High-throughput online monitoring and analysis device and method for chiral drug synthesis process

Abstract

The present invention discloses a high-throughput online monitoring and analysis device and method for a chiral drug synthesis process, wherein the device comprises: a chiral drug synthesis reaction unit, a sample delivery unit, and an automatic sequence injection unit; the present invention is an analysis method for online monitoring of a chiral drug synthesis process that integrates a chiral drug synthesis reactor, an automatic sequence injection device, and a capillary electrokinetic chromatography detection technology, and high-throughput online monitoring of the content and configuration changes of different enantiomers in the chiral drug synthesis process. The present invention helps to obtain accurate information on the kinetics of chiral drug synthesis reactions, provides support for the route design, precise regulation of chiral drug synthesis reactions, and the improvement of the synthesis efficiency of single chiral drugs, and provides a solid guarantee for the rationality and safety of chiral drugs in clinical applications.

Description

Technical Field

[0001] The present invention relates to the technical field of drug synthesis process analysis and detection, and in particular provides a high-throughput online monitoring and analysis device and method for a chiral drug synthesis process. Background Art

[0002] Chiral drugs have attracted much attention from drug regulatory agencies and drug developers due to the special pharmacology, toxicology and pharmacokinetics of their isomers in the body. Among the drugs currently on the market, chiral drugs account for more than 50%, and most of them are still produced and administered in the form of racemic mixtures. Inactive or poorly active isomers not only cannot effectively act on the target, but may even have toxic side effects or antagonistic effects. For example, R-epinephrine is 1.2 times more potent than S-epinephrine; R-ethambutol has antibacterial and anti-tuberculosis effects, while S-ethambutol may cause blindness. Therefore, with the increasing advocacy of safe drug use, the research and development and use of single active isomers in chiral drug molecules have become extremely urgent in the pharmaceutical industry, which is conducive to effectively controlling pharmacokinetics, exerting the best therapeutic effect of drugs, and ensuring the safety and rationality of drug use. Chiral drug synthesis technology has become an important means of obtaining single chiral drugs. It has the advantages of high synthesis efficiency, controllable production costs, high enantiomeric selectivity, and is conducive to separation and purification. It is a new technology that is expected to be industrialized. It has important research significance and application value in the fields of pharmaceutical research and development, and is in line with the development direction of the national pharmaceutical industry.

[0003] In recent years, the research on chiral drug synthesis has mainly focused on the design and synthesis of new, efficient, and highly selective chiral catalysts and chiral ligands, as well as the development of new methods and strategies for synthetic catalytic reactions. The detection of chiral drug synthesis reactions still remains at the offline detection stage, that is, a certain amount of reaction liquid is extracted from the chiral drug synthesis reaction vessel, the reaction is stopped, and the product is separated, detected, and structurally characterized after pre-treatment such as filtration and dilution (such as high performance liquid chromatography (HPLC), gas chromatography, capillary electrophoresis, nuclear magnetic resonance (NMR), etc.). This method of offline detection of chiral drug synthesis process is cumbersome and has large human errors, making it difficult to achieve accurate high-time resolution kinetic analysis of chiral drug synthesis process. In addition, for the chiral drug synthesis reaction process, it is necessary not only to efficiently separate the main substances (reactants, catalysts, intermediates, chiral products, and by-products) involved in the asymmetric synthesis reaction process, but also to achieve high time resolution and high sensitivity detection of the evolution of these substances along the reaction process and the unequal enantiomers of chiral separation in order to obtain accurate reaction kinetic information.

[0004] Therefore, it is very meaningful to provide an analytical method for online monitoring of the synthesis process of chiral drugs. Summary of the invention

[0005] In view of the problem that the technology for detecting the synthesis process of chiral drugs in the prior art is still at the offline detection stage, the present invention provides a high-throughput online monitoring and analysis device and method for the synthesis process of chiral drugs;

[0006] In order to achieve the above-mentioned object, the present invention provides a high-throughput online monitoring and analysis device for a chiral drug synthesis process, comprising: a chiral drug synthesis reaction unit, a sample delivery unit, and an automatic sequence injection unit;

[0007] The chiral drug synthesis reaction unit comprises a three-necked flask and a constant temperature magnetic stirrer;

[0008] The sample delivery unit includes a sample delivery U-shaped tube, a constant flow pump, a filter, a three-way interface, and a pressure regulating valve;

[0009] The automatic sequence injection unit comprises a sample introduction capillary, a four-way interface, a first conduit, a second conduit, a solenoid valve, a syringe pump filled with a buffer solution, a separation capillary, a buffer solution device, a negative high-voltage power supply, a waste liquid collection bottle, and a ground electrode, wherein a detection window is opened on the separation capillary;

[0010] The three-necked flask is placed on a constant temperature magnetic stirrer, and the two ports of the sample delivery U-shaped tube are immersed in the synthetic reaction liquid through the two reaction ports of the three-necked flask respectively, wherein the filter is installed at one port of the sample delivery U-shaped tube, and with the filter as the starting point, a three-way interface, a pressure regulating valve and a constant current pump are sequentially installed on the sample delivery U-shaped tube body, one port of the three-way interface is connected with a sample introduction capillary, the sample introduction capillary and the separation capillary are horizontally connected through a four-way interface, the separation capillary is connected with a buffer solution bottle, the conduit 1 and the conduit 2 are vertically connected through the four-way interface, the injection pump filled with buffer solution is connected with the conduit 1, the solenoid valve is installed on the conduit 1, the conduit 2 is connected with a waste liquid collection device, the negative high-voltage power supply is arranged on the buffer solution bottle side, and the grounding electrode is arranged on the waste liquid collection bottle side.

[0011] Preferably, a temperature detector is placed in a reaction port of the three-necked flask.

[0012] Preferably, the filter is provided with two layers of filter membranes with pore sizes of 2.7 μm and 0.7 μm respectively.

[0013] Preferably, the inner diameter of the sampling capillary is 50 μm, the outer diameter is 365 μm, and the length is 5 cm; the inner diameter of the separation capillary is 50 μm, the outer diameter is 365 μm, and the length is 20 cm.

[0014] In a second aspect, the present invention also provides an analytical method for online monitoring of a chiral drug synthesis process using the device, comprising:

[0015] 1) Carrying out a chiral drug synthesis reaction process in a three-necked flask placed on a constant temperature magnetic stirrer;

[0016] 2) The chiral drug synthesis reaction liquid is filtered by a filter under the action of a constant flow pump and a pressure regulating valve, and the outflowing synthesis liquid passes through a three-way interface. A part of it enters the sample introduction capillary under the back pressure of the pressure regulating valve and accumulates at the four-way interface, and the other part circulates back to the three-necked flask to continue the reaction;

[0017] 3) Add negative high voltage to the side of the buffer solution bottle, and ground the side of the waste liquid collection bottle to form a voltage difference between the four-way interface and the buffer solution bottle, so that the synthetic liquid is electrically injected from the four-way interface into the separation capillary for separation and detection. At the detection window, a capillary electrophoresis ultraviolet detector is used to perform real-time online continuous high-time resolution separation and analysis detection on the sample to complete the detection of the synthesis process of the chiral drug;

[0018] 4) Open the solenoid valve to allow the synthetic liquid to accumulate at the four-way interface for 2 seconds, and apply the injection voltage to allow the synthetic liquid to enter the separation capillary for 1 second; close the solenoid valve to flush the excess synthetic liquid into the waste liquid collection device for 2 seconds, apply the separation high pressure, and perform online monitoring and chiral separation on the chiral drug synthetic liquid.

[0019] The present invention provides a high-throughput online monitoring and analysis device and method for a chiral drug synthesis process, which is an analysis method for online monitoring of a chiral drug synthesis process that integrates a chiral drug synthesis reactor, an automatic sequence injection device, and a capillary electrokinetic chromatography detection technology, and carries out high-throughput online monitoring of the content and configuration changes of different enantiomers in the chiral drug synthesis process. The present invention helps to obtain accurate information on the kinetics of chiral drug synthesis reactions, provides support for the route design, precise regulation of chiral drug synthesis reactions, and the improvement of the synthesis efficiency of single chiral drugs, and provides a solid guarantee for the rationality and safety of chiral drugs in clinical applications. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] The present invention is further described in detail below with reference to the accompanying drawings and embodiments:

[0021] Figure 1 A structural diagram of a high-throughput online monitoring and analysis device for a chiral drug synthesis process provided by the present invention; wherein: a three-necked flask 1, a constant flow pump 2, a filter 3, a constant temperature magnetic stirrer 4, a three-way interface 5, a pressure regulating valve 6, a sample introduction capillary 7, a four-way interface 8, a solenoid valve 9, a syringe pump 10, a separation capillary 11, a buffer solution bottle 12, and a negative high-voltage power supply 13;

[0022] Figure 2Optimization of separation and analysis conditions of chiral drug synthesis solution in Example 1. (A) cyclodextrin type, (B) cyclodextrin concentration, (CD) buffer solution concentration, (EF) buffer solution pH, (GH) separation voltage;

[0023] Figure 3 This is the electrophoresis spectrum of 10 consecutive automatic injections of the standard mixed solution in Example 1;

[0024] Figure 4 The electrophoresis spectrum of the high-throughput online monitoring of the synthesis process of the chiral drug omeprazole in Example 2;

[0025] Figure 5 The effects of different reaction temperatures on the conversion rate of omeprazole sulfide (A), the conversion rate of iodobenzene diacetate (B), the yield of R-omeprazole (C), the yield of S-omeprazole (D), and the yield of iodobenzene (E) in the high-throughput online monitoring process of the synthesis of the chiral drug omeprazole in Example 3 are shown;

[0026] Figure 6 The effects of different catalyst contents on the omeprazole sulfide conversion rate (A), iodobenzene diacetate conversion rate (B), R-omeprazole yield (C), S-omeprazole yield (D), and iodobenzene yield (E) in the high-throughput online monitoring process of the chiral drug omeprazole synthesis in Example 3 are shown. DETAILED DESCRIPTION

[0027] The present invention will be further explained below in conjunction with specific implementation schemes, but the present invention is not limited thereto.

[0028] In view of the fact that the technology for detecting the synthesis process of chiral drugs in the prior art is still at the offline detection stage, this embodiment provides a high-throughput online monitoring and analysis device and method for the synthesis process of chiral drugs, wherein the device comprises: a chiral drug synthesis reaction unit, a sample delivery unit, and an automatic sequence injection unit;

[0029] The chiral drug synthesis reaction unit comprises a three-necked flask 1 and a constant temperature magnetic stirrer 4;

[0030] The present invention adopts a three-necked flask equipped with a temperature sensor as a chiral drug synthesis reaction container, and controls the temperature of the reactor by using a heating device such as an oil bath for high-temperature synthesis reactions.

[0031] The sample delivery unit includes a sample delivery U-shaped tube, a constant flow pump 2, a filter 3, a three-way interface 5, and a pressure regulating valve 6;

[0032] The present invention adopts flow gate injection technology as the automatic sequence injection method of the present invention. A small amount of reaction mixture (including reactants, intermediates, chiral products and by-products) is continuously drawn out from the reactor through a constant flow pump at one outlet of the three-necked flask, a part of which enters the automatic sequence injection device through the three-way interface 5 under the action of the back pressure device, and the other part returns to the original reaction container.

[0033] The automatic sequence injection unit comprises a sample introduction capillary 7, a four-way interface 8, a catheter 1, a catheter 2, a solenoid valve 9, a syringe pump 10 filled with a buffer solution, a separation capillary 11, a buffer solution device 12, a negative high-voltage power supply 13, a waste liquid collection bottle, and a ground electrode, wherein a detection window is opened on the separation capillary 11;

[0034] The three-necked flask 1 is placed on a constant temperature magnetic stirrer 4, and the two ports of the sample delivery U-shaped tube are immersed in the synthetic reaction liquid through the two reaction ports of the three-necked flask 1 respectively, wherein the filter 3 is installed at one port of the sample delivery U-shaped tube, and with the filter as the starting point, the three-way interface 5, the pressure regulating valve 6 and the constant current pump are sequentially installed on the sample delivery U-shaped tube body, one port of the three-way interface 5 is connected with the sample introduction capillary 7, the sample introduction capillary 7 and the separation capillary 11 are horizontally connected through the four-way interface 8, the separation capillary 11 is connected with the buffer solution bottle 12, the conduit 1 and the conduit 2 are vertically connected through the four-way interface 8, the injection pump 10 filled with buffer solution is connected with the conduit 1, the solenoid valve is installed on the conduit 1, the conduit 2 is connected with the waste liquid collection device, the negative high-voltage power supply is arranged on the buffer solution bottle side, and the grounding electrode is arranged on the waste liquid collection bottle side.

[0035] The chiral drug synthesis reaction liquid is filtered by the filter 3 under the action of the constant flow pump 2 and the pressure regulating valve 6, and a part of it enters the sample introduction capillary 7 through the three-way interface 5, and the other part circulates back to the three-necked flask 1. The four-way interface 8 is provided with four ports, and the injection pump 10 filled with buffer solution enters the waste liquid collection device through the catheter through the four-way interface 8 under the action of the electromagnetic valve 9.

[0036] Preferably, the filter 3 is provided with two layers of filter membranes with pore sizes of 2.7 μm and 0.7 μm respectively;

[0037] The inner diameter of the sampling capillary 7 is 50 μm, the outer diameter is 365 μm, and the length is 5 cm. The inner diameter of the separation capillary 11 is 50 μm, the outer diameter is 365 μm, and the length is 20 cm.

[0038] In addition, this embodiment also provides an analytical method for flux online monitoring of chiral drug synthesis process, which comprises:

[0039] 1) Carrying out the chiral drug synthesis reaction process in a three-necked flask placed on a constant temperature magnetic stirrer;

[0040] 2) The chiral drug synthesis reaction solution is filtered by a filter under the action of a constant flow pump and a pressure regulating valve, and the outflowing synthesis solution passes through a three-way interface, a part of which enters the sample introduction capillary under the back pressure of the pressure regulating valve, and the other part circulates back to the three-necked flask;

[0041] 3) The sample introduction capillary and the separation capillary are connected, and high voltage is applied to both ends of the separation capillary, so that the sample described in step 2) is electrically injected from the four-way interface into the separation capillary for separation and detection, and a capillary electrophoresis ultraviolet detector is used to perform real-time online continuous high time resolution separation and analysis detection on the sample to complete the detection of the synthesis process of the chiral drug.

[0042] 4) Automatic sequence injection device: open the solenoid valve to accumulate the chiral drug synthesis liquid at the four-way interface for 2 seconds, apply the injection voltage to allow the synthesis liquid to enter the separation capillary for 1 second; close the solenoid valve to flush the excess synthesis liquid into the waste liquid collection device for 2 seconds, apply the separation high pressure, and perform online monitoring and chiral separation on the chiral drug synthesis liquid.

[0043] The present invention combines capillary electrokinetic chromatography with an automatic sequential sampling device to achieve efficient separation and analysis of reactants, catalysts and chiral products in chiral drug synthesis solutions and automatic online monitoring of the entire process with high time resolution. Compared with existing offline detection methods, this method does not require sample pretreatment and cumbersome manual sampling steps, integrates chiral drug synthesis, online chiral separation and real-time analysis and detection, has a simple analysis and operation process, and can obtain accurate kinetic information of the chiral drug synthesis process.

[0044] The technical solution of the present invention is further described below through specific implementation details.

[0045] Example 1

[0046] The device provided by the present invention was used to evaluate the analytical performance of the proposed device and method using standard mixed solutions of omeprazole sulfide (Ome Sul), R-omeprazole (R-Ome), S-omeprazole (S-Ome), diacetic acid iodobenzene (PhI(OAc)2) and iodobenzene (PhI). The factors affecting online separation and detection were explored;

[0047] The resolution of chiral drugs in the process of continuous online detection of chiral drug synthesis is the key. By introducing appropriate chiral selectors into volatile buffer solutions, capillary electrokinetic chromatography can successfully separate chiral drug enantiomers. Among them, cyclodextrin (CD) is used as a chiral selector in this embodiment.

[0048] This example investigates the effects of several uncharged CDs (at a concentration of 25 mM) on the separation of (R,S)-Ome, including β-CD, methyl-β-CD, dimethyl-β-CD, and hydroxypropyl-β-CD. Figure 2 As shown in (A), baseline separation of R-Ome and S-Ome was achieved using methyl-β-CD as a chiral selector.

[0049] After selecting methyl-β-CD as the best chiral selector type, the effect of CD concentration on the migration time and separation of R-Ome and S-Ome was studied. Figure 2 (B) shows that the migration time and resolution of R-Ome and S-Ome increased slightly with increasing CD concentration. However, when the CD concentration exceeded 25 mM, the migration time and resolution began to decrease. Therefore, 25 mM methyl-β-CD was selected as the optimal concentration.

[0050] In addition, the effects of PB buffer concentration and pH in the range of 10 mM to 50 mM and pH 1.8 to 4.0 on the resolution and migration time were investigated. Figure 2 (CD) and Figure 2 Similarly, the effect of separation voltage between -3kV and -15kV was studied. Figure 2 (GH). Considering the analysis speed and separation degree of the analytes, the buffer and separation voltage of the subsequent experiments were optimized, which were 30mM PB (pH 2.2) and -10kV separation voltage, respectively. Therefore, the optimal separation analysis parameters were pH = 2.2, 30mM PB buffer, 25mM methyl-β-CD and -10kV separation voltage. In order to avoid the oxidation of Ome during the capillary electrokinetic chromatography separation and analysis, 5mM sodium disulfide was added to the buffer solution as an antioxidant.

[0051] Based on the above results, the optimal capillary electrokinetic chromatography separation and analysis conditions are pH = 2.2, 30mM PB buffer, 25mM methyl-β-CD, 5mM sodium disulfide and -10kV separation voltage.

[0052] The reproducibility study of the device of the present invention (such as Figure 3 ): Figure 3 The electropherograms of 10 consecutive automatic injections of the standard mixed solution are shown. In order to evaluate the accuracy of the proposed method, 10 consecutive runs of the mixed standard solution were performed under the optimal conditions, and a typical electropherogram was obtained. Figure 3As shown in the inset, the method achieved baseline separation of five analytes at a time resolution of 6 minutes. The results showed that the device of the invention had good reproducibility, and the relative standard deviations (RSDs) of the peak areas, migration times and resolutions of the five analytes were 1.3%, 0.98% and 1.1%, respectively. Therefore, the device of the invention can achieve quantitative detection of each analyte in the synthesis process of chiral drugs.

[0053] Example 2

[0054] The device and method provided by the present invention are used to continuously monitor the synthesis process of the chiral drug omeprazole in real time on-line, and the specific operation is as follows:

[0055] The synthesis process is carried out in a three-necked flask 1 with a temperature sensor. Taking the synthesis of the chiral drug omeprazole as an example, 3.29 g of Ome Sul (0.01 M), 70 mL of methyl chloroform, 2 mL of methanol and 0.66 g of anhydrous AlCl3 (0.005 M)) are added to a 250 mL three-necked flask 1. Stir for 15 min at a temperature range of 25-30°C. Then 3.22 g of PhI(OAc)2 (0.01 M) is added, and the reaction mixture is magnetically stirred at 400 rpm. Figure 1 The inset diagram shows the flow chart of the synthesis reaction of R-Ome and S-Ome. Under the action of the constant flow pump 2, the chiral drug synthesis reaction solution is filtered through the filter 3, and the pore sizes of the filter membrane are 2.7μm and 0.7μm respectively. The constant flow pump 2 circulates the reaction solution in the reactor at a flow rate of 10mL / min. At the same time, a part of the reaction solution enters the sample introduction capillary 7 (inner diameter / outer diameter is 50μm / 365μm, length is 5cm) through the three-way interface 5, and the other part returns to the original reaction synthesizer three-necked flask 1 and continues to participate in the reaction. After the chiral drug synthesis reaction mixture enters the sample introduction capillary 7, it is electrokinetically injected into the separation capillary 11 (inner diameter / outer diameter is 50μm / 365μm, Z total length / separation length is 20 / 15cm) for capillary electrokinetic chromatography analysis. The entire automated analysis process is controlled by a computer program for sampling (100nL / min) and capillary electrokinetic chromatography detection. Therefore, the real-time continuous online monitoring electrophoresis spectrum of the synthesis process of chiral drug omeprazole was obtained ( Figure 4 A).

[0056] Through careful analysis, the present invention can determine the enantiomeric excess of the two isomers of omeprazole at each specified time point, calculated according to formula (1):

[0057]

[0058] Wherein, ee (%) is the enantiomeric excess of R-Ome, [R-Ome] is the concentration of R-Ome at reaction time point t, and [S-Ome] is the concentration of S-Ome at reaction time point t.

[0059] Figure 4 B is the conversion curve of the reactants (Ome Sul and PhI(OAc)2) and the yield curve of the products (R-Ome, S-Ome and PhI), and the calculation formula is as follows:

[0060]

[0061]

[0062] Example 3

[0063] The device and method provided by the present invention are used to investigate the real-time online continuous monitoring of the synthesis process of the chiral drug omeprazole under conditions of different temperatures and different catalyst contents. The specific operation is as follows:

[0064] The synthesis process is carried out in a three-necked flask 1 with a temperature sensor. Taking the synthesis of the chiral drug omeprazole as an example, 3.29 g of Ome Sul (0.01 M), 70 mL of methyl chloroform, 2 mL of methanol and anhydrous AlCl3 (2.5 mol%, 5 mol%, 10 mol%) are added to a 250 mL three-necked flask 1. Stir for 15 min at different temperatures (5°C, 25°C, 45°C). Then, 3.22 g of PhI(OAc)2 (0.01 M) is added, and the reaction mixture is magnetically stirred at 400 rpm. Figure 1 The inset shows the flow chart of the synthesis reaction of R-Ome and S-Ome. Under the action of the constant flow pump 2, the chiral drug synthesis reaction solution is filtered through the filter 3, and the pore sizes of the filter membrane are 2.7μm and 0.7μm respectively. The constant flow pump 2 circulates the reaction solution in the reactor at a flow rate of 10mL / min. At the same time, a part of the reaction solution enters the sample introduction capillary 7 (inner diameter / outer diameter is 50μm / 365μm, length is 5cm) through the three-way interface 5, and the other part returns to the original reaction synthesizer three-necked flask 1 and continues to participate in the reaction. After the chiral drug synthesis reaction mixture enters the sample introduction capillary 7, it is electrokinetically injected into the separation capillary 11 (inner diameter / outer diameter is 50μm / 365μm, total length / separation length is 20 / 15cm) for capillary electrokinetic chromatography analysis. The entire automated analysis process is controlled by a computer program for sampling (100nL / min) and capillary electrokinetic chromatography detection. Therefore, a real-time continuous online monitoring electrophoresis spectrum of the synthesis process of the chiral drug omeprazole was obtained. The drug concentration corresponding to the electrophoresis spectrum was converted into the conversion rate of the reactant and the yield of the product by formula (2) and (3), and the curve was calculated and drawn.

[0065] like Figure 5 As shown in Figure 2, the conversion of the reactants is significantly affected by the reaction temperature. At lower temperatures (5°C), the reaction kinetics are slower, resulting in lower conversions. As the temperature increases to 45°C, the reaction rate accelerates, resulting in increased conversions of Ome Sul and PhI(OAc)2 ( Figure 5 A and 5B). However, once the temperature exceeded 25 °C, we noticed a sharp increase in the formation of peroxidation products. As the temperature was further increased, the yield of the total product gradually decreased ( Figure 5 CE). It can also be seen that at 45 °C, the ee value of the reactant was determined to be over 30%. In general, 45 °C was selected as the optimal reaction temperature. This choice not only maximizes the yield of S-Ome, but also helps maintain the purity and quality of the final product.

[0066] The amount of AlCl3 catalyst used plays a key role in promoting the reaction and improving the yield. Figure 6 As shown in the figure, when the amount of catalyst is small (2.5 mol%), its effect of promoting the reaction is not significant. With the increase of catalyst concentration, the yield of (R, S)-Ome shows an upward trend, which clearly shows that the catalyst has a positive role in promoting the formation of S-Ome. However, when the catalyst concentration exceeds 5 mol%, an abnormal phenomenon occurs, and instead of further improving the conversion rate and yield, they tend to decrease. The reason may be that the increase in the amount of AlCl3 leads to an increase in the acidity of the system. With the increase in acidity, the oxidation of sulfides becomes more and more difficult. The acidic environment is conducive to the formation of by-products or the generation of intermediates that compete with S-Ome, thereby reducing the total yield. In addition, the increase in the amount of catalytic addition did not lead to a significant increase in the reaction ee value. Therefore, considering the reaction kinetics, practical application and economic cost, 5 mol% was selected as the optimal amount of the catalyst.

[0067] In summary, the detection method proposed by the present invention has successfully realized the online monitoring and chiral separation of the synthesis of the chiral drug omeprazole based on EKC and automatic sequence sample introduction device. The analytical ability and practical feasibility of evaluating the synthesis process of omeprazole have been comprehensively studied. By effectively separating and detecting all the components involved, real-time feedback can be obtained, and more accurate control and optimization can be achieved. Therefore, the research of the present invention not only helps to improve the productive rate of the desired isomer, but also improves the overall efficiency of the synthesis process. The present invention has important guiding significance for the accurate control of the synthesis reaction of chiral drugs, and is of great significance to ensuring the clinical rationality and safe application of chiral drugs.

[0068] The detailed description of the present invention is written in a progressive manner, emphasizing the differences between the various implementations, and similar parts thereof can be referred to each other.

[0069] The embodiments of the present invention are described in detail above with reference to the accompanying drawings, but the present invention is not limited to the above embodiments, and various changes can be made within the knowledge scope of ordinary technicians in this field without departing from the purpose of the present invention.

Claims

1. A high-throughput online monitoring and analysis device for a chiral drug synthesis process, characterized in that: include: Chiral drug synthesis reaction unit, sample delivery unit, automatic sequence injection unit; The chiral drug synthesis reaction unit comprises a three-necked flask (1) and a constant temperature magnetic stirrer (4); The sample delivery unit comprises a sample delivery U-shaped tube, a constant flow pump (2), a filter (3), a three-way interface (5), and a pressure regulating valve (6); The automatic sequence injection unit comprises a sample introduction capillary (7), a four-way interface (8), a first conduit, a second conduit, a solenoid valve (9), a syringe pump (10) filled with a buffer solution, a separation capillary (11), a buffer solution bottle (12), a negative high-voltage power supply (13), a waste liquid collection bottle, and a grounding electrode, wherein a detection window is provided on the separation capillary (11); The three-necked flask (1) is placed on a constant temperature magnetic stirrer (4), and the two ends of the sample delivery U-shaped tube are immersed in the synthetic reaction liquid through the two reaction ports of the three-necked flask (1), wherein the filter (3) is installed at one end of the sample delivery U-shaped tube. With the filter as the starting point, a three-way interface (5), a pressure regulating valve (6) and a constant current pump are sequentially installed on the sample delivery U-shaped tube body, one end of the three-way interface (5) is connected to a sample introduction capillary (7), the sample introduction capillary (7) and the separation capillary (11) are horizontally connected through a four-way interface (8), the separation capillary (11) is connected to a buffer solution bottle (12), the conduit 1 and the conduit 2 are vertically connected through the four-way interface (8), the injection pump (10) filled with buffer solution is connected to the conduit 1, the solenoid valve is installed on the conduit 1, the conduit 2 is connected to a waste liquid collection device, the negative high-voltage power supply is arranged on the side of the buffer solution bottle, and the grounding electrode is arranged on the side of the waste liquid collection bottle.

2. The high-throughput online monitoring and analysis device for a chiral drug synthesis process according to claim 1, characterized in that: A temperature detector is placed in a reaction port of the three-necked flask (1).

3. The high-throughput online monitoring and analysis device for a chiral drug synthesis process according to claim 1, characterized in that: The filter (3) is provided with two layers of filter membranes with pore sizes of 2.7 μm and 0.7 μm respectively.

4. The high-throughput online monitoring and analysis device for a chiral drug synthesis process according to claim 1, characterized in that: The inner diameter of the sample introduction capillary (7) is 50 μm, the outer diameter is 365 μm, and the length is 5 cm; the inner diameter of the separation capillary (11) is 50 μm, the outer diameter is 365 μm, and the length is 20 cm.

5. An analytical method for online monitoring of a chiral drug synthesis process using the device according to any one of claims 1 to 4, characterized in that: include: 1) Carry out the chiral drug synthesis reaction process in a three-necked flask placed on a constant temperature magnetic stirrer; 2) The chiral drug synthesis reaction liquid is filtered by the filter under the action of the constant flow pump and the pressure regulating valve. The outflowing synthesis liquid passes through the three-way interface. A part of it enters the sample introduction capillary under the back pressure of the pressure regulating valve and accumulates at the four-way interface. The other part circulates back to the three-necked flask to continue the reaction. 3) Add negative high voltage to the side of the buffer solution bottle, and ground the side of the waste liquid collection bottle to form a voltage difference between the four-way interface and the buffer solution bottle, so that the synthetic liquid is electrically injected from the four-way interface into the separation capillary for separation and detection. At the detection window, a capillary electrophoresis ultraviolet detector is used to perform real-time online continuous high-time resolution separation and analysis detection on the sample to complete the detection of the synthesis process of the chiral drug; 4) Open the solenoid valve to allow the synthetic liquid to accumulate at the four-way interface for 2 s. Apply the injection voltage to allow the synthetic liquid to enter the separation capillary for 1 s. Close the solenoid valve to flush the excess synthetic liquid into the waste liquid collection device for 2 s. Apply separation high pressure to perform online monitoring and chiral separation of the chiral drug synthetic liquid.

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