Synthetic method of isoterpinene 4, 8-epoxide

Abstract

The invention relates to an isoterpinene 4, 8-epoxide synthesis method, which comprises: blending an isoterpinene raw material, a catalyst, a catalyst auxiliary agent and a solvent, stirring to form a mixture solution, carrying out a mixing reaction on the mixture solution and an oxidizing agent in a reactor, purifying, and drying to obtain the isoterpinene 4, 8-epoxide. And 2, 8-epoxide. According to the synthesis method of the isoterpinene 4, 8-epoxide, an adopted reaction system is moderate in oxidability and mild in reaction condition, double bonds at the fourth position can be directionally oxidized, high oxidation selectivity is achieved, and finally the highest selectivity of the isoterpinene 4, 8-epoxide can reach 95% or above; meanwhile, the method overcomes the defect that the existence of water in a catalytic system in the prior art easily causes ring-opening hydrolysis of epoxidation reaction, accelerates the epoxidation reaction process, shortens the reaction time, and increases the yield of the product, and the highest yield can reach 88% or above.

Description

Technical Field

[0001] The 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, terpinene-4-ol is distributed in many natural plants. It is the main component and key active substance in many Chinese herbal essential oils such as Melaleuca alternifolia essential oil and coral ginger essential oil. However, due to the uncertainty of supplying terpinene-4-ol from natural plants, the industry often further reacts terpinene 4,8-epoxide obtained through the epoxidation of terpinene to obtain terpinene-4-ol. However, the selective epoxidation of terpinene has always been a bottleneck in this industrial production route. This is because terpinene has double bonds on the carbons at positions 1 and 4 (the structural formula of terpinene and the epoxidation reaction route are shown in Figure 2). Figure 1 As shown in the figure, it is very active and can be easily completely oxidized to form terpinene 1,2-4,8-diepoxide, which reduces the selectivity of the reaction; and the double bond has strong reactivity. Under certain conditions, it is easy to undergo a series of reactions such as isomerization, polymerization, and double bond cleavage, making the reaction process difficult to control. This is also the main technical difficulty in the synthesis of terpinene 4,8-epoxide.

[0003] As far as oxidation reactions are concerned, the use of hydrogen peroxide as an oxidant is relatively cheap and environmentally friendly. A widely used heterogeneous catalyst in organic synthesis is γ-alumina, which has a high specific surface area and a pore size distribution with a high mesopore ratio. It is used both as a catalyst and as a carrier for active metals. Dalmo Mandelli pointed out that the activity of the catalyst was significantly improved when anhydrous hydrogen peroxide was used as an oxidant and ethyl acetate as a solvent for this type of reaction. Studies on the reusability of alumina in the epoxidation of limonene and terpenes have shown that after several cycles, the selectivity of alumina remains almost unchanged, while in the epoxidation of limonene, the activity of continuous cycles decreases significantly due to the long reaction time. 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, the increase in reaction temperature will reduce the selectivity of the reaction.

[0004] Patent CN108947939A mentions a method for selective oxidation using a catalyst including any one of 2,2,2-trifluoroacetophenone, 1,1,1-trifluoroacetone, hexafluoroacetylacetone, perfluoroacetone or p-fluoroacetophenone, toluene as solvent, hydrogen peroxide as oxidant, and acetonitrile as catalyst aid. The cost of the reaction solvent catalyst trifluoroacetophenone is relatively high, the residual trifluoroacetophenone is difficult to remove, the reaction time in the reactor is long at low temperature, the water produced during the reaction process is easy to cause the hydrolysis of the epoxy product, and the product selectivity is only 85% at most; in addition, the mass fraction of the patented oxidant hydrogen peroxide solution is 30-80%, and it is difficult to obtain a concentration of more than 30% with commercially available hydrogen peroxide, and the higher the concentration, the more dangerous the reaction.

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

[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. Provided is a method for preparing terpene 4,8-epoxide by co-oxidation, and proposed a scheme for preparing terpene 4,8-epoxide by catalytic epoxidation reaction by adding alumina to ethyl acetate at 60°C for 72 hours with an oxidant. However, the maximum conversion rate of this method is only 77.6%, and the product selectivity is only 6.5%.

[0007] Uguina AM, Delgado AJ, 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. Provided is a method for preparing terpinene 4,8-epoxide by co-oxidation, which proposes adding alumina to ethyl acetate at a temperature of 140°C to oxidize the substrate under high pressure, so that the alumina can be recovered and used as a catalyst to participate in the reaction, and the reaction time is reduced to 8 hours. The method is to prepare terpinene 4,8-epoxide by catalytic epoxidation reaction. However, the method not only increases 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 widely used in the synthesis of drugs, pesticides, materials and other fields.

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

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

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

[0012] 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;

[0013] in,

[0014] The catalyst adjuvant is 4-dimethylaminopyridine;

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

[0016] The oxidant is a hydrogen peroxide solution;

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

[0018] Furthermore, the mass fraction of terpinene in the terpinene 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 auxiliary agent, 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 an intermittent tank reactor.

[0023] Furthermore, 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.

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

[0025] Furthermore, 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 residence time of the reaction is 10-20min.

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

[0027] (1) The present invention provides a method for synthesizing terpinolene 4,8-epoxide. The reaction system used has moderate oxidizing properties and mild reaction conditions. The double bond at position 4 can be oxidized in a targeted manner and has high oxidation selectivity. The final selectivity for the target product terpinolene 4,8-epoxide can reach a maximum of more than 95%. At the same time, the present invention overcomes the disadvantage that the presence of water in the catalytic system of the prior art easily leads to ring-opening hydrolysis in the epoxidation reaction, accelerates the reaction process of the epoxidation reaction, shortens the reaction time, and increases the yield of the product, which can reach a maximum of more than 88%.

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

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

[0030] (4) The epoxidation reaction of the present invention can be carried out in an intermittent reactor, where the reaction conditions are mild, the reaction speed is fast, a complex cooling system is not required, the energy consumption is low, the equipment requirements are low, and the equipment investment is small. It can also be carried out in a continuous microchannel reactor. Since hydrogen peroxide is used as an oxidant, the reaction exotherm is large. The use of a microchannel reactor can remove the reaction heat in time, greatly improving the safety of the reaction process, and at the same time greatly improving the reaction rate by enhancing mass transfer.

[0031] (5) The method of the present invention has high selectivity and yield for the target product terpinene 4,8-epoxide, is easy to industrialize and is environmentally friendly. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] Figure 1 The structural formula of terpinene and the epoxidation reaction route are shown. DETAILED DESCRIPTION

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

[0034] The words "preferred", "preferably", "more preferably", etc. in the present invention refer to embodiments of the present invention that can provide certain beneficial effects in certain circumstances. However, other embodiments may also be preferred under the same circumstances or other circumstances. In addition, the description of one or more preferred embodiments does not imply that other embodiments are not applicable, 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 where otherwise indicated, all numbers indicating, for example, the amounts of ingredients used in the specification and claims should be understood to be modified in all cases by the term "about". Therefore, unless indicated to the contrary, the numerical parameters set forth in the following specification and the appended claims are approximate values ​​that vary depending on the desired properties to be obtained by the present invention.

[0036] The mass fraction of terpinolene in the terpinolene raw material of the present invention and the comparative example is 95%.

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

[0038] Example 1

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

[0040] 100g of terpinene raw material, 17.1g of 4-dimethylaminopyridine, 91.1g of propionic anhydride and 1L of dichloromethane were mixed and stirred to form a mixture solution, which was then mixed with 480g of hydrogen peroxide solution and placed in an intermittent reactor to react at room temperature for 2h. The reaction liquid at the reactor outlet was collected in a flask placed in ice water, allowed to stand for stratification, the organic layer was quenched with water and then washed with saturated sodium sulfite aqueous solution to remove excess hydrogen peroxide, and the organic phase was collected for gas chromatography analysis to obtain terpinene 4,8-epoxide.

[0041] Example 2

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

[0043] Example 3

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

[0045] Example 4

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

[0047] 100g of terpinene raw material, 17.1g of 4-dimethylaminopyridine, 91.1g of propionic anhydride and 1L of dichloromethane were mixed and stirred to form a mixture solution, and then added into a continuous microchannel reactor with 320g of hydrogen peroxide solution in two streams, with a total flow rate of 20mL / min, a reaction temperature of 30°C, a reaction pressure of normal pressure, and a residence time of 15min. The reaction liquid at the outlet of the reactor was collected in a flask placed in ice water, allowed to stand for stratification, the organic layer was quenched with water, and then washed with saturated sodium sulfite aqueous solution to remove excess hydrogen peroxide, the organic phase was collected, and gas chromatography analysis was performed to obtain terpinene 4,8-epoxide.

[0048] Comparative Example

[0049] A method for synthesizing terpinene 4,8-epoxide, the method is derived from patent CN108947939A, the synthesis of terpinene 4,8-epoxide described by the team of Fuzhou University has a maximum conversion rate of 95.96% and a best product selectivity of 80.86%. In order to verify and compare the conversion rate and product selectivity of our existing method, a comparative experiment is conducted, and the method comprises the following steps:

[0050] 10g of terpinene raw material (mass fraction 84%), 3g of 2,2,2-trifluoroacetophenone, 5g of acetonitrile and 6g of toluene were mixed evenly to obtain a mixture solution, which was transferred to an intermittent reactor, and 10g of a 50% hydrogen peroxide solution was slowly added to the mixture solution at 30°C for 2 hours. After the addition was completed, the mixture was stirred for 9 hours, and then allowed to stand. After the mixture was separated, the organic phase and the aqueous phase were collected separately, and 9g of sodium sulfite solution (mass fraction 15%) was added to the organic phase, stirred for 30 minutes, and the remaining hydrogen peroxide was removed. The remaining organic phase was sampled for chromatographic analysis.

[0051] The conversion and selectivity results of Examples 1-4 and Comparative Examples are shown in Table 1.

[0052] Table 1 Conversion rate and selectivity results of Examples 1-4 and Comparative Examples

[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 higher than that of the Fuzhou University team. Under the condition of ensuring the best product selectivity, the conditions in Example 3 are the best.

[0055] It will be apparent to those skilled in the art that the present invention is not limited to the details of the exemplary embodiments described above and that the present invention can be implemented in other specific forms without departing from the spirit or essential features of the present invention. Therefore, the embodiments should be considered exemplary and non-restrictive in all respects, and the scope of the present invention is defined by the appended claims rather than the above description, and it is intended that all changes falling within the meaning and scope of the equivalent elements of the claims be included in the present invention.

[0056] In addition, it should be understood that although the present specification is described according to implementation modes, not every implementation mode contains only one independent technical solution. This description of the specification is only for the sake of clarity. Those skilled in the art should regard the specification as a whole. The technical solutions in each embodiment may also be appropriately combined to form other implementation modes 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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