, preferably from 0.7% to 5%, of the (Z,Z) isomer and / or from 0.3% to 10% of the (Z,E) isomer, preferably from 0.7% to 5%. Advantageously, the mixture M1 comprises less than 30% of the (E,E) isomer.

[0048] Advantageously, the mixture M1 comprises at least 15% of (E,E) isomer, at least 70% of (E,Z) isomer, at least 0.8% of (Z,Z) isomer and at least 0.9% of (Z,E) isomer.

[0049] The first step (b1) involves contacting the mixture M1 of enolphosphate isomers of formula 1, as defined above, with a hydrolyzable dienophile DH in a continuous flow reactor (Rt>i) to give a reaction medium comprising the mixture M2 of enolphosphate isomers and an adduct formed between the (E,E) isomer and the hydrolyzable dienophile DH. Indeed, only the E,E) isomer reacts with the hydrolyzable dienophile DH to form an adduct which, after basic hydrolysis, becomes soluble in water and can be very easily removed. This yields a mixture of isomers M2 essentially devoid of the (E,E) isomer, which can then be used to prepare the mixture of isomers of 7,9-dodecadienyl-1-acetate.

[0050] Step b1) is carried out in an organic solvent S1, advantageously comprising an aromatic solvent. The aromatic solvent is preferably chosen from the group consisting of toluene, xylenes, benzene, ethylbenzene, and mixtures thereof; more preferably, the aromatic solvent is toluene. The organic solvent S is advantageously a mixture of solvents comprising an aromatic solvent, preferably chosen from the group consisting of toluene, xylenes, and mixtures thereof, preferably toluene, and a solvent chosen from the group consisting of N-methyl-2-pyrrolidone (NMP), N-butyl-2-pyrrolidone (NBP), N-methylcaprolactam, 2-methyltetrahydrofuran, and mixtures thereof. Preferably, S is a solvent mixture comprising toluene and NMP or NBP.Advantageously, the organic solvent S is a mixture of toluene and NMP. When S is a solvent mixture comprising toluene and either NMP or NBP, then the toluene:(NMP or NBP) volume ratio is advantageously a volume ratio of 70:30 to 30:70, preferably of 60:40 to 40:60, preferably of 55:45 to 45:55, typically about 50:50. More preferably, the organic solvent S is a toluene:NMP mixture with a volume ratio of 70:30 to 30:70, preferably of 60:40 to 40:60, preferably of 55:45 to 45:55, typically about 50:50.

[0051] Step b1) can be carried out at a temperature Tt>i ranging from 120 °C to 220 °C, preferably from 130 °C to 200 °C, and / or at a pressure Pt>i ranging from 3 bar to 30 bar, preferably from 5 bar to 25 bar, preferably from 10 bar to 20 bar, and in particular from 10 bar to 15 bar. Advantageously, step b1) is carried out at a temperature Tt>i ranging from 140 °C to 200 °C, typically about 190 °C, and at a pressure Pbi ranging from 10 bar to 20 bar, in particular from 10 bar to 15 bar, typically about 12 bar.

[0052] Step b1) can also be carried out at a temperature Tt>i ranging from 120 °C to 180 °C, preferably from 130 °C to 160 °C, and / or at a pressure Pt>i ranging from 3 bar to 30 bar, preferably from 5 bar to 25 bar, preferably from 10 bar to 20 bar, and in particular from 10 bar to 15 bar. Advantageously, step b1) is carried out at a temperature Tt>i ranging from 140 °C to 160 °C, typically about 150 °C, and at a pressure Pbi ranging from 10 bar to 20 bar, in particular from 10 bar to 15 bar, typically about 12 bar.

[0053] The hydrolyzable dienophile DH can be added in step b1) at a number of equivalents ranging from 0.2 to 2, preferably ranging from 0.3 to 1.5, typically about 1.2, relative to the enolphosphate of mixture M1.

[0054] This step is carried out in an Rt>i reactor.

[0055] The mixture M1 of enolphosphate isomers of formula 1 can be introduced into reactor R as a solution in solvent Sbi as defined previously. This solution advantageously has a concentration of mixture M1 of enolphosphate isomers of formula 1 ranging from 0.05% to 0.5% w / w, preferably ranging from 0.1% to 0.3% w / w, typically 0.16% w / w.

[0056] The hydrolyzable dienophile DH can be introduced into reactor R as a solution in solvent Sbi as defined previously. This solution advantageously has a concentration of hydrolyzable dienophile DH ranging from 0.05% to 65% w / w, preferably ranging from 0.5% to 30% w / w, typically 2% to 15% w / w.

[0057] The mixture M1 can be introduced into the reactor Rt>i at a molar flow rate DMI and the hydrolyzable dienophile DH can be introduced into the reactor Rt>i at a molar flow rate DDH, the DDH / DMI ratio advantageously ranging from 0.5 to 2.0, preferably from 0.9 to 1.5, preferably from 1 to 1.2.

[0058] Advantageously, tRbi is less than or equal to 10 min, preferably less than or equal to 6 min, for example tRbi goes from 1 min to 6 min, typically about 3 or 5 min.

[0059] Step b2) consists of contacting the reaction mixture obtained in step b1) with a base. This can be carried out by adding a basic aqueous solution to the reaction mixture obtained in step b1), preferably after cooling. Step b2) can be performed at room temperature and atmospheric pressure.

[0060] NaOH or KOH can be used as a base in this step. The basic aqueous solution in step b2) advantageously has a pH greater than or equal to 8, preferably greater than or equal to 10; typically, it has a pH of approximately 11, 12, 13, or 14. Step b2) thus leads to the production of a hydrolyzed medium comprising the mixture M2 of enolphosphate isomers and an adduct formed between the (E,E) isomer and the hydrolyzed dienophile DH. Step b2) can be carried out in batch mode.

[0061] Step b3) consists of removing the hydrolyzed adduct from the hydrolyzed medium obtained in step b2) to obtain the M2 mixture of enolphosphate isomers. Indeed, the hydrolyzed adduct is soluble in water and is therefore easily removed from the medium by washing.

[0062] This removal step can, for example, be carried out by washing with water or an aqueous solution, possibly loaded with salts such as sodium chloride.

[0063] In all embodiments, the resulting M2 mixture can be separated from the reaction medium by methods well known to those skilled in the art, such as extraction, solvent evaporation, or precipitation and filtration. The compounds can also be purified, if necessary, by techniques well known to those skilled in the art. Furthermore, the solvents used can be recovered from the collected organic and aqueous phases. For example, toluene or xylenes can be recycled by distillation, while NMP or NBP can be recycled by decanting the aqueous phase (obtained during washing) brought to a pH of 12 to 14.

[0064] Indeed, when the solvent St>i is a mixture of toluene and NMP, step b3) leads to the formation of two phases: an organic phase comprising the M2 mixture and the toluene, and an aqueous phase comprising the hydrolyzed adduct and the majority of the NMP. After phase separation and washing, the toluene in the organic phase can be at least partially recycled by solvent evaporation. The aqueous phase can be brought to a strongly basic pH, and the NMP can then be recycled by decantation.

[0065] The process according to the invention may also further comprise the following steps: a1) contacting trans-2-hexenal with potassium tert-butylate or sodium tert-butylate in a continuous-flow Rai reactor to obtain an enolate of trans-2-hexenal, and a2) contacting the trans-2-hexenal enolate with diethyl chlorophosphate in a continuous-flow Ra2 reactor to obtain mixture M1 as defined above. Steps a1) and a2) provide mixture M1 of enolphosphate isomers of formula 1. These two steps are carried out before step b1) as defined above.

[0066] Step a1) involves contacting trans-2-hexenal with potassium tert-butylate or sodium tert-butylate in a continuous-flow Rai reactor to obtain an enolate of trans-2-hexenal. Trans-2-hexenal, potassium tert-butylate, and sodium tert-butylate can be obtained from commercial sources. Potassium tert-butylate and sodium tert-butylate are strong, weakly nucleophilic bases that allow the deprotonation of trans-2-hexenal to form the corresponding enolate. This enolate can then react with diethyl chlorophosphate to give mixture M1.

[0067] Step a1) is advantageously carried out in an organic solvent S ai and step a2) is advantageously carried out in an organic solvent S a 2. Organic solvents S ai and S aTwo, identical or different, are chosen from the group consisting of aromatic solvents, NMP, NBP, N-methylcaprolactam, 2-methyltetrahydrofuran, and mixtures thereof. The aromatic solvent is preferably chosen from the group consisting of toluene, xylenes, benzene, ethylbenzene, and mixtures thereof; preferably, the aromatic solvent is chosen from the group consisting of toluene, xylenes, and mixtures thereof; preferably, it is toluene. Organic solvents S ai and S a 2, identical or different, may be chosen from the group consisting of toluene, xylenes, NMP, NBP, N-methylcaprolactam, 2-methyltetrahydrofuran and mixtures thereof

[0068] Preferably, the organic solvents St>i and Sb2, whether identical or different, are a solvent mixture comprising an aromatic solvent selected from the group consisting of toluene, xylenes, and mixtures thereof, preferably toluene, and a solvent selected from the group consisting of NMP, N-butyl-2-pyrrolidone, N-methylcaprolactam, 2-methyltetrahydrofuran, and mixtures thereof. Preferably, the organic solvents St>i and Sb2, whether identical or different, are a solvent mixture comprising toluene and NMP or NBP. Particularly advantageously, the organic solvents Sbi and Sb2, whether identical or different, are a mixture of toluene and NMP.When the organic solvents Sbi and / or Sb2 are a solvent mixture comprising toluene and NMP or NBP, then the toluene:(NMP or NBP) volume ratio is advantageously a volume ratio of 70:30 to 30:70, preferably of 60:40 to 40:60, preferably of 55:45 to 45:55, typically about 50:50. More preferably, the organic solvents Sbi and Sb2, whether identical or different, are a toluene:NMP mixture with a volume ratio of 70:30 to 30:70, preferably of 60:40 to 40:60, preferably of 55:45 to 45:55, typically about 50:50.

[0069] According to an advantageous embodiment, when the process according to the invention comprises steps a1) and a2), the solvents S a i, S a 2 and St>i are identical, preferably the solvents S a i, S a2 and Sbi are a mixture of toluene and NMP, more preferably a toluene:NMP mixture with a volume ratio of 70:30 to 30:70, preferably ranging from 60:40 to 40:60, preferably ranging from 55:45 to 45:55, typically about 50:50. The use of solvents S a i, S a The identical nature of 2 and St>i facilitates the recycling of the solvents used. Furthermore, the use of solvent mixtures according to the invention is particularly advantageous as it allows for all steps requiring heating or cooling of the reaction medium to be carried out while controlling its viscosity.

[0070] Performing steps a1), a2), and b1) sequentially in the same solvent or solvent mixture is advantageous because it avoids time-consuming and costly solvent changeovers. The Applicant has surprisingly discovered that the toluene:NMP mixture is particularly well-suited to these steps, as it allows for the execution of both the low-temperature steps (a1) and a2) and step b1), which is carried out at higher temperatures and pressures. This significantly optimizes the production of mixture M2.

[0071] Step a1) can be carried out at a temperature T ai from -70 °C to -40 °C, preferably from -60 °C to -50 °C, typically around -55 °C, and / or step a2) is carried out at a temperature T a 2 ranging from -70 °C to 0 °C, preferably from -60 °C to 0 °C, typically around -50 °C.

[0072] In step a1), trans-2-hexenal can be introduced into the Rai reactor at a molar flow rate DT2H and potassium tert-butylate or sodium tert-butylate can be introduced into the Rai reactor at a molar flow rate DB, the DB / DT2H ratio ranging from 0.5 to 2.0, preferably 0.9 to 1.5, preferably 1 to 1.2.

[0073] In step a2), diethyl chlorophosphate can be introduced into reactor Ra2 at a molar flow rate DCD, with the DCD / DT2H ratio ranging from 0.5 to 2.0, preferably 0.9 to 1.5, typically 1 to 1.2. Trans-2-hexenal can be introduced into reactor Rai as a solution in solvent S. ai As defined previously, it can also be introduced pure into the Rai reactor. This solution advantageously presents a w / w concentration of trans-2-hexenal ranging from 2% to 100%.

[0074] Potassium tert-butylate or sodium tert-butylate can be introduced into the Rai reactor as a solution in solvent S ai as defined previously. This solution advantageously has a w / w concentration of potassium tert-butylate or sodium tert-butylate ranging from 0.05% to 30%, preferably from 0.08% to 20%, typically 0.1% to 15%.

[0075] Diethyl chlorophosphate can be introduced into reactor Ra2 as a solution in solvent S a 2. As defined previously, it can also be introduced in its pure form into reactor R a 2. This solution advantageously presents a w / w concentration of diethyl chlorophosphate ranging from 2% to 100%.

[0076] The residence time tRai in reactor R ailess than or equal to 15 min, preferably less than or equal to 10 min, preferably less than or equal to 5 min. tRai advantageously goes from 1 min to 4 min, typically about 2 or 3 min.

[0077] The length of stay tR a 2 in reactor R a 2 less than or equal to 15 min, preferably less than or equal to 10 min, preferably less than or equal to 5 min. tR a 2 is advantageously from 1 min to 4 min, typically around 2 or 3 min.

[0078] The sequential execution of steps a1), a2), and b1) is particularly advantageous as it eliminates the need for intermediate treatments, such as the separation / purification of the M1 mixture of enolphosphate isomers of formula 1. These intermediate treatments generate effluents and are costly on a large scale. They also require a significant amount of time. Production cycles are therefore improved, resulting in reduced costs. Furthermore, thanks to the process according to the invention, the reaction times of steps a1), a2), and b1) are reduced compared to prior art processes. Consequently, the quantity of enolphosphate mixture M2 produced per hour is significantly increased.

[0079] An example of a process according to the invention comprising steps a1), a2), b1), b2), and b3) is shown in Figures 1A and 1B. In Figure 1A, a solution of potassium tert-butylate or sodium tert-butylate is introduced into a Csase vessel, and a solution of trans-2-hexenal (or pure trans-2-hexenal) is introduced into a CT2H vessel. The trans-2-hexenal is introduced into a first reactor section R ai by a pump at a molar flow rate DT2H. This first section allows the trans-2-hexenal to be cooled to temperature T a i. Potassium tert-butylate or sodium tert-butylate is introduced into a second reactor section R ai by a pump at a molar flow rate DB. This second section allows the potassium tert-butylate or sodium tert-butylate to be cooled to temperature T a i. The mixing of the reactants is then carried out in a third reactor section R ai always at temperature Ta i. This reaction yields the enolate of trans-2-hexenal (step a1). A solution of diethyl chlorophosphate (or pure diethyl chlorophosphate) is introduced into a CCD cell. This solution is then introduced into reactor R a ? by a pump at a molar flow rate DCD. The thermal inertia of the reaction mixture obtained in step a1) allows step a2) to be carried out at temperature T a ? without active cooling of reactor R a or the CCD tank. Mixture M1 is therefore produced in reactor R aIn Figure 1B, a hydrolyzable dienophile solution is introduced into a CDH vessel. This solution is then pumped into reactor Rbi at a temperature Tbi and a pressure Pbi using a pump with a molar flow rate DDH. The reaction mixture, comprising the M2 mixture of enolphosphate isomers and an adduct formed between the (E,E) isomer and the hydrolyzable dienophile, is collected from the outlet of reactor Rbi to then carry out steps b2) and b3) in batch mode.

[0080] Process for preparing a mixture M1 of enolphosphate isomers

[0081] Another object of the invention relates to a process for preparing a mixture M1 of enolphosphate isomers of the following formula 1: comprising at least 10% of the (E,E) isomer, at least 60% of the (E,Z) isomer, at least 0.1% of the (Z,Z) isomer, and at least 0.1% of the (Z,E) isomer, comprising the following steps: a1) contacting trans-2-hexenal with potassium tert-butylate or sodium tert-butylate in a continuous-flow Rai reactor at a temperature T ai ranging from -70 °C to -40 °C, to obtain a trans-2-hexenal enolate, and a2) contacting the trans-2-hexenal enolate with diethyl chlorophosphate, preferably in an organic solvent S, in a continuous flow Ra2 reactor a 2 comprising an aromatic solvent, preferably toluene, and at a temperature T a 2 going from -70 °C to 0 °C to obtain mixture M1.

[0082] Step a1) is more specifically carried out in an organic solvent S aicomprising an aromatic solvent, preferably toluene. In this other object of the invention, the mixture M1 of enolphosphate isomers of formula 1 and the steps a1) and a2) are as defined above.

[0083] The process for preparing the M1 mixture of enolphosphate isomers according to the invention allows working at very low temperatures which limit the formation of minor isomers of the M1 isomer mixture.

[0084] Continuous flow stage reactors

[0085] Within the scope of the present invention, any type of reactor suitable for use in a continuous flow reaction under the temperature and pressure conditions of the stage can be used as an Rbi, Rai, and R reactor. a2. These reactors can be made from various materials such as polytetrafluoroethylene (PTFE), glass, ceramics, or metals. They are preferably made of metal such as stainless steel or Hastelloy. When required by the conditions of the stage, they can be cooled or heated by any means known to those skilled in the art, for example, by circulating a heat transfer fluid.

[0086] The Rt>i, Rai and / or Ra2 reactors are advantageously tubular in shape.

[0087] Preferably, the Rbi, Rai, and / or Ra2 reactors are tubular with a circular cross-section having an internal diameter of 8 mm or less, advantageously 7 mm or less, or advantageously 6.5 mm or less. Typically, the internal diameter ranges from 0.76 mm to 6.5 mm, preferably from 4.75 mm to 6 mm, particularly 4.75 mm or 6 mm. When the step is carried out at low temperature, one section of the tubular reactor, ranging from 30 cm² to 360 cm², may be dedicated to pre-cooling the reactants, and another section of the tubular reactor may be dedicated to the reaction itself, this other section advantageously ranging from 30 cm² to 360 cm². For example, the Rai reactor may include a first reactor section, ranging from 30 cm² to 360 cm², particularly about 60 cm², dedicated to cooling the trans-2-hexenal in solution in solvent S. ai at temperature T ai. Similarly, the Rai reactor may include a second reactor section of 30 cm to 360 cm, in particular of approximately 60 cm, dedicated to cooling potassium tert-butylate or sodium tert-butylate in solution in solvent S ai at temperature T a i. Only one or both reactants can be cooled. The Rai reactor may also include a third reactor section of 30 cm to 360 cm, specifically approximately 60 cm, dedicated to the reaction at temperature T ai between trans-2-hexenal in solution in solvent S ai and previously cooled to temperature T ai and potassium tert-butylate or sodium tert-butylate in solution in solvent S ai and previously cooled to temperature T ai. The Ra2 reactor may include a first reactor section of 30 cm to 360 cm, in particular of approximately 60 cm, dedicated to cooling the diethyl chlorophosphate in solution in solvent S a ? at temperature T a Similarly, the Ra2 reactor may include a second reactor section of 30 cm to 360 cm, specifically approximately 60 cm, dedicated to the passage of temperature T ai at temperature T a ? for the enolate of trans-2-hexenal. Finally, the Ra2 reactor may include a third reactor section of 30 cm to 360 cm, specifically approximately 60 cm, dedicated to the reaction at temperature T a 2 between diethyl chlorophosphate in solution in solvent S a 2 which can optionally be pre-cooled to temperature T a 2 and the enolate of trans-2-hexenal in solution in solvent S a 2 which can optionally be pre-cooled to temperature T a2. The first two sections of reactor Ra2 are optional, since step a1 is preferably carried out at a low temperature, the reaction mixture can already be at a suitable temperature for step a2. Reactor Rt>i may include a first reactor section of 30 cm to 360 cm, specifically approximately 60 cm, dedicated to heating the mixture M1 in solution in solvent Sbi to temperature Tbi. Similarly, reactor Rt>i may include a second reactor section of 30 cm to 360 cm, specifically approximately 60 cm, dedicated to heating the hydrolyzable dienophile DH in solution in solvent Sbi to temperature Tbi.Finally, the Rbi reactor may include a third reactor section, 30 cm³ to 360 cm³ in diameter, specifically approximately 60 cm³, dedicated to the reaction at temperature Tbi between the M1 mixture in solution in solvent Sbi (optionally at temperature Tbi) and the trans-2-hexenal of the hydrolyzable dienophile DH in solution in solvent Sbi at temperature Tbi and pressure Pbi. The first two sections of the Rbi reactor are optional; the reactor may consist of only the third section described above.

[0088] The reactors particularly suited to the present invention are the reactors marketed by the company Khi mod®, in particular the K1 reactor.

[0089] The reaction media can be mixed by any means known to those skilled in the art. In particular, the reactors according to the invention can be equipped with static mixers. The Rbi, Rai, and / or Ra2 reactors advantageously have an internal volume occupied by static mixers, ranging from 10% to 60%, preferably from 20% to 50%. Examples of static mixers include balls, rings, ribbon mixers, and helical mixers.

[0090] The reagents can be introduced into the reactors by means well known to those skilled in the art. Examples include piston pumps or peristaltic pumps. The Rbi, Rai, and / or Ra2 reactors can be interconnected by means also known to those skilled in the art. In particular, they can be connected in series with fittings that allow the introduction of the required reagents at each stage. It is understood that each continuous flow stage of the process according to the invention can be carried out in a single reactor or in a series of several reactors.

[0091] The following examples illustrate particular embodiments of the invention without limiting its scope.

[0092] EXAMPLES

[0093] The following abbreviations are used in the examples:

[0094] AcOEt - ethyl acetate

[0095] GC - gas chromatography

[0096] MeTHF - 2-methyltetrahydrofuran

[0097] NMP - N-methyl-2-pyrrolidone

[0098] HDPE - high-density polyethylene

[0099] PTFE - polytetrafluoroethylene tBuOK - potassium tert-butylate t s - residence time in the reactor

[0100] Raw materials and solvents were sourced commercially (Sigma Aldrich). The analytical method consisted of GC analysis on an HP 5890 Series II instrument equipped with a FID detector. The chromatographic column was an Innowax 30m, 0.25 mm, 0.25 pm column, with helium as the carrier gas and a pressure of 11 psi. The oven followed the following temperature profile: T0 = 150 °C, initial time 10 min, gradient 20°C / min, final temperature: 200 °C, duration 7 min. The injector was at 250 °C and the detector at 300 °C. The injected volume was 1 pL. The sample concentration was 4 g / L in AcOEt.

[0101] The continuous flow reactions in Examples 3, 5, 6, and 7 are carried out in a Khimod K1 reactor, a tubular reactor comprising 12 parallel tubes with a 1 / 8" cylindrical cross-section, connected by two metal flanges. The reactor body and flanges are made of Hastelloy. The flanges allow for various tube connection configurations.

[0102] The tubes used in the examples have the following internal diameters: 1 / 16” = 0.76 mm, 1 / 8” = 2.4 to 1.6 mm and 1 / 4” = 4.75 to 5 mm).

[0103] Example 1 (outside the scope of this invention): Batch synthesis of the mixture of isomers of crude diethyl hexa-1,3-dien-1-yl phosphate

[0104] In a dry, nitrogen-inerted 250 mL round-bottom flask equipped with a thermometer and a magnetic stir bar, 2.35 g (20.94 mmol, 1.2 eq) of tBuOK and 9.7 mL of 2-methyltetrahydrofuran are introduced. NMP (9.7 mL) is immediately added, and the mixture is stirred at room temperature for 30 min. A color change is observed in the reaction medium, changing from dark blue (10 min) to yellow (20 min). The flask is then immersed in an acetone bath cooled to -60 °C using a cryostat. Trans-2-hexenal (2.0 mL, 1.0 eq) is added dropwise from an addition funnel over 10 min. Once the temperature has stabilized, the mixture is stirred for 10 min. Next, diethyl chlorophosphate (3.28 mL, 1.1 eq) is added dropwise over 10 min. The brown reaction mixture is stirred for 1 h at -60°C, before being brought back up to -10°C and quenched by the dropwise addition of 16 mL of water.The organic phase was then extracted, washed with 3 x 10 mL of water, dried over MgSO4, and concentrated under vacuum. 3.58 g of diethyl-hexa-1,3-dien-1-yl phosphate were obtained (88.4% crude yield) with the following isomeric ratios: 0.3% (Z,Z), 1.4% (Z,E), 77.8% (E,Z), 20.5% (E,E). In total, this production took 3 h, resulting in a productivity of 4.77 kg / h. 1 .m' 3 of crude enolphosphate. Continuous synthesis of a mixture M1 of diethyl hexa-1,3-dien-1-yl phosphate in PTFE tubular reactors (steps a1) and a2) according to the invention on a laboratory scale)

[0105] The setup consists of two 40 cm lengths of 1 / 8" tubing, A and B, at room temperature, followed by a 2 m cooling loop immersed in a -55 °C bath. These two lengths converge in a PTFE tee, followed by a 6.5 cm diameter 1 / 4" PTFE tubular reactor (containing a 5.5 cm stainless steel static mixer), then a 0.88 m PTFE reactor immersed in a -55 °C bath, and finally 20 cm of insulated 1 / 8" tubing at room temperature. A 3-way valve followed by 20 cm of 1 / 8" tubing is placed at the end of the setup to allow the mixture to be added directly to a diethyl chlorophosphate solution under N₂O at -50 °C.

[0106] Solution A (10.75 mL of trans-2-hexenal in 44.6 mL of NMP and 44.6 mL of MeTHF) is prepared in a 100 mL volumetric flask under N₂O. The pump flow rate is set at 4.62 mL / min. Solution B (12.53 g of tBuOK in 44.6 mL of NMP and 44.6 mL of MeTHF) is prepared in a 100 mL volumetric flask under N₂O. The pump flow rate is set at 4.62 mL / min. Solution B is pre-shaken at room temperature for 30 min.

[0107] The setup, conditioned with THF under nitrogen, is cooled to -55 °C. Both pumps are started simultaneously (t0), and the reaction mixture is collected from the reactor outlet in the waste container (16 minutes). The reaction mixture is then added for 9 minutes (Ts = 1.92 min) to a diethyl chlorophosphate solution (6.15 mL in 12.3 mL of MeTHF) at -50 °C, placed in a 100 mL three-necked flask with temperature control and mechanical stirring. The initial temperature at addition is -50 °C, and the final temperature at addition is -42.5 °C. The setup is rinsed with THF immediately after the reagents have been added.

[0108] The solution was stirred at -50 °C for 1 h and then quenched at -50 °C with 60 mL of water added slowly (T = -50 °C to -24 °C). The reaction mixture was decanted. The organic phase was washed with 2 x 60 mL of water and then concentrated under vacuum. 7 g of enolphosphate were obtained with the following isomeric ratios: 0.5% (Z, Z), 1.4% (Z, E), 78.1% (E, Z), 20.0% (E, E). In total, this production lasted 2.15 h, resulting in a productivity of 27.5 kg / h. 1 .m' 3 of crude enolphosphate. Continuous synthesis at -55°C of the M1 mixture of diethyl hexa-1,3-dien-1-yl phosphate in a K1 Hastelloy reactor with treatment according to the invention (steps a1) and a2) according to the invention at pilot scale)

[0109] Solution 1 (trans-2-hexenal, 409 mL) is placed under N₂O in a 1 L glass Schlenk. Solution 2 (tBuOK, 168.4 g in 0.949 L of NMP and 0.949 L of toluene) is prepared in a 10 L HDPE container under N₂O. Solution 3 (diethyl chlorophosphate, 0.19 L) is placed in a 500 mL glass Schlenk under N₂O. Solutions 1 (221 g / h) and 2 (2951 g / h) are introduced into the previously inerted apparatus using two piston pumps. The enolate of trans-2-hexenal is produced in a 60 cm³ Khimod® K1 reactor made of Hastelloy, equipped with five stainless steel PT100 thermocouples and stainless steel static mixers, and cooled to -55 °C (ts = 1 min 2 s). The reactor outlet is a 1 / 16" PTFE tube, and the reaction mixture then meets solution 3 in a tee fitting. Solution 3 is introduced via a 3 émePiston pump (5.9 mL / min). Mixing is carried out rapidly (ts = 8 s) in a 30 cm 1 / 4" PTFE tube (equipped with static mixers) before being poured into a tank at ambient temperature. The process is performed at a pressure of 4 bar.

[0110] Once pre-filling is complete, 10 minutes are required to reach steady flow for solutions 1 and 2. 3 minutes are required to reach steady flow for solution 3. The product is collected only when steady flow is reached.

[0111] Enolphosphate was collected in a 10 L HDPE container inert with nitrogen for 103 min. The reaction mixture was quenched by the dropwise addition of 16 mL (8V) of water. The organic phase was then extracted, washed with 3 x 10 mL (3 x 5V) of water, and concentrated under vacuum. 853 g of enolphosphate were obtained (94% gross yield) with the following isomeric ratios: 0.6% (Z,Z), 1.2% (Z,£j, 76.3% E,Z), 21.9% (E,E). In total, this production took 2.8 h, resulting in a productivity of 4352 kg / h. 1 .m' 3 of crude enolphosphate.

[0112] Example 4: Continuous synthesis at 14°C of crude diethyl-1,3-dien-1-yl phosphate mixture with purification in a batch reactor without changing solvents.

[0113] The setup consists of 40 cm of 1 / 8" tubing at room temperature on channels A and B, followed by a 2 m cooling loop immersed in a -40 °C bath. These two channels converge in a stainless steel tee, followed by a 60 cm 1 / 4" stainless steel reactor and then 20 cm of insulated 1 / 8" tubing at room temperature. A 3-way valve followed by 20 cm of 1 / 8" tubing is placed at the end of the setup to allow the mixture to be added directly to a diethyl chlorophosphate solution under N₂O at -35 °C.

[0114] Solution A (53.8 mL of trans-2-hexenal in 223.1 mL of NMP and 223.1 mL of toluene) is prepared in a 500 mL volumetric flask under N₂O. The pump flow rate is set at 9.24 mL / min. Solution B (62.61 g of tBuOK in 218.7 mL of NMP and 218.7 mL of toluene) is prepared in a 500 mL volumetric flask under N₂O. The pump flow rate is set at 9.24 mL / min. Solution B is pre-shaken at room temperature for 30 min.

[0115] The apparatus, conditioned with toluene under nitrogen, is cooled to -35 °C. Both pumps are started simultaneously (t0), and the reaction mixture is collected from the reactor outlet (Ts = 1.44 min) in the waste container (16 min). The reaction mixture is then added for 30 min to a diethyl chlorophosphate solution (41 mL in 82 mL of toluene) at -35 °C, placed in a 500 mL three-necked flask with temperature control and mechanical stirring. The apparatus is rinsed with toluene immediately after the reagents have been added. The enolphosphate is obtained in solution as a mixture of isomers in the following proportions: 1.1% (Z,Z), 2.6% (Z,E), 73.3% (E,Z), 23% (E,E).

[0116] To this solution, 40.59 g of maleic anhydride is added, and the reaction mixture is heated to 70 °C for 3 h. After complete conversion of the (E,E) isomer, the mixture is cooled to 0 °C and then hydrolyzed with 240 mL of 3 M sodium hydroxide (pH 11-12). After settling, the organic phase is washed twice with 124 g of a 3.5% w / w aqueous NaCl solution. The organic phase is distilled under reduced pressure to yield 41.9 g of enolphosphate with the following isomeric ratios: 1.4% (Z,Z), 3.4% (Z,£j), 94.9% (E,Z), 0.3% (E,E), and 198 g of toluene, representing a toluene recycling rate of 70%. The aqueous phase is adjusted to pH > 14 by adding sodium hydroxide at room temperature. After complete dissolution, the NMP separates from the aqueous phase. Distillation under reduced pressure yields 152 g of NMP, representing an NMP recycling rate of 60%.

[0117] The total reaction volume for this example was 6.3 mL for tubular reactors and 500 mL for the batch reactor.

[0118] In total, this production lasted 7 hours, representing a productivity of 11.85 kg / h. 1 .m' 3 of purified enolphosphate. This example shows that not changing solvents after a first continuous step leads to significant productivity gains.

[0119] Example 5: Continuous synthesis of the M2 isomer mixture of diethyl hexa-1,3-dien-1-yl phosphate by the process according to the invention in a Khimod® reactor at -55°C (steps a1 and a2) according to the invention)

[0120] Preparation and assembly:

[0121] Solution 1 (trans-2-hexenal, 1.45 L) is placed in a 2 L glass slender under N₂O. Solution 2 (tBuOK, 1.178 kg in 6.6445 L of NMP and 6.6445 L of toluene) is prepared in two 10 L HDPE containers under N₂O. Solution 3 (diethyl chlorophosphate, 1.619 L) is placed in a 2 L glass slender under N₂O. Solutions 1 (221 g / h) and 2 (2951 g / h) are introduced into the previously inerted apparatus using two piston pumps. The trans-2-hexenal enolate is produced in a 60 cm³ Khimod® K1 reactor made of Hastelloy, equipped with five stainless steel PT100 thermocouples and stainless steel static mixers, and cooled to -55 °C. The reactor outlet is a 1 / 16" PTFE tube, and the reaction mixture then meets solution 3 in a 1 / 8" tee fitting. Solution 3 is introduced via a 3 émePiston pump (5.9 mL / min). Mixing is rapid in a 30 cm 1 / 4" PTFE tube equipped with static mixers before flowing into a tank at ambient temperature. The process outlet pressure is 4 bar.

[0122] Summary:

[0123] Once pre-filling is complete, 10 minutes are required to reach steady flow for solutions 1 and 2. 3 minutes are required to reach steady flow for solution 3. The product is collected only when steady flow is reached.

[0124] The crude enolphosphate is collected in a 20 L HDPE container inert with nitrogen for 258 min. 15.510 kg of crude solution are obtained with the following isomeric ratios: 0.6% (Z,Z), 1.1% (Z,£j), 75.9% (E,Z), 22.4% (E,E). Performing steps a1) and a2) in continuous flow allows for a productivity of 4352 kg. h' 1 me 3of the M1 mixture of enolphosphate. This value is significantly higher than that of the batch process (example 1). For comparison, the same reaction carried out under the conditions of document WO 2018 / 162739 A1 with an equivalent mass of aldehyde would have required a 20 L reactor with an additional cost due to a 7% excess of raw material. The reaction time would have been 8 hours followed by 6 hours of treatment to purify the enolphosphate.

[0125] In a dry, nitrogen-inerted 50 L reactor, 1.240 kg of maleic anhydride are introduced, followed by 15.51 kg of crude enolphosphate mixture. The mixture is heated to 70 °C and stirred at 300 rpm. After 2 hours and 40 minutes, the conversion of the (E,E) isomer is complete. The reaction mixture is hydrolyzed with 10.42 kg of 15% sodium hydroxide (pH 11-12). After settling, the organic phase is washed twice with 5 kg of a 3.5% w / w aqueous NaCl solution. The organic phase is concentrated under reduced pressure to yield 1.4 kg of product (62% crude yield) with the following isomeric ratios: 0.8% (Z,Z), 1.4% (Z,E), 97.8% (E,Z), 0% (E,E).

[0126] In total, this production lasted 10.1 hours, resulting in a productivity of 2.75 kg / h. 1 me 3 of purified enolphosphate. This productivity is penalized by performing step b) in batch mode, for which productivity drops to 5.89 kg. h' 1 me 3 .

[0127] Example 6: Continuous purification by Diels-Alder reaction of crude diethyl hexa-1,3-dien-1-yl phosphate on K1 at 150°C (steps b1), b2) and b3) according to the invention)

[0128] To 90.9 g of enolphosphate (0.9% (Z,Z), 1.5% (Z,E), 76.1% (E,Z), 21.6% (E,E)) in a mixture of NMP (245.5 mL) and toluene (245.4 mL), 49.5 g of 7.5% w / w maleic anhydride in a 50 / 50 toluene / NMP mixture are added. The reaction mixture is introduced into a 60 cm² Khimod® tubular reactor made of Hastelloy, equipped with four stainless steel PT100 thermocouples and stainless steel static mixers. The reactor has been previously inerted and heated to 150 °C at a pressure of 12–13 bar for a residence time of 5 minutes. After 10 minutes, to allow the flow rate to reach steady state, the reaction mixture is collected in a reactor at room temperature for 13 minutes. The reaction mixture is then hydrolyzed with 157 g of 3M sodium hydroxide (pH = 11-12). After decantation, the organic phase is washed twice with 78 g of a 3.5% w / w aqueous NaCl solution.The organic phase is concentrated under reduced pressure to yield 16.4 g of product with the following isomeric ratios: 1.0% (Z,Z), 2.0% (Z,£j), 96.8% (E,Z), 0.2% (E,E). This production took a total of 43 minutes, resulting in a productivity of 323 kg / h. 1 .m' 3 of purified enolphosphate. For comparison, the same reaction carried out under the conditions of document WO 2018 / 162739 A1 would have required a 20 L reactor with a residence time of 3 h for a productivity of 15.7 kg.h' 1 .m' 3 of purified enolphosphate. Synthesis and improvement of the isomeric purity of a mixture of isomers of diethyl hexa-1,3-dien-1-yl phosphate in continuous (steps a1), a2), b1), b2) and b3) according to the invention

[0129] Solution 1 (trans-2-hexenal, 1.45 L) is placed in a 2 L glass Schlenk under N₂O. Solution 2 (tBuOK, 1.178 kg in 6.6445 L of NMP and 6.6445 L of toluene) is prepared in two 10 L HDPE containers under N₂O. Solution 3 (diethyl chlorophosphate, 1.619 L) is placed in a 2 L glass Schlenk under N₂O. Solutions 1 (221 g / h) and 2 (2951 g / h) are introduced into the previously inerted apparatus using two piston pumps. The enolate of trans-2-hexenal is produced in a 60 cm³ Khimod® K1 reactor made of Hastelloy, equipped with five stainless steel PT100 thermocouples and stainless steel static mixers, and cooled to -55 °C. The reactor outlet is a 1 / 16" PTFE tube, and the reaction mixture then meets solution 3 in a 1 / 8" tee fitting. Solution 3 is introduced via a 3 éme Piston pump (5.9 mL / min). Mixing occurs rapidly in a 30cm 1 / 4" PTFE tube equipped with static mixers. The process outlet pressure is 4 bar. (of the reactor in step b1):

[0130] Continuing from the PTFE reactor of the previous step, it is connected using 2 tee fittings. The first tee fitting is connected to a drain on one side and to a valve on the other, which is itself connected to the second tee fitting. This second tee fitting connects, on one side, a supply of 10 L of maleic anhydride solution at a concentration of 0.86 mol / L (8.6% w / w) in a 50 / 50 toluene / NMP mixture, and on the other side, a 3.6 m long tubular reactor made of 316R stainless steel with a circular cross-section of 1 / 8" diameter. A 2 m section of this reactor is filled with static mixers and placed in a furnace preheated to 150 °C. At the furnace outlet, a 1 m section is placed in an ice bath, and the end of the reactor is connected to a safety valve set at 3 bar. The final solution is discharged into a 20 L container.The maleic anhydride solution is pumped into the tee using a peristaltic pump at a flow rate of 2.8 L / h (i.e. a molar flow rate equal to 1.07 times that of trans-2 hexenal).

[0131] Once pre-filling is complete, 10 minutes are required for solutions 1 and 2 to reach steady-state flow. Three minutes are required for solution 3 to reach steady-state flow in the PTFE reactor before being transferred to the reactor in step b1. Three minutes are required for it to reach steady-state flow in this reactor. The product is collected only once steady-state flow is reached.

[0132] The final enolphosphate is collected in a reactor container, and after 2 hours of collection, 12.7 kg of solution is recovered. This solution is then hydrolyzed with a 5% sodium hydroxide solution and washed several times with 5 L of demineralized water. The organic phase is recovered, and the toluene is distilled under partial vacuum. This yields 598 g of product with the following isomeric ratios: 2.1% (Z,Z), 1.0% (Z,E), 96.4% (E,Z), 0.5% (E,E). The productivity is 996 kg / h. 1 .m' 3 of purified enolphosphate. Thus, carrying out the process according to the invention is particularly advantageous by combining steps a1), a2), b1), b2) and b3).

[0133] BIBLIOGRAPHICAL REFERENCES

[0134] Witzgall, P., Tasin, M., Buser, H. R., Wegner-Kiss, G., Mancebôn, V. S., loriatti, C., Backman, A. C., Bengtsson, M., Lehmann, L., & Francke, W. (2005). New pheromone components of the grapevine moth Lobesia botrana. Journal of chemical ecology, 31(12), 2923-2932.

Claims

DEMANDS 1. Process for preparing a mixture M2 of enolphosphate isomers of the following formula 1: comprising less than 5%, preferably less than 2%, of (E,E) isomer and comprising at least 93% of (E,Z) isomer, at least 0.1% of (Z,Z) isomer and at least 0.1% of (Z,E) isomer, comprising the following steps: b1) contacting in a continuous flow reactor Rt>i a mixture M1 of enolphosphate isomers of formula 1 comprising at least 10% of (E,E) isomer, at least 60% of (E,Z) isomer, at least 0.1% of (Z,Z) isomer and at least 0.1% of (Z,E) isomer, with a hydrolyzable dienophile DH being maleic anhydride, in an organic solvent St>i comprising an aromatic solvent, at a temperature Tt>i ranging from 110 °C to 250 °C, and at a pressure Pt>i ranging from 2 bars to 50 bars, to give a reaction medium comprising the mixture M2 of enolphosphate isomers and an adduct formed between the (E,E) isomer and the hydrolyzable dienophile DH,b2) contacting the reaction medium obtained in step b1) with a base to give a hydrolyzed medium comprising the mixture M2 of enolphosphate isomers and an adduct formed between the (E,E) isomer and the hydrolyzed dienophile DH, and b3) removing the hydrolyzed adduct from the hydrolyzed medium obtained in step b2) to obtain the mixture M2 of enolphosphate isomers.

2. A preparation process according to claim 1, wherein the organic solvent St>i is a mixture of solvents comprising an organic solvent selected from the group consisting of toluene, xylenes, and mixtures thereof, and a solvent selected from the group consisting of N-methyl-2-pyrrolidone (NMP), N-butyl-2-pyrrolidone (NBP), N-methylcaprolactam, 2-methyltetrahydrofuran, and mixtures thereof, preferably the organic solvent St>i is a mixture of toluene and NMP, more preferably the organic solvent St>i is a toluene:NMP mixture with a volume ratio from 70:30 to 30:70, typically about 50:

50.

3. Preparation process according to claim 1 or 2, wherein the residence time tRbi in the reactor Rbi is less than or equal to 15 min, advantageously tRbi is less than or equal to 10 min, preferably less than or equal to 6 min, typically about 3 or 5 min. TJ 4. A preparation method according to any one of claims 1 to 3, wherein: - step b1) is carried out at a temperature Tt>i ranging from 120 °C to 220 °C, preferably ranging from 130 °C to 200 °C, and / or - step b1) is carried out at a pressure Pt>i ranging from 3 bars to 30 bars, preferably ranging from 10 bars to 20 bars.

5. A preparation method according to any one of claims 1 to 4, wherein the reactor Rt>i, preferably tubular, has an internal volume occupied at a rate of 10% to 60%, preferably 20% to 50%, by static mixers.

6. A preparation method according to any one of claims 1 to 5, wherein the mixture M1 is introduced into the reactor Rt>i at a molar flow rate DMI and the hydrolyzable dienophile DH is introduced into the reactor Rt>i at a molar flow rate DDH, the DDH / DMI ratio ranging from 0.5 to 2.0, preferably from 0.9 to 1.5, preferably from 1 to 1.

2.

7. A preparation method according to any one of claims 1 to 6, further comprising the following steps: a1) contacting trans-2-hexenal with potassium tert-butylate or sodium tert-butylate in a continuous flow Rai reactor to obtain an enolate of trans-2-hexenal, and a2) contacting the trans-2-hexenal enolate with diethyl chlorophosphate in a continuous flow Ra2 reactor to obtain the mixture M1 as defined in claim 1.

8. A preparation method according to claim 7, wherein step a1) is carried out in an organic solvent S ai and step a2) is carried out in an organic solvent S a 2. Organic solvents S ai and S a2, identical or different, being chosen from the group consisting of aromatic solvents, N-methyl-2-pyrrolidone (NMP), N-butyl-2-pyrrolidone (NBP), N-methylcaprolactam, 2-methyltetrahydrofuran and mixtures thereof, preferably organic solvents S ai and S a 2, identical or different, being a mixture of toluene and NMP, more preferably a toluene:NMP mixture with a volume ratio of 70:30 to 30:70, preferably ranging from 60:40 to 40:60, preferably ranging from 55:45 to 45:55, typically about 50:

50.

9. A preparation method according to claim 7 or 8, wherein the solvents S a i, S a 2 and Sbi are identical.

10. A preparation method according to claim 9, wherein the solvents S a i, S a2 and Sbi are a mixture of toluene and NMP, more preferably a toluene:NMP mixture with a volume ratio of 70:30 to 30:70, preferably ranging from 60:40 to 40:60, preferably ranging from 55:45 to 45:55, typically about 50:

50.

11. A preparation method according to any one of claims 7 to 10, wherein: - step a1) is carried out at a temperature T ai ranging from -70 °C to -40 °C, preferably from -60 °C to -50 °C, typically around -55 °C, and / or - step a2) is carried out at a temperature T a 2 ranging from -70 °C to 0 °C, preferably from -60 °C to 0 °C, typically around -50 °C.

12. A preparation method according to any one of claims 7 to 11, wherein: - the Rai reactor, preferably tubular, has an internal volume occupied by static mixers, and / or - the Ra2 reactor, preferably tubular, has an internal volume occupied from 10% to 60%, preferably from 20% to 50%, by static mixers.

13. A preparation method according to any one of claims 7 to 12, wherein trans-2-hexenal is introduced into the Rai reactor at a molar flow rate DT2H and potassium tert-butylate or sodium tert-butylate is introduced into the Rai reactor at a molar flow rate DB, the DB / DT2H ratio ranging from 0.5 to 2.0, preferably 0.9 to 1.5, typically from 1 to 1.

2.

14. A preparation method according to claim 13, wherein diethyl chlorophosphate is introduced into the Ra2 reactor at a molar flow rate DCD, the DCD / DT2H ratio ranging from 0.5 to 2.0, preferably 0.9 to 1.5, typically from 1 to 1.

2.

15. Process for preparing a mixture M1 of enolphosphate isomers of the following formula 1: comprising at least 10% of the (E,E) isomer, at least 60% of the (E,Z) isomer, at least 0.1% of the (Z,Z) isomer, and at least 0.1% of the (Z,E) isomer, comprising the following steps: a1) contacting trans-2-hexenal with potassium tert-butylate or sodium tert-butylate in a continuous-flow Rai reactor, in an organic solvent S ai comprising an aromatic solvent, preferably toluene, and at a temperature T ai ranging from -70 °C to -40 °C, to obtain a trans-2-hexenal enolate, and a2) contacting the trans-2-hexenal enolate with diethyl chlorophosphate, preferably in an organic solvent S, in a continuous flow Ra2 reactor a 2 comprising an aromatic solvent, preferably toluene, and at a temperature T a 2 going from -70 °C to 0 °C to obtain mixture M1.

16. A preparation method according to claim 15, wherein the organic solvents S aiand Sa2, identical or different, are a mixture of solvents comprising an aromatic solvent selected from the group consisting of toluene, xylenes, and mixtures thereof, and a solvent selected from the group consisting of N-methyl-2-pyrrolidone (NMP), N-butyl-2-pyrrolidone, N-methylcaprolactam, 2-methyltetrahydrofuran, and mixtures thereof, preferably organic solvents S ai and S a 2, identical or different, are a mixture of toluene and NMP, more preferably organic solvents S ai and Sa2, identical or different, are a toluene:NMP mixture with a volume ratio ranging from 70:30 to 30:70, preferably ranging from 60:40 to 40:60, preferably ranging from 55:45 to 45:55, typically about 50:

50.

17. A preparation method according to claim 15 or 16, wherein: - step a1) is carried out at a temperature T ai ranging from -60 °C to -50 °C, typically around -55 °C, and / or - step a2) is carried out at a temperature T a 2 ranging from -60 °C to 0 °C, typically around -50 °C.

18. A preparation method according to any one of claims 15 to 17, wherein: - the Rai reactor, preferably tubular, has an internal volume occupied by static mixers, and / or - the Ra2 reactor, preferably tubular, has an internal volume occupied from 10% to 60%, preferably from 20% to 50%, by static mixers.

19. A preparation method according to any one of claims 15 to 18, wherein trans-2-hexenal is introduced into reactor Rai at a molar flow rate DT2H and potassium tert-butylate or sodium tert-butylate is introduced into reactor Rai at a molar flow rate DB, the DB / DT2H ratio ranging from 0.5 to 2.0, preferably 0.9 to 1.5, typically from 1 to 1.

2.

20. A preparation method according to claim 19, wherein diethyl chlorophosphate is introduced into reactor Ra2 at a molar flow rate DCD, the DCD / DT2H ratio ranging from 0.5 to 2.0, preferably 0.9 to 1.5, typically from 1 to 1.2.

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