Solid-phase synthesis device

Abstract

The utility model belongs to the technical field of solid-phase synthesis, and particularly relates to a solid-phase synthesis device which comprises a liquid conveying device, a gas guide pipe, a piston assembly, a reaction tank, a sampling emptying device, a stirring assembly, a lower end cover, a waste liquid tank, a reaction tank supporting device and a conveying pipeline. The device has the beneficial effects that the reaction tank and a solid-phase carrier are cleaned in a flowing liquid manner, so that the use of a solvent is greatly reduced, and the whole solid-phase synthesis solvent can be reduced by about two thirds; the valve is closed to isolate oxygen and moisture in the air, so that closed reaction is realized, and side reaction is effectively avoided; a sampling emptying device is added, so that the problem of difficulty in sampling in a traditional reaction kettle and a continuous flow synthesis process is solved.

Description

TECHNICAL FIELD

[0001] The utility model relates to solid phase synthesis technical field, especially relates to a solid phase synthesis device. BACKGROUND

[0002] At present, solid phase synthesis device mostly adopts double-layer glass reaction kettle, connects a filter device made of PTFE material at the bottom, connects with the kettle body through flange, in order to ensure uniform reaction, mostly adopts stirring mode, removes reaction solvent through suction filtration or pump after reaction, and solid phase carrier remains in the reaction kettle, and through multiple and large amount of solvent washing, it is guaranteed that the material of the previous step reaction is completely removed. However, a large amount of solvent is needed during each washing, which will lead to cost increase, and is not friendly to the environment. Therefore, improving the solid phase synthesis device to reduce the excessive use of solvent is the current urgent research topic. CONTENT OF THE UTILITY MODEL

[0003] Therefore, in order to overcome the defects of the prior art, the utility model provides a solid phase synthesis device, which can improve the uniform reaction of solid-liquid phase, greatly reduce the excessive use of solvent, reduce the cost and improve the efficiency.

[0004] In order to achieve the above purpose, the utility model adopts the following technical scheme:

[0005] A solid phase synthesis device, comprising: a liquid delivery device, a gas conduit, a piston assembly, a reaction tank, a sampling and emptying device, a stirring assembly, a lower end cover, a waste liquid tank, a temperature control jacket and a conveying pipeline;

[0006] The liquid delivery device comprises: a liquid storage tank, a multi-channel selection valve and a pump, the liquid storage tank is connected with the multi-channel selection valve and the pump in sequence through the conveying pipeline; the liquid storage tank is used for storing material solution, reagent, solvent and the like; different liquids are selected according to needs and enter the pipeline through the multi-channel selection valve, without cross contamination risk; the pump pumps the liquid into the reaction tank, and controls the liquid feeding time and flow rate.

[0007] The gas conduit can introduce compressed air or nitrogen, which is used for blowing out the residual liquid in the gap of the solid phase carrier in the reaction tank, so that the solid phase carrier can be better cleaned, and the material concentration in the next step reaction liquid is not affected. Nitrogen can also be used to replace the air in the reaction tank, so as to avoid the influence of moisture and oxygen in the air on the reaction.

[0008] The piston assembly comprises a piston rod, a piston head, a distributor, a motor, a first sieve plate and a sealing ring, the piston head is installed on the piston rod, the distributor is arranged below the piston head, the first sieve plate is arranged below the distributor, and the sealing ring is arranged between the piston head and the inner wall of the reaction tank to seal the gap between the piston assembly and the reaction tank; the piston assembly is inserted into the inside of the reaction tank and moves up and down along the inner wall of the reaction tank through the motor; a first communication hole is arranged on the piston assembly, and the reaction tank is communicated with the liquid conveying device and the gas guide pipe through the first communication hole; the piston assembly is isolated from the outside through the sealing ring, and the distributor can uniformly distribute the liquid, so that the solid-phase carrier in the cavity can uniformly contact the solution during the cleaning process, and the solid-phase carrier is cleaned in a flowing manner through the liquid conveying device. The first sieve plate has a smaller diameter than the diameter of the solid-phase carrier, preventing the solid-phase carrier from leaking out.

[0009] The sampling and emptying device is arranged on the side of the reaction tank below the piston assembly and above the liquid surface during solid-phase synthesis; when liquid needs to be introduced, the sampling and emptying device can be opened to avoid pressure in the reaction tank; when sampling is needed, the sampling and emptying device is opened to achieve sampling; when nitrogen protection is needed, the sampling and emptying device can be combined with the gas guide pipe to replace the gas in the reaction tank with nitrogen, thereby reducing the occurrence of side reactions.

[0010] The stirring assembly comprises a transmission rod, a stirring motor, a liquid inlet and outlet, a liquid seal plate and a stirring paddle, and is installed on the piston assembly or below the lower end cover; the stirring paddle is fixed to the transmission rod and faces the inside of the reaction tank, and the transmission rod and the stirring paddle are driven by the stirring motor; during the reaction, the stirring motor is turned on to uniformly stir the reaction liquid.

[0011] The lower end cover comprises a second sieve plate and a bottom cover, and the second sieve plate has a smaller diameter than the diameter of the solid-phase carrier to prevent the solid-phase carrier from leaking out; a second communication hole is arranged on the lower end cover, and the reaction tank is communicated with the waste liquid tank through the second communication hole and the conveying pipeline;

[0012] When the stirring assembly is installed on the piston assembly, the transmission lifting rod (6-1) is the piston rod (3-1), and the first communication hole is communicated with the liquid inlet and outlet on the liquid seal plate (6-4); when the stirring assembly is installed below the lower end cover, the second communication hole is communicated with the liquid inlet and outlet (6-3) on the liquid seal plate (6-4); the liquid seal plate can prevent liquid leakage.

[0013] Preferably, when the stirring assembly is installed under the lower end cover, the lower end cover increases the lower end cover distributor, and simultaneously increases the delivery pipe so that the first communication hole is communicated with the waste liquid tank, and the second communication hole is communicated with the liquid delivery device and the gas guide pipe; the delivery pipe increases a three-way valve assembly, which comprises a first three-way valve, a second three-way valve and a third three-way valve, and the liquid of the liquid delivery device is selected to enter the first communication hole or the second communication hole through the three-way valve assembly; the waste liquid in the reaction tank enters the waste liquid tank through the first communication hole, the second three-way valve and the delivery pipe, or enters the waste liquid tank through the second communication hole, the third three-way valve and the delivery pipe. When the reaction tank is large, a larger stirring paddle is required, which brings a certain dead volume, and the structure can realize forward washing and reverse washing, effectively solving the problem of incomplete cleaning in some positions.

[0014] Preferably, a temperature control jacket is further arranged outside the reaction tank, which is used for controlling the reaction condition and reducing the occurrence of side reactions.

[0015] The beneficial effects of the utility model are as follows:

[0016] (1) The solid phase carrier is compacted during the cleaning process, and the reaction tank and the solid phase carrier are cleaned by using a flowing liquid mode, which greatly

[0017] reduces the use of solvents, and can reduce the solvent for the entire solid phase synthesis by about two-thirds;

[0018] (2) The piston position is dynamically adjusted according to the expansion of the solid phase carrier during the reaction process and the cleaning process, effectively solving the problem that the volume of the reaction tank cannot be adjusted in the traditional continuous flow synthesis process;

[0019] (3) The valve and the pipeline are increased, forward washing and reverse washing are realized, and the problem of dead angle caused by the large cross-section stirring paddle of the large reaction tank and the problem of difficult cleaning are effectively solved;

[0020] (4) The closed reaction can be realized, the oxygen and moisture in the air are isolated, and the occurrence of side reactions is effectively avoided;

[0021] (5) The sampling and emptying port is arranged, and the problem of difficult sampling in the traditional reaction kettle and the continuous flow synthesis process is solved;

[0022] (6) The inclined insertion sampling port is arranged, and the deposition of the solid phase carrier and the reaction liquid in the sampling port pipeline is avoided. BRIEF DESCRIPTION OF DRAWINGS

[0023] In order to more clearly illustrate the technical scheme of the utility model, the following will briefly introduce the drawings needed to be used in the embodiment or the prior art description, and obviously, the drawings in the following description are only some embodiments of the utility model, and those skilled in the art can also obtain other drawings according to these drawings without creating creative labor.

[0024] Figure 1 It is a structural schematic view of the embodiment 1 of the utility model;

[0025] Figure 2 It is a structural schematic view of the piston assembly and the stirring assembly of the embodiment 1;

[0026] Figure 3 It is a structural schematic view of the lower end cover of the embodiment 1;

[0027] Figure 4 It is a structural schematic view of the embodiment 2 of the utility model;

[0028] Figure 5 It is a structural schematic view of the piston assembly of the embodiment 2;

[0029] Figure 6 It is a structural schematic view of the lower end cover and the stirring assembly of the embodiment 2;

[0030] Figure 7 It is a structural schematic view of the embodiment 3 of the utility model;

[0031] Figure 8 It is a structural schematic view of the piston assembly of the embodiment 3;

[0032] Figure 9 It is a structural schematic view of the lower end cover and the stirring assembly of the embodiment 3;

[0033] Wherein, 1-liquid delivery device, 1-1-liquid storage tank, 1-2-multichannel selector valve, 1-3-pump, 2-gas conduit, 3-piston assembly, 3-1-piston rod, 3-2-piston head, 3-3-distributor, 3-4-first sieve plate, 3-5-sealing ring, 3-6-motor, 4-reaction tank, 5-sampling and emptying device, 6-stirring assembly, 6-1-transmission rod, 6-2-transmission rod, 6-3-liquid inlet and outlet, 6-4-liquid seal plate, 6-5-stirring paddle, 7-lower end cover, 7-1-second sieve plate, 7-2-bottom cover, 8-waste liquid tank, 9-reaction tank support device, 10-temperature control jacket, 11-three-way valve assembly, 11-1-first three-way valve, 11-2-second three-way valve, 11-3-third three-way valve. DETAILED DESCRIPTION

[0034] The technical solutions in the embodiments of the utility model will be clearly and completely described below with reference to the drawings in the embodiments of the utility model. Obviously, the described embodiments are only part of the embodiments of the utility model, rather than all the embodiments. Based on the embodiments in the utility model, all other embodiments obtained by those skilled in the art without creative labor fall within the protection scope of the utility model.

[0035] Embodiment 1

[0036] As shown in Figure 1 A solid phase synthesis device, comprising a solid phase synthesis device, comprising: liquid delivery device 1, gas conduit 2, piston assembly 3, reaction tank 4, sampling and emptying device 5, stirring assembly 6, lower end cover 7, waste liquid tank 8, reaction tank support device 9, temperature control jacket 10 and conveying pipeline;

[0037] Among them, the liquid delivery device 1 comprises: liquid storage tank 1-1, multi-channel selection valve 1-2, pump 1-3; the liquid storage tank 1-1 is connected with the multi-channel selection valve 1-2 and the pump 1-3 in sequence through the conveying pipeline;

[0038] The piston assembly 3 comprises: piston rod 3-1, piston head 3-2, distributor 3-3, first sieve plate 3-4, sealing ring 3-5 and motor 3-6, the piston head 3-2 is installed on the piston rod 3-1, the distributor 3-3 is placed below the piston head 3-2, the first sieve plate 3-4 is placed below the distributor 3-3, the sealing ring 3-5 is placed between the piston head 3-2 and the inner wall of the reaction tank 4, used for sealing the gap between the piston assembly and the reaction tank, the piston assembly 3 is inserted into the inside of the reaction tank 4, and can move up and down along the inner wall of the reaction tank 4 through the motor 3-6;

[0039] The first communication hole is arranged on the piston assembly 3, the reaction tank 4 is communicated with the liquid delivery device 1 and the gas conduit 2 through the first communication hole; the sampling and emptying device 5 is placed on the side of the reaction tank 4, below the piston assembly and above the liquid level during solid phase synthesis;

[0040] The stirring assembly 6 comprises: piston rod 3-1, stirring motor 6-2, liquid inlet and outlet 6-3, liquid seal plate 6-4, stirring paddle 6-5, the stirring assembly is installed on the piston assembly 3, the stirring paddle 6-5 is fixed on the piston rod 3-1 and faces the inside of the reaction tank, the piston rod 3-1 and the stirring paddle 6-5 are driven by the stirring motor 6-2; the first communication hole is communicated with the liquid inlet and outlet 6-3 on the liquid seal plate (6-4);

[0041] The lower end cover 7 comprises a second sieve plate 7-1 and a bottom cover 7-2, the second sieve plate 7-1 is placed on the bottom cover 7-2, the second sieve plate has a smaller diameter than the solid phase carrier, preventing the solid phase carrier from leaking out, the second communication hole is arranged on the lower end cover 7, the reaction tank 4 is communicated with the waste liquid tank 8 through the second communication hole; the reaction tank support device 9 is placed on the outer wall of the reaction tank, and the temperature control jacket 10 is arranged on the outside of the reaction tank 4.

[0042] Work flow (for the convenience of description, the solvents, reagents and operation parameters used in the reaction are only for example purposes):

[0043] a) Solid phase carrier swelling: open the sampling vent 5, start the motor 3-6, lift the piston assembly 3 by the piston rod 3-1, pour 1200 g of solid phase carrier into the cavity of the reactor tank 4. Use the motor 3-6 to cover the reactor tank 4 by the piston assembly 3 through the piston rod 3-1. Switch the multi-channel switch valve 1-2 to the dissolving and washing solvent tank 1-1, and use the pump 1-3 to deliver 10200 ml of solution into the reactor tank 4. Close the sampling vent 5, and start the stirring motor 6-2 to drive the stirring paddle 6-5 through the piston rod 3-1 to stir the reaction solution in the reactor tank 4;

[0044] b) Solid phase carrier washing: close the sampling vent 5, start the motor 3-6, and adjust the piston assembly 3 to contact the solid phase carrier and then press it down by 0.2 cm through the piston rod 3-1. At this time, the height of the solid phase carrier is about 17 cm. Switch the multi-channel switch valve 1-2 to the dissolving and washing solvent tank, and use the pump 1-3 to deliver 4800 ml of solution into the reactor tank 4. The washing solution is discharged from the lower end cover 7 to the waste liquid tank 8. Open the compressed air or nitrogen gas conduit 2 to blow out the residual liquid in the gap of the solid phase carrier in the reactor tank 4;

[0045] c) Solid phase carrier coupling: open the sampling vent 5, start the motor 3-6, and lift the piston assembly 3 by the piston rod 3-1. Switch the multi-channel switch valve 1-2 to the material tank 1-1, the condensing agent tank, and the solution tank in sequence, and use the pump 1-3 to deliver a total of 4800 ml of solution into the reactor tank 4. Make the piston assembly 3 have a gap of 1-5 cm from the liquid surface, and at this time, the total height in the cavity of the reactor tank 4 is between 21-25 cm. Close the sampling vent 5, and start the stirring motor 6-2 to drive the stirring paddle 6-5 through the piston rod 3-1 to stir the reaction solution in the reactor tank 4;

[0046] d) Solid phase carrier detection: close the stirring motor 6-2, open the sampling vent 5, and perform sampling detection. After the reaction is completed, proceed to the next step;

[0047] e) Post-coupling solid phase carrier washing:

[0048] Close the sampling vent 5, start the motor 3-6, and adjust the piston assembly 3 to contact the solid phase carrier and then press it down by 0.2 cm through the piston rod 3-1. At this time, the height of the solid phase carrier is about 17 cm. Switch the multi-channel switch valve 1-2 to the dissolving and washing solvent tank, and use the pump 1-3 to deliver 9000 ml of solution into the reactor tank 4. The washing solution is discharged from the lower end cover 7 to the waste liquid tank 8. Open the compressed air or nitrogen gas conduit 2 to blow out the residual liquid in the gap of the solid phase carrier in the reactor tank 4;

[0049] f) deprotection: open the sampling and venting device 5, start the motor 3-6, lift the piston assembly 3 by the piston rod 3-1, switch the multi-channel switch valve 1-2 to the deprotection liquid tank and the washing solvent tank, and deliver 12000ml of solution to the reaction tank 4 by the pump 1-3. The piston assembly 3 is 1-5cm apart from the liquid level. Close the sampling and venting device 5. Start the stirring motor 6-2 to drive the stirring paddle 6-5 by the piston rod 3-1 to stir the reaction liquid in the reaction tank 4;

[0050] g) solid phase carrier detection: close the stirring motor 6-2, open the sampling and venting device 5, and perform sampling detection. After the reaction is completed, proceed to the next step;

[0051] h) post-deprotection washing:

[0052] Close the sampling and venting device 5, start the motor 3-6, and adjust the piston assembly 3 to be in contact with the solid phase carrier and then press it down by 0.2cm by the piston rod 3-1. At this time, the height of the solid phase carrier is about 17cm. Switch the multi-channel switch valve 1-2 to the dissolution and washing solvent tank, deliver 10800ml of solution to the reaction tank 4 by the pump 1-3, and discharge the washing liquid from the lower end cover 7 to the waste liquid tank 8. Open the compressed air or nitrogen gas conduit 2 to blow out the residual liquid in the gap between the solid phase carrier in the reaction tank 4. Perform gas phase detection on the last blowout liquid, and the piperidine content is 92ppm, which meets the limit requirement;

[0053] j) when the reaction needs to be carried out in a closed manner, the sampling and venting device can be closed; when nitrogen protection is needed, open the sampling and venting device 5, and use nitrogen to replace the air inside the reaction tank 4;

[0054] k) repeat the operations of c, d, e, f, g, and h to couple each amino acid.

[0055] l) the amount of washing solvent used after each amino acid coupling and deprotection is 19800ml.

[0056] Example 2

[0057] As shown in Figure 4 , a solid phase synthesis device includes a liquid delivery device 1, a gas conduit 2, a piston assembly 3, a reaction tank 4, a sampling and venting device 5, a stirring assembly 6, a lower end cover 7, a waste liquid tank 8, a reaction tank support device 9, a temperature control jacket 10, and a delivery pipeline;

[0058] The liquid delivery device 1 comprises a liquid storage tank 1-1, a multi-channel selection valve 1-2, and a pump 1-3; the liquid storage tank 1-1 is connected to the multi-channel selection valve 1-2 and the pump 1-3 in sequence through a delivery pipeline;

[0059] The piston assembly 3 comprises a piston rod 3-1, a piston head 3-2, a distributor 3-3, a first sieve plate 3-4, a sealing ring 3-5, and a motor 3-6; the piston head 3-2 is installed on the piston rod 3-1; the distributor 3-3 is arranged below the piston head 3-2; the first sieve plate 3-4 is arranged below the distributor 3-3; the sealing ring 3-5 is arranged between the piston head 3-2 and the inner wall of the reaction tank 4, and is used for sealing the gap between the piston assembly and the reaction tank; the piston assembly 3 is inserted into the inside of the reaction tank 4, and can move up and down along the inner wall of the reaction tank 4 through the motor 3-6;

[0060] A first communication hole is arranged on the piston assembly 3; the reaction tank 4 is communicated with the liquid delivery device 1 and the gas pipeline 2 through the first communication hole; a sampling and emptying device 5 is arranged on the side of the reaction tank 4, below the piston assembly and above the liquid surface during solid-phase synthesis;

[0061] The stirring assembly 6 comprises a transmission rod 6-1, a stirring motor 6-2, a liquid inlet and outlet 6-3, a liquid seal plate 6-4, and a stirring paddle 6-5; the stirring assembly is installed below the lower end cover 7; the stirring paddle 6-5 is fixed on the transmission rod 6-1 and faces the inside of the reaction tank; the transmission rod 6-1 and the stirring paddle 6-5 are driven by the stirring motor 6-2; a second communication hole is arranged on the liquid seal plate 6-4 and communicated with the liquid inlet and outlet 6-3;

[0062] The lower end cover 7 comprises a second sieve plate 7-1 and a bottom cover 7-2; the second sieve plate 7-1 is arranged above the bottom cover 7-2; the second sieve plate has a smaller hole diameter than the solid-phase carrier, so as to prevent the solid-phase carrier from leaking out; a second communication hole is arranged on the lower end cover 7; the reaction tank 4 is communicated with the waste liquid tank 8 through the second communication hole; a reaction tank supporting device 9 is arranged on the outer wall of the reaction tank; a temperature control jacket 10 is arranged on the outside of the reaction tank 4.

[0063] Work flow (for the convenience of description, the solvents, reagents and operation parameters used in the reaction are only for example purposes):

[0064] a) Solid-phase carrier swelling: open the sampling and emptying device 5, start the motor 3-6, and completely lift the piston assembly 3 through the piston rod 3-1; pour 1200g of solid-phase carrier into the cavity of the reaction tank 4; use the motor 3-6 to cover the reaction tank 4 with the piston assembly 3 through the piston rod 3-1; switch the multi-channel selection valve 1-2 to the 1-1 dissolved and washed solvent tank; deliver 10800ml of solution to the reaction tank 4 through the pump 1-3; close the sampling and emptying device 5, and start the stirring motor 6-2 to drive the stirring paddle 6-5 through the transmission rod 6-1, so as to stir the reaction liquid in the reaction tank 4;

[0065] b) solid phase carrier washing: close the sampling vent 5, open the motor 3-6, adjust the piston assembly 3 to contact the solid phase carrier by the piston rod 3-1 and then press it down 0.2 cm again, at this time the height of the solid phase carrier is about 17 cm. Switch the multi-channel switch valve 1-2 to the dissolving and washing solvent tank, and then pump 1-3 to deliver 4800 ml of solution into the reaction tank 4, and the washing liquid is discharged from the lower end cover 7 to the waste liquid tank 8. Open the compressed air or nitrogen gas conduit 2 to blow out the residual liquid in the gap of the solid phase carrier in the reaction tank 4;

[0066] c) solid phase carrier coupling: open the sampling vent 5, open the motor 3-6, lift the piston assembly 3 by the piston rod 3-1, and then switch the multi-channel switch valve 1-2 to the material tank, the condensing agent tank and the solution tank in turn, and then pump 1-3 to deliver a total of 4800 ml of solution into the reaction tank 4. Make the piston assembly 3 have a gap of 1-5 cm from the liquid surface, at this time the total height in the cavity of the reaction tank 4 is between 21-25 cm. Close the sampling vent 5. Open the stirring motor 6-2 to drive the stirring paddle 6-5 through the transmission rod 6-1 to stir the reaction liquid in the reaction tank 4;

[0067] d) solid phase carrier detection: close the stirring motor 6-2, open the sampling vent 5, and then sample and detect, and then enter the next step after the reaction is completed;

[0068] e) washing of the solid phase carrier after coupling:

[0069] Close the sampling vent 5, open the motor 3-6, adjust the piston assembly 3 to contact the solid phase carrier by the piston rod 3-1 and then press it down 0.2 cm again, at this time the height of the solid phase carrier is about 17 cm. Switch the multi-channel switch valve 1-2 to the dissolving and washing solvent tank, and then pump 1-3 to deliver 4800 ml of solution into the reaction tank 4, and the washing liquid is discharged from the lower end cover 7 to the waste liquid tank 8. Open the compressed air or nitrogen gas conduit 2 to blow out the residual liquid in the gap of the solid phase carrier in the reaction tank 4;

[0070] f) deprotection: open the sampling vent 5, open the motor 3-6, lift the piston assembly 3 by the piston rod 3-1, and then switch the multi-channel switch valve 1-2 to the deprotection liquid tank and the washing solvent tank, and then pump 1-3 to deliver 12000 ml of solution into the reaction tank 4. Make the piston assembly 3 have a gap of 1-5 cm from the liquid surface. Close the sampling vent 5. Open the stirring motor 6-2 to drive the stirring paddle 6-5 through the transmission rod 6-1 to stir the reaction liquid in the reaction tank 4;

[0071] g) solid phase carrier detection: close the stirring motor 6-2, open the sampling vent 5, and then sample and detect, and then enter the next step after the reaction is completed;

[0072] h) Cleaning after deprotection: Close the sampling venting device 5, turn on the motor 3-6, and adjust the piston assembly 3 to contact the solid support using the piston rod 3-1, then press it down another 0.2 cm. At this point, the solid support height is approximately 17 cm. Switch the multi-channel switching valve 1-2 to the dissolution and cleaning solvent tank, and pump 1-3 to deliver 10800 ml of solution to the reaction tank 4. The cleaning solution is discharged from the lower end cover 7 into the waste liquid tank 8. Open the compressed air or nitrogen gas conduit 2 to blow out the residual liquid in the gap between the solid support in the reaction tank 4; perform gas phase analysis on the last blown-out liquid, and the piperidine content is 90 ppm, which meets the limit requirements.

[0073] i) Repeat steps c, d, e, f, g, and h in a cyclical manner to couple the solid-phase carrier until all sequence connections are completed. During the process, the height of piston assembly 3 needs to be adjusted according to the actual situation.

[0074] j) When the reaction needs to be carried out in a closed system, the sampling and venting device 5 can be turned off; when nitrogen protection is required, the sampling and venting device 5 can be turned on and nitrogen can be used to replace the air inside the reaction vessel 4.

[0075] k) Repeat steps c, d, e, f, g, and h to couple each amino acid;

[0076] l) The amount of solvent used for washing after each amino acid coupling and after deprotection is 19800 ml.

[0077] Example 3

[0078] like Figure 7 As shown, a solid-phase synthesis apparatus includes: a liquid conveying device 1, a gas conduit 2, a piston assembly 3, a reaction vessel 4, a sampling and venting device 5, a stirring assembly 6, a lower end cover 7, a waste liquid tank 8, a reaction vessel support device 9, a temperature control jacket 10, and a conveying pipeline.

[0079] The liquid conveying device 1 includes: a liquid storage tank 1-1, a multi-channel selector valve 1-2, and a pump 1-3; the liquid storage tank 1-1 is connected to the multi-channel selector valve 1-2 and the pump 1-3 in sequence through a conveying pipeline;

[0080] Piston assembly 3 includes: piston rod 3-1, piston head 3-2, distributor 3-3, first sieve plate 3-4, sealing ring 3-5, and motor 3-6. Piston head 3-2 is mounted on piston rod 3-1, distributor 3-3 is placed below piston head 3-2, first sieve plate 3-4 is placed below distributor 3-3, and sealing ring 3-5 is placed between piston head 3-2 and the inner wall of reaction vessel 4 to seal the gap between piston assembly and reaction vessel. Piston assembly 3 is inserted into the interior of reaction vessel 4 and can move up and down along the inner wall of reaction vessel 4 via motor 3-6.

[0081] The piston assembly 3 is provided with a first communication hole, the reaction tank 4 is communicated with the liquid delivery device 1 and the gas conduit 2 through the first communication hole; the sampling and emptying device 5 is arranged on the side of the reaction tank 4, below the piston assembly and above the liquid surface during solid-phase synthesis;

[0082] The stirring assembly 6 comprises a transmission rod 6-1, a stirring motor 6-2, a liquid inlet and outlet 6-3, a liquid seal plate 6-4 and a stirring paddle 6-5, the stirring assembly is installed below the lower end cover 7, the stirring paddle 6-5 is fixed on the transmission rod 6-1 and faces the inside of the reaction tank, the transmission rod 6-1 and the stirring paddle 6-5 are driven by the stirring motor 6-2; a second communication hole is communicated with the liquid inlet and outlet 6-3 on the liquid seal plate 6-4;

[0083] The lower end cover 7 comprises a second sieve plate 7-1, a bottom cover 7-2 and a distributor 7-3, the second sieve plate 7-1 is arranged above the bottom cover 7-2, the second sieve plate has a smaller hole diameter than the diameter of the solid-phase carrier, so as to prevent the solid-phase carrier from leaking out, the lower end cover 7 is provided with a second communication hole, the reaction tank 4 is communicated with the waste liquid tank 8 through the second communication hole; the reaction tank support device 9 is arranged on the outer wall of the reaction tank, and the outer side of the reaction tank 4 is provided with a temperature control jacket 10.

[0084] The conveying pipeline is provided with a three-way valve assembly 11, the three-way valve assembly 11 comprises a first three-way valve 11-1, a second three-way valve 11-2 and a third three-way valve 11-3, the liquid of the liquid delivery device 1 is selected to enter the first communication hole or the second communication hole through the three-way valve assembly 11-1; the waste liquid in the reaction tank enters the waste liquid tank 8 through the first communication hole, the first three-way valve 11-2 and the conveying pipeline, or enters the waste liquid tank 8 through the second communication hole, the third three-way valve 11-3 and the conveying pipeline.

[0085] Work flow (for the convenience of description, the solvents, reagents and operation parameters used in the reaction are only for example purposes):

[0086] a) solid phase carrier swelling: open the valve of the sampling and emptying device 5, start the motor 3-6, and lift the piston assembly 3 completely by the piston rod 3-1, pour 1200g of the solid phase carrier into the cavity of the reaction tank 4, cover the reaction tank 4 with the piston assembly 3 by the piston rod 3-1 using the motor 3-6, switch the multi-channel switch valve 1-2 to the dissolving and washing solvent tank 1-1, and deliver 10800ml of the solution into the reaction tank 4 by the pump 1-3, close the sampling and emptying device 5, and start the stirring motor 6-2 to drive the stirring paddle 6-5 by the transmission rod 6-1 to stir the reaction liquid in the reaction tank 4; b) solid phase carrier washing: close the sampling and emptying device 5, start the motor 3-6, and adjust the piston assembly 3 to contact the solid phase carrier and then press it down by 0.2cm by the piston rod 3-1, at this time the height of the solid phase carrier is about 17cm, switch the multi-channel switch valve 1-2 to the dissolving and washing solvent tank, deliver 5400ml of the solution into the reaction tank 4 by the pump 1-3, and discharge the washing liquid from the lower end cover 7 to the waste liquid tank 8, open the compressed air or nitrogen gas conduit 2 to blow out the residual liquid in the gap of the solid phase carrier in the reaction tank 4;

[0087] c) solid phase carrier coupling: open the valve of the sampling and emptying device 5, start the motor 3-6, and lift the piston assembly 3 by the piston rod 3-1, switch the multi-channel switch valve 1-2 to the material tank, the condensing agent tank and the solution tank 1-1 in sequence, and deliver a total of 4800ml of the solutions into the reaction tank 4 by the pump 1-3, make the piston assembly 3 have a gap of 1-5cm from the liquid surface, at this time the total height in the cavity of the reaction tank 4 is between 21-25cm, close the sampling and emptying device 5, and start the stirring motor 6-2 to drive the stirring paddle 6-5 by the transmission rod 6-1 to stir the reaction liquid in the reaction tank 4;

[0088] d) solid phase carrier detection: close the stirring motor 6-2, open the valve of the sampling and emptying device 5, and perform sampling detection, after the reaction is completed, proceed to the next step;

[0089] e) post-coupling solid phase carrier washing:

[0090] close the sampling and emptying device 5, start the motor 3-6, and adjust the piston assembly 3 to contact the solid phase carrier and then press it down by 0.2cm by the piston rod 3-1, at this time the height of the solid phase carrier is about 17cm, switch the multi-channel switch valve 1-2 to the dissolving and washing solvent tank, deliver 9600ml of the solution into the reaction tank 4 by the pump 1-3, and discharge the washing liquid from the lower end cover 7 to the waste liquid tank 8, open the compressed air or nitrogen gas conduit 2 to blow out the residual liquid in the gap of the solid phase carrier in the reaction tank 4;

[0091] f) deprotection: open the valve of the sampling and emptying device 5, start the motor 3-6, lift the piston assembly 3 by the piston rod 3-1, switch the multi-channel switch valve 1-2 to the deprotection liquid tank and the washing solvent tank, and deliver 12000ml of solution into the reaction tank 4 by the pump 1-3. Make the piston assembly 3 have a gap of 1-5cm from the liquid level. Close the sampling and emptying device 5. Start the stirring motor 6-2 to drive the stirring paddle 6-5 by the transmission rod 6-1, and stir the reaction liquid in the reaction tank 4;

[0092] g) solid phase carrier detection: close the stirring motor 6-2, open the valve of the sampling and emptying device 5, and perform sampling detection. After the reaction is completed, proceed to the next step;

[0093] h) post-deprotection washing: close the sampling and emptying device 5, start the motor 3-6, and adjust the piston assembly 3 to be in contact with the solid phase carrier and then press it down by 0.2cm again by the piston rod 3-1. At this time, the height of the solid phase carrier is about 17cm. Switch the multi-channel switch valve 1-2 to the dissolution and washing solvent tank, connect the first three-way valve 11-1 to the third three-way valve 11-3, and connect the third three-way valve 11-3 to the second communication hole. Deliver 8400ml of solution into the reaction tank 4 by the pump 1-3, and the washing liquid is discharged from the piston assembly 3 and the second three-way valve 11-2 to the waste liquid tank 8. Open the compressed air or nitrogen gas conduit 2 to blow out the residual liquid in the gap of the solid phase carrier in the reaction tank 4. To prevent incomplete washing, perform secondary washing. At this time, the washing liquid enters from the lower end cover. The specific operation is as follows: switch the multi-channel switch valve 1-2 to the dissolution and washing solvent tank, connect the first three-way valve 11-1 to the second three-way valve 11-2, and connect the second three-way valve 11-2 to the first communication hole. Deliver 4800ml of solution into the reaction tank 4 by the pump 1-3, and the washing liquid is discharged from the lower end cover 7 and the third three-way valve 11-3 to the waste liquid tank 8. Open the compressed air or nitrogen gas conduit 2 to blow out the residual liquid in the gap of the solid phase carrier in the reaction tank 4. Perform gas phase detection on the last blown-out liquid, and the piperidine content is 70ppm, which meets the limit requirement;

[0094] i) repeat c, d, e, f, g, h, and perform cyclic operation to couple the solid phase carrier until all sequence connections are completed. Adjust the height of the piston assembly 3 according to the actual situation during the process;

[0095] j) when the reaction needs to be carried out in a sealed manner, the sampling and emptying device 5 can be closed. When nitrogen protection is needed, open the sampling and emptying device 5, and use nitrogen to replace the air inside the reaction tank 4;

[0096] k) repeat the operations of c, d, e, f, g, and h to couple each amino acid;

[0097] l) the amount of washing solvent used after each amino acid coupling and after deprotection is 22800ml.

[0098] Comparative Example

[0099] a) Swelling of solid phase carrier: A glass reaction tank was used, 1200g of solid phase carrier was weighed into it. 10200ml of solvent was added, and the solid phase carrier was swelled by stirring;

[0100] b) Washing of solid phase carrier: The reaction liquid was pumped out using the bottom vacuum liquid discharge device, after discharge, 7800ml of solution was added, and the liquid was discharged again by stirring, and the operation was repeated twice, a total of 15600ml of solution was used;

[0101] c) Coupling of solid phase carrier: After the material was dissolved, the solution and condensing agent, a total of 4800ml, were added to the reaction tank. Stirring was started, and coupling was carried out;

[0102] d) Detection of solid phase carrier: After the reaction was completed, the next step was entered after sampling detection showed;

[0103] e) Washing of solid phase carrier after coupling: The reaction liquid was pumped out using the bottom vacuum liquid discharge device, after discharge, 8400ml of solution was added, and the liquid was discharged again by stirring, and the operation was repeated three times, a total of 25200ml of solution was used;

[0104] f) Deprotection: 12000ml of deprotection solution was added to the reaction tank. Stirring was started, and the solid phase carrier was deprotected;

[0105] g) Detection of solid phase carrier: After the deprotection was completed, the next step was entered after sampling detection showed;

[0106] h) Washing after deprotection: The reaction liquid was pumped out using the bottom vacuum liquid discharge device, after discharge, 8400ml of solution was added, and the liquid was discharged again by stirring, and the operation was repeated six times, a total of 50400ml of solution was used; The last discharge liquid was detected by gas phase,

[0107] The piperidine content is 110ppm, which meets the limit requirement;

[0108] i) → Repeat the coupling operation steps c, d, e, f, g, h until the sequence coupling is completed, once coupling repeats the operation, that is, the operation steps c, d, e, f, g, h, and the amount of washing solvent used after coupling and deprotection is 75600ml.

[0109] By comparison, the amount of solvent used for washing after each amino acid coupling and deprotection using the utility model type solid phase synthesis device is 19800ml, 19800ml, and 22800ml, respectively, compared with the traditional glass reaction tank using solvent 75600ml, each step of amino acid coupling reaction can save 73.81%, 73.81%, and 69.84% of the solvent usage.

[0110] In the utility model, the "up" and "down" directions refer to the two directions of up and down in nature in the using state.

[0111] The above is only a preferred embodiment of the utility model, and of course cannot limit the scope of the utility model, so equivalent changes made according to the utility model claims still belong to the scope covered by the utility model.

Claims

1. A solid phase synthesis apparatus comprising: Liquid delivery device (1), gas conduit (2), piston assembly (3), reaction tank (4), sampling and emptying device (5), stirring assembly (6), lower end cover (7), waste liquid tank (8), reaction tank support device (9) and delivery pipeline; Its characterized in that: The liquid delivery device (1) comprises a liquid storage tank (1-1), a multi-channel selector valve (1-2) and a pump (1-3), and the liquid storage tank (1-1) is connected to the multi-channel selector valve (1-2) and the pump (1-3) in sequence through the delivery pipeline; The piston assembly (3) comprises a piston rod (3-1), a piston head (3-2), a distributor (3-3), a first sieve plate (3-4), a sealing ring (3-5) and a motor (3-6), the piston head (3-2) is installed on the piston rod (3-1), the distributor (3-3) is arranged below the piston head (3-2), the first sieve plate (3-4) is arranged below the distributor (3-3), and the sealing ring (3-5) is arranged between the piston head (3-2) and the inner wall of the reaction tank (4) to seal the gap between the piston assembly (3) and the reaction tank (4); the piston assembly (3) is inserted into the inside of the reaction tank (4) and can move up and down along the inner wall of the reaction tank (4); a first communication hole is formed in the piston assembly (3), and the reaction tank (4) is communicated with the liquid delivery device (1) and the gas conduit (2) through the first communication hole and the delivery pipeline; The sampling and emptying device (5) is arranged on the side of the reaction tank (4) below the piston assembly and above the liquid surface during solid-phase synthesis; The stirring assembly (6) comprises a transmission rod (6-1), a stirring motor (6-2), a liquid inlet and outlet (6-3), a liquid seal plate (6-4) and a stirring paddle (6-5); The stirring assembly is installed on the piston assembly (3) or below the lower end cover (7), the stirring paddle (6-5) is fixed to the transmission rod (6-1) and faces the inside of the reaction tank, and the transmission rod (6-1) and the stirring paddle (6-5) are driven by the stirring motor (6-2); The lower end cover (7) comprises a second sieve plate (7-1) and a bottom cover (7-2), the second sieve plate (7-1) is arranged above the bottom cover (7-2), the second sieve plate has a smaller hole diameter than the diameter of the solid-phase carrier to prevent the solid-phase carrier from leaking out, and a second communication hole is formed in the lower end cover (7), and the reaction tank (4) is communicated with the waste liquid tank (8) through the second communication hole and the delivery pipeline; The reaction tank support device (9) is arranged on the outer wall of the reaction tank (4); When the stirring assembly is installed on the piston assembly (3), the transmission rod (6-1) is the piston rod (3-1), and the first communication hole is communicated with the liquid inlet and outlet (6-3) on the liquid seal plate (6-4); When the stirring assembly is installed below the lower end cover (7), the second communication hole is communicated with the liquid inlet and outlet (6-3) on the liquid seal plate (6-4). A temperature control jacket (10) is further arranged on the outside of the reaction tank (4).

2. The solid phase synthesis apparatus of claim 1, wherein ​ 3. The solid phase synthesis apparatus of claim 1, wherein When the stirring assembly (6) is installed below the lower end cover (7), the lower end cover increases the lower end cover distributor (7-3), and meanwhile increases the conveying pipeline so that the first communication hole is communicated with the waste liquid tank (8), and the second communication hole is communicated with the liquid conveying device (1) and the gas guide pipe (2); the three-way valve assembly (11) is increased on the conveying pipeline, which includes a first three-way valve (11-1), a second three-way valve (11-2) and a third three-way valve (11-3), and the liquid of the liquid conveying device (1) is selected to enter the first communication hole or the second communication hole through the three-way valve assembly (11); the waste liquid in the reaction tank enters the waste liquid tank (8) through the first communication hole, the second three-way valve (11-2) and the conveying pipeline, or enters the waste liquid tank (8) through the second communication hole, the third three-way valve (11-3) and the conveying pipeline.

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