Continuous synthesizer and control system thereof

Abstract

The invention discloses a continuous synthesizer and a control system thereof.The continuous synthesizer comprises a box body, an activation mechanism and a reaction mechanism, a partition plate is fixedly arranged in the box body and divides the box body into a first cavity and a second cavity, and an emergency stop switch is fixedly arranged on the box body; a positive pressure nitrogen pressure regulating valve, an activated positive pressure nitrogen pressure regulating valve and a tilt cylinder compressed air pressure regulating valve are fixedly arranged on the outer side wall of the box body at intervals in the height direction of the box body, a plunger pump is fixedly arranged in the first cavity, and a plurality of rotating core valves are fixedly arranged in the first cavity and located above the plunger pump. The plunger pump, the rotary core valve, the activation mechanism and the reaction mechanism are communicated through pipelines, and a solvent valve is further fixedly arranged on the box body and used for controlling liquid adding of the reaction mechanism. The technical problems of large labor force and low scientific research efficiency are solved.

Description

Technical Field

[0001] The invention belongs to the technical field of full-automatic control of biopharmaceuticals, and in particular relates to a continuous synthesizer and a control system thereof. Background Art

[0002] The continuous synthesizer is an advanced chemical instrument. It is mainly designed to allow reactants to flow continuously in the reactor and undergo chemical reactions during the flow. This instrument can efficiently synthesize the target compound and achieve rapid separation and purification of the product. The working principle is that the reactants continuously enter the reactor through the feed port, and chemical reactions occur in the reactor to generate the target product. The product then flows out continuously through the discharge port to achieve continuous production. At the same time, the continuous synthesizer can also accurately control the reaction conditions, such as temperature and pressure, to ensure the smooth progress of the reaction and the quality of the product. The continuous synthesizer plays an important role in the fields of chemistry, biology, and pharmacy, providing strong support for scientific research and industrial production.

[0003] Polypeptides are compounds composed of multiple amino acids linked by peptide bonds in a certain order, and are also produced by continuous synthesizers. With the development of peptide science, scientists have also put forward higher requirements for continuous synthesizers, thus driving the development of synthesizers. The full automation of synthesizers can greatly reduce the labor of scientific researchers and improve scientific research efficiency. It is a major development direction of synthesizers in the future. Summary of the invention

[0004] The present invention provides a continuous synthesizer and a control system thereof to solve the existing technical problems of large labor force and low scientific research efficiency.

[0005] In view of this, the present invention provides a continuous synthesizer and its control system, comprising a box body with a hollow interior and an opening on one side, an activation mechanism arranged on the outer top surface of the box body, and a reaction mechanism arranged in the box body, the box body is fixedly provided with a partition arranged along its height direction, and the box body is divided into a first chamber and a second chamber, the box body is fixedly provided with an emergency stop switch, and a positive pressure nitrogen pressure regulating valve, an activation positive pressure nitrogen pressure regulating valve, and a swing cylinder compressed air pressure regulating valve are fixedly provided on the outer side wall of the box body at intervals along its height, a plunger pump is fixedly provided in the first chamber, and a plurality of rotary core valves are fixedly provided above the plunger pump in the first chamber, the plunger pump, the rotary core valve, the activation mechanism, and the reaction mechanism are connected by a pipeline, and a solvent valve is also fixedly provided on the box body, and the solvent valve is used to control the liquid addition of the reaction mechanism.

[0006] Optionally, the activation mechanism comprises a plurality of activation bottles, and the plurality of activation bottles are evenly arranged and detachably connected to the outer top surface of the box body.

[0007] Optionally, the reaction mechanism includes a reactor that is detachably arranged in the second chamber along the height direction of the box body, the reactor is hollow inside and is connected to a plunger pump and an activation bottle through a pipeline, the top surface of the reactor is fixedly provided with a solvent interface, and the bottom surface is fixedly provided with a solvent outlet, solvent tubes are respectively extended into the solvent interface and the solvent outlet, and the two solvent tubes are connected to the interior of the reactor.

[0008] Optionally, filter plates are detachably provided on the top and bottom ends of the reactor.

[0009] Optionally, a chromatography column is further provided on one side of the housing, and the chromatography column is used for continuous flow reaction.

[0010] Optionally, a UV detector is fixedly provided on the box.

[0011] Optionally, a transparent protective cover is also provided outside the box.

[0012] Optionally, a control system is provided on the box, and the control system is used to control the operation of the continuous synthesizer.

[0013] It can be seen from the above technical solutions that the embodiments of the present invention have the following advantages: When in use, after installing all the components, turn on the power, click the mouse on the left side of the "Manual Mode" interface, and the interface will switch to the manual mode interface; then add a method, add a task first, in the method interface, use the "Add" function to add the required task, click the "Add" button, a window will pop up, edit the method name in this window, click Confirm, the newly added method will be displayed in the list on the left, click "Edit Method Process and Parameters" below, an editing window will pop up; then add method steps, select "Add Category" in the lower left corner, edit the method category, such as DMF liquid addition, click "Add Process" in the lower left corner, a process parameter window will pop up, select the basic process in this window, select the side process to be executed, enter the required liquid addition volume and pipe blowing time in the process parameter window, click Confirm to complete the basic process parameter setting, click Save to complete the method task editing. Create a new project: Select "+ Category" under the project, and the "Project Category" window will pop up. Enter the project category name in this window and click "OK". The newly created project category will be displayed in the "Project Category". Select the newly created category and click "+ Project" in the lower left corner to create a new project. Enter the project (secondary project) name and click "OK". The newly created project will be displayed in the "Project Category". Specific information is displayed on the right side of the project: such as amino acid information, resin name, substitution value, weight, whether the amino acid ends with a carboxyl or amino group, etc. Click "Modify" to enter the project information modification window. Fill in the project information in the window: resin name, substitution value, weight, scale, planned output, amino acid concentration, amino acid ending method and remarks. You can also import information from previously created project batches. Amino acid pre-method sequence, in this window, add amino acids in sequence according to the process, as well as the corresponding methods for amino acids. Enter the software homepage again, click the "Run Program" interface in the lower left corner, and then click Select Project to pop up the project selection interface. Double-click the project to be selected to pop up the project batch confirmation box. In this interface, you can reconfirm the project data, add / insert / modify the length of the amino acid sequence, and then run a method separately. You can also query the project operation record or system operation record, and you can also back up the data. The entire synthesizer is controlled by a computer, which greatly reduces labor and improves scientific research efficiency. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] The present invention is further described in detail below in conjunction with the accompanying drawings and specific implementation methods.

[0015] Figure 1 It is a schematic diagram of the overall structure of the present invention.

[0016] Figure 2 It is a schematic diagram of the overall left side structure and right side structure of the present invention.

[0017] Figure 3It is a schematic diagram to show part of the structure of the reactor.

[0018] Description of Reference Numerals 1. Box body; 11. Partition; 12. First chamber; 13. Second chamber; 14. Emergency stop switch; 15. Protective cover; 2. Activation mechanism; 21. Activation bottle; 3. Reaction mechanism; 31. Reactor; 32. Quick-release clamp; 33. Solvent interface; 34. Solvent outlet; 35. Filter plate; 4. Chromatographic column; 5. Pressure regulating valve; 51. Positive pressure nitrogen pressure regulating valve; 52. Activation positive pressure nitrogen pressure regulating valve; 53. Swing cylinder compressed air pressure regulating valve; 6. Plunger pump; 7. Rotary core valve. DETAILED DESCRIPTION

[0019] In order to make the technical scheme of the present invention better understood by the personnel of the technical field, the technical scheme in the embodiment of the present invention is clearly and completely described below. Obviously, the described embodiment is only a part of the embodiment of the present invention, rather than all the embodiments. Based on the embodiment in the present invention, all other embodiments obtained by ordinary technicians in the field without making creative work are within the scope of protection of the present invention. Unless otherwise specified, various raw materials, reagents, instruments and equipment used in the present invention can be purchased from the market or can be prepared by existing methods.

[0020] Reference Figure 1 A continuous synthesizer includes a housing 1, an activation mechanism 2, a reaction mechanism 3, and a chromatography column 4. The housing 1 is hollow inside and has an opening on one side. A partition 11 is fixedly provided inside the housing 1. The partition 11 is arranged along the height direction of the housing 1 and divides the housing 1 into a first chamber 12 and a second chamber 13. An emergency stop switch 14 is fixedly provided on the outer wall of the housing 1, and a transparent protective cover 15 is provided on the outer cover of the housing 1. The activation mechanism 2 is arranged on the outer top surface of the housing 1 for amino acid activation. The reaction mechanism 3 is arranged in the second chamber 13 for amino acid synthesis reaction. The chromatography column 4 is arranged on one side outside the housing 1 for continuous flow reaction.

[0021] Reference Figure 1-Figure 3, a pressure regulating valve 5 is fixedly arranged on the outer wall of the box 1 away from the chromatography column 4, which is used to adjust the pressure in the box 1. The pressure regulating valve 5 includes a positive pressure nitrogen pressure regulating valve 51, an activated positive pressure nitrogen pressure regulating valve 52, and a swing cylinder compressed air pressure regulating valve 53, and the three are arranged in sequence from top to bottom along the height of the box 1. A plunger pump 6 is fixedly arranged at the bottom end of the first chamber 12, and a plurality of rotary core valves 7 are fixedly arranged above the plunger pump 6 in the first chamber 12. The number of rotary core valves 7 in this embodiment is 11, which are used for solvent quantification and pipetting. The activation mechanism 2 includes an activation bottle 21, and the number of the activation bottles 21 is multiple, which is 24 in this embodiment, and the activation bottles 21 are evenly arranged on the outer top surface of the box 1, and are detachably connected to the outer top surface of the box 1. The plunger pump 6 is connected to the rotary core valve 7 through a pipeline, the rotary core valve 7 is connected to the activation bottle 21 through a pipeline, and the activation bottle 21 is also connected to the reaction mechanism 3 through a pipeline. The box body 1 is also provided with a solvent valve (not shown in the figure), and the solvent valve controls the plunger pump 6 to complete the addition of solvent to the reaction mechanism 3 .

[0022] When in use, the solvent valve is opened to add liquid into the reaction mechanism 3, and then the core valve 7 can transfer the liquid by using the pump transfer of the plunger pump 6 as power, and transfer the liquid to the activation bottle 21 for aeration activation, and then transfer it to the reaction mechanism 3 by using the pump transfer of the plunger pump 6 as power.

[0023] Reference Figure 1 and Figure 3 The reaction mechanism 3 includes a reactor 31, which is arranged in the second chamber 13 along the height direction of the box body 1. The reactor 31 is hollow inside, and the reactor 31 is connected to the activation bottle 21 through a pipeline. A fixing piece is fixed on the second chamber 13, and quick-release clamps 32 are respectively sleeved on the top and bottom ends of the reactor 31. The quick-release clamp 32 at the bottom end of the reactor 31 is fixed to the fixing piece by bolts, thereby fixing the reactor 31 to the box body 1. A solvent interface 33 is fixed at the center of the top surface of the quick-release clamp 32 at the top, and a solvent outlet 34 is fixed at the center of the bottom surface of the quick-release clamp 32 at the bottom, and the solvent interface 33 and the solvent outlet 34 are respectively connected to the inside of the reactor 31. A solvent tube (not shown in the figure) is inserted into the solvent interface 33 for adding liquid and blowing; a solvent tube is also inserted into the solvent outlet 34 for draining liquid. Both solvent tubes are connected to the inside of the reactor 31. The two quick-release clamps 32 are respectively provided with filter plates 35 detachably.

[0024] A UV detector (not shown in the figure) is fixed on the outer wall of the box 1, and a dual-light path optical system is used to achieve dual-wavelength detection. The switch button is set on the rear panel of the UV detector. When in use, pressing the switch "1" means "turning on" the power; pressing the switch "0" means "turning off" the power; each time the power is turned on, the UV detector performs a self-test operation, and the touch screen displays the words "detector abnormality", which is a normal situation and takes 5 minutes to complete the self-test; after the self-test is completed, the instrument enters the wavelength setting main interface, and the UV detector is in standby mode at this time; after the self-test is completed, due to the thermal stabilization process of the UV detector lamp, the system needs 15-30 minutes of stabilization time.

[0025] A control system (not shown in the figure) is provided on the box 1, which is used to control the operation of the continuous synthesizer. The control system as a whole is mainly installed in the control cabinet of the box 1, and the outside of the control cabinet includes a power switch, a power access port, a data line interface, etc. The control mode of the control system is computer control, and all tasks are controlled by software. After the control cabinet is powered on, the user logs in and displays the control panel of the control system software. The homepage interface mainly displays the main interface of the device, which displays the task execution status, operation dynamic display, alarm information, etc. of the current channel. The main interface displays the operation information of the device. Click "manual mode" to enter the task interface: click manual mode to enter the single-step test interface, click stop to stop all running tasks immediately, click start to start channel operation, and click pause to temporarily set the channel.

[0026] Press "Ctrl+F12" with the mouse, enter the developer's mobile phone number and verification code in the pop-up window, and click OK to enter the software background: click Start to start the polypeptide method of this channel; click Pause to pause the running method; click Stop to stop the executing task; click Peptide Information to display the polypeptide name, production batch number, molecular weight and theoretical yield, etc.; click Peptide Synthesis Method to display the current amino acid method, such as condensation method and deprotection method; click Running Process to display the specific method of the current amino acid method, such as DMF washing, etc.; click Manual for manual operation, such as a heating task, stirring, draining, etc.; click Running Chart to display the current channel running dynamic chart, such as color changes, dynamic changes, etc.

[0027] Set the user management content: user information, user rights, project rights, account password login; parameter settings: set the software language Chinese or English, login method, number of allowed password errors, number of password repetitions, lock screen time, etc.; operating parameter settings: set the parameters of each operation module in the process; user rights setting: different operation functions in the industrial control system software need to be determined according to the user's login name, and the user type in the software system is customized by the user. According to the process needs, you can create user types by yourself, such as operators, technicians, etc., and define the rights of each type according to your needs. In user management, when adding a new user, enter the user name, number, permission level, password validity period, whether to start the ID card, etc. in the new window, and click "OK" after editing. Permission level maintenance: set the permissions of user types in the system and create new user types. Project permissions: set the user's permission to use the project. If you need to open a certain project permission to the user, select the user and check the corresponding item on the right to indicate that the user has permission to use it. Login password reset: modify the password of the current account. The background settings are mainly the connection and communication settings between the control system and the hardware, as well as the basic process parameter settings. The raw material setting interface is mainly used to set the amino acid, resin, and reagent names, and edit the raw material information by adding on the right. The substitution value is the substitution value of the resin amino acid; the particle size is the resin particle size; the amino acid is if the resin already has amino acids, you need to select the amino acid name and position; the amino acid protection method, such as Fmoc; the abbreviation is the English abbreviation of the amino acid; the position is mainly used to specify the storage position of a certain amino acid during mechanical movement; the reagent position is mainly used to select the corresponding position of the reagent during mechanical movement.

[0028] The method interface is mainly used to set the program running process and process parameters. The project menu is mainly used to edit project classification, project amino acid sequence and amino acid method. The data menu is mainly used to record historical data, including project batches and system operation logs. The data can be printed in PDF format. The help menu is mainly used to display company information and instruction manuals.

[0029] When in use, first install all parts, the activation bottle 21 is filled with amino acids, and resin is needed in the polypeptide synthesis process. As a carrier for polypeptide synthesis, the resin can be combined with the end group of the peptide chain through a unique functional group, so that the peptide chain is fixed on the resin, so the resin is first mixed with an organic solvent to obtain a liquid. Start the control system, open the regulating valve 5, adjust the pressure, start the solvent valve, so that the liquid enters the reactor 31 through the solvent interface 33, and then the core valve 7 can use the pump transfer of the plunger pump 6 as the power to transfer the liquid, transfer the liquid to the activation bottle 21, and activate the liquid and the amino acid by aeration, and then use the pump transfer of the plunger pump 6 as the power to transfer the activated amino acid to the reactor 31, and then use the control system to make the reactor 31 shake and react. After the reaction is completed, start the solvent valve again, so that the reacted liquid is discharged from the solvent outlet 34 through the solvent pipe, and then shrink, crack, precipitate, centrifuge, wash and dry to obtain the polypeptide. The resin may also adhere to the reactor 31. Then disassemble the reactor 31, remove the quick-release clamp 32 and the filter plate 35, and then receive the resin in the reactor 31. If there is resin on the inner wall of the reactor 31, flush it with a small amount of liquid or brush it off with other tools. Repeat this process to complete all reactions required for the synthesis. When a continuous flow reaction is required, add the liquid into the chromatography column for a continuous flow reaction.

[0030] Then turn on the power, click the "Manual Mode" on the left side of the mouse motor interface, and the interface will switch to the manual mode interface; then add a method, add a task first, in the method interface, use the "Add" function to add the required task, click the "Add" button, a window will pop up, edit the method name in this window, click Confirm, the newly added method will be displayed in the list on the left, click "Edit Method Process and Parameters" below, an editing window will pop up; then add method steps, select "Add Category" in the lower left corner, edit the method category, such as DMF liquid addition, click "Add Process" in the lower left corner, a process parameter window will pop up, select the basic process in this window, select the side process to be executed, enter the required liquid addition volume and pipe blowing time in the process parameter window, click Confirm to complete the basic process parameter setting, click Save to complete the method task editing. Create a new project: Select "+ Category" under the project, and the "Project Category" window will pop up. Enter the project category name in this window and click "OK". The newly created project category will be displayed in the "Project Category". Select the newly created category and click "+ Project" in the lower left corner to create a new project. Enter the project (secondary project) name and click "OK". The newly created project will be displayed in the "Project Category". Specific information is displayed on the right side of the project: such as amino acid information, resin name, substitution value, weight, whether the amino acid ends with a carboxyl or amino group, etc. Click "Modify" to enter the project information modification window. Fill in the project information in the window: resin name, substitution value, weight, scale, planned output, amino acid concentration, amino acid ending method and remarks. You can also import information from previously created project batches. Amino acid pre-method sequence, in this window, add amino acids in sequence according to the process, as well as the corresponding methods for amino acids. Enter the software homepage again, click the "Run Program" interface in the lower left corner, and then click Select Project to pop up the project selection interface. Double-click the project to be selected to pop up the project batch confirmation box. In this interface, you can reconfirm the project data, add / insert / modify the length of the amino acid sequence, and then run a method separately. You can also query the project operation record or system operation record, and you can also back up the data. The entire synthesizer is controlled by a computer, which greatly reduces labor and improves scientific research efficiency.

[0031] As described above, the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit the same. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that the technical solutions described in the aforementioned embodiments may still be modified, or some of the technical features thereof may be replaced by equivalents. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A continuous synthesizer and a control system thereof, characterized in that: The invention comprises a box (1) which is hollow inside and open on one side, an activation mechanism (2) arranged on the top surface of the box (1), and a reaction mechanism (3) arranged inside the box (1); a partition (11) arranged along its height direction is fixed inside the box (1) to divide the box (1) into a first chamber (12) and a second chamber (13); an emergency stop switch (14) is fixed on the box (1); positive pressure nitrogen pressure regulating valves (5) are fixedly arranged on the outer wall of the box (1) along its height. 1), an activated positive pressure nitrogen pressure regulating valve (52), a swing cylinder compressed air pressure regulating valve (53), a plunger pump (6) is fixedly arranged in the first chamber (12), a plurality of rotary core valves (7) are fixedly arranged above the plunger pump (6) in the first chamber (12), the plunger pump (6), the rotary core valve (7), the activation mechanism (2), and the reaction mechanism (3) are connected through a pipeline, and a solvent valve is also fixedly arranged on the box body (1), and the solvent valve is used to control the addition of liquid to the reaction mechanism (3).

2. The continuous synthesizer and control system thereof according to claim 1, characterized in that: The activation mechanism (2) comprises a plurality of activation bottles (21), wherein the plurality of activation bottles (21) are evenly arranged and detachably connected to the outer top surface of the box body (1).

3. The continuous synthesizer and control system thereof according to claim 1, characterized in that: The reaction mechanism (3) comprises a reactor (31) which is detachably arranged in the second chamber (13) along the height direction of the box body (1); the reactor (31) is hollow inside and is connected to the plunger pump (6) and the activation bottle (21) through a pipeline; a solvent interface (33) is fixedly provided on the top surface of the reactor (31) and a solvent outlet (34) is fixedly provided on the bottom surface; solvent tubes are respectively inserted into the solvent interface (33) and the solvent outlet (34), and the two solvent tubes are connected to the interior of the reactor (31).

4. The continuous synthesizer and control system thereof according to claim 3, characterized in that: Filter plates (35) are detachably provided on the top and bottom ends of the reactor (31).

5. The continuous synthesizer and control system thereof according to claim 1, characterized in that: A chromatography column (4) is also provided on one side of the housing (1), and the chromatography column (4) is used for continuous flow reaction.

6. The continuous synthesizer and control system thereof according to claim 1, characterized in that: The box (1) is provided with a UV detector.

7. The continuous synthesizer and control system thereof according to claim 1, characterized in that: The box body (1) is also provided with a transparent protective cover (15).

8. The continuous synthesizer and control system thereof according to claim 1, characterized in that: The box (1) is provided with a control system, and the control system is used to control the operation of the continuous synthesizer.

Images