Method for synthesizing high purity high myrcene

Abstract

The application provides a synthesis method of high-purity high-myrcene, comprising the following steps: carrying out [2+2] cycloaddition reaction of 8-methyl-2,7-nonadiene-4-ketone and ethenone to obtain a beta-lactone intermediate, and carrying out retro-cycloaddition reaction of the beta-lactone intermediate to obtain high-purity high-myrcene product. The synthesis route of the application is novel and short, high-myrcene is prepared simply and efficiently by taking simple and easily obtained 8-methyl-2,7-nonadiene-4-ketone and ethenone as raw materials through two-step reaction of cycloaddition and ring-opening, the overall yield of the route is high, compared with the traditional process of Grignard addition-dehydration method, the content of the target isomer is significantly improved, and the development of high-myrcene downstream derivatives is facilitated.

Description

Technical Field

[0001] This invention belongs to the fields of fine chemicals and fragrances, and specifically relates to a method for synthesizing high-purity myrcene. Background Technology

[0002] Georgeywood, invented and discovered by Givaudan, has the following molecular structure: it is a mixture of two isomers, with the main aroma derived from isomer 1. Georgeywood is a synthetic fragrance, similar to ambroxol, possessing an elegant amber and woody scent. Its aroma is pure, fresh, and slightly sweet with a hint of green mint. It is frequently used by Givaudan perfumers in their fragrance blends to create woody notes.

[0003]

[0004] The synthesis of George's incense typically begins with high myrcene as a starting material, which undergoes a DA addition reaction with 3-methyl-3-buten-2-one, followed by cyclization under acidic conditions. High myrcene can be obtained by addition and dehydration of methyl Grignard reagent and citral. This method usually yields a mixture of three isomers, 5, 6, and 7. To obtain a higher purity intermediate 8, isomer 6 needs to be removed first, resulting in a mixture of isomers 5 and 7. This mixture then undergoes a DA reaction with 3-methyl-3-buten-2-one. Since isomer 5 is more reactive than 7, a higher purity intermediate 8 can be obtained. Due to the presence of isomers 6 and 7, the yield of this synthetic route is low; it is estimated that 80% of intermediate 4 is converted into byproducts (Chimia, 2006, 60, 574-579). There are also other synthetic routes for George's wood reported. For example, in 2009, Givaudan reported that George's wood was obtained by using high myrcene and methacrylonitrile as raw materials through DA addition, cyclization, Grignard addition, etc. The yield was much higher than that of the previous route. Isomer 5 is still an essential raw material (Tetrahydron, 2009, 65, 10495-10505).

[0005]

[0006] In summary, George's wood is an excellent woody and amber fragrance with an elegant and delicate aroma, widely used in high-end perfumes and fragrances. Currently, the main synthetic route for this product uses myrcene as a raw material, obtained through DA addition and cyclization reactions, with myrcene being the key raw material. Since current methods for synthesizing myrcene typically yield a mixture of three isomers, with only one isomer being a useful intermediate, increasing the content of the useful intermediate from the key raw material myrcene and reducing its synthesis cost would allow for a more economical and cost-effective preparation of George's wood. Summary of the Invention

[0007] The purpose of this invention is to provide a simple and efficient method for synthesizing high myrcene using 8-methyl-2,7-nonadien-4-one and ketene as raw materials. The two raw materials first undergo a [2+2] cycloaddition reaction to obtain a β-lactone intermediate, which then undergoes a reverse cycloaddition reaction to release one molecule of carbon dioxide, yielding a high-purity high myrcene product.

[0008] To achieve the above objectives and technical effects, the present invention adopts the following technical solution:

[0009] A method for synthesizing high-purity myrcene includes the following steps:

[0010] 1) 8-Methyl-2,7-nonadien-4-one and ketene undergo a [2+2] cycloaddition reaction under the action of a catalyst to give a β-lactone intermediate;

[0011] 2) The β-propiolactone intermediate undergoes a reverse cycloaddition reaction, releasing one molecule of CO2 to obtain high-purity myrcene.

[0012] The synthetic route for high myrcene described in this invention is shown below:

[0013]

[0014] In this invention, the catalyst in step 1) is a Lewis acid catalyst, preferably one or more of boron trifluoride diethyl ether, boron trifluoride acetic acid, zinc chloride, zinc bromide, zinc acetate, zinc acetylacetone, ferric chloride, aluminum trichloride, scandium trifluoromethanesulfonate, and yttrium trifluoromethanesulfonate; and

[0015] Preferably, the amount of catalyst used in step 1) is 0.2% to 3.0% of the molar amount of 8-methyl-2,7-nonadien-4-one, for example, 0.5%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, etc.

[0016] More preferably, the molar ratio of 8-methyl-2,7-nonadien-4-one and ketene in step 1) is 1.0:1.1 to 1.5, for example, 1:1.1, 1:1.2, 1:1.3, 1:1.4, etc.

[0017] In this invention, the [2+2] cycloaddition reaction described in step 1) is carried out under solvent conditions;

[0018] Preferably, the solvent is selected from one or more polar or nonpolar aprotic solvents, and more preferably from one or more of toluene, diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, methyl acetate, ethyl acetate, butyl acetate, ethyl butyrate, dichloromethane, chloroform, and dichloroethane.

[0019] More preferably, the amount of solvent used is 3.0 to 5.0 times the mass of 8-methyl-2,7-nonadien-4-one, for example, 3.5 times, 4 times, 4.5 times, etc.

[0020] In this invention, the [2+2] cycloaddition reaction in step 1) has a reaction temperature of 0 to 40°C, such as 5°C, 10°C, 15°C, 20°C, 25°C, 30°C, 35°C, 40°C, etc.; and a reaction time of 3 to 6 hours, such as 4 hours, 5 hours, etc.; the reaction time is calculated from the start of the ketene feed.

[0021] Preferably, the [2+2] cycloaddition reaction is carried out in a semi-continuous process, with 8-methyl-2,7-nonadien-4-one, solvent and catalyst added at one time, while ketene is continuously added to the above mixture.

[0022] In this invention, after the [2+2] cycloaddition reaction described in step 1) is completed, a terminator is added to quench the reaction;

[0023] Preferably, the terminating agent is an inorganic weak base, and more preferably one or more of sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, potassium monohydrogen phosphate, ammonium phosphate, diammonium hydrogen phosphate, and lithium carbonate.

[0024] Preferably, the amount of the terminator is 100-120% of the molar amount of the catalyst, such as 105%, 110%, 115%, etc.

[0025] In this invention, the reverse cycloaddition reaction in step 2) is carried out in a reactive distillation column. The β-lactone intermediate is continuously fed into the bottom of the column and undergoes a reverse cycloaddition reaction to generate products high myrcene and CO2, which are vaporized and evaporated and collected from the top of the column.

[0026] In this invention, solvent is added to the bottom of the reactive distillation column in step 2);

[0027] Preferably, the solvent may be, but is not limited to, any one of dimethyl phthalate, diethyl phthalate, dipropyl phthalate, diisopropyl phthalate, dibutyl phthalate, and diisobutyl phthalate;

[0028] Preferably, the amount of solvent used is 60 to 200 times the feed rate of the β-lactone intermediate per minute, for example, 80 times, 100 times, 120 times, 150 times, 180 times, etc.

[0029] In this invention, the reverse cycloaddition reaction in step 2) uses an organophosphoric acid as a catalyst, which can be, but is not limited to, any one of phenylphosphoric acid, diphenylphosphoric acid, diphenyl phosphate, di(4-methylphenyl) phosphate, bis(2,4-di-tert-butylphenyl) phosphate, bis(p-nitrophenyl) phosphate, etc.

[0030] Preferably, the amount of the organophosphoric acid catalyst is 0.02-0.5% of the molar amount of the β-lactone intermediate, for example, 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.35%, 0.4%, etc., and the organophosphoric acid catalyst is added to the solvent in the bottom of the column in one go.

[0031] In this invention, the reactive distillation conditions are as follows: 10-20 trays, for example 12, 15, 18, etc.; top temperature 90-95℃, for example 91℃, 92℃, 93℃, 94℃, etc.; bottom temperature 105-120℃, for example 110℃, 115℃, etc.; reflux ratio 5:1 to 1:1, for example 4:1, 3:1, 2:1, etc.; top pressure 0.5-2.0 kPaA, for example 1.0 kPaA, 1.5 kPaA, etc.; continuous feed to the bottom of the β-lactone intermediate column; high myrcene and CO2 are collected at the top of the column, wherein the high myrcene is condensed and liquefied and collected in a receiving bottle, and the CO2 is discharged in gaseous form.

[0032] The present invention, by adopting the above technical solution, has the following positive effects:

[0033] 1. The method of this invention has a short and novel synthetic route. It uses readily available 8-methyl-2,7-nonadien-4-one as raw material and obtains high myrcene products in a simple and efficient two-step reaction of [2+2] cycloaddition and anti-cycloaddition. The overall yield of the route is high. Compared with the traditional process of citral addition-dehydration, it significantly improves the yield and product content, which is beneficial to the development of downstream derivatives such as George's wood of high myrcene.

[0034] 2. The reverse cycloaddition reaction in the method of the present invention adopts a reactive distillation process. High-boiling-point phthalic acid esters are used as buffer solvents in the bottom of the column. After the raw material is cracked into products in the bottom of the column, it can be quickly evaporated and vaporized, avoiding side reactions such as isomerization and polymerization of polyene products under the action of catalysts in the bottom of the column.

[0035] 3. This invention uses a trace amount of organic phosphoric acid as a catalyst for the reverse cycloaddition reaction, which realizes the efficient ring-opening reaction of β-lactone intermediate, and obtains the target product high myrcene with high conversion rate and selectivity. The catalyst has high activity, long life and low cost. Detailed Implementation

[0036] The present invention is described in detail below through embodiments, but the present invention is not limited to the embodiments described below.

[0037] The main raw material information is as follows:

[0038] Boron trifluoride diethyl ether, Sigma-Aldrich reagent, 99%. Ethyl acetate, Aladdin reagent, chromatographic grade; Sodium bicarbonate, Sinopharm reagent, AR. Boron trifluoride acetic acid, Alfa reagent, 99%; Zinc bromide, aluminum trichloride, Aladdin reagent, 99%. Anhydrous tetrahydrofuran, dichloroethane, butyl acetate, Aladdin reagent, chromatographic grade. Potassium bicarbonate, sodium carbonate, West Asia reagent, 99%; Diammonium hydrogen phosphate, Merrill reagent, AR.

[0039] Dibutyl phthalate, diethyl phthalate, diisopropyl phthalate, dimethyl phthalate, Aladdin Reagent, AR. Diphenyl phosphate, diphenyl phosphate, Wengjiang Reagent, 99%. Di(4-methylphenyl) phosphate, Bailingwei Reagent, 98%. Bis(2,4-di-tert-butylphenyl) phosphate, Bidex Pharmaceutical, 97%. 8-Methyl-2,7-nonadien-4-one, Aituo Reagent, 98%.

[0040] The gas chromatography test conditions of this invention are as follows:

[0041] Instrument model: Agilent 7890B; Column: HB-5 capillary column (30m × 0.30mm × 0.25μm); Initial temperature 80℃, increased to 150℃ at a rate of 10℃ / min; then increased to 220℃ at a rate of 20℃ / min and held for 5.0 min; finally increased to 240℃ at a rate of 10℃ / min and held for 3.0 min. Carrier gas: high-purity nitrogen, split ratio 40:1, split flow rate 40 mL / min. Carrier gas savings: 38 mL / min, initial waiting time 5.0 min. Injection temperature 220℃, detector: FID, detector temperature 250℃, air flow rate 350 mL / min, hydrogen flow rate 30 mL / min, make-up gas flow rate 60 mL / min, injection volume 0.2 μL.

[0042] Example 1

[0043] Boron trifluoride diethyl ether catalyzes the synthesis of β-lactone intermediates from 8-methyl-2,7-nonadien-4-one and ketene.

[0044] Weigh out boron trifluoride diethyl ether (1.41 g, 9.9 mmol), anhydrous ethyl acetate (150.71 g), and 8-methyl-2,7-nonadien-4-one (50.24 g, 0.33 mol), and add them sequentially to a 1000 mL three-necked flask that has been purged with nitrogen beforehand. Place the flask in a low-temperature cold bath, turn on the stirrer, and lower the temperature of the reaction solution in the flask to 0 °C and maintain it. Then, slowly introduce ketene gas into the reaction flask. The ketene gas is obtained by high-temperature cracking of diketene, and its feed rate is maintained at 45.2 mL / min (0.12 mol / h). The ketene gas feed tube is inserted below the liquid surface so that the ketene can quickly dissolve into the reaction solution and participate in the reaction. To prevent the reaction flask from being pressurized, the tail gas is discharged through the tube, absorbed by sodium hydroxide aqueous solution, and then discharged into the fume hood. After 3 hours of continuous feeding, the ketene feed was stopped; the reaction solution was sampled and its composition was determined by GC. The reaction of the starting material 8-methyl-2,7-nonadien-4-one was essentially complete, with a selectivity of 98% for the [2+2] cycloaddition product proprolactone intermediate. The reaction was then quenched by adding sodium bicarbonate aqueous solution (18.3 g, 5.0 wt%, 10.9 mmol). After the reaction solution was allowed to stand, the phases were separated. The aqueous phase was extracted with ethyl acetate (30 mL); the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and then the solvent and product were separated by vacuum distillation. The target product yield was 95%. High-resolution mass spectrometry (HRMS-EI M) was used to analyze the product. + calcd C 12 H 18 O2:194.1307,found 194.1306. 1 HNMR(400MHz)δ1.57(t,2H),1.67(d,3H),1.79(d,3H),1.96(m,2H),2.05(d,3H),3.40(dd,2H),5.20(m,1H),5.67-5.69(m,2H).

[0045] Example 2

[0046] Boron trifluoride diethyl ether catalyzes the synthesis of β-lactone intermediates from 8-methyl-2,7-nonadien-4-one and ketene.

[0047] Weigh out boron trifluoride diethyl ether (0.11 g, 0.8 mmol), anhydrous ethyl acetate (182.68 g), and 8-methyl-2,7-nonadien-4-one (60.89 g, 0.40 mol), and add them sequentially to a 1000 mL three-necked flask that has been purged with nitrogen beforehand. Place the flask in a low-temperature cold bath, turn on the stirrer, and lower the temperature of the reaction solution in the flask to 20 °C and maintain it. Then, slowly introduce ketene gas into the reaction flask. The ketene gas is obtained by high-temperature cracking of diketene, and its feed rate is maintained at 37.3 mL / min (0.10 mol / h). The ketene gas feed tube is inserted below the liquid surface so that the ketene can quickly dissolve into the reaction solution and participate in the reaction. To prevent the reaction flask from being pressurized, the tail gas is discharged through the tube, absorbed by sodium hydroxide aqueous solution, and then discharged into the fume hood. After 6 hours of continuous feeding, the ketene feed was stopped; the reaction solution was sampled and its composition was determined by GC. The reaction of the starting material 8-methyl-2,7-nonadien-4-one was essentially complete, and the [2+2] cycloaddition product proprolactone intermediate had a selectivity of 97%. The reaction was then quenched by adding an aqueous sodium bicarbonate solution (8.1 g, 1.0 wt%, 1.0 mmol). After the reaction solution was allowed to stand, the phases were separated. The aqueous phase was extracted with ethyl acetate (30 mL). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and then the solvent and product were separated by vacuum distillation. The yield of the target product was 94%.

[0048] Example 3

[0049] Boron trifluoride diethyl ether catalyzes the synthesis of β-lactone intermediates from 8-methyl-2,7-nonadien-4-one and ketene.

[0050] Weigh out boron trifluoride diethyl ether (0.41 g, 2.9 mmol), anhydrous ethyl acetate (220.74 g), and 8-methyl-2,7-nonadien-4-one (44.15 g, 0.29 mol), and add them sequentially to a 1000 mL three-necked flask that has been purged with nitrogen beforehand. Place the flask in a low-temperature cold bath, turn on the stirrer, raise the temperature of the reaction solution in the flask to 30 °C and keep it stable. Then slowly introduce ketene gas into the reaction flask. The ketene gas is obtained by high-temperature cracking of diketene, and its feed rate is maintained at 46.9 mL / min (0.126 mol / h). The ketene gas feed tube is inserted below the liquid surface so that the ketene can quickly dissolve into the reaction solution and participate in the reaction. To prevent the reaction flask from being pressurized, the tail gas is discharged through the tube, absorbed by sodium hydroxide aqueous solution, and then discharged into the fume hood. After 3 hours of continuous feeding, the ketene feed was stopped, and the reaction was continued at 30°C for 10 minutes. The reaction solution was sampled, and GC analysis revealed that the starting material, 8-methyl-2,7-nonadien-4-one, had essentially completed the reaction, with a 98% selectivity for the [2+2] cycloaddition product, proprolactone intermediate. The reaction was then quenched by adding an aqueous sodium bicarbonate solution (13.4 g, 2.0 wt%, 3.2 mmol). After the reaction solution was allowed to stand, the phases were separated. The aqueous phase was extracted with ethyl acetate (30 mL). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and then the solvent and product were separated by vacuum distillation. The target product yield was 97%.

[0051] Example 4

[0052] Boron trifluoride acetic acid catalyzes the synthesis of β-lactone intermediates from 8-methyl-2,7-nonadien-4-one and ketene.

[0053] Weigh out boron trifluoride acetic acid (0.52 g, 4.1 mmol), dichloroethane (164.4 g), and 8-methyl-2,7-nonadien-4-one (41.1 g, 0.27 mol), and add them sequentially to a 1000 mL three-necked flask that has been purged with nitrogen beforehand. Place the flask in a low-temperature cold bath, turn on the stirrer, and lower the temperature of the reaction solution in the flask to 20 °C and keep it stable. Then, slowly introduce ketene gas into the reaction flask. The ketene gas is obtained by high-temperature cracking of diketene, and its feed rate is maintained at 30.2 mL / min (0.081 mol / h). The ketene gas feed tube is inserted below the liquid surface so that the ketene can quickly dissolve into the reaction solution and participate in the reaction. To prevent the reaction flask from being pressurized, the tail gas is discharged through the tube, absorbed by sodium hydroxide aqueous solution, and then discharged into the fume hood. After 4 hours of continuous feeding, the ketene feed was stopped, and the reaction continued at 20°C for 0.5 hours. The reaction solution was sampled, and GC analysis revealed that the starting material, 8-methyl-2,7-nonadien-4-one, had essentially completed the reaction, with a 98% selectivity for the [2+2] cycloaddition product, proprolactone intermediate. The reaction was then quenched with an aqueous solution of potassium bicarbonate (22.3 g, 2.0 wt%, 4.5 mmol). After the reaction solution was allowed to stand, the phases were separated. The aqueous phase was extracted with dichloroethane (30 mL). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and then the solvent and product were separated by vacuum distillation. The target product yield was 96%.

[0054] Example 5

[0055] Zinc bromide catalysis for the synthesis of β-lactone intermediates from 8-methyl-2,7-nonadien-4-one and ketene

[0056] Weigh zinc bromide (1.31 g, 5.8 mmol), anhydrous butyl acetate (220.74 g), and 8-methyl-2,7-nonadien-4-one (44.15 g, 0.29 mol), and add them sequentially to a 1000 mL three-necked flask that has been purged with nitrogen beforehand. Place the flask in a low-temperature cold bath, turn on the stirrer, raise the temperature of the reaction solution in the flask to 40 °C and keep it constant. Then slowly introduce ketene gas into the reaction flask. The ketene gas is obtained by high-temperature cracking of diketene, and its feed rate is maintained at 26.0 mL / min (0.07 mol / h). The ketene gas feed tube is inserted below the liquid surface so that the ketene can quickly dissolve into the reaction solution and participate in the reaction. To prevent the reaction flask from being pressurized, the tail gas is discharged through the tube, absorbed by sodium hydroxide aqueous solution, and then discharged into the fume hood. After 5 hours of continuous feeding, the ketene feed was stopped, and the reaction was continued at 40°C for 10 minutes. The reaction solution was sampled, and its composition was determined by GC. The reaction of the starting material 8-methyl-2,7-nonadien-4-one was essentially complete, with a selectivity of 96% for the [2+2] cycloaddition product proprolactone intermediate. The reaction was then quenched by adding an aqueous sodium carbonate solution (20.5 g, 3.0 wt%, 5.8 mmol). After the reaction solution was allowed to stand, the phases were separated. The aqueous phase was extracted with butyl acetate (30 mL). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and then the solvent and product were separated by vacuum distillation. The target product yield was 93%.

[0057] Example 6

[0058] Aluminum trichloride catalyzes the synthesis of β-lactone intermediates from 8-methyl-2,7-nonadien-4-one and ketene.

[0059] Weigh out aluminum trichloride (0.70 g, 5.0 mmol), anhydrous tetrahydrofuran (226.07 g), and 8-methyl-2,7-nonadien-4-one (50.24 g, 0.33 mol), and add them sequentially to a 1000 mL three-necked flask that has been purged with nitrogen beforehand. Place the flask in a low-temperature cold bath, turn on the stirrer, and lower the temperature of the reaction solution in the flask to 20 °C and maintain it. Then, slowly introduce ketene gas into the reaction flask. The ketene gas is obtained by high-temperature cracking of diketene, and its feed rate is maintained at 22.6 mL / min (0.061 mol / h). The ketene gas feed tube is inserted below the liquid surface so that the ketene can quickly dissolve into the reaction solution and participate in the reaction. To prevent the reaction flask from being pressurized, the tail gas is discharged through the tube, absorbed by sodium hydroxide aqueous solution, and then discharged into the fume hood. After 6 hours of continuous feeding, the ketene feed was stopped; the reaction solution was sampled and its composition was determined by GC. The reaction of the starting material 8-methyl-2,7-nonadien-4-one was essentially complete, and the [2+2] cycloaddition product proprolactone intermediate had a selectivity of 98%. The reaction was then quenched by adding diammonium hydrogen phosphate aqueous solution (15.7 g, 5.0 wt%, 5.9 mmol). After the reaction solution was allowed to stand, the phases were separated, and the aqueous phase was extracted with ethyl acetate (30 mL). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and then the solvent and product were separated by vacuum distillation. The yield of the target product was 96%.

[0060] Example 7:

[0061] The reactive distillation cracking of the β-lactone intermediate yields high myrcene.

[0062] In a nitrogen atmosphere at room temperature, dibutyl phthalate (73.8 g) and diphenylphosphoric acid (0.415 g, 1.9 mmol) were added sequentially to a 250 mL three-necked flask equipped with a magnetic stirrer. After stirring, a clear and transparent liquid was obtained. A 0.5 m long distillation column and reflux ratio controller were connected directly above the three-necked flask. The distillation column was filled with 3*3 triangular spiral packing, with a total of approximately 15 trays. The three-necked flask was placed in a 115 °C oil bath, and the stirring and condensation water were turned on. The top vacuum system was started, and the top pressure was controlled at 0.5 kPa. After the bottom temperature rose to 105 °C, β-lactone intermediate (1.23 g / min) was slowly fed into the bottom three-necked flask using a horizontal flow pump. No product was collected from the bottom; the cracking product was collected at the top of the column. After condensation and gas-liquid separation, the target product was obtained. Top-of-the-column sample was analyzed, with a certain amount of n-decane added as an internal standard, followed by GC chromatography. The conversion rate of the β-lactone intermediate was >99%, and the selectivity for the target isomer of myrcene was 96%. High-resolution mass spectrometry data of the product myrcene are shown below (HRMS-EI M). + calcd C 11 H 18 :150.1409,found 150.1407.1 H NMR (400MHz) δ1.58(d,3H),1.65(s,3H),1.72(s,3H),2.25(m,4H),5.02(m,2H),5.18(m,1H),5.22(m,1H),6.41(m,1H).

[0063] Example 8:

[0064] The reactive distillation cracking of the β-lactone intermediate yields high myrcene.

[0065] In a nitrogen atmosphere at room temperature, dibutyl phthalate (95.8 g) and diphenylphosphoric acid (0.081 g, 0.4 mmol) were added sequentially to a 250 mL three-necked flask equipped with a magnetic stirrer. After stirring, a clear and transparent liquid was obtained. A 0.5 m long distillation column and reflux ratio controller were connected directly above the three-necked flask. The distillation column was filled with 3*3 triangular spiral packing, with a total of approximately 15 trays. The three-necked flask was placed in a 120 °C oil bath, and the stirring and cooling water were turned on. The top vacuum system was started, and the top pressure was controlled at approximately 0.8 kPa. After the bottom temperature rose to 110 °C, the β-lactone intermediate was slowly fed into the three-necked flask of the bottom using a horizontal flow pump (0.8 g / min). No product was collected from the bottom; the cracking product was collected at the top of the column. After condensation and gas-liquid separation, the target product was obtained. Top-of-the-column sample analysis was performed, with a certain amount of n-decane added as an internal standard, followed by GC chromatography analysis. The conversion rate of the β-lactone intermediate was >99%, and the selectivity of the target isomer of myrcene was 92%.

[0066] Example 9:

[0067] The reactive distillation cracking of the β-lactone intermediate yields high myrcene.

[0068] In a nitrogen atmosphere at room temperature, dibutyl phthalate (113.3 g) and diphenylphosphoric acid (0.153 g, 0.7 mmol) were added sequentially to a 250 mL three-necked flask equipped with a magnetic stirrer. After stirring, a clear and transparent liquid was obtained. A 0.5 m long distillation column and reflux ratio controller were connected directly above the three-necked flask. The distillation column was filled with 3*3 triangular spiral packing, with a total of approximately 15 trays. The three-necked flask was placed in a 130 °C oil bath, and the stirring and cooling water were turned on. The top vacuum system was started, and the top pressure was controlled at approximately 2.0 kPa. After the bottom temperature reached 120 °C, β-lactone intermediate (0.57 g / min) was slowly fed into the bottom three-necked flask using a horizontal flow pump. No product was collected from the bottom; the cracking product was collected at the top of the column. After condensation and gas-liquid separation, the target product was obtained. Top-of-the-column sample analysis was performed, with a certain amount of n-decane added as an internal standard, followed by GC chromatography analysis. The conversion rate of the β-lactone intermediate was >99%, and the selectivity of the target isomer of myrcene was 93%.

[0069] Example 10:

[0070] The reactive distillation cracking of the β-lactone intermediate yields high myrcene.

[0071] In a nitrogen atmosphere at room temperature, diethyl phthalate (77.7 g) and diphenyl phosphate (0.080 g, 0.3 mmol) were added sequentially to a 250 mL three-necked flask equipped with a magnetic stirrer. After stirring, a clear and transparent liquid was obtained. A 0.5 m long distillation column and reflux ratio controller were connected directly above the three-necked flask. The distillation column was filled with 3*3 triangular spiral packing, with a total of approximately 15 trays. The three-necked flask was placed in a 125 °C oil bath, and the stirring and cooling water were turned on. The top vacuum system was started, and the top pressure was controlled at approximately 1.0 kPa. After the bottom temperature reached 115 °C, the β-lactone intermediate was slowly fed into the three-necked flask of the bottom using a horizontal flow pump (0.52 g / min). No product was collected from the bottom; the cracking product was collected at the top of the column. After condensation and gas-liquid separation, the target product was obtained. Top-of-the-column sample analysis was performed, with a certain amount of n-decane added as an internal standard, followed by GC chromatography analysis. The conversion rate of the β-lactone intermediate was >99%, and the selectivity of the target isomer of myrcene was 92%.

[0072] Example 11:

[0073] The reactive distillation cracking of the β-lactone intermediate yields high myrcene.

[0074] In a nitrogen atmosphere at room temperature, diisopropyl phthalate (93.3 g) and di(4-methylphenyl) phosphate (0.050 g, 0.2 mmol) were added sequentially to a 250 mL three-necked flask equipped with a magnetic stirrer. After stirring, a clear and transparent liquid was obtained. A 0.5 m long distillation column and reflux ratio controller were connected directly above the three-necked flask. The distillation column was filled with 3*3 triangular spiral packing, with a total of approximately 15 trays. The three-necked flask was placed in a 125 °C oil bath, and the stirring and cooling water were turned on. The top vacuum system was started, and the top pressure was controlled at approximately 1.0 kPa. After the bottom temperature reached 115 °C, the β-lactone intermediate was slowly fed into the three-necked flask of the bottom using a horizontal flow pump (0.58 g / min). No product was collected from the bottom; the cracking product was collected at the top of the column. After condensation and gas-liquid separation, the target product was obtained. Top-of-the-column sample analysis was performed, with a certain amount of n-decane added as an internal standard, followed by GC chromatography analysis. The conversion rate of the β-lactone intermediate was >99%, and the selectivity of the target isomer of myrcene was 94%.

[0075] Example 12:

[0076] The reactive distillation cracking of the β-lactone intermediate yields high myrcene.

[0077] In a nitrogen atmosphere at room temperature, dimethyl phthalate (113.65 g) and bis(2,4-di-tert-butylphenyl) phosphate (0.037 g, 0.1 mmol) were added sequentially to a 250 mL three-necked flask equipped with a magnetic stirrer. After stirring, a clear and transparent liquid was obtained. A 0.3 m long distillation column and reflux ratio controller were connected directly above the three-necked flask. The distillation column was filled with 3*3 triangular spiral packing, with a total of approximately 10 trays. The three-necked flask was placed in a 120 °C oil bath, and the stirring and cooling water were turned on. The top vacuum system was started, and the top pressure was controlled at approximately 0.8 kPa. After the bottom temperature reached 110 °C, the β-lactone intermediate was slowly fed into the three-necked flask of the bottom using a horizontal flow pump (0.76 g / min). No product was collected from the bottom; the cracking product was collected at the top of the column. After condensation and gas-liquid separation, the target product was obtained. Top-of-the-column sample analysis was performed, with a certain amount of n-decane added as an internal standard, followed by GC chromatography analysis. The conversion rate of the β-lactone intermediate was >99%, and the selectivity of the target isomer of myrcene was 95%.

Claims

1. A method for synthesizing high-purity myrcene, characterized in that, The steps include the following: 1) 8-Methyl-2,7-nonadien-4-one and ketene undergo a [2+2] cycloaddition reaction under the action of a catalyst to obtain a β-lactone intermediate; the catalyst is a Lewis acid catalyst, selected from one or more of boron trifluoride diethyl ether, boron trifluoride acetic acid, zinc chloride, zinc bromide, zinc acetate, zinc acetylacetone, ferric chloride, aluminum trichloride, scandium trifluoromethanesulfonate, and yttrium trifluoromethanesulfonate; After the [2+2] cycloaddition reaction is completed, the step of adding a terminator to quench the reaction is also included; the terminator is an inorganic weak base; 2) The β-lactone intermediate undergoes a reverse cycloaddition reaction, releasing one molecule of CO2 to obtain high-purity myrcene; The reverse cycloaddition reaction uses an organophosphoric acid as a catalyst, wherein the organophosphoric acid is selected from any one of phenylphosphoric acid, diphenylphosphoric acid, diphenyl phosphate, di(4-methylphenyl) phosphate, bis(2,4-di-tert-butylphenyl) phosphate, and bis(p-nitrophenyl) phosphate. The reverse cycloaddition reaction is carried out in a reactive distillation column. The β-lactone intermediate is continuously fed into the bottom of the column and undergoes a reverse cycloaddition reaction to generate the products myrcene and CO2. The products are vaporized and evaporated and collected from the top of the column. The chemical structural formula of the high myrcene is: .

2. The synthesis method according to claim 1, characterized in that, The catalyst in step 1) is selected from one or more of boron trifluoride diethyl ether, boron trifluoride acetic acid, zinc bromide, and aluminum trichloride.

3. The synthesis method according to claim 2, characterized in that, The amount of catalyst used is 0.2 to 3.0% of the molar amount of 8-methyl-2,7-nonadien-4-one.

4. The synthesis method according to claim 3, characterized in that, The molar ratio of 8-methyl-2,7-nonadien-4-one to ketene is 1.0:1.1~1.

5.

5. The synthesis method according to claim 1 or 2, characterized in that, The [2+2] cycloaddition reaction described in step 1) is carried out under solvent conditions.

6. The synthesis method according to claim 5, characterized in that, The solvent is selected from one or more polar or nonpolar aprotic solvents.

7. The synthesis method according to claim 6, characterized in that, The solvent is one or more of toluene, diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, methyl acetate, ethyl acetate, butyl acetate, ethyl butyrate, dichloromethane, chloroform, and dichloroethane.

8. The synthesis method according to claim 7, characterized in that, The amount of solvent used is 3.0 to 5.0 times the mass of 8-methyl-2,7-nonadien-4-one.

9. The synthesis method according to any one of claims 1-3, characterized in that, Step 1) describes the [2+2] cycloaddition reaction, with a reaction temperature of 0~40℃ and a reaction time of 3~6h.

10. The synthesis method according to claim 9, characterized in that, The [2+2] cycloaddition reaction is carried out in a semi-continuous process. 8-methyl-2,7-nonadien-4-one, solvent and catalyst are fed in one batch, while ketene is fed into the above mixture continuously.

11. The synthesis method according to any one of claims 1-4, characterized in that, Step 1) The terminating agent is one or more of sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, potassium monohydrogen phosphate, ammonium phosphate, diammonium hydrogen phosphate, and lithium carbonate.

12. The synthesis method according to claim 11, characterized in that, The amount of the terminator is 100-120% of the molar amount of the catalyst.

13. The synthesis method according to claim 6, characterized in that, Solvent is added to the bottom of the reactive distillation column.

14. The synthesis method according to claim 13, characterized in that, The solvent is selected from any one of dimethyl phthalate, diethyl phthalate, dipropyl phthalate, diisopropyl phthalate, dibutyl phthalate, and diisobutyl phthalate.

15. The synthesis method according to claim 14, characterized in that, The amount of solvent used is 60 to 200 times the feed mass of the β-lactone intermediate per minute.

16. The synthesis method according to claim 1, characterized in that, Step 2) The organic phosphoric acid is selected from any one of diphenyl phosphoric acid, diphenyl phosphate, di(4-methylphenyl) phosphate, and bis(2,4-di-tert-butylphenyl) phosphate.

17. The synthesis method according to claim 16, characterized in that, The amount of the organophosphoric acid catalyst used is 0.02-0.5% of the molar amount of the β-lactone intermediate.

18. The synthesis method according to claim 17, characterized in that, The organophosphate catalyst is added to the bottom solvent of the tower in one step.

19. The synthesis method according to any one of claims 13 to 18, characterized in that, The reactive distillation conditions are as follows: 10-20 trays, top temperature 90-95℃, bottom temperature 105-120℃, reflux ratio 5:1 to 1:1, and top pressure 0.5-2.0 kPaA.

20. The synthesis method according to claim 19, characterized in that, During the reactive distillation process, the β-lactone intermediate is continuously fed into the bottom of the column, and myrcene and CO2 are collected from the top of the column. The myrcene is condensed and liquefied and collected in a receiving bottle, while the CO2 is discharged in gaseous form.

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