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

Abstract

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 (E,Z) isomer and essentially devoid of the (E,E) isomer.

Description

Title of the invention: Continuous flow process for preparing a mixture of isomers of hexa-l,3-dien-l-yl-diethylphosphate. FIELD OF THE INVENTION

[0001] The present invention relates to a continuous flow process for preparing a mixture of hexa-1,3-dien-1-yl-diethylphosphate isomers, mainly composed of the (JE,9Z) isomer and essentially devoid of the EIE,9E isomer. PRIOR TECHNIQUE

[0002] (E,Z)-7,9-dodecadienyl-1-acetate is the major component of the pheromone bouquet of Eobesia 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 the isomers of 7,9-dodecadienyl-1-acetate in the following proportions: (EZ): 94.1%, (E,E): 3.0%, (Z,E): 2.7%, (Z,Z): 0.1% (Witzgall et al. 2005). This pheromone bouquet is to be used in diffusers placed in the vineyards, which generate mating confusion by drowning the signal emitted by the females of the species in a cloud of pheromones.

[0003] The different isomers of (Σ',Z)-7,9-dodecadienyl-l-acetate are shown in Table 1.

[0004] [Tables 1] U ... ov ï (E,Z)-7,9-dodecadienyl-l-acetate i ...... .... ..... ox " J (Z,Z)-7,9-dodecadienyl-l-acetate L î (Z,E)-7,9-dodecadienyl-l-acetate

[0005] It is used in the form of a mixture of isomers composed mainly of the (7E,9Z) isomer and often of the (JE,9E9) isomer, the ratio of which varies significantly from one commercial product to another. Thus, apart from the products manufactured The Plaintiff states that the (7Z,9Z) and (7Z,9E) isomers are generally absent, which weakens the pheromone bouquet. In the remainder of this text, isomers will be referred to solely by the numbers corresponding to the position of the unsaturates. For example, the (JE,9Z) isomer will be abbreviated as (E,Z).

[0006] Documents WO 2016 / 001383 A1 and WO 2018 / 162739 A1 relate to processes for the synthesis of (β',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 that they make possible. Indeed, the synthesis of a mixture of (E,Z) and (E,E9) had already been described previously. However, the preparation of a mixture of isomers containing nearly 94% of (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.

[0007] Furthermore, it is known that the excessive use of sexual confusion products based on incomplete pheromone bouquets leads to the development of insects more sensitive to minor components and risks of developing resistance to sexual confusion treatments become real.

[0008] It is therefore evident that access to a pheromonal bouquet with a composition closer to the natural pheromonal bouquet under economical conditions is essential for the sustainable development of these alternative technologies to insecticides.

[0009] In documents WO 2016 / 001383 A1 and WO 2018 / 162739 A1, the processes for preparing the pheromone bouquet of Eobesia 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 allowing the formation of 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-l-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-l-acetate isomers.

[0010] The natural content of the (EJE) isomer of the pheromone is approximately 3%. However, step c) of the process described above naturally induces partial isomerization of the other isomers into (EJE) because step c) involves heating the medium reaction in the presence of metals facilitating this isomerization. It is therefore necessary that the dienolphosphate intermediate used for this step be poor in (E,E) isomer.

[0011] The distribution of the 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 distribution of the isomers by eliminating almost all of the (E,E) isomer. O 1

[0012] Better technical and economic control of these steps has a direct impact on the industrial availability of a mixture of 7,9-dodecadienyl-l-acetate isomers with a composition close to the natural composition.

[0013] 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 from an investment cost perspective because, in this type of process, reaction volumes are minimal, thus reducing the need for complex reactors, and 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.

[0014] 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 dienolphosphate isomers of formula 1 with control of the isomeric ratio. FIGURES

[0015] [Fig. 1A]: Diagram of a process according to the invention comprising steps a1), a2), b1), b2) and b3) in which steps a1), a2), b1) are carried out in continuous flow. Steps b1), b2) and b3) are shown in more detail in [Fig. 1B].

[0016] [Fig.1B]: Diagram of a process according to the invention comprising steps a1), a2), b1), b2) and b3) in which steps a1), a2), b1) are carried out in continuous flow. Steps a1) and a2) are shown in more detail in [Fig.1A]. Summary of the invention

[0017] The present invention therefore reveals an innovative way of accessing the qualities of pheromones described in WO 2016 / 001383 Al and WO 2018 / 162739 Al by simplifying the manufacture of the dienolphosphate intermediates described in these patents.

[0018] Thus, a first object of the invention is a process for preparing a mixture M2 of enolphosphate isomers of the following formula 1: O 1

[0019] 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 R1 of a mixture M1 of enolphosphate isomers of formula 1 comprising at least 10% of isomer (E,E), at least 60% of isomer (E,Z), at least 0.1% of isomer (Z,Z) and at least 0.1% of isomer (Z,E), 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 isomer (E,E) 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 isomer (E,E) and the hydrolyzed hydrolyzable dienophile DH, and b3) the removal of the hydrolyzed adduct from the hydrolyzed medium obtained in step b2) to obtain the mixture M2 of enolphosphate isomers.

[0020] Preferably, step bl) is carried out in an organic solvent S bi comprising an aromatic solvent, preferably toluene, at a temperature T bi ranging from 110 °C to 200 °C, and at a pressure P bi ranging from 2 bar to 50 bar. Preferably, the residence time tRbi in the reactor Rbi is less than or equal to 15 min.

[0021] Preferably, the process further comprises the following steps: al) contacting trans-2-hexenal with potassium tert-butylate or sodium tert-butylate in a continuous flow reactor R ai to obtain an enolate of trans-2-hexenal, and a2) the contacting in a continuous flow reactor R a2 of the enolate of trans-2-hexenal with diethyl chlorophosphate to obtain the mixture Ml as defined previously.

[0022] A second object of the invention is a process for preparing a mixture Ml of enolphosphate isomers of the following formula 1:

[0023] 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: (a) contacting trans-2-hexenal with potassium tert-butylate or sodium tert-butylate in a continuous flow reactor R ai, to obtain an enolate of trans-2-hexenal, and a2) the contacting in a continuous flow reactor R a2 of the enolate of trans-2-hexenal with diethyl chlorophosphate, to obtain the mixture Ml.

[0024] 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 a2 ranging from -70 °C to 0 °C. DETAILED DESCRIPTION OF THE INVENTION

[0025] The various embodiments presented throughout the description can be used alone or in combination with each other, without limitation of combination. Definitions

[0026] Any interval of values ​​designated by the expression "between a and b" as well as by the expression "from a to b" designates the domain of values ​​going from a to b (that is to say including the bounds a and b).

[0027] For the purposes of this invention, "ambient temperature" means a temperature of 15 to 40°C, preferably 15 to 30°C, in particular 20 to 25°C.

[0028] 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.

[0029] 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.

[0030] For the purposes of this invention, the term "(Ci-C6) alkyl group" refers to a monovalent, saturated, linear or branched hydrocarbon chain comprising 1 to 6 carbon atoms. Examples of (Ci-C6) alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl.

[0031] By "xylene" is meant 1,2-dimethylbenzene, 1,3-dimethylbenzene, 1,4-dimethylbenzene or mixtures thereof.

[0032] 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 value indicated.

[0033] 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).

[0034] 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 is composed 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.

[0035] Process for preparing a mixture M2 of enolphosphate isomers

[0036] The present invention relates to a process for preparing a mixture M2 of enolphosphate isomers of the following formula 1: O 1 O Uul

[0037] 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 R1 of a mixture M1 of enolphosphate isomers of formula 1 comprising at least 10% of isomer (E,E), at least 60% of isomer (E,Z), at least 0.1% of isomer (Z,Z) and at least 0.1% of isomer (Z,E), 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 isomer (E,E) 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 isomer (E,E) and the hydrolyzed dienophile DH, and b3) the removal of the hydrolyzed adduct from the hydrolyzed medium obtained in step b2) to obtain the mixture M2 of enolphosphate isomers.

[0038] Step bl) is more particularly carried out in an organic solvent S bi comprising an aromatic solvent, at a temperature T bi ranging from 110 °C to 200 °C, and at a pressure Pbi ranging from 2 bars to 50 bars. Preferably, the residence time tRbi in the RM reactor is less than or equal to 15 min.

[0039] 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.

[0040] The M2 mixture of enolphosphate isomers of formula 1 may comprise: - less than 2% of the (E,E) isomer, preferably less than 1%, or even less than 0.5%, typically less than 0.3% or less than 0.1% of the (E,E) isomer; and / or - at least 93% of the (E,Z) isomer, preferably at least 94%, or at least 95%, typically at least 96% 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.

[0041] Advantageously, the mixture M2 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.

[0042] The mixture M2 may comprise from 0.3% to 10%, preferably from 0.5% to 5%, of (Z,Z) isomer and / or from 0.3% to 10% isomer, preferably from 0.5% to 5% of (Z,E) isomer.

[0043] Thus, the mixture M2 of enolphosphate isomers of formula 1 can be prepared in two successive steps from the mixture Ml of enolphosphate isomers of formula 1.

[0044] The mixture Ml of enolphosphate isomers of formula 1 comprises, on the one hand, a proportion of (E,E) isomer substantially greater than that of the mixture M2 of enolphosphate isomers, and on the other hand, a proportion of (E,Z) isomer less than that of the mixture M2.

[0045] The Ml mixture of enolphosphate isomers of formula 1 may therefore comprise: - at least 10% of the (E,E) isomer, preferably at least 12%, or even 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 around 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.

[0046] The mixture Ml 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 Ml comprises less than 30% of the (E,E) isomer.

[0047] Advantageously, the mixture Ml 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.

[0048] The first step bl) is a step of contacting in a continuous flow reactor R bi the mixture Ml of enolphosphate isomers of formula 1 as defined above with a hydrolyzable dienophile DH 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.

[0049] 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 makes it possible to obtain a mixture of isomer M2 essentially devoid of the (E,E) isomer, which can then be used for the preparation of the mixture of isomers of 7,9-dodecadienyl-l-acetate.

[0050] Step bl) is carried out in an organic solvent S bi 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 chosen from the group consisting of toluene, xylenes, and mixtures thereof; again, preferably, the aromatic solvent is toluene. The organic solvent S bi is advantageously a mixture of solvents comprising an aromatic solvent, preferably chosen from the group consisting of toluene, xylenes, and mixtures thereof, preferably being 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 bi is a solvent mixture comprising toluene and NMP or NBP.The solvent is particularly advantageous. Organic solvent Sbi is a mixture of toluene and NMP. When Sbi 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 Sbi 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 bl) can be carried out at a temperature Tbi ranging from 120 °C to 180 °C, preferably from 130 °C to 160 °C, and / or at a pressure Pbi 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 bl) is carried out at a temperature Tbi 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.

[0052] The hydrolyzable dienophile DH can be added in step bl) 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 the mixture Ml.

[0053] This step is carried out in an R bi reactor.

[0054] The mixture Ml of enolphosphate isomers of formula 1 can be introduced into the reactor R bi as a solution in the solvent SM as defined above. This solution advantageously has a concentration in the mixture Ml 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.

[0055] The hydrolyzable dienophile DH can be introduced into the reactor Rbi as a solution in the solvent Sbi as defined above. 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.

[0056] The mixture Ml can be introduced into the reactor R bi at a molar flow rate D Mi and the hydrolyzable dienophile DH can be introduced into the reactor R bi at a molar flow rate D DH, the ratio D dh / D mi advantageously ranging from 0.5 to 2.0, preferably 0.9 to 1.5, preferably from 1 to 1.2.

[0057] 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.

[0058] Step b2) consists of contacting the reaction medium obtained in step bl) with a base. It can be carried out by adding the base to the reaction medium obtained In step b1), preferably after cooling, a basic aqueous solution is used. Step b2) can be carried out at room temperature and atmospheric pressure.

[0059] As a usable base in this step, NaOH or KOH may be mentioned. The basic aqueous solution of 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 about 11, 12, 13 or 14.

[0060] Step b2) therefore leads to obtaining 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 mixture M2 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 decantation of the aqueous phase (obtained during washing) brought to a pH of 12 to 14.

[0064] Indeed, when the solvent Sbi is a mixture of toluene and NMP, step b3) leads to the formation of two phases: an organic phase comprising the mixture M2 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 evaporation of the solvent. The aqueous phase can be brought to a strongly basic pH, and the NMP can then be recycled by decantation.

[0065] The method according to the invention may also further comprise the following steps: al) contacting trans-2-hexenal with potassium tert-butylate or sodium tert-butylate in a continuous flow reactor R ai to obtain an enolate of trans-2-hexenal, and a2) the contacting in a continuous flow reactor R a2 of the enolate of trans-2-hexenal with diethyl chlorophosphate to obtain the mixture Ml as defined previously.

[0066] Steps a1) and a2) allow the mixture M1 of enolphosphate isomers of formula 1 to be obtained. These two steps are carried out before step bl) as defined above.

[0067] Step a1a) consists of contacting trans-2-hexenal with potassium tert-butylate or sodium tert-butylate in a continuous flow reactor R1a 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.

[0068] Step a1) is advantageously carried out in an organic solvent Sai and step a2) is advantageously carried out in an organic solvent Sa2. The organic solvents Sai and Sa2, whether 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, it is toluene. The organic solvents Sai and Sa2, identical or different, may be chosen from the group consisting of toluene, xylenes, NMP, NBP, N-methylcaprolactam, 2-methyltetrahydrofuran and mixtures thereof.

[0069] Preferably, the organic solvents Sbi 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 Sbi 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 S bi and / or S b2 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 . from 55:45 to 45:55, typically about 50:50. More preferably, the organic solvents S bi and S b2, identical or different, are a toluene:NMP mixture with a volume ratio from 70:30 to 30:70, preferably from 60:40 to 40:60, preferably from 55:45 to 45:55, typically about 50:50.

[0070] According to an advantageous embodiment, when the process according to the invention comprises steps a1) and a2), the solvents Sai, Sa2, and Sbi are identical, preferably the solvents Sai, Sa2, 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 from 60:40 to 40:60, preferably from 55:45 to 45:55, typically about 50:50. The use of identical solvents Sai, Sa2, and Sbi facilitates the recycling of the solvents used. Furthermore, the use of the solvent mixtures according to the invention is particularly advantageous since it allows all the steps requiring heating or cooling of the reaction medium to be carried out while controlling its viscosity.

[0071] Performing steps a1), a2), and b1) sequentially in the same solvent or solvent mixture is advantageous because it avoids time-consuming and costly solvent changeover steps. The Applicant has surprisingly discovered that the toluene:NMP mixture is particularly well-suited to these steps, as this mixture allows both the low-temperature steps (a1) and a2)) and step b1), which is carried out at higher temperatures and pressures, to be performed. This significantly optimizes the production of mixture M2.

[0072] Step a1) can be carried out at a temperature T ai of -70 °C to -40 °C, preferably from -60 °C to -50 °C, typically about -55 °C, and / or step a2) is carried out at a temperature T a2 ranging from -70 °C to 0 °C, preferably from -60 °C to 0 °C, typically about -50 °C.

[0073] In step a1a), trans-2-hexenal can be introduced into reactor R ai at a molar flow rate D T2H and potassium tert-butylate or sodium tert-butylate can be introduced into reactor R ai at a molar flow rate DB, the ratio DB / D T2H ranging from 0.5 to 2.0, preferably 0.9 to 1.5, preferably from 1 to 1.2.

[0074] In step a2), diethyl chlorophosphate can be introduced into reactor R a2 at a molar flow rate D CD, the ratio D cd / D T2H ranging from 0.5 to 2.0, preferably 0.9 to 1.5, typically from 1 to 1.2.

[0075] Trans-2-hexenal can be introduced into reactor Rai as a solution in solvent Sa[ as defined above; it can also be introduced pure into reactor Rai. This solution advantageously has a w / w concentration of trans-2-hexenal ranging from 2% to 100%.

[0076] Potassium tert-butylate or sodium tert-butylate can be introduced into reactor Rai as a solution in solvent Sai as defined above. 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%.

[0077] Diethyl chlorophosphate can be introduced into reactor R a2 as a solution in solvent S a2 as defined above; it can also be introduced pure into reactor R a2. This solution advantageously has a w / w concentration of diethyl chlorophosphate ranging from 2% to 100%.

[0078] The residence time tRa[ in the reactor Ra[ is less than or equal to 15 min, preferably less than or equal to 10 min, preferably less than or equal to 5 min. tRai advantageously ranges from 1 min to 4 min, typically about 2 or 3 min.

[0079] The residence time tRa2 in the reactor Ra2 is less than or equal to 15 min, preferably less than or equal to 10 min, preferably less than or equal to 5 min. tRa2 advantageously ranges from 1 min to 4 min, typically about 2 or 3 min.

[0080] The successive execution of steps a1), a2), and b1) is particularly advantageous since it eliminates the need for intermediate treatments, such as the separation / purification of the mixture M1 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. The quantity of enolphosphate mixture M2 produced per hour is thus significantly increased.

[0081] An example of a process according to the invention comprising steps a1), a2), b1), b2), and b3) is shown in Figures IA and IB. In [Fig. 1A], a solution of potassium tert-butylate or sodium tert-butylate is introduced into a CBase vessel and a solution of trans-2-hexenal (or pure trans-2-hexenal) is introduced into a CT2h vessel. Trans-2-hexenal is introduced into a first reactor section Ra[ by a pump at a molar flow rate DT2H. This first section cools the trans-2-hexenal to temperature Tab. Potassium tert-butylate or sodium tert-butylate is introduced into a second reactor section Ra[ 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 Tap. The mixing of the reactants is then carried out in a third reactor section Ra[, still at temperature Tab. This reaction allows the enolate of trans-2-hexenal to be obtained (step a1)). A solution of diethyl chlorophosphate (or chlorophosphate of . Pure diethyl) is introduced into a vessel CCd-. This solution is introduced into reactor Ra2 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 Ta2 without active cooling of reactor Ra2 or vessel Ccd-. The mixture M1 is therefore produced in reactor Ra2. In [Fig. 1B], a solution of hydrolyzable dienophile is introduced into a CDH vessel. This solution is introduced into reactor RM at a temperature Tbi and a pressure Pb[ by a pump at 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 recovered at the outlet of reactor Rbi to then carry out steps b2) and b3) in batch mode.

[0082] Process for preparing a mixture of Ml of enolphosphate isomers

[0083] Another object of the invention relates to a process for preparing a mixture Ml of enolphosphate isomers of the following formula 1: O 1

[0084] 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 reactor R ai, at a temperature T ai ranging from -70 °C to -40 °C, to obtain an enolate of trans-2-hexenal, and a2) contacting trans-2-hexenal enolate in a continuous flow reactor R a2 with diethyl chlorophosphate, preferably in an organic solvent S a2 comprising an aromatic solvent, preferably toluene, and at a temperature T a2 ranging from -70 °C to 0 °C to obtain the mixture Ml.

[0085] Step a1) is more particularly carried out in an organic solvent S ai comprising an aromatic solvent, preferably toluene.

[0086] In this other object of the invention, the mixture Ml of enolphosphate isomers of formula 1 and the steps a1) and a2) are as defined above.

[0087] The process for preparing the Ml mixture of enolphosphate isomers according to the invention allows working at very low temperatures which limit the formation of minority isomers of the Ml isomer mixture. Continuous flow stage reactors

[0088] 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 reactor Rbi, Rai, and Ra2. These reactors They can be manufactured from various materials such as polytetrafluoroethylene (PTFE), glass, ceramics, or metals. Preferably, they are 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.

[0089] The reactors R bi, R ai and / or R a2 are advantageously tubular in shape.

[0090] Preferably, the reactors Rbi, Rai, and / or Ra2 are tubular with a circular cross-section having an internal diameter less than or equal to 8 mm, advantageously less than or equal to 7 mm, or advantageously less than or equal to 6.5 mm. 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 cm-1 to 360 cm-1, can be dedicated to pre-cooling the reactants, and another section of the tubular reactor can be dedicated to the reaction itself, this other section advantageously ranging from 30 cm-1 to 360 cm-1.For example, reactor R ai may include a first reactor section of 30 cm to 360 cm, in particular of about 60 cm, dedicated to cooling trans-2-hexenal in solution in solvent Sa[ at temperature Tab. Similarly, reactor R ai may include a second reactor section of 30 cm to 360 cm, in particular of about 60 cm, dedicated to cooling potassium tert-butylate or sodium tert-butylate in solution in solvent Sai at temperature Tap. Only one of the two reactants or both reactants simultaneously may be cooled.The reactor Rai may include a third reactor section, approximately 60 cm² in diameter, measuring 30 cm² to 360 cm², dedicated to the reaction at temperature TA between trans-2-hexenal in solution in solvent SA, previously cooled to temperature TA, and potassium tert-butylate or sodium tert-butylate in solution in solvent SA, previously cooled to temperature TA. The reactor Ra2 may include a first reactor section, approximately 60 cm², measuring 30 cm² to 360 cm², dedicated to cooling diethyl chlorophosphate in solution in solvent SA2 to temperature TA2. Similarly, the reactor Ra2 may include a second reactor section, approximately 60 cm², measuring 30 cm² to 360 cm², dedicated to cooling the enolate of trans-2-hexenal from temperature TA to temperature TA2.Finally, the reactor R a2 may include a third reactor section of 30 cm to 360 cm, specifically approximately 60 cm, dedicated to the reaction at temperature Ta2 between diethyl chlorophosphate in solution in solvent Sa2, which may optionally be pre-cooled to temperature Ta2, and trans-2-hexenal enolate in solution in solvent Sa2, which may optionally be pre-cooled to temperature Ta2. The first two sections of the reactor R a2 are. Optional, since step a1) is preferentially carried out at a low temperature, the reaction mixture may already be at a suitable temperature for step a2). The reactor Rbi may include a first reactor section of 30 cm to 360 cm, in particular approximately 60 cm, dedicated to heating the mixture Ml in solution in solvent Sbi to temperature Tbi. Similarly, the reactor Rbi may include a second reactor section of 30 cm to 360 cm, in particular approximately 60 cm, dedicated to heating the hydrolyzable dienophile DH in solution in solvent Sbi to temperature TM. Finally, the R bi reactor may include a third reactor section of 30 cm to 360 cm, in particular of about 60 cm, dedicated to the reaction at temperature Tbi between the mixture Ml 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 Tb[ and pressure Pb[.The first two sections of the Rbi reactor are optional; the reactor may consist of only the third section described above.

[0091] The reactors particularly suited to the present invention are the reactors marketed by Khimod®, in particular the KL reactor

[0092] 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.

[0093] The reactants can be introduced into the reactors by means well known to those skilled in the art. For example, piston pumps or peristaltic pumps may be cited. The reactors Rbi, Rai, and / or Ra2 can be connected to each other 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 reactants 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 succession of several reactors in series.

[0094] The following examples illustrate particular embodiments of the invention without limiting its scope. EXAMPLES

[0095] The following abbreviations are used in the examples: - AcOEt - ethyl acetate - GC - gas chromatography - MeTHF - 2-methyltetrahydrofuran - NMP - N-methyl-2-pyrrolidone - HDPE - high-density polyethylene - PTFE - polytetrafluoroethylene - tBuOK - potassium tert-butoxide - ts - residence time in the reactor

[0096] The raw materials and solvents are commercially sourced (Sigma Aldrich). The analytical method consists of GC analysis on an HP 5890 Series II instrument equipped with an FID detector. The chromatographic column is an Innowax 30m, 0.25 mm, 0.25 pm column, with helium as the carrier gas and a pressure of 11 psi. The oven follows the following temperature profile: T0 = 150 °C, initial time 10 min. Gradient 20° / min, final temperature: 200 °C. Duration 7 min. The injector is at 250 °C and the detector at 300 °C. The injected volume is 1 pL. The sample concentration is 4 g / L in AcOEt.

[0097] The continuous flow reactions of Examples 3, 5, 6, and 7 are carried out in a Kl reactor from Khimod, which is a tubular reactor comprising 12 parallel tubes with a cylindrical cross-section of 1 / 8" and connected to each other by means of 2 metal flanges. The metal of the reactor body and the flanges is Hastelloy. The flanges allow for different tube connection options.

[0098] 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).

[0099] Example 1 (outside the scope of the invention): Batch synthesis of the mixture of isomers of crude diethyl hexa-l,3-dien-l-yl phosphate

[0100] 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 of the reaction medium is observed, 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 1h at -60°C, before being brought back up to -10°C and then quenched by the dropwise addition of 16 mL of water.The organic phase is then extracted, washed with 3x10 mL of water, dried over MgSO4 and then concentrated under vacuum. 3.58 g of diethyl-hexa-l,3-dien-l-yl phosphate are obtained (88.4% crude yield) with the following isomeric ratio: 0.3% (Z,Z), 1.4% (Z,E). 77.8% (E,Z), 20.5% (E,E). In total, this production lasted 3 hours, resulting in a productivity of 4.77 kg.h*.m3 of raw enolphosphate.

[0101] Example 2: Continuous synthesis of a mixture of Ml of diethyl hexa-l,3-dien-l-yl phosphate in PTFE tubular reactors (steps a1) and a2) according to the invention on laboratory scale)

[0102] The assembly 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 bath at -55 °C. 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), followed by a 0.88 m PTFE reactor immersed in a bath at -55 °C, 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 assembly to allow the mixture to be added directly to a diethyl chlorophosphate solution under N2 at -50 °C.

[0103] 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 N2. 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 N2. The pump flow rate is set at 4.62 mL / min. Solution B is pre-shaken at room temperature for 30 min.

[0104] The apparatus, conditioned with THF under N2, is cooled to -55°C. The two 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 min (Ts = 1.92 min) to a solution C of diethyl chlorophosphate (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 the start of the addition is -50°C, and the final temperature at the end is -42.5°C. The apparatus is rinsed with THF immediately after the reagents have been added.

[0105] The solution is 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 is decanted. The organic phase is washed with 2 x 60 mL of water and then concentrated under vacuum. 7 g of enolphosphate are obtained with the following isomeric ratios: 0.5% (Z,Z), 1.4% (Z,E), 78.1% (E,Z), 20.0% (E,Ej). In total, this production lasted 2.15 h, resulting in a productivity of 27.5 kg.h⁻³.m³ of crude enolphosphate.

[0106] Example 3: Continuous synthesis at -55°C of the mixture Ml of diethyl hexa-1,3-dien-1-yl phosphate in a Kl Hastelloy reactor with treatment according to the invention (steps a1a) and a2) according to the invention at pilot scale) Preparation and assembly Kl:

[0107] Solution 1 (trans-2-hexenal, 409 mL) is placed under N2 in a 1 L glass shlenko. 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 N2. Solution 3 (diethyl chlorophosphate, 0.19 L) is placed in a 500 mL glass shlenko under N2. 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® Kl reactor made of Hastelloy, equipped with five stainless steel PT100 thermocouples and stainless steel static mixers, and cooled to -55 °C (ts = 1 min 1 / 2 s). The reactor outlet is a 1 / 16" PTFE tube, and the reaction mixture is then fed into a T-fitting containing solution 3. Solution 3 is introduced via a third piston pump (5.9 mL / min).The mixture is mixed rapidly (ts= 8s) in a 30 cm 1 / 4” PTFE tube (equipped with static mixers) before being poured into a tank at ambient temperature. The process is carried out at a pressure of 4 bar. Summary:

[0108] Once pre-filling has been carried out, 10 minutes are required to reach steady flow of solutions 1 and 2. 3 minutes are required to reach steady flow of solution 3. The product is only collected when steady flow is reached.

[0109] Enolphosphate is collected in a 10 L HDPE container inert with nitrogen for 103 min. The reaction mixture is quenched by the dropwise addition of 16 mL (8V) of water. The organic phase is then extracted, washed with 3 x 10 mL (3 x 5V) of water, and concentrated under vacuum. 853 g of enolphosphate are obtained (94% crude yield) with the following isomeric ratios: 0.6% (Z,Z), 1.2% (ZE), 76.3% (E,Z), 21.9% (E,E). In total, this production took 2.8 h, resulting in a productivity of 4352 kg·h⁻³·m³ of crude enolphosphate.

[0110] Example 4: Continuous synthesis of crude diethyl hexa-1,3-dien-l-yl phosphate mixture M2 in stainless steel at -40°C with purification in a batch reactor without changing solvent.

[0111] 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 bath at -40°C. These two channels join 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 N2 at -35°C.

[0112] 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 N2. 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 N2. The pump flow rate is set at 9.24 mL / min. Solution B is pre-shaken at room temperature for 30 min.

[0113] The apparatus, conditioned with toluene under N2, is cooled to -35 °C. The two pumps are started simultaneously (t0), and the reaction mixture is collected from the reactor outlet (Ts = 1.44 min) in the waste container (16 minutes). The reaction mixture is then added for 30 minutes 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).

[0114] 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% (ZE), 94.9% (E,Z), 0.3% (E,E), and 198 g of toluene, representing a toluene recycling rate of 70%.

[0115] The aqueous phase is brought to pH > 14 by adding sodium hydroxide at room temperature. After complete solubilization, the NMP separates from the aqueous phase. Distillation under reduced pressure yields 152 g of NMP, representing an NMP recycling rate of 60%.

[0116] The total reaction volume for this example was 6.3 mL for tubular reactors and 500 mL for the batch reactor.

[0117] In total, this production lasted 7 hours, resulting in a productivity of 11.85 kg.h*.m3 of purified enolphosphate. This example shows that not changing the solvent after a first continuous step leads to significant productivity gains.

[0118] Example 5: Continuous synthesis of the M2 isomer mixture of diethyl hexa-1,3-dien-l-yl phosphate by the process according to the invention in a Khimod® reactor at -55°C (steps a1a) and a2) according to the invention) Preparation and setup:

[0119] Solution 1 (trans-2-hexenal, 1.45 L) is placed in a 2 L glass slender under N2. 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 N2. Solution 3 (diethyl chlorophosphate, 1.619 L) is placed in a 2 L glass slender. Under nitrogen (N2), solutions 1 (221 g / h) and 2 (2951 g / h) are introduced into the previously inerted setup using two piston pumps. The trans-2-hexenal enolate is produced in a 60 cm³ Khimod® Kl 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 mixes with solution 3 in a 1 / 8" tee fitting. Solution 3 is introduced via a third piston pump (5.9 mL / min). Mixing is rapid in a 30 cm³ 1 / 4" PTFE tube equipped with static mixers before flowing into a tank at ambient temperature. The process outlet pressure is 4 bar. Summary:

[0120] Once pre-filling has been carried out, 10 minutes are required to reach steady flow of solutions 1 and 2. 3 minutes are required to reach steady flow of solution 3. The product is only collected when steady flow is reached.

[0121] 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% (ZE), 75.9% (E,Z), 22.4% (E,E). Performing steps a1) and a2) in continuous flow allows a productivity of 4352 kg / h per m³ of enolphosphate mixture. 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 h followed by 6 h of treatment to purify the enolphosphate.

[0122] 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 h 40 min, 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).

[0123] In total, this production lasted 10.1 h, resulting in a productivity of 2.75 kg.h 1 m 3 of purified enolphosphate. This productivity is negatively impacted by the batch execution of step b), for which the productivity drops to 5.89 kg.h 1 m3.

[0124] Example 6: Continuous purification by Diels-Alder reaction of crude diethyl hexa-1,3-dien-l-yl phosphate on Kl at 150°C (steps b1), b2) and b3) according to the invention)

[0125] 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 PtlOO 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% (ZE), 96.8% (E,Z), 0.2% (E,E). This production took a total of 43 min, resulting in a productivity of 323 kg·h⁻³·m³ of purified enolphosphate. For comparison, the same reaction carried out under the conditions of document WO 2018 / 162739 A₁I would have required a 20 L reactor with a residence time of 3 h for a productivity of 15.7 kg·h⁻³·m³ of purified enolphosphate.

[0126] Example 7: Synthesis and improvement of the isomeric purity of a mixture of isomers of diethyl hexa-l,3-dien-l-yl phosphate by continuous synthesis (steps a1), a2), b1), b2) and b3) according to the invention Preparation and assembly of steps a1) and a2):

[0127] Solution 1 (trans-2-hexenal, 1.45 L) is placed in a 2 L glass Schlenk container under N2. 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 N2. Solution 3 (diethyl chlorophosphate, 1.619 L) is placed in a 2 L glass Schlenk container under N2. 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® Kl reactor made of Hastelloy, equipped with five stainless steel ptlOO thermocouples and stainless steel static mixers, and cooled to -55 °C. The reactor outlet is a 1 / 16" PTFE tube, and the reaction mixture is then fed into a 1 / 8" tee fitting containing solution 3. Solution 3 is introduced via a third piston pump (5.9 mL / min). Mixing occurs rapidly in a 30 cm³ 1 / 4" PTFE tube equipped with static mixers. The process outlet pressure is 4 bar. Preparation of the reactor for step bl):

[0128] Continuing from the PTFE reactor of the previous step, connection is made using two 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 which connects, On one hand, a 10 L maleic anhydride solution at a concentration of 0.86 mol / L (8.6% w / w) in a 50 / 50 toluene / NMP mixture is supplied, and on the other hand, a 3.6 m long tubular reactor made of 316R stainless steel with a 1 / 8" circular cross-section is supplied. A 2 m section of this tubular 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 reactor end 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 through the tee using a peristaltic pump at a flow rate of 2.8 L / h (a molar flow rate 1.07 times that of trans-2 hexenal). Summary:

[0129] Once pre-filling is complete, 10 minutes are required to reach steady-state flow rates for solutions 1 and 2. Three minutes are required to reach steady-state flow rates for solution 3 in the PTFE reactor before it is sent to the reactor in step 1b), and three minutes are required to reach steady-state flow in this last reactor. The product is collected only when steady-state flow is reached.

[0130] The final enolphosphate is collected in a reactor container, and at the end of the collection period, after 2 hours, 12.7 kg of solution are recovered. The 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% (ZE), 96.4% (E,Zy), and 0.5% (E,E). The productivity is 996 kg·h⁻³·m³ of purified enolphosphate. Thus, the implementation of the process according to the invention is particularly advantageous when combining steps a₁), a₂), b₁), b₂), and b₃). BIBLIOGRAPHICAL REFERENCES

[0131] Witzgall, P., Tasin, M., Buser, HR, Wegner-Kiss, G., Mancebôn, VS, loriatti, C., Bâckman, AC, 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. A process for preparing a mixture M2 of enolphosphate isomers of the following formula 1: O 1 comprising less than 5%, preferably less than 2%, of the (E,E) isomer and comprising at least 93% 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: b1) Contacting 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, maleic anhydride, in an organic solvent S1 comprising an aromatic solvent, at a temperature T1 ranging from 110 °C to 200 °C, and at a pressure P1 ranging from 2 bar to 50 bar, 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 medium hydrolyzed comprising the M2 mixture of enolphosphate isomers and an adduct formed between the (E,E) isomer and the hydrolyzable dienophile DH hydrolyzed, and b3) the removal of the hydrolyzed adduct from the hydrolyzed medium obtained in step b2) to obtain the mixture M2 of enolphosphate isomers.

2. A preparation method according to claim 1, wherein the organic solvent S bi 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 S bi is a mixture of toluene and NMP, more preferably the organic solvent S bi is a toluene:NMP mixture with a volume ratio from 70:30 to 30:70, typically about 50:

50.

3. A preparation method 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.

4. A preparation method according to any one of claims 1 to 3, wherein: - step bl) is carried out at a temperature T bi ranging from 120 °C to 180 °C, preferably ranging from 130 °C to 160 °C, and / or - step bl) is carried out at a pressure P bi 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 R bi reactor, 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 Ml is introduced into the reactor R bi at a molar flow rate ΔMi and the hydrolyzable dienophile DH is introduced into the reactor R bi at a molar flow rate ΔDH, the ratio Δdh / Δmi ranging from 0.5 to 2.0, preferably 0.9 to 1.5, preferably from 1 to 1.9

7. 1,Zr. 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 reactor R ai to obtain an enolate of trans-2-hexenal, and a2) contacting the trans-2-hexenal enolate with diethyl chlorophosphate in a continuous flow reactor R a2 to obtain the mixture Ml as defined in claim 1.

8. A preparation method according to claim 7, wherein step a1) is carried out in an organic solvent Sai and step a2) is carried out in an organic solvent Sa2, the organic solvents Sai and Sa2, whether identical or different, being selected 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 the organic solvents S ai and S a2, 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 al, S a2 and S bi are identical.

10. A preparation process according to claim 9, wherein the solvents Sai, Sa2 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 from 60:40 to 40:60, preferably 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 about -55 °C, and / or - step a2) is carried out at a temperature T a2 ranging from -70 °C to 0 °C, preferably from -60 °C to 0 °C, typically about -50 °C.

12. A preparation method according to any one of claims 7 to 11, wherein: - the reactor R al, preferably tubular, has an internal volume occupied from 10% to 60%, preferably from 20% to 50%, by static mixers, and / or - the reactor R a2, 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 reactor R ai at a molar flow rate D T2H and potassium tert-butylate or sodium tert-butylate is introduced into reactor R al at a molar flow rate DB, the ratio DB / D T2H 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 reactor Ra2 at a molar flow rate D CD, the ratio D cd / D T2H ranging from 0.5 to 2.0, preferably 0.9 to 1.5, typically from 1 to 1.

2.

15. A process for preparing a mixture Ml of enolphosphate isomers of the following formula 1: O1 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 reactor R1a1, in an organic solvent S1a1 comprising an aromatic solvent, preferably toluene, and at a temperature T1a1 from -70 °C to -40 °C, to obtain an enolate of trans-2-hexenal, and a2) contacting the trans-2-hexenal enolate with diethyl chlorophosphate in a continuous flow reactor R1a2. preferably in an organic solvent S a2 comprising an aromatic solvent, preferably toluene, and at a temperature T a2 ranging from -70 °C to 0 °C to obtain the mixture Ml.

16. A preparation method according to claim 15, wherein the organic solvents Sai and Sa2, identical or different, are a solvent mixture 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 the organic solvents Sai and Sa2, identical or different, are a mixture of toluene and NMP, more preferably the organic solvents Sai and Sa2, identical or different, are a toluene:NMP mixture with a volume ratio ranging from 70:30 to 30:70, preferably from 60:40 to 40:60, preferably from 55:45 to 45:55, typically approximately 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 a2 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 reactor R ai, preferably tubular, has an internal volume occupied from 10% to 60%, preferably from 20% to 50%, by static mixers, and / or - the reactor R a2, 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 R ai at a molar flow rate ΔT2h and potassium tert-butylate or sodium tert-butylate is introduced into reactor R al at a molar flow rate DB, the ratio DB / ΔT2h 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 ratio Dcd / DT2H ranging from 0.5 to 2.0, preferably 0.9 to 1.5, typically from 1 to 1.2.

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