Continuous flow synthesis method of natural product

Abstract

The invention relates to a method for continuously synthesizing L-camphor by using a continuous flow reactor. The method specifically comprises the following steps: (1) taking a sodium hypochlorite aqueous solution as a solution A; (2) dissolving L-borneol in a solvent, then adding a catalytic oxidant and acetic acid, and uniformly mixing to form a solution B; (3) simultaneously feeding the solution A and the solution B into a reaction channel of a continuous flow reactor according to a metering proportion for reaction; and (4) collecting the reaction product, and carrying out post-treatment to obtain the L-camphor finished product. The method solves the problems of long reaction time, easiness in racemization, high safety risk and the like of the existing L-camphor, and has the advantages of low production cost, simplicity in operation, environmental friendliness, simplicity in post-treatment and facilitation of industrial production.

Description

Technical Field

[0001] The present invention relates to the synthesis technology of levocamphor, and specifically relates to a method for continuously synthesizing levocamphor by using a continuous flow reactor. Background Art

[0002] Levocamphor, also known as L-camphor or L-borneol, is a natural chemical substance, usually extracted from the leaves of eucalyptus or gum trees. It is a white solid with a strong mint odor and can be dissolved in water. Levocamphor has a wide range of applications. It can be used as a preservative, insecticide, medicine, fragrance, etc. In the medical field, it is used to treat diseases such as headache, cold, cough, muscle pain and arthritis. In the fragrance field, it is widely used in the manufacture of products such as chewing gum, oral fresheners, perfumes and soaps to provide a fresh mint fragrance.

[0003] Levocamphor can also be obtained by chemical synthesis. However, the existing synthesis technologies of levocamphor have some disadvantages. The existing synthesis technologies of levocamphor usually require multi-step reactions and complex synthesis routes, resulting in the complexity of the synthesis process and the increase in cost. At the same time, multi-step reactions also increase the risk of side reactions that may occur during the synthesis process, thereby reducing the purity and yield of the product.

[0004] Enzyme catalysts are suitable for reactions that require high selectivity and mild conditions, but they are costly; transition metal catalysts are suitable for reactions that require high activity and reaction rate, but they may produce side reactions; acid catalysts and base catalysts are suitable for acid-base neutralization reactions, but they may cause side reactions; nano-catalysts have high activity selectivity, but the preparation cost is high. Some catalysts may be toxic or have environmental pollution risks, and some solvents may be volatile organic compounds, causing pollution to the atmospheric environment. N-methylmorpholine N-oxide (NMO) is a commonly used organic catalyst and is widely used in organic synthesis reactions. In itself, NMO does not cause pollution to the environment. It is a relatively stable compound and is not easily decomposed or volatilized. On the other hand, the reaction conditions in the existing synthesis technologies of levocamphor usually require high temperature, high pressure or special conditions. These conditions not only increase the complexity of the synthesis process, but also may lead to an increase in energy consumption and an increase in equipment costs. In addition, the purity and yield of the products in the existing synthesis technologies of levocamphor are unstable. Due to the existence of side reactions and incomplete reactions during the synthesis process, the purity and yield of the products may fluctuate to a certain extent, which is unacceptable for industrial production.

[0005] In summary, the existing synthesis technologies of levocamphor have disadvantages such as complex synthesis process, high cost, large environmental impact, unstable product purity and yield, and low specific rotation of levocamphor, and further research and development of more efficient and environmentally friendly synthesis technologies of levocamphor are needed. Summary of the Invention

[0006] The object of the present invention is to provide a method for continuously synthesizing levocamphor by using a continuous flow reactor to solve the above problems.

[0007] The object of the present invention is achieved by the following technical solutions:

[0008] A method for continuously synthesizing levocamphor by using a continuous flow reactor, which conducts a continuous flow reaction by using a continuous flow reactor, specifically includes the following steps:

[0009] (1) Using an aqueous sodium hypochlorite solution as solution A;

[0010] (2) Dissolving levoborneol in a suitable solvent, and then adding a mixed oxidant and acetic acid, and mixing evenly to form solution B;

[0011] (3) Simultaneously feeding solution A and solution B into the reaction channel of the continuous flow reactor according to a metered ratio for reaction;

[0012] (4) The reaction product is collected and post-treated to obtain the finished product of levocamphor.

[0013] Furthermore, the mixed oxidant is composed of oxidant A and oxidant B.

[0014] (1) Oxidant A is selected from one or more of N-methylmorpholine N-oxide (NMO), 4-(benzylamino)-2,2,6,6-tetramethyl-1-piperidinyloxy, 2,2,6,6-tetramethylpiperidinyloxy (TEMPO), 9-azabicyclo[3.3.1]nonane-N-oxide (ABNO);

[0015] (2) Oxidant B is selected from one or more of sodium hypochlorite, calcium hypochlorite, hydrogen peroxide, potassium peroxymonosulfate, tert-butyl hydroperoxide, trimethylsilyl peroxide, m-chloroperbenzoic acid, silver(II) picolinate, chromium(III) oxide, dichromic acid (H2Cr2O7), 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ), trichloroisocyanuric acid (TCCA);

[0016] Furthermore, the solvent is selected from one or more of dichloromethane, 1,2-dichloroethane, tetrahydrofuran, ethanol, methanol, ethyl acetate, acetonitrile.

[0017] As a preferred technical solution of the present invention, the catalytic oxidant is N-methylmorpholine N-oxide (NMO), and the weight ratio of the amount of the catalytic oxidant to levoborneol is 1:8 to 12, preferably 1:9 to 11. For example, in a specific embodiment, the weight ratio of N-methylmorpholine N-oxide (NMO) to levoborneol is 1:10.

[0018] As a preferred technical solution of the present invention, the aqueous sodium hypochlorite solution is a sodium hypochlorite solution with a concentration of 6wt% - 14wt%.

[0019] As a preferred technical solution of the present invention, the weight ratio of the amount of acetic acid used to borneol is 1:2 - 3, preferably 1:2.5 - 3. For example, in a specific embodiment, the weight ratio of acetic acid to borneol is 1:2.63.

[0020] As a preferred technical solution of the present invention, the molar ratio of borneol to sodium hypochlorite is 1:1 - 3, preferably 1:1.5 - 2.5. For example, the specific molar ratios that can be listed are 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2, 1:2.1, 1:2.2, 1:2.3, 1:2.4, 1:2.5, etc.

[0021] As a preferred technical solution of the present invention, the reaction temperature for the continuous flow reaction of solution A and solution B is 0 - 30°C, preferably 0 - 25°C. For example, the specific reaction temperatures that can be listed are 0°C, 5°C, 10°C, 15°C, 20°C, 25°C, etc.

[0022] As a preferred technical solution of the present invention, the reaction time for the continuous flow reaction of solution A and solution B in the continuous flow reactor is 10 - 120 s, preferably 30 - 90 s. For example, the reaction times that can be listed are 10 s, 20 s, 25 s, 30 s, 35 s, 40 s, 50 s, 60 s, 70 s, 80 s, 90 s, etc.

[0023] As a preferred technical solution of the present invention, when the continuous flow reaction is carried out using a continuous flow reactor, the process conditions are as follows: the molar ratio of borneol to sodium hypochlorite is 1:1.5 - 2.5, the reaction time is 30 - 90 s, and the reaction temperature is 0 - 25°C. For example, the molar ratio of borneol to sodium hypochlorite is 1:2, the reaction time is 30 s, and the reaction temperature is 0°C; the molar ratio of borneol to sodium hypochlorite is 1:2.2, the reaction time is 60 s, and the reaction temperature is 0°C; the molar ratio of borneol to sodium hypochlorite is 1:2.2, the reaction time is 30 s, and the reaction temperature is 10°C; the molar ratio of borneol to sodium hypochlorite is 1:2, the reaction time is 90 s, and the reaction temperature is 10°C; the molar ratio of borneol to sodium hypochlorite is 1:2.5, the reaction time is 30 s, and the reaction temperature is 25°C; the molar ratio of borneol to sodium hypochlorite is 1:1.8, the reaction time is 30 s, and the reaction temperature is 10°C.

[0024] As a preferred technical solution of the present invention, the solvent is selected from one or more of methylene chloride, 1,2-dichloroethane, tetrahydrofuran, ethanol, methanol, ethyl acetate, and acetonitrile, and is preferably 1,2-dichloroethane.

[0025] As a preferred technical solution of the present invention, the amount of the solvent should be able to completely dissolve borneol. The dosage ratio of borneol to the solvent is 1 g: 8 - 12 mL. For example, the dosage ratio of borneol to 1,2-dichloroethane is 1 g: 10 mL.

[0026] As a preferred technical solution of the present invention, after forming solution A or solution B, the temperature is controlled to the required temperature (such as 25 °C) by using a circulating thermostat, and the temperature is monitored in real time with a thermometer.

[0027] As a preferred technical solution of the present invention, the post-treatment specifically includes the following methods:

[0028] (1) Collect the reaction solution coming out of the microchannel, and then transfer and separate the liquid (for example, separate the liquid through a separating funnel);

[0029] (2) Add a small amount of aqueous sodium bicarbonate solution to the obtained organic phase to wash away the excess acetic acid;

[0030] (3) Wash with water multiple times (such as 2 - 5 times), combine the aqueous phases, and extract the aqueous phase with a certain amount of 1,2-dichloroethane each time until all the products are taken out.

[0031] (4) Combine the obtained organic phases and add anhydrous sodium sulfate to remove water.

[0032] (5) Concentrate the organic phase. After concentration, a crude product with impurities is obtained. Through separation (such as a chromatographic column), a pure product is obtained.

[0033] Compared with the prior art, the present invention changes the traditional batch process to a continuous process, solves a series of problems such as long reaction time and high safety risk in batch reactions, avoids using expensive raw materials or solvents by optimizing the reaction parameters of borneol camphor, the raw materials are simple and easy to obtain, and it has the advantages of low production cost, simple operation, environmental friendliness, simple post-treatment, and is conducive to industrial production.

[0034] The present invention has the following obvious technical improvements compared with the prior art:

[0035] 1. Mild reaction conditions and greatly shortened reaction time: Compared with the traditional method of synthesizing borneol camphor, which usually requires reacting at a high temperature of 105 °C for 2 hours, the continuous flow synthesis process of borneol camphor in the present invention can be carried out under low temperature conditions of 0 - 25 °C, and the reaction time is 30 s - 90 s. The reaction efficiency is greatly improved, better reaction control and optimization can be achieved, and the generation of side reactions is reduced.

[0036] 2. Improvement in the purity of the reaction product: The continuous flow synthesis of levocamphor can obtain a product with a higher purity (≥99%), and the continuous flow synthesis can achieve a better separation and purification process.

[0037] 3. Specific rotation: The specific rotation values of levocamphor synthesized by traditional methods are all between -38 and -40, while the specific rotation of levocamphor synthesized by continuous flow can reach -42, indicating that the synthesis of levocamphor by continuous flow process is not prone to racemization.

[0038] 4. Suitable for large-scale industrial production: The traditional method for synthesizing levocamphor is usually suitable for small-scale synthesis, while the continuous flow synthesis of levocamphor can be applied to large-scale synthesis, and the continuous flow synthesis can achieve better reaction control and scalability.

[0039] 5. Safer process: The continuous flow synthesis of levocamphor usually has better reaction safety because the continuous flow synthesis can achieve better temperature and pressure control, reducing the risk of accidents.

[0040] In view of the disadvantages of the existing levocamphor synthesis technology, such as complex synthesis process, high cost, large environmental impact, unstable product purity and yield, the inventor has creatively developed a new method that is cheap and efficient, providing a new way for the process synthesis of levocamphor.

[0041] The present invention first continuously synthesizes levocamphor by using a continuous flow reactor, changing the traditional batch process to a continuous process, solving a series of problems such as long reaction time and high safety risk in batch reactions, and optimizing the reaction parameters of levocamphor. It avoids the use of expensive raw materials or solvents, and the raw materials are simple and easily available. It has the advantages of low production cost, simple operation, environmental friendliness, mild reaction, short reaction time, higher reaction safety compared with conventional methods, high conversion rate, few impurities, and simple post-treatment, which is beneficial to industrial production, and has made obvious technological progress compared with the existing technology.

[0042] On the one hand, the present invention provides a method for continuously synthesizing levocamphor by using a continuous flow reactor. The continuous flow reaction is carried out by using a continuous flow reactor, and specifically includes the following steps:

[0043] (1) Using a sodium hypochlorite solution with a concentration of 6wt%-14wt% as solution A;

[0044] (2) Dissolving levoborneol in a solvent, and then adding a catalytic oxidant and acetic acid, and mixing evenly to form solution B. Specifically, it is prepared by the following method: Add 1,2-dichloroethane (such as 500 mL) to a conical flask equipped with a magnetic stirrer, start stirring, slowly add levoborneol (such as 50 g) until completely dissolved, and then add N-methylmorpholine N-oxide (NMO, such as 3.75 g) and acetic acid (such as 19 g) until all are dissolved;

[0045] (3) Feed solution A and solution B into the reaction channel of the continuous flow reactor simultaneously according to the metered ratio for reaction;

[0046] (4) After the reaction product is collected and post-treated, the finished product of levocamphor is obtained.

[0047] The specific synthesis route is as follows:

[0048]

[0049] The post-treatment specifically includes the following methods:

[0050] (1) Collect the reaction solution coming out of the microchannel, and then transfer and separate the liquid;

[0051] (2) Add a small amount of aqueous sodium bicarbonate solution to the obtained organic phase to wash away the excess acetic acid;

[0052] (3) Wash with water 2 - 5 times again, combine the aqueous phases, and extract the aqueous phase with a certain amount of 1,2-dichloroethane each time until all the product is taken out.

[0053] (4) Combine the obtained organic phases and add anhydrous sodium sulfate to remove water.

[0054] (5) Concentrate the organic phase. After concentration, a crude product with impurities is obtained, and through column chromatography separation, the pure product is obtained.

[0055] In the experiment of the present invention, a continuous flow device is used. The model of the continuous flow reactor is VMRSIC0609, and the material is silicon carbide. Place the reaction materials A and B in the raw material tanks respectively; connect the heat exchange fin integrated with the reaction sheet in the continuous flow reactor to the external constant temperature heat exchanger. The heat exchange medium in the heat exchange fin is heat-conducting oil, and set the reaction temperature of the continuous flow reactor through the constant temperature heat exchanger. After the reactor reaches the expected temperature, start the metering pump and adjust it to the set flow rate, and flow the reaction materials in the raw material tanks into the reactor simultaneously according to the set molar ratio. After mixing, reacting and staying in the microchannel module for a period of time, after post-treatment at the reactor outlet, it is sent to a liquid chromatograph for analysis. The experiment is carried out under normal pressure.

[0056] The present invention determines the flow rate through the following formula:

[0057] F1×C1:F2×C2 = n1:n2

[0058] (F1 + F2)×t = V 总

[0059] In the above formula:

[0060] F1 and F2 are the flow rates of the bornyl chloride solution and the sodium hypochlorite solution respectively;

[0061] C1 and C2 are the molar concentrations of the bornyl chloride solution and the sodium hypochlorite solution respectively;

[0062] n1:n2 is the molar ratio of the borneol solution and the sodium hypochlorite solution;

[0063] t is the reaction time;

[0064] V 总 is the volume of the continuous flow reactor.

[0065] The product purity is determined by gas chromatography (GC), such as Figure 1 the GC chart of the camphor product shown.

[0066] GC determination conditions:

[0067] Chromatographic column: SH-Rtx-5 (30m×0.25mm i.d), flow rate: 1mL / min; FID 1 Temperature 320℃; SPL 1 Temperature 250℃; injection volume: 1μL; column temperature: 40℃.

[0068] The structure of the obtained product is determined by nuclear magnetic resonance spectroscopy ( 1 HNMR) to determine the compound structure, such as Figure 2 the nuclear magnetic resonance spectrum of the corresponding product.

[0069] The specific rotation of the obtained product is measured by a polarimeter. Polarimeter conditions: Conc.: 1.000g / 100mL, Lg.: 100.00mm,

[0070] The calculation formula for the specific rotation:

[0071] [α]=α / L×C;

[0072] In the formula: C: the concentration of the solution (g / mL); L: the length of the polarimeter tube (dm). Brief Description of the Drawings

[0073] Figure 1 is the HPLC chart of the camphor product obtained in the example.

[0074] Figure 2 is the hydrogen spectrum of the camphor obtained in the example. Detailed Description of the Invention

[0075] The present invention will be described in detail below with reference to specific examples / comparative examples.

[0076] Comparative Example 1

[0077] Synthesis of L-Camphor by Batch Reaction Process: In a conical flask equipped with a magnetic stirrer under an ice bath, add 1,2-dichloroethane (DCM, 25 mL), start stirring, slowly add synthetic L-borneol (2.6 g) to dissolve, then add N-methylmorpholine N-oxide (NMO, 0.19 g) and acetic acid (AcOH, 1 mL), and wait until all are dissolved. Then add sodium hypochlorite solution (12%, 20 g) dropwise. During the dropping process, the temperature will rise to 10 °C. After 10 min of dropping, continue stirring for 10 min. Wait until the temperature drops to 0 °C, let it stand for phase separation, take the organic phase for TLC monitoring (TLC plate development with DCM:PE = 1:3). After the reaction is completed, separate the layers. Add a small amount of aqueous sodium bicarbonate solution to the organic phase to wash away the excess acetic acid, and then wash three times with water (50 mL of water each time). Combine the aqueous phases, and extract the aqueous phase with 1,2-dichloroethane (DCM, 25 mL) each time until no more product is obtained. Combine the organic phases, add anhydrous sodium sulfate to remove water, concentrate the organic phase. After concentration, 1.87 g of the product is obtained, with a yield of 72.9% and a specific rotation value of -39.1.

[0078] Comparative Example 2 (without NMO)

[0079] Synthesis of L-Camphor by Batch Reaction Process: In a conical flask equipped with a magnetic stirrer under an ice bath, add 1,2-dichloroethane (DCM, 25 mL), start stirring, slowly add synthetic L-borneol (2.6 g) to dissolve, then add acetic acid (AcOH, 1 mL), and wait until all are dissolved. Then add sodium hypochlorite solution (12%, 20 g) dropwise. During the dropping process, the temperature will rise to 10 °C. After 10 min of dropping, continue stirring for 3 h. Let it stand for phase separation, take the organic phase for TLC monitoring (TLC plate development with DCM:PE = 1:3). After the reaction is completed, separate the layers. Add a small amount of aqueous sodium bicarbonate solution to the organic phase to wash away the excess acetic acid, and then wash three times with water (50 mL of water each time). Combine the aqueous phases, and extract the aqueous phase with 1,2-dichloroethane (DCM, 25 mL) each time until no more product is obtained. Combine the organic phases, add anhydrous sodium sulfate to remove water, concentrate the organic phase. After concentration, 0.57 g of the product is obtained, with a yield of 22.2% and a specific rotation value of -30.1.

[0080] Table 1 Comparison between Continuous Flow Process and Batch Reaction

[0081]

[0082] For Examples 1 - 9, the main process conditions are shown in Table 2.

[0083] Table 2

[0084]

[0085] Example 1

[0086] Solution A is sodium hypochlorite solution (12%); Solution B is a conical flask equipped with a magnetic stirrer. Add 1,2-dichloroethane (DCM, 550 mL) and start stirring. Slowly add synthetic borneol (55 g) to dissolve, then add N-methylmorpholine N-oxide (NMO, 4.1 g) and acetic acid (AcOH, 20.9 g), and wait until all are dissolved.

[0087] Solution A is pumped into the continuous flow reactor through a piston pump, and Solution B is pumped into the continuous flow reactor through a piston pump. The two streams of materials react in the reactor. The reaction time is 30 s, the reaction temperature is 25 °C, n(borneol):n(sodium hypochlorite) = 1:1.8. The reaction solution is allowed to stand for liquid separation. The organic phase is washed successively with saturated sodium bicarbonate aqueous solution and saturated brine three times (50 mL each time), dried with anhydrous Na2SO4, filtered to remove sodium sulfate, and concentrated in vacuo to obtain 53.20 g of the product. The yield is 98.0%, and the optical rotation value is -39.0.

[0088] Example 2

[0089] Solution A is sodium hypochlorite solution (12%); Solution B is a conical flask equipped with a magnetic stirrer. Add 1,2-dichloroethane (DCM, 550 mL) and start stirring. Slowly add synthetic borneol (55 g) to dissolve, then add N-methylmorpholine N-oxide (NMO, 4.1 g) and acetic acid (AcOH, 20.9 g), and wait until all are dissolved.

[0090] Solution A is pumped into the continuous flow reactor through a piston pump, and Solution B is pumped into the continuous flow reactor through a piston pump. The two streams of materials react in the reactor. The reaction time is 30 s, the reaction temperature is 0 °C, n(borneol):n(sodium hypochlorite) = 1:2.0. The reaction solution is allowed to stand for liquid separation. The organic phase is washed successively with saturated sodium bicarbonate aqueous solution and saturated brine three times (50 mL each time), dried with anhydrous Na2SO4, filtered to remove sodium sulfate, and concentrated in vacuo to obtain 53.63 g of the product. The yield is 98.8%, and the optical rotation value is -40.3.

[0091] Example 3

[0092] Solution A is sodium hypochlorite solution (12%); Solution B is a conical flask equipped with a magnetic stirrer. Add 1,2-dichloroethane (DCM, 550 mL) and start stirring. Slowly add synthetic borneol (55 g) to dissolve, then add N-methylmorpholine N-oxide (NMO, 4.1 g) and acetic acid (AcOH, 20.9 g), and wait until all are dissolved.

[0093] Solution A was pumped into the continuous flow reactor by a plunger pump, and solution B was pumped into the continuous flow reactor by a plunger pump. The two feeds reacted in the reactor for 60 s at a reaction temperature of 0 °C, with n(borneol):n(sodium hypochlorite) = 1:2.2. The reaction solution was allowed to stand and separated. The organic phase was washed successively with saturated aqueous sodium bicarbonate solution and saturated brine three times (50 mL each time), dried over anhydrous Na2SO4, filtered to remove sodium sulfate, and concentrated in vacuo to obtain 53.47 g of the product with a yield of 98.5% and an optical rotation value of -39.1.

[0094] Example 4

[0095] Solution A was a sodium hypochlorite solution (12%); solution B was prepared by adding 1,2-dichloroethane (DCM, 550 mL) to a conical flask equipped with a magnetic stirrer, starting the stirring, slowly adding synthetic borneol (55 g) to dissolve, and then adding N-methylmorpholine N-oxide (NMO, 4.1 g) and acetic acid (AcOH, 20.9 g) until completely dissolved.

[0096] Solution A was pumped into the continuous flow reactor by a plunger pump, and solution B was pumped into the continuous flow reactor by a plunger pump. The two feeds reacted in the reactor for 30 s at a reaction temperature of 10 °C, with n(borneol):n(sodium hypochlorite) = 1:1.8. The reaction solution was allowed to stand and separated. The organic phase was washed successively with saturated aqueous sodium bicarbonate solution and saturated brine three times (50 mL each time), dried over anhydrous Na2SO4, filtered to remove sodium sulfate, and concentrated in vacuo to obtain 54.07 g of the product with a yield of 99.6% and an optical rotation value of -42.4. Figure 2 The structure of the compound was determined by the 1H NMR spectrum of the obtained product.

[0097] Example 5

[0098] Solution A was a sodium hypochlorite solution (12%); solution B was prepared by adding 1,2-dichloroethane (DCM, 550 mL) to a conical flask equipped with a magnetic stirrer, starting the stirring, slowly adding synthetic borneol (55 g) to dissolve, and then adding N-methylmorpholine N-oxide (NMO, 4.1 g) and acetic acid (AcOH, 20.9 g) until completely dissolved.

[0099] Solution A was pumped into the continuous flow reactor by a plunger pump, and solution B was pumped into the continuous flow reactor by a plunger pump. The two feeds reacted in the reactor for 90 s at a reaction temperature of 10 °C, with n(borneol):n(sodium hypochlorite) = 1:2.0. The reaction solution was allowed to stand and separated. The organic phase was washed successively with saturated aqueous sodium bicarbonate solution and saturated brine three times (50 mL each time), dried over anhydrous Na2SO4, filtered to remove sodium sulfate, and concentrated in vacuo to obtain 53.80 g of the product with a yield of 99.1% and an optical rotation value of -39.4.

[0100] Example 6

[0101] Solution A is sodium hypochlorite solution (12%); In the conical flask with a magnetic stirrer, add 1,2-dichloroethane (DCM, 550 mL), start stirring, slowly add synthetic borneol (55 g) to dissolve, then add N-methylmorpholine N-oxide (NMO, 4.1 g) and acetic acid (AcOH, 20.9 g), and wait until all are dissolved.

[0102] Solution A is pumped into the continuous flow reactor through a plunger pump, and solution B is pumped into the continuous flow reactor through a plunger pump. The two streams of materials react in the reactor. The reaction time is 30 s, the reaction temperature is 10 °C, n(borneol):n(sodium hypochlorite)=1:2.2. The reaction solution is allowed to stand for liquid separation. The organic phase is washed successively with saturated sodium bicarbonate aqueous solution and saturated brine three times (50 mL each time), dried with anhydrous Na2SO4, filtered to remove sodium sulfate, and concentrated in vacuo to obtain 53.69 g of the product. The yield is 98.9%, and the optical rotation value is -39.9.

[0103] The above description of the embodiments is to enable those of ordinary skill in the art to understand and use the invention. It is obvious that those skilled in the art can easily make various modifications to these embodiments and apply the general principles described herein to other embodiments without creative efforts. Therefore, the present invention is not limited to the above embodiments, and all improvements and modifications made by those skilled in the art without departing from the scope of the present invention should be within the protection scope of the present invention.

Claims

1. A method for continuously synthesizing levocamphor using a continuous flow reactor, characterized in that, The continuous flow reaction is carried out using a continuous flow reactor, which specifically includes the following steps: (1) Using an aqueous sodium hypochlorite solution as solution A; (2) Dissolving borneol in a suitable solvent, and then adding a mixed oxidant and acetic acid, and mixing evenly to form solution B; (3) Simultaneously feeding solution A and solution B into the reaction channel of the continuous flow reactor according to a metered ratio for reaction; (4) The reaction product is collected and post-treated to obtain the finished product of borneol camphor.

2. The method for continuously synthesizing levocamphor by using a continuous flow reactor according to claim 1, characterized in that, The mixed oxidant is composed of oxidant A and oxidant B. (1) Oxidant A is selected from one or more of N-methylmorpholine N-oxide (NMO), 4-(benzylamino)-2,2,6,6-tetramethyl-1-piperidine oxide, 2,2,6,6-tetramethylpiperidine oxide (TEMPO), 9-azabicyclo[3.3.1]nonane-N-oxide (ABNO); (2) Oxidant B is selected from one or more of sodium hypochlorite, calcium hypochlorite, hydrogen peroxide, potassium peroxymonosulfate, tert-butyl hydroperoxide, trimethylsilyl peroxide, m-chloroperbenzoic acid, silver(II) picolinate, chromium(III) oxide, dichromic acid (H2Cr2O7), 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ), trichloroisocyanuric acid (TCCA); The solvent is selected from one or more of dichloromethane, 1,2-dichloroethane, tetrahydrofuran, ethanol, methanol, ethyl acetate, acetonitrile.

3. A method for continuously synthesizing levocamphor by using a continuous flow reactor according to claim 1, characterized in that, The dosage ratio of the mixed oxidant to the weight of borneol is 1:8 - 12.

4. A method for continuously synthesizing levocamphor using a continuous flow reactor according to claim 1, characterized in that The dosage ratio of acetic acid to the weight of borneol is 1:2 - 3.

5. A method for continuously synthesizing levocamphor using a continuous flow reactor according to claim 1, characterized in that, The molar ratio of borneol to sodium hypochlorite is 1:1 - 3.

6. A method for continuously synthesizing levocamphor using a continuous flow reactor according to claim 1, characterized in that, The reaction temperature for the continuous flow reaction of solution A and solution B is -20 - 50°C.

7. A method for continuously synthesizing levocamphor by using a continuous flow reactor according to claim 1, characterized in that, The reaction temperature for the continuous flow reaction of solution A and solution B is -10 - 30°C.

8. A method for continuously synthesizing levocamphor by using a continuous flow reactor according to claim 1, characterized in that, The reaction time of solution A and solution B in the continuous flow reactor is 10 - 120 s.

9. A method for continuously synthesizing levocamphor by using a continuous flow reactor according to claim 1, characterized in that, When carrying out the continuous flow reaction using a continuous flow reactor, the process conditions are: the molar ratio of borneol to sodium hypochlorite is 1:1.5 - 2.5, the reaction time is 30 - 90 s, and the reaction temperature is 0 - 25°C.

10. A method for continuously synthesizing levocamphor by using a continuous flow reactor according to claim 1, characterized in that, The post-treatment specifically includes the following methods: (1) Collect the reaction solution coming out of the microchannel, and then transfer and separate the liquid; (2) Add a small amount of aqueous sodium bicarbonate solution to the obtained organic phase to wash away the excess acetic acid; (3) Wash with water multiple times, combine the aqueous phases, and extract the aqueous phase with 1,2-dichloroethane each time until all the products are taken out; (4) Combine the obtained organic phases and add anhydrous sodium sulfate to remove water; (5) Concentrate the organic phase, and after concentration, obtain a crude product with impurities. Through separation, the pure product is obtained.

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