A novel method for continuous pheromone production.

Abstract

The present invention relates to a method for the reaction n H 2n-2P+i where n is a natural number equal to or greater than 9, and p is an integer between 1 and 4. The method is characterized in that it is carried out continuously in a polar solvent in the presence of a copper-based catalytic system at a temperature between 30 and 200°C and at a pressure above 1 bar.

Description

[Technical field]

[0001] The present invention relates to a method for producing a process for the reaction: [ka] [In the formula, R is a compound of the formula: n H 2n-2p+1 where n is a natural number of 9 or more, and p is an integer of 1 to 4. The present invention relates to a novel method for the synthesis of aldehyde-terminated pheromones by the method of the present invention, which is characterized in that the method is carried out continuously in a polar solvent at a temperature of 30-200°C and at an atmospheric pressure of more than 1 bar in the presence of a copper-based catalyst system. The method has the advantages of high productivity and high reaction selectivity.

[0002] Insect pheromones are communication tools that are unique to each species. For this communication to be effective, the mixture of compounds, referred to as the pheromonal bouquet, must be very precise. Thus, the sex pheromone of Cydalima perspectalis, commonly known as the box tree moth, is a mixture of Z and E-11 hexadecenal in a precise 80 / 20 ratio. If this ratio is not met, males will not be properly attracted to the attractant. Moreover, trace amounts of Z / E-11-hexadecenol completely neutralize the effect of the pheromone.

[0003] Furthermore, the synthesis of industrially applicable pheromones is part of a regulatory framework to significantly limit the possibility of producing pheromones containing uncontrolled numbers and amounts of impurities.

[0004] These two limitations pose significant technical challenges for those skilled in the art, especially since these molecules are used for occasional communication between individuals of the same species, which then causes them to be released into the atmosphere and rapidly decompose. Due to this fragile nature, synthetic methods inevitably increase the appearance of impurities.

[0005] This is a compound whose main component has the general formula: [ka] wherein R is a linear aliphatic radical containing zero or one to four unsaturations in the form of conjugated double or triple bonds. This is particularly true in the case of Lepidoptera sex pheromones, which have compounds of the formula: n H 2n-2p+1 In the formula, n is an integer of 9 or greater, and p, which represents the number of unsaturations, is an integer of 1 to 4 (a triple bond counts as 2 unsaturations).

[0006] As one skilled in the art would readily appreciate, the terminal alcohol R-CHOH is a precursor to an aldehyde or acetate. Acetylation of the alcohol can be easily achieved by reacting the alcohol with an acetylating agent such as acetic anhydride or acetyl chloride in the presence of a base such as a tertiary amine, whereas preparation of the aldehyde is more complicated.

[0007] In fact, the known methods to obtain aldehydes of this series are firstly oxidation in the presence of organic peracids (chloroperbenzoic acid, peracetic acid, perpropionic acid). These oxidizing agents are aggressive and also attack the unsaturations present on the fatty chain, generating a large number of impurities such as epoxides or oligomers. Moreover, peroxidation of fatty acids is difficult to avoid. Another method is the use of sodium hypochlorite or sodium hypobromite in the presence of nitroxides or nitroxonium salts. In this method, peroxidation can be avoided, but chlorination or bromination of the unsaturations is observed, which is very troublesome from a regulatory point of view. To counteract this effect, the bleaching agent can be replaced by iodobenzene peracetate, but at the expense of the economy of the synthesis.

[0008] Furthermore, all of these methods are batch processes requiring very large reaction volumes.

[0009] Therefore, it is important to find a productive and selective oxidation technology for the successful industrialization of pheromones in the form of RCHO.

[0010] Only two patents report attempts to combine the synthesis of pheromones with the concept of continuous chemistry. The first work was reported in patent US9,789,455B2, where the inventors described a continuous synthesis device for the production of perfumes or pheromones, among other things. This very special device allows the creation of a vortex between two reagent solutions that are injected in succession.

[0011] The second study is reported in patent US10,071,944B2, which reports a method for the continuous production of aldehydes or acids by ozonolysis of unsaturated compounds in a continuous tubular reactor. Such a method is not applicable to pheromones with multiple bonds that are sensitive to oxidation states.

[0012] The academic literature reports several studies that allow the use of sequential oxidation chemistry to produce pheromones. Namely, in V. Liautard & al. Catalysts 2018, 8, 529, the authors report the conversion of the secondary alcohol ferrugineol to a ketone in the presence of magnesium and a donor aldehyde by an Oppenauer oxidation reaction. However, apart from the fact that obtaining a ketone is easier than obtaining an aldehyde, the yield of this work is very low, since only 10% of the alcohol is actually converted to a ketone. Moreover, the structure of the pheromones does not contain any chemical functions that are sensitive to secondary reactions.

[0013] A solution considered by the skilled artisan could have consisted of a transposition of the work published by L. Vannoye & al. in volume 357, issue 4, March 9, 2015, pages 739-746. In fact, the latter shows the possibility of converting primary vinyl alcohols or aromatic alcohols using successive aerobic oxidations in the presence of catalysts formed from CuOTf or Cu(OTf)2 in the presence of bipyridine and N-methylimidazole. In the case of linear aliphatic compounds, this catalytic system gives low conversions that do not match the purity required for pheromones. Moreover, the copper catalyst considered in this publication requires a molar fraction of 5%, while the molecular weight of the catalyst is very high. Without an effective reuse of the catalyst, the method is not interesting from an economic point of view, but also from the point of view of the carbon footprint.

[0014] This last approach would be particularly interesting for the synthesis of pheromones, since if more economical catalysts could be applied, these pheromones could be produced by aerobic oxidation, mimicking biological respiration.

[0015] The Applicant has now discovered a novel process characterized in that the oxidation reaction is carried out continuously under oxygen pressure in a reactor, advantageously in an HER reactor (Heat Exchange Reactor) sold by the company Khimod, and which is characterized in that it is possible to reduce the influence of the catalyst by recycling the catalyst, carrying out the following reaction: [ka]

[0016] Thus, according to a first embodiment, the present invention provides a compound of general formula (II): [ka] [In the formula, R is a compound of the formula: n H 2n-2p+1 is a linear hydrocarbon chain, where: - n is a natural number ranging from 9 to 24, - p corresponds to the number of unsaturations in the hydrocarbon chain, which is an integer ranging from 1 to 4. A method for producing an aldehyde represented by the following formula: The method is continuous and comprises the following concomitant steps: a. In a continuous reactor under oxygen pressure of 1 to 30 bar - in solution in a non-polar organic liquid phase (A) having a density strictly less than 0.7, of general formula (I): [ka] [In the formula, R, n and p are as defined above in the compound of formula (II)] Alcohols represented by - a copper-based catalyst in solution in a polar liquid phase (B) with a density of 0.75 or more; The step of introducing Phase (A) and phase (B) are immiscible with each other; the molar ratio of alcohol / copper catalyst is in the range of 0.01-0.5; b. Recovering the aldehyde in phase (A) by liquid / liquid separation.

[0017] According to another embodiment, the process according to the invention comprises the step of: [ka] [Wherein, X is -C(O)-R1, -C(O)O - , -C(O)-OR1, -CF3, -SO3R1 and sulfonates: -SO3 - and R1 is a straight or branched C1-C8 alkyl group. The compound further comprises at least one copper ligand represented by the formula:

[0018] Advantageously, the copper-based catalyst further comprises (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO), or a derivative such as hydroxy-TEMPO, amino-TEMPO or acetamido-TEMPO.

[0019] According to an advantageous embodiment, the process is characterized in that the copper-based catalyst further comprises a base selected from the group consisting of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1-methylimidazole (NMI) and acetates, in particular sodium acetate or potassium acetate.

[0020] Furthermore advantageously, the process according to the invention is characterized in that the copper-based catalyst comprises a bipyridine, in particular 2,2'-bipyridine.

[0021] Advantageously, said process is characterized in that the non-polar organic liquid phase (A) is selected from the group consisting of C5-C8 alkanes, in particular linear alkanes, and more particularly hexane.

[0022] According to an advantageous embodiment, the process according to the invention is characterized in that the polar liquid phase (B) is selected from the group consisting of acetonitrile, dimethylsulfoxide (DMSO), sulfolane, salts of 1-(C1-C6)-alkyl-3-methylimidazolium and salts of 1-(C1-C6)-alkyl-2,3-dimethylimidazolium, and mixtures thereof.

[0023] Advantageously, the counterions of said salts are fluorinated counterions, in particular selected from trifluoromethylsulfonate (triflate), hexafluorophosphate and tetrafluoroborate.

[0024] According to a particularly preferred embodiment, said copper-based catalyst is a copper II salt, advantageously selected from the group consisting of copper II halides and copper II carboxylates.

[0025] Advantageously, the copper halides are chosen from CuI2, CuCl2 and CuBr2; the copper carboxylates are chosen from copper acetate, Cu(OAc)2, and copper II acetylacetonate, Cu(Acac)2.

[0026] According to a particularly advantageous embodiment, the process according to the invention is characterized in that step a) is carried out in a stirred reactor of the heat exchange reactor type.

[0027] According to a particular embodiment, the continuous oxidation reaction is characterized in that it is carried out by co-injecting two solutions, one containing the reactants and the other containing the catalyst, into a continuous reactor.

[0028] Thus, in a particular embodiment, the method according to the invention is characterized in that it comprises the following accompanying steps: a. oxidation of an alcohol (I) by co-injecting in a continuous reactor, under an oxygen pressure of 1-30 bar, an alcohol of formula (I) in solution in a non-polar organic liquid phase (A) having a density strictly less than 0.7, and a copper-based catalyst in solution in a polar liquid phase (B) having a density of 0.75 or more; b. subjecting the polar liquid phase (B) containing the catalyst and the non-polar organic liquid phase (A) containing the product (II) to a reduced pressure to effect liquid / liquid separation; c. recovering the product (II) in solution in the upper non-polar organic liquid phase (A); d. Optionally, recovering the product (II) by evaporating the non-polar organic liquid phase (A).

[0029] According to an embodiment involving the co-dosing of two solutions in a series of reactors, the invention is characterized in that all or part of the catalyst-containing polar liquid phase (B) separated in step b) is reintroduced into the co-dosing step a).

[0030] Also advantageously, the embodiment comprising the co-dosing of two solutions into the reactor is characterized in that the molar ratio of compound (I) to copper-based catalyst in the co-dosing step a) is between 10:1 and 20:1.

[0031] In an alternative embodiment of the process according to the invention, the preparation of a homogeneous two-phase mixture is carried out comprising an alcohol of formula (I) in solution in a non-polar organic liquid phase (A) having a density strictly less than 0.7, and a copper-based catalyst in solution in a polar liquid phase (B) having a density of 0.75 or more.

[0032] Since the two phases are immiscible, this two-phase mixture is dosed under oxygen pressure to a continuous reactor in which the continuous oxidation of the alcohol (I) takes place.

[0033] According to this particular embodiment providing for the preparation of a homogeneous two-phase premixture, a recirculation loop is provided between the mixer M, in which the homogeneous two-phase mixture is kept stirred, and the continuous reactor under pressure, in which the oxidation reaction takes place. This recirculation loop allows the alcohol (I) to be depleted of its medium and concentrated with the aldehyde (II) formed; this recirculation loop operates until the alcohol (I) of the two-phase mixture is substantially depleted, i.e. substantially completely oxidized to the aldehyde (II).

[0034] The expression "homogeneous two-phase mixture" as used herein means that a mixture can be produced and maintained by stirring in a mixer in which the two phases (A and B) are immiscible but uniformly distributed in each other, indistinguishable to the naked eye, and do not separate in the mixer. A homogeneous two-phase mixture is characterized by the fact that when a sample is taken from said mixture, it contains substantially equal amounts of both phases.

[0035] Thus, in the case of an embodiment according to the invention comprising the preparation of a homogeneous two-phase mixture, said method is characterized in that it comprises the steps associated with: a. preparing in a mixer M a homogeneous two-phase mixture comprising an alcohol of formula (I) in solution in a non-polar organic liquid phase (A) having a density strictly less than 0.7, and a copper-based catalyst in solution in a polar liquid phase (B) having a density of 0.75 or more; b. oxidizing the alcohol (I) by feeding the homogeneous two-phase mixture in a continuous reactor under oxygen pressure of 1-30 bar; c. establishing a recirculation loop between the stirred reactor and mixer M until substantially complete conversion of alcohol (I) to aldehyde (II); d. subjecting the polar liquid phase (B) containing the catalyst and the non-polar organic liquid phase (A) containing the product (II) to a reduced pressure to effect liquid / liquid separation; e. recovering the product (II) in solution in the non-polar organic liquid phase (A); f. Optionally, recovering the product (II) by evaporating the non-polar organic liquid phase (A).

[0036] According to a particular embodiment of the process according to the above embodiments involving the preparation of a homogeneous two-phase mixture, the oxygen that has not reacted in a continuous reactor, in particular a continuous HER reactor (heat exchange reactor), is depressurized at the outlet of the reactor, captured, recompressed and reinjected into the reactor at the time of input.

[0037] According to a particular embodiment of the process according to one of the above mentioned embodiments, said continuous reactor is an HER reactor (heat exchange reactor).

[0038] The process according to the invention is characterized in that it is carried out continuously in a polar solvent at temperatures between 30° C. and 200° C., in particular between 40° C. and 180° C., under an air pressure of more than 1 bar and less than 30 bar, in the presence of an inexpensive copper-based catalyst.

[0039] The residence time in the oxidation reactor is preferably less than 240 minutes, more preferably the residence time is between 5 minutes and 80 minutes.

[0040] This method has the advantages of low cost and high reaction selectivity.

[0041] A fully continuous solution oxidation process generally includes three main steps or zones: · Process / Zone 1: Catalyst and alcohol preparation process; · Step / Zone 2: Alcohol oxidation step (I); · Process / Zone 3: Aldehyde recovery process (II).

[0042] Step / Zone 1: Preparation of the catalyst The catalyst used is obtained by mixing a copper halide, in particular an equivalent of a copper(II) salt such as CuI2, copper triflate, copper acetate, copper acetylacetonate, copper hydroxide, with a polar solvent or mixture of solvents of high density, to obtain a polar liquid phase (B) with a density of 0.75 or more, in particular 0.8 or more, 0.9 or more or 1 or more.

[0043] Suitable solvents are acetonitrile, dimethylsulfoxide (DMSO), sulfolane, 1-(C1-C6)-alkyl-3-methylimidazolium salts and 1-(C1-C6)-alkyl-2,3-dimethylimidazolium, and mixtures thereof. Advantageously, the counterions of said salts are fluorinated counterions, in particular selected from trifluoromethylsulfonate (triflate), hexafluorophosphate and tetrafluoroborate acetonitrile, or preferably ionic liquids, such as 1-alkyl, 3-methylimidazolium or 1-alkyl-2,3-dimethylimidazolium salts.

[0044] The concentration of the catalyst thus obtained is 0.01M to 1M.

[0045] General formula: [ka] [Wherein, X is -C(O)-R1, -C(O)O - , -C(O)-OR1, -CF3, -SO3R1 and sulfonates: -SO3 - and R1 is a straight or branched C1-C8 alkyl group. The ligand can be added in an amount of 1 to 4 molar equivalents, or even 1.8 to 2.5 molar equivalents.

[0046] 0.5 to more than 2 equivalents, particularly 1 equivalent, of (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO) or a derivative thereof may be added.

[0047] Finally, 0 to 4 equivalents, in particular 1 to 3 equivalents, or 1 to 2.2 equivalents of a base selected from the group consisting of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1-methylimidazole (NMI) and acetates, in particular sodium acetate or potassium acetate.

[0048] The mixture containing the alcohol (I) is prepared by conventional methods by mixing the alcohol (I) in a non-polar organic solvent to obtain a non-polar organic liquid phase (A) having a density strictly less than 0.7 or less than 0.6, the alcohol concentration in said non-polar organic liquid phase being 0.1M to 10M, preferably 0.1M to 1M.

[0049] Step / Zone 2: Alcohol oxidation step (I) As mentioned before, the continuous oxidation process can be carried out in two different ways / paths: either the two phases are co-charged into the continuous reactor, or a pre-prepared homogenous two-phase mixture is charged into the continuous reactor and kept stirred in a mixer. The process can be implemented in two ways:

[0050] Route No.1: The catalyst mixture is prepared in a stirred reactor or reaction tube as described above and then pumped towards the continuous reaction zone in a continuous reactor, in particular in the HER (for heat exchange reactor) type. At the inlet of the continuous reactor, the phase containing alcohol (I) and oxygen is also injected under a pressure of 1 to 30 bar. Such an embodiment is shown in FIG.

[0051] The injection was controlled by a flow meter so that the conversion at the output of the HER was greater than 99%. newcata , F 基質 and F O2 The flow rate is controlled at the rate indicated as:

[0052] The reaction is carried out in a continuous reactor at temperatures between 20 ° C and 200 ° C, and the reaction products arrive in zone 3 for separation of the catalyst, gases and solution containing the aldehyde (II).

[0053] The continuous reactor is continuously charged with a phase containing the alcohol (I), a phase containing the catalyst system and oxygen.

[0054] The reinjected catalyst flow (F recyccata ) is carried out in the fresh catalyst stream, and the two streams are controlled so that the molar ratio of alcohol substrate (I) to catalyst (combination of fresh and recycled catalyst streams) is maintained in a ratio of 10 / 1 to 20 / 1. 基質 Flow and F O2 If the flow is constant, F newcata +F recyccata is constant. As a result, the catalyst rate is controlled by three UV detectors: UV1 gives the concentration of fresh catalyst, UV3 gives the concentration of recycled catalyst, and UV2 ensures that the desired concentration of catalyst is essentially continuously injected into the reactor.

[0055] It will be recalled that in a continuous reactor, the concentration in the reaction medium corresponds to the concentration at the reactor outlet.

[0056] The operating pressure of the reactor is advantageously between 1 bar and 200 bar, more advantageously between 1 bar and 100 bar. In a particular embodiment, the operating pressure of the reactor is between 1 bar and 50 bar.

[0057] The oxidation temperature is advantageously between 15 and 100° C., in particular between 20 and 80° C. The oxidation temperature is of course below the decomposition temperature of the products.

[0058] The oxidation temperature is advantageously kept constant. For this purpose, means known to those skilled in the art can be used. By way of example, mention can be made of a heat exchanger inside the reactor, an external heat exchanger, by controlling the input temperature.

[0059] The continuous reactor may advantageously be equipped with stirring means such as a static mixer. Indeed, sufficient stirring makes it possible to ensure a good level of mixing and thus to avoid dead zones or segregation of the reaction medium.

[0060] Preferably, the continuous reactor is a continuous reactor of the HER (Heat Exchange Reactor) type sold by the company Khimod.

[0061] By definition, a continuous reactor has at least one inlet and at least one outlet that are systematically open. As known to those skilled in the art, the outlet of the reactor must be far enough away from the inlet to avoid preferential path problems. Ideally, the inlet and outlet of the reactor are as far apart as possible.

[0062] In the case of a two-phase reactor, the outlet is of course in contact with the liquid phase.

[0063] The discharge from the stirred reactor is sent to an oxidation product recovery process.

[0064] Process / Zone 3: Aldehyde Recovery Process (II) This zone 3 is characterized firstly by a pressure reducer to evacuate the oxygen allowing its optional reuse, and then by a continuous decanter where the high density solution containing the catalyst is pumped from the bottom of the decanter and sent by overflow through a (thermal or chemical) desiccator to zone / step 1.

[0065] Recovery of the aldehyde from the solution and separation of the solvent therefrom can be performed according to any method known to those skilled in the art, which can isolate the aldehyde and reduce it to a level of less than 1% by weight volatiles.

[0066] Route No.2: A second route to carrying out this method involves producing a homogeneous two-phase mixture comprising the catalyst as one phase and the alcohol reactant (I) as another phase, the two phases being immiscible. Such an embodiment is illustrated in FIG.

[0067] In this case, a mixture of a solution of the catalyst and a solution of the reagent R-CH2OH is prepared in a mixer which is itself connected by a circulation loop at a flow rate D1 to a continuous reactor, for example of the HER type. Upstream of the continuous reactor, for example of the HER type, oxygen is introduced at a flow rate D2 and at a pressure of 0.2 to 30 bar. Unreacted oxygen is decompressed at the outlet of the continuous reactor and optionally recycled at the inlet of the continuous reactor, for example of the HER type. The continuous reactor is kept under stirring and the recirculation loop is operated until the total conversion (I) of the alcohol.

[0068] In this embodiment, the temperature of the mixer and the continuous reactor, particularly the HER reactor, is preferably the same and is comprised between 15°C and 80°C, particularly between 20°C and 60°C.

[0069] The advantage of the process according to route 1 or route 2 is, on the one hand, that it allows the complete conversion of the alcohol to aldehydes, in particular to pheromones with aldehyde function in very satisfactory purity. On the other hand, these two routes make it possible to avoid resorting to large-capacity reactors that can withstand high pressures, the phase under gas pressure being limited to that part of the reaction that takes place in continuous reactors under pressure, in particular HER-type reactors. [Brief description of the drawings]

[0070] Figure legend

[0071] [Figure 1] Implementation of the method of feeding two phases into the reactor.

[0072] [Diagram 2] The practice of the method comprises continuously feeding the homogenous two-phase mixture pre-prepared in the mixer to a reactor having a recirculation loop between the reactor and the mixer. EXAMPLES

[0073] Raw material (CuI 2、Bipyridine, TEMPO) and solvents are commercially available from Sigma Aldrich.

[0074] Z11-hexadecenol is produced at the Salin de Giraud (M2I Development) site according to methods known to those skilled in the art and has a purity of 92% by weight. The main impurity (3.2%) is E11-hexadecenal.

[0075] The HER reactor is manufactured and supplied by Kimodo.

[0076] Example 1: Example of preparing a homogeneous two-phase mixture.

[0077] In a 10 L reactor maintained under vigorous stirring, 480 g of Z11-hexadecenol are prepared in 3.3 L of hexane, then 3 L of an acetonitrile solution containing: 19 g of copper iodide (CuI2), 15.6 g of bipyridine, 16.4 g of N-methylimidazole, 15.6g TEMPO.

[0078] The two-phase mixture is stirred to ensure uniform distribution of the two phases.

[0079] This solution is pumped through the HER at a rate of 50 mL / min by a high-pressure pump, while oxygen is introduced at a rate of 1 L / min at 12 bar. The entire system is maintained at 25°C.

[0080] Regular samples are taken from the 1 L reactor and the reaction is stopped after 10 hours when conversion of Z11-hexadecenol is complete.

[0081] At the end of the reaction, the recirculation is stopped as well as the stirring. The lower phase is vented and optionally recycled (see Example 3). The upper phase is kept in the reactor and washed twice with distilled water, then the solvent is evaporated under vacuum, and 456 g of Z11-hexadecenal (92.0% purity) is recovered. It is interesting to note that in the initial product there is 3.4% E11-hexadecenol and in the final product there is 3.5% E11-hexadecenal.

[0082] Example 2: Co-feeding of the reactor with two phases without catalyst recycling In a 5 L reactor kept under vigorous stirring, 0.564 L of Z11-hexadecenol in 1.436 L of hexane (concentration 1 Mol / L) is prepared.

[0083] In a separate 5 L reactor, 2 L of acetonitrile solution containing: 19 g of copper iodide (CuI2), 15.6 g of bipyridine, 16.4 g of N-methylimidazole, 15.6g TEMPO.

[0084] The two solutions are pumped into the HER reactor by an HPLC pump at a flow rate of 4.2 mL / min for each solution. The molar ratio of copper catalyst to alcohol is now 0.02. Oxygen is introduced at a flow rate of 0.2 L / min at 12 bar and the reaction product is recovered after decompression in a 10 L separating funnel decanter. The residence time is 2 hours and the total reaction time is 4 hours. Finally the two phases are separated (blueish phase containing the catalyst at the bottom) and then the organic phase is washed until it completely fades. The hexane is evaporated to obtain 460 g of hexadecenal with a purity of 93%.

[0085] The results are similar to those in Example 1.

[0086] Example 3: Co-feeding of the reactor with two phases and catalyst recycling

[0087] In a 5 L reactor kept under vigorous stirring, 0.564 L of Z11-hexadecenol in 1.436 L of hexane (concentration 1 Mol / L) are prepared.

[0088] In a separate 2 L reactor, 1 L of a solution of 1-butyl-2,3-dimethylimidazolium hexafluorophosphate containing: 38 g of copper iodide (CuI2), 31.2 g of bipyridine, 32.8 g of N-methylimidazole, - 31.2g TEMPO.

[0089] The two solutions are pumped into the HER reactor by the HPLC pump. The flow rate of the reagent solutions is 42 mL / min for the two reagents. The molar ratio of the copper catalyst to the alcohol is now 0.22.

[0090] The reaction product is collected in a 10 L separatory funnel decanter after depressurization. The lower phase is pumped continuously as such to re-feed the catalyst reserve.

[0091] Oxygen is introduced at 12 bar with a flow rate of 2 L / min.

[0092] The residence time is 24 min, the total reaction time is 48 min. After washing and evaporation of the hexane, Z11-hexadecenal is recovered with a weight of 447 g and a purity of 91.8%.

[0093] Example 4: Co-feeding of the reactor with two phases and catalyst recycling

[0094] In a 50 L reactor kept under vigorous stirring, 5.6 L of Z11-hexadecenol are prepared in 14 L of hexane (concentration 1 Mol / L).

[0095] In a separate 2 L reactor, prepare 1 L of a solution of 1-butyl-2,3-dimethylimidazolium hexafluorophosphate containing: 38 g of copper iodide (CuI2), 31.2 g of bipyridine, 32.8 g of N-methylimidazole, - 31.2g TEMPO.

[0096] The two solutions are pumped into the HER reactor by the HPLC pump. The flow rate of the reagent solutions is 42 mL / min for the two reagents. The molar ratio of copper catalyst to alcohol is 0.22. And the reaction product is collected in a 10 L separatory funnel decanter after decompression. The lower phase is pumped continuously as such to resupply the catalyst reserve. The organic phase is periodically pumped from the top of the funnel into a 50 L buffer tank.

[0097] Oxygen is introduced at 12 bar with a flow rate of 2 L / min.

[0098] The residence time is 24 minutes and the total reaction time is 8 hours.

[0099] After washing and evaporation of the organic phase, 4.56 kg of Z11-hexadecenal are obtained at 92.3% by weight.

Claims

1. General formula (II): 【Chemical 1】 [wherein, R is a linear hydrocarbon chain of the formula: C n H 2n-2p+1 , and here - n is a natural number in the range of 9 to 24, - p corresponds to the number of unsaturations in the hydrocarbon chain, which is an integer in the range of 1 to 4] A process for producing an aldehyde represented by, The process is continuous and comprises the following attendant steps: a) In a continuous reactor under an oxygen pressure of 1 to 30 bar i) In a solution of a non-polar organic liquid phase (A) with a density strictly less than 0.7, a general formula (I): 【Chemical 2】 [Wherein R, n and p are as defined above in the compound of formula (II)] An alcohol represented by, ii) A copper-based catalyst in a solution of a polar liquid phase (B) with a density of 0.75 or more, The step of introducing, Phase (A) and phase (B) are immiscible with each other, The molar ratio of the alcohol / copper-based catalyst is 0.01 to 0.5, the step; b) The step of recovering the aldehyde in phase (A) by liquid / liquid separation.

2. The copper-based catalyst is represented by the general formula: [Chemical Formula 3] [Wherein, X is selected from the group consisting of -C(O)-R1, -C(O)O - , -C(O)-OR1, -CF 3 , -SO 3 R 1 and sulfonate: -SO 3 - and R1 is a linear or branched C1-C8 alkyl group]] The method according to claim 1, further comprising at least one copper ligand represented by.

3. The copper-based catalyst further comprises (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO), or a derivative, such as hydroxy-TEMPO, amino-TEMPO or acetamido-TEMPO. The method according to claim 1, characterized in that.

4. The copper-based catalyst further comprises a base selected from the group consisting of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]nona-5-ene (DBN), 1-methylimidazole (NMI) and acetate. The method according to claim 1, characterized in that.

5. The copper-based catalyst comprises bipyridine. The method according to claim 1, characterized in that.

6. The non-polar organic liquid phase (A) is selected from the group consisting of C5-C8 alkanes. The method according to claim 1, characterized in that.

7. The non-polar organic liquid phase (A) is hexane. The method according to claim 6, characterized in that.

8. The method according to claim 1, characterized in that the polar liquid phase (B) is selected from the group consisting of acetonitrile, dimethyl sulfoxide (DMSO), sulfolane, salts of 1-(C1-C6)-alkyl-3-methylimidazolium and salts of 1-(C1-C6)-alkyl-2,3-dimethylimidazolium, and mixtures thereof.

9. The method according to claim 8, characterized in that the counterion of the salt is a fluorinated counterion.

10. The method according to claim 8, characterized in that the counterion of the salt is selected from trifluoromethylsulfonate (triflate), hexafluorophosphate and tetrafluoroborate.

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

12. The method according to claim 1, characterized in that the copper-based catalyst is selected from the group consisting of copper II halides and copper II carboxylates.

13. The copper halide is CuI 2 , CuCl 2 and CuBr 2 are selected; the copper carboxylate is selected from copper acetate Cu(OAc) 2 and copper II acetylacetonate Cu(Acac) 2 The method according to claim 12, characterized in that it is selected from.

14. The method according to claim 1, characterized in that step a) is carried out in a continuous reactor of a heat exchange reactor type.

15. The method according to claim 1, characterized by including the following accompanying steps: a. Oxidation of the alcohol (I) by co-feeding into a continuous reactor under an oxygen pressure of 1 to 30 bar, an alcohol represented by formula (I) in a solution of a non-polar organic liquid phase (A) having a density strictly less than 0.7, and a copper-based catalyst in a solution of a polar liquid phase (B) having a density of 0.75 or more; b. Reducing the pressure of the polar liquid phase (B) containing the catalyst and the non-polar organic liquid phase (A) containing the product (II) to perform liquid / liquid separation; c. Recovering the product (II) in the upper solution of the non-polar organic liquid phase (A); d. Optionally, recovering the product (II) by evaporating the non-polar organic liquid phase (A).

16. The method according to claim 15, characterized in that all or part of the separated polar liquid phase (B) containing the catalyst is reintroduced in the co-feeding step a).

17. The method according to claim 15, characterized in that the molar ratio between the compound (I) and the copper-based catalyst in the co-feeding step is 10:1 to 20:

1.

18. The method according to claim 1, characterized by including the following accompanying steps: a. A step of producing a homogeneous two-phase mixture containing an alcohol represented by formula (I) in a solution of a non-polar organic liquid phase (A) with a density strictly less than 0.7 and a copper-based catalyst in a solution of a polar liquid phase (B) with a density of 0.75 or more in a mixer M; b. A step of oxidizing the alcohol (I) by introducing the homogeneous two-phase mixture into a continuous reactor under an oxygen pressure of 1 to 30 bar; c. A step of providing a recirculation loop between the stirred reactor and the mixer M until the conversion of the alcohol (I) to the aldehyde (II) is substantially complete; d. A step of performing liquid / liquid separation by reducing the pressure of the polar liquid phase (B) containing the catalyst and the non-polar organic liquid phase (A) containing the product (II); e. A step of recovering the product (II) in the solution of the non-polar organic liquid phase (A); f. Optionally, a step of recovering the product (II) by evaporating the non-polar organic liquid phase (A).

19. The method according to claim 18, characterized in that oxygen that did not react in the reactor is depressurized at the outlet of the reactor, captured, recompressed, and reinjected into the reactor at the time of charging.

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