CN111939854A - Solid-phase synthesis product cutting deprotection system and method - Google Patents
Solid-phase synthesis product cutting deprotection system and method Download PDFInfo
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- CN111939854A CN111939854A CN202010873513.9A CN202010873513A CN111939854A CN 111939854 A CN111939854 A CN 111939854A CN 202010873513 A CN202010873513 A CN 202010873513A CN 111939854 A CN111939854 A CN 111939854A
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- 238000005520 cutting process Methods 0.000 title claims abstract description 268
- 238000010511 deprotection reaction Methods 0.000 title claims abstract description 189
- 238000010532 solid phase synthesis reaction Methods 0.000 title claims abstract description 116
- 238000000034 method Methods 0.000 title claims abstract description 8
- 238000006243 chemical reaction Methods 0.000 claims description 111
- 239000003153 chemical reaction reagent Substances 0.000 claims description 50
- 239000012459 cleaning agent Substances 0.000 claims description 35
- 239000003795 chemical substances by application Substances 0.000 claims description 33
- 238000007599 discharging Methods 0.000 claims description 24
- 238000003776 cleavage reaction Methods 0.000 claims description 23
- 230000007017 scission Effects 0.000 claims description 22
- 239000003755 preservative agent Substances 0.000 claims description 11
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 5
- 239000007788 liquid Substances 0.000 description 17
- 238000004140 cleaning Methods 0.000 description 10
- 238000004321 preservation Methods 0.000 description 7
- 230000009471 action Effects 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 238000005070 sampling Methods 0.000 description 6
- 239000000523 sample Substances 0.000 description 5
- 239000002699 waste material Substances 0.000 description 4
- 230000002335 preservative effect Effects 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000002349 favourable effect Effects 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000036632 reaction speed Effects 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 230000004075 alteration Effects 0.000 description 1
- 238000010923 batch production Methods 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000012351 deprotecting agent Substances 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J19/0006—Controlling or regulating processes
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J4/00—Feed or outlet devices; Feed or outlet control devices
- B01J4/001—Feed or outlet devices as such, e.g. feeding tubes
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J4/00—Feed or outlet devices; Feed or outlet control devices
- B01J4/008—Feed or outlet control devices
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2204/00—Aspects relating to feed or outlet devices; Regulating devices for feed or outlet devices
- B01J2204/002—Aspects relating to feed or outlet devices; Regulating devices for feed or outlet devices the feeding side being of particular interest
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- Chemical & Material Sciences (AREA)
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Abstract
The invention belongs to the field of solid phase synthesis, and discloses a solid phase synthesis product cutting deprotection system and a method, wherein the solid phase synthesis product cutting deprotection system comprises a feeding assembly, a solid phase synthesis cutting assembly and a deprotection reaction device; the feeding assembly comprises an inlet end and an outlet end, the outlet end of the feeding assembly is communicated with the inlet end of the solid-phase synthesis cutting assembly, the outlet end of the solid-phase synthesis cutting assembly is communicated with the inlet end of the deprotection reaction device, the outlet end of the deprotection reaction device is provided with a plurality of outlet ends, and at least one outlet end of the deprotection reaction device is a discharge port. The solid-phase synthesis product cutting and the deprotection reaction of the cutting product are continuously carried out, and the large-scale production can be realized.
Description
Technical Field
The invention belongs to the field of solid phase synthesis, and particularly relates to a solid phase synthesis product cutting deprotection system and a solid phase synthesis product cutting deprotection method.
Background
Solid phase synthesis refers to a synthetic method in which reactants are attached to an insoluble solid phase support, and after completion of the solid phase synthesis reaction, the solid phase synthesis product is cleaved from the support and deprotected to obtain the product. At present, most of solid-phase synthesis products are cut and deprotected in a small scale in a laboratory, and large-scale batch production is not performed, for example, a shaking table is adopted, after a preset reaction time is reached, sampling detection is performed, whether the reaction is complete or the reaction rate reaches a preset value is observed, if so, the reaction is stopped, and if not, the reaction is continued. The scheme can only complete small batch reaction each time, and can not achieve large-scale production.
Disclosure of Invention
The invention aims to overcome the defects of the prior art, provides a solid-phase synthesis product cutting deprotection system and a solid-phase synthesis product cutting deprotection method, and can realize large-scale production.
The technical scheme is as follows:
the solid-phase synthesis product cutting deprotection system comprises a feeding assembly, a solid-phase synthesis cutting assembly and a deprotection reaction device; the feeding assembly comprises an inlet end and an outlet end, the outlet end of the feeding assembly is communicated with the inlet end of the solid-phase synthesis cutting assembly, the outlet end of the solid-phase synthesis cutting assembly is communicated with the inlet end of the deprotection reaction device, the outlet end of the deprotection reaction device is provided with a plurality of outlet ends, and at least one outlet end of the deprotection reaction device is a discharge port.
When the solid-phase synthesis product is cut and subjected to deprotection reaction, a reaction reagent is introduced through the outlet end of the feeding assembly, enters the solid-phase synthesis cutting assembly, is subjected to cutting reaction in the solid-phase synthesis cutting assembly, and enters the deprotection reaction device along a pipeline after being cut, and is subjected to deprotection reaction in the deprotection reaction device to obtain a deprotection product, the deprotection product in the reaction process is discharged through the discharge port, manual material taking operation is not needed, and the deprotection reaction is also not needed through a shaking table, and the whole set of device is communicated from the feeding assembly to the final deprotection reaction protection device, so that continuous large-scale production is realized.
The solid-phase synthesis cutting assembly comprises a cutting valve group and a solid-phase synthesis cutting device, the cutting valve group is communicated with the solid-phase synthesis cutting device, and the inlet end and the outlet end of the cutting valve group form the inlet end and the outlet end of the solid-phase synthesis cutting assembly. The cutting valve set is connected with the solid-phase synthesis cutting device, the reaction reagent firstly passes through the cutting valve set, the flow direction is controlled, and then the reaction reagent enters the solid-phase synthesis cutting device, so that the cutting reaction can be controlled.
The cutting valve group comprises a first cutting valve, a second cutting valve, a third cutting valve, a fourth cutting valve, a first branch pipe and a second branch pipe, and the solid-phase synthesis cutting device comprises a cutting reaction column; the inlet ends and the outlet ends of the first branch pipe and the second branch pipe are communicated, the first cutting valve and the second cutting valve are installed on the first branch pipe, and the third cutting valve and the fourth cutting valve are installed on the second branch pipe; the starting end of the cutting reaction column is connected to the first branch pipe and located between the first cutting valve and the second cutting valve, and the tail end of the cutting reaction column is connected to the second branch pipe and located between the third cutting valve and the fourth cutting valve. The first cutting valve, the second cutting valve, the third cutting valve and the fourth cutting valve which are included by the cutting valve group are closed and opened to control the forward flow and the reverse flow of the reaction reagent so as to control the forward cutting and the reverse cutting of the cutting reaction column. When the cutting reaction column needs to be positively cut, the first cutting valve and the fourth cutting valve are opened, the second cutting valve and the third cutting valve are closed, the reaction reagent enters the first branch pipe through the first cutting valve at the moment and is then blocked by the second cutting valve, the reaction reagent enters the initial end of the cutting reaction column, the solid-phase synthesis product of the cutting reaction column is cut to form a cutting product, and then the cutting product and the reaction reagent flow into the second branch pipe together through the tail end of the cutting reaction column and flow out through the fourth cutting valve. When the cutting reaction column needs to be cut reversely, the first cutting valve and the fourth cutting valve are closed, the second cutting valve and the third cutting valve are opened, and the reaction reagent enters from the tail end of the cutting reaction column and flows out from the initial end.
The cutting valve assembly further comprises a fifth cutting valve and a third branch pipe, the inlet end and the outlet end of the third branch pipe are respectively communicated with the inlet ends and the outlet ends of the first branch pipe and the second branch pipe, and the fifth cutting valve is installed on the third branch pipe. When the reaction reagent directly crosses the cutting reaction column, the first cutting valve, the second cutting valve, the third cutting valve and the fourth cutting valve are closed, the fifth cutting valve is opened, and the reaction reagent directly enters the third branch pipe to bypass the cutting reaction column.
Pressure sensors are arranged at the inlet end and the outlet end of the solid-phase synthesis cutting assembly, so that the liquid pressure is detected in real time, and safety accidents caused by overlarge pressure are avoided.
The deprotection reaction device comprises a discharge port, the outlet end of the solid-phase synthesis cutting assembly is communicated with the discharge port, a tank bottom valve and an emptying valve are mounted on the discharge port, and the tank bottom valve of the discharge port of the deprotection reaction device is communicated with the feeding assembly. Cutting products and reaction reagents enter the deprotection reaction device through the discharge port, deprotection reaction is carried out on the cutting products at the position to form deprotection products, in order to enable the reaction to be more thorough, the discharge port of the deprotection reaction device is communicated with the feeding assembly, the tank bottom valve is opened, the reaction reagents, the deprotection products and the like enter the feeding assembly together, and then circular cutting and deprotection reaction are carried out until the complete or preset reaction rate is reached. The circular reaction can be beneficial to complete reaction, so that the labor is saved, and the reaction efficiency can be improved.
The row's entry is provided with a plurality ofly, and at least one is located deprotection reaction unit's top, deprotection reaction unit is inside to be provided with the shower head, the shower head with at least one be located deprotection reaction unit's top the row entry is linked together. The shower head can be with liquid dispersion, when wasing deprotection reaction unit's inside, disperses the cleaner through the shower head, is favorable to wasing.
The feeding assembly comprises a deprotection product branch pipe, a feeding branch pipe and a feeding valve, the feeding valve is installed on the feeding branch pipe, one end of the deprotection product branch pipe is communicated with the inlet end of the solid-phase synthesis cutting assembly, and the other end of the deprotection product branch pipe is communicated with the tank bottom valve. Wherein the inlet valve of the inlet branch pipe controls the inflow of the reaction reagent, and the branch pipe of the deprotection product can lead the deprotection product in the deprotection reaction device to realize the cycle of the deprotection reaction.
The feeding branch pipes comprise a deprotection agent branch pipe, a preservative agent branch pipe, a first cleaning agent branch pipe, a second cleaning agent branch pipe, a shielding gas branch pipe and a cutting agent branch pipe, and independent control valves are respectively arranged on the deprotection agent branch pipe, the preservative agent branch pipe, the first cleaning agent branch pipe, the second cleaning agent branch pipe, the shielding gas branch pipe and the cutting agent branch pipe; the deprotection agent branch pipe, the preservative agent branch pipe, the first cleaning agent branch pipe, the second cleaning agent branch pipe, the shielding gas branch pipe and the cutting agent branch pipe are communicated with the inlet end of the solid-phase synthesis cutting assembly. Here the entry of different reagents is achieved by controlling the opening of the control valves of the different feed manifolds.
The deprotection reaction device is of a double-layer structure, has a certain heat preservation effect, is provided with a temperature probe for detecting the temperature inside the deprotection reaction device, and can be butted with an external cold and heat source to realize temperature control reaction on the deprotection reaction device. A stirrer is arranged in the deprotection reaction device, and the reaction speed can be increased through stirring;
solid phase synthesis result cutting deprotection system still includes ejection of compact subassembly, ejection of compact subassembly includes circulating valve, bleeder valve, circulation branch pipe and ejection of compact branch pipe, the circulating valve is installed on the circulation branch pipe, the bleeder valve is installed on the ejection of compact branch pipe, the circulation branch pipe with the entrance point of ejection of compact branch pipe all with the exit end intercommunication of solid phase synthesis cutting assembly, the exit end of circulation branch pipe with the mouth of discharging is linked together. The discharge valve controls the opening and closing of the discharge branch pipe, and waste liquid is led out by opening the discharge valve when the waste liquid needs to be discharged; and the circulating branch pipe is respectively communicated with the solid-phase synthesis cutting assembly and the discharge inlet, so that the solid-phase synthesis cutting assembly is communicated with the deprotection reaction device by opening the circulating valve.
The circulation branch pipe is provided with two first circulation branch pipes and two second circulation branch pipes, the first circulation branch pipes and the second circulation branch pipes are respectively provided with a first circulating valve and a second circulating valve, the deprotection reaction device is provided with two discharge inlets, one of the discharge inlets is a discharge inlet for cleaning, the other is a discharge inlet for feeding, the first circulation branch pipe is connected with the discharge inlet for cleaning, and the second circulation branch pipe is connected with the discharge inlet for feeding.
The discharging port of the deprotection reaction device is provided with one discharging port, the branch pipe of the deprotection products communicated with the discharging port is provided with an emptying branch pipe in parallel, and the emptying branch pipe is correspondingly provided with an emptying valve which can empty the liquid in the deprotection reaction device. The lower part of the deprotection reaction device is also provided with a sampling valve which can sample the liquid in the deprotection reaction device.
And a conductivity detector and/or an ultraviolet detector are/is arranged between the solid-phase synthesis cutting assembly and the discharging assembly. And respectively detecting or combining and detecting through a conductivity detector and an ultraviolet detector to know whether the deprotection reaction is complete or not, and further controlling whether the reaction is continued or not.
The deprotection reaction devices are arranged in two and are arranged in parallel. By arranging two deprotection reaction devices in parallel, the space for deprotection reaction can be increased, and when one of the deprotection reaction devices stops working, the other one can also work normally.
A system pump is arranged between the feeding component and the solid-phase synthesis cutting component, so that liquid can be driven to flow and a pressurization effect can be achieved. In addition, a one-way valve is arranged between the solid-phase synthesis cutting assembly and the discharging assembly to prevent liquid from flowing back.
The solid phase synthesis product cutting deprotection method includes the following steps: the feeding assembly inputs a reaction reagent through an inlet end, and the reaction reagent flows out through an outlet end of the feeding assembly; the reaction reagent flows out from the outlet end of the feeding assembly and flows into the cutting assembly through the inlet end of the solid-phase synthesis cutting assembly, the reaction reagent cuts the solid-phase synthesis product in the cutting assembly, and the reaction reagent and the formed cutting product flow out from the outlet end of the solid-phase synthesis cutting assembly; the cutting product and the reaction reagent flow into a deprotection reaction device through the inlet end of the deprotection reaction device, and the cutting product and the reaction reagent react in the deprotection reaction device to form a deprotection product; the deprotection product is led out through the discharge port of the deprotection reaction device.
Drawings
The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate embodiments of the invention and, together with the description, serve to explain the principles and effects of the invention.
Unless otherwise specified or defined, the same reference numerals in different figures refer to the same or similar features, and different reference numerals may be used for the same or similar features.
FIG. 1 is a schematic diagram of a pipeline connection according to a first embodiment of the present invention;
FIG. 2 is a schematic view of a solid phase synthesis cleavage assembly embodying the present invention;
FIG. 3 is a schematic diagram of an apparatus for carrying out a deprotection reaction according to the present invention;
FIG. 4 is a schematic view of the piping connection according to the second embodiment of the present invention;
fig. 5 is a schematic view of the pipeline connection according to the third embodiment of the present invention.
Description of reference numerals:
10. a feed assembly; 11. removing protection of a product branch pipe; 12. a feed valve; 131. branch pipes of the deprotection agent; 132. a preservative branch pipe; 133. a first cleaning agent branch pipe; 134. a second cleaning agent branch pipe; 135. a shielding gas branch pipe; 136. a cutting agent branch pipe; 14. a control valve; 20. a solid phase synthesis cleavage module; 21. a solid-phase synthesis cutting device; 22. cutting the valve group; 221. a first cutting valve; 222. a second cutting valve; 223. a third cutting valve; 224. a fourth cutting valve; 225. a fifth cutting valve; 226. a first branch pipe; 227. a second branch pipe; 228. a third branch pipe; 30. a deprotection reaction device; 31. an outlet port; 311. a tank bottom valve; 32. a discharge port; 33. a shower head; 34. a stirrer; 35. emptying the branch pipe; 351. an evacuation valve; 36. a sampling valve; 40. a discharge assembly; 41. a circulation valve; 42. a discharge valve; 43. a circulation branch pipe; 44. a discharge branch pipe; 50. a conductivity detector; 60. an ultraviolet detector; 70. a pressure sensor; 80. a system pump; 90. a one-way valve.
Detailed Description
In order to facilitate an understanding of the invention, specific embodiments thereof will be described in more detail below with reference to the accompanying drawings.
Unless specifically stated or otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In the case of combining the technical solutions of the present invention in a realistic scenario, all technical and scientific terms used herein may also have meanings corresponding to the purpose of achieving the technical solutions of the present invention.
As used herein, unless otherwise specified or defined, "first" and "second" … are used merely for name differentiation and do not denote any particular quantity or order.
As used herein, the term "and/or" includes any and all combinations of one or more of the associated listed items, unless specified or otherwise defined.
It will be understood that when an element is referred to as being "secured to" another element, it can be directly secured to the other element or intervening elements may also be present; when an element is referred to as being "connected" to another element, it can be directly connected to the other element or intervening elements may also be present; when an element is referred to as being "mounted on" another element, it can be directly on the other element or intervening elements may also be present. When an element is referred to as being "on" another element, it can be directly on the other element or intervening elements may also be present.
The first embodiment is as follows:
as shown in fig. 1, the solid-phase synthesis product cutting deprotection system comprises a feeding assembly 10, a solid-phase synthesis cutting assembly 20 and a deprotection reaction device 30; the feeding assembly 10 comprises an inlet end and an outlet end, the outlet end of the feeding assembly 10 is communicated with the inlet end of the solid-phase synthesis cutting assembly 20, the outlet end of the solid-phase synthesis cutting assembly 20 is communicated with the inlet end of the deprotection reaction device 30, the outlet end of the deprotection reaction device 30 is provided with a plurality of outlet ends, and at least one outlet end of the deprotection reaction device 30 is a discharge port 31.
When the solid-phase synthesis product is cut and subjected to deprotection reaction, a reaction reagent is introduced through the outlet end of the feeding assembly 10, the reaction reagent enters the solid-phase synthesis cutting assembly 20, the cutting reaction is carried out in the solid-phase synthesis cutting assembly 20, the cut solid-phase synthesis compound enters the deprotection reaction device 30 along a pipeline, the deprotection reaction is carried out in the deprotection reaction device 30 on the solid-phase synthesis compound, a deprotection product is obtained, the deprotection product in the reaction process is discharged through the discharge port 31, manual material taking operation is not needed, the deprotection reaction is not needed to be carried out through a shaking table, the whole set of device is communicated from the feeding assembly 10 to a final deprotection reaction protection device, and continuous large-scale production is realized.
As shown in fig. 1, the solid phase synthesis cutting assembly 20 includes a cutting valve set 22 and a solid phase synthesis cutting device 21, the cutting valve set 22 is communicated with the solid phase synthesis cutting device 21, and an inlet end and an outlet end of the cutting valve set 22 form an inlet end and an outlet end of the solid phase synthesis cutting assembly 20. Here is connected with solid phase synthesis cutting device 21 through cutting valves 22, and reaction reagent passes through cutting valves 22 earlier, and the control flow direction is then got into solid phase synthesis cutting device 21, is favorable to controlling going on of cutting reaction.
As shown in fig. 2, the cutting valve set 22 includes a first cutting valve 221, a second cutting valve 222, a third cutting valve 223, a fourth cutting valve 224, a first branch pipe 226 and a second branch pipe 227, and the solid phase synthesis cutting device 21 includes a cutting reaction column; the inlet and outlet ends of the first and second branch pipes 226 and 227 are communicated, the first and second cutting valves 221 and 222 are installed on the first branch pipe 226, and the third and fourth cutting valves 223 and 224 are installed on the second branch pipe 227; the start end of the cutting reaction column is connected to the first branch pipe 226 and is located between the first cutting valve 221 and the second cutting valve 222, and the end of the cutting reaction column is connected to the second branch pipe 227 and is located between the third cutting valve 223 and the fourth cutting valve 224.
The first, second, third and fourth cutting valves 221, 222, 223 and 224 included in the cutting valve set 22 are used to control the forward and reverse flows of the reaction reagents by closing and opening, thereby controlling the forward and reverse cutting of the cutting reaction column. When the cutting reaction column needs to be cut in the forward direction, the first cutting valve 221 and the fourth cutting valve 224 are opened, the second cutting valve 222 and the third cutting valve 223 are closed, at the moment, the reaction reagent enters the first branch pipe 226 through the first cutting valve 221 and is then blocked by the second cutting valve 222, the reaction reagent enters the initial end of the cutting reaction column, the solid-phase synthesis product of the cutting reaction column is cut to form a cutting product, and then the cutting product and the reaction reagent flow into the second branch pipe 227 through the tail end of the cutting reaction column and flow out through the fourth cutting valve 224. When the cutting reaction column needs to be cut reversely, the first cutting valve 221 and the fourth cutting valve 224 are closed, and the second cutting valve 222 and the third cutting valve 223 are opened, so that the reaction reagent enters from the tail end of the cutting reaction column and flows out from the initial end.
As shown in fig. 2, the cutting valve block 22 further comprises a fifth cutting valve 225 and a third branch pipe 228, wherein the inlet end and the outlet end of the third branch pipe 228 are respectively communicated with the inlet end and the outlet end of the first branch pipe 226 and the second branch pipe 227, and the fifth cutting valve 225 is mounted on the third branch pipe 228. When the reaction reagent needs to directly pass through the cutting reaction column, the first cutting valve 221, the second cutting valve 222, the third cutting valve 223 and the fourth cutting valve 224 are closed, the fifth cutting valve 225 is opened, and the reaction reagent directly enters the third branch pipe 228 to bypass the cutting reaction column.
Specifically, the inlet end and the outlet end of the solid-phase synthesis cutting assembly 20 are provided with pressure sensors 70 for detecting the liquid pressure in real time, so as to avoid safety accidents caused by overlarge pressure.
As shown in FIGS. 1 and 3, the deprotection reaction apparatus 30 comprises a discharge port 32, an outlet end of the solid phase synthesis and cutting assembly 20 is communicated with the discharge port 32, a tank bottom valve 311 and an exhaust valve 351 are installed on the discharge port 31, and the tank bottom valve 311 of the discharge port 31 of the deprotection reaction apparatus is communicated with the feeding assembly 10. Cutting products and reaction reagents enter the deprotection reaction device 30 through the discharge port 32, the cutting products are subjected to deprotection reaction at the discharge port to form deprotection products, the discharge port 31 of the deprotection reaction device 30 is communicated with the feeding assembly 10 for more complete reaction, the tank bottom valve 311 is opened, the reaction reagents, the deprotection products and the like enter the feeding assembly 10 together, and then cyclic cutting and deprotection reaction are carried out until the complete or preset reaction rate is reached. The circular reaction can be beneficial to complete reaction, so that the labor is saved, and the reaction efficiency can be improved. Finally, the reaction is complete and the deprotected product can be removed via the purge valve 351.
As shown in fig. 3, a plurality of the inlet vents 32 are provided, and at least one of the inlet vents is located at the top of the deprotection reaction device 30, a shower head 33 is provided inside the deprotection reaction device 30, and the shower head 33 is communicated with at least one of the inlet vents 32 located at the top of the deprotection reaction device 30. The shower head 33 can disperse the liquid, and when the inside of the deprotection reaction apparatus 30 is cleaned, the cleaning agent is dispersed by the shower head 33, which is advantageous for cleaning.
As shown in fig. 1, the feeding assembly 10 includes a branch deprotected product 11, a branch feeding pipe, and a feeding valve 12, wherein the feeding valve 12 is installed on the branch feeding pipe, one end of the branch deprotected product 11 is communicated with the inlet end of the solid-phase synthesis cutting assembly 20, and the other end is communicated with the tank bottom valve 311. Wherein, the inlet valve 12 of the inlet branch pipe controls the inflow of the reaction reagent, and the branch pipe 11 of the deprotection product can lead the deprotection product in the deprotection reaction device 30 to realize the cycle of the deprotection reaction.
As shown in fig. 1, the feeding branch pipe comprises a deprotection agent branch pipe 131, a preservation agent branch pipe 132, a first cleaning agent branch pipe 133, a second cleaning agent branch pipe 134, a shielding gas branch pipe 135 and a cutting agent branch pipe 136, and the deprotection agent branch pipe 131, the preservation agent branch pipe 132, the first cleaning agent branch pipe 133, the second cleaning agent branch pipe 134, the shielding gas branch pipe 135 and the cutting agent branch pipe 136 are all provided with independent control valves 14; the deprotection agent branch pipe 131, the preservation agent branch pipe 132, the first cleaning agent branch pipe 133, the second cleaning agent branch pipe 134, the shielding gas branch pipe 135 and the cutting agent branch pipe 136 are all communicated with the inlet end of the solid phase synthesis cutting assembly 20. Here the admission of different reagents is achieved by controlling the opening of the control valves 14 of the different feed manifolds.
Specifically, the deprotection reaction device 30 has a double-layer structure and a certain heat preservation effect, and is provided with a temperature probe for detecting the temperature inside the deprotection reaction device 30, and the deprotection reaction device 30 can be butted with an external cold source and heat source to realize temperature control reaction of the deprotection reaction device 30. A stirrer 34 is arranged in the deprotection reaction device 30, and the reaction speed can be increased through stirring;
as shown in fig. 1, the solid-phase synthesis product cutting deprotection system further includes a discharging assembly 40, the discharging assembly 40 includes a circulating valve 41, a discharging valve 42, a circulating branch pipe 43 and a discharging branch pipe 44, the circulating valve 41 is installed on the circulating branch pipe 43, the discharging valve 42 is installed on the discharging branch pipe 44, the inlet ends of the circulating branch pipe 43 and the discharging branch pipe 44 are both communicated with the outlet end of the solid-phase synthesis cutting assembly 20, and the outlet end of the circulating branch pipe 43 is communicated with the discharging port 32. The discharge valve 42 controls the opening and closing of the discharge branch pipe 44, and when waste liquid needs to be discharged, the waste liquid is led out by opening the discharge valve 42; and the circulation branch pipe 43 is respectively communicated with the solid-phase synthesis cutting assembly 20 and the discharge port 32, so that the solid-phase synthesis cutting assembly 20 is communicated with the deprotection reaction device 30 by opening the circulation valve 41.
Specifically, the circulation branch pipe 43 is provided with two first circulation branch pipes 43 and two second circulation branch pipes 43, the first circulation branch pipes 43 and the second circulation branch pipes 43 are respectively provided with a first circulation valve 41 and a second circulation valve 41, the deprotection reaction device 30 is provided with two discharge ports 32, one of the discharge ports 32 is a discharge port 32 for cleaning, the other is a discharge port 32 for feeding, the first circulation branch pipes 43 are connected with the discharge port 32 for cleaning, and the second circulation branch pipes 43 are connected with the discharge port 32 for feeding.
The discharge port 31 of the deprotection reaction device 30 is provided with one evacuation branch pipe 35 in parallel with the branch pipe 11 of the deprotected product communicated with the discharge port 31, and the evacuation branch pipe 35 is correspondingly provided with an evacuation valve 351 capable of evacuating the liquid in the deprotection reaction device 30. The lower portion of the deprotection reaction apparatus 30 is further provided with a sampling valve 36 for sampling the liquid in the deprotection reaction apparatus 30.
As shown in FIG. 1, a conductivity detector 50 and/or an ultraviolet detector 60 is/are installed between the solid-phase synthesis cutting assembly 20 and the discharging assembly 40. The conductivity detector 50 and the ultraviolet detector 60 detect respectively or in combination to know whether the deprotection reaction is complete or not, and further control whether the reaction is continued or not.
Specifically, a system pump 80 is disposed between the feeding module 10 and the solid phase synthesis cutting module 20, which can drive the liquid flow and can perform the pressurization effect. In addition, a check valve 90 is disposed between the solid phase synthesis cutting assembly 20 and the discharging assembly 40 to prevent the liquid from flowing back.
The solid phase synthesis product cutting deprotection method includes the following steps: the feeding assembly 10 inputs a reaction reagent through an inlet end, and the reaction reagent flows out through an outlet end of the feeding assembly 10; the reaction reagent flows out from the outlet end of the feeding assembly 10 and flows into the cutting assembly through the inlet end of the solid-phase synthesis cutting assembly 20, the reaction reagent cuts the solid-phase synthesis product in the cutting assembly, and the reaction reagent and the formed cutting product flow out from the outlet end of the solid-phase synthesis cutting assembly 20; the cutting product and the reaction reagent flow into the deprotection reaction device 30 through the inlet end of the deprotection reaction device 30, and the cutting product and the reaction reagent react in the deprotection reaction device 30 to form a deprotection product; the deprotected product is discharged through the outlet 31 of the deprotection reaction apparatus 30.
The reaction reagent comprises one or more combinations of a cutting agent, a deprotection agent, a preservative agent, a first cleaning agent, a second cleaning agent and a shielding gas, and is respectively introduced through a cutting agent branch pipe 136, a deprotection agent branch pipe 131, a preservative agent branch pipe 132, a first cleaning agent branch pipe 133, a second cleaning agent branch pipe 134 and a shielding gas branch pipe 135.
Specifically, the working modes of this embodiment include a cutting mode, a deprotection mode, a cleaning mode, a preservation mode, a drying mode, and a temperature-controlled reaction mode, which can be implemented independently.
Cutting mode: the cutting agent flows in from the cutting agent branch pipe 136 through the action of the system pump 80, then enters the cutting reaction column through the first cutting valve 221, cuts the solid-phase synthesis product, then conveys the cutting product to flow through the fourth cutting valve 224, then flows through the second circulating valve 41, enters the deprotection reaction device 30, flows through the tank bottom valve 311 and the feed valve 12, and enters the solid-phase synthesis cutting assembly 20 and the deprotection reaction device 30 together with the newly input cutting agent, and continuously performs the solid-phase synthesis product cutting reaction circulation until the conductivity detector 50 and the ultraviolet detector 60 detect that the solid-phase synthesis product cutting reaction is complete, and the solid-phase synthesis product cutting reaction stops.
Deprotection mode: the cutting mode is started, meanwhile, a deprotection agent flows in from a deprotection agent branch pipe 131 under the action of a system pump 80, then enters the deprotection reaction device 30 through a fifth cutting valve 225 and a second circulating valve 41, and the deprotection agent and a cutting product perform deprotection reaction in the deprotection reaction device 30; the deprotected product flows through the tank bottom valve 311 and the feed valve 12, and enters the solid phase synthesis cutting assembly 20 and the deprotection reaction device 30 together with a newly input deprotecting agent, and the deprotection reaction cycle is continuously performed until the deprotection reaction is completely detected from the sample extracted from the sampling valve 36, the deprotection reaction is stopped, and the deprotected product is discharged through the exhaust valve 351.
It should be noted that the deprotection mode includes a cleavage mode, and after the cleavage mode is stopped, the deprotection reaction may continue to circulate until the deprotection reaction is completely stopped or forcibly stopped.
A cleaning mode: the first cleaning agent flows in from the first cleaning agent branch pipe 133 under the action of the system pump 80, flows through the first cutting valve 221, the cutting reaction column, the fourth cutting valve 224, the first circulating valve 41 and the deprotection reaction device 30, and is continuously circulated, so that the cleaning is completed; or the first cleaning agent flows in from the first cleaning agent branch pipe 133 under the action of the system pump 80, flows through the fifth cutting valve 225, the first circulating valve 41 and the deprotection reaction device 30, and is circulated continuously, so that the cleaning is finished; or the first cleaning agent flows in from the first cleaning agent branch pipe 133 under the action of the system pump 80, flows through the third cutting valve 223, the cutting reaction column, the second cutting valve 222, the first circulating valve 41 and the deprotection reaction device 30, and is continuously circulated until the conductivity detector 50 and the ultraviolet detector detect that the system is completely cleaned, and the cleaning is stopped. Similarly, the second cleaning agent is different from the first cleaning agent in that the second cleaning agent flows in from the second cleaning agent branch pipe 134.
A storage mode: the preservative is pumped by the system pump 80 from the preservative manifold 132 to fill the entire system circuit, completing the preservation.
Drying mode: the shielding gas flows from the shielding gas branch pipe 135 into the system pipeline under the action of the system pump 80, and the residual liquid is dried.
Temperature-controlled reaction mode: the deprotection reaction device 30 controls the temperature of the deprotection reaction device 30 through a temperature probe and an external cold heat source, so as to realize the control reaction.
Example two:
as shown in fig. 4, the present embodiment is different from the first embodiment in that there are two deprotection reaction devices 30, a third circulation branch pipe 43, a fourth circulation branch pipe 43, a third circulation valve 41, a fourth circulation valve 41, and two separate deprotection reaction branch pipes. Wherein the third circulation branch 43 and the fourth circulation branch 43 are connected to the deprotection reaction apparatus 30 in the same manner as the first circulation branch 43 and the second circulation branch 43, and the connection of the deprotection reaction branch to each deprotection reaction apparatus 30 is in the same manner.
Here, the two deprotection reaction apparatuses 30 have different capacities, and the two deprotection reaction apparatuses 30 having different capacities may be selected according to different reaction capacity requirements by installing the two deprotection reaction apparatuses 30, or may be used for reaction in the two deprotection reaction apparatuses 30 at the same time.
The rest of the structure is the same as the first embodiment, and will not be described herein.
Example three:
as shown in FIG. 5, the present embodiment is different from the second embodiment in that a fifth circulation branch pipe 43 and a fifth circulation valve 41 are provided, wherein one end of the fifth circulation branch pipe 43 is communicated with the outlet end of the solid phase synthesis and cutting module 20, and the other end is communicated with the feeding module 10. In the cutting mode, in order to increase the efficiency of the circulation, the fifth circulation valve 41 is opened, and the fifth circulation branch 43 is directly introduced into the feeding module 10, so as to realize rapid flow through the solid phase synthesis cutting module 20.
The rest of the structure is the same as the embodiment, and will not be described herein.
When the drawing description is quoted, the new characteristics are explained; in order to avoid that repeated reference to the drawings results in an insufficiently concise description, the drawings are not referred to one by one in the case of clear description of the already described features.
The above embodiments are provided to illustrate, reproduce and deduce the technical solutions of the present invention, and to fully describe the technical solutions, the objects and the effects of the present invention, so as to make the public more thoroughly and comprehensively understand the disclosure of the present invention, and not to limit the protection scope of the present invention.
The above examples are not intended to be exhaustive of the invention and there may be many other embodiments not listed. Any alterations and modifications without departing from the spirit of the invention are within the scope of the invention.
Claims (10)
1. The solid-phase synthesis product cutting deprotection system is characterized by comprising a feeding assembly, a solid-phase synthesis cutting assembly and a deprotection reaction device;
the feeding assembly comprises an inlet end and an outlet end, the outlet end of the feeding assembly is communicated with the inlet end of the solid-phase synthesis cutting assembly, the outlet end of the solid-phase synthesis cutting assembly is communicated with the inlet end of the deprotection reaction device, the outlet end of the deprotection reaction device is provided with a plurality of outlet ends, and at least one outlet end of the deprotection reaction device is a discharge port.
2. The cleavage deprotection system for solid phase synthesis product of claim 1, wherein the solid phase synthesis cleavage assembly comprises a cleavage valve set and a solid phase synthesis cleavage apparatus, the cleavage valve set is in communication with the solid phase synthesis cleavage apparatus, and the inlet end and the outlet end of the cleavage valve set form the inlet end and the outlet end of the solid phase synthesis cleavage assembly.
3. The cleavage deprotection system for solid phase synthesis product of claim 2, wherein the cleavage valve set comprises a first cleavage valve, a second cleavage valve, a third cleavage valve, a fourth cleavage valve, a first branch pipe and a second branch pipe, and the cleavage device for solid phase synthesis comprises a cleavage reaction column;
the inlet ends and the outlet ends of the first branch pipe and the second branch pipe are communicated, the first cutting valve and the second cutting valve are installed on the first branch pipe, and the third cutting valve and the fourth cutting valve are installed on the second branch pipe;
the starting end of the cutting reaction column is connected to the first branch pipe and located between the first cutting valve and the second cutting valve, and the tail end of the cutting reaction column is connected to the second branch pipe and located between the third cutting valve and the fourth cutting valve.
4. The cut deprotection system for solid phase synthesis product of claim 3, wherein the cut valve assembly further comprises a fifth cut valve and a third branch tube, wherein the inlet end and the outlet end of the third branch tube are respectively communicated with the inlet end and the outlet end of the first branch tube and the second branch tube, and the fifth cut valve is mounted on the third branch tube.
5. A cleavage deprotection system for solid phase synthesis product as claimed in any one of claims 1 to 4, wherein said deprotection reaction apparatus comprises a discharge port, an outlet end of said solid phase synthesis cleavage assembly is connected to said discharge port, a tank valve and an evacuation valve are mounted on said discharge port, and a tank valve of said discharge port of said deprotection reaction apparatus is connected to a feed assembly.
6. The cleavage deprotection system for solid phase synthesis product as claimed in claim 5, wherein the plurality of the inlet ports are provided, and at least one of the inlet ports is located on the top of the deprotection reaction apparatus, and a shower head is provided inside the deprotection reaction apparatus, and the shower head is communicated with at least one of the inlet ports located on the top of the deprotection reaction apparatus.
7. The cut deprotection system for solid phase synthesis product of claim 6, wherein the feeding assembly comprises a branch for deprotection product, a branch for feeding, and a feeding valve, wherein the feeding valve is installed on the branch for feeding, and one end of the branch for deprotection product is communicated with the inlet end of the solid phase synthesis cutting assembly and the other end is communicated with the tank bottom valve.
8. The cut deprotection system for solid phase synthesis product as claimed in claim 7, wherein the feeding branch pipe comprises a deprotection agent branch pipe, a preservative agent branch pipe, a first cleaning agent branch pipe, a second cleaning agent branch pipe, a shielding gas branch pipe and a cutting agent branch pipe, and the deprotection agent branch pipe, the preservative agent branch pipe, the first cleaning agent branch pipe, the second cleaning agent branch pipe, the shielding gas branch pipe and the cutting agent branch pipe are all provided with independent control valves;
the deprotection agent branch pipe, the preservative agent branch pipe, the first cleaning agent branch pipe, the second cleaning agent branch pipe, the shielding gas branch pipe and the cutting agent branch pipe are communicated with the inlet end of the solid-phase synthesis cutting assembly.
9. The cut deprotection system for solid phase synthesis product of claim 5, further comprising a discharging component, wherein the discharging component comprises a circulating valve, a discharging valve, a circulating branch pipe and a discharging branch pipe, the circulating valve is installed on the circulating branch pipe, the discharging valve is installed on the discharging branch pipe, the inlet ends of the circulating branch pipe and the discharging branch pipe are both communicated with the outlet end of the solid phase synthesis cutting component, and the outlet end of the circulating branch pipe is communicated with the discharging port.
10. The solid phase synthesis product cutting deprotection method is characterized by comprising the following steps:
the feeding assembly inputs a reaction reagent through an inlet end, and the reaction reagent flows out through an outlet end of the feeding assembly;
the reaction reagent flows out from the outlet end of the feeding assembly and flows into the cutting assembly through the inlet end of the solid-phase synthesis cutting assembly, the reaction reagent cuts the solid-phase synthesis product in the cutting assembly, and the reaction reagent and the formed cutting product flow out from the outlet end of the solid-phase synthesis cutting assembly;
the cutting product and the reaction reagent flow into a deprotection reaction device through the inlet end of the deprotection reaction device, and the cutting product and the reaction reagent react in the deprotection reaction device to form a deprotection product;
the deprotection product is led out through the discharge port of the deprotection reaction device.
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| CN202010873513.9A CN111939854B (en) | 2020-08-26 | 2020-08-26 | System and method for cutting and deprotection of solid phase synthesis product |
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| CN202010873513.9A CN111939854B (en) | 2020-08-26 | 2020-08-26 | System and method for cutting and deprotection of solid phase synthesis product |
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| US5240680A (en) * | 1991-12-19 | 1993-08-31 | Chiron Corporation | Automated apparatus for use in peptide synthesis |
| US5460786A (en) * | 1993-02-26 | 1995-10-24 | Shimadzu Corporation | Cleavage apparatus |
| CN106518966A (en) * | 2016-10-24 | 2017-03-22 | 合肥国肽生物科技有限公司 | Synthetic method of RGD cyclopeptide |
| CN212328254U (en) * | 2020-08-26 | 2021-01-12 | 广州市锐博生物科技有限公司 | Solid phase synthesis product cutting deprotection system |
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2020
- 2020-08-26 CN CN202010873513.9A patent/CN111939854B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5240680A (en) * | 1991-12-19 | 1993-08-31 | Chiron Corporation | Automated apparatus for use in peptide synthesis |
| US5460786A (en) * | 1993-02-26 | 1995-10-24 | Shimadzu Corporation | Cleavage apparatus |
| CN106518966A (en) * | 2016-10-24 | 2017-03-22 | 合肥国肽生物科技有限公司 | Synthetic method of RGD cyclopeptide |
| CN212328254U (en) * | 2020-08-26 | 2021-01-12 | 广州市锐博生物科技有限公司 | Solid phase synthesis product cutting deprotection system |
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