Automatic experiment method capable of covering more reaction types

Abstract

The invention discloses an automatic experiment method capable of covering more reaction types, and belongs to the technical field of chemical synthesis. The unit operation is divided into material transmission (solid-liquid-gas feeding), heat transfer (evaporation and condensation), treatment processes (distillation, extraction and adsorption) and thermal processes (temperature, pressure and liquefaction) according to chemical operation units. All equipment and mechanisms are operated, the accuracy of feeding, reaction and the like can be kept, and the conditions of cross contamination and work errors are reduced; the device has the advantages that the device is simple in structure and convenient to operate, harm to experimenters caused by toxic substances can be effectively reduced without manual operation, all-weather use can be achieved through programs and equipment, a Python instruction can be directly copied and used, different reactants can be prepared according to different requirements, and compared with labor, the device has the advantages that the cost is lower, and benefits are higher.

Description

Technical Field

[0001] The invention relates to the technical field of chemical synthesis, and in particular to an automated experimental method capable of covering more reaction types. Background Art

[0002] Organic synthesis occupies an important position in the discipline of chemistry. The effective transformation and application of its research results and knowledge have significantly improved the development of industry and people's living standards. At present, outside of a few fields such as peptide and oligonucleotide chemistry, the automation of chemical synthesis is limited to large-scale customized industrial processes, and laboratory-scale and discovery-scale synthesis is still mainly a manual process.

[0003] These areas are often defined by the ability to synthesize complex molecules through serial iterations of similar reaction sets, allowing products to be synthesized through the automation of relatively small, standardized reactions. Recent advances in areas such as flow chemistry synthesis, oligonucleotide synthesis, and iterative cross-coupling are expanding the number of compounds that can be synthesized through automated methods. However, there are no universal and interoperable standards that would enable automation of other organic chemical syntheses more generally.

[0004] In the traditional process of synthesizing organic compounds, a single person cannot carry out the experimental process continuously around the clock, and cannot effectively handle the synthesis of compounds of different processes (people need to be trained to complete it); people who work on stabilizing the process flow often perform repetitive operations for a long time, and there are often many unstable quotations during the feeding, reaction control, and reaction treatment processes, resulting in unstable material control accuracy.

[0005] Based on this, it is necessary to propose an automated experimental operation that can perform multiple types of reactions. Summary of the invention

[0006] The object of the present invention is to provide an automated experimental method that can cover more reaction types, so as to solve the above technical problems to at least a certain extent, so as to improve the accuracy during operation and improve the workflow.

[0007] To achieve the above object, the present invention provides the following technical solutions: including unitized operation, wherein the unitized operation is divided into material transmission (solid-liquid-gas feeding), heat transfer (evaporation, condensation), treatment process (distillation, extraction, adsorption), thermal process (temperature, pressure, liquefaction), mechanical process (solid / paste conveying, crushing, screening) according to the chemical operation unit; Unitized operations also include the feeding stage: involving the addition of solids, liquids, gases, and other types of reagents such as pastes; Material transfer stage: involves various mechanisms driving the transfer of materials between different devices, that is, the material transfer between different systems such as reaction systems, post-processing bodies, and subsequent material collection; Material reaction stage: involving quenching, reflux, crystallization, filtration, extraction, using different devices to meet process requirements; Preferably, the automated control unit includes structures such as a syringe pump, an electronic balance, a switching valve, an overhead stirrer, a magnetic stirrer, a conductivity meter, a vacuum pump, and a gas valve.

[0008] Preferably, the automation control unit also includes filters, high and low temperature circulation pumps, oxygen sensors, pH meters, peristaltic pumps, thermometers, robotic arms, PDU controllers, vacuum distillation, switch controllers, flow mixers, etc. combined with controllers capable of communication control, that is, the central control module is connected to the industrial control / PC.

[0009] Preferably, the preparation for laying out the automated synthesis process can be completed by organically combining the experimental process flow.

[0010] Preferably, the unitized operation adopts a modular setting to reduce the complexity of pipeline connections between instruments and equipment as an optimization step.

[0011] Preferably, the modularization includes a liquid drive module (pump valve), a comprehensive sampling platform (electronic balance, robotic arm), a reaction module (container, stirring, temperature control, sensor), an extraction and liquid separation module (container, stirring, conductivity), a filtration and drying module (container, stirring, filter element, negative pressure), a vacuum distillation module (container, stirring, negative pressure, condensation), a water and oxygen module (gas source, negative pressure source, gas valve, oxygen sensor) and a comprehensive analysis platform (liquid phase, mass spectrometry, infrared sensor).

[0012] Preferably, the unitized operation also includes Python instructions, and the instruction type is specified, so that a fixed type of instruction file can be formed, which reduces the difficulty of writing and adapts the transplantation and copying of the unitized operation to different types of automated synthesis reactions.

[0013] Preferably, the Python instructions include raw material setting instructions, instrument setting instructions, mass transfer instructions, instrument control instructions, waiting instructions, judgment instructions, instruction sets, module instructions and cleaning instructions.

[0014] Preferably, the waiting instruction stage includes mass transfer waiting, instrument status waiting and judgment waiting.

[0015] Preferably, the allocation files related to equipment, quantity and type of raw materials currently require manual settings and physical pipeline connections between equipment.

[0016] Compared with the prior art, the present invention has the following beneficial effects: When the present invention is used, Python instructions are used for staged control, and further, the signal output of each module is used to enable each device and mechanism to operate, so that the accuracy of feeding, reaction, etc. can be maintained, and cross contamination and work errors can be reduced; no manual operation is required, which can effectively reduce the harm of toxic substances to experimenters; the program and equipment can be used around the clock to improve the work thread; the Python instructions can be directly copied and used, and different reactants can be prepared according to different needs, thereby improving work efficiency, lowering the cost and increasing the benefits compared to manual labor. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the accompanying drawings required for describing the embodiments will be briefly introduced below. Obviously, the accompanying drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other accompanying drawings can be obtained based on these accompanying drawings without paying creative work.

[0018] Figure 1 This is a schematic diagram of the unit operation process of this embodiment; Figure 2 The schematic diagram of the process flow of synthesizing aspirin in this embodiment; Figure 3 This is a schematic diagram of the connection pipelines of the module equipment when aspirin is used in this embodiment; Figure 4 This is a schematic diagram of the process for synthesizing 2-methyl-2-hexanol in this embodiment; Figure 5 This is a schematic diagram of the module equipment connection pipeline when using 2-methyl-2-hexanol in this embodiment; Figure 6 This is a schematic diagram of the process for synthesizing p-hydroxybiphenyl in this embodiment; Figure 7 This is a schematic diagram of the connecting pipelines of the module equipment for synthesizing p-hydroxybiphenyl in this embodiment. DETAILED DESCRIPTION

[0019] The following will be combined with the drawings in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0020] For example, see Figure 1-7The present invention provides a technical solution: an automated experimental method that can cover more reaction types, including unitized operation, which is divided into material transmission (solid-liquid-gas feeding), heat transfer (evaporation, condensation), treatment process (distillation, extraction, adsorption), thermodynamic process (temperature, pressure, liquefaction) according to the chemical operation unit, and an automated control unit. The automated control unit includes a syringe pump, an electronic balance, a switching valve, an overhead stirring, a magnetic stirring, a conductivity meter, a vacuum pump, and a gas valve. The automated control unit also includes a filter, a high and low temperature circulation pump, an oxygen sensor, a pH meter, a peristaltic pump, a thermometer, a robotic arm, a PDU controller, a vacuum distillation, a switch controller, a flow mixer, etc., combined with a controller capable of communication control, that is, the central control module is connected to the industrial control / PC, and the preparation for laying the automated synthesis process can be completed by organically combining according to the experimental process flow.

[0021] In this application, all material transfers are fixed-point transfers, and the transfer method varies according to the requirements of the chemical reaction (for liquids, injection pumps, switching valves, and pipeline connections are used for transmission; for solids, robotic arms, three-axis robots, and solid containers are used to complete fixed-point transfers).

[0022] The above transmission methods are all carried out by machines, without the need for manual filling or delivery, in order to reduce errors caused by human intervention, and ensure the accuracy of material transmission through the rigor and precision of the machine.

[0023] The name of the equipment in this application document is "fully automatic molecular synthesis workstation". The "fully automatic molecular synthesis workstation" is connected and used by a variety of equipment and instruments. The instruments required for chemical reactions are combined with the corresponding instrument operation procedures and are divided into modules according to chemical unit operations.

[0024] Filter: used for separation of solid-liquid phases produced during the experiment; high and low temperature circulation pump: providing and controlling the reaction heat source during the experiment; peristaltic pump / syringe pump: usually used as a liquid feeding device; vacuum distillation: usually composed of a vacuum pump, a reactor container, and a condensing device, used for vacuum distillation operations in chemical experiments; flow mixer: a type of reaction container; PDU, switch controller: equipment controller; oxygen sensor: monitors the oxygen content in the reactor, used for anaerobic systems; pH meter: detects the pH value during the reaction; thermometer: detects the temperature of the reaction system.

[0025] The above structures are included but not limited to in the "Fully Automatic Molecular Synthesis Workstation", but are necessary equipment.

[0026] Supplementary functions of each device: Syringe pump / peristaltic pump, liquid extraction / injection, cooperate with switching valve to complete liquid fixed-point transmission. Switching valve, set each liquid material transmission point. Container: including various types of glass containers / flow mixers, etc., used for reaction and post-processing material loading. Electronic balance: used for weighing materials other than gas removal and liquid phase to determine the amount of material added. Overhead stirring / magnetic stirring; that is, mechanical stirring provides a power source for material mixing. Conductivity instrument / oxygen sensor / pH meter / thermometer / and other sensors: detect various parameters in the reaction process, such as conductivity / oxygen content / pH value / temperature / and corresponding parameters. Vacuum pump: negative pressure source of the reaction system, and provides a negative pressure environment for processes such as filtration and reduced pressure distillation. Robotic arm: solid material transmission, device transfer, etc. PDU / switch controller: adapt to different equipment (instruments that do not support protocol control) control.

[0027] See also Figure 2 and Figure 3 In a preferred embodiment, the automatic synthesis of aspirin is proposed. According to the traditional aspirin synthesis process description: "1. Place 1.38 g of salicylic acid, 1.6 mL-1.8 mL of acetic anhydride and 4 drops of phosphoric acid in a dry 25 mL conical flask, add a magnetic stirrer, heat and shake for 5 min-8 min in a water bath at 70-80 ° C, cool and filter to obtain crude aspirin." The unit operations obtained by parsing the reaction file are: 1. Feeding; 2. Mixing; 3. Heating / cooling; 4. Crystallization; 5. Filtration and other unit operations. The process flow of synthesizing aspirin is simplified as follows: Figure 6 , combined with the unit operation configuration equipment to form the corresponding modules: 1. Central control module; 2. Liquid drive module; 3. Reaction module; 4. Filtration module. According to the process flow chart, the module equipment is connected to the pipeline to obtain Figure 3 .

[0028] In the second embodiment, the unitized operation also includes a feeding stage: involving the addition of other types of reagents such as solid, liquid, gas, and paste; Material transfer stage: It involves various mechanisms driving the transfer of materials on different devices, that is, the material transfer between different systems such as reaction systems, post-processing bodies, and subsequent material collection. The unit operation adopts modular settings to reduce the complexity of pipeline connections between instruments and equipment. It is an optimization step. The modularization includes liquid drive module (pump valve), comprehensive sampling platform (electronic balance, robotic arm), reaction module (container, stirring, temperature control, sensor), extraction and separation module (container, stirring, conductivity), filtration and drying module (container, stirring, filter element, negative pressure), vacuum distillation module (container, stirring, negative pressure, condensation), water and oxygen module (gas source, negative pressure source, gas valve, oxygen sensor) and comprehensive analysis platform (liquid phase, mass spectrometry, infrared sensor).

[0029] Material reaction stage: involves quenching, reflux, crystallization, filtration, and extraction, and uses different devices to meet process requirements. Unitized operations also include Python instructions. By specifying instruction types, fixed types of instruction files can be formed to reduce the difficulty of writing. At the same time, the unitized operations can be adapted to be transplanted and copied to different types of automated synthesis reactions. Python instructions include raw material setting instructions, instrument setting instructions, mass transfer instructions, instrument control instructions, waiting instructions, judgment instructions, instruction sets, module instructions, and cleaning instructions. The waiting instruction stage includes mass transfer waiting, instrument status waiting, and judgment waiting.

[0030] The various process flows in this application document are different, but the unit operations in different process flows are basically the same. Whether it is the synthesis of p-hydroxybiphenyl or aniline, it involves feeding operations and reaction operations. The difference is that the materials added are different and the amount added is different, which can be understood as different raw material setting instructions, but the mass transfer instructions are the same. They are all adding liquids, so the instrument operation instructions are also the same. They all need to control the pump valve to complete the addition and control the high and low temperature circulation pump to complete the temperature control. These instructions are edited into an instruction set (library) and can be called according to the process flow settings. There is no concept of order and influence. The difference lies in the inclusion and inclusion of instructions. Often a module instruction includes an instruction set and other instructions, and the instruction set includes all instructions except module instructions.

[0031] The python instruction is one of the instruction types used in this application document, and other programming language instructions can also be used.

[0032] Material catalysis stage: heating / cooling, mixing, cleaning, and testing are different stages before, during, and after the reaction. The allocation files involving equipment, quantity and type of raw materials currently require manual settings and physical pipeline connections between equipment.

[0033] See also Figure 4 and Figure 5 In a preferred embodiment, the automatic synthesis of 2-methyl-2-hexanol is proposed. According to the traditional 2-methyl-2-hexanol synthesis process description: "1. Install a spherical condenser and a dropping funnel on a 100mL three-necked flask, and install a calcium chloride drying tube on the condenser and the dropping funnel. Put 1.5g of magnesium chips and 10mL of anhydrous ether in the flask. Add 6.5mL of n-butyl bromide and 10mL of anhydrous ether to the dropping funnel and mix well. First add 3-4mL of the mixed solution to the three-necked flask to initiate the reaction, ..., dry with anhydrous potassium carbonate to obtain the product ether solution." The unit operations obtained by parsing the reaction file are: 1. Feeding; 2. Flow mixing; 3. Heating / cooling; 4. Reflux; 5. Extraction and other unit operations. The corresponding modules of the equipment configuration combined with the unit operations are: 1. Central control module; 2. Liquid drive module; 3. Reaction module; 4. Flow module; 5. Extraction module. According to the process flow chart, the module equipment is connected with pipelines to obtain Figure 5 .

[0034] Embodiment 3 See also Figure 6 and Figure 7 In a preferred embodiment, the automatic synthesis of p-hydroxybiphenyl is proposed, according to the traditional p-hydroxybiphenyl synthesis process description: “0.13 g phenylboronic acid, 0.42 g K2CO3, and 0.22 g 4-iodophenol were mixed in a 50 mL round bottom flask and then 10 mL of water was added. … The solid was dissolved in methanol and the Pd / C was removed by filtration. It was recrystallized from a 50:50 methanol:water mixture. Purity: 55–80% 4-phenylphenol (p-hydroxybiphenyl).” The unit operations obtained by analyzing the reaction file are: 1. Feeding; 2. Heating / cooling; 3. Filtration; 4. Crystallization and other unit operations. According to the process flow chart, the module equipment is connected to the pipeline to obtain Figure 7 .

[0035] In the description of the present invention, it is necessary to understand that the terms "coaxial", "bottom", "one end", "top", "middle", "the other end", "upper", "one side", "top", "inside", "front", "center", "both ends" and the like indicate orientations or positional relationships based on the orientations or positional relationships shown in the accompanying drawings, and are only for the convenience of describing the present invention and simplifying the description, and do not indicate or imply that the device or element referred to must have a specific orientation, be constructed and operated in a specific orientation, and therefore should not be understood as a limitation on the present invention.

[0036] In the present invention, unless otherwise clearly stipulated and limited, the terms such as "installation", "setting", "connection", "fixation" and "screw-on" should be understood in a broad sense. For example, it can be a fixed connection, a detachable connection, or an integral one; it can be a mechanical connection or an electrical connection; it can be a direct connection or an indirect connection through an intermediate medium; it can be the internal connection of two elements or the interaction relationship between two elements. Unless otherwise clearly defined, ordinary technicians in this field can understand the specific meanings of the above terms in the present invention according to the specific circumstances.

[0037] Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions and variations may be made to the embodiments without departing from the principles and spirit of the present invention, and that the scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. An automated experimental method that can cover more reaction types, including unitized operations, characterized in that: The unitized operation is divided into material transmission (solid, liquid and gas feeding), heat transfer (evaporation, condensation), treatment process (distillation, extraction, adsorption), thermal process (temperature, pressure, liquefaction) and mechanical process (solid / paste transportation, crushing, screening) according to the chemical operation unit; Unit operations also include unit operations that follow the basic laws of fluid dynamics (fluid transport, sedimentation, filtration, solid fluidization, etc.), unit operations that follow the basic laws of heat transfer (heating, cooling, condensation, evaporation, etc.), unit operations that follow the basic laws of mass transfer (distillation, absorption, extraction, crystallization, drying, membrane separation, etc.), and involve the addition of other types of reagents such as solids, liquids, gases, and pastes; Material transfer stage: involves various mechanisms driving materials (phases that change with the progress of chemical reactions) to be transferred between different devices, that is, material transfer between different systems such as reaction systems, post-processing processes, and subsequent material collection operations; Material reaction stage: involves quenching, reflux, crystallization, filtration, extraction, and uses different devices to meet process requirements.

2. The automated experimental method according to claim 1, which can cover more reaction types, is characterized in that: The automatic control unit includes a syringe pump, an electronic balance, a switching valve, an overhead stirrer, a magnetic stirrer, a conductivity meter, a vacuum pump, a gas valve and other structures.

3. The automated experimental method according to claim 2, which can cover more reaction types, is characterized in that: The automation control unit also includes filters, high and low temperature circulation pumps, oxygen sensors, pH meters, peristaltic pumps, thermometers, robotic arms, PDU controllers, vacuum distillation, switch controllers, flow mixers, etc. combined with controllers capable of communication control, that is, the central control module is connected to the industrial control / PC.

4. The automated experimental method according to claim 1, which can cover more reaction types, is characterized in that: By organically combining the experimental process flow, the preparation for laying the automated synthesis process can be completed.

5. The automated experimental method capable of covering a large number of reaction types according to claim 1, characterized in that: The unit operation adopts a modular setting to reduce the complexity of pipeline connections between instruments and equipment as an optimization step.

6. The automated experimental method capable of covering more reaction types according to claim 5, characterized in that: The modularization includes a liquid drive module (pump valve), a comprehensive injection platform (electronic balance, robotic arm), a reaction module (container, stirring, temperature control, sensor), an extraction and liquid separation module (container, stirring, conductivity), a filtration and drying module (container, stirring, filter element, negative pressure), a vacuum distillation module (container, stirring, negative pressure, condensation), a water oxygen module (gas source, negative pressure source, gas valve, oxygen sensor) and a comprehensive analysis platform (liquid phase, mass spectrometry, infrared sensor) ； The liquid drive module, which consists of a syringe pump, a peristaltic pump, and a multi-channel switching valve, is used to add liquid materials during chemical reactions; The integrated sample introduction platform is basically composed of an electronic balance, a mechanical arm (or other transmission device), and a material sampler (including but not limited to solid, paste, oily and other sampler types), and is used for adding liquid-phase materials; The reaction module usually consists of a reaction vessel, a mechanical mixing device (stirring), a temperature control device (high and low temperature circulation pump), and various sensors (temperature, pH, oxygen, turbidity meter, etc.). This module is usually used in the reaction process of chemical synthesis. The more equipment and instruments are configured, the more reaction types it can adapt to. Extraction and liquid separation usually only requires three devices: container, mechanical mixing device, and conductivity meter. Together with the liquid drive module, this can realize the liquid separation and extraction operation in chemical reactions and achieve liquid-liquid separation. The filter drying module is usually composed of a container, a mechanical stirring device, a filter device, a negative pressure source, a heat source, etc., and is mainly used to achieve solid-liquid separation in chemical reactions and the required drying; The vacuum distillation module is usually composed of a container, a mechanical stirring device, a heating source, a condenser, and a negative pressure source. It is generally used for concentration operations in chemical synthesis and is considered a separation device. The water-oxygen module is mainly composed of gas sources (inert gases, reaction gases, etc.), gas valves, and sensors (various gas sensors). It is used to maintain the atmosphere in the reaction system and add reaction gases. The comprehensive analysis platform is actually various large-scale detection instruments used for the analysis of synthetic products.

7. The automated experimental method capable of covering a large number of reaction types according to claim 1, characterized in that: Unitized operations also include Python instructions, which specify instruction types and can form fixed-type instruction files, thereby reducing the difficulty of writing and adapting the transplantation and copying of unitized operations to different types of automated synthesis reactions.

8. The automated experimental method capable of covering more reaction types according to claim 7, characterized in that: The Python instructions include raw material setting instructions, instrument setting instructions, mass transfer instructions, instrument control instructions, waiting instructions, judgment instructions, instruction sets, module instructions and cleaning instructions.

9. An automated experimental method capable of covering more reaction types according to claim 8, characterized in that: The waiting instruction stage includes mass transfer waiting, instrument status waiting and judgment waiting.

10. The automated experimental method capable of covering a large number of reaction types according to claim 1, characterized in that: Currently, the allocation files involving equipment, raw material quantity and type require manual settings and physical pipeline connections between equipment.

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