Method for preparing teprenone by adopting continuous flow process

Abstract

The invention belongs to the field of organic chemistry, particularly relates to a teprenone preparation method adopting a continuous flow process, and improves the existing teprenone synthesis process. The first continuous flow reaction system disclosed by the invention can safely and continuously carry out Carroll reaction at high temperature and high pressure, and the system does not need to adopt a high-boiling-point solvent, so that the reaction efficiency is greatly improved, and the risk of blasting boiling or material flushing in a traditional kettle type reaction process is solved; according to the second continuous flow reaction system, the metal Grignard reagent can be sealed in the pipeline and is not exposed outside, the reaction temperature is increased, the reaction retention time is shortened, and the safety of the Grignard reaction is ensured. The continuous synthesis method provided by the invention can realize safe, stable and continuous amplification reaction, and is more suitable for industrial production of teprenone.

Description

Technical Field

[0001] This invention belongs to the field of organic chemistry, and specifically relates to a continuous synthesis method for teprenone. Background Technology

[0002] Teprenone, a terpene compound, chemically named 6,10,14,18-tetramethyl-5,9,13,17-nonadecantetraen-2-one, is composed of two geometric isomers, (5Z, 9E, 13E) and (5E, 9E, 13E), in a 5Z:5E ratio of 0.6 to 0.7. It can promote the synthesis and secretion of key 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:

[0003]

[0004] Commonly used preparation routes for teprenone, as described in the Chinese Journal of Pharmaceutical Industry, 2004, 35(8), 449-450, mainly include the following steps:

[0005]

[0006] Among them, trans-nerolidol 1 is used as a raw material and reacts with methyl acetoacetate 2 via a Carroll reaction to obtain cis-trans isomer compound 3. After purification, (5E,9E)farnesylacetone 4 is obtained, which undergoes a Grignard reaction with vinyl magnesium chloride to generate geranyl linalool 5. Then, it is reacted with methyl acetoacetate 2 via a Carroll reaction to prepare teprenone.

[0007] The Carroll reaction requires high temperatures and typically uses high-boiling-point methyl acetoacetate as both a reactant and a solvent. At atmospheric pressure, the reaction concentration is high, and the reaction temperature is limited by the solvent reflux temperature, making further increases difficult. The catalyst, aluminum isopropoxide, has low solubility in methyl acetoacetate, limiting its usage. The reaction time is long, resulting in low efficiency. Excess methyl acetoacetate after the reaction requires cumbersome steps such as vacuum distillation or large-volume water washing to remove it. Furthermore, the lower alcohols and carbon dioxide produced during the reaction may cause boiling over or overflow risks in batch reactor processes. The Grignard reaction requires harsh conditions and a long reaction time, and may produce ethylene gas, posing a high process risk. Therefore, it is necessary to develop a safe, efficient, and environmentally friendly industrial synthesis process for teprenone. Summary of the Invention

[0008] The first aspect of this invention provides a method for synthesizing teprenone, comprising the following steps:

[0009] First step: Compound 1, Compound 2, organoaluminum catalyst, and hydrocarbon solvent are pumped into the first continuous reaction system to react. The reaction solution is collected, extracted, and purified to obtain Compound 4.

[0010]

[0011] The second step involves pumping pre-cooled vinyl Grignard reagent and ether solvent into the second continuous reaction system. After a period of time, pre-cooled compound 4 and ether solvent are simultaneously pumped in to react. The reaction solution is collected, quenched, and extracted to obtain compound 5.

[0012]

[0013] The third step: Compound 5, Compound 2, organoaluminum catalyst, and hydrocarbon solvent are pumped into the first continuous reaction system to react. The reaction solution is collected, extracted, and purified to obtain Compound 6.

[0014]

[0015] The first or second continuous reaction system each independently comprises an injector, a reaction device, and a receiver connected in series via pipes.

[0016] In some embodiments, the hydrocarbon solvent is n-heptane, n-hexane, cyclohexane, toluene, or xylene, more preferably n-heptane or xylene, and even more preferably n-heptane.

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

[0018] In some embodiments, the ether solvent is diethyl ether or tetrahydrofuran, preferably tetrahydrofuran.

[0019] In some embodiments, the vinyl Grignard reagent is vinyl magnesium bromide or vinyl magnesium chloride, preferably vinyl magnesium chloride.

[0020] In some embodiments, the purification process in the first step is crystallization, and the crystallization conditions are conventional conditions in the art, as can be found in CN108047011B.

[0021] In some embodiments, the purification process in the third step is distillation, and the distillation conditions are conventional conditions in the art, as can be found in CN108047011B.

[0022] In some embodiments, the injector includes a pump.

[0023] In some embodiments, the reaction apparatus includes one or more reactors;

[0024] Preferably, the reactor is a tubular reactor;

[0025] More preferably, the outer diameter of the tubular reactor is one-eighth inch to one-quarter inch, and even more preferably one-eighth inch.

[0026] In some embodiments, the molar ratio of the organoaluminum catalyst to compound 1 in the first step or the molar ratio of the organoaluminum catalyst to compound 5 in the third step is independently 0.03-0.20:1, preferably 0.04-0.15:1, more preferably 0.04-0.13:1, for example 0.05:1, 0.10:1, 0.12:1 or any value or range thereof.

[0027] In some embodiments, the molar ratio of compound 2 and compound 1 in the first step or the molar ratio of compound 2 and compound 5 in the third step is independently 1.0-3.0:1, preferably 1.2:1-2.5:1, more preferably 1.3:1-2.3:1, for example 1.5:1 or 2.0:1.

[0028] In some embodiments, the volume-to-mass ratio of the hydrocarbon solvent in the first step to compound 1 or the hydrocarbon solvent in the third step to compound 3 is 1-5 mL / g, preferably 2-4 mL / g, for example 3 mL / g.

[0029] In some embodiments, the first continuous reaction system includes an injector, a reaction device, a receiver, a pressure controller, and a heater connected in series via piping.

[0030] In some embodiments, the injector of the first continuous reaction system is a plunger pump, a diaphragm pump, or a syringe pump, preferably a plunger pump, and more preferably a PTFE plunger pump.

[0031] In some embodiments, the pressure controller of the first continuous reaction system is a back pressure valve.

[0032] In some embodiments, the heater of the first continuous reaction system is an oil bath, a vapor column oven, or a heating inner tube, preferably an oil bath.

[0033] In some embodiments, the reaction apparatus of the first continuous reaction system includes a reactor.

[0034] In some embodiments, the reaction device of the first continuous reaction system is a stainless steel coil;

[0035] Preferably, the reaction apparatus is an SS316 stainless steel coil; and / or

[0036] Preferably, the volume of the reaction apparatus is 50-150 mL, more preferably 60-140 mL, and even more preferably 60-135 mL, for example 64.2 mL or 131.2 mL.

[0037] In some embodiments, the reaction temperature of the first continuous reaction system is ≥200°C, preferably ≥220°C, more preferably ≥240°C, for example 245°C.

[0038] In some embodiments, the reaction pressure of the first continuous reaction system is ≥1.00 MPa, preferably ≥1.50 MPa, more preferably ≥2.00 MPa, for example 2.00, 2.10, 2.20, 2.25, 2.30, 2.40, 2.50 MPa or any value or range thereof.

[0039] In some embodiments, the pump flow rate into the first continuous reaction system is 1-20 mL / min, preferably 1.0-10 mL / min, more preferably 3.0-7.0 mL / min, for example 6.0 mL / min.

[0040] In some embodiments, the reaction flux of the first or third step 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.

[0041] In some embodiments, the first or third step further includes the following steps: pumping in a hydrocarbon solvent to flush out all the reaction solution.

[0042] In some embodiments, the concentration of the vinyl Grignard reagent in the pre-cooled vinyl Grignard reagent and ether solvent is 1.2-2.0M, preferably 1.4-1.8M, more preferably 1.5-1.7M, for example 1.6M.

[0043] In some embodiments, the molar ratio of the vinyl Grignard reagent to compound 4 is 1.0-2.5, preferably 1.0-2.0.

[0044] In some embodiments, the volume-to-mass ratio of the ether solvent to the pre-cooled compound 4 is 3-10 mL / g, preferably 4-8 mL / g, more preferably 5-7 mL / g, for example 6 mL / g.

[0045] In some embodiments, the quenching is achieved by adding a second reaction solution to a quenching solution, wherein the quenching solution is acetic acid and n-heptane.

[0046] In some embodiments, the molar ratio of acetic acid to compound 4 is 3.0-5.0, preferably 3.5-4.5, for example 4.0.

[0047] In some embodiments, the volume-to-mass ratio of n-heptane to compound 4 is 2-5 mL / g, preferably 2-4 mL / g, for example 3 mL / g.

[0048] In some embodiments, the second continuous reaction system includes a sampler, a reaction device, a receiver, a mixer, and a precooling device connected in series via pipes.

[0049] In some embodiments, the injector of the second continuous reaction system is a peristaltic pump or an injection pump, preferably a peristaltic pump.

[0050] In some embodiments, the receiver of the second continuous reaction system is filled with a quenching fluid.

[0051] In some embodiments, the reaction apparatus of the second continuous reaction system includes two reactors: a pre-reactor and a post-reactor.

[0052] In some embodiments, a mixer is connected before the reactor of the second continuous reaction system; preferably, the mixer is a static mixer.

[0053] In some embodiments, a precooling device is connected after the sampler of the second continuous reaction system.

[0054] In some embodiments, the precooling device includes a precooling pipe;

[0055] Preferably, the precooling pipe is a PFA coil, a PTFE coil, or an FEP coil, more preferably a PFA coil; and / or

[0056] Preferably, the outer diameter of the precooling tube is one-eighth of an inch to one-quarter of an inch, more preferably one-eighth of an inch; and / or

[0057] Preferably, the volume of the precooling tube is 3-20 mL, more preferably 3-10 mL, and even more preferably 3-5 mL, for example 4.28 mL.

[0058] In some embodiments, the reaction apparatus of the second continuous reaction system is a PFA coil, a PTFE coil, or an FEP coil, preferably a PFA coil; and / or

[0059] Preferably, the volume of the reaction device is 20-40 mL, more preferably 30-40 mL, and even more preferably 30-35 mL, for example 32 mL.

[0060] In some embodiments, the temperature of the precooling tube, the pre-reactor, and the receiver is controlled at 0-10°C, preferably 0-5°C.

[0061] In some embodiments, the temperature of the post-reactor is controlled at 15-30°C, preferably 15-25°C, more preferably 17-23°C, for example 20°C.

[0062] In some embodiments, the pump flow rate for pumping in vinyl Grignard reagents and ether solvents is 2-10 mL / min, preferably 3-7 mL / min, more preferably 3-5 mL / min, for example 4.8 mL / min.

[0063] In some embodiments, the flow rate of the pumped compound 4 and the ether solvent is 5-15 mL / min, preferably 7-13 mL / min, more preferably 8-12 mL / min, for example 10.2 mL / min.

[0064] In some embodiments, the reaction flux of the second step is 1.0-2.0 g / min, preferably 1.0-1.5 g / min, more preferably 1.3-1.5 g / min, for example 1.4 g / min.

[0065] In some embodiments, the second step further includes the following steps: pumping in an ether solvent to flush out all the reaction solution.

[0066] A second aspect of the present invention provides teprenone, which is prepared by the synthesis method described in the first aspect of the present invention.

[0067] For Carroll reactions, batch processes typically use an excess of high-boiling-point compound 2 (methyl acetoacetate) as both a solvent and a reactant, which is difficult to remove and recover, increasing the complexity of post-processing. In continuous flow processes, high-temperature feed places high demands on the injection pump, while low-temperature compound 2 has low solubility for aluminum isopropoxide, easily clogging the injection pump. Further screening is needed for solvents that are both easy to post-process and suitable for continuous flow processes to improve the efficiency of the process route.

[0068] For Grignard reactions, batch processes require controlled low-temperature reactions. During scale-up at a plant, temperature control is critical, and the exposure of metallic reagents can pose certain risks. Continuous flow processes, on the other hand, can increase the reaction temperature without requiring a cryogenic cooling medium, ensuring that the metallic reagents remain within the piping and are not exposed. This improves efficiency while also being more environmentally friendly and safer.

[0069] This invention improves upon existing teprenone synthesis processes by providing a continuous synthesis method for teprenone. The specific process flow can be found in [reference needed]. Figure 1Compared to existing technologies or traditional batch reaction processes, the first continuous flow reaction system of this invention can safely and continuously carry out the Carroll reaction under high temperature and high pressure. The system does not require high-boiling-point solvents, greatly improving reaction efficiency and eliminating the risks of boiling over or material overflow in traditional batch reaction processes. The second continuous flow reaction system of this invention can enclose the metallic Grignard reagent in pipelines, preventing it from being exposed to the outside, increasing the reaction temperature, shortening the reaction residence time, and ensuring the safety of the Grignard reaction. The continuous synthesis method of this invention enables safe, stable, and continuous scale-up reactions, making it more suitable for the industrial production of teprenone. Attached Figure Description

[0070] Figure 1 : A flowchart of the continuous synthesis method of teprenone according to the present invention;

[0071] Figure 2 Apparatus used in the first and third processes (1-Three-necked round-bottom flask, 2-5mL syringe tube connected to nitrogen balloon, 3-Precision plunger pump, 4-1 / 8-inch 64.2mL SS316 stainless steel coil, 5-Straight connector, 6-Back pressure valve, 7-High temperature oil bath, 8-Ambient temperature water bath, 9-Erconical flask, 10-1 / 8in.PFA tube);

[0072] Figure 3 The equipment used in the second process includes: (1-GL45 reagent bottle, 2-three-necked round-bottom flask, 3-5mL syringe tube connected to nitrogen balloon, 4-first peristaltic pump unit, 5-second peristaltic pump unit, 6-1 / 8in. pre-cooled PFA coil, 7-T-connector, 8-1 / 8in. PFA coil reactor, 9-static mixer, 10-ultrasonic 0-5℃ water bath, 11-room temperature 20℃ water bath, 12-jacketed bottle, 13-temperature controlled circulating bath, 14-circulating bath connecting pipe, 15-nitrogen flow, 16-1 / 8in. PFA tube). Detailed Implementation

[0073] 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.

[0074] 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.

[0075] 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.

[0076] 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.

[0077] 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%.

[0078] 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.

[0079] Unless otherwise specified, the concentrations in this invention are mass percentage concentrations. For example, in this invention, the concentration of the hydroxylamine solution is 2-10%, which means that the mass percentage of hydroxylamine in the solution is 2-10%, such as 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, or any value or range thereof.

[0080] The "Carroll reaction" described in this invention, also known as the "Carroll rearrangement" or "Carroll-Claisen rearrangement reaction", refers to the reaction of allyl alcohol and β-keto ester, which is esterified to form an ester, then the carbonyl group of the ester is isomerizes to an enol, and then rearranges under heating conditions to obtain a β-keto ester with a γ-ene bond, and finally decarboxylates to obtain a γ-keto olefin.

[0081] 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.

[0082] 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.

[0083] 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.

[0084] 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.

[0085] The continuous flow process described in this invention allows for continuous reaction and maintains a relatively stable system. In principle, each step of the continuous flow process can operate continuously for 24 hours, with a short residence time for reactant units in the reactor, typically 50-100 times shorter than that of a batch reactor. The term "residence time" refers to the actual residence time of the material in the reactor. In CN103058839B, after slowly heating to 140-170°C and reacting for 10-14 hours, teprenone is produced, with a residence time of 10-14 hours. For continuous flow reactions, the residence time is calculated as: residence time = volume in the tube / flow rate. For example, in Example 5, the residence time for teprenone production is 64.2 / 6.0 = 10.7 min.

[0086] The term "reaction scale" in this invention refers to the amount of raw material compound input. The term "reaction flux" in this invention refers to the amount of raw material compound passing through the continuous flow reaction system per unit time, such as the reaction flux of 1.3 g / min in Examples 3 and 5, and the reaction flux of 1.4 g / min in Example 4.

[0087] 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.

[0088] In the embodiments of this application, the purity and stereochemical ratio of the product are determined by HPLC, and the conditions for the HPLC method are as follows:

[0089] Chromatographic column: Agilent Poroshell 120 EC-C18 2.7μg 4.6*100mm

[0090] Mobile phase A: Take 1000 mL of deionized water and mix it with 1.0 mL of phosphoric acid, and sonicate to mix well.

[0091] Mobile phase B: Acetonitrile

[0092] Diluent: Acetonitrile

[0093]

[0094] 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.

[0095] The technical solution of the present invention will be further described and explained below with reference to specific embodiments.

[0096] 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.

[0097] Example 1: Optimization of conditions for the first and third processes

[0098] 1. Solvent screening

[0099] Table 1 shows the dissolution of aluminum isopropoxide in different solvents at different temperatures:

[0100] Table 1

[0101]

[0102] 2. Temperature screening

[0103] according to Figure 2 Prepare the experimental setup. Isopropanol (0.05 eq.), n-heptane (3V), compound 1 (10 g, 1.0 eq.), and compound 2 (1.5 eq.) were ultrasonically dissolved and dispersed. The mixture was then pumped directly into the pipeline for reaction using a plunger pump. The residence time was 10.7 min, and the back pressure valve pressure was approximately 2.2-2.3 MPa. The reaction temperature was varied during continuous flow, and the results are shown in Table 2. Similarly, when compound 1 was replaced with compound 5, the reaction results are shown in Table 3.

[0104] Table 2

[0105]

[0106] Table 3

[0107]

[0108]

[0109] 3. Catalyst equivalent

[0110] according to Figure 2 Prepare the experimental setup. Prepare a clear solution by mixing certain equivalents of isopropanol, n-heptane (3V), compound 1 (10g, 1.0 eq.), and compound 2 (1.5 eq.). Pump this solution into a 62.4mL 1 / 8in.SS316 stainless steel coil at a flow rate of 6.0mL / min, with a residence time of 10.7min. Maintain a back pressure of 2.2-2.3MPa and allow the reaction to proceed at 245℃. The reaction results are shown in Table 4 when the equivalent of isopropanol is varied. Similarly, the reaction results are shown in Table 5 when compound 1 is replaced with compound 5.

[0111] Table 4

[0112]

[0113] Table 5

[0114]

[0115] Example 2: Optimization of conditions for the second process

[0116] Numbers 1-7 Figure 3 Prepare the experimental setup by replacing coil reactor 8 with a Corning reactor. Dissolve compound 4 (2.6 g, 1.0 eq.) in tetrahydrofuran (6 V) and feed it into the Corning reactor simultaneously via peristaltic pump 5 at a flow rate of approximately 6.8 mL / min. Simultaneously feed vinyl magnesium chloride (1.4 eq.) / THF into the Corning reactor via peristaltic pump 4 at a flow rate of approximately 3.2 mL / min, and change the temperature to allow the reaction to proceed.

[0117] Numbers 8-10 Figure 3 Prepare the experimental setup. Dissolve compound 4 (2.6 g, 1.0 eq.) in tetrahydrofuran (6 V). Simultaneously feed the solution via peristaltic pump 5 and vinyl magnesium chloride (1.4 eq.) / THF via peristaltic pump 4 into a pre-coil reactor 8 connected to a static mixer 7, and then into a post-coil reactor 8 for continuous flow reaction. Adjust the flow rate, control the temperature and residence time of the coil reactors to ensure complete reaction. The flow rate was set at 10.2 mL / min for pump 5, 4.8 mL / min for pump 4, and a total flow rate of 15.0 mL / min.

[0118] The reaction results are shown in Table 6:

[0119] Table 6

[0120]

[0121] Example 3: Synthesis of Compound 3 using a continuous flow process

[0122]

[0123] according to Figure 2 Prepare the experimental setup. After cleaning the Jingjin Jingrui PTFE pump and pipelines, continuously pump in n-heptane, heat the high-temperature oil bath to 245°C, and set the back pressure valve pressure to approximately 2.25 MPa.

[0124] Aluminum isopropoxide (0.10 eq.), compound 1 (50 g, 1.0 eq.), and compound 2 (1.5 eq.) were dissolved in n-heptane (3V) to prepare a clear solution, which was placed in a three-necked flask 1. The n-heptane pump was stopped, and the feed tube was switched to three-necked flask 1 (the volume of the mixed solution was approximately 240 mL). After purging with a water pump using an N2 balloon 2, the plunger pump 3 was started, and the timer was set to t = 0 min, with the temperature set to 245 °C. From t = 0 min, all liquid flowing out of the collection tube in the receiving flask was collected. At t = 38 min, the pump feed was completed, with a total reaction volume of approximately 240 mL. Pump 3 was stopped, and the feed tube was quickly switched to a round-bottom flask containing n-heptane. Immediately, the pump was started, and n-heptane (>300 mL) was pumped in to flush out all the reaction solution. At t = 85 min, the pump was stopped, and the receiving of the solution was stopped, with a total received volume of approximately 510 mL.

[0125] 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).

[0126] The crude compound 3 was crystallized at low temperature to obtain all-trans (5E,9E) farnesylacetone compound 4 (purity 96%, yield 96%). The crystallization conditions were conventional in the art and can be found in CN108047011B.

[0127] Example 4: Synthesis of Compound 5 using a continuous flow process

[0128]

[0129] according to Figure 2Prepare the experimental setup and clean the Lange peristaltic pump and tubing. Then continuously pump in tetrahydrofuran (>500mL). Simultaneously, place the 1 / 8-inch 32mL coil reactor 8 in an ultrasonic water bath 10 at 0-5℃, and place the 1 / 8-inch 32mL coil reactor 11 in an ultrasonic water bath 11 at room temperature (20-25℃).

[0130] Add quenching solution acetic acid (4.0 eq.) and n-heptane (3 V) to jacketed flask 12, shake well, and place in a temperature-controlled circulating bath 13 to maintain the system at 0-5°C under nitrogen protection 15. Add compound 4 (39 g, 1.0 eq.) and tetrahydrofuran (234 mL, 6 V) to a three-necked round-bottom flask 2, shake well, and place under nitrogen protection; the volume should be approximately 280 mL. Place a tetrahydrofuran solution of vinyl magnesium chloride (1.6 min THF, 1.4 eq.) in GL45 reagent bottle 1 under nitrogen protection. Insert the feed tube of pump 5 into three-necked round-bottom flask 2 and set the flow rate to 10.2 mL / min; insert the feed tube of pump 4 into GL45 reagent bottle 1 and set the flow rate to 4.8 mL / min.

[0131] Start pump 4. After approximately 1 minute, ensuring that vinyl magnesium chloride reaches reactor 8 first, quickly start pump 5 and begin timing (t = 0 min). At t = 30 s, begin receiving the reaction solution into the jacketed flask 12 under stirring, and control the temperature inside the flask by adding ice (5-10°C). At t = 28 min, the pump feed is complete, with a total reaction solution of approximately 280 mL. Stop the pumps and quickly switch the feed lines of pumps 4 and 5 to a round-bottom flask containing tetrahydrofuran (>250 mL). Immediately start pumps 4 and 5 to pump in tetrahydrofuran to flush out all the reaction solution. At t = 35 min, stop pumps 4 and 5, and stop receiving the solution; the total received volume is approximately 525 mL.

[0132] The received reaction solution was concentrated by rotary evaporation under reduced pressure to remove the organic solvent, yielding a residue. Heptane and diatomaceous earth were added, and the mixture was stirred at 0-10°C for 40 min. The mixture was then filtered under reduced pressure. The residue was washed with heptane (3V) and concentrated by rotary evaporation. The residue was then dissolved in heptane (6V) to obtain an organic phase, which was washed with water and saturated brine, respectively. The organic phase was dried over sodium sulfate, filtered, concentrated, and then evaporated to dryness to obtain crude compound 5 (purity 93.57%, yield 85% by weight).

[0133] Example 5: Synthesis of Compound 6 using a continuous flow process

[0134]

[0135] according to Figure 3 Prepare the experimental setup, clean the Jingjin Jingrui PTFE pump and pipelines, and slowly heat the high-temperature oil bath to 245°C. Set the back pressure valve pressure to approximately 2.25 MPa.

[0136] Aluminum isopropoxide (0.10 eq.), n-heptane (3 V), and compound 5 (100 g, 1.0 eq.) were prepared into a clear solution and placed in a three-necked flask 1. The n-heptane pump was stopped, and the feed tube was switched to three-necked flask 1 (mixture volume approximately 480 mL). After purging with N2 under reduced pressure, the plunger pump was started, and a stopwatch was started at t = 0 min, with the temperature set to 245 °C. From t = 0 min, all liquid flowing out of the collection tube was collected in the receiving flask. At t = 77 min, the pump feed was completed, with a total reaction volume of approximately 480 mL. The pump was stopped, and the feed tube was quickly switched to a round-bottom flask containing n-heptane. Immediately, the pump was started, and n-heptane (>500 mL) was pumped in to flush out all the reaction liquid. At t = 120 min, the pump was stopped, and the receiving of the solution was stopped, with a total received volume of approximately 720 mL.

[0137] The collected reaction solution (approximately 720 mL) was filtered through a sintered glass funnel, washed with n-heptane, and the collected filtrate was concentrated by rotary evaporation. The residue was washed with water. All aqueous phases were combined and extracted with n-heptane. All organic phases washed with water and the extracted organic phase were combined, washed with saturated brine (100 mL, 1V), dried over sodium sulfate, filtered, concentrated, and evaporated to dryness to give the crude compound 6-teprenone (purity 5Z / 5E = 34.94%: 53.09%, yield approximately 80% by weight).

[0138] The crude compound 6 was distilled to obtain the final product of compound 6 (purity 99.0%, yield 87.2%). The distillation conditions were conventional in the art and can be found in CN108047011B.

[0139] Examples 6-7: Comparison of results of large-scale reactions under different conditions

[0140] Under the conditions of Example 3, some parameters were changed to obtain reaction results for scaled-up reactions under different conditions, as shown in Table 7:

[0141] Table 7

[0142]

Claims

1. A method for synthesizing teprenone, characterized in that, The process includes the following steps: First step: Compound 1, Compound 2, organoaluminum catalyst, and hydrocarbon solvent are pumped into the first continuous reaction system to react. The reaction solution is collected, extracted, and purified to obtain Compound 4. The second step involves pumping pre-cooled vinyl Grignard reagent and ether solvent into the second continuous reaction system. After a period of time, pre-cooled compound 4 and ether solvent are simultaneously pumped in to react. The reaction solution is collected, quenched, and extracted to obtain compound 5. The third step: Compound 5, Compound 2, organoaluminum catalyst, and hydrocarbon solvent are pumped into the first continuous reaction system to react. The reaction solution is collected, extracted, and purified to obtain Compound 6. The first or second continuous reaction system each independently comprises an injector, a reaction device, and a receiver connected in series via pipes.

2. The synthesis method according to claim 1, characterized in that, The hydrocarbon solvent is n-heptane, n-hexane, cyclohexane, toluene, or xylene, more preferably n-heptane or xylene, and even more preferably n-heptane; and / or The organoaluminum catalyst comprises aluminum isopropoxide, aluminum sec-butoxide, aluminum acetylacetonate, or aluminum triacetyl ethyl acetate, preferably aluminum isopropoxide; and / or The ether solvent is diethyl ether or tetrahydrofuran, preferably tetrahydrofuran; and / or The vinyl Grignard reagent is vinyl magnesium bromide or vinyl magnesium chloride, preferably vinyl magnesium chloride; and / or The injector includes a pump; and / or The reaction apparatus comprises one or more reactors, preferably tubular reactors, more preferably tubular reactors with an outer diameter of one-eighth inch to one-quarter inch, and even more preferably one-eighth inch; and / or The molar ratio of the organoaluminum catalyst to compound 1 in the first step or the molar ratio of the organoaluminum catalyst to compound 5 in the third step is independently 0.03-0.20:1, preferably 0.04-0.15:1, more preferably 0.04-0.13:1; and / or The molar ratio of compound 2 and compound 1 in the first step or the molar ratio of compound 2 and compound 5 in the third step is independently 1.0-3.0:1, preferably 1.2:1-2.5:1, more preferably 1.3:1-2.3:1; and / or The volume-to-mass ratio of the hydrocarbon solvent in the first step to compound 1 or the hydrocarbon solvent in the third step to compound 3 is 1-5 mL / g, preferably 2-4 mL / g.

3. The synthesis method according to claim 1 or 2, characterized in that, The first continuous reaction system includes an injector, a reaction device, a receiver, a pressure controller, and a heater connected in series via pipes; The injector of the first continuous reaction system is a plunger pump, a diaphragm pump, or a syringe pump, preferably a plunger pump, more preferably a PTFE plunger pump; and / or The pressure controller for the first continuous reaction system is a back pressure valve; and / or The heater of the first continuous reaction system is an oil bath, a vapor column oven, or a heating inner tube, preferably an oil bath; and / or The reaction apparatus of the first continuous reaction system includes a reactor; and / or the reaction apparatus of the first continuous reaction system is a stainless steel coil; Preferably, the reaction apparatus is an SS316 stainless steel coil; and / or Preferably, the volume of the reaction device is 50-150 mL, more preferably 60-140 mL, and even more preferably 60-135 mL.

4. The synthesis method according to any one of claims 1-3, characterized in that, The reaction temperature of the first continuous reaction system is ≥200℃, preferably ≥220℃, more preferably ≥240℃; and / or The reaction pressure of the first continuous reaction system is ≥1.00 MPa, preferably ≥1.50 MPa, more preferably ≥2.00 MPa; and / or The pump flow rate into the first continuous reaction system is 1-20 mL / min, preferably 1.0-10 mL / min, more preferably 3.0-7.0 mL / min; and / or The reaction flux of the first or third step is 1.0-2.0 g / min, preferably 1.2-1.8 g / min; and / or The first or third step further includes the following steps: pumping in a hydrocarbon solvent to flush out all reaction solutions; and / or The concentration of the vinyl Grignard reagent in the pre-cooled vinyl Grignard reagent and ether solvent is 1.2-2.0 M, preferably 1.4-1.8 M, more preferably 1.5-1.7 M; and / or The molar ratio of the vinyl Grignard reagent to compound 4 is 1.0-2.5, preferably 1.0-2.0; and / or The volume-to-mass ratio of the pre-cooled compound 4 to the ether solvent is 3-10 mL / g, preferably 4-8 mL / g, more preferably 5-7 mL / g; and / or The quenching is achieved by adding a second reaction solution to a quenching solution, wherein the quenching solution is acetic acid and n-heptane; Preferably, the molar ratio of acetic acid to compound 4 is 3.0-5.0, more preferably 3.5-4.5; and / or Preferably, the volume-to-mass ratio of n-heptane to compound 4 is 2-5 mL / g.

5. The synthesis method according to any one of claims 1-4, characterized in that, The second continuous reaction system includes an injector, a reaction device, a receiver, a mixer, and a precooling device connected in series via pipes; Preferably, the injector of the second continuous reaction system is a peristaltic pump or a syringe pump, more preferably a peristaltic pump; and / or Preferably, the receiver of the second continuous reaction system is filled with a quenching liquid.

6. The synthesis method according to any one of claims 1-5, characterized in that, The reaction apparatus of the second continuous reaction system includes two reactors: a pre-reactor and a post-reactor; a pre-cooling device is connected after the sampler of the second continuous reaction system. Preferably, the precooling device includes a precooling pipe; More preferably, the precooling pipe is a PFA coil, a PTFE coil, or an FEP coil, and even more preferably a PFA coil; and / or More preferably, the outer diameter of the precooling tube 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 volume of the precooling tube is 3-20 mL, even more preferably 3-10 mL, and still more preferably 3-5 mL; and / or The reaction device of the second continuous reaction system is a PFA coil, a PTFE coil or an FEP coil, preferably a PFA coil; Preferably, the volume of the reaction device is 20-40 mL, more preferably 30-40 mL, and even more preferably 30-35 mL.

7. The synthesis method according to claim 6, characterized in that, The temperature of the precooling tube, the pre-reactor, and the receiver is controlled at 0-10℃, preferably 0-5℃; and / or The temperature of the post-reactor is controlled at 15-30℃, preferably 15-25℃, and more preferably 17-23℃.

8. The synthesis method according to any one of claims 1-7, characterized in that, The pump flow rate for introducing vinyl Grignard reagents and ether solvents is 2-10 mL / min, preferably 3-7 mL / min, more preferably 3-5 mL / min; and / or The flow rate of the pumped compound 4 and the ether solvent is 5-15 mL / min, preferably 7-13 mL / min, and more preferably 8-12 mL / min.

9. The synthesis method according to any one of claims 1-8, characterized in that, The reaction flux of the second step is 1.0-2.0 g / min, preferably 1.0-1.5 g / min, more preferably 1.3-1.5 g / min; and / or The second step also includes the following steps: pumping in ether solvents to flush out all the reaction solution.

10. A teprenone, characterized in that, The teprenone is prepared by the synthetic method according to any one of claims 1-18.

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