Method for preparing gamma, delta-unsaturated ketone by adopting continuous flow process

Abstract

The invention belongs to the field of organic chemistry, and particularly relates to a preparation method of gamma, delta-unsaturated ketone by adopting a continuous flow process. According to the present invention, the existing Karol rearrangement reaction is improved, and the gamma, delta-unsaturated ketone preparation method using the continuous flow process is provided, and is successfully used in the synthesis of farnesyl acetone and teprenone. The preparation method disclosed by the invention can be safely, rapidly and continuously carried out at high temperature and high pressure, greatly improves the reaction efficiency, reduces unnecessary heat energy loss, and is green, environment-friendly, economical and more suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of organic chemistry, and specifically relates to a method for preparing γ,δ-unsaturated ketones using a continuous flow process. Background Technology

[0002] The Carroll rearrangement, also known as the Carroll-Claisen rearrangement, was first discovered in 1940. It refers to the reaction of allyl tertiary alcohols with a certain structure with acetoacetate esters in the presence of a catalyst to produce γ,δ-unsaturated ketones, as shown below.

[0003] Common catalysts mainly include organoaluminum salt systems, alkaline catalytic systems, and palladium noble metal systems.

[0004]

[0005] The Carol rearrangement has wide applications in industry. The Carol rearrangement of allyl tertiary alcohols and methyl acetoacetate under the catalysis of aluminum isopropoxide is an important intermediate. It is one of the most commonly used industrial methods for preparing compounds such as farnesylacetone 3 and the anti-peptic gastric ulcer drug teprenone 6. Their structures are as follows:

[0006]

[0007] CN103058839B describes a reaction where the temperature is slowly raised to 140-170°C, followed by a reaction time of 10-14 hours to produce teprenone. CN108047011B describes a reaction where (6E,10E)-geranyl linalool and aluminum isopropoxide are stirred and heated to 170°C, then methyl acetoacetate is added dropwise, and the temperature is raised to 200°C and held for 2 hours to produce teprenone; this reaction requires a distillation apparatus. Such reactions at high temperatures produce gases such as lower alcohols and carbon dioxide, which can lead to boiling over or material overflow risks in batch reactor processes.

[0008] Therefore, it is necessary to develop a safe, efficient, green, and scale-up-friendly Carroll rearrangement reaction process to meet the industrial demand for the preparation of γ,δ-unsaturated ketones. Summary of the Invention

[0009] The first aspect of this invention provides a method for preparing γ,δ-unsaturated ketones, comprising the following steps:

[0010]

[0011] In an organic solvent, the compounds shown in Formula I and Formula II react with an organoaluminum catalyst to yield compound III. The reaction is carried out in a continuous flow reaction system.

[0012] Among them, R 1 and R2 Each is an optional substitution of -C. 1-20 Alkyl or -C 2-20 Hydrocarbon group, wherein the substituent is -C 1-6 Alkyl, -C 2-10 hydrocarbon group, -C 1-10 alkynyl group, -C 3-6 cycloalkyl, -C 3-6 Heterocyclic alkyl, -C 6-10 Aryl, -C 5-10 heteroaryl; R 3 -C 1-5 alkyl.

[0013] In some embodiments, the reaction temperature is ≥200°C, preferably ≥220°C, more preferably ≥240°C, for example 245°C.

[0014] In some embodiments, the reaction pressure is ≥1.50 MPa, preferably ≥2.00 MPa, more preferably ≥2.10 MPa, for example 2.10, 2.20, 2.25, 2.30, 2.40, 2.50 MPa or any value or range thereof.

[0015] In some implementations, R 1 Or R 2 One of them is -C 1-10 Alkyl, the other is -C 5-20 An olefin, wherein the olefin has one or more double bonds; preferably, R 1 Or R 2 One of them is -C 1-5 Alkyl, the other is -C 10-20 An olefin, wherein the olefin has two or three double bonds; more preferably, R 1 Or R 2 One is methyl, and the other is...

[0016] In some implementations, R 3 It is methyl, ethyl, n-propyl or isopropyl, preferably methyl.

[0017] In some embodiments, the organoaluminum catalyst is aluminum isopropoxide, aluminum sec-butoxide, aluminum acetylacetone, or aluminum triacetyl ethyl acetate, preferably aluminum isopropoxide.

[0018] In some embodiments, the continuous flow reaction system includes an injector, a reaction apparatus, a pressure controller, and a receiver connected in series via piping, and the reaction system also includes a heater for heating the reaction apparatus.

[0019] In some embodiments, the reaction apparatus includes one or more reactors.

[0020] In some embodiments, the reactor is a tubular reactor.

[0021] In some embodiments, the reactor is a stainless steel coil;

[0022] Preferably, the stainless steel coil is an SS316 stainless steel coil; and / or

[0023] Preferably, the outer diameter of the stainless steel coil is one-eighth of an inch to one-quarter of an inch, more preferably one-eighth of an inch; and / or

[0024] Preferably, the inner volume of the stainless steel coil is 50-150 mL, more preferably 60-140 mL, and even more preferably 60-135 mL, such as 64.2 mL or 131.2 mL.

[0025] In some embodiments, the injector connected in series via tubing includes a pump.

[0026] In some embodiments, the pump is a plunger pump, a diaphragm pump, or a syringe pump, preferably a plunger pump, and more preferably a PTFE plunger pump.

[0027] In some implementations, the pressure controller is a back pressure valve.

[0028] In some embodiments, the heater is an oil bath, a vapor column oven, or a heating inner tube, preferably an oil bath.

[0029] In some embodiments, the molar ratio of the organoaluminum catalyst to the compound shown in Formula I is 0.03-0.20, preferably 0.04-0.15, more preferably 0.04-0.13, for example 0.05, 0.10, 0.12 or any value or range thereof.

[0030] In some embodiments, the molar ratio of the compounds represented by Formula II and Formula I is 1.0-3.0, preferably 1.2-2.5, more preferably 1.3-2.3, for example 1.5 or 2.0.

[0031] In some embodiments, the organic solvent is a hydrocarbon solvent, preferably n-heptane, n-nonane, cyclohexane, toluene, or xylene, more preferably n-heptane or xylene, and even more preferably n-heptane.

[0032] In some embodiments, the volume-to-mass ratio of the organic solvent to the compound represented by Formula I is 1-5 mL / g, preferably 2-4 mL / g, for example 3 mL / g.

[0033] In some embodiments, the preparation method includes the following steps:

[0034] (1) Prepare solutions of organoaluminum catalyst, compound II and compound I in organic solvent as materials;

[0035] (2) Set the reaction temperature and reaction pressure of the continuous flow reaction system, pump the material into the continuous flow reaction system at a certain pump flow rate for reaction, and collect the effluent.

[0036] (3) Stop the pump, then pump in the organic solvent at a certain pump flow rate and collect the effluent;

[0037] (4) Extract all the eluent obtained, dry and concentrate to obtain the compound shown in Formula III.

[0038] In some embodiments, the pump flow rate in step (2) or step (3) is independently 1-20 mL / min, preferably 1.0-10 mL / min, more preferably 3.0-7.0 mL / min, for example 6.0 mL / min.

[0039] In some embodiments, the reaction flux of step (2) is 1.0-2.0 g / min, preferably 1.2-1.8 g / min, for example 1.3 g / min, 1.7 g / min or 1.8 g / min.

[0040] In some embodiments, the organic solvents in step (1) or step (3) are each independently hydrocarbon solvents, preferably n-heptane, n-nonane, cyclohexane, toluene or xylene, more preferably n-heptane or xylene, and even more preferably n-heptane.

[0041] In some embodiments, the preparation method further includes the following steps:

[0042] (a1) At a certain pump flow rate, the pump and pipeline are cleaned sequentially with dilute hydrochloric acid and water;

[0043] (a2) Clean the pump and pipeline with organic solvent at a certain pump flow rate;

[0044] (a3) Slowly reduce the pump flow rate, continuously pump in organic solvent to clean the pump and pipeline, and slowly heat to the reaction temperature and set the reaction pressure.

[0045] In some embodiments, the pump flow rate in step (a1) is 20-80 mL / min, preferably 25-60 mL / min, and more preferably 30-50 mL / min.

[0046] In some embodiments, the concentration of the dilute hydrochloric acid in step (a1) is 0.2-0.8M, preferably 0.3-0.7M, more preferably 0.4-0.6M, for example 0.5M.

[0047] In some embodiments, the amount of dilute hydrochloric acid or water in step (a1) is independently 100-500 mL, preferably 200-400 mL, more preferably 250-350 mL, for example 300 mL.

[0048] In some embodiments, the pump flow rate in step (a2) is 10-40 mL / min, preferably 15-35 mL / min, and more preferably 20-30 mL / min.

[0049] In some embodiments, the organic solvent in step (a2) is methanol, ethanol, or acetone, preferably methanol or ethanol, and more preferably ethanol.

[0050] In some embodiments, the amount of organic solvent in step (a2) is 100-500 mL, preferably 200-400 mL, more preferably 250-350 mL, for example 300 mL.

[0051] In some implementations, the pump flow rate in step (a3) ​​is slowly reduced from the pump flow rate in step (a2) at intervals until the pump flow rate in step (3) is reduced.

[0052] Preferably, the interval is 1-5 minutes, more preferably 2-4 minutes, for example 3 minutes; and / or

[0053] Preferably, the reduced pump flow rate is 1-5 mL / min, more preferably 1-3 mL / min, for example 2 mL / min.

[0054] In some embodiments, the organic solvent in step (a3) ​​is a hydrocarbon solvent, preferably n-heptane, n-nonane, cyclohexane, toluene or xylene, more preferably n-heptane or xylene, and even more preferably n-heptane.

[0055] In some embodiments, the amount of organic solvent in step (a3) ​​is >300 mL, preferably >500 mL, and more preferably >600 mL.

[0056] In some embodiments, the cleaning time in step (a3) ​​is 30-120 min, preferably 40-100 min, more preferably 50-80 min, for example 60 min.

[0057] A second aspect of the present invention provides a method for preparing teprenone intermediate compound 3, comprising the following steps (a):

[0058] (a) Using compounds 1 and 2 as raw materials, compound 3 is prepared by the preparation method described in the first aspect of the present invention.

[0059]

[0060] In some embodiments, step (a) includes: reacting compound 1 and compound 2 in n-heptane with aluminum isopropoxide to obtain compound 3, wherein the reaction is carried out in a continuous flow reaction system, the reaction temperature is ≥200°C, and the reaction pressure is ≥1.50 MPa;

[0061] Preferably, the reaction temperature is ≥220℃ and the reaction pressure is ≥2.00MPa; more preferably, the reaction temperature is ≥240℃ and the reaction pressure is ≥2.10MPa.

[0062] A third aspect of the present invention provides a method for preparing teprenone, comprising the following or step (b):

[0063] (b) Using compounds 5 and 2 as raw materials, compound 6 is prepared by the preparation method described in the first aspect of the present invention.

[0064]

[0065] In some embodiments, step (b) includes: reacting compound 5 and compound 2 in n-heptane with aluminum isopropoxide to obtain compound 6, wherein the reaction is carried out in a continuous flow reaction system, the reaction temperature is ≥200°C, and the reaction pressure is ≥1.50 MPa;

[0066] Preferably, the reaction temperature is ≥220℃ and the reaction pressure is ≥2.00MPa; more preferably, the reaction temperature is ≥240℃ and the reaction pressure is ≥2.10MPa.

[0067] In some embodiments, compound 5 is obtained by reacting compound 4 via a Grignard reaction, wherein the Grignard reaction is prepared under conventional conditions in the art, as described in CN108047011B.

[0068]

[0069] In some embodiments, compound 4 is obtained by crystallizing compound 3 under conventional conditions in the art, as described in CN108047011B.

[0070]

[0071] In some embodiments, compound 3 is obtained by the preparation method described in the second aspect of the present invention.

[0072] Beneficial effects:

[0073] This invention improves upon existing Carroll rearrangement reactions by providing a continuous flow process for the preparation of γ,δ-unsaturated ketones, which has been successfully applied to the synthesis of farnesylacetone and teprenone. Compared to existing technologies or traditional batch reactor processes, the preparation method of this invention can be safely carried out continuously under high temperature and pressure, greatly improving reaction efficiency, reducing unnecessary heat loss, and is green, environmentally friendly, and economical. Furthermore, regarding the lower alcohols and carbon dioxide gases produced by the reaction, this invention controls the gas release in the pipeline through a pressure controller in the reaction module, eliminating the risks of boiling over or material overflow in traditional batch reactor processes, making it more suitable for industrial production. Attached Figure Description

[0074] Figure 1 Example 2: Schematic diagram of the experimental setup. Detailed Implementation

[0075] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. Unless stated to the contrary, the terms used in the specification and claims have the following meanings.

[0076] The terms “including,” “comprising,” “having,” “containing,” or “involving,” and their other variations herein, are inclusive or open-ended and do not exclude other unlisted elements or method steps.

[0077] In this invention, "optional", "any" or "any" means that the event or condition described below may or may not occur, and the description includes both the occurrence and non-occurrence of the event or condition.

[0078] The "medicine" described in this invention refers to a substance used to prevent, treat, and diagnose diseases. It can be a natural chemical substance and its preparation, a synthetic compound and its preparation, or a recombinant protein, antibody, and its preparation formed by bioengineering.

[0079] In this invention, all figures disclosed herein are approximate values, regardless of whether the words "approximately" or "about" are used. Based on the disclosed figures, the value of each figure may vary by less than ±10% or by a difference that is considered reasonable by those skilled in the art, such as ±1%, ±2%, ±3%, ±4%, or ±5%.

[0080] With regard to numerical ranges in this invention, it should be understood that each intermediate value between the upper and lower limits of the range is also specifically disclosed. Every smaller range between any stated value or intermediate value within a stated range, and any other stated value or intermediate value within said range, is also included in this invention. The upper and lower limits of these smaller ranges may be independently included or excluded from the range.

[0081] The teprenone described in this invention is a terpene compound with the chemical name 6,10,14,18-tetramethyl-5,9,13,17-nonadecantetraen-2-one, composed of a mixture of two geometric isomers (5Z, 9E, 13E) and (5E, 9E, 13E) in a mixing ratio of 0.6-0.7. It can promote the synthesis and secretion of major regenerative defense factors, high-molecular-weight glycoproteins, and phospholipids in the gastric mucosa and gastric mucus, thus protecting the gastric mucosa. It has good effects on acute gastritis, chronic gastritis, and gastric ulcers. Its structure is shown below:

[0082]

[0083] The "Carroll rearrangement" described in this invention, also known as the "Carroll reaction," "Carroll rearrangement," or "Carroll-Claisen rearrangement," refers to the reaction of allyl alcohol and β-keto ester, which undergoes esterification to form an ester. The carbonyl group of the ester is then isomerized to an enol, which is then rearranged under heating conditions to obtain a β-keto ester with a γ-ene bond. Finally, decarboxylation is performed to obtain a γ,δ-unsaturated ketone.

[0084] In this invention This indicates that the double bond exhibits cis-trans isomerism, and compounds containing this bond are mixtures of cis-trans isomers, such as compounds... refer to A mixture, refer to A mixture. Similarly, in R 1 and R 2 At the same time, the compound of formula III of the present invention is a mixture of the corresponding cis-trans isomers, and the proportion of the cis-trans isomers can be any value or range between 0 and 1, such as 0.1, 0.2, 0.3, 0.6, 0.7 or 0.8-0.9.

[0085] Unless otherwise stated, compound 3 of the present invention is a mixture of compound 3a and compound 3b, wherein the ratio of compound 3b to compound 3a is 0.6-0.7; compound 6 of the present invention is a mixture of compound 6a and 6b, wherein the ratio of compound 6b to 6a is 0.6-0.7.

[0086] The term "continuous flow process" and similar terms are used to refer to chemical processes utilizing flow chemistry and techniques. Both one-step and multi-step chemical reactions can be carried out using flow chemistry. Those skilled in the art will recognize that flow chemistry involves using channels or pipes to carry out chemical reactions (or a series of chemical reactions) in a continuous flow rather than using conventional containers in different batches. Those skilled in the art are also aware of a variety of continuous flow reactors capable of carrying out flow chemical reactions, such as tubular reactors (including spinneret reactors), microreactors, rotating disc reactors, multi-unit flow reactors, oscillating flow reactors, hexagonal reactors, and getter reactors. Continuous flow methods can be scaled up or down and therefore do not necessarily imply a specific continuous flow reactor size.

[0087] The term "reaction scale" in this invention refers to the amount of compound represented by Formula I added to the reaction, such as 50g for Example 2. The term "reaction flux" in this invention refers to the amount of compound represented by Formula I passing through the continuous flow reaction system per unit time.

[0088] The term "breeding reaction" refers to a reaction using a batch reactor, such as a reaction vessel. The term "breeding reactor" refers to a reactor equipped with a stirrer, in which the reaction fluids inside are thoroughly mixed so that the concentration and temperature can be considered homogeneous at any point within the reactor.

[0089] The continuous flow process described in this invention allows for continuous reaction and maintains a relatively stable system. The continuous flow process steps described in this invention can theoretically operate continuously for 24 hours. The residence time of reactant units in the reactor is short, typically 40-100 times shorter than that in a batch reactor. For example, in Example 2 of this invention, the residence time of the reactant unit is 10.7 minutes, while the average batch reactor reaction time is 5-6 hours.

[0090] The continuous flow process described in this invention can be repeatedly synthesized using the same steps after a single experimental setup. For example, after the experimental setup described in Example 1, Example 2 can be performed, and then Example 2 can be performed continuously without needing to re-rinse the setup or the pipelines. The steps can be cyclically repeated for 3 hours or more, preferably 4 hours or more, and more preferably 6 hours or more.

[0091] In Examples 2-5 of this application, the purity and stereochemical ratio of the product were determined by HPLC. The conditions for the HPLC method were as follows:

[0092] Chromatographic column: Agilent Poroshell 120 EC-C18 2.7μg 4.6*100mm

[0093] Mobile phase A: Take 1000 mL of deionized water and mix it with 1.0 mL of phosphoric acid, and sonicate to mix well.

[0094] Mobile phase B: Acetonitrile

[0095] Diluent: Acetonitrile

[0096]

[0097] In the various embodiments of this application, the order of the above-mentioned processes does not imply the order of execution. Some or all steps may be executed in parallel or sequentially. The execution order of each process should be determined by its function and internal logic, and should not constitute any limitation on the implementation process of the embodiments of this application.

[0098] For experiments not specifically described in this embodiment, the procedures and conditions should be followed according to the conventional experimental procedures described in the literature in this field. Reagents or instruments whose manufacturers are not specified are all commercially available conventional reagent products.

[0099] The technical solution of the present invention will be further described and explained below with reference to specific embodiments.

[0100] The embodiments described herein are only a part of the embodiments of the present invention, and not all of them. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without inventive effort are within the protection scope of the present invention.

[0101] Example 1: Solvent Screening

[0102] Methyl acetoacetate (compound 2) has a high boiling point and is difficult to remove and recover. Using it as a solvent will increase the difficulty of post-processing. High-temperature feed places high demands on the injection pump. At low temperatures, compound 2 has low solubility for aluminum isopropoxide and is prone to clogging the injection pump. Further screening of solvents more suitable for continuous flow processes is needed.

[0103]

[0104] Example 2: Preparation of Experimental Apparatus

[0105] according to Figure 1Prepare the experimental setup, including one Jingjin Jingrui PTFE plunger pump, a reactor consisting of a 1 / 8-inch 64.2 mL SS316 stainless steel coil, a heater, an oil bath, and a back pressure valve. At a pump flow rate of 50-30 mL / min, the plunger pump and tubing were sequentially cleaned with dilute hydrochloric acid (0.5 M, 300 mL) and water (300 mL). Then, at a pump flow rate of 30-20 mL / min, ethanol (300 mL) was used for cleaning. The pump flow rate was then reduced by 2 mL / min every 3 minutes, from 20 mL / min to 6.0 mL / min, while continuously pumping in n-heptane (>600 mL) to clean the Jingjin Jingrui PTFE pump and tubing. The system was then slowly heated to 245°C, with the back pressure valve set at approximately 2.25 MPa, for a total of approximately 1 hour.

[0106] Example 3: Synthesis of Compound 3 using a continuous flow process

[0107]

[0108] Prepare the experimental apparatus according to Example 2. Dissolve aluminum isopropoxide (0.10 eq.), compound 1 (50 g, 1.0 eq.) and compound 2 (1.5 eq.) in n-heptane (3 V) to prepare a clear solution, and place it in a three-necked flask R2 as the material.

[0109] Stop pumping heptane, switch the feed line to R2 (mixed liquid volume approximately 240 mL), and after three pressure purging cycles using an N2 balloon pump, start the plunger pump and begin timing at t = 0 min, setting the temperature to 245 °C. From t = 0 min, collect all liquid flowing out of the collection tube in the receiving flask. At t = 38 min, the pump feed is complete, with a total reaction liquid volume of approximately 240 mL. Stop the pump and quickly switch the feed line to the round-bottom flask R3 containing heptane. Immediately start the pump and pump in heptane (>300 mL) to flush out all the reaction liquid. At t = 85 min, stop the pump and stop receiving the solution, with a total received volume of approximately 510 mL.

[0110] The reaction solution was washed three times with dilute hydrochloric acid (0.2 M, 50 mL, 1V*3). The upper organic phase was separated, washed three times with water (50 mL, 1V*3), washed once with saturated brine (50 mL, 1V), dried over sodium sulfate, filtered, concentrated and evaporated to dryness to obtain crude compound 3 (purity 5Z / 5E = 34.61%: 54.71%, yield approximately 84% by weight).

[0111] Example 4: Synthesis of Compound 6 using a continuous flow process

[0112]

[0113] Prepare the experimental apparatus according to Example 1. Dissolve aluminum isopropoxide (0.10 eq.), compound 5 (100 g, 1.0 eq.) and compound 2 (2.0 eq.) in n-heptane (3 V) to prepare a clear solution, and place it in a three-necked flask R2 as the material.

[0114] Stop pumping heptane, switch the feed line to R2 (mixed liquid volume approximately 480 mL), and after three pressure purging cycles using an N2 balloon pump, start the plunger pump and begin timing at t = 0 min, setting the temperature to 245 °C. From t = 0 min, collect all liquid flowing out of the collection tube in the receiving flask. At t = 77 min, pumping is complete, with a total reaction liquid volume of approximately 480 mL. Stop the pump and quickly switch the feed line to the round-bottom flask R3 containing heptane. Immediately start the pump and pump in heptane (>500 mL) to flush out all the reaction liquid. At t = 120 min, stop the pump and stop receiving the solution, with a total received volume of approximately 720 mL.

[0115] A sintered glass funnel (approximately 20 cm in diameter) was filled with silica gel (200-300 mesh, approximately 10 cm thick), sodium sulfate (2-3 cm), and two layers of filter paper. The collected reaction solution (approximately 720 mL) was filtered through the sintered glass funnel, washed five times with n-heptane (2V*5), and the collected filtrate was concentrated to dryness by rotary evaporation to obtain the residue. Water (500 mL, 5V) was added to the residue, stirred for 10 min, and allowed to stand for separation. The upper organic phase was separated and washed five times with water (3V*5). All aqueous phases were combined and extracted three times with n-heptane (100 mL, 1V*3). All water-washed organic phases and extracted organic phases were combined, washed once with saturated brine (100 mL, 1V), dried over sodium sulfate, filtered, and concentrated by rotary evaporation to obtain the crude compound 6-teprenone (purity 5Z / 5E = 34.94%: 53.09%, yield approximately 80% by weight).

[0116] Examples 5-6: Comparison of results of large-scale reactions under different conditions

[0117] Under the conditions of Example 2, some parameters were changed to obtain reaction results for scaled-up reactions under different conditions, as shown in the table below:

[0118]

[0119]

[0120] Residence time = volume in tube / flow rate, such as residence time in Example 2 = 64.2 / 6.0 = 10.7 min. Feed time = reaction scale / reaction flux, such as feed time in Example 2 = 50 / 1.3 = 38 min.

Claims

1. A method for preparing a γ,δ-unsaturated ketone, characterized in that, Includes the following steps: In an organic solvent, the compounds shown in Formula I and Formula II react with an organoaluminum catalyst to yield compound III. The reaction is carried out in a continuous flow reaction system. Among them, R 1 and R 2 Each is an optional substitution of -C. 1-20 Alkyl or -C 2-20 Hydrocarbon group, wherein the substituent is -C 1-6 Alkyl, -C 2-10 hydrocarbon group, -C 1-10 alkynyl group, -C 3-6 cycloalkyl, -C 3-6 Heterocyclic alkyl, -C 6-10 Aryl, -C 5-10 heteroaryl; R 3 -C 1-5 alkyl.

2. The preparation method according to claim 1, characterized in that, The reaction temperature is ≥200℃, preferably ≥220℃, more preferably ≥240℃; and / or The reaction pressure is ≥1.50 MPa, preferably ≥2.00 MPa, more preferably ≥2.10 MPa; and / or R 1 Or R 2 One of them is -C 1-10 Alkyl group, one of which is -C 5-20 An olefin, wherein the olefin has one or more double bonds; preferably, R 1 Or R 2 One of them is -C 1-5 Alkyl group, one of which is -C 10-20 An olefin having two or three double bonds; more preferably, R 1 Or R 2 One is methyl, and the other is... and / or R 3 It is methyl, ethyl, n-propyl or isopropyl, preferably methyl; and / or The organoaluminum catalyst is aluminum isopropoxide, aluminum sec-butoxide, aluminum acetylacetonate, or aluminum triacetyl ethyl acetate, preferably aluminum isopropoxide; and / or The continuous flow reaction system includes an injector, a reaction device, a pressure controller, and a receiver connected in series via pipes. The reaction system also includes a heater for heating the reaction device.

3. The preparation method according to claim 1 or 2, characterized in that, The reaction apparatus includes one or more reactors; Preferably, the reactor is a tubular reactor, and more preferably, it is a stainless steel coil. More preferably, the stainless steel coil is an SS316 stainless steel coil; and / or More preferably, the outer diameter of the stainless steel coil is one-eighth of an inch to one-quarter of an inch, and even more preferably one-eighth of an inch; and / or More preferably, the internal volume of the stainless steel coil is 50-150 mL, even more preferably 60-140 mL, and still more preferably 60-135 mL; and / or The syringe connected in series via tubing includes a pump, preferably a plunger pump, a diaphragm pump, or a syringe pump, more preferably a plunger pump, and more preferably a PTFE plunger pump; and / or The pressure controller is a back pressure valve; and / or The heater is an oil bath, a vapor column oven, or a heating inner tube, preferably an oil bath.

4. The preparation method according to any one of claims 1-3, characterized in that, The molar ratio of the organoaluminum catalyst to the compound shown in Formula I is 0.03-0.20, preferably 0.04-0.15, more preferably 0.04-0.13; and / or The molar ratio of the compounds shown in Formula II and Formula I is 1.0-3.0, preferably 1.2-2.5, more preferably 1.3-2.3; and / or The organic solvent is a hydrocarbon solvent, preferably n-heptane, n-nonane, cyclohexane, toluene, or xylene, more preferably n-heptane or xylene, and even more preferably n-heptane; and / or The volume-to-mass ratio of the organic solvent to the compound shown in Formula I is 1-5 mL / g, preferably 2-4 mL / g.

5. The preparation method according to any one of claims 1-4, characterized in that, Includes the following steps: (1) The materials are an organoaluminum catalyst, a solution of the compound shown in Formula II and the compound shown in Formula I in an organic solvent; (2) Set the reaction temperature and reaction pressure of the continuous flow reaction system, pump the material into the continuous flow reaction system at a certain pump flow rate for reaction, and collect the effluent. (3) Stop the pump, then pump in the organic solvent at a certain pump flow rate and collect the effluent; (4) Extract all the eluent obtained, dry and concentrate to obtain the compound shown in Formula III.

6. The preparation method according to claim 5, characterized in that, The pump flow rate described in step (2) or step (3) is independently 1-20 mL / min, preferably 1.0-10 mL / min, more preferably 3.0-7.0 mL / min; and / or The reaction flux of step (2) is 1.0-2.0 g / min, preferably 1.2-1.8 g / min; and / or The organic solvents described in step (1) or step (3) are each independently hydrocarbon solvents, preferably n-heptane, n-nonane, cyclohexane, toluene or xylene, more preferably n-heptane or xylene, and even more preferably n-heptane.

7. The preparation method according to any one of claims 1-6, characterized in that, The preparation method further includes the following steps: (a1) At a certain pump flow rate, the pump and pipeline are cleaned sequentially with dilute hydrochloric acid and water; (a2) Clean the pump and pipeline with organic solvent at a certain pump flow rate; (a3) Slowly reduce the pump flow rate, continuously pump in organic solvent to clean the pump and pipeline, and slowly heat to the reaction temperature and set the reaction pressure.

8. The preparation method according to claim 7, characterized in that, The pump flow rate in step (a1) is 20-80 mL / min, preferably 25-60 mL / min, more preferably 30-50 mL / min; and / or The concentration of the dilute hydrochloric acid in step (a1) is 0.2-0.8M, preferably 0.3-0.7M, more preferably 0.4-0.6M; and / or The amount of dilute hydrochloric acid or water mentioned in step (a1) is independently 100-500 mL, preferably 200-400 mL; and / or The pump flow rate in step (a2) is 10-40 mL / min, preferably 15-35 mL / min, more preferably 20-30 mL / min; and / or The organic solvent in step (a2) is methanol, ethanol, or acetone, preferably methanol or ethanol, more preferably ethanol; and / or The amount of organic solvent in step (a2) is 100-500 mL, preferably 200-400 mL, more preferably 250-350 mL; and / or The pump flow rate in step (a3) ​​is slowly reduced from the initial pump flow rate described in step (a2), decreasing by a certain amount at intervals until the pump flow rate in step (3) is reached; preferably, the interval is 1-5 min, more preferably 2-4 min; and / or preferably, the reduced pump flow rate is 1-5 mL / min, more preferably 1-3 mL / min; and / or The organic solvent in step (a3) ​​is a hydrocarbon solvent, preferably n-heptane, n-nonane, cyclohexane, toluene, or xylene, more preferably n-heptane or xylene, and even more preferably n-heptane; and / or The amount of organic solvent in step (a3) ​​is >300 mL, preferably >500 mL, more preferably >600 mL; and / or The cleaning time in step (a3) ​​is 30-120 min, preferably 40-100 min, and more preferably 50-80 min.

9. A method for preparing teprenone intermediate compound 3, characterized in that, Includes the following steps (a): (a) Using compounds 1 and 2 as raw materials, compound 3 is prepared by the preparation method according to any one of claims 1-11. Preferably, step (a) includes: reacting compound 1 and compound 2 in n-heptane under the action of aluminum isopropoxide to obtain compound 3, wherein the reaction is carried out in a continuous flow reaction system, the reaction temperature is ≥200°C, and the reaction pressure is ≥1.50 MPa; more preferably, the reaction temperature is ≥220°C, and the reaction pressure is ≥2.00 MPa; even more preferably, the reaction temperature is ≥240°C, and the reaction pressure is ≥2.10 MPa.

10. A method for preparing teprenone, characterized in that, Includes the following or step (b): (b) Using compounds 5 and 2 as raw materials, compound 6 is prepared by the preparation method according to any one of claims 1-11. Preferably, step (b) comprises: reacting compound 5 and compound 2 in n-heptane under the action of aluminum isopropoxide to obtain compound 6, wherein the reaction is carried out in a continuous flow reaction system, the reaction temperature is ≥200°C, and the reaction pressure is ≥1.50 MPa; preferably, the reaction temperature is ≥220°C, and the reaction pressure is ≥2.00 MPa; more preferably, the reaction temperature is ≥240°C, and the reaction pressure is ≥2.10 MPa; and / or Preferably, compound 5 is obtained by reacting compound 4 via a Grignard reaction. More preferably, compound 4 is obtained by crystallizing compound 3. More preferably, compound 3 is obtained by the preparation method according to claim 12.

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