A method for synthesizing terpinolene 4,8-epoxide

Abstract

The present invention relates to a method for synthesizing terpinolene 4,8-epoxide. The method for synthesizing terpinolene 4,8-epoxide comprises the following steps: mixing a terpinolene raw material, a catalyst, a catalyst promoter and a solvent, and stirring to form a mixture solution, then mixing and reacting with an oxidant in a reactor, and purifying and drying to obtain terpinolene 4,8-epoxide. The present invention provides a method for synthesizing terpinolene 4,8-epoxide. The oxidation property of the reaction system adopted is moderate, the reaction conditions are mild, the double bond at the 4th position can be oxidized directionally, and the oxidation selectivity is very high. Finally, the selectivity to terpinolene 4,8-epoxide can reach more than 95% at most; meanwhile, the present invention overcomes the defect that the presence of water in the existing catalytic system easily causes ring-opening hydrolysis of the epoxidation reaction, accelerates the epoxidation reaction process, shortens the reaction time, increases the yield of the product, and the yield can reach more than 88% at most.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and in particular to a method for synthesizing terpinolene 4,8-epoxide. Background Art

[0002] As a cyclic monoterpenoid compound, terpineol-4 is distributed in a variety of natural plants and is the main component and key active substance in many traditional Chinese medicine essential oils such as cajuput essential oil and zingiber corallinum essential oil. However, due to the uncertainty of supplying terpineol-4 from natural plants as raw materials, industrially, terpineol-4 is often obtained by further reacting terpinolene 4,8-epoxide obtained through the epoxidation pathway of terpinolene. However, the selective epoxidation reaction of terpinolene has always been a bottleneck in this industrial production route. This is because both the 1st and 4th carbon atoms of terpinolene have double bonds (the structural formula of terpinolene and the epoxidation reaction route are as Figure 1 shown), and their properties are very active, and it is extremely easy to be completely oxidized to form terpinolene 1,2-4,8-diepoxide, reducing the selectivity of the reaction; moreover, the double bond has strong reactivity and is prone to a series of reactions such as isomerization, polymerization, and double bond cleavage under certain conditions, making the reaction process difficult to control. This is also the main technical difficulty in the synthesis of terpinolene 4,8-epoxide at present.

[0003] In terms of the oxidation reaction, using hydrogen peroxide as an oxidant has the characteristics of being relatively cheap and environmentally friendly. A heterogeneous catalyst widely used in organic synthesis is γ-alumina, which has a high specific surface area and a pore size distribution with a high mesopore ratio, and is used both as a catalyst and as a carrier for active metals. Dalmo Mandelli pointed out that when using anhydrous hydrogen peroxide as an oxidant and ethyl acetate as a solvent for this type of reaction, the activity of the catalyst has been significantly improved. The study on the reusability of alumina in the epoxidation reaction of limonene and terpenes shows that after several cycles, the selectivity of alumina remains almost unchanged, while in the epoxidation reaction of limonene, due to the long reaction time, the activity of continuous cycles decreases significantly. The research group of Complutense University of Madrid, Spain A. Uguina et al. proposed to increase the reaction temperature to activate alumina, but at the same time, increasing the reaction temperature will reduce the selectivity of the reaction.

[0004] Patent CN108947939A mentions a method of selective oxidation using a catalyst including any one of 2,2,2-trifluoroacetophenone, 1,1,1-trifluoroacetone, hexafluoroacetylacetone, perfluoroacetone or p-fluoropropiophenone, with toluene as the solvent, hydrogen peroxide as the oxidant, and acetonitrile as the catalyst promoter. The reaction solvent catalyst trifluoroacetophenone has a high cost, and the residual trifluoroacetophenone is difficult to remove. The reaction time in the reaction kettle is long at low temperature, and the water generated during the reaction easily causes hydrolysis of the epoxy product, and the product selectivity is only up to 85% at most; in addition, the mass fraction of the oxidant hydrogen peroxide solution in this patent is 30-80%, and it is difficult to obtain commercially available hydrogen peroxide with a concentration above 30%, and the greater the concentration, the more dangerous the reaction.

[0005] Patent CN114621162A discloses a co-oxidation preparation method of terpinolene 4,8-epoxide, and proposes a scheme for preparing terpinolene 4,8-epoxide by catalytic epoxidation reaction using the epoxidation reagent d-limonene hydroperoxide and the catalyst hexacarbonylmolybdenum. However, the conversion rate of this method is only up to 88% at most, and at this conversion rate, the product selectivity is only up to 74% at most.

[0006] Uguina M, Delgado J, Rodríguez A, et al. Alumina as heterogeneous catalyst for the regioselective epoxidation of terpenic diolefins with hydrogen peroxide[J]. Journal of Molecular Catalysis. A, Chemical, 2006, 256(1): 208-215. provides a co-oxidation preparation method of terpinolene 4,8-epoxide, and proposes a scheme for preparing terpinolene 4,8-epoxide by catalytic epoxidation reaction by adding alumina to oxidize the substrate in ethyl acetate at 60 °C for 72 h. However, the conversion rate of this method only reaches 77.6% at most, and the product selectivity is only 6.5%.

[0007] Uguina A M, Delgado A J, Carretero J. Regioselective Synthesis of Monoepoxides from Terpenic Diolefins over Alumina at High Temperature and Pressure[J]. Industrial & Engineering Chemistry Research, 2009, 48(10): 4671 - 4680. A co - oxidation preparation method of terpinolene 4,8 - epoxide is provided. It is proposed that at a temperature of 140 °C, an oxidant is added to alumina in ethyl acetate under high pressure to oxidize the substrate, enabling the alumina to be recycled and continuously participate in the reaction as a catalyst. The reaction time is reduced to 8 h. A scheme for preparing terpinolene 4,8 - epoxide through catalytic epoxidation reaction is presented. However, this method not only raises the temperature and pressure, but also has a maximum conversion rate of only 89.9% and a maximum product selectivity of only 72.4%.

[0008] The advantages of 4 - dimethylaminopyridine include small dosage, mild reaction conditions, short reaction time, high yield, few side reactions, etc. These advantages make 4 - dimethylaminopyridine one of the commonly used catalysts in organic synthesis and are widely used in the synthesis of drugs, pesticides, materials and other fields.

[0009] In summary, it is urgent to explore a method for synthesizing terpinolene 4,8 - epoxide that is green, economical, simple, efficient, has mild reaction conditions, excellent regioselective epoxidation, and prospects for industrial application to solve the problems existing in the prior art. Summary of the Invention

[0010] Aiming at the problems of high catalyst price, poor oxidation selectivity and low conversion rate in the existing terpinolene epoxidation reaction, the present invention proposes a method for synthesizing terpinolene 4,8 - epoxide. The reaction system involved in this method (such as the propionic anhydride - DMAP system) has mild reaction conditions and high oxidation selectivity, showing excellent regioselectivity at room temperature in a short time; at the same time, the reaction time is short, the conversion rate is high, the side reactions are few, and the product is not easily hydrolyzed.

[0011] An object of the present invention is to provide a method for synthesizing terpinolene 4,8 - epoxide, and the method for synthesizing terpinolene 4,8 - epoxide includes the following steps:

[0012] Mix and stir a terpinolene raw material, a catalyst, a catalyst assistant and a solvent to form a mixture solution, then mix and react with an oxidant in a reactor, and purify and dry to obtain terpinolene 4,8 - epoxide;

[0013] Wherein,

[0014] The catalyst promoter is 4-dimethylaminopyridine;

[0015] The catalyst is selected from one or more of acetic anhydride, propionic anhydride or isobutyric anhydride;

[0016] The oxidant is an aqueous hydrogen peroxide solution;

[0017] The mass fraction of hydrogen peroxide in the aqueous hydrogen peroxide solution is 10-20%.

[0018] Furthermore, the mass fraction of terpinolene in the terpinolene raw material is 85-95%.

[0019] Furthermore, the solvent is selected from one or more of acetonitrile, acetone, ethyl acetate or dichloromethane.

[0020] Furthermore, the molar ratio of the terpinolene raw material, the catalyst promoter, the catalyst and the oxidant is 1:(0.05-0.25):(0.75-2.25):(2.0-4.0).

[0021] Furthermore, the mass ratio of the terpinolene raw material to the solvent is 1:(5-15).

[0022] Furthermore, the reactor is a batch stirred tank reactor.

[0023] Furthermore, when using a batch stirred tank reactor as the reactor for the reaction, the oxidant is directly mixed into the mixture solution, the reaction temperature is 20-40 °C, and the total reaction time is 0.5-3 h.

[0024] Furthermore, the reactor is a microchannel continuous reactor.

[0025] Furthermore, when using a microchannel continuous reactor as the reactor for the reaction, the oxidant and the mixture solution are simultaneously added into the microchannel continuous reactor through different channels, the reaction temperature is 20-40 °C, the reaction pressure is atmospheric pressure, and the residence time of the reaction is 10-20 min.

[0026] The present invention has the following beneficial effects:

[0027] (1) The present invention provides a method for synthesizing terpinolene 4,8-epoxide. The oxidation property of the reaction system adopted is moderate, the reaction conditions are mild, the double bond at the 4th position can be oxidized directionally, and it has a very high oxidation selectivity. Finally, the selectivity to the target product terpinolene 4,8-epoxide can reach more than 95% at most. At the same time, the present invention overcomes the disadvantage that the presence of water in the existing catalytic system easily leads to ring-opening hydrolysis of the epoxidation reaction, accelerates the reaction process of the epoxidation reaction, shortens the reaction time, increases the yield of the product, and the yield can reach more than 88% at most.

[0028] (2) The present invention uses a hydrogen peroxide aqueous solution with a low mass fraction (10 - 20%) as the oxidant. The hydrogen peroxide with a low mass fraction is cheap and environmentally friendly.

[0029] (3) After the epoxidation reaction of the synthesis method of the present invention is completed and left to stand, the product can be automatically separated into an oil phase and a water phase. The oil phase is the reaction product, and the water phase mainly contains water, catalyst assistants, and the remaining hydrogen peroxide in the reaction. The present invention treats the hydrogen peroxide in the water phase by adding an aqueous sodium sulfite solution. After adding dichloromethane to extract the catalyst assistants, the obtained wastewater can easily meet the discharge standard. The treatment process is simple and meets the environmental protection requirements, solving the problem of water treatment in the existing epoxidation reaction system, and the obtained catalyst assistants can be recycled.

[0030] (4) The epoxidation reaction of the present invention can be carried out in a batch stirred tank reactor. The reaction conditions are mild, the reaction rate is fast, no complex cooling system is required, the energy consumption is low, the requirements for equipment are also low, and the equipment investment is small. It can also be carried out in a continuous microchannel reactor. Since hydrogen peroxide is used as the oxidant, the reaction exotherm is large. Using a microchannel reactor can remove the reaction heat in time, greatly improving the safety of the reaction process. At the same time, by strengthening mass transfer, the reaction rate is greatly increased.

[0031] (5) The method of the present invention has high selectivity and yield to the target product terpinolene 4,8-epoxide, is easy to industrialize, and is environmentally friendly. Description of the Drawings

[0032] Figure 1 Shows the structural formula of terpinolene and the epoxidation reaction route. Detailed Embodiments

[0033] In order to more clearly illustrate the technical solutions of the present invention, the following examples are listed. Unless otherwise specified, the raw materials, reactions, and post-treatment means in the examples are common raw materials on the market and technical means well-known to those skilled in the art.

[0034] The terms "preferred", "preferably", "more preferred", etc. in the present invention refer to embodiments of the present invention that can provide certain beneficial effects in certain cases. However, in the same cases or other cases, other embodiments may also be preferred. In addition, the description of one or more preferred embodiments does not imply that other embodiments are not available, nor is it intended to exclude other embodiments from the scope of the present invention.

[0035] It should be understood that, except in any operating examples or otherwise indicated, all numbers representing amounts of ingredients or otherwise used in the specification and claims should be understood to be modified in all instances by the term "about". Accordingly, unless indicated to the contrary, the numerical parameters set forth in the following specification and attached claims are approximations that vary depending upon the desired properties sought to be obtained by the present invention.

[0036] In the examples and comparative examples of the present invention, the mass fraction of terpinolene in the terpinolene raw material is 95%.

[0037] In the hydrogen peroxide aqueous solution in the examples and comparative examples of the present invention, the mass fraction of hydrogen peroxide is 15%.

[0038] Example 1

[0039] A method for synthesizing terpinolene 4,8-epoxide, the method for synthesizing terpinolene 4,8-epoxide comprising the following steps:

[0040] Mix 100 g of terpinolene raw material, 17.1 g of 4-dimethylaminopyridine, 91.1 g of propionic anhydride and 1 L of dichloromethane, stir evenly to form a mixture solution, then mix evenly with 480 g of hydrogen peroxide aqueous solution, place it in a batch reactor, and react at room temperature for 2 h. The reaction solution at the reactor outlet is collected in a flask placed in ice water, allowed to stand for liquid separation, the organic layer is taken, quenched with water and then washed with saturated sodium sulfite aqueous solution to remove excess hydrogen peroxide, and the organic phase is collected for gas chromatography analysis to obtain terpinolene 4,8-epoxide.

[0041] Example 2

[0042] A method for synthesizing terpinolene 4,8-epoxide, the difference between this example and Example 1 is that the addition amount of 4-dimethylaminopyridine is adjusted to 15 g, the addition amount of hydrogen peroxide is adjusted to 320 g, and other components and preparation methods are the same as those in Example 1.

[0043] Example 3

[0044] A method for synthesizing terpinolene 4,8-epoxide, the difference between this example and Example 1 is that the addition amount of 4-dimethylaminopyridine is adjusted to 20 g, the addition amount of hydrogen peroxide is adjusted to 500 g, and other components and preparation methods are the same as those in Example 1.

[0045] Example 4

[0046] A method for synthesizing terpinolene 4,8-epoxide, the method for synthesizing terpinolene 4,8-epoxide comprising the following steps:

[0047] Mix 100 g of terpinolene raw material, 17.1 g of 4-dimethylaminopyridine, 91.1 g of propionic anhydride and 1 L of dichloromethane, stir evenly to form a mixture solution, and then add it to a continuous microchannel reactor in two streams together with 320 g of hydrogen peroxide solution. The total flow rate is 20 mL / min, the reaction temperature is 30 °C, the reaction pressure is normal pressure, and the residence time is 15 min. The reaction solution at the reactor outlet is collected in a flask placed in ice water, allowed to stand and separate layers. The organic layer is taken, quenched with water and then washed with saturated sodium sulfite aqueous solution to remove excess hydrogen peroxide. The organic phase is collected and subjected to gas chromatography analysis to obtain terpinolene 4,8-epoxide.

[0048] Comparative Example

[0049] A method for synthesizing terpinolene 4,8-epoxide. In the method for synthesizing terpinolene 4,8-epoxide described by the Fuzhou University team in the source patent CN108947939A, the highest conversion rate is 95.96% and the best product selectivity is 80.86%. To confirm and compare the conversion rate and product selectivity of our existing method, a comparative experiment is carried out. The method comprises the following steps:

[0050] Mix 10 g of terpinolene raw material (mass fraction 84%), 3 g of 2,2,2-trifluoroacetophenone, 5 g of acetonitrile and 6 g of toluene evenly to obtain a mixture solution. Transfer it to a batch autoclave reactor. At 30 °C, slowly add 10 g of 50% hydrogen peroxide solution dropwise to the mixture solution, and the dropping time is 2 h. After the dropping is completed, continue to stir and react for 9 h, then let it stand. After the mixture is layered, the organic phase and the aqueous phase are collected separately. Add 9 g of sodium sulfite solution (mass fraction 15%) to the organic phase, stir for 30 min to remove the remaining hydrogen peroxide, and sample the remaining organic phase for chromatographic analysis.

[0051] The conversion rate and selectivity results of Examples 1-4 and the comparative example are shown in Table 1.

[0052] Table 1 Conversion rate and selectivity results of Examples 1-4 and the comparative example

[0053] Project Example 1 Example 2 Example 3 Example 4 Comparative Example Terpinolene conversion rate (%) 95.23 93.67 95.18 95.67 90.02 Product selectivity (%) 90.09 87.97 93.27 91.89 75.11

[0054] As can be seen from Table 1, compared with the Fuzhou University team, the raw material conversion rate and product selectivity of the method described in this patent are both higher than theirs. Under the condition of ensuring the best product selectivity, the conditions of Example 3 are the optimal.

[0055] It is obvious to those skilled in the art that the present invention is not limited to the details of the above-described exemplary embodiments, and that the present invention can be implemented in other specific forms without departing from the spirit or essential characteristics of the present invention. Therefore, in any regard, the embodiments should be regarded as exemplary and non-limiting. The scope of the present invention is defined by the appended claims rather than the above description. Therefore, all changes falling within the meaning and scope of the equivalent elements of the claims are intended to be embraced within the present invention.

[0056] In addition, it should be understood that although this specification is described in terms of embodiments, not every embodiment only contains an independent technical solution. This narrative manner of the specification is only for clarity. Those skilled in the art should regard the specification as a whole, and the technical solutions in each embodiment can also be appropriately combined to form other embodiments that can be understood by those skilled in the art.

Claims

1. A method for synthesizing terpinene 4,8-epoxide, characterized in that: The method for synthesizing terpinolene 4,8-epoxide comprises the following steps: The terpinolene raw material, catalyst, catalyst auxiliary agent and solvent are mixed and stirred to form a mixture solution, and then mixed with an oxidant in a reactor for reaction, purified and dried to obtain terpinolene 4,8-epoxide; in, The catalyst adjuvant is 4-dimethylaminopyridine; The catalyst is selected from one or more of acetic anhydride, propionic anhydride or isobutyric anhydride; The oxidant is a hydrogen peroxide solution; The mass fraction of hydrogen peroxide in the hydrogen peroxide solution is 10-20%.

2. The method for synthesizing terpinene 4,8-epoxide according to claim 1, characterized in that: The mass fraction of terpinene in the terpinene raw material is 85-95%.

3. The method for synthesizing terpinene 4,8-epoxide according to claim 1, characterized in that: The solvent is selected from one or more of acetonitrile, acetone, ethyl acetate or dichloromethane.

4. The method for synthesizing terpinolene 4,8-epoxide according to claim 1, characterized in that: The molar ratio of the terpinolene raw material, the catalyst auxiliary agent, the catalyst and the oxidant is 1:(0.05-0.25):(0.75-2.25):(2.0-4.0).

5. The method for synthesizing terpinolene 4,8-epoxide according to claim 1, characterized in that: The mass ratio of the terpinolene raw material to the solvent is 1:(5-15).

6. The method for synthesizing terpinolene 4,8-epoxide according to claim 1, characterized in that: The reactor is a batch reactor.

7. The method for synthesizing terpinolene 4,8-epoxide according to claim 6, characterized in that: When an intermittent tank reactor is used as the reactor for the reaction, the oxidant is directly mixed into the mixture solution, the reaction temperature is 20-40° C., and the total reaction time is 0.5-3 h.

8. The method for synthesizing terpinolene 4,8-epoxide according to claim 1, characterized in that: The reactor is a microchannel continuous reactor.

9. The method for synthesizing terpinolene 4,8-epoxide according to claim 8, characterized in that: When a microchannel continuous reactor is used as a reactor for the reaction, the oxidant and the mixture solution are added to the microchannel continuous reactor simultaneously through different channels, the reaction temperature is 20-40°C, the reaction pressure is normal pressure, and the reaction residence time is 10-20 minutes.

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