Stirring structure, reactor and solid-phase polypeptide synthesis device

Abstract

The invention provides a stirring structure, a reactor and a solid-phase polypeptide synthesis device. The stirring structure comprises a stirring rod; the first-stage stirring paddle is mounted on the stirring rod, the first-stage stirring paddle comprises a first-stage stirring blade, the first-stage stirring blade is obliquely arranged relative to the central axis of the stirring rod, and the blade mounting angle alpha of the first-stage stirring blade is larger than or equal to 10 degrees and smaller than or equal to 30 degrees, so that the first-stage stirring paddle can push materials to flow in the axial direction of the stirring rod; the first-stage stirring paddle is installed on the stirring rod, the second-stage stirring paddle is installed on the stirring rod, the first-stage stirring paddle and the second-stage stirring paddle are arranged at intervals in the axial direction of the stirring rod, the second-stage stirring paddle comprises second-stage stirring blades, the second-stage stirring blades are obliquely arranged relative to the central axis of the stirring rod, and the blade installation angle beta of the second-stage stirring blades is larger than or equal to 35 degrees and smaller than or equal to 55 degrees. Therefore, the secondary stirring paddle can push materials to flow along the axial direction of the stirring rod. The stirring structure provided by the technical scheme of the invention can solve the problem that the stirring and mixing effects are poor when the existing stirred tank reactor is used for polypeptide synthesis.

Description

Technical Field

[0001] The present invention relates to the technical field of solid phase polypeptide synthesis, in particular to a stirring structure, a reactor and a solid phase polypeptide synthesis device. Background Art

[0002] In the field of solid-phase peptide synthesis (SPPS), mechanical stirring is the mainstream method for peptide synthesis. This method was first proposed by Merrifield in 1963 and is still widely used in oligonucleotide synthesis, combinatorial organic synthesis and oligosaccharide synthesis. Especially in the large-scale production of peptide drugs, the above method can achieve a yield of up to 100~500kg. When synthesizing peptides, one of the reactant molecules is attached to an insoluble solid carrier (polymer resin), while the other reactants are dissolved in the solution. During the reaction, since the reaction system is multiphase, good mixing conditions are required to ensure effective contact and reaction between the reactants.

[0003] At present, stirred tank reactors (STRs) are commonly used equipment for peptide synthesis, but they have certain limitations. During the peptide synthesis process, when resin particles are suspended in a liquid, as the solid particle content increases, the inertial force and viscous force exerted by the liquid on the solid particles also increase, which makes the relative movement of the solid particles in the liquid more difficult, resulting in poor multiphase mixing effect. Summary of the invention

[0004] The main purpose of the present invention is to provide a stirring structure, a reactor and a solid phase peptide synthesis device, which can solve the problem that the stirring and mixing effect of the existing stirred tank reactor is poor when performing peptide synthesis.

[0005] In order to achieve the above-mentioned purpose, according to one aspect of the present invention, a stirring structure is provided, comprising: a stirring rod; a first-level stirring paddle installed on the stirring rod, the first-level stirring paddle including a first-level stirring blade, the first-level stirring blade is tilted relative to the central axis of the stirring rod, and the blade installation angle α of the first-level stirring blade is in the range of 10°≤α≤30°, so that the first-level stirring paddle can push the material to flow along the axial direction of the stirring rod; and a second-level stirring paddle installed on the stirring rod, the first-level stirring paddle and the second-level stirring paddle are spaced apart along the axial direction of the stirring rod, the second-level stirring paddle includes a second-level stirring blade, the second-level stirring blade is tilted relative to the central axis of the stirring rod, and the blade installation angle β of the second-level stirring blade is in the range of 35°≤β≤55°, so that the second-level stirring paddle can push the material to flow along the axial direction of the stirring rod.

[0006] Further, the value range of the blade installation angle α of the primary stirring blade is 12°≤α≤15°; and / or the value range of the blade installation angle β of the secondary stirring blade is 45°≤β≤48°.

[0007] Furthermore, there are multiple primary stirring blades and multiple secondary stirring blades, and the multiple primary stirring blades are evenly arranged along the circumference of the stirring rod, and the multiple secondary stirring blades are evenly arranged along the circumference of the stirring rod.

[0008] Furthermore, the plurality of primary stirring blades are grouped in pairs, and the two primary stirring blades in each group of primary stirring blades form an S-shaped structure.

[0009] Furthermore, the number of the primary stirring blades is two, the number of the secondary stirring blades is four, the two primary stirring blades are centrally symmetrically distributed, and the four secondary stirring blades are evenly arranged along the circumference of the stirring rod.

[0010] Furthermore, the primary stirring paddle is located below the secondary stirring paddle, and the stirring range of the primary stirring blade is greater than the stirring range of the secondary stirring blade.

[0011] Furthermore, the secondary stirring blade includes a first stirring section and a second stirring section, one end of the second stirring section is connected to an end of the first stirring section close to the primary stirring paddle, and the other end of the second stirring section is bent to a side away from the primary stirring paddle.

[0012] Furthermore, the first stirring section and the second stirring section both have cambered surfaces on their sides facing away from the primary stirring paddle.

[0013] According to one aspect of the present invention, a reactor is provided, comprising: a reaction kettle having a containing chamber; and the above-mentioned stirring structure, wherein the stirring structure is installed in the containing chamber.

[0014] Furthermore, the distance between the bottom of the first-stage stirring paddle and the bottom of the accommodating chamber is H1, the accommodating chamber is cylindrical, the inner diameter of the accommodating chamber is D1, and the value range of H1 / D1 is 0.005~0.01.

[0015] Furthermore, the outer diameter of the first-stage stirring paddle is D2, and the value range of D2 / D1 is 0.97~0.98; and / or, the outer diameter of the second-stage stirring paddle is D3, and the value range of D3 / D1 is 0.39~0.40.

[0016] Furthermore, the distance between the bottom of the secondary stirring paddle and the bottom of the accommodating chamber is H2, and the value range of H2 / D1 is 0.3~0.5; and / or, the distance between the primary stirring paddle and the secondary stirring paddle is L, and the value range of L / D1 is 0.09~0.29.

[0017] Furthermore, the height of the accommodating cavity is H3, and the value range of H3 / D1 is 1.24~1.58.

[0018] Furthermore, a discharge port communicating with the accommodating cavity is arranged on the side wall of the reaction kettle.

[0019] According to another aspect of the present invention, a solid phase peptide synthesis device is provided, comprising: the above-mentioned reactor; and a sintered plate, wherein the sintered plate is installed at the bottom of the reactor.

[0020] By applying the technical solution of the present invention, the rotation of the stirring rod can drive the primary stirring paddle and the secondary stirring paddle to rotate. The primary stirring blade and the secondary stirring blade are both inclined relative to the central axis of the stirring rod, and the blade installation angles of the two are different. During the material mixing process, the material can flow along the axial direction of the stirring rod. Compared with the radial flow stirring paddle in the prior art, the stirring structure of the present application can improve the stirring effect of the stirring structure by the primary stirring paddle and the secondary stirring paddle arranged at intervals along the axial direction of the stirring rod, so that the stirred materials are fully mixed. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] The accompanying drawings constituting a part of the present invention are used to provide a further understanding of the present invention. The exemplary embodiments of the present invention and their descriptions are used to explain the present invention and do not constitute an improper limitation of the present invention. In the accompanying drawings:

[0022] Figure 1 A schematic structural diagram of a stirring structure according to an embodiment of the present invention is shown;

[0023] Figure 2 A schematic structural diagram showing another angle of the stirring structure of an embodiment of the present invention;

[0024] Figure 3 A schematic structural diagram showing another angle of the stirring structure of an embodiment of the present invention;

[0025] Figure 4 A schematic structural diagram of a stirring structure according to an embodiment of the present invention is shown;

[0026] Figure 5 A schematic structural diagram of a first-stage stirring paddle according to an embodiment of the present invention is shown;

[0027] Figure 6 A schematic structural diagram showing another angle of a first-stage stirring paddle according to an embodiment of the present invention;

[0028] Figure 7 A cross-sectional view of the heel end of a primary stirring paddle according to an embodiment of the present invention is shown;

[0029] Figure 8 A top view of a primary stirring paddle according to an embodiment of the present invention is shown;

[0030] Fig. 9A structural schematic diagram showing another angle of the primary stirring paddle of an embodiment of the present invention;

[0031] Fig.10 A schematic diagram showing the structure of a two-stage stirring paddle according to an embodiment of the present invention is shown;

[0032] Fig.11 A schematic structural diagram of a secondary stirring paddle in another angle of an embodiment of the present invention is shown;

[0033] Fig.12 A cross-sectional view of the heel end of a secondary stirring paddle according to an embodiment of the present invention is shown;

[0034] Fig.13 A structural schematic diagram showing another angle of the secondary stirring paddle of an embodiment of the present invention;

[0035] Fig.14 A schematic structural diagram of a stirring structure according to an embodiment of the present invention is shown;

[0036] Fig.15 A schematic structural diagram of a stirring structure according to an embodiment of the present invention is shown;

[0037] Fig.16 A cross-sectional view of a solid phase peptide synthesis device according to an embodiment of the present invention is shown;

[0038] Fig.17 A schematic structural diagram of a stirring structure according to an embodiment of the present invention is shown;

[0039] Fig.18 A schematic diagram showing the structure of a solid phase peptide synthesis device according to an embodiment of the present invention;

[0040] Fig.19 The solid phase suspension distribution diagram in the reactor before stirring is shown when the stirring speed is 15 RPM;

[0041] Fig. 20 The figure shows the distribution diagram of the solid phase suspension in the reactor after stirring when the stirring speed is 15 RPM;

[0042] Fig.21 A fluid profile directional flow velocity distribution diagram is shown;

[0043] Fig. 22 A fluid flow velocity profile is shown;

[0044] Fig.23 A fluid flow velocity cloud diagram is shown;

[0045] Fig.24 shows the nitrogen velocity distribution diagram in the reactor;

[0046] Fig.25shows the nitrogen velocity distribution diagram in the reactor;

[0047] Fig.26 The energy dissipation and average velocity of the system are shown as a function of time.

[0048] The above drawings include the following reference numerals:

[0049] 10. Stirring rod; 11. First mounting block; 12. Second mounting block; 13. Guide groove; 20. Primary stirring paddle; 21. Primary stirring blade; 22. First sleeve; 30. Secondary stirring paddle; 31. Secondary stirring blade; 311. First stirring section; 312. Second stirring section; 32. Second sleeve; 40. Reactor; 41. Accommodating chamber; 50. Discharge port; 60. Sintering plate; 61. Second conveying pipeline; 70. Activation tank; 71. First feed pipeline; 72. Second feed pipeline; 73. First drive motor; 74. First conveying pipeline; 75. Rotating shaft; 76. Stirring paddle; 80. Collecting tank; 90. Conveying pump; 100. Second drive motor. DETAILED DESCRIPTION

[0050] It should be noted that, in the absence of conflict, the embodiments of the present invention and the features in the embodiments can be combined with each other. The present invention will be described in detail below with reference to the accompanying drawings and in combination with the embodiments.

[0051] At present, in order to achieve good fluid flow and material mixing, reactors usually use agitators that can generate radial flow fields. These agitators are widely used in various chemical production processes, including the mixing of medium-viscosity or high-viscosity materials. These materials usually need to be mixed in a laminar or transient flow environment. The most ideal operating condition is to achieve sufficient mixing at a lower energy input.

[0052] In order to solve the above problems, refer to Figures 1 to 18 As shown, the present invention provides a stirring structure, which includes: a stirring rod 10; a first-level stirring paddle 20, which is installed on the stirring rod 10, and the first-level stirring paddle 20 includes a first-level stirring blade 21, which is tilted relative to the central axis of the stirring rod 10, and the blade installation angle α of the first-level stirring blade 21 is in the range of 10°≤α≤30°, so that the first-level stirring paddle 20 can push the material to flow along the axial direction of the stirring rod 10; and a second-level stirring paddle 30, which is installed on the stirring rod 10, and the first-level stirring paddle 20 and the second-level stirring paddle 30 are spaced apart along the axial direction of the stirring rod 10, and the second-level stirring paddle 30 includes a second-level stirring blade 31, which is tilted relative to the central axis of the stirring rod 10, and the blade installation angle β of the second-level stirring blade 31 is in the range of 35°≤β≤55°, so that the second-level stirring paddle 30 can push the material to flow along the axial direction of the stirring rod 10.

[0053] In the present embodiment, the rotation of the stirring rod 10 can drive the primary stirring paddle 20 and the secondary stirring paddle 30 to rotate, wherein the primary stirring blade 21 and the secondary stirring blade 31 are both inclined relative to the central axis of the stirring rod 10, and the blade installation angles of the two are different, so that the primary stirring paddle 20 and the secondary stirring paddle 30 are both axial flow stirring paddles, that is, during the material mixing process, the material can flow along the axial direction of the stirring rod 10. Compared with the radial flow stirring paddle in the prior art, the stirring structure of the present application can improve the stirring effect of the stirring structure by the primary stirring paddle 20 and the secondary stirring paddle 30 arranged at intervals along the axial direction of the stirring rod 10, so that the stirred materials are fully mixed. At the same time, compared with the radial flow stirring paddle, the material can also be better suspended in the reactor 40. At the same time, it can also promote the mixing uniformity of the heterogeneous system (a heterogeneous system refers to a system composed of two or more substances in different phases; mixing uniformity refers to the state in which substances in different phases in the heterogeneous system can be mixed to achieve a macroscopically uniform distribution).

[0054] In addition, the stirring structure of the present application has a good mixing effect, can achieve good gas dispersion and solid suspension, and has lower shear force. In the prior art, the bottom stirring paddle blade is flat and the blade has a large inclination angle (usually 90°), and the shear force generated is also greater, while the primary stirring blade 21 and the secondary stirring blade 31 of the present application have a smaller inclination angle. When the primary stirring paddle 20 and the secondary stirring paddle 30 rotate clockwise or counterclockwise, the shear force generated at the ends of the primary stirring blade 21 and the secondary stirring blade 31 is lower. The above-mentioned setting can reduce the energy input to the system, thereby reducing the mechanical stress of the primary stirring blade 21, the secondary stirring blade 31, the stirring rod 10, and the driving structure for driving the stirring rod 10 to rotate.

[0055] It should be noted that the primary stirring paddle 20 and the secondary stirring paddle 30 can rotate clockwise or counterclockwise under the drive of the stirring rod 10. The combination of the primary stirring paddle 20 and the secondary stirring paddle 30 can achieve better mixing, heat transfer and mass transfer effects. The blade installation angle refers to the acute angle between the end of the stirring blade (primary stirring blade, secondary stirring blade) connected to the stirring rod 10 and the central axis of the stirring rod 10.

[0056] In one embodiment of the present invention, the blade installation angle α of the primary stirring blade 21 is in the range of 12°≤α≤15°. The blade installation angle β of the secondary stirring blade 31 is in the range of 45°≤β≤48°.

[0057] In this embodiment, through the stirring cooperation of the primary stirring blade 21 and the secondary stirring blade 31, the flow pattern of the stirred material can be changed, so that the stirred material flows along the axial direction of the stirring rod 10, and the stirred material is evenly mixed. At the same time, the setting of the blade installation angles of the primary stirring blade 21 and the secondary stirring blade 31 can also avoid uneven stirring, thereby ensuring the stirring quality.

[0058] In one embodiment of the present invention, there are multiple primary stirring blades 21 and multiple secondary stirring blades 31 , and the multiple primary stirring blades 21 are evenly arranged along the circumference of the stirring rod 10 , and the multiple secondary stirring blades 31 are evenly arranged along the circumference of the stirring rod 10 .

[0059] In this embodiment, multiple primary stirring blades 21 and multiple secondary stirring blades 31 are evenly arranged along the circumference of the stirring rod 10, which can more effectively promote the flow of materials, reduce the stirring dead zone, and improve the stirring efficiency. At the same time, the evenly arranged primary stirring blades 21 and secondary stirring blades 31 can make the material flow more orderly, help to form a good circulation flow, and improve the stirring effect. In addition, through the above-mentioned setting, the impact and wear of the materials on the primary stirring blades 21 and the secondary stirring blades 31 can also be dispersed, the service life of the stirring structure can be extended, and at the same time, it can also help to reduce the vibration and noise during the stirring process and improve the operation stability of the stirring structure.

[0060] See also Figures 1 to 18 As shown, in one embodiment of the present invention, a first mounting block 11 and a second mounting block 12 are further provided on the stirring rod, the first-stage stirring paddle 20 also includes a first sleeve 22, and the first-stage stirring blade 21 is arranged on the outer periphery of the first sleeve 22, the second-stage stirring paddle 30 also includes a second sleeve 32, and the second-stage stirring blade 31 is arranged on the outer periphery of the second sleeve 32, the first sleeve 22 is fixedly sleeved on the second mounting block 12, and the second sleeve 32 is fixedly sleeved on the first mounting block 11. Through the above arrangement, the installation of the first-stage stirring paddle 20 and the second-stage stirring paddle 30 can be realized.

[0061] See also Figures 1 to 18 As shown, in one embodiment of the present invention, a guide groove 13 is provided on the stirring rod, and the second sleeve 32 is slidably disposed on the guide groove 13 to facilitate adjustment of the position of the secondary stirring paddle 30 .

[0062] See also Figures 1 to 18 As shown, in one embodiment of the present invention, a plurality of primary stirring blades 21 are grouped in pairs, and the two primary stirring blades 21 in each group of primary stirring blades 21 form an S-shaped structure.

[0063] In this embodiment, the number of the first-level stirring blades 21 is an even number, and the multiple first-level stirring blades 21 are grouped in pairs, and the two first-level stirring blades 21 in each group of first-level stirring blades 21 form an S-shaped structure. On the one hand, the S-shaped structure formed by the two first-level stirring blades 21 can increase the contact area between the first-level stirring paddle 20 and the solid material and enhance the mixing effect. On the other hand, the S-shaped structure can reduce the direct impact of the material on the first-level stirring blades 21, thereby reducing wear and extending the service life of the first-level stirring blades 21.

[0064] See also Figures 1 to 18 As shown, in one embodiment of the present invention, the number of the first-level stirring blades 21 is two, the number of the second-level stirring blades 31 is four, the two first-level stirring blades 21 are centrally symmetrically distributed, and the four second-level stirring blades 31 are evenly arranged along the circumference of the stirring rod 10.

[0065] In this embodiment, the two primary stirring blades 21 are distributed symmetrically along the center, and the four secondary stirring blades 31 are evenly arranged along the circumference of the stirring rod 10. This can not only ensure the structural stability of the stirring structure, but also reduce vibration and noise during the stirring process, thereby improving the operating stability of the stirring structure.

[0066] See also Figures 1 to 18 As shown, in one embodiment of the present invention, the primary stirring paddle 20 is located below the secondary stirring paddle 30 , and the stirring range of the primary stirring blade 21 is greater than the stirring range of the secondary stirring blade 31 .

[0067] In this embodiment, the stirring range of the primary stirring paddle 20 located below the secondary stirring paddle 30 is greater than the stirring range of the secondary stirring blade 31. In this way, the material at the bottom can flow along the axial direction of the stirring rod 10 to the location of the secondary stirring paddle 30 under the stirring action of the primary stirring paddle 20, so that the material mixing is more uniform.

[0068] In addition, when the stirring structure is used for solid phase peptide synthesis, the stirring structure is installed in the reactor 40. At this time, the setting positions of the primary stirring paddle 20 and the secondary stirring paddle 30 can ensure the uniformity of the solid material and resin in the reactor 40 in the vertical direction.

[0069] See also Figures 1 to 18 As shown, in one embodiment of the present invention, the secondary stirring blade 31 includes a first stirring section 311 and a second stirring section 312, one end of the second stirring section 312 is connected to an end of the first stirring section 311 close to the primary stirring paddle 20, and the other end of the second stirring section 312 is bent toward a side away from the primary stirring paddle 20.

[0070] In this embodiment, the other end of the second stirring section 312 is bent toward a side away from the primary stirring paddle 20 , so that the material can flow along the axial direction of the stirring rod 10 when stirring the material.

[0071] In one embodiment of the present invention, the first stirring section 311 and the second stirring section 312 are both arc surfaces on the sides facing away from the primary stirring paddle 20 .

[0072] In this embodiment, the first stirring section 311 and the second stirring section 312 have a curved surface on the side facing away from the primary stirring paddle 20, which can not only reduce the resistance during the stirring process and reduce energy consumption, but also reduce the direct impact of the material on the secondary stirring blade 31, thereby reducing wear and extending the service life of the secondary stirring blade 31.

[0073] See also Figures 1 to 11 As shown, in one embodiment of the present invention, the angle γ between the end of the first stirring section 311 away from the stirring rod 10 and the end of the second stirring section 312 away from the stirring rod 10 is in the range of 140°≤γ≤160°. This arrangement can ensure that the secondary stirring blade 31 pushes the material to flow along the axial direction of the stirring rod 10, that is, the axial flow stirring effect of the secondary stirring blade 31 is ensured.

[0074] like Fig.16 As shown, according to another aspect of the present invention, a reactor is further provided, comprising: a reaction kettle 40 having a containing chamber 41 ; and the above-mentioned stirring structure, wherein the stirring structure is installed in the containing chamber 41 .

[0075] In this embodiment, the stirring structure of the reactor has all the technical solutions and all the technical effects of the above stirring structure, which will not be described in detail here.

[0076] See also Figures 1 to 18 As shown, in one embodiment of the present invention, the distance between the bottom of the first-stage stirring paddle 20 and the bottom of the accommodating chamber 41 is H1, the accommodating chamber 41 is cylindrical, the inner diameter of the accommodating chamber 41 is D1, and the value range of H1 / D1 is 0.005~0.01.

[0077] In this embodiment, a sintering plate 60 is provided at the bottom of the accommodating chamber, and the sintering plate 60 is located below the first-stage stirring paddle 20. A discharge port 50 is provided on the side wall of the reactor 40, and the discharge port 50 is connected to the accommodating chamber 41. Through the above arrangement, the first-stage stirring paddle 20 can push the solid material to the discharge port 50 more effectively when rotating, thereby reducing the residue of material on the sintering plate 60 during the unloading process.

[0078] See also Figures 1 to 18 As shown, in one embodiment of the present invention, the outer diameter of the first-stage stirring paddle 20 is D2, and the value range of D2 / D1 is 0.97-0.98.

[0079] Through the above arrangement, it is possible to ensure that the material in the accommodating chamber 41 is fully stirred, thereby preventing the material from being deposited in the accommodating chamber 41 .

[0080] See also Figures 1 to 18 As shown, in one embodiment of the present invention, the outer diameter of the secondary stirring paddle 30 is D3, and the value range of D3 / D1 is 0.39-0.40.

[0081] Through the above arrangement, the material in the accommodating chamber 41 can be fully stirred while ensuring that the accommodating chamber 41 has sufficient mixing space.

[0082] See also Figures 1 to 18 As shown, in one embodiment of the present invention, the distance between the bottom of the secondary stirring paddle 30 and the bottom of the accommodating chamber 41 is H2, and the value range of H2 / D1 is 0.3~0.5. The distance between the primary stirring paddle 20 and the secondary stirring paddle 30 is L, and the value range of L / D1 is 0.09~0.29.

[0083] Through the above arrangement, the mixing effect of the materials can be improved.

[0084] It should be noted that in practical applications, the value of the distance L between the primary stirring paddle 20 and the secondary stirring paddle 30 can be flexibly adjusted within a feasible range according to the volume of the reaction system in the reactor 40 to achieve a good mixing effect.

[0085] See also Figures 1 to 18 As shown, in one embodiment of the present invention, the height of the accommodating cavity 41 is H3, and the value range of H3 / D1 is 1.24-1.58.

[0086] Through the above arrangement, the suspension and dispersion of solid materials can be improved and the heat transfer efficiency can be ensured.

[0087] See also Figures 1 to 18 As shown, in one embodiment of the present invention, a discharge port 50 communicating with the accommodating chamber 41 is disposed on the side wall of the reaction kettle 40 .

[0088] In this embodiment, the discharge port 50 is disposed on the side wall of the reaction kettle 40 to enable lateral discharge.

[0089] In one embodiment, the first-stage stirring paddle 20 and the discharge port 50 are located at the same height of the reactor 40. When unloading is required, the stirring rod 10 drives the first-stage stirring paddle 20 to rotate. During the rotation of the first-stage stirring paddle 20, the material can be pushed to the discharge port 50, thereby realizing automatic unloading. There is no need to set up other structures for unloading, which can reduce costs.

[0090] In one embodiment, a valve is provided at the discharge port 50 and is sealed with a metal sealing ring. The valve has an automatic fault protection function, and the metal sealing ring is pressure-resistant and does not react with the solvent. Therefore, the discharge port 50 can be used to discharge slurry or wet filter cake (solid conjugate of resin and polypeptide with solvent).

[0091] Specifically, the valve may be a check valve.

[0092] When the reactor is used for solid phase peptide synthesis, as the bottom first-stage stirring blade 21 slowly rotates, the solid (solid conjugate of resin and peptide) is easily peeled off from the filter cake (solid conjugate of resin and peptide with solvent). The design of SPPS improves the flexibility of unloading and allows wet solid, slurry and even liquid unloading.

[0093] In order to test the stirring structure and reactor, a computational fluid dynamics (CFD) simulation of a 2000L reactor was carried out, and the CFD solver MSTAR was used to solve the numerical solution of the 3D mixing system, and the large eddy simulation (LES) algorithm model was used to simulate the three-phase system. The reactor was simulated based on the MSTAR software. The capacity of the reactor was 2000L, the diameter and height of the reactor 40 were 1.3m and 1.5m respectively, the liquid level in the reactor chamber 41 was 1.02m, the outer diameter D2 of the first-stage stirring paddle 20 was 1.27m, the distance H2 between the bottom of the second-stage stirring paddle 30 and the bottom of the chamber 41 and the ratio of the inner diameter D1 of the chamber 41 were in the range of 0.3~0.5, the stirring structure rotated at a speed of 15RPM, the speed of the ends of the first-stage stirring blade 21 and the second-stage stirring blade 31 was about 1.1m / s, and the fluid in the chamber 41 was N,N-dimethylformamide (DMF). The mesh resolution of the free surface modeling is uniform, and the mesh resolution of the reactor 40 is set to 150~250. For the simulation of the conventional reactor stirring process, based on the above resolution setting, simulation calculations on power dissipation rate (EDR) and fluid velocity can be performed, and the calculation is easy to converge.

[0094] like Fig.19 The figure shows the solid suspension distribution in the reactor before stirring when the stirring speed is 15RPM. Fig. 20 The figure shows the distribution of the solid suspension in the reactor when the stirring speed is 15RPM and the stirring is performed for 60 seconds. Under this condition, a steady-state flow field (such as quasi-stable fluid kinetic energy) is generated. The color scale is linear, and light blue indicates smaller particle diameters, while red to yellow indicates larger particle diameters. At 60 seconds, the solid particles are well dispersed in the liquid. Fig.21 The directional flow velocity distribution diagram of the fluid profile is shown, as Fig. 22 The fluid flow velocity distribution diagram is shown as Fig.23shows a fluid flow velocity cloud diagram, Fig.23 The predicted fluid velocity contour at t=59.20 seconds is shown, where blue represents a lower fluid velocity and red represents a higher fluid velocity. Fig. 22 and Fig.23 It shows that the fluid flow velocity is the largest near the outer end of the primary stirring blade 21 (the end of the primary stirring blade 21 away from the stirring rod 10), with the maximum flow velocity being 1 m / s, and the shear force of the primary stirring blade 21 on the material is relatively low; the fluid flow velocity is the smallest near the stirring rod 10; based on the design of the sizes of the primary stirring paddle 20 and the secondary stirring paddle 30, the fluid velocity is relatively large in the main flow area of ​​the system and the flow velocity can be relatively evenly distributed, thereby achieving good mixing of the system.

[0095] In order to investigate the distribution of bubbles in the containing chamber 41, nitrogen was introduced into the containing chamber 41 at a flow rate of 180 L / min. Fig.24 The nitrogen velocity distribution diagram in the reactor 40 is shown. Fig.25 The nitrogen velocity distribution diagram in the reactor 40 is shown, where blue represents low to medium velocity, and red to yellow represents medium to high velocity. Fig.24 and Fig.25 It is shown that the speed of nitrogen reaches the maximum at the position close to the sintering plate 60, and the speed at the cross section of the sintering plate 60 is relatively uniform, which indicates that nitrogen is introduced into the reactor 40 from the bottom of the reactor 40, and the nitrogen can be more evenly dispersed into the material through the micropores on the sintering plate 60. As the bubbles rise, the bubbles can be evenly distributed in the material under the stirring action of the stirring structure, which is helpful for mixing the material. Fig.26 The graph showing the energy dissipation and average velocity of the system changing with time shows that the average velocity of the fluid flow is 0.31 m / s, the average energy dissipation of the material is 0.03 W / kg, and the stirring structure can achieve a good mixing effect.

[0096] According to another aspect of the present invention, a solid phase peptide synthesis device is provided, comprising: the above-mentioned reactor; and a sintering plate 60 , wherein the sintering plate 60 is installed at the bottom of the reaction kettle 40 .

[0097] In this embodiment, the reactor of the solid phase peptide synthesis device has all the technical solutions and all the technical effects of the above reactors, which will not be described in detail here.

[0098] In one embodiment, the mesh number of the sintered plate 60 is 300 mesh.

[0099] It should be noted that the solid-phase peptide synthesis device also includes a control system. The solid-phase peptide synthesis device can perform solid-liquid-gas multiphase reaction, filtration, washing, beating, drying, and automatic unloading of the dried solid material, and is controlled by the control system. The solvent can be filtered and removed from the solid product through the sintering plate 60, that is, the solid product is retained on the sintering plate 60 in the reactor 40, and the solvent is discharged from the reactor 40 through the micropores on the sintering plate 60. After the filtration is completed, fresh solvent is added to the reactor 40, and the stirring structure starts stirring and nitrogen is introduced into the accommodating chamber 41 at the same time, the solid product is washed, and residual substances are removed. Beating is to stir and mix the heterogeneous system of the solid product and the solvent, which can improve the uniformity of the solid-liquid mixing in the reactor 40.

[0100] It should be noted that the stirring structure can rotate both clockwise and counterclockwise. Operations such as reaction, washing and filtration can be carried out by clockwise stirring, while solid unloading can be carried out by clockwise stirring, which helps the solid material to turn over and increase the unloading rate.

[0101] See also Figures 1 to 18 As shown, in one embodiment of the present invention, the solid phase peptide synthesis device further includes an activation tank 70, a collection tank 80, a first feed pipeline 71, a second feed pipeline 72, a first drive motor 73, a first delivery pipeline 74, a rotating shaft 75, a stirring blade 76, a delivery pump 90 and a second drive motor 100. The first feed pipeline 71 and the second feed pipeline 72 are both connected to the activation tank 70, the stirring blade 76 is installed on the rotating shaft 75 and is located in the inner cavity of the activation tank 70, and the first drive motor 73 drives the first delivery pipeline 74. The movable shaft 75 rotates, and the rotation of the shaft 75 drives the stirring blade 76 to rotate. One end of the first delivery pipeline 74 is connected to the inner cavity of the activation tank 70, and the other end of the first delivery pipeline 74 is connected to the accommodating cavity 41 of the reactor 40. The second drive motor 100 is used to drive the stirring rod 10 to rotate. One end of the second delivery pipeline 61 is connected to the accommodating cavity 41 of the reactor 40, and the other end of the second delivery pipeline 61 is connected to the inner cavity of the collection tank 80. A delivery pump 90 is arranged on the second delivery pipeline 61.

[0102] When performing solid phase peptide synthesis, amino acids are added to the inner cavity of the activation tank 70 through the first feed pipeline 71, and solvents (N,N-dimethylformamide, dichloromethane, N-methylpyrrolidone, N,N-dimethylacetamide, dimethyl sulfoxide, trifluoroacetic acid) are added to the inner cavity of the activation tank 70 through the second feed pipeline 72. The solvent is used to activate the amino acids. The containing cavity 41 of the reactor 40 is filled with resin and N,N-dimethylformamide, so that the resin swells in the reactor 40 and is used as a solid carrier for standby. The activated amino acids in the activation tank 70 are added to the containing cavity 41 through the first delivery pipeline 74 to synthesize peptides by amino acid coupling reaction. During the reaction, the stirring structure introduces nitrogen into the containing cavity 41 while stirring, and the nitrogen is better dispersed into the system through the micropores on the sintering plate 60. The introduction of nitrogen helps to suspend and disperse the solid resin in the entire system and improve the mixing effect. At the same time, nitrogen as a protective gas can isolate the reaction system from the air to avoid the occurrence of side reactions. The solid (solid conjugate of resin and polypeptide) in the reaction process is retained in the containing cavity 41 by the sintering plate 60 , and the solvent is discharged from the containing cavity 41 through the micropores on the sintering plate 60 and enters the collecting tank 80 through the second delivery line 61 .

[0103] In one embodiment, the solid phase peptide synthesis device further includes an isolation glove box, which is integrated at the discharge port 50, so as to better protect the operator during the unloading operation, prevent product and environmental pollution, and improve the safety of the unloading process. Through the ergonomically designed isolation glove box, the operator can remove the residual materials in the kettle and recover the product under safe conditions. The isolation glove box is an isolation glove box of the prior art, and the specific structure is not repeated here.

[0104] In one embodiment, the solid phase peptide synthesis device also includes a temperature control unit, a vacuum pump and a jacket. The reactor 40 and the stirring structure can be heated to dry the wet material. The temperature of the reactor 40 is controlled by the temperature control unit. The reactor 40 has the following two drying methods. The first is vacuum drying, which is achieved by evacuating the reactor 40 with a vacuum pump. The vacuum is used to reduce the boiling point of the solvent, thereby reducing the temperature required for drying the material. Especially for the drying of heat-sensitive materials, the vacuum degree in the reactor 40 is increased, so that the solvent in the wet material is more easily volatilized, thereby significantly shortening the drying time. The second is convection drying, in which high-pressure nitrogen is purged to achieve solid drying. In actual application, nitrogen can form convection at the material, generating a large number of tiny gas channels, which is more conducive to the evaporation of the solvent. The above two drying methods both depend on the good heat transfer performance of the reactor 40. The jacket is filled with a heat transfer medium (hot water) for heating the side walls, bottom wall and stirring structure of the reactor 40. Through the heat transfer at the bottom of the reactor 40, the heat can be directly and effectively transferred from the bottom of the reactor 40 to the material above. The heat transfer accounts for about 25% of the total heat required for drying. The most efficient heat transfer comes from the side walls of the reactor 40. The side walls of the reactor 40 are in direct contact with the wet filter cake (solid conjugate of resin and polypeptide with solvent) above the sintering plate 60. The heat transferred accounts for about 50% of the total heat required for drying. During the drying process, the evaporated solvent can be prevented from condensing and flowing back into the product.

[0105] It should be noted that the stirring structure also has excellent heat transfer performance and can provide more than 25% of the heat used for drying. As the stirring proceeds, the heat can be effectively transferred to the surface of the wet cake in the reactor 40. The reactor has good heat transfer performance and can efficiently transfer heat to the reaction mixture.

[0106]

[0107] From the above description, it can be seen that the above-mentioned embodiments of the present invention achieve the following technical effects: the rotation of the stirring rod can drive the primary stirring paddle and the secondary stirring paddle to rotate, the primary stirring blade and the secondary stirring blade are both inclined relative to the central axis of the stirring rod, and the blade installation angles of the two are different, so that the material can flow along the axial direction of the stirring rod during the material mixing process. Compared with the radial flow stirring paddle in the prior art, the stirring structure of the present application can improve the stirring effect of the stirring structure through the primary stirring paddle and the secondary stirring paddle arranged at intervals along the axial direction of the stirring rod, so that the stirred materials can be fully mixed.

[0108] Obviously, the above-described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work should fall within the scope of protection of the present invention.

[0109] It should be noted that the terms used herein are only for describing specific embodiments and are not intended to limit the exemplary embodiments according to the present application. As used herein, unless the context clearly indicates otherwise, the singular form is also intended to include the plural form. In addition, it should be understood that when the terms "comprise" and / or "include" are used in this specification, it indicates the presence of features, steps, operations, devices, components and / or combinations thereof.

[0110] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A stirring structure, characterized in that: include: Stirring rod (10); a first-level stirring paddle (20) mounted on the stirring rod (10), the first-level stirring paddle (20) comprising a first-level stirring blade (21), the first-level stirring blade (21) being arranged obliquely relative to the central axis of the stirring rod (10), the blade installation angle α of the first-level stirring blade (21) being in the range of 10°≤α≤30°, so that the first-level stirring paddle (20) can push the material to flow along the axial direction of the stirring rod (10); as well as A secondary stirring paddle (30) is mounted on the stirring rod (10); the primary stirring paddle (20) and the secondary stirring paddle (30) are spaced apart along the axial direction of the stirring rod (10); the secondary stirring paddle (30) comprises a secondary stirring blade (31); the secondary stirring blade (31) is arranged obliquely relative to the central axis of the stirring rod (10); the blade installation angle β of the secondary stirring blade (31) is in the range of 35°≤β≤55°, so that the secondary stirring paddle (30) can push the material to flow along the axial direction of the stirring rod (10).

2. The stirring structure according to claim 1, characterized in that: The blade installation angle α of the primary stirring blade (21) has a value range of 12°≤α≤15°; and / or the blade installation angle β of the secondary stirring blade (31) has a value range of 45°≤β≤48°.

3. The stirring structure according to claim 1, characterized in that: The first-stage stirring blade (21) and the second-stage stirring blade (31) are both multiple, the multiple first-stage stirring blades (21) are evenly arranged along the circumference of the stirring rod (10), and the multiple second-stage stirring blades (31) are evenly arranged along the circumference of the stirring rod (10).

4. The stirring structure according to claim 3, characterized in that: The plurality of primary stirring blades (21) are grouped in pairs, and the two primary stirring blades (21) in each group of primary stirring blades (21) form an S-shaped structure.

5. The stirring structure according to any one of claims 1 to 4, characterized in that: The number of the first-level stirring blades (21) is two, the number of the second-level stirring blades (31) is four, the two first-level stirring blades (21) are centrally symmetrically distributed, and the four second-level stirring blades (31) are evenly arranged along the circumference of the stirring rod (10).

6. The stirring structure according to any one of claims 1 to 4, characterized in that: The primary stirring paddle (20) is located below the secondary stirring paddle (30), and the stirring range of the primary stirring blade (21) is greater than the stirring range of the secondary stirring blade (31).

7. The stirring structure according to any one of claims 1 to 4, characterized in that: The secondary stirring blade (31) comprises a first stirring section (311) and a second stirring section (312), one end of the second stirring section (312) being connected to an end of the first stirring section (311) close to the primary stirring paddle (20), and the other end of the second stirring section (312) being bent towards a side away from the primary stirring paddle (20).

8. The stirring structure according to claim 7, characterized in that: The first stirring section (311) and the second stirring section (312) have a curved surface on the side facing away from the primary stirring paddle (20).

9. A reactor, characterized in that: include: A reaction kettle (40) having a containing chamber (41); The stirring structure according to any one of claims 1 to 8, wherein the stirring structure is installed in the accommodating cavity (41).

10. The reactor according to claim 9, characterized in that The distance between the bottom of the primary stirring paddle (20) and the bottom of the accommodating chamber (41) is H1, the accommodating chamber (41) is cylindrical, the inner diameter of the accommodating chamber (41) is D1, and the value range of H1 / D1 is 0.005-0.

01.

11. The reactor according to claim 10, characterized in that The outer diameter of the first-stage stirring paddle (20) is D2, and the value range of D2 / D1 is 0.97-0.98; and / or the outer diameter of the second-stage stirring paddle (30) is D3, and the value range of D3 / D1 is 0.39-0.

40.

12. The reactor according to claim 10, characterized in that The distance between the bottom of the secondary stirring paddle (30) and the bottom of the accommodating chamber (41) is H2, and the value range of H2 / D1 is 0.3-0.5; and / or the distance between the primary stirring paddle (20) and the secondary stirring paddle (30) is L, and the value range of L / D1 is 0.09-0.

29.

13. The reactor according to claim 10, characterized in that The height of the accommodating cavity (41) is H3, and the value range of H3 / D1 is 1.24-1.

58.

14. The reactor according to claim 9, characterized in that A discharge port (50) communicating with the accommodating chamber (41) is provided on the side wall of the reaction kettle (40).

15. A solid phase peptide synthesis device, characterized in that: include: The reactor according to any one of claims 10 to 14; A sintering plate (60), wherein the sintering plate (60) is installed at the bottom of the reaction kettle (40).

Images