New method for continuous production of pheromones
By using a continuous oxidation reaction with a copper-based catalyst under oxygen pressure, the problems of impurity generation and low economic efficiency in the industrial-scale synthesis of insect pheromones have been solved, achieving highly selective and efficient production of aldehyde pheromones.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- MELCHIOR MATERIAL & LIFE SCI FRANCE
- Filing Date
- 2022-05-27
- Publication Date
- 2026-06-09
AI Technical Summary
Existing technologies are insufficient for the efficient and selective synthesis of insect pheromones, especially sex pheromones of lepidopteran pests, on an industrial scale. Furthermore, traditional methods suffer from problems such as impurity generation, oxidant erosion, and low economic efficiency.
A continuous oxidation reaction is carried out under oxygen pressure using a copper-based catalyst. Aldehydes are recovered through liquid/liquid separation in non-polar and polar solvents. Alcohols are continuously oxidized using a heat exchange reactor to form a homogeneous two-phase mixture and recycle the catalyst. The reaction conditions are controlled to achieve high selectivity and high-efficiency production.
It achieves highly selective and efficient aldehyde pheromone production, reduces impurity generation, lowers production costs, and avoids the need for large-volume reactors.
Smart Images
Figure CN117396456B_ABST
Abstract
Description
Background Technology
[0001] A novel method for synthesizing aldehyde-terminated pheromones based on the following reaction:
[0002] [Chemical Formula 1]
[0003]
[0004] Where R is the expression C n H 2n-2p+1 The method involves a straight-chain aliphatic chain, where n is a natural number greater than or equal to 9, and p is an integer from 1 to 4. The method is characterized by continuous operation in a polar solvent in the presence of a copper-based catalytic system at a pressure greater than 1 bar and a temperature of 30 to 200 °C. This method offers the advantages of high productivity and high reaction selectivity.
[0005] Insect pheromones are communication tools unique to each species. For this communication to be effective, the mixture of compounds known as a pheromone bouquet must be extremely precise. Therefore, the sex pheromone of the boxwood moth (Cydalima perspectalis) is a mixture of Z-11 and E-11-hexadecenol in a precise 80 / 20 ratio. Beyond this ratio, males will not be attracted to the attractant. Furthermore, trace amounts of Z / E-11-hexadecenol completely neutralize the pheromone's effects.
[0006] Furthermore, the synthesis of pheromones for industrial applications is part of a regulatory framework that greatly limits the possibility of producing pheromones with uncontrolled numbers and quantities of impurities.
[0007] These two limitations present significant technical challenges to those skilled in the art, especially since these molecules are occasionally used for communication between individuals of the same species, leading to their rapid degradation once released into the atmosphere. This fragile nature inevitably increases the likelihood of impurities in the synthetic process. This is particularly true for sex pheromones of lepidopteran pests, whose main components are compounds with the following general formula:
[0008] [Chemical Formula 2]
[0009]
[0010] R is a straight-chain aliphatic group comprising 1 to 4 unsaturated groups, which may or may not be present in the form of conjugated double or triple bonds. Therefore, the general formula for these straight-chain groups R can be written as: C n H 2n-2p+1, where n is an integer greater than 9, and p represents the number of unsaturated elements, which is an integer from 1 to 4 (one triple bond represents two unsaturated elements).
[0011] As readily apparent to those skilled in the art, terminal alcohols R-CH2OH are precursors to aldehydes or acetates. While alcohols can be readily acetylated by reacting them with acetyling agents (such as acetic anhydride or acetyl chloride) in the presence of a base (such as a tertiary amine), the preparation of aldehydes is more complex.
[0012] In fact, known methods for obtaining these aldehydes primarily involve oxidation in the presence of organic peracids (chloroperbenzoic acid, peracetic acid, perpropionic acid). These oxidizing agents are corrosive and attack unsaturated fatty acids present on the aliphatic chain, producing numerous impurities such as epoxides or oligomers. Furthermore, fatty acid peroxidation is difficult to avoid. Another method involves using sodium hypochlorite or sodium hypobromite in the presence of nitrogen oxides or nitrosium salts. This method avoids peroxidation, but unsaturated chlorination or bromination is observed, which is highly problematic from a regulatory perspective. To limit this effect, iodobenzene peracetic acid can be used instead of bleaching agents, but this sacrifices the economic efficiency of the synthesis.
[0013] Furthermore, all of these methods are intermittent, which requires very large reaction volumes.
[0014] Therefore, it is important to successfully industrialize pheromones in the form of RCH2O in order to find a productive selective oxidation technique.
[0015] Only two patent reports attempt to combine the concepts of pheromone synthesis and continuous chemistry. The first work is reported in patent US9,789,455B2. In this patent, the inventors describe a continuous synthesis apparatus for producing fragrances or pheromones, etc. This very specialized apparatus is capable of generating vortices between two continuously injected reagent solutions.
[0016] The second work is reported in patent US10,071,944B2. This patent discloses a method for the continuous preparation of aldehydes or acids via an unsaturated ozone decomposition reaction using a tubular continuous reactor. This method cannot be applied to pheromones carrying multi-bonded substances that are sensitive to oxidation conditions.
[0017] Several studies have reported on the use of sequential oxidation chemistry to produce pheromones. For example, in Catalysts 2018, 8,529, V. Liautard et al. reported the conversion of ferrugin (a secondary alcohol) to ketones in the presence of magnesium and a donor aldehyde, according to the Oppenauer oxidation reaction. However, aside from the fact that obtaining ketones is easier than obtaining aldehydes, the yield in this work was very low, with only about 10% of the alcohol being converted to a ketone. Furthermore, the structure of the pheromone does not include any chemical functions sensitive to secondary reactions.
[0018] One solution that might be conceived by those skilled in the art would involve transposing the work published, such as that of L. Vannoye et al., Vol. 357, No. 4, March 9, 2015, pp. 739-746. Indeed, the latter has demonstrated the possibility of using continuous aerobic oxidation to convert primary vinyl alcohols or aromatic alcohols in the presence of bipyridine and N-methylimidazole, in the presence of a catalyst formed from CuOTf or Cu(OTf)₂. In the case of straight-chain aliphatic compounds, the catalytic system results in low conversion rates incompatible with the required purity of pheromones. Furthermore, the copper catalyst considered in that publication requires a 5% molar ratio, while the molecular weight of the catalyst is very high. Without efficient catalyst recovery, these methods are unattractive from both an economic and carbon footprint perspective.
[0019] This last method, if used with a more economical catalyst, would be particularly significant for the synthesis of pheromones, as it involves producing these pheromones through aerobic oxidation that mimics biological respiration. Summary of the Invention
[0020] The applicant has discovered a new method characterized by an oxidation reaction carried out continuously in a reactor under oxygen pressure, advantageously in a HER reactor (heat exchange reactor), such as those sold by Khimod, and it allows the following reaction to proceed by recycling the catalyst to limit its effects: [Formula 3]
[0021]
[0022] Therefore, according to the first embodiment, the present invention relates to a method for preparing aldehydes of general formula (II):
[0023] [Chemical Formula 4]
[0024]
[0025] Where R is the expression C n H 2n-2p+1 A straight-chain hydrocarbon chain, wherein:
[0026] -n is a natural number between 9 and 24.
[0027] -p corresponds to the number of unsaturated hydrocarbon chains, which is an integer from 1 to 4;
[0028] The method is continuous and includes the following accompanying steps:
[0029] a. Feeding into a continuous reactor at an oxygen pressure of 1-30 bar:
[0030] - Alcohols of general formula (I):
[0031] [Chemical Formula 5]
[0032]
[0033] Where R, n, and p are as defined above for compounds of formula (II), in a solution in a nonpolar organic liquid phase (A) with a density strictly less than 0.7.
[0034] - A solution of a copper-based catalyst in a polar liquid phase (B) with a density greater than or equal to 0.75, where phases (A) and (B) are immiscible with each other.
[0035] The molar ratio of alcohol to copper-based catalyst is 0.01 to 0.5.
[0036] b. Recover aldehydes from phase (A) by liquid / liquid separation.
[0037] According to another embodiment, the method according to the invention is characterized in that the copper-based catalyst further comprises at least one copper ligand of the following general formula:
[0038] [Chemical Formula 6]
[0039]
[0040] X is selected from the following groups: -C(O)-R1, -C(O)O - -C(O)-OR1, -CF3, -SO3R1 and sulfonate-SO3 - R1 is a straight-chain or branched C1-C8 alkyl group.
[0041] Advantageously, the copper-based catalyst also includes (2,2,6,6-tetramethylpiperidin-1-yl)oxy (TEMPO) or its derivatives, such as hydroxy-TEMPO, amino-TEMPO or acetamido-TEMPO.
[0042] According to an advantageous embodiment, the method is characterized in that the copper-based catalyst further comprises a selection from 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1-methylimidazolium (NMI) and acetates, particularly sodium acetate or potassium acetate.
[0043] Further advantageously, the method according to the invention is characterized in that the copper-based catalyst comprises bipyridine, particularly 2,2'-bipyridine.
[0044] Advantageously, the method is characterized in that the nonpolar organic liquid phase (A) is selected from the group consisting of C5-C8 alkanes, particularly straight-chain alkanes, especially hexane.
[0045] According to an advantageous embodiment, the method according to the invention is characterized in that the polar liquid phase (B) is selected from the group consisting of acetonitrile, dimethyl sulfoxide (DMSO), sulfolane, 1-(C1-C6)-alkyl-3-methylimidazolium salt and 1-(C1-C6)-alkyl-2,3-dimethylimidazolium salt and mixtures thereof.
[0046] Advantageously, the counterions of the salt are fluorinated counterions, particularly selected from trifluoromethanesulfonate (triflate), hexafluorophosphate and tetrafluoroborate.
[0047] According to a specific and preferred embodiment, the copper-based catalyst is a copper II salt, advantageously selected from the group consisting of copper halide II and copper carboxylate II.
[0048] Advantageously, the copper halide is selected from CuI2, CuCl2 and CuBr2; the copper carboxylate is selected from copper acetate Cu(OAc)2 and copper acetylacetonate IICu(Acac)2.
[0049] According to a particularly advantageous embodiment, the method according to the invention is characterized in that step a) is carried out in a continuous reactor of the heat exchange reactor type.
[0050] In a specific implementation plan, the continuous oxidation reaction is carried out by feeding two solutions together into a continuous reactor: one solution contains reactants and the other contains a catalyst.
[0051] Therefore, in a specific embodiment, the method according to the invention is characterized by comprising the following accompanying steps:
[0052] a. Under an oxygen pressure of 1-30 bar, a solution of alcohol of formula (I) in a nonpolar organic liquid phase (A) with a density strictly less than 0.7 and a solution of copper-based catalyst in a polar liquid phase (B) with a density greater than or equal to 0.75 are co-fed into a continuous reactor to oxidize alcohol (I);
[0053] b. Reduce pressure and separate the polar liquid phase (B) containing the catalyst and the nonpolar organic liquid phase (A) containing the product (II) by liquid / liquid separation;
[0054] c. Solution of recovered product (II) in the upper nonpolar organic liquid phase (A);
[0055] d. Optionally, evaporate the nonpolar organic liquid phase (A) to recover product (II).
[0056] According to an embodiment that includes co-feeding two solutions to a continuous reactor, the method is further characterized by reintroducing all or part of the polar liquid phase (B) containing the catalyst separated in step b) in the co-feeding step a).
[0057] Furthermore, the embodiment comprising co-feeding two solutions to the reactor is characterized in that the molar ratio between compound (I) and the copper-based catalyst in the co-feeding step a) is 10:1 to 20:1.
[0058] In an alternative embodiment of the method according to the invention, preparation of a homogeneous two-phase mixture is provided, the mixture comprising a solution of an alcohol of formula (I) in a nonpolar organic liquid phase (A) with a density strictly less than 0.7 and a solution of a copper-based catalyst in a polar liquid phase (B) with a density greater than or equal to 0.75.
[0059] The two phases are immiscible, so the mixture is fed into a continuous reactor under oxygen pressure for continuous oxidation of alcohol (I).
[0060] According to this specific embodiment of the preparation of a homogeneous two-phase preliminary mixture, a recirculation loop is provided between a mixer M (in which the homogeneous two-phase mixture is kept stirred) and a continuous reactor (in which an oxidation reaction occurs under pressure). This recirculation loop can deplete the alcohol (I) in the medium and enrich it with the aldehyde (II) formed; the recirculation loop operates until the two-phase mixture has substantially depleted the alcohol (I), that is, it has been substantially completely oxidized to the aldehyde (II).
[0061] The term "homogeneous two-phase mixture" as used herein refers to a mixture produced and maintained by stirring in a mixer, wherein the two phases (A and B), although immiscible, are uniformly distributed, indistinguishable to the naked eye, and do not separate within the mixer. A homogeneous two-phase mixture is characterized in that, if a sample is taken from the mixture, it contains substantially equal amounts of the two phases.
[0062] Therefore, in the embodiment of the method according to the invention for preparing a homogeneous two-phase mixture, the method is characterized by comprising the following accompanying steps:
[0063] a. A homogeneous two-phase mixture is prepared in a mixer M, the mixture comprising a solution of an alcohol of formula (I) in a nonpolar organic liquid phase (A) with a density strictly less than 0.7 and a solution of a copper-based catalyst in a polar liquid phase (B) with a density greater than or equal to 0.75;
[0064] b. The homogeneous two-phase mixture is fed into a continuous reactor at an oxygen pressure of 1-30 bar to oxidize the alcohol (I);
[0065] c. Establish a recirculation loop between the stirred reactor and the mixer M until the alcohol (I) is substantially completely converted into the aldehyde (II);
[0066] d. Reduced pressure and liquid / liquid separation of a polar liquid phase (B) containing the catalyst and a nonpolar organic liquid phase (A) containing the product (II);
[0067] e. A solution in which product (II) is recovered in a nonpolar organic liquid phase (A);
[0068] f. Optionally, evaporate the nonpolar organic liquid phase (A) to recover product (II).
[0069] According to a specific embodiment of the method for preparing a homogeneous two-phase mixture according to the above-described embodiments, unreacted oxygen in a continuous reactor, particularly a continuous HER reactor (heat exchange reactor), is depressurized at the reactor outlet, captured, recompressed, and reinjected into the reactor at the feed.
[0070] According to a specific embodiment of the method of one of the embodiments described above, the continuous reactor is a HER reactor (heat exchange reactor).
[0071] The method according to the invention is characterized by being carried out continuously in a polar solvent at a pressure greater than 1 bar and less than 30 bar and a temperature of 30 to 200°C, particularly 20 to 180°C, in the presence of an inexpensive copper-based catalyst.
[0072] The residence time in the oxidation reactor is advantageously less than 240 minutes, and more advantageously 5 to 80 minutes.
[0073] This method has the advantages of high reaction selectivity and low cost.
[0074] A complete continuous solution oxidation method typically includes three main steps or zones:
[0075] • Step / Section 1: Catalyst and alcohol preparation steps;
[0076] • Step / Section 2: Alcohol oxidation step (I);
[0077] • Step / Section 3: Aldehyde recovery step (II).
[0078] Step / Section 1: Catalyst Preparation
[0079] The catalyst used is obtained by mixing equal amounts of copper (II) salts such as copper halides, particularly CuI2, copper trifluoromethanesulfonate, copper acetate, copper acetylacetonate, and copper hydroxide with a high-density polar solvent or solvent mixture to obtain a polar liquid phase (B) with a density greater than or equal to 0.75, particularly greater than or equal to 0.8, or even greater than or equal to 0.9 or even greater than or equal to 1.
[0080] Suitable solvents are acetonitrile, dimethyl sulfoxide (DMSO), sulfolane, 1-(C1-C6)-alkyl-3-methylimidazolium salts and 1-(C1-C6)-alkyl-2,3-dimethylimidazolium salts and mixtures thereof. Advantageously, the counter ion of the salt is a fluorinated counter ion, particularly selected from trifluoromethanesulfonate (trifluoromethanesulfonate), hexafluorophosphate, and tetrafluoroborate acetonitrile, or preferably an ionic liquid, such as 1-alkyl-3-methylimidazolium or 1-alkyl-2,3-dimethylimidazolium.
[0081] The concentration of the catalyst obtained in this way is from 0.01M to 1M.
[0082] Ligands of the following general formula can be added in amounts of 1 to 4, or even 1.8 to 2.5 molar equivalents:
[0083] [Chemical Formula 7]
[0084]
[0085] X is selected from the following groups: -C(O)-R1, -C(O)O - -C(O)-OR1, -CF 、 -SO3R1 and sulfonate-SO3 - R1 is a straight-chain or branched C1-C8 alkyl group.
[0086] Greater than 0.5 to 2 equivalents, particularly 1 equivalent, of (2,2,6,6-tetramethylpiperidin-1-yl)oxy (TEMPO) or a derivative thereof may be added.
[0087] Ultimately, bases of 0 to 4 equivalents, particularly 1 to 3, or even 1 to 2.2 equivalents, are 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, particularly sodium acetate or potassium acetate.
[0088] The mixture containing alcohol (I) is produced in a conventional manner by mixing the alcohol (I) in a nonpolar organic solvent to obtain a nonpolar organic liquid phase (A) with a density strictly less than 0.7, or even less than 0.6. The concentration of alcohol in the nonpolar organic liquid phase is from 0.1 M to 10 M, preferably from 0.1 M to 1 M.
[0089] Step / Section 2: Alcohol oxidation step (I);
[0090] As previously mentioned, the continuous oxidation step can be carried out in two different ways. Either by co-feeding both phases into the continuous reactor, or by feeding a pre-prepared homogeneous two-phase mixture into the continuous reactor and maintaining agitation in the mixer. This method can be implemented in two ways:
[0091] Method n1:
[0092] The catalyst mixture is prepared in a stirred reactor or reaction tube as described above, and then pumped to the continuous reaction zone of a continuous reactor, particularly a HER (for heat exchange reactor) type continuous reactor. At the inlet of the continuous reactor, a phase containing alcohol (I) and oxygen is also injected at a pressure of 1 to 30 bar. Such an embodiment... Figure 1 As shown in the image.
[0093] Injection is controlled by a flow meter, and the flow rate is expressed as F. newcata F substrate and F O2 This results in a conversion rate of over 99% at the HER output.
[0094] The reaction was carried out in a continuous reactor at temperatures ranging from 20°C to 200°C, and the reaction products reached zone 3, which was used to separate the catalyst, gas, and solution containing aldehyde (II).
[0095] The continuous reactor is continuously fed with a phase containing alcohol (I), a phase containing a catalytic system, and oxygen.
[0096] Reinjected catalyst stream (F recyccata The reaction is carried out in a fresh catalyst stream, and both streams are controlled such that the molar concentrations of the alcohol substrate (I) and the catalyst (combination of fresh catalyst stream and recycled catalyst stream) are maintained at a ratio of 10 / 1 to 20 / 1. When the flow rate F... substrate and F O2 When F is a constant, then newcata +F recyccata It is a constant. Therefore, the catalyst rate is controlled by three UV detectors: UV1 can determine the concentration of fresh catalyst, UV3 can determine the concentration of recycled catalyst, and UV2 can check whether the desired concentration of catalyst is indeed continuously injected into the reactor.
[0097] It should be remembered that in a continuous reactor, the concentration in the reaction medium corresponds to the concentration at the reactor outlet.
[0098] The reactor operating pressure is advantageously from 1 bar to 200 bar, more advantageously from 1 bar to 100 bar. In some embodiments, the reactor operating pressure is from 1 bar to 50 bar.
[0099] The oxidation temperature is advantageously between 15 and 100°C, particularly between 20 and 80°C. The oxidation temperature is, of course, lower than the decomposition temperature of the product.
[0100] The oxidation temperature is advantageously kept constant. Any method known to those skilled in the art can be used for this purpose. For example, the heat exchangers inside and outside the reactor can be referenced by controlling the feed temperature.
[0101] Continuous reactors can be advantageously equipped with stirring devices, such as static mixers. In fact, thorough stirring can ensure a good level of mixing, thereby avoiding dead zones or separation of the reaction medium.
[0102] Preferably, the continuous reactor is a HER (heat exchange reactor) type continuous reactor sold by Khimod.
[0103] By definition, a continuous reactor has at least one inlet open by the system and at least one outlet. As is known to those skilled in the art, the reactor outlet must be sufficiently far from the inlet to avoid preferred path problems. Ideally, the distance between the reactor inlet and outlet should be as great as possible.
[0104] In the case of a two-phase reactor, the outlet is naturally in contact with the liquid phase.
[0105] The effluent from the stirred reactor is sent to the oxidation product recovery step.
[0106] Step / Section 3: Aldehyde Recovery Step (II)
[0107] The first feature of zone 3 is the depressurization device that expels oxygen, allowing it to be optionally recirculated, and then passes it through a continuous decanter, from which a more concentrated solution containing the catalyst is pumped out from the bottom of the decanter and sent to zone / step 1 via an overflow through a (thermal or chemical) dryer.
[0108] The recovery of aldehydes from solution and the separation of their solvent can be carried out by any method known to those skilled in the art, in order to separate them and reduce the level of their volatile substances to less than 1 wt%.
[0109] Method n2:
[0110] A second method involves producing a homogeneous two-phase mixture, wherein one phase contains the catalyst and the other phase contains the alcohol reactant (I), and these two phases are immiscible. Such an implementation... Figure 2 As shown in the image.
[0111] In this configuration, a solution mixture of catalyst and reagent R-CH2OH is prepared in a mixer, which itself is connected to a continuous reactor, such as a HER-type continuous reactor, via a circulation loop at a flow rate of D1. Upstream of the continuous reactor (e.g., a HER-type continuous reactor), oxygen is introduced at a pressure of 0.2 to 30 bar at a flow rate of D2. Unreacted oxygen is depressurized at the outlet of the continuous reactor to optionally be recycled at the inlet of the continuous reactor (e.g., a HER-type reactor). The continuous reactor is kept under stirring, and the circulation loop operates until the alcohol (I) is completely converted.
[0112] In this embodiment, the temperatures of the mixer and the continuous reactor (especially the HER reactor) are preferably the same, including and preferably 15 to 80°C, particularly 20 to 60°C.
[0113] On the one hand, the advantage of methods 1 or 2 is that they allow for the complete conversion of alcohols into aldehydes, particularly pheromones with aldehyde functional groups of very satisfactory purity. On the other hand, these two methods allow for the avoidance of resorting to large-volume reactors subjected to high pressure, where the phase is limited to partial reactions occurring under pressure in continuous reactors, especially HER-type reactors. Attached Figure Description
[0114] Figure 1 Implementation of the method using a two-phase co-feed reactor.
[0115] Figure 2 The method is implemented by pre-preparing a homogeneous two-phase mixture in a mixer, continuously feeding it into a reactor, and having a recirculation loop between the reactor and the mixer. Detailed Implementation
[0116] Example
[0117] Raw materials (CuI2, bipyridine, TEMPO) and solvents are available at Sigma Aldrich.
[0118] Z11-Hexadecenol was produced at the Salin de Giraud (M2I Development) plant according to methods known to those skilled in the art, with a purity of 92% by weight. The major impurity (3.2%) was E11-hexadecenal.
[0119] The HER reactor was manufactured and supplied by Khimod.
[0120] Example 1: Implementation plan for preparing a homogeneous two-phase mixture.
[0121] In a 10L reactor under vigorous stirring, 480g of Z11-hexadecenol was prepared in 3.3L of hexane and 3L of acetonitrile solution, wherein the acetonitrile solution contained:
[0122] -19g copper iodide (CuI2),
[0123] -15.6g bipyridine,
[0124] -16.4g N-methylimidazole,
[0125] -15.6g TEMPO.
[0126] Stir the two-phase mixture to ensure that the two phases are evenly distributed.
[0127] The solution was pumped to the heater at a rate of 50 mL / min using a high-pressure pump, while oxygen was introduced at 1 L / min and 12 bar. The entire system was maintained at 25 °C.
[0128] A standard sample was taken from the 1L reactor, and the reaction was stopped when the conversion of Z11-hexadecenol was completed after 10 hours.
[0129] At the end of the reaction, recirculation and stirring were stopped. The lower phase was evacuated for optional recirculation (see Example 3). The upper phase was retained in the reactor, washed twice with distilled water, and then the solvent was evaporated under vacuum to recover 456 g of E11-hexadecenal (92.0% purity). Interestingly, 3.4% E11-hexadecenol was observed in the initial product and 3.5% E11-hexadecenal was found in the final product.
[0130] Example 2: Implementation scheme of co-feeding two phases into the reactor without recycling the catalyst.
[0131] In a 5L reactor with vigorous stirring, 0.564L of Z11-hexadecenol (concentration of 1 mol / L) was prepared in 1.436L of hexane.
[0132] In another 5L reactor, 2L of acetonitrile solution was added. This solution contained:
[0133] -19g copper iodide (CuI2),
[0134] -15.6g bipyridine,
[0135] -16.4g N-methylimidazole,
[0136] -15.6g TEMPO.
[0137] Two solutions were pumped into the HER reactor at a flow rate of 4.2 mL / min for each solution using an HPLC pump. The molar ratio between the copper catalyst and the alcohol was now 0.02. Oxygen was introduced at a flow rate of 0.2 L / min under 12 bar. The reaction product was recovered under reduced pressure in a 10 L separatory funnel-type decanter. The residence time was 2 h, and the total reaction time was 4 h. Finally, the two phases were separated (the bottom phase was the blue phase containing the catalyst), and the organic phase was washed until complete discoloration. Hexane was evaporated to give 460 g of hexadecenal with a purity of 93 wt%.
[0138] The results were similar to those in Example 1.
[0139] Example 3: An implementation scheme for co-feeding two phases into the reactor and recycling the catalyst.
[0140] In a 5L reactor with vigorous stirring, 0.564L of Z11-hexadecenol (concentration of 1 mol / L) was prepared in 1.436L of hexane.
[0141] In another 2L reactor, 1L of 1-butyl-2,3-dimethylimidazolium hexafluorophosphate solution was added. This solution contained:
[0142] -38g copper iodide (CuI2),
[0143] -31.2g bipyridine,
[0144] -32.8g N-methylimidazole,
[0145] -31.2g TEMPO.
[0146] Both solutions were pumped into the HER reactor using an HPLC pump. The flow rate for both reagent solutions was 42 mL / min. The molar ratio between the copper catalyst and the alcohol was now 0.22.
[0147] The reaction products were recovered under reduced pressure in a 10L separatory funnel-type decanter. The lower phase itself was continuously pumped to replenish the catalyst reserve.
[0148] Oxygen was introduced at a flow rate of 2 L / min at 12 bar.
[0149] The residence time was 24 minutes, and the total reaction time was 48 minutes. After washing and evaporation of hexane, 447 g of Z11-hexadecenal with a purity of 91.8% by weight was recovered.
[0150] Example 4: An implementation scheme for co-feeding two phases into the reactor and recycling the catalyst.
[0151] 5.6 L of Z11-hexadecenol (concentration 1 mol / L) was prepared in 14 L of hexane in a 50 L reactor under vigorous stirring.
[0152] In another 2L reactor, a 1L solution of 1-butyl-2,3-dimethylimidazolium hexafluorophosphate was prepared, which contained:
[0153] -38g copper iodide (CuI2),
[0154] -31.2g bipyridine,
[0155] -32.8g N-methylimidazole,
[0156] -31.2g TEMPO.
[0157] Both solutions were pumped into the HER reactor using an HPLC pump. The flow rate of the reagent solutions was 42 mL / min for both reagents. The molar ratio between the copper catalyst and the alcohol was 0.22. The reaction products were recovered under reduced pressure in a 10 L separatory funnel-type decanter. The lower phase itself was continuously pumped to replenish the catalyst reserve. The organic phase was periodically pumped from the top of the funnel into a 50 L buffer tank.
[0158] Oxygen was introduced at a flow rate of 2 L / min at 12 bar.
[0159] The stay time was 24 minutes, and the total reaction duration was 8 hours.
[0160] After washing and evaporating the organic phase, 4.56 kg of 92.3% by weight Z11-hexadecenal was obtained.
Claims
1. A method for preparing aldehydes of general formula (II): Where R is the expression C n H 2n-2p+1 A straight-chain hydrocarbon chain, wherein: -n is a natural number between 9 and 24, and -p corresponds to the number of unsaturated hydrocarbon chains, which is an integer from 1 to 4; The method described therein is continuous and includes the following accompanying steps: a) Feeding into a continuous reactor at an oxygen pressure of 1-30 bar: i) Alcohols of general formula (I): Where R, n, and p are as defined above for compounds of formula (II), in a solution in a nonpolar organic liquid phase (A) with a density strictly less than 0.
7. ii) A solution of copper-based catalyst in a polar liquid phase (B) with a density greater than or equal to 0.
75. Phases (A) and (B) are immiscible. The molar ratio of alcohol to copper-based catalyst is 0.01 to 0.
5. b) Recover aldehydes from phase (A) by liquid / liquid separation.
2. The method according to claim 1, characterized in that... The copper-based catalyst further comprises at least one copper ligand of the following general formula: in: -X is selected from the following groups: -C(O)-R1, -C(O)O - -C(O)-OR1, -CF3, -SO3R1 and sulfonate-SO3 - ,and -R1 is a straight-chain or branched C1-C8 alkyl group.
3. The method according to claim 1, characterized in that... The copper-based catalyst further includes (2,2,6,6-tetramethylpiperidin-1-yl)oxy (TEMPO), hydroxy-TEMPO, amino-TEMPO, or acetamido-TEMPO.
4. The method according to claim 1, characterized in that... The copper-based catalyst comprises 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-methylimidazolium (NMI) and acetate.
5. The method according to claim 4, characterized in that... The acetate is sodium acetate or potassium acetate.
6. The method according to claim 1, characterized in that... The copper-based catalyst includes bipyridine.
7. The method according to claim 6, characterized in that... The bipyridine is 2,2'-bipyridine.
8. The method according to claim 1, characterized in that... The nonpolar organic liquid phase (A) is selected from the group consisting of C5-C8 alkanes.
9. The method according to claim 8, characterized in that... The nonpolar organic liquid phase (A) is hexane.
10. 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, 1-(C1-C6)-alkyl-3-methylimidazolium salt, 1-(C1-C6)-alkyl-2,3-dimethylimidazolium salt and mixtures thereof.
11. The method according to claim 10, characterized in that... The counter ion of the salt is a fluoride counter ion.
12. The method according to claim 11, characterized in that... The fluorinated counterions are selected from trifluoromethanesulfonate (trifluoromethanesulfonate), hexafluorophosphate, and tetrafluoroborate.
13. The method according to claim 1, characterized in that... The copper-based catalyst is a copper II salt.
14. The method according to claim 13, characterized in that... The copper II salt is selected from the group consisting of copper halide II and copper carboxylate II.
15. The method according to claim 14, characterized in that... The copper halide is selected from CuI2, CuCl2 and CuBr2; and the copper carboxylate is selected from copper acetate Cu(OAc)2 and copper acetylacetonate IICu(Acac)2.
16. The method according to claim 1, characterized in that... Step a) is carried out in a continuous reactor of the heat exchange reactor type.
17. The method according to claim 1, characterized in that... The method includes the following accompanying steps: a. Under an oxygen pressure of 1-30 bar, a solution of the alcohol of formula (I) in a nonpolar organic liquid phase (A) with a density strictly less than 0.7 and a solution of a copper-based catalyst in a polar liquid phase (B) with a density greater than or equal to 0.75 are co-fed into a continuous reactor to oxidize the alcohol (I). b. Reduced pressure and liquid / liquid separation of a polar liquid phase (B) containing the catalyst and a nonpolar organic liquid phase (A) containing product (II); and c. Solution of the recovered product (II) in the upper nonpolar organic liquid phase (A).
18. The method of claim 17, wherein the method further comprises an accompanying step d of evaporating a nonpolar organic liquid phase (A) to recover product (II).
19. The method according to claim 17, characterized in that... All or part of the polar liquid phase (B) containing the separated catalyst is reintroduced in the co-feed step a).
20. The method according to claim 17, characterized in that... In the co-feeding step, the molar ratio between compound (I) and the copper-based catalyst is 10:1 to 20:
1.
21. The method according to claim 1, characterized in that... The method includes the following accompanying steps: a. A homogeneous two-phase mixture is prepared in a mixer M, the mixture comprising a solution of an alcohol of formula (I) in a nonpolar organic liquid phase (A) with a density strictly less than 0.7 and a solution of a copper-based catalyst in a polar liquid phase (B) with a density greater than or equal to 0.75; b. The homogeneous two-phase mixture is fed into a continuous reactor at an oxygen pressure of 1-30 bar to oxidize the alcohol (I); c. Establish a recirculation loop between the stirred reactor and the mixer M until the alcohol (I) is completely converted into the aldehyde (II); d. Reduced pressure and liquid / liquid separation of a polar liquid phase (B) containing the catalyst and a nonpolar organic liquid phase (A) containing the product (II); e. Solution of the recovered product (II) in a nonpolar organic liquid phase (A).
22. The method of claim 21, wherein the method further comprises an accompanying step f of evaporating a nonpolar organic liquid phase (A) to recover product (II).
23. The method according to claim 21, characterized in that... Unreacted oxygen in the reactor is depressurized, captured, recompressed at the reactor outlet, and reinjected into the reactor at the feed inlet.