Multi-stereocenter chiral compound isomer in-situ rapid detection device and method

Abstract

The invention belongs to the technical field of pharmaceutical engineering, and particularly relates to a multi-stereocenter chiral compound isomer in-situ rapid detection device and method. The device comprises a reactor, a pump, a continuous filter, a storage tank, a solvent storage tank, a continuous oil-water separator, a continuous distiller and an ion mobility mass spectrometer. The method comprises the steps of reaction liquid extraction, continuous filtration, continuous oil-water separation, continuous distillation, continuous sample introduction and the like. The method provided by the invention solves the difficult problem of rapid and accurate determination of the stereoisomer in the synthesis process of the multi-stereocenter chiral compound, and has the advantages of high detection speed, high sensitivity, high accuracy, high reliability and the like.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical engineering, and in particular relates to a device and method for rapid in-situ detection of isomers of a multi-stereocenter chiral compound. Background Art

[0002] Chiral pharmaceuticals are a cutting-edge field in the pharmaceutical industry, accounting for over 70% of existing drugs. Drug safety and efficacy are directly linked to human health and even life. Therefore, rigorous quality control during the API synthesis process, including analysis, testing, and control of impurities, is crucial for effectively controlling the quality of the final marketed product. Impurities can reduce the content of active pharmaceutical ingredients, impacting both therapeutic efficacy and stability. Furthermore, impurities can cause toxic side effects during medication use, posing a threat to human health. Therefore, analyzing and identifying impurities and controlling their content are crucial to ensuring drug safety and efficacy, and guaranteeing and improving drug quality.

[0003] Chiral drugs often have complex structures, especially those containing multiple stereocenters (i.e., ≥2 stereocenters). Their synthesis steps are long, reaction conditions are demanding, and side reactions are numerous. Without rapid and accurate stereoisomer analysis and detection technology during the synthesis of chiral drugs, process control becomes difficult, stereoisomer impurities increase, and product quality decreases. Existing analytical and detection methods for chiral molecules have numerous limitations. For example, polarimetry cannot distinguish between different stereoisomers, nuclear magnetic resonance requires pure products, and X-ray diffraction analysis requires crystals, leading to complex data processing. Chiral chromatography requires comparison with standards, which takes a long time to analyze. Furthermore, stereoisomer impurities generated during the synthesis process are difficult to obtain standards, or the synthesis of standards for stereoisomer impurities is difficult and time-consuming. Existing analytical and detection methods struggle to meet the requirements for rapid analysis and detection of stereoisomers during the synthesis process, thereby helping to achieve process optimization and strict quality control. Therefore, there is an urgent need to research and develop rapid and accurate stereoisomer analysis and detection technologies for chiral molecules, especially those with multiple stereocenters. Summary of the Invention

[0004] The purpose of the present invention is to overcome the shortcomings of the existing technology and provide an in situ rapid detection device and method for isomers of multi-stereocenter chiral compounds, which has the advantages of high speed, high sensitivity, high accuracy and high reliability, and solves the problem of rapid and accurate detection of stereoisomers in the synthesis process of multi-stereocenter chiral compounds.

[0005] The in-situ rapid detection device for isomers of chiral compounds with multiple stereocenters provided by the present invention comprises six pumps, three storage tanks, two solvent storage tanks, a reactor, a continuous filter, a continuous oil-water separator, a continuous distiller, and an ion mobility mass spectrometer connected by pipelines; wherein:

[0006] The first pump inlet is connected to the reactor for extracting the reaction liquid from the reactor; the first pump outlet is connected to the inlet of the continuous filter; the outlet of the continuous filter is connected to the first storage tank;

[0007] The inlet of the second pump is connected to the first solvent storage tank to extract the solvent therefrom, and the outlet of the second pump is connected to the first storage tank to input the extracted solvent into the first storage tank;

[0008] The inlet of the third pump is connected to the first storage tank to extract liquid from it, and the outlet of the third pump is connected to the inlet of the continuous oil-water separator to input the extracted liquid into the continuous oil-water separator; the outlet of the continuous oil-water separator is connected to the second storage tank;

[0009] The inlet of the fourth pump is connected to the second storage tank to extract liquid therefrom, and the outlet of the fourth pump is connected to the inlet of the continuous distiller to input the extracted liquid into the continuous distiller; the outlet of the continuous distiller is connected to the third storage tank;

[0010] The inlet of the fifth pump is connected to the second solvent storage tank to extract solvent therefrom, and the outlet of the fifth pump is connected to the third storage tank to input the extracted solvent into the third storage tank;

[0011] The sixth pump inlet is connected to the third storage tank to extract liquid therefrom, and the sixth pump outlet is connected to the ion mobility mass spectrometer to send the extracted liquid into the ion mobility mass spectrometer for detection.

[0012] The ion mobility mass spectrometer can also be connected to a computer, the computer is connected to a controller, and the controller is connected to the reactor; the detection information of the ion mobility mass spectrometer is transmitted to the computer, the computer automatically analyzes the detection signal of the ion mobility mass spectrometer, and controls the operating parameters of the reactor such as temperature, pressure, stirring speed and material flow through the controller, thereby optimizing the reaction conditions in the reactor and ultimately optimizing the reaction results.

[0013] Further:

[0014] The reactor is at least one of a stirred reactor, a loop reactor, a fixed bed reactor, a slurry bed reactor, a bubble column reactor, and a microreactor. The reactor can be replaced to meet the requirements of different synthesis processes.

[0015] The pump is at least one of a plunger pump, a metering pump, a centrifugal pump and a diaphragm pump, preferably a plunger pump or a metering pump.

[0016] The first storage tank has a stirring and mixing function, which can achieve efficient mixing between different fluids.

[0017] The third storage tank has a stirring and mixing function, which can achieve efficient mixing between different fluids.

[0018] The second storage tank is a conventional container.

[0019] The continuous filter is used to filter nanometer-micrometer-sized solid particles. The continuous filter material is resistant to acidic or alkaline solutions.

[0020] The continuous oil-water separator is a water-organic phase continuous separator, which realizes the continuous separation of the water phase and the organic phase.

[0021] The continuous distiller is used for rapid distillation of the solvent.

[0022] The ion mobility mass spectrometer is at least one of a Thermo Fisher ion mobility mass spectrometer, a Waters ion mobility mass spectrometer, a Bruker ion mobility mass spectrometer, a Shimadzu ion mobility mass spectrometer, a Hitachi ion mobility mass spectrometer, a PerkinElmer ion mobility mass spectrometer, a Beijing Zhike Huazhi Scientific Instrument ion mobility mass spectrometer, an Agilent Technologies ion mobility mass spectrometer, and a SCIEX ion mobility mass spectrometer.

[0023] Based on the above detection device, the present invention also provides a method for rapid in-situ detection of isomers of a multi-stereocenter chiral compound, the specific steps of which are:

[0024] (S1) extracting the reaction liquid from the reactor using a first pump, and the reaction liquid flowing out of the outlet of the first pump immediately enters a continuous filter;

[0025] (S2) the reaction liquid flowing out of the continuous filter in step (S1) then enters the first storage tank, and simultaneously a second pump is used to draw solvent from the first solvent storage tank into the first storage tank, and then a third pump is used to draw liquid from the first storage tank, and the liquid flowing out of the outlet of the third pump then enters the continuous oil-water separator;

[0026] (S3) the liquid flowing out of the continuous oil-water separator in step (S2) then enters the second storage tank, and then the liquid is pumped out of the second storage tank by a fourth pump, and the liquid flowing out of the outlet of the fourth pump then enters the continuous distiller;

[0027] (S4) The liquid flowing out of the continuous distiller in step (S3) then enters the third storage tank. At the same time, the fifth pump is used to extract the solvent from the second solvent storage tank and enter the third storage tank. Thereafter, the sixth pump is used to extract the liquid from the third storage tank. The liquid flowing out of the outlet of the sixth pump then enters the ion mobility mass spectrometer for detection.

[0028] Further:

[0029] The flow rate of the reaction liquid extracted from the reactor by the first pump in step (S1) is controlled to be 0.001 ml / min to 100 ml / min.

[0030] The flow rate of the solvent extracted by the second pump from the first solvent storage tank in the control step (S2) is 0.001 ml / min to 100 ml / min.

[0031] The solvent in the first solvent storage tank in step (S2) can be any one of water, a polar organic solvent and a non-polar organic solvent.

[0032] The flow rate of the liquid extracted from the first storage tank by the third pump in the control step (S2) is 0.001 ml / min to 100 ml / min.

[0033] The flow rate of the liquid extracted from the second storage tank by the fourth pump in the control step (S3) is 0.001 ml / min to 100 ml / min.

[0034] The operating temperature of the continuous distiller in step (S3) is controlled to be room temperature to 350°C.

[0035] The flow rate of the solvent extracted by the fifth pump from the second solvent storage tank in the control step (S4) is 0.001 ml / min to 100 ml / min.

[0036] The solvent in the second solvent storage tank may be any one of water, a polar organic solvent and a non-polar organic solvent.

[0037] The sixth pump in the control step (S4) extracts the liquid from the third storage tank at a flow rate of 0.001 ml / min to 100 ml / min.

[0038] Beneficial effects of the present invention:

[0039] The present invention solves the difficult problem of rapid and accurate detection of stereoisomers in the synthesis process of multi-stereocenter chiral compounds, and has the advantages of high speed, high sensitivity, high accuracy and high reliability. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 This is the device used in Examples 1 to 7. Figure 2 This is the device used in Example 8. DETAILED DESCRIPTION

[0040] The present invention is further described below through embodiments in conjunction with the accompanying drawings.

[0041] The devices used in Examples 1 to 7 are as shown in the attached Figure 1 shown.

[0042] Pump A is used to extract the reaction liquid from the reactor, and the reaction liquid flowing out of the outlet of pump A immediately enters the continuous filter; the reaction liquid flowing out of the continuous filter immediately enters storage tank A, and at the same time, pump B is used to extract the solvent from the first solvent storage tank and enter storage tank A, and then pump C is used to extract liquid from storage tank A, and the liquid flowing out of the outlet of pump C then enters the continuous oil-water separator; the liquid flowing out of the continuous oil-water separator immediately enters storage tank B, and then pump D is used to extract liquid from storage tank B, and the liquid flowing out of the outlet of pump D immediately enters the continuous distiller; the liquid flowing out of the continuous distiller immediately enters storage tank C, and at the same time, pump E is used to extract the solvent from the second solvent storage tank and enter storage tank C, and then pump F is used to extract liquid from storage tank C, and the liquid flowing out of the outlet of pump F then enters the ion mobility mass spectrometer.

[0043] The device used in Example 8 is as shown in the attached Figure 2 shown.

[0044] Pump A is used to extract the reaction liquid from the reactor, and the reaction liquid flowing out of the outlet of pump A immediately enters the continuous filter; the reaction liquid flowing out of the continuous filter immediately enters storage tank A, and at the same time, pump B is used to extract the solvent from the first solvent storage tank and enter storage tank A, and then pump C is used to extract liquid from storage tank A, and the liquid flowing out of the outlet of pump C then enters the continuous oil-water separator; the liquid flowing out of the continuous oil-water separator immediately enters storage tank B, and then pump D is used to extract liquid from storage tank B, and the liquid flowing out of the outlet of pump D immediately enters the continuous distiller; from the continuous distiller The liquid flowing out of the reactor then enters storage tank C. At the same time, pump E is used to extract solvent from the second solvent storage tank and enter storage tank C. Thereafter, pump F is used to extract liquid from storage tank C. The liquid flowing out of the outlet of pump F then enters the ion mobility mass spectrometer. The ion mobility mass spectrometer is connected to a computer, the computer is connected to a controller, and the controller is connected to the reactor. The detection information of the ion mobility mass spectrometer is transmitted to the computer, and the computer automatically analyzes the detection signal of the ion mobility mass spectrometer. The operating parameters of the reactor, such as temperature, pressure, stirring speed, and material flow rate, are controlled by the controller.

[0045] Example 1

[0046] The preparation of (3aS,6aR)-lactone by reduction and ring closure of (4S,5R)-half ester (reaction formula 1) is one of the important steps in the production of vitamin H. In a batch stirred reactor, (4S,5R)-half ester and LiBH4 are first reduced, and then ring-closed in the presence of hydrochloric acid to prepare (3aS,6aR)-lactone. After the reduction product reacts with hydrochloric acid at 90°C for a period of time, the reaction liquid is extracted from the reactor by plunger pump A, and the flow rate of pump A is controlled to be 2.5ml / min. The reaction liquid flowing out of the outlet of pump A then enters the continuous filter; the reaction liquid flowing out of the continuous filter then enters the storage tank A, and at the same time, ethyl acetate is extracted from the first solvent storage tank by plunger pump B and enters the storage tank A, and the flow rate of pump B is controlled to be 2.3ml / min. Then, the liquid is extracted from the storage tank A by plunger pump C, and the flow rate of pump C is controlled to be 2.0ml / min. The liquid flowing out of the outlet of pump C then enters the continuous oil-water separator; the liquid flowing out of the continuous oil-water separator The liquid then enters storage tank B. Plunger pump D then draws liquid from storage tank B, controlling the flow rate of pump D at 1.5 ml / min. The liquid flowing from pump D's outlet then enters a continuous still. The operating temperature of the continuous still is controlled at 50°C. The liquid flowing from the continuous still then enters storage tank C. Simultaneously, plunger pump E draws methanol from a second solvent storage tank into tank C, controlling the flow rate of pump E at 1.0 ml / min. Plunger pump F then draws liquid from tank C again. The liquid flowing from pump F's outlet then enters a Waters ion mobility mass spectrometer, controlling the flow rate of pump F at 0.2 ml / min. In this example, the measured (3aS,6aR)-lactone content was approximately 98%, and the (3aR,6aS)-lactone content was approximately 1%. The total time from sampling from the reactor by pump A to the measurement results was only approximately 7 minutes.

[0047]

[0048] Example 2

[0049] This example was identical to Example 1 in all other conditions, with the only difference being that the operating temperature of the continuous distiller in this example was controlled at 60°C. In this example, the measured (3aS,6aR)-lactone content was approximately 98%, and the (3aR,6aS)-lactone content was approximately 1%. The total time from when pump A sampled the reactor to when the measurement results were obtained was only approximately 6 minutes.

[0050] Example 3

[0051] This example was identical to Example 1 in all other conditions, except that pump B was used to draw dichloroethane from the first solvent storage tank into storage tank A, with the flow rate of pump B controlled at 2.3 ml / min. In this example, the measured (3aS,6aR)-lactone content was approximately 98%, and the (3aR,6aS)-lactone content was approximately 1%. The total time from pump A drawing a sample from the reactor to the measurement result was only approximately 8 minutes.

[0052] Example 4

[0053] This example was identical to Example 1 in all other conditions, except that the liquid flowing out of the outlet of Pump F in this example subsequently entered the SCIEX ion mobility mass spectrometer, and the flow rate of Pump F was controlled at 0.2 ml / min. In this example, the measured content of (3aS,6aR)-lactone was approximately 98%, and the content of (3aR,6aS)-lactone was approximately 1%. The total time from sampling from the reactor by Pump A to the measurement of the results was only approximately 7 minutes.

[0054] Example 5

[0055] This example was identical to Example 1 in all other conditions, except that a 1:1 volume ratio of methanol and acetonitrile was pumped from a second solvent storage tank into storage tank C using pump E, with the flow rate of pump E controlled at 1.0 ml / min. In this example, the measured content of (3aS,6aR)-lactone was approximately 98%, and the content of (3aR,6aS)-lactone was approximately 1%. The total time from sampling from the reactor by pump A to the measurement result was only approximately 7 minutes.

[0056] Example 6

[0057] This example was identical to Example 1 in all other conditions, except that the flow rate of pump F was controlled at 0.1 ml / min. The measured (3aS,6aR)-lactone content in this example was approximately 98%, and the (3aR,6aS)-lactone content was approximately 1%. The total time from pump A drawing a sample from the reactor to the measurement result was only approximately 7 minutes.

[0058] Example 7

[0059] This example was identical to Example 1 in all other conditions, except that the flow rate of pump D was controlled at 1.8 ml / min. The measured (3aS,6aR)-lactone content in this example was approximately 98%, and the (3aR,6aS)-lactone content was approximately 1%. The total time from pump A drawing a sample from the reactor to the measurement result was only approximately 6.5 minutes.

[0060] Example 8

[0061] The preparation of (3aS,6aR)-lactone by reduction and ring closure of (4S,5R)-half ester (reaction formula 1) is one of the important steps in the production of vitamin H. In a batch stirred reactor, (4S,5R)-half ester and LiBH4 are first reduced, and then ring-closed in the presence of hydrochloric acid to prepare (3aS,6aR)-lactone. After the reduction product reacts with hydrochloric acid at 110°C for a period of time, the reaction liquid is extracted from the reactor by plunger pump A, and the flow rate of pump A is controlled at 2.5ml / min. The reaction liquid flowing out of the outlet of pump A then enters the continuous filter; the reaction liquid flowing out of the continuous filter then enters the storage tank A, and at the same time, ethyl acetate is extracted from the first solvent storage tank by plunger pump B and enters the storage tank A, and the flow rate of pump B is controlled at 2.3ml / min. Then, the liquid is extracted from the storage tank A by plunger pump C, and the flow rate of pump C is controlled at 2.0ml / min. The liquid flowing out of the outlet of pump C then enters the continuous oil-water separator; from the continuous oil-water separator The outflowing liquid then enters storage tank B. Plunger pump D then pumps liquid from storage tank B at a controlled flow rate of 1.5 ml / min. The liquid flowing from pump D then enters a continuous still, the operating temperature of which is controlled at 50°C. The liquid flowing from the continuous still then enters storage tank C. Simultaneously, plunger pump E pumps methanol from a second solvent storage tank into tank C at a controlled flow rate of 1.0 ml / min. Plunger pump F then pumps liquid from tank C again. The liquid flowing from pump F then enters a Waters ion mobility mass spectrometer at a controlled flow rate of 0.2 ml / min. In this example, the ion mobility mass spectrometer initially measured (3aS,6aR)-lactone content at approximately 96% and (3aR,6aS)-lactone content at approximately 1.7%. The total time from pump A sampling from the reactor to the measurement results was only approximately 7 minutes.

[0062] The information obtained from the initial ion mobility mass spectrometer measurement was transmitted to a computer, which automatically analyzed the signal and, through a controller, adjusted the temperature within the reactor from 110°C to 90°C. After a two-hour reaction, the above measurement process was repeated, keeping all other parameters and operating procedures unchanged. The ion mobility mass spectrometer measured the (3aS,6aR)-lactone content at approximately 98% and the (3aR,6aS)-lactone content at approximately 1%. The total time from pump A drawing a sample from the reactor to the measurement result was only approximately 7 minutes.

[0063] Comparative Example 1

[0064] This example is the same as Example 1 in other conditions, except that manual sampling is used in this example, followed by manual sample post-processing and chiral liquid chromatography. The measured content of (3aS, 6aR)-lactone is approximately 98%, and the content of (3aR, 6aS)-lactone is approximately 1%. The total time from sampling to measurement is more than 5 hours.

[0065] Through comparison, it was found that compared with traditional detection methods, the method of the present invention has a faster detection speed and higher accuracy.

[0066] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit the scope of protection of the present invention. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that the technical solutions of the present invention may be modified or replaced by equivalents without departing from the essence and scope of the technical solutions of the present invention.

Claims

1. A device for rapid in-situ detection of isomers of multi-stereocenter chiral compounds, characterized in that: The system comprises six pumps, three storage tanks, two solvent storage tanks, a reactor, a continuous filter, a continuous oil-water separator, a continuous distiller and an ion mobility mass spectrometer connected by pipelines; wherein: The first pump inlet is connected to the reactor for extracting the reaction liquid from the reactor; the first pump outlet is connected to the inlet of the continuous filter; the outlet of the continuous filter is connected to the first storage tank; The inlet of the second pump is connected to the first solvent storage tank to extract the solvent therefrom, and the outlet of the second pump is connected to the first storage tank to input the extracted solvent into the first storage tank; The inlet of the third pump is connected to the first storage tank to extract liquid from it, and the outlet of the third pump is connected to the inlet of the continuous oil-water separator to input the extracted liquid into the continuous oil-water separator; the outlet of the continuous oil-water separator is connected to the second storage tank; The inlet of the fourth pump is connected to the second storage tank to extract liquid therefrom, and the outlet of the fourth pump is connected to the inlet of the continuous distiller to input the extracted liquid into the continuous distiller; the outlet of the continuous distiller is connected to the third storage tank; The inlet of the fifth pump is connected to the second solvent storage tank to extract solvent therefrom, and the outlet of the fifth pump is connected to the third storage tank to input the extracted solvent into the third storage tank; The sixth pump inlet is connected to the third storage tank to extract liquid therefrom, and the sixth pump outlet is connected to the ion mobility mass spectrometer to send the extracted liquid into the ion mobility mass spectrometer for detection.

2. The detection device according to claim 1, characterized in that The ion mobility mass spectrometer is also connected to a computer, the computer is connected to a controller, and the controller is connected to the reactor; the detection information of the ion mobility mass spectrometer is transmitted to the computer, the computer automatically analyzes the detection signal of the ion mobility mass spectrometer, and controls the operating parameters of the reactor such as temperature, pressure, stirring speed and material flow through the controller, thereby optimizing the reaction conditions in the reactor and ultimately optimizing the reaction results.

3. The detection device according to claim 1 or 2, characterized in that: The reactor is at least one of a stirred reactor, a loop reactor, a fixed bed reactor, a slurry bed reactor, a bubble column reactor and a microreactor; the reactor can be replaced to meet the requirements of different synthesis processes.

4. The detection device according to claim 1 or 2, characterized in that: The pump is at least one of a plunger pump, a metering pump, a centrifugal pump and a diaphragm pump; The first and third storage tanks have stirring and mixing functions for efficient mixing of different fluids; The continuous filter is used to filter nano-micron-sized solid particles; Continuous filter material: acid-resistant or alkaline material; The continuous oil-water separator is an aqueous phase-organic phase continuous separator, which is used for continuous separation of aqueous phase and organic phase; The continuous distiller is used for rapid distillation of the solvent.

5. The detection device according to claim 1 or 2, characterized in that: The ion mobility mass spectrometer is at least one of a Thermo Fisher ion mobility mass spectrometer, a Waters ion mobility mass spectrometer, a Bruker ion mobility mass spectrometer, a Shimadzu ion mobility mass spectrometer, a Hitachi ion mobility mass spectrometer, a PerkinElmer ion mobility mass spectrometer, a Beijing Zhike Huazhi Scientific Instrument ion mobility mass spectrometer, an Agilent Technologies ion mobility mass spectrometer, and a SCIEX ion mobility mass spectrometer.

6. A method for rapid in-situ detection of isomers of a multi-stereocenter chiral compound based on the detection device according to any one of claims 1 to 5, characterized in that: The specific steps are: (S1) extracting the reaction liquid from the reactor by using a first pump, and the reaction liquid flowing out of the outlet of the first pump immediately enters the continuous filter; (S2) the reaction liquid flowing out of the continuous filter in step (S1) then enters the first storage tank, and simultaneously the solvent is pumped from the first solvent storage tank into the first storage tank by a second pump, and then the liquid is pumped from the first storage tank by a third pump, and the liquid flowing out of the outlet of the third pump then enters the continuous oil-water separator; (S3) the liquid flowing out of the continuous oil-water separator in step (S2) then enters the second storage tank, and then the liquid is pumped out of the second storage tank by a fourth pump, and the liquid flowing out of the outlet of the fourth pump then enters the continuous distiller; (S4) The liquid flowing out of the continuous distiller in step (S3) then enters the third storage tank. Simultaneously, the fifth pump draws the solvent from the second solvent storage tank into the third storage tank. Thereafter, the sixth pump draws the liquid from the third storage tank. The liquid flowing out of the outlet of the sixth pump then enters the ion mobility mass spectrometer for detection.

7. The detection method according to claim 6, wherein: The flow rate of the reaction liquid extracted from the reactor by the first pump in step (S1) is controlled to be 0.001 ml / min to 100 ml / min; The second pump in step (S2) extracts the solvent from the first solvent storage tank at a flow rate of 0.001 ml / min to 100 ml / min; The solvent in the first solvent storage tank in step (S2) is selected from water, a polar organic solvent and a non-polar organic solvent.

8. The detection method according to claim 6, wherein: The flow rate of the third pump in the control step (S2) for extracting liquid from the first storage tank is 0.001 ml / min to 100 ml / min; The fourth pump in step (S3) is controlled to extract liquid from the second storage tank at a flow rate of 0.001 ml / min to 100 ml / min; The temperature of the continuous distiller in step (S3) is controlled to be room temperature to 350°C.

9. The detection method according to claim 6, wherein: The fifth pump in step (S4) is controlled to extract the solvent from the second solvent storage tank at a flow rate of 0.001 ml / min to 100 ml / min; The sixth pump in step (S4) is controlled to extract liquid from the third storage tank at a flow rate of 0.001 ml / min to 100 ml / min; The solvent in the second solvent storage tank in step (S4) is selected from water, a polar organic solvent and a non-polar organic solvent.

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