Preparation method and application of perillaldehyde

Abstract

The invention discloses a preparation method and application of perillaldehyde, and belongs to the technical field of organic compound synthesis, limonene is used as a substrate, potassium hydrogen persulfate composite salt is used as an oxidizing agent, limonene 1, 2-epoxide is prepared through an oxidation reaction in the presence of a surfactant, then isomerization reaction is performed to prepare iso-carveol, and the iso-carveol is obtained. Isomerization reaction is carried out on the iso-carveol again to prepare perillyl alcohol, and oxidation reaction is carried out again to prepare perillaldehyde. According to the invention, through the cascade amplification effect, the yield can be increased stage by stage in four-stage reaction, finally, the yield is obviously increased, the yield of single-step reaction can be increased by 50%, and the production cost is reduced. The method is suitable for preparing perillaldehyde and analogues thereof, and is used for preparing food additives such as perillaldehyde perfume, drug intermediates or preservatives.

Description

Technical Field

[0001] The invention belongs to the technical field of organic compound synthesis and relates to a preparation method and application of perillaldehyde. Background Art

[0002] Perillaldehyde, a natural aromatic compound and the primary component of perilla essential oil, has garnered widespread attention in recent years for its diverse biological activities, including antifungal, antibacterial, antioxidant, anticancer, antidepressant, and anti-inflammatory properties. Perillaldehyde holds significant application value in areas such as food additives, perfume ingredients, and traditional medicines. However, existing methods for preparing perillaldehyde suffer from numerous drawbacks, severely limiting its industrial production and widespread application.

[0003] Natural extraction is the traditional method for obtaining perillaldehyde, primarily from perilla or citrus fruits. However, the perillaldehyde content is typically less than 10 wt%, and selective isolation requires sodium bisulfite addition. This method suffers from low yields and unstable purity, making it difficult to meet the demands of industrial production. Consequently, natural extraction methods cannot achieve efficient, high-purity, large-scale production.

[0004] Chemical synthesis is currently the primary route for preparing perillaldehyde, but existing processes still present significant challenges. The synthetic route using α-pinene requires the use of highly toxic selenium dioxide as an oxidant. Furthermore, the critical isomerization steps, such as the conversion of myrtle alcohol to perillyl alcohol or myrtle aldehyde to perillyl aldehyde, require high temperatures of 430°C and high vacuum conditions of 0.67-0.90 kPa. These harsh reaction conditions and high energy consumption make them difficult to adapt to large-scale industrial production.

[0005] Synthesis routes using β-pinene as a raw material also have significant shortcomings. For example, the method reported by Li Qianhe, Yin Dulin, and others involves steps such as peracetic acid epoxidation, ammonium nitrate-catalyzed isomerization, and sodium dichromate oxidation. Not only does this result in a low overall yield and purity of perillaldehyde, but the peracetic acid is also unstable and difficult to store. The reaction also produces a large amount of acidic waste liquid, making it incompatible with the requirements of green chemistry and sustainable development. Summary of the Invention

[0006] In view of the above shortcomings of the prior art, the purpose of the present invention is to provide a method for preparing perillaldehyde, which uses limonene as a raw material, obtains limonene 1,2-epoxide through an oxidation reaction in the presence of a surfactant, then undergoes two isomerizations to obtain perillyl alcohol, and finally oxidizes again to obtain perillaldehyde, so as to solve the problems of high toxicity, harsh reaction conditions, low yield, and large waste emissions in the existing perillaldehyde preparation method.

[0007] Another object of the present invention is to provide the application of the above preparation method in the preparation of perillaldehyde perfume, pharmaceutical intermediates or food additives.

[0008] In order to achieve the above object, the technical solution adopted by the present invention is: a method for preparing perillaldehyde, which uses limonene as a substrate and potassium persulfate complex salt as an oxidant, and in the presence of a surfactant, an oxidation reaction is performed to obtain limonene 1,2-epoxide, which is then subjected to an isomerization reaction to obtain isocarveol, which is further subjected to an isomerization reaction to obtain perillyl alcohol, and then subjected to a further oxidation reaction to obtain perillaldehyde.

[0009] As a limitation of the present invention, the surfactant is cetyltrimethylammonium bromide, cetyltrimethylammonium hydrogen sulfate, cetyltrimethylammonium chloride, sodium lauryl sulfate, sodium lauryl sulfonate, dodecyltrimethylammonium chloride or dodecyltrimethylammonium bromide.

[0010] As another limitation of the present invention, the mass ratio of the limonene to the surfactant is 1:0.01-0.5; the molar ratio of the limonene to the potassium persulfate complex is 1:0.1-2.0.

[0011] As a further limitation of the present invention, the following steps are included in sequence:

[0012] S1. Take limonene, a surfactant and potassium persulfate complex salt and a solvent I, and maintain the reaction system pH = 7.0 ~ 8.0, and separate the limonene 1,2-epoxide by oxidation reaction;

[0013] The potassium persulfate compound salt is added once or in batches. When the potassium persulfate compound salt is added in batches, the oxidation reaction efficiency is higher.

[0014] S2. limonene 1,2-epoxide, a transition metal catalyst, and a phenolic modifier are subjected to an isomerization reaction under an inert atmosphere to separate isocarveol;

[0015] S3. Under an inert atmosphere, taking isocarveol, a vanadium metal catalyst, a phenolic antioxidant and a solvent III having a boiling point of 150 to 250 ° C at a reaction temperature, and isomerizing the reaction to separate perillyl alcohol;

[0016] S4. Under reflux temperature conditions, manganese dioxide is added to perillyl alcohol and solvent IV in portions, and perillaldehyde is separated and obtained through oxidation reaction.

[0017] As a further limitation of the present invention, in step S1, the limonene is dissolved in acetone; the pH of the reaction system is maintained by adding sodium bicarbonate, potassium bicarbonate or sodium carbonate; the solvent I is water; the reaction temperature of the oxidation reaction is 10 to 50° C., and the reaction time is 0.5 to 8 hours.

[0018] As a further limitation of the present invention, in step S2, the transition metal catalyst is a chromium (III) compound;

[0019] The phenolic modifier is p-aminophenol, m-aminophenol, catechol or o-aminophenol;

[0020] The mass ratio of the limonene 1,2-epoxide to the transition metal catalyst is 1:0.1 to 3.0;

[0021] The mass ratio of the limonene 1,2-epoxide to the phenolic modifier is 1:0.1-2.0;

[0022] The reaction temperature of the isomerization reaction is 100-200° C., and the reaction time is 5-24 hours.

[0023] As a further limitation of the present invention, the chromium (III) compound is chromium acetate, chromium butyrate or chromium 2-ethylhexanoate;

[0024] The reaction system of the isomerization reaction further includes a solvent II;

[0025] The solvent II is toluene, xylene or o-dichlorobenzene.

[0026] As a further limitation of the present invention, in step S3, the vanadium-containing metal catalyst is ammonium metavanadate, ammonium metaniobate, ethyl metavanadate, n-hexyl metavanadate or vanadyl acetylacetonate;

[0027] The phenolic antioxidant is 2,4-diaminophenol, tert-butylhydroquinone or butylated hydroxyanisole; the solvent III is triethylene glycol, diethylene glycol or glycerol;

[0028] The mass ratio of isocarveol to the vanadium-containing metal catalyst is 1:0.1% to 1%;

[0029] The mass ratio of isocarveol to phenolic antioxidant is 1:0.04% to 1:1%;

[0030] The reaction temperature of the isomerization reaction is 120-190° C., and the reaction time is 8-12 hours.

[0031] As a further limitation of the present invention, in step S4, the solvent IV is ethyl acetate, ethanol or methanol;

[0032] The mass ratio of the perillyl alcohol to the total amount of manganese dioxide is 1:1 to 10;

[0033] The mass and volume ratio of the perillyl alcohol to solvent IV is 1 g: 10-30 mL;

[0034] The reaction temperature is 60-90°C;

[0035] The reaction time is 5 to 10 hours.

[0036] The present invention also provides an application of the preparation method of perillaldehyde, specifically for preparing perillaldehyde perfume, pharmaceutical intermediates or food additives. The food additives include preservatives and sweeteners.

[0037] Furthermore, the perilla aldehyde is subjected to an oximation reaction to obtain the food additive Perilla frutescens, which is a sweetener for cigarettes.

[0038] The main principle of the present invention is that the epoxidation reaction of olefins in an aqueous medium is carried out in a completely incompatible heterogeneous two-phase system, which will lead to limited mass transfer and reduced yield. The presence of a surfactant is conducive to the establishment of a microemulsion system, which can significantly improve the reaction rate and selectivity. In the presence of a surfactant, the conversion rate of the limonene raw material can be significantly improved.

[0039] Due to the adoption of the above technical solution, the present invention has the following technical advancements compared with the prior art:

[0040] The perillaldehyde preparation method of the present invention uses Oxone as an oxidant to synthesize limonene 1,2-epoxide in a mild and environmentally friendly manner. By regulating the surfactant, the amount of the oxidant, the solvent, and the temperature, the effects of few reaction by-products and high reaction efficiency are achieved. Limonene 1,2-epoxide is successfully synthesized from limonene. When Oxone is added in batches, the reaction efficiency is further improved.

[0041] The perillaldehyde preparation method of the present invention significantly improves the yield of 1,2-epoxide, and also discovers a route for directly isomerizing isocarveol to generate perillaldehyde, which shortens the preparation cycle. The present invention can improve the yield step by step in the four-step reaction of oxidation, two consecutive isomerizations and re-oxidation through a cascade amplification effect, and ultimately achieves a significant yield improvement. Compared with the existing technology in the comparative example, the single-step reaction yield can be increased by 50%, reducing production costs and facilitating industrialization.

[0042] The perillaldehyde preparation method of the present invention has mild process conditions and high operational safety. Since the boiling point range of the product obtained by the preparation method of the present invention and that of impurities are greatly different, the post-processing process is simple and only requires vacuum distillation, without the need for column chromatography which is relatively costly and inefficient. Product purification is achieved through vacuum distillation, which is more conducive to industrial production. The method is suitable for preparing perillaldehyde perfumes, sweeteners, pharmaceutical intermediates, preservatives and other additives. BRIEF DESCRIPTION OF THE DRAWINGS

[0043] Figure 1 This is a reaction diagram of Example 1 of the present invention;

[0044] Figure 2 This is the H NMR spectrum of limonene 1,2-epoxide prepared in Example 1 of the present invention;

[0045] Figure 3 This is a liquid chromatography-mass spectrometry detection result diagram of limonene 1,2-epoxide prepared in Example 1 of the present invention;

[0046] Figure 4 This is the H NMR spectrum of isocarveol prepared in Example 1 of the present invention;

[0047] Figure 5 This is a liquid chromatography-mass spectrometry detection result diagram of isocarveol prepared in Example 1 of the present invention;

[0048] Figure 6 This is a liquid chromatogram of isocarveol prepared in Example 1 of the present invention;

[0049] Figure 7 This is the H NMR spectrum of perillyl alcohol prepared in Example 1 of the present invention;

[0050] Figure 8 This is the H NMR spectrum of perillaldehyde prepared in Example 1 of the present invention;

[0051] Figure 9 This is a liquid chromatography-mass spectrometry detection result diagram of perillaldehyde prepared in Example 1 of the present invention;

[0052] Figure 10 This is a liquid chromatogram of perillaldehyde prepared in Example 1 of the present invention. DETAILED DESCRIPTION

[0053] The present invention will be further described in detail below by way of specific examples. It should be understood that the described examples are only used to illustrate the present invention and are not intended to limit the present invention.

[0054] Unless otherwise specified, the experimental methods used in the following examples are conventional methods in the art.

[0055] Unless otherwise specified, the materials and reagents used in the following examples can be obtained from commercial sources.

[0056] Example 1

[0057] This embodiment is a method for preparing perillaldehyde, using limonene as a substrate and potassium persulfate as an oxidant, in the presence of a surfactant, an oxidation reaction is performed to obtain limonene 1,2-epoxide, which is then subjected to an isomerization reaction to obtain isocarveol, which is then subjected to another isomerization reaction to obtain perillyl alcohol, which is then subjected to another oxidation reaction to obtain perillaldehyde. The reaction formula is as follows: Figure 1 As shown, it specifically includes the following steps performed in sequence:

[0058] S1. Preparation of limonene 1,2-epoxide by oxidation of limonene:

[0059] In a 50 mL round-bottom glass flask, 336.63 g of deionized water (solvent I) and 10.0 g of sodium lauryl sulfate (surfactant) were added sequentially, and electric stirring was started. 20.0 g (0.147 mol) of limonene was added and dissolved in 60 mL of acetone. When the system became translucent, 100.95 g (0.073 mol) of Oxone was slowly added in three portions: 30 g of Oxone was added first, reacted for 1 hour, 40.95 g of Oxone was added second, the reaction continued for 1 hour, and 30 g of Oxone was added third. The pH value was monitored during the reaction and maintained between 7 and 8 by adding 46.18 g (0.55 mol) of sodium bicarbonate to avoid excessive heating. The initial reaction temperature was 30°C, and the reaction time was 3 hours.

[0060] The mass ratio of limonene to surfactant is 1:0.5; the molar ratio of limonene to potassium persulfate complex salt (Oxone) is 1:0.5.

[0061] After the reaction, the reaction was quenched with 10% sodium thiosulfate solution, extracted with ethyl acetate, dried over magnesium sulfate, and the solvent was removed by cyclopentane. The product was then distilled under reduced pressure to obtain 7.6 g of colorless, transparent, oily liquid limonene 1,2-epoxide. The yield of this step was 68.04%.

[0062] The prepared limonene 1,2-epoxide was detected to obtain a hydrogen nuclear magnetic spectrum, such as Figure 2 , specifically a mixture of cis- and trans-limonene 1,2-epoxide, with the following H NMR characterization data: 1 H NMR(400MHz,Chloroform-d)δ4.73(s,1H),4.67(s,3H),3.05(s,1H),2.99(d,J=5.2Hz,1H),2 .16-1.98(m,4H),1.92-1.80(m,3H),1.74-1.64(m,9H),1.57-1.50(m,1H),1.41-1.15(m,9H).

[0063] Liquid chromatography-mass spectrometry test results, such as Figure 3 , characterization data are: LC-MS (ESI) m / z [M+H] +c alculated for C10H16O: 152.1 found: 152.94.

[0064] S2. Preparation of isocarveol by isomerization reaction of limonene 1,2-epoxide:

[0065] Under a nitrogen atmosphere, 10.01 g (66.77 mmol) of limonene 1,2-epoxide, 2.33 g of 2-ethylchromium acetate (as a transition metal catalyst), and 1.0 g of o-aminophenol (as a phenolic modifier) were added in sequence, and the reaction was carried out at 170°C for 7 h.

[0066] The mass ratio of limonene 1,2-epoxide to transition metal catalyst is 1:0.23; the mass ratio of limonene 1,2-epoxide to phenolic modifier is 1:0.1;

[0067] After the reaction, 10% hydrochloric acid solution was added to the reaction solution and stirred for 30 minutes. 10 mL of saturated sodium thiosulfate solution was then added to the reaction solution and stirred for 30 minutes. The solution was extracted with ethyl acetate and dried over magnesium sulfate. The solvent was removed by evaporation and vacuum distillation to obtain 7.53 g of isocarveol as a light yellow transparent oily liquid. The yield of this step was 75.30%.

[0068] The prepared isocarveol was detected to obtain a hydrogen nuclear magnetic spectrum, such as Figure 4 , the H NMR characterization data are: 1 H NMR (400 MHz, Chloroform-d) δ 4.86-4.76 (m, 2H), 4.71 (s, 2H), 4.37 (t, J = 3.2 Hz, 1H), 2.58-2.43 (m, 2H), 2.02-1.96 (m, 1H), 1.73 (s, 3H), 1.57-1.49 (m, 2H), 1.37-1.19 (m, 2H). Liquid chromatography-mass spectrometry results, such as Figure 5 The characterization data are as follows: LC-MS (ESI) m / z [M + H] + calculated for C10H16O: 152.1 found: 152.93; the liquid chromatography results are as follows Figure 6 .

[0069] S3. Preparation of perillyl alcohol by isomerization reaction of isocarveol:

[0070] At 155°C under a nitrogen atmosphere, 0.003 g of vanadium acetylacetonate (a vanadium-containing metal catalyst), 0.006 g of tert-butylhydroquinone (phenolic antioxidant), 2 mL of triethylene glycol (solvent III) and 1.0 g (6.57 mmol) of isocarveol were added in sequence to a 25 mL four-necked flask and reacted at 165°C for 12 h.

[0071] The mass ratio of isocarveol to the vanadium-containing metal catalyst is 1:0.3%; the mass ratio of isocarveol to the phenolic antioxidant is 1:0.06%;

[0072] After the reaction, the product was washed with saturated sodium thiosulfate solution and saturated brine respectively, dried over magnesium sulfate, and separated by column chromatography to obtain 0.73 g of perillyl alcohol. The yield of this step was 73.0%.

[0073] The prepared perillyl alcohol was detected to obtain a hydrogen nuclear magnetic spectrum, such as Figure 7 , the H NMR characterization data are: 1 H NMR(400MHz,Chloroform-d)δ5.70(s,1H),4.72(d,J=4.8Hz,2H),4.00(s,2H),2.18 -2.07(m,4H),2.00-1.92(m,1H),1.90-1.83(m,1H),1.74(s,3H),1.58-1.44(m,2H).

[0074] S4. Preparation of perillyl aldehyde by oxidation reaction of perillyl alcohol:

[0075] Under reflux temperature, 10 g (65.7 mmol) of perillyl alcohol and 180 mL of ethyl acetate (solvent IV) were added to a 250 mL four-necked flask in turn, and 50 g of manganese dioxide was added in five portions, 10 g each time. The reaction was stirred for 2 h after each addition. The total oxidation reaction time was 10, and the reaction temperature was 60 ° C.

[0076] The mass ratio of perillyl alcohol to the total amount of manganese dioxide is 1:5, and the mass-to-volume ratio of perillyl alcohol to solvent IV is 1 g:18 mL.

[0077] After the reaction, the mixture was extracted with ethyl acetate, dried over magnesium sulfate, and the solvent was removed to separate the final product. The final product was distilled under reduced pressure to obtain 8.38 g of perillaldehyde, with a yield of 84.92% and a purity of 98.89%.

[0078] In this example, the yield of perillaldehyde prepared from limonene was 28.86%.

[0079] The prepared perillaldehyde was detected to obtain a hydrogen nuclear magnetic spectrum, such as Figure 8 , the H NMR characterization data are: 1 H NMR (500MHz, Chloroform-d) δ9.44 (s, 1H), 6.83 (t, J = 2.0Hz, 1H), 4.79 (s, 1H), 4.74 (s, 1H), 2.50-2. 43(m,2H),2.29-2.22(m,2H),2.16-2.10(m,1H),1.94-1.90(m,1H),1.77(s,3H),1.49-1.41(m,1H).

[0080] Liquid chromatography-mass spectrometry test results, such as Figure 9The characterization data are: LC-MS (ESI) m / z [M+H] + c alculated for C10H14O: 150.1 found: 151.11. The liquid chromatography results are as follows Figure 10 .

[0081] Comparative Example 1

[0082] The difference between this comparative example and Example 1 is that in step S1, m-chloroperbenzoic acid is used as an oxidant to prepare limonene 1,2-epoxide from limonene, as follows:

[0083] At 0°C, 20 mL of dichloromethane, 0.89 g of sodium bicarbonate, and 2 g (14.7 mmol) of limonene were added sequentially to a 100 mL jacketed reactor. When the reaction temperature reached 0°C, m-chloroperbenzoic acid was added portionwise to avoid excessive heating. After completion of the reaction, the mixture was quenched with a saturated sodium thiosulfate solution, extracted with dichloromethane, washed with saturated brine, dried over magnesium sulfate, and the solvent removed. After column chromatography, 0.78 g of limonene 1,2-epoxide was obtained as a light yellow oily liquid. The yield for this step was 33.19%.

[0084] The remaining steps of this comparative example are the same as those of Example 1, and perillaldehyde is finally prepared. The yield of perillaldehyde prepared from limonene in this comparative example is 14.08%.

[0085] Comparative Example 2

[0086] The difference between this comparative example and Example 1 is that in step S1, hydrogen peroxide is used as an oxidant to prepare limonene 1,2-epoxide from limonene, as follows:

[0087] To a 250 mL four-necked flask, 5.01 g (3.67 mmol) of limonene, 5.03 g of acetone, 3.01 g of magnesium oxide, 41.1 g of acetonitrile, and 25.2 g of distilled water were added sequentially with stirring. 5.2 g (8.01 mmol) of hydrogen peroxide was slowly added dropwise at 50°C and allowed to react for 10 hours. After completion of the reaction, the mixture was quenched with saturated sodium thiosulfate solution, extracted with dichloromethane, washed with saturated brine, dried over magnesium sulfate, and the solvent removed. After column chromatography, 0.12 g of limonene 1,2-epoxide was obtained as a pale yellow oily liquid. The yield for this step was 21.48%.

[0088] The remaining steps of this comparative example are the same as those of Example 1, and perillaldehyde is finally obtained. The yield of perillaldehyde prepared from limonene is 5.97%.

[0089] Comparison of Comparative Examples 1 and 2 with Example 1 shows that the yield of limonene 1,2-epoxide prepared by using other oxidants in step S1 is significantly lower than that by using Oxone as the oxidant.

[0090] Comparative Example 3

[0091] The difference between this comparative example and Example 1 is that in step S1, limonene 1,2-epoxide is prepared from limonene using Oxone as an oxidant without adding a surfactant, as follows:

[0092] In a 50 mL round-bottom glass flask, add 336.63 g of deionized water and 46.18 g of sodium bicarbonate in sequence, and start electric stirring. Add 20.0 g (0.147 mol) of limonene and dissolve it in 60 mL of acetone. When the system is translucent, add 100.95 g (0.073 mol) of Oxone slowly in batches, and monitor the pH value to maintain the pH value between 7 and 8 to avoid heating too quickly. After the reaction is completed, quench the reaction with 10% sodium thiosulfate solution, extract with ethyl acetate, dry over magnesium sulfate, spin-dry the solvent, and distill under reduced pressure to obtain 3.65 g of colorless, transparent, oily liquid limonene 1,2-epoxide. The yield of this step is 32.68%.

[0093] The remaining steps of this comparative example are the same as those of Example 1, and perillaldehyde is finally obtained. The yield of perillaldehyde from limonene is 13.87%.

[0094] Comparative Example 3 compared with Example 1, the results show that the surfactant can significantly increase the yield of limonene 1,2-epoxide.

[0095] The above results show that the method for preparing perillaldehyde of the present invention uses Oxone as an oxidant to synthesize limonene 1,2-epoxide in a mild and environmentally friendly manner. By regulating the surfactant, oxidant dosage, solvent and temperature, the reaction has few by-products, high selectivity and high reaction efficiency, and limonene 1,2-epoxide is successfully synthesized from limonene.

[0096] Comparative Example 4

[0097] The difference between this comparative example and Example 1 lies in the different reaction systems for isomerization preparation of isocarveol in step S2, as follows:

[0098] Under a nitrogen atmosphere, 0.11 g of ferric chloride, 5 mL of dimethyl sulfoxide, and 1.0 g (6.68 mmol) of limonene 1,2-epoxide were added sequentially, and the mixture was allowed to react at 80°C for 8 h. After completion, the reaction was quenched with distilled water, extracted with ethyl acetate, washed with saturated brine, dried over magnesium sulfate, and the solvent removed. After column chromatography, 0.152 g of isocarveol was obtained, with a yield of 15.2%.

[0099] The remaining steps of this comparative example are the same as those of Example 1, and perillaldehyde is finally obtained. The yield of perillaldehyde prepared from limonene is 5.83%.

[0100] Comparative Example 5

[0101] The difference between this comparative example and Example 1 lies in the different reaction systems for isomerization preparation of isocarveol in step S2, as follows:

[0102] Under a nitrogen atmosphere, 0.63 g of titanocene dichloride, 0.44 g of manganese powder, 21 mL of tetrahydrofuran, and 0.136 g (0.89 mmol) of limonene 1,2-epoxide were added sequentially, and the mixture was allowed to react at 25°C for 6 h. After completion, the reaction was quenched with saturated potassium bisulfate solution, extracted with ethyl acetate, washed with saturated brine, dried over magnesium sulfate, and the solvent removed. After column chromatography, 0.022 g of isocarveol was obtained, with a yield of 16.18%.

[0103] The remaining steps of this comparative example are the same as those of Example 1, and perillaldehyde is finally obtained. The yield of perillaldehyde prepared from limonene is 6.20%.

[0104] Comparing Comparative Examples 4 to 5 with Example 1, the results show that the yield of isocarveol is significantly improved by using the isomerization reaction system of the present invention in step S2, with the maximum increase being 15.2%.

[0105] Comparative Example 6

[0106] This comparative example is the same as steps S1 to S3 of Example 1, except for step S4, which is as follows:

[0107] To a 25mL four-necked flask, 1.5g (9.85mmol) of perillyl alcohol, 13.9g (22.83mmol) of Oxone, 0.016g (0.10mmol) of 2,2,6,6-tetramethylpiperidin-1-oxyl, 0.13g (0.41mmol) of tetrabutylammonium bromide, and 10mL of dichloromethane were added in sequence and allowed to react at room temperature for 20h. After completion of the reaction, the product was extracted with dichloromethane, dried over magnesium sulfate, and the solvent removed to isolate the final product. Purification by column chromatography afforded 0.18g of perillaldehyde, a yield of 12.3%.

[0108] The remaining steps of this comparative example are the same as those of Example 1, and perillaldehyde is finally obtained. The yield of perillaldehyde prepared from limonene is 4.19%.

[0109] Comparative Example 6 is compared with Example 1. The results show that the yield of perillaldehyde using the oxidation reaction system of the present invention in step S4 is significantly improved, from 12.3% to 63.8%.

[0110] Comparative Example 7

[0111] In a 250mL four-necked flask, 10g (65.7mmol) of perillyl alcohol, 50g of manganese dioxide, and 180mL of ethyl acetate were reacted at 80°C for 8h. After completion of the reaction, the mixture was extracted with ethyl acetate, dried over magnesium sulfate, and the solvent removed to isolate the final product. The final product was distilled under reduced pressure to yield 4.58g of perillaldehyde, a yield of 45.8%. The yield of perillaldehyde from limonene is 15.56%.

[0112] Comparative Example 7 adopts the method of adding manganese dioxide at one time. Compared with the batch addition method of Example 1, the single-step yield and the overall yield are both lower, indicating that adding manganese dioxide in batches can significantly improve the oxidation efficiency and increase the yield.

[0113] The above comparative examples show that the present invention can improve the yield step by step in the four-step reaction of oxidation, two consecutive isomerizations and re-oxidation through the cascade amplification effect, and ultimately achieve a significant yield improvement. Compared with the existing technology in the comparative example, the single-step reaction yield can be increased by 50%.

[0114] Example 2

[0115] The difference between this embodiment and embodiment 1 is that in step S3, an equal amount of ammonium metavanadate is used instead of vanadyl acetylacetonate, as follows:

[0116] S3. To a 25 mL four-necked flask at 155°C under a nitrogen atmosphere, 0.003 g of ammonium metavanadate, 0.006 g of tert-butylhydroquinone, 2 mL of triethylene glycol, and 1.0 g (6.57 mmol) of isocarveol were added sequentially and reacted at 165°C for 18 h. After the reaction, the product was washed with saturated sodium thiosulfate solution and saturated brine, respectively, dried over magnesium sulfate, and separated by column chromatography to obtain 0.43 g of perillyl alcohol (a yield of 43%).

[0117] The preparation method of steps S1 to S2 and step S4 of this embodiment is the same as that of embodiment 1 to prepare perillaldehyde. The yield of perillaldehyde prepared from limonene is 17.02%.

[0118] Example 3

[0119] The difference between this embodiment and embodiment 1 is that in step S2, xylene is additionally added as solvent II to the reaction system for isomerization preparation of isocarveol, as follows:

[0120] Under a nitrogen atmosphere, 10.01 g (66.77 mmol) of limonene 1,2-epoxide, 2.33 g of 2-ethylchromium acetate, 1.0 g of o-aminophenol, and 5 mL of xylene were added sequentially, and the mixture was allowed to react at 150°C for 12 hours. After the reaction, 10% hydrochloric acid solution was added to the reaction mixture, and the mixture was stirred for 30 minutes. Then, 10 mL of saturated sodium thiosulfate solution was added to the reaction mixture, and the mixture was stirred for 30 minutes. Extraction with ethyl acetate and drying over magnesium sulfate were performed, and the solvent was removed by spunbond. The mixture was then distilled under reduced pressure to yield 3.61 g of isocarveol as a light yellow, transparent, oily liquid, with a yield of 36.10%.

[0121] The remaining steps of this example are the same as those of Example 1 to prepare perillaldehyde. The yield of perillaldehyde prepared from limonene is 13.84%.

[0122] Example 4

[0123] This embodiment is an application of perillaldehyde prepared by the preparation method of Examples 1 to 3 for preparing perfume, specifically: perillaldehyde, alcohol, fixative and deionized water are used as main raw materials, mixed, sterilized, and packaged to prepare perfume.

[0124] Example 5

[0125] This example is a method for preparing perillaldehyde, which is basically the same as the method in Example 3, except that some of the reaction system components, dosages, and reaction parameters are different. The specific differences are as follows:

[0126] In step S1, the pH of the reaction system is maintained at 7.0-8.0 by adding potassium bicarbonate; the surfactant is cetyltrimethylammonium bromide; the mass ratio of limonene to the surfactant is 1:0.01; the molar ratio of limonene to potassium persulfate complex salt is 1:2.0; the reaction temperature of the oxidation reaction is 18° C., and the reaction time is 0.5 h.

[0127] In step S2, the transition metal catalyst is chromium acetate; the phenolic modifier is p-aminophenol; the mass ratio of limonene 1,2-epoxide to the transition metal catalyst is 1:1.8; the mass ratio of limonene 1,2-epoxide to the phenolic modifier is 1:0.9; the reaction temperature of the isomerization reaction is 100° C., and the reaction time is 5 h; and the solvent II in the reaction system of the isomerization reaction is toluene.

[0128] In step S3, the vanadium-containing metal catalyst is ammonium metavanadate; the phenolic antioxidant is 2,4-diaminophenol; the solvent III is triethylene glycol; the mass ratio of isocarveol to the vanadium-containing metal catalyst is 1:1%; the mass ratio of isocarveol to the phenolic antioxidant is 1:1%; the reaction temperature of the isomerization reaction is 120° C.; and the reaction time is 12 h.

[0129] In step S4, solvent IV is ethanol; the mass ratio of perillyl alcohol to the total amount of manganese dioxide is 1:7; the mass and volume ratio of perillyl alcohol to solvent IV is 1 g:10 mL; the reaction temperature is 60° C.; and the reaction time is 5 h.

[0130] Example 6

[0131] This example is a method for preparing perillaldehyde, which is basically the same as the method in Example 3, except that some of the reaction system components, dosages, and reaction parameters are different. The specific differences are as follows:

[0132] In step S1, the pH of the reaction system is maintained at 7.0-8.0 by adding sodium carbonate; the surfactant is hexadecyltrimethylammonium hydrogen sulfate; the mass ratio of limonene to the surfactant is 1:0.5; the molar ratio of limonene to potassium persulfate complex salt is 1:1.5; the reaction temperature of the oxidation reaction is 30° C., and the reaction time is 4.5 hours.

[0133] In step S2, the transition metal catalyst is chromium butyrate; the phenolic modifier is m-aminophenol; the mass ratio of limonene 1,2-epoxide to the transition metal catalyst is 1:3.0; the mass ratio of limonene 1,2-epoxide to the phenolic modifier is 1:0.1; the reaction temperature of the isomerization reaction is 150° C., and the reaction time is 24 h; and the solvent II in the reaction system of the isomerization reaction is toluene.

[0134] In step S3, the vanadium-containing metal catalyst is ammonium metavanadate; the phenolic antioxidant is 2,4-diaminophenol; the solvent III is diethylene glycol; the mass ratio of isocarveol to the vanadium-containing metal catalyst is 1:0.9%; the mass ratio of isocarveol to the phenolic antioxidant is 1:0.04%; the reaction temperature of the isomerization reaction is 130° C.; and the reaction time is 9 hours.

[0135] In step S4, solvent IV is ethyl acetate; the mass ratio of perillyl alcohol to the total amount of manganese dioxide is 1:1; the mass and volume ratio of perillyl alcohol to solvent IV is 1 g:25 mL; the reaction temperature is 90° C.; and the reaction time is 5 h.

[0136] Example 7

[0137] This example is a method for preparing perillaldehyde, which is basically the same as the method in Example 3, except that some of the reaction system components, dosages, and reaction parameters are different. The specific differences are as follows:

[0138] In step S1, the pH of the reaction system is maintained at 7.0-8.0 by adding potassium bicarbonate; the surfactant is hexadecyltrimethylammonium chloride; the mass ratio of limonene to the surfactant is 1:0.3; the molar ratio of limonene to potassium persulfate complex salt is 1:0.1; the reaction temperature of the oxidation reaction is 50° C., and the reaction time is 8 hours.

[0139] In step S2, the transition metal catalyst is chromium 2-ethylhexanoate; the phenolic modifier is catechol; the mass ratio of limonene 1,2-epoxide to the transition metal catalyst is 1:2.1; the mass ratio of limonene 1,2-epoxide to the phenolic modifier is 1:1.5; the reaction temperature of the isomerization reaction is 200° C., and the reaction time is 5 h; the solvent II in the reaction system of the isomerization reaction is toluene.

[0140] In step S3, the vanadium-containing metal catalyst is ammonium metavanadate; the phenolic antioxidant is 2,4-diaminophenol; the solvent III is glycerol; the mass ratio of isocarveol to the vanadium-containing metal catalyst is 1:1%; the mass ratio of isocarveol to the phenolic antioxidant is 1:0.53%; the reaction temperature of the isomerization reaction is 190° C.; and the reaction time is 8 hours.

[0141] In step S4, solvent IV is methanol; the mass ratio of perillyl alcohol to the total amount of manganese dioxide is 1:10; the mass and volume ratio of perillyl alcohol to solvent IV is 1 g:30 mL; the reaction temperature is 60° C.; and the reaction time is 9 h.

[0142] Example 8

[0143] This example is a method for preparing perillaldehyde, which is basically the same as the method in Example 3, except that some of the reaction system components, dosages, and reaction parameters are different. The specific differences are as follows:

[0144] In step S1, the oxidant potassium persulfate complex salt is added all at once to the reaction container before the reaction; the pH of the reaction system is maintained at 7.0-8.0 by adding potassium bicarbonate; the surfactant is sodium lauryl sulfate; the mass ratio of limonene to the surfactant is 1:0.01; the molar ratio of limonene to the potassium persulfate complex salt is 1:1.2; the reaction temperature of the oxidation reaction is 10° C., and the reaction time is 3 hours.

[0145] In step S2, the transition metal catalyst is chromium acetate; the phenolic modifier is o-aminophenol; the mass ratio of limonene 1,2-epoxide to the transition metal catalyst is 1:0.1; the mass ratio of limonene 1,2-epoxide to the phenolic modifier is 1:2.0; the reaction temperature of the isomerization reaction is 100° C., and the reaction time is 20 h; and the solvent II in the reaction system of the isomerization reaction is o-dichlorobenzene.

[0146] In step S3, the vanadium-containing metal catalyst is ammonium metavanadate; the phenolic antioxidant is 2,4-diaminophenol; the solvent III is triethylene glycol; the mass ratio of isocarveol to the vanadium-containing metal catalyst is 1:0.1%; the mass ratio of isocarveol to the phenolic antioxidant is 1:0.9%; the reaction temperature of the isomerization reaction is 120° C.; and the reaction time is 10 h.

[0147] In step S4, solvent IV is ethanol; the mass ratio of perillyl alcohol to the total amount of manganese dioxide is 1:8; the mass and volume ratio of perillyl alcohol to solvent IV is 1 g:10 mL; the reaction temperature is 70° C.; and the reaction time is 10 h.

[0148] After testing, Examples 5 to 8 all successfully produced perillaldehyde. The food additive Perilla frutescens was produced by oximation of perillaldehyde, which is a sweetener for cigarettes.

[0149] In other embodiments, the surfactant is sodium dodecylsulfonate, dodecyltrimethylammonium chloride or dodecyltrimethylammonium bromide, and the vanadium-containing metal catalyst is vanadyl acetylacetonate, and perillaldehyde is successfully prepared.

[0150] In other embodiments, the perillaldehyde prepared in the examples of the present invention is used to prepare pharmaceutical intermediates, food preservatives or sweeteners.

[0151] It should be noted that the above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. Although the present invention has been described in detail with reference to the above embodiments, those skilled in the art may still modify the technical solutions described in the above embodiments or replace some of the technical features therein with equivalents. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention shall be included within the scope of protection of the claims of the present invention.

Claims

1. A method for preparing perillaldehyde, characterized in that: With limonene as substrate and potassium persulfate complex as oxidant, in the presence of surfactant, limonene 1,2-epoxide is obtained through oxidation reaction, which is then isomerized to obtain isocarveol, which is further isomerized to obtain perillyl alcohol, which is then oxidized again to obtain perillaldehyde.

2. The method for preparing perillaldehyde according to claim 1, wherein The surfactant is cetyltrimethylammonium bromide, cetyltrimethylammonium hydrogen sulfate, cetyltrimethylammonium chloride, sodium lauryl sulfate, sodium lauryl sulfonate, dodecyltrimethylammonium chloride or dodecyltrimethylammonium bromide.

3. The method for preparing perillaldehyde according to claim 2, wherein The mass ratio of the limonene to the surfactant is 1:0.01-0.5; The molar ratio of the limonene to the potassium persulfate composite salt is 1:0.1-2.

0.

4. The method for preparing perillaldehyde according to claim 3, wherein The process includes the following steps: S1. Take limonene, a surfactant and potassium persulfate complex salt and a solvent I, and maintain the reaction system pH = 7.0 ~ 8.0, and the oxidation reaction is separated to obtain limonene 1,2-epoxide; S2. limonene 1,2-epoxide, a transition metal catalyst, and a phenolic modifier are subjected to an isomerization reaction under an inert atmosphere to separate isocarveol; S3. Under an inert atmosphere, isocarveol, a vanadium-containing metal catalyst, a phenolic antioxidant and solvent III are subjected to an isomerization reaction to separate perillyl alcohol; S4. Under reflux temperature conditions, manganese dioxide is added to perillyl alcohol and solvent IV in portions, and perillaldehyde is separated and obtained through oxidation reaction.

5. The method for preparing perillaldehyde according to claim 4, wherein In step S1, the limonene is dissolved in acetone; the pH of the reaction system is maintained by adding sodium bicarbonate, potassium bicarbonate or sodium carbonate; the solvent I is water; the reaction temperature of the oxidation reaction is 10-50° C., and the reaction time is 0.5-8 h.

6. The method for preparing perillaldehyde according to claim 5, wherein In step S2, the transition metal catalyst is a chromium (III) compound; The phenolic modifier is p-aminophenol, m-aminophenol, catechol or o-aminophenol; The mass ratio of the limonene 1,2-epoxide to the transition metal catalyst is 1:0.1-3.0; The mass ratio of the limonene 1,2-epoxide to the phenolic modifier is 1:0.1-2.0; The reaction temperature of the isomerization reaction is 100-200° C., and the reaction time is 5-24 hours.

7. The method for preparing perillaldehyde according to claim 6, wherein The chromium (III) compound is chromium acetate, chromium butyrate or chromium 2-ethylhexanoate; The reaction system of the isomerization reaction further includes a solvent II; The solvent II is toluene, xylene or o-dichlorobenzene.

8. The method for preparing perillaldehyde according to claim 7, wherein In step S3, the vanadium-containing metal catalyst is ammonium metavanadate, ammonium metaniobate, ethyl metavanadate, n-hexyl metavanadate or vanadyl acetylacetonate; The phenolic antioxidant is 2,4-diaminophenol, tert-butylhydroquinone or butylated hydroxyanisole; the solvent III is triethylene glycol, diethylene glycol or glycerol; The mass ratio of isocarveol to the vanadium-containing metal catalyst is 1:0.1%~1%; The mass ratio of isocarveol to phenolic antioxidant is 1:0.04% to 1:1%; The reaction temperature of the isomerization reaction is 120-190° C., and the reaction time is 8-12 hours.

9. The method for preparing perillaldehyde according to claim 8, wherein In step S4, the solvent IV is ethyl acetate, ethanol or methanol; The mass ratio of the perillyl alcohol to the total amount of manganese dioxide is 1:1-10; The mass and volume ratio of perillyl alcohol and solvent IV is 1g: 10~30mL; The reaction temperature is 60-90°C; The reaction time is 5 to 10 hours.

10. An application of the method for preparing perillaldehyde according to any one of claims 1 to 9, characterized in that: Preparation of perillaldehyde perfume, pharmaceutical intermediates or food additives.

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