Method for continuous synthesis of cis-13-octadecenal based on microchannel reactor

Abstract

The application discloses a method for continuously synthesizing cis-13-octadecenal based on a micro-channel reactor, and belongs to organic synthesis. The method comprises unilateral bromination, acetylene coupling, selective hydrogenation, oxidation and purification. The method uses dodecanediol and 1-hexyne as raw materials, forms a method for continuously synthesizing cis-13-octadecenal, a key component of insect sex pheromone, in a high-efficiency and high-selectivity manner by using a micro-channel reactor, and effectively solves the problems of low cis selectivity, poor reaction efficiency and incapability of amplification effect in the synthesis of cis-13-octadecenal in the prior art.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, and in particular relates to a method for continuous synthesis of cis-13-octadecenal based on a microchannel reactor. Background Technology

[0002] (Z)-13-Octadecenal is a core component of the sex pheromone of agricultural pests such as the rice stem borer and the rice leaf folder. It is a key component in sex pheromone trapping and mating interference technologies, and therefore has significant application value in the monitoring and green control of these pests. Existing technologies disclose the synthesis of (Z)-13-Octadecenal, a sex pheromone component of the rice stem borer (Liu Bin, Zeng Ruichang, Lou Dawei); and the synthesis of 13cis-octadecenal, a pheromone component of the rice stem borer, etc. (Xiao Lingxiang, Huang Fei, Zhang Yushun, Tao Yunhai). However, the current synthesis processes are all traditional. Traditional batch reactor processes have the following drawbacks: long reaction time, harsh operating conditions (low temperature / anhydrous and oxygen-free); low selectivity of key steps (such as olefin construction), insufficient purity of cis isomers (usually <90%); intense exothermic reaction leading to many side reactions and large yield fluctuations; low mass / heat transfer efficiency and high safety risks during scale-up production. Summary of the Invention

[0003] Purpose of the invention: To address the deficiencies and shortcomings of existing technologies, this invention provides a method for the continuous synthesis of cis-13-octadecenal based on a microchannel reactor. This invention uses dodecanediol and 1-hexyne as raw materials to form a method for the efficient and selective continuous synthesis of cis-13-octadecenal, a key component of insect sex pheromones, using a microchannel reactor. This effectively solves the problems of low cis selectivity, poor reaction efficiency, and inability to produce continuously in the synthesis of cis-13-octadecenal in existing technologies.

[0004] Technical Solution: To achieve the above objectives, this invention provides a method for the continuous synthesis of cis-13-octadecenal based on a microchannel reactor, comprising the following steps:

[0005] (1) Unilateral bromination reaction: In microchannel reactor A, dodecanediol and brominating reagent are subjected to unilateral selective bromination at low temperature to generate 12-bromo-dodecanediol;

[0006] (2) Alkyne coupling reaction: 12-bromo-dodecanool and 1-hexyne are continuously coupled in a microchannel reactor B with a catalyst to generate 13-yne-octadecanool intermediate;

[0007] (3) Selective hydrogenation: The triple bond of the 13-yne-octadecyl alcohol intermediate is selectively hydrogenated in a microchannel reactor C to generate cis-13-octadecyl alcohol with a cis olefin structure.

[0008] (4) Oxidation reaction: cis-13-octadecenol is oxidized to the target aldehyde compound cis-13-octadecenol in microchannel reactor D.

[0009] In step (1), the microchannel reactor A is a multi-layer stacked reactor or a dynamic tubular reactor, and the brominating reagent includes any one or more of PBr3, NBS, and HBr.

[0010] In step (1), the reaction temperature of the microchannel reactor is -10~0℃ and the residence time is 30-60 seconds.

[0011] In step (2), the microchannel reactor B is a dynamic tubular reactor or a multi-layer stacked reactor; the catalyst is any one or more of CuI / Pd, NH3 / Li, and C4H9Li catalysts.

[0012] Preferably, the catalyst in step (2) is a catalyst containing Pd(PPh3)2Cl2, CuI and Et3N.

[0013] In step (2), the reaction temperature of the microchannel reactor is 60-80℃ and the residence time is 3-5 minutes.

[0014] In step (3), the microchannel reactor C is a packed bed microreactor or a dynamic tubular reactor. The temperature of the microchannel reactor is 25-35℃, the hydrogen pressure is 0.2-0.4 MPa, the catalyst is any one or more of Lindlar, Raney nickel or LiAlH4, and the residence time is 5-8 minutes.

[0015] In step (4), the microchannel reactor D is a dynamic tubular reactor, a capillary microreactor, or a multi-layer stacked reactor, and the oxidant is a TEMPO / NaClO / NaBr system, MnO2, or PDC.

[0016] In step (4), the temperature of the microchannel reactor is 0-5℃ and the residence time is 1-3 minutes.

[0017] This invention is the first to continuously synthesize the long-chain enaldehyde pheromone cis-13-octadecenal using dodecanediol unilateral bromination product and 1-hexyne as raw materials. The microchannel reactor used in this process can significantly enhance the multiphase reaction process due to its ultra-high specific surface area, millisecond-level mixing efficiency and precise temperature control.

[0018] This invention achieves precise control of the selectivity of unilateral bromination through a microreactor, avoiding dibromination byproducts; continuous flow operation enables efficient alkyne coupling and highly cis-selective hydrogenation; the total residence time of the multi-step reaction is significantly shortened, and the yield is ≥85%, which is far higher than that of traditional processes.

[0019] This invention reduces reaction time from hours to minutes; significantly improves unilateral bromination selectivity and reduces byproduct formation; product purity meets the requirements for field application of insect pheromones (>95%); a single unit can achieve an annual production capacity of hundreds of kilograms, and with the addition of automated control equipment, production costs are reduced by more than 40%. Based on the final step of the cis-13-octadecenal reaction in this invention: the yield is 180 ml per hour; the daily yield is: 0.18 liters x 0.27 mol / L x 266 g / mol = 13 g / hour = 13 x 24 = 312 g / day; the annual yield is: 312 g / day x 365 days = 113.88 kg.

[0020] This invention employs a novel microchannel technology for the synthesis of cis-13-octadecenal, which utilizes a traditional batch reactor. The advantages are: 1. Higher heat transfer efficiency: The microchannel reactor rapidly removes reaction heat, preventing localized overheating and reducing side reactions. Traditional batch reactors, on the other hand, have slow heat dissipation, easily leading to increased side reactions. 2. Better reaction selectivity: The microchannel reactor allows for precise control of reaction conditions, improving the selectivity of unilateral bromination and avoiding dibromination byproducts. Traditional batch reactors exhibit lower selectivity at critical steps. 3. Shorter reaction time: Using a microchannel reactor, the reaction time is instantaneous, on the order of milliseconds.

[0021] Furthermore, the proportions, temperature, and reaction time are all crucial in this invention. Adjusting the proportions in the first step will decrease the proportion of the product 1-bromo-dodecanool and increase the proportion of the byproduct 1,12-dibromododecane. Adjusting the temperature may lead to other non-product side reactions, and increasing or decreasing the reaction time may result in incomplete or excessive reactions, leading to an increase in 1,12-dibromododecane and requiring subsequent post-processing of the reaction products. Correct proportions, temperature, and reaction time can reduce post-processing steps and shorten the reaction time.

[0022] Beneficial effects: Compared with the prior art, the present invention has the following significant advantages:

[0023] This invention provides a method for the efficient and selective continuous synthesis of cis-13-octadecenal, a key component of insect sex pheromones, using dodecanediol and 1-hexyne as raw materials via a microchannel reactor. The reaction route is as follows: 1,12-dodecanediol reacts with phosphorus tribromide to generate 1-bromo-dodecaneol; 1-bromo-dodecaneol reacts with 1-hexyne to generate 13-octadecyn-1-ol; 13-octadecyn-1-ol reacts with Lindra reagent under hydrogen to undergo alkyne bond reduction, generating cis-13-octadecenol; and hydroxylation occurs in a TEMPO / NaClO / NaBr system to generate cis-13-octadecenal. This invention utilizes novel microchannel technology to produce cis-13-octadecenal, effectively avoiding the problems associated with continuous production processes that are typically carried out in batch reactors. Attached Figure Description

[0024] Figure 1 This is the spectrum of cis-13-octadecenal synthesized in this invention. Detailed Implementation

[0025] The present invention will be further described below with reference to the embodiments.

[0026] Unless otherwise specified, the experimental methods described in the examples are conventional methods; the materials and reagents used in the examples are commercially available unless otherwise specified.

[0027] The dynamic tubular reactor, multi-layer stacked reactor, packed bed microreactor (fixed bed reactor), and capillary microreactor (microchannel reactor) used in this invention are all existing conventional microchannel reactors, and were all purchased from Shandong Weijing Chemical Technology Co., Ltd.

[0028] The dynamic tubular reactor features reactants that continuously flow into the pipe from one end, undergoing a chemical reaction during the flow, and products that continuously exit from the other end. A static mixer is installed at the front end to mix the reactants before they enter the reactor. The microchannel reactor is made of 316L stainless steel and is equipped with a temperature control system.

[0029] Multi-layer stacked reactor: Independent flat plate units are stacked together to form a complete reaction system. The stacked material is Hastelloy, equipped with a static mixer and a temperature control system.

[0030] Packed bed microreactor: A continuous flow chemical reaction device filled with solid particles in a microchannel reactor. The material is Hastelloy, and it is equipped with a temperature control system.

[0031] Capillary microreactor: A continuous flow chemical reaction device that uses a slender tube with an inner diameter of 0.3 mm as the reaction channel. The tube material is PTFE. It is equipped with a static mixer and a temperature control system.

[0032] Example 1

[0033] 1. Unilateral bromination reaction

[0034] Microreactor type: Dynamic tubular reactor

[0035] 1,12-dodecanediol was dissolved in dichloromethane to prepare a 0.5 mol / L solution. The feed flow rate was 2 mL / min.

[0036] Phosphorus tribromide (PBr3, 1.05 eq) was dissolved in dichloromethane to prepare a 0.525 mol / L solution. The feed flow rate was 2 mL / min.

[0037] Conditions: Temperature -5℃, residence time 30 seconds, yielding 12-bromo-dodecanool with a selectivity of 95%.

[0038] 2. Alkyne Coupling Reaction

[0039] Microreactor: Dynamic Tubular Reactor

[0040] The crude 12-bromo-dodecanool product obtained in step 1 was prepared into a THF solution (0.45 mol / L) with a feed flow rate of 1.5 mL / min.

[0041] 1-Hexyne was dissolved in a THF / triethylamine (4:1, v / v) mixed solvent to prepare a 1.0 mol / L solution. The feed flow rate was 1.5 mL / min.

[0042] Catalyst / alkali mixture: THF as solvent, containing Pd(PPh3)2Cl2 (0.02 mol / L), CuI (0.04 mol / L), Et3N (2.5 mol / L), feed flow rate: 1.5 mL / min.

[0043] Conditions: Temperature 50℃, residence time 3 min, 13-yne-octadecyl alcohol is produced, yield 92%.

[0044] 3. Selective hydrogenation

[0045] Microreactor: Packed bed microreactor (filled with Lindlar catalyst poisoned with 10% quinoline)

[0046] The 13-yne-octadecyl alcohol intermediate obtained in step 2 was dissolved in hexane to prepare a 0.3 mol / L solution. The feed flow rate was 3 mL / min.

[0047] Conditions: Temperature 25℃, hydrogen pressure 0.2 MPa, residence time 5 min, producing cis-13-octadecenol, a cis-olefin structure, with a cis selectivity of 96%.

[0048] 4. Oxidation reaction

[0049] Oxidizing agent: TEMPO / NaClO / NaBr system

[0050] Microreactor type: Dynamic tubular reactor

[0051] The cis-13-octadecenol obtained in step 3 was dissolved in dichloromethane to prepare a 0.28 mol / L solution. The feed flow rate was 3 mL / min.

[0052] Oxidizing agent: dichloromethane as solvent, containing TEMPO (2,2,6,6-tetramethylpiperidine oxide, 0.028 mol / L), NaClO (0.45 mol / L), NaBr (0.056 mol / L), NaHCO3 (pH 8.5), feed flow rate: 3 mL / min.

[0053] Conditions: Temperature 3℃, residence time 1 min, yielding cis-13-octadecenal with an aldehyde conversion rate of 97%.

[0054] The reaction formula is shown below:

[0055]

[0056] The gas chromatography-mass spectra of the synthesized cis-13-octadecenal in this embodiment are as follows: Figure 1 As shown.

[0057] Example 2

[0058] 1. Unilateral bromination reaction

[0059] Microreactor type: Dynamic tubular reactor

[0060] 1,12-dodecanediol was dissolved in dichloromethane to prepare a 0.5 mol / L solution. The feed flow rate was 4 mL / min.

[0061] Phosphorus tribromide (PBr3, 1.05 eq) was dissolved in dichloromethane to prepare a 0.525 mol / L solution. The feed flow rate was 4 mL / min.

[0062] Conditions: Temperature -5℃, residence time 20 seconds, yielding 12-bromo-dodecanool, selectivity >92%.

[0063] 2. Alkyne Coupling Reaction

[0064] Microreactor: Dynamic Tubular Reactor

[0065] The crude 12-bromo-dodecanoic acid product solution obtained in step 1 was prepared to a concentration of 0.45 mol / L, with a feed flow rate of 3 mL / min.

[0066] 1-Hexyne was dissolved in a THF / triethylamine (4:1, v / v) mixed solvent to prepare a 1.0 mol / L solution. The feed flow rate was 3 mL / min.

[0067] Catalyst / alkali mixture: THF as solvent, containing Pd(PPh3)2Cl2 (0.02 mol / L), CuI (0.04 mol / L), Et3N (2.5 mol / L), feed flow rate: 3 mL / min.

[0068] Conditions: Temperature 65℃, residence time 2 min, 13-yne-octadecyl alcohol is produced, yield 90%.

[0069] 3. Selective hydrogenation

[0070] Microreactor: Packed bed microreactor (filled with Lindlar catalyst poisoned with 10% quinoline)

[0071] The 13-yne-octadecyl alcohol intermediate obtained in step (2) was dissolved in hexane to prepare a 0.3 mol / L solution with a feed flow rate of 4 mL / min.

[0072] Conditions: Temperature 25℃, hydrogen pressure 0.2 MPa, residence time 5 min, producing cis-13-octadecenol, a cis-olefin structure, with a cis selectivity of 96%.

[0073] 4. Oxidation reaction

[0074] Oxidizing agent: TEMPO / NaClO / NaBr system

[0075] Microreactor type: Dynamic tubular reactor

[0076] The cis-13-octadecenol obtained in step 3 was dissolved in dichloromethane to prepare a 0.28 mol / L solution. The feed flow rate was 4 mL / min.

[0077] Oxidizing agent: dichloromethane as solvent, containing TEMPO (0.028mol / L), NaClO (0.45mol / L), NaBr (0.056mol / L), and NaHCO3 (pH 8.5). Feed flow rate: 4 mL / min.

[0078] Conditions: Temperature 2℃, residence time 2 min, yielding cis-13-octadecenal with an aldehyde conversion rate of 94%.

[0079] Example 3

[0080] 1. Unilateral bromination reaction

[0081] Microreactor type: Dynamic tubular reactor

[0082] 1,12-dodecanediol was dissolved in dichloromethane to prepare a 0.5 mol / L solution. The feed flow rate was 1 mL / min.

[0083] Phosphorus tribromide (PBr3, 1.05 eq) was dissolved in dichloromethane to prepare a 0.525 mol / L solution. The feed flow rate was 1 mL / min.

[0084] Conditions: Temperature -8℃, residence time 50 seconds, yielding 12-bromo-dodecanool with a selectivity of 91%.

[0085] 2. Alkyne Coupling Reaction

[0086] Microreactor: Dynamic Tubular Reactor

[0087] The crude 12-bromo-dodecanool product obtained in step (1) was prepared into a THF solution (0.45 mol / L) with a feed flow rate of 2 mL / min.

[0088] 1-Hexyne was dissolved in a THF / triethylamine (4:1, v / v) mixed solvent to prepare a 1.0 mol / L solution. The feed flow rate was 2 mL / min.

[0089] Catalyst / alkali mixture: using THF as solvent, containing Pd(PPh3)2Cl2 (0.02 mol / L), CuI (0.04 mol / L), Et3N (2.5 mol / L), feed flow rate: 1 mL / min.

[0090] Conditions: Temperature 40℃, residence time 5 min, 13-yne-octadecyl alcohol is produced, yield 90%.

[0091] 3. Selective hydrogenation

[0092] Microreactor: Packed bed microreactor (filled with Lindlar catalyst poisoned with 10% quinoline)

[0093] The 13-yne-octadecyl alcohol intermediate obtained in step 2 was dissolved in hexane to prepare a 0.3 mol / L solution. The feed flow rate was 2 mL / min.

[0094] Conditions: Temperature 25℃, hydrogen pressure 0.2 MPa, residence time 6 min, producing cis-13-octadecenol, a cis-olefin structure, with a cis selectivity of 94%.

[0095] 4. Oxidation reaction

[0096] Oxidizing agent: TEMPO / NaClO / NaBr system

[0097] Microreactor type: Dynamic tubular reactor

[0098] The cis-13-octadecenol obtained in step 3 was dissolved in dichloromethane to prepare a 0.28 mol / L solution. The feed flow rate was 4 mL / min.

[0099] Oxidizing agent: dichloromethane as solvent, containing TEMPO (0.028 mol / L), NaClO (0.42 mol / L), NaBr (0.056 mol / L), and NaHCO3 (pH 8.5). Feed flow rate: 4 mL / min.

[0100] Conditions: Temperature 0℃, residence time 3 min, yielding cis-13-octadecenal with aldehyde conversion rate >92%.

[0101] Comparative Example 1

[0102] The method of Example 1 was followed, but the reaction temperature of the unilateral bromination step was increased to 10°C or the residence time was extended to 5 minutes. The results showed that the selectivity of 12-bromo-dodecanool decreased to approximately 85%, while the proportion of the byproduct 1,12-dibromododecane increased significantly.

[0103] Comparative Example 2

[0104] The method of Example 1 was followed, but the amount of Et3N in the catalyst / base mixture was halved in the yne coupling reaction step. As a result, the yield of 13-yne-octadecyl alcohol decreased to approximately 80%.

Claims

1. A method for continuous synthesis of cis-13-octadecenal based on a microchannel reactor, characterized in that, Includes the following steps: (1) Unilateral bromination reaction: In microchannel reactor A, dodecanediol and brominating reagent are subjected to unilateral selective bromination at low temperature to generate 12-bromo-dodecanediol; (2) Alkyne coupling reaction: 12-bromo-dodecanool and 1-hexyne are continuously coupled in a microchannel reactor B with a catalyst to generate 13-yne-octadecanool intermediate; (3) Selective hydrogenation: The triple bond of the 13-yne-octadecyl alcohol intermediate is selectively hydrogenated in a microchannel reactor C to generate cis-13-octadecyl alcohol with a cis olefin structure. (4) Oxidation reaction: cis-13-octadecenol is oxidized to the target aldehyde compound cis-13-octadecenol in microchannel reactor D.

2. The method for continuous synthesis of cis-13-octadecenal based on a microchannel reactor according to claim 1, characterized in that, In step (1), the microchannel reactor A is a falling film microreactor or a dynamic tubular reactor, and the brominating reagent includes any one or more of PBr3, NBS, and HBr.

3. The method for continuous synthesis of cis-13-octadecenal based on a microchannel reactor according to claim 1, characterized in that, In step (1), the reaction temperature of the microchannel reactor is -10~0℃ and the residence time is 30-60 seconds.

4. The method for continuous synthesis of cis-13-octadecenal according to claim 1, characterized in that, In step (2), the microchannel reactor B is a dynamic tubular reactor or a multi-layer stacked reactor; the catalyst is any one or more of CuI / Pd, NH3 / Li, C4H9Li, and Et3N catalysts.

5. The method for continuous synthesis of cis-13-octadecenal based on a microchannel reactor according to claim 1, characterized in that, In step (2), the reaction temperature in the microchannel reactor is 60-80℃, and the residence time is 3-5 minutes.

6. The method for continuous synthesis of cis-13-octadecenal based on a microchannel reactor according to claim 1, characterized in that, In step (3), the microchannel reactor C is a packed bed microreactor or a fixed bed microreactor, and the catalyst is any one or more of Lindlar, Raney nickel or LiAlH4.

7. The method for continuous synthesis of cis-13-octadecenal based on a microchannel reactor according to claim 1, characterized in that, In step (3), the reaction temperature of the microchannel reactor is 25-35℃, the hydrogen pressure is 0.2-0.4 MPa, and the residence time is 5-8 minutes.

8. The method for continuous synthesis of cis-13-octadecenal based on a microchannel reactor according to claim 1, characterized in that, In step (4), the microchannel reactor D is a dynamic tubular reactor, a capillary microreactor, or a multi-layer stacked reactor, and the oxidant is a TEMPO / NaClO / NaBr system, MnO2, or PDC.

9. The method for continuous synthesis of cis-13-octadecenal based on a microchannel reactor according to claim 1, characterized in that, In step (4), the temperature of the microchannel reactor is 0-5℃ and the residence time is 1-3 minutes.

10. The application of the method for continuous synthesis of cis-13-octadecenal based on a microchannel reactor as described in claim 1 in the highly selective and efficient continuous production of cis-13-octadecenal.

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