CN106824037B - The continuous flowing reaction tube of air pressure driving, reactor, reaction unit and its application - Google Patents
The continuous flowing reaction tube of air pressure driving, reactor, reaction unit and its application Download PDFInfo
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- CN106824037B CN106824037B CN201710070782.XA CN201710070782A CN106824037B CN 106824037 B CN106824037 B CN 106824037B CN 201710070782 A CN201710070782 A CN 201710070782A CN 106824037 B CN106824037 B CN 106824037B
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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
- B01J19/24—Stationary reactors without moving elements inside
- B01J19/2415—Tubular reactors
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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
- B01J19/0053—Details of the reactor
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
- C07K1/04—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length on carriers
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- B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
- B01J2219/00583—Features relative to the processes being carried out
- B01J2219/0059—Sequential processes
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- B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J2219/00781—Aspects relating to microreactors
- B01J2219/0095—Control aspects
- B01J2219/00952—Sensing operations
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- B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J2219/24—Stationary reactors without moving elements inside
- B01J2219/2401—Reactors comprising multiple separate flow channels
- B01J2219/2402—Monolithic-type reactors
- B01J2219/2423—Separation means, e.g. membrane inside the reactor
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Abstract
The present invention provides the continuous flowing reaction tube of air pressure driving, reactor, reaction unit and its application, the reaction tube both ends open, when being disposed vertically, its top end opening is entrance, bottom end opening is outlet, as mwco membrane, the top of the microporous membrane is equipped in an interference fit fixes the microporous membrane between pressure ring, with tube body setting microporous membrane in the reaction tube.Reaction tube of the present invention, which can be realized the continuous flowing solid phase reaction of air pressure driving, can develop high throughput automated micro or a small amount of solid phase synthetic instrument whereby, solve this field and think solution but unsolved technical problem for a long time.
Description
Technical field
The present invention relates to the reaction kit for solid-state chemical reaction method, in particular to the continuous flowing reaction tube of air pressure driving,
Reactor, reaction unit and its application belong to solid-state chemical reaction method technical field.
Background technique
The basic skills of solid-state chemical reaction method is connected to reactant on the solid phase high polymer skeleton with active group,
Chemosynthesis reaction occurs for the active group mutually introduced on reactant and solid phase carrier by fluid, and impurity and by-product then stay in
It is cleaned and remove in fluid phase, finally target synthetic product is cleaved using chemical method appropriate.Since solid phase is closed
At product be fixed in solid phase, and impurity and by-product retain in the liquid phase, are readily isolated, solid-state chemical reaction method energy
Enough obtain higher yield and purity.From American scientist Merrifield found (J.Am.Chem.Soc., 1963,85,
After 2149-2154.), deep development is had been obtained in solid-state chemical reaction method, therefore Merrifield also obtains Nobel's chemistry
Prize.The macromolecular that current many large biological molecules, especially polypeptide and DNA etc. are of great significance in biological study, it is past
It is past to be prepared by solid-state chemical reaction method method.
Solid phase peptide synthssis is an important application direction of solid-state chemical reaction method.In recent years, with proteomics etc.
High-throughput technology is gradually popularized, and the demand to high throughput synthesis polypeptide also increases increasingly.It can be with using high throughput method
Synthesize a large amount of polypeptide samples, carry out quantitative proteomics research, high capacity peptide library can also be constructed, by with target molecule
Interaction, screening obtain polypeptide drugs or disease markers etc..However, although Solid phase peptide synthssis has developed for many years, quotient
Product instrument is also widely applied, but these equipment are generally basede on the big yield Peptide systhesis of small throughput, need a large amount of manual operations,
It is not suitable for the needs of proteomics research.
CN201459000U discloses a kind of Solid phase peptide synthssis device, which can realize semi-automatic at low cost
Change, reduces probability, the workload of simple repeated work and instrument and some experimental articles that staff contacts toxic solvent
Application, improve efficiency.However, commercialization glass sand core tube is due to the limitation of processing technology, volume is larger, is not suitable for milli
The Peptide systhesis of gram quantity grade, and since Peptide systhesis reagent corrosivity is stronger, triple valve used in the device, blow valve etc.
It needs to manufacture using glass material, needs not accomplishing to be fully automated and high-flux parallel controls using being operated by hand,
And the synthesis of high-throughput micro or a small amount of polypeptide is not suitable for it.
Although Micro-solid Phase chemical synthesising technology reported (Science, 2007,318,1888-1888.,
Proteomics,2003,3,2135-2141.；Application for a patent for invention: assembling compound array chip and preparation method,
03112772.X), but these synthesis in solid state are often static reaction, cannot convey fresh reactant liquid in time, and are needed multiple
The external equipment and special reaction reagent of miscellaneous valuableness.Therefore, development structure is simple, is easy to high-throughput integrated Micro-solid Phase
Learning synthesizer has very tempting prospect.
Micro-fluidic chip (Sens.Actutors, B, 1990,1,244-248.) is the sciemtifec and technical sphere quickly grown in recent years
One of, and construct chemical microreactor be one of important application direction of micro-fluidic chip (Tetrahedron, 2005,61:
2733-2742；Chem.Rev.,2007,107,2300-2318.).It is micro- using microfluidic chip technology building solid-state chemical reaction method
Reactor is suitable for microchemistry molecule synthesis, therefore the reactor of solid-state chemical reaction method is used for based on microfluidic chip technology
(Lab Chip, 2013,13:3347-3350 are also had been reported that in recent years；Lab Chip,2011,11:929-935).But miniflow
Chip is controlled since scale is too small, runner blocking, post-processing is inconvenient, auxiliary equipment is complicated for being easy to happen when Solid phase peptide synthssis
The problems such as, it limits such device and carries out high throughput synthesis.Meanwhile solid-state chemical reaction method such as Solid phase peptide synthssis is needed using two
The strong organic solvent such as methylformamide (DMF), methylene chloride (DCM), trifluoroacetic acid (TFA) and volatility strong acid, thus it is conventional
Pump, valve etc. for controlling reaction reagent are all difficult to directly use.
Since the Peptide systhesis equipment applied in industry is not suitable for Micro-solid Phase Peptide systhesis, and micro-fluidic chip etc. is suitable
It is not easy to carry out together in minute amount of polypeptide synthetic method high throughput automated integrated, thus both the above approach is not able to satisfy egg
White matter studies the urgent need to multiple types minute amount of polypeptide.In summary, this field is looked on the bright side of things for a long time sends out reaction instrument a kind of, to
It can be realized high throughput automated micro or a small amount of synthesis in solid state, but do not solved effectively.
Summary of the invention
In order to solve the above technical problems, one of the objects of the present invention is to provide a kind of air pressures to drive continuous flowing reactive
Pipe, the reaction tube can be realized the continuous flowing solid phase reaction of air pressure driving, whereby, can develop high throughput automated micro
Or a small amount of solid phase synthetic instruments, it solves this field and thinks solution but unsolved technical problem for a long time.
Another object of the present invention is to provide the reactor comprising previous reaction pipe, reaction unit and reaction systems.
A further object of the present invention is to provide the applications of previous reaction pipe, reactor, reaction unit or reaction system.
To achieve the above object, the present invention provides a kind of continuous flowing reaction tube of air pressure driving, wherein the reaction tube both ends
Opening, when being disposed vertically, top end opening is entrance (can be packed into solid phase carrier, reaction reagent and input pressure etc.), bottom end
Opening is outlet (can be the outfluxes such as cleaning solution, reaction solution), and setting microporous membrane is described as mwco membrane in the reaction tube
The top of microporous membrane is equipped with and in an interference fit fixes the microporous membrane between pressure ring, with tube body.
When carrying out solid phase reaction using previous reaction pipe, solid phase carrier and reaction reagent are added to reaction tube from entrance
In, when reaction reagent is not driven by external pressure, it is trapped in pipe or slowly flows out, when reaction reagent is by external pressure
(seal of tube will be reacted for example, by using plug, the syringe with piston is then used to inflate into reaction tube) when driving, reaction examination
Agent flows through solid phase carrier, realizes the solid-state chemical reaction method continuously flowed, can pressure size according to setting and pressure time, by institute
The rate needed realizes solid-state chemical reaction method.
The present invention is fixed using microporous membrane as mwco membrane with pressure ring, and sealing effect is preferable, and liquid is not easy from side
It is flowed through in side seam gap.And existing synthesis in solid state pipe uses glass sand core as retention plate, one side needs custom-made；It is another
Aspect is frangible to be not easy to place, the bonding for needing to realize it with glass reaction tube using heat treatment process；Furthermore condition of equivalent thickness
When, the effect that glass sand core retains reaction reagent is weaker than microporous membrane (such as silica gel material microporous membrane).The above reason makes
Glass sand core synthesis in solid state pipe may be only available for the biggish synthesis in solid state of structure size, be not suitable for micro or a small amount of synthesis in solid state,
And the continuous flowing reaction tube of air pressure driving of the present invention can be suitably used for micro or a small amount of synthesis in solid state, whereby, can develop high pass
Measure the micro or a small amount of solid phase synthetic instrument of automation.Previous reaction pipe is able to achieve micro or a small amount of solid-state chemical reaction methods, and is easy to
It is extended to corresponding reactor, reaction unit and system, to realize high throughput automated solid-state chemical reaction method.
As a specific embodiment of the invention, reaction tube (such as in top outer) of the present invention is equipped with carry knot
Structure.Such as the hanging structure is baffle, reaction tube can be made to be placed on porose bracket or carrier using the baffle, thus
It is integrated to be easy to implement more reaction tube high throughputs.
Microporous membrane in reaction tube of the present invention is commercially available to be obtained, the setting of the number of plies can according to the actual situation depending on, make
For a specific embodiment of the invention, the number of plies of microporous membrane of the present invention is 4~12 layers, and aperture is less than 1 micron.
As a specific embodiment of the invention, the material of microporous membrane of the present invention is selected from silica gel or PTFE；
The material of the reaction tube is selected from polypropylene or FEP；
As a specific embodiment of the invention, the material of the pressure ring is identical as the material of the reaction tube.
As a specific embodiment of the invention, reaction tube of the present invention has reaction tube main body and is directly connected to
Conical outlet part, the microporous membrane is located near the connectivity part of reaction tube main body and conical outlet part；
Preferably, the internal diameter of the reaction tube main body gradually decreases, and the upper end internal diameter is 6~8mm, bottom diameter 4.5
~5.5mm, the length of the reaction tube main body are 4~6mm.
It is further preferred that the length of the conical outlet part is 6~12mm, exit inside diameter is 0.5~0.8mm.
When being applied to the synthesis in solid state of concrete type and demand, the present invention can adjust reaction tube master according to the actual situation
The high ratio of the diameter of body, for example, usually adjusting diameter height than accommodating reaction tube for micro or a small amount of Solid phase peptide synthssis
Reagent can carry out the Solid phase peptide synthssis of 0.1~10 nanogram range, to meet the needs of micro or a small amount of Peptide systhesis.
On the other hand, the present invention provides a kind of air pressure driving continuous flow reactor, before the reactor includes of the invention
State the continuous flowing reaction tube of air pressure driving and the sealing element for sealing the reaction tube；
The sealing element is jacket structure, and innermost layer is snorkel, the flexible silicon that the outer surface cover axial cross section of snorkel is T
Glue, the stainless steel base that the outer surface cover axial cross section of the elastic silica gel is T, stainless steel base outside sleeve spring are described
Stainless steel base is nearby equipped with groove close to upper surface can fix entire sealing element by circlip, the elastic silica gel lower end
Face is smooth, and the diameter of the end face is greater than the outer diameter of the top inlet of the reaction tube, so that salable institute under the effect of the pressure
State reaction tube.
Aforementioned seal part of the present invention is flexible, ventable multilayered structure, sealing element for sealing the reaction tube
In snorkel can be connect with gas source, can after sealing reaction tube to reaction tube apply air pressure, so that liquid in pipe is flowed out.It is stainless
Steel matrix structure lower end surface can also set off elastic silica gel, it is ensured that sealing effect.It can be more square in view of use sealing element of the present invention
Just by the reaction seal of tube, and pressure can be imposed on into reaction tube by snorkel, therefore, be easier to based on previous reaction device
It is extended to corresponding reaction unit and system, to realize high throughput automated micro or a small amount of solid-state chemical reaction method.
On the other hand, the present invention provides a kind of air pressure driving continuous flow reactor, and described device aforementioned including covering more
Air pressure drives continuous flow reactor, mechanical, horizontally movable machinery moving up and down, and air pressure drives continuous flowing reactive
Sealing element in device be fixed on it is described it is moving up and down mechanically, air pressure drive continuous flow reactor in reaction tube place
It is described it is horizontally movable mechanically, pass through this it is moving up and down mechanical and this it is horizontally movable it is mechanical it is mobile can will
The reaction seal of tube.
Preferably, the reaction tube be vertically disposed in it is described it is horizontally movable mechanically and its top end opening upward.
It is highly preferred that the center line of the reaction tube and the axle center of the sealing element are coaxial.
In general, by the horizontally movable mechanical lower section that the reaction tube is moved to the sealing element, then
The sealing realized to reaction tube is moved down by machinery moving up and down, operating by opposite mode can be realized to reaction
The deblocking of pipe.It is anti-to may make that reaction tube and reaction seals can both seal the continuous flowing of realization using this integration mode
It answers, and can separate to be loaded (as shown in Figure 3), each operating procedure, may be implemented according to needed for synthesis in solid state
The synthesis in solid state (as shown in Figure 4) of automation, can be loaded on integrated conveyer belt or disk due to described device, be easy to logical
It crosses and automatically delivers the automatic switchover that structure transfer described device realizes synthesis step, and then is automation easy to accomplish, high-throughput
Multiple synthetic reactions are carried out simultaneously.
" machinery moving up and down " or " horizontally movable machinery " of the present invention are machine commonly used in the prior art
Tool structure, for example, it is moving up and down mechanical including a fixing piece moving up and down, and which, which can be driven by a motor, makes it
It moves up and down, to realize sealing or deblocking of the sealing element to the reaction tube." horizontally movable machinery " is similarly existing
There is mechanical structure common in technology, such as horizontally movable mechanical including bracket or carrier, the bracket or carrier can
Being driven by a motor moves horizontally it.
On the other hand, the present invention also provides a kind of air pressures to drive continuous flowing reaction system, which includes aforementioned
Air pressure drives continuous flow reactor, air valve and positive pressure gas source, the air valve that can control the reaction in a manner of pneumatic pressure pulses
Air pressure in pipe, the positive pressure source outlet and the sealing element Center Vent tube are arranged by piping connection, the air valve at this
In pipeline.
Positive pressure gas source of the present invention can be selected from business air compressor or nitrogen cylinder.
The air valve for being able to achieve the function in the prior art can be selected in air valve of the present invention, wherein control mode is also existing
There is technology, it, can be according to reality for example, by using the software control air valve the air pressure in reaction tube can be controlled in a manner of pneumatic pressure pulses
Border is selected, and is not repeated separately herein.
Using the reaction system carry out solid-state chemical reaction method method be in the reaction tube be packed into solid phase carrier and
Then reaction reagent seals reaction tube, control air pressure in tube body by pneumatic pressure pulses, promote the reagent in reaction tube with continuous flow
Flowing mode constantly passes through solid phase carrier, and different reagent flow rates is realized in different reaction steps, carries out solid state chemistry conjunction
At (as shown in Figure 4).Since air pressure provides in a pulsed fashion, the parallel control of multiple reaction tubes easy to accomplish.Method is
It is quickly a reaction tube gas supply within single time point, that is, gives a pneumatic pressure pulses, then switching gas circuit, is next anti-
Should pipe gas supply, until for all reaction tubes supply.This mode will not because individual reaction tube air-tightness are bad influence it is other anti-
Ying Guan.By control pressure, burst length, pulse spacing, pulse number, the demand of differential responses step can satisfy, so that
Reaction reagent is reacted by scheduled flow velocity with continuous stream mode.Due to can be by being switched fast in the way of pneumatic pressure pulses
To multiple reaction tubes are controlled simultaneously, therefore the system is easier to realize high throughput automated micro or a small amount of synthesis in solid state.
In another aspect, the present invention provides the continuous flowing reaction tube of air pressure driving above-mentioned, air pressure above-mentioned drives continuous flow
Dynamic reactor, air pressure above-mentioned drive continuous flow reactor, the continuous flowing reaction system of air pressure above-mentioned driving in solid phase
Application in synthesis.
Preferably, the synthesis in solid state is high throughput micro-scale or a small amount of synthesis in solid state, it is further preferred that the solid phase is closed
As high throughput automated micro or a small amount of synthesis in solid state.
Preferably, the synthesis in solid state is Solid phase peptide synthssis.
It is of the present invention high-throughput with definition well known in the art, it generally refers to carry out ten or more solid phases simultaneously
It synthesizes (such as Solid-phase synthesis peptides).
It is of the present invention micro or it is a small amount of synthesis have definition well known in the art, generally refer to synthesis amount (such as
The amount of target polypeptides) 0.1 to 10mg.Typically, micro to refer to that synthesis yield in 0.1mg to 1mg, and refers to synthesis in a small amount
Amount in 1mg to 10mg.
As a specific embodiment of the invention, the application includes the following steps:
(1) solid phase carrier and reaction reagent are packed into the reaction tube；
Preferably, required reaction reagent is directly all loaded in the reaction tube；
(2) reaction tube is then sealed；
(3) by controlling the reaction intraductal atmospheric pressure, the reaction reagent is promoted to pass through with the continuous type of flow described solid
Phase carrier, and different reagent flow rates is realized in different response procedures, carry out synthesis in solid state.
When application previous reaction pipe carries out the solid phase reaction, after being packed into solid phase carrier and reaction reagent, can be used
Plug (plug can be plug in the prior art) is sealed the reaction tube, and pressure is then given into reaction tube makes institute
It states reaction reagent and the solid phase carrier is passed through with the continuous type of flow.
When application air pressure of the present invention driving continuous flow reactor carries out the solid phase reaction, it is being packed into solid phase
After carrier and reaction reagent, the reaction tube is sealed by the sealing element, pressure is then given into reaction tube makes
The reaction reagent passes through the solid phase carrier with the continuous type of flow.
When application air pressure of the present invention drives continuous flow reactor to carry out the solid phase reaction, it is being packed into solid phase
After carrier and reaction reagent, pass through the mobile realization sealing of the mechanical and horizontally movable machinery moving up and down
Sealing of the part to the reaction tube, pressure is then given into reaction tube makes the reaction reagent pass through institute with the continuous type of flow
State solid phase carrier.
When the continuous flowing reaction system of application air pressure of the present invention driving carries out the solid phase reaction, it is being packed into solid phase
After carrier and reaction reagent, pass through the mobile realization sealing element of the mechanical and horizontally moveable machinery moving up and down
Sealing to the reaction tube, pressure is then given into reaction tube by the positive pressure gas source and the air valve makes the reaction
Reagent passes through the solid phase carrier with the continuous type of flow.
The invention has the benefit that by design reaction tube structure and reactive mode, it can be relatively simple in structure
Charging, liquid storage, continuous flowing reactive are realized in reaction tube, be appropriate for micro or waits solid-state chemical reaction methods in a small amount, such as micro
Or a small amount of Peptide systhesis, the polypeptide magnitude that can be synthesized, between ten milligrams, can satisfy most of proteomics in hectogamma
The demand of equal polypeptides research, more conventional large-tonnage polypeptide synthesis method have cost advantage.Reaction tube manufacture does not need any
Accurate micro-nano technology, can be by being opened large scale preparation, therefore manufacturing process is simple, low in cost.System of the present invention
Pneumatic pressure pulses control can be used, be easy to implement it is high-throughput integrated, for the synthesis of high-volume bioactive substance is (such as more
Peptide).Reaction tube, reactor, reaction unit and reaction system of the present invention have high throughput automated micro or a small amount of synthesis
Ability has significant advantage for fields such as proteomics research, medicament research and developments.When by the present invention apply Solid phase peptide synthssis
When, technical solution provided by the present invention quick, efficient, inexpensive can obtain free polypeptide, and polypeptide yield can reach milligram
Level is sufficiently used for the major experimental of proteinology, can solve proteomics very well for the main of high throughput synthesis polypeptide
Problem, to solve the technical bottleneck for lacking high-throughput, Fully automated synthesis milligram magnitude or the free polypeptide of trace level at present at all.
Detailed description of the invention
Fig. 1 is the structural schematic diagram of the continuous flowing reaction tube of the driving of air pressure described in the embodiment of the present invention 1.
Fig. 2 is the structural schematic diagram of the sealing element of the embodiment of the present invention 1.
Fig. 3 is the course of work schematic diagram of reactor described in the embodiment of the present invention 1.
Fig. 4 is that the reaction system of the embodiment of the present invention 2 carries out the process schematic of Peptide systhesis.
Fig. 5 is the liquid-phase chromatographic analysis result figure for the polypeptide product that the embodiment of the present invention 2 synthesizes.
Fig. 6 is the mass spectral results figure for the polypeptide product that the embodiment of the present invention 2 synthesizes.
Label in figure has as significant:
1: reaction tube matrix；2: pressure ring；3: microporous membrane (multilayer)；4: reaction tube matrix axial section；5: reaction tube；
6: spring；7: stainless steel base；8: elastic silica gel；9: snorkel；10: sealing element；11: circlip (fixed reaction tube seal structure
With)；12: fixing piece (can be moved up and down by motor control) moving up and down；13: reagent pipetting volume needle；14: reaction reagent；15:
Solid phase carrier；16: reaction system workflow schematic diagram；17: cleaning reagent and the evacuation step that pressurizes is added；18: remove-insurance is added
Protect reagent and the evacuation step that pressurizes；19: cleaning reagent and the evacuation step that pressurizes is added；20: coupling reagent and emptying of pressurizeing is added
Step.
Specific embodiment
Below by specific embodiment to the continuous flowing reaction tube of air pressure driving of the invention, reactor, reaction unit,
Reaction system and its application in Solid phase peptide synthssis are described in detail.It unless otherwise specified, is routine in embodiment
Method；Experimental material and component used is unless otherwise specified to be commercially available from conventional biochemical reagent manufacturer or opticians
's.
Embodiment 1
Right side referring to Figure 1, in this present embodiment, continuous flowing 5 both ends open of reaction tube of air pressure driving, when being disposed vertically
When, 5 top end opening of reaction tube is entrance (can be packed into solid phase carrier, reaction reagent and input pressure etc.), and bottom end opening is
It exports (can be the outfluxes such as cleaning solution, reaction solution), 4 layers of microporous membrane 3 is provided in the reaction tube 5, the micropore is thin
The top of film 3 is equipped with pressure ring 2, in an interference fit that the microporous membrane 3 is fixed between tube body；The reaction tube top
Outer is held to be equipped with multiple baffles.Using baffle, reaction tube 5 can carry on porose bracket or carrier, the present embodiment bracket
Or multiple carry holes are provided on carrier, can more reaction tubes 5 of carry simultaneously, to assemble multiple reactors as described below.
Reaction tube 5 described in the present embodiment has reaction tube main body (solid phase carrier and reaction reagent can be loaded in pipe)
And the conical outlet part being directly connected to, the microporous membrane 3 is located at reaction tube main body and the connectivity part of conical outlet part is attached
Closely.
The internal diameter of reaction tube main body described in the present embodiment gradually decreases, the upper end internal diameter be 8mm, bottom diameter 5.5mm,
The length of the reaction tube main body is 5cm.
The length of conical outlet part described in the present embodiment is 10mm, exit inside diameter 0.5mm.
The number of plies of microporous membrane 3 described in the present embodiment is 4 layers, and miillpore filter aperture is 0.5 micron.
The material of microporous membrane 3 described in the present embodiment is selected from silica gel；The material of the reaction tube 5 is selected from polypropylene；It is described
The material of pressure ring 2 is identical as the material of the reaction tube.
When reaction tube 5 is through gas pressure described in the present embodiment, reaction reagent flows through solid phase carrier with the continuous type of flow, ginseng
With synthetic reaction；Waste liquid is discharged from outlet at bottom.
The present embodiment reaction tube 5 can be opened manufacture, be subsequently filled miillpore filter 3, become actually available reaction tube, please join
See the left side Fig. 1 and intermediate institute diagram, concretely:
It is opened batch machining reaction tube matrix 1 (reaction tube matrix axial section 4) first, is then made using puncher
Or consigned processing makes diameter and the comparable round microporous membrane 3 (miillpore filter) of reaction tube base diameter, by 4 layers of microporous membrane
3 neat fillings are then filled with pressure ring 2 and compress to bottom of the tube is reacted, and 4 layers of miillpore filter dense packing effect are being reacted bottom of the tube,
The filling effect for ensuring microporous membrane 3 finally obtains the reaction tube 5 actually used for completing assembly.
Air pressure driving continuous flow reactor provided in this embodiment includes the continuous flowing reaction tube of air pressure above-mentioned driving
And the sealing element for sealing the reaction tube；It please refers on the right side of Fig. 2, in this present embodiment, the sealing element 10 is jacket structure,
Innermost layer is snorkel 9, the elastic silica gel 8 that the outer surface cover axial cross section of snorkel is T, the elastic silica gel 8 outer surface cover axial direction
Section is to fall the stainless steel base 7 of T, and the 7 outside sleeve spring 6 of stainless steel base, the stainless steel base 7 is attached close to upper surface
It is equipped with groove closely can fix entire sealing element by circlip 11,8 lower end surface of elastic silica gel is smooth, the diameter of the end face
Greater than the outer diameter of the top inlet of the reaction tube 5, so that the salable reaction tube 5 under the effect of the pressure；
7 lower end surface of stainless steel base can set off silicone elastomer structure, it is ensured that sealing effect.
Air pressure can be applied to reaction tube 5 after sealing reaction tube by snorkel 9, flow out liquid in pipe.
When actual installation, it can successively install from innermost layer to outermost layer, then entire sealing structure is consolidated by circlip
It is fixed.It please refers on the left of Fig. 2, the manufacturing process of specific sealing element 10 can are as follows:
Match the internal diameter of spring 6 and the outer diameter of stainless steel base 7, the internal diameter of stainless steel base 7 and elastic silica gel 8 it is outer
Diameter matching, the internal diameter of elastic silica gel 8 are matched with the outer diameter of snorkel 9.Four are socketed in order, and sealing element can be obtained
10.The monomer lower end surface of sealing structure 10 be silica gel material, be under pressure act on when, reaction tube 5 can be fitted closely, it is ensured that
Sealing to reaction tube 5, while air pressure can be applied into reaction tube 5 by snorkel 9, promote the reagent in reaction tube 5 with even
Afterflow flowing mode participates in reacting and flowing out.
The present embodiment provides air pressure drive continuous flow reactor include air pressure driving continuous flow reactor above-mentioned,
Fixing piece 12, horizontally movable bracket or carrier moving up and down, the air pressure drive in continuous flow reactor
Sealing element 10 can be fixed on the fixing piece moving up and down and can be by the reaction by the fixing piece moved up and down
Pipe 5 seals；Reaction tube 5 in the air pressure driving continuous flow reactor can be placed in the horizontally movable bracket or hold
On load plate.
Horizontally movable bracket or carrier are on porose bracket or carrier in the present embodiment, and reaction tube 5 can be inserted
Enter into the hole.By motor control, it is moved up and down the present embodiment fixing piece moving up and down.
Referring again on the right side of Fig. 2, in this present embodiment, sealing element 10 is fixed on fixation moving up and down by circlip 11
On part 12.The reaction tube 5 is placed on can be on horizontal direction mobile bracket or carrier, to make the fixing piece 12 moved up and down
The reaction tube 5 can be sealed, the present embodiment ensures that the open-topped center of reaction tube 5 and the axle center of sealing element 10 are coaxial.It is logical
It crosses on fixing piece 12 moving up and down and multiple installation hole locations is set, can install simultaneously and control multiple sealing elements 10, phase
It answers, the more reaction tubes 5 is placed on porose bracket or carrier, more reactors are controlled simultaneously with realizing.
After sealing element 10, which moves up, to be released to the sealing of reaction tube 5, reagent pipetting volume can be carried out, and sealing element 10 to
Reaction tube 5 is implemented after sealing and applying air pressure in lower movement, and continuous flowing reactive may be implemented.Thus described device may be implemented
Reagent pipetting volume, continuous flowing reactive, the function that waste reaction solution is discharged.The present embodiment is at horizontally movable mechanical (bracket) and can
The multiple reaction tubes 5 of the mechanically placement moved up and down and sealing element 10, and ensure reaction tube 5 and corresponding sealing element respectively
10 is coaxial, and the high throughput for realizing multiple reaction units integrates and the parallel control to multiple reaction units.
The present embodiment also provides air pressure driving continuous flowing reaction system, which includes that aforementioned air pressure driving is continuous
Flow reactor, air valve and positive pressure gas source, the air valve can control the air pressure in the reaction tube 5 in a manner of pneumatic pressure pulses,
By piping connection, the air valve is arranged in the pipeline for the positive pressure source outlet and 10 Center Vent tube 9 of sealing element.
Referring to Fig. 3, reaction system workflow schematic diagram 16 are as follows: solid phase required for synthesizing is added in reaction tube 5
Carrier 15, reaction system enter course of normal operation, move horizontally bracket or carrier first, so that sealing element 10 is no longer at
5 top of reaction tube, needed for being added using reagent pipetting volume needle 13 (such as the reagent pipetting volume needle of three-dimensional machinery arm) from the top of reaction tube 5
The reaction reagent 14 of quantity completes sample-adding process；Then bracket or carrier are moved horizontally again, so that the position again of sealing element 10
Above reaction tube 5 and the axle center of sealing element and the axle center of reaction tube 5 are coaxial；Followed by moving up and down mechanical downward
Movement makes to form excellent sealing between sealing element 10 and reaction tube 5, opens 9 (this reality of snorkel among the sealed part 10 of air valve
Example is applied by the software control air valve the air pressure in reaction tube can be controlled in the way of pneumatic pressure pulses, these air valves and software are equal
For the prior art, can be selected, not repeated separately herein according to actual needs) air pressure is provided into reaction tube 5, so that reaction
Reagent 14 participates in reacting with the continuous type of flow under the influence of air pressure, and flows out from 5 bottom of reaction tube, after a certain period of time, complete
It is complete to empty reaction reagent 14, only retain solid phase carrier 15 in reaction tube 5.
Embodiment 2
Referring to Fig. 4, in this present embodiment, the reaction system progress solid-phase polypeptide conjunction to how to be provided using embodiment 1
At being explained as follows:
(a) loading is connected with the resin of first amino acid of C-terminal (according to the polypeptide sequence to be synthesized, in advance in reaction tube 5
WANG resin is such as commercialized in the amino acid of connecting peptides C-terminal on resin), Solid phase peptide synthssis is used for after being swollen；
(b) cleaning reagent and the evacuation step 17 that pressurizes is added: being directly loadable into cleaning reagent in reaction tube 5, seals reaction tube 5
Cleaning reagent is emptied using air pressure, realizes cleaning effect；
(c) deprotecting regent and the evacuation step 18 that pressurizes is added: being directly loadable into deprotecting regent in reaction tube 5, sealing is anti-
Should pipe 5 continuous flowing reactive is realized under gas pressure, and finally empty deprotecting regent；
(d) cleaning reagent and the evacuation step 19 that pressurizes is added: being directly loadable into cleaning reagent in reaction tube 5, seals reaction tube 5
Cleaning reagent is emptied using air pressure, realizes cleaning effect；
(e) coupling reagent and the evacuation step 20 that pressurizes is added: being directly loadable into coupling reagent in reaction tube 5, seals reaction tube 5
Continuous flowing reactive is realized under gas pressure, to connect second amino acid, and finally empties deprotecting regent；
(f) by the circulation of several wheel (b)~(e) steps, each required amino acid is connected one by one, finally obtains target
Polypeptide；
(g) through subsequent cleavage step, free target polypeptides are obtained.Due to the reaction system be easily achieved it is multiple simultaneously
Row control also realizes high-throughput Solid phase peptide synthssis after carrying out multiple reaction systems to integrate.
Based on above-mentioned steps, the polypeptide sequence that the present embodiment prepares synthesis is GKTVIEY.This example uses commercially available Fmoc-Y
The Solid phase peptide synthesis carrier of modification is as solid phase carrier.
Specific synthesis step is as follows:
(i) synthetic vectors are packed into: being poured into using pipettor from the top entry of reaction tube 5 and is scattered in N ' N- dimethyl formyl
The Solid phase peptide synthesis carrier (resin) of Fmoc-Y modification in amine (DMF) is into reaction tube 5, and Solid phase peptide synthesis carrier dry weight is about
10mg。
(ii) reagent prepares: by the amino-acid reagent of next step coupling needs, (such as first round is coupled as Fmoc-E, the second wheel
Coupling be Fmoc-I) etc. respectively with benzotriazole-N, N, N ', N '-tetramethylurea hexafluorophosphate (HBTU) mixing, be added live
Change reagent (DMF solution that molar concentration is the N- methylmorpholine of 0.4mol/L) and is made into amino acid coupling reagents, configuration quality
The DMF solution for the hexahydropyridine that percentage composition is 20% is deprotecting regent, in addition takes DMF as after coupling and after deprotection
Cleaning solvent.
(iii) clean: control mechanical structure is opened so that sealing element 10 is aligned reaction tube 5 and lower means of press seals reaction tube 5
Air pressure valve applies positive pressure into reaction tube 5 by snorkel 9, and the DMF reagent in reaction tube 5 is promoted all to flow out, and realizes clear
Wash effect.
(iv) be deprotected: control mechanical structure utilizes automatic sample arm that step (b) is added so that being sky above reaction tube 5
The deprotecting regent of configuration.Then mechanical structure is controlled, so that sealing structure alignment reaction tube 5 and lower means of press seals reaction tube 5, benefit
With software control air pressure valve, pneumatic pressure pulses are provided in a manner of quick on-off, so that pressure is maintained at appropriate model in reaction tube
It encloses, deprotecting regent in reaction tube 5 is promoted slowly to flow out with the continuous type of flow, realize the remove-insurance of Fmoc group on solid phase carrier
Shield, waste reaction solution guarantee that fresh reagent is effectively contacted with solid phase carrier constantly from reaction bottom of the tube outflow.
(v) clean after being deprotected: control mechanical structure utilizes automatic sample arm to be added and walks so that being sky above reaction tube 5
Suddenly the cleaning reagent of (b) configuration.Mechanical structure is controlled again, so that sealing element 5 is aligned reaction tube 5 and lower means of press seals reaction tube 5, is beaten
Air pressure valve is opened, positive pressure is applied into reaction tube 5 by snorkel 9, promotes the DMF reagent in reaction tube 5 all to flow out, realizes
Cleaning effect.
(vi) be coupled: control mechanical structure is added step (b) using automatic sample arm and matches so that being sky above reaction tube 5
The coupling reagent set.Then mechanical structure is controlled, so that sealing element 10 is aligned reaction tube 5 and lower means of press seals reaction tube 5, utilization is soft
Part control pressure valve, provides pneumatic pressure pulses in a manner of quick on-off, so that pressure is maintained at proper range in reaction tube 5,
Promote coupling reagent in reaction tube 5 slowly to flow out with the continuous type of flow, new amino acid residue is connected on solid phase carrier, instead
It answers waste liquid constantly from reaction bottom of the tube outflow, and guarantees that fresh reagent is effectively contacted with solid phase carrier.
(vii) mechanical structure is controlled, so that being sky above reaction tube 5, utilizes automatic sample arm that step (b) configuration is added
Cleaning reagent.
(viii) step (b)~step (g), every extension for executing a wheel and realizing a wheel polypeptide are repeated.Until institute
There is amino acid residue to be connected on polypeptide.
(ix) after target sequence synthesis terminates, wheel (b)~(e) step is continued to execute, it will most latter linked amino acid
FMOC blocking group slough.
(x) it cracks: taking out the solid phase carrier for having synthesized and having finished from reaction tube 5, be placed in lytic reagent (mass percentage
For the aqueous solution of 97.5% trifluoroacetic acid (TFA)) in cracking.Be dried with nitrogen, anhydrous ether precipitating and etc. after, swum
From target polypeptides.
(k) it analyzes and identifies: verifying product correctness, result such as Fig. 5 and figure using high performance liquid chromatography-mass spectrometry instrument
Shown in 6.As can be seen from Figure 5 synthetic product purity is very high, only one individual main peak, and synthesis produces as can be seen from Figure 6
Object is consistent with target polypeptides molecular weight, it was demonstrated that synthesized product is strictly target polypeptides.
Continuous flowing reaction tube, reactor, reaction unit and reaction system are driven using air pressure proposed by the invention, it can
To carry out Solid phase peptide synthssis.Based on specific synthesis system designed by embodiment 1, the reaction of single-wheel Solid phase peptide synthssis can be
It is completed in 0.5-1 hours, the polypeptide of embodiment 2 can be completed in 3-6 hours, reaction of ten hours compared to conventional polypeptide composite number
Period, reaction efficiency greatly improve.Gas pulses drive response fluid and coutroi velocity can be used in reaction system, can be according to not
Needs with reaction step realize the optimized control to each step.Reaction system is easy to carry out parallelization operation, to realize
The automation Peptide systhesis of higher flux.
Detailed features and method detailed of the invention that the present invention is explained by the above embodiments, but the present invention not office
It is limited to above-mentioned detailed features and method detailed, that is, does not mean that the present invention must rely on above-mentioned detailed features and method detailed
It could implement.It should be clear to those skilled in the art, any improvement in the present invention, to proposed by the invention anti-
It answers device structure to carry out equivalence replacement and addition, the selection of concrete mode of auxiliary element etc., all falls within protection scope of the present invention
Within the open scope.
Claims (19)
1. a kind of air pressure drives continuous flow reactor, the reactor, which includes that air pressure driving is continuous, flows reaction tube and for close
Seal the sealing element of the reaction tube；
The continuous flowing reaction tube both ends open of air pressure driving, when being disposed vertically, top end opening is entrance, bottom end opening
For outlet, the interior setting microporous membrane of the reaction tube is as mwco membrane, and the top of the microporous membrane is equipped with pressure ring, with tube body
Between the microporous membrane is fixed in an interference fit；
The sealing element is jacket structure, and innermost layer is snorkel, and surface cover axial cross section is the elastic silica gel of T outside snorkel,
The stainless steel base that the outer surface cover axial cross section of the elastic silica gel is T, stainless steel base outside sleeve spring are described stainless
Steel matrix is nearby equipped with groove can fix entire sealing element by circlip close to upper surface, and the elastic silica gel lower end surface is flat
Whole, the diameter of the end face is greater than the outer diameter of the top inlet of the reaction tube, so that salable described anti-under the effect of the pressure
Ying Guan.
2. air pressure according to claim 1 drives continuous flow reactor, wherein the air pressure drives continuous flowing reactive
Pipe is equipped with hanging structure.
3. air pressure according to claim 1 drives continuous flow reactor, wherein the number of plies of the microporous membrane is 4~
12 layers, aperture is less than 1 micron.
4. air pressure according to claim 1 drives continuous flow reactor, wherein:
The material of the microporous membrane is selected from silica gel or PTFE；
The material of the reaction tube is selected from polypropylene or FEP.
5. air pressure according to claim 4 drives continuous flow reactor, wherein the material of the pressure ring is reacted with described
The material of pipe is identical.
6. air pressure according to any one of claims 1 to 5 drives continuous flow reactor, wherein the reaction tube tool
The conical outlet part for having reaction tube main body and being directly connected to, the microporous membrane are located at reaction tube main body and conical outlet part
Connectivity part near.
7. air pressure according to claim 6 drives continuous flow reactor, wherein the internal diameter of the reaction tube main body is gradually
It reduces, the upper end internal diameter is 6~8mm, and bottom diameter is 4.5~5.5mm, and the length of the reaction tube main body is 4~6mm.
8. air pressure according to claim 7 drives continuous flow reactor, wherein the length of the conical outlet part is 6
~12mm, exit inside diameter are 0.5~0.8mm.
9. a kind of air pressure drives continuous flow reactor, described device includes more set described in any item gas of claim 1-8
Pressure driving continuous flow reactor, mechanical, horizontally movable machinery moving up and down, air pressure drive continuous flow reactor
In sealing element be fixed on it is described it is moving up and down mechanically, air pressure driving continuous flow reactor in reaction tube be placed on
It is described it is horizontally movable mechanically, by this it is moving up and down mechanical and this it is horizontally movable it is mechanical it is mobile can be by institute
State the reaction seal of tube.
10. air pressure according to claim 9 drives continuous flow reactor, wherein the center line of the reaction tube with
The axle center of the sealing element is coaxial.
11. a kind of continuous flowing reaction system of air pressure driving, which includes that the air pressure driving of claim 9 or 10 connects
Continuous flow reactor, air valve and positive pressure gas source, the air valve can control the air pressure in the reaction tube in a manner of pneumatic pressure pulses,
By piping connection, the air valve is arranged in the pipeline for the positive pressure source outlet and the sealing element Center Vent tube.
12. the continuous flowing reaction system of air pressure driving according to claim 11, wherein the positive pressure gas source is selected from air
Compressor or nitrogen cylinder.
13. air pressure described in the described in any item air pressure driving continuous flow reactors of claim 1-8, claim 9 or 10
Drive the continuous flowing reaction system of the driving of air pressure described in continuous flow reactor, claim 11 or 12 in synthesis in solid state
Application.
14. application according to claim 13, wherein the synthesis in solid state is high throughput micro-scale or a small amount of synthesis in solid state.
15. application according to claim 14, wherein the synthesis in solid state is high throughput automated micro or a small amount of solid
It is combined to.
16. application according to claim 14, wherein the synthesis in solid state is Solid phase peptide synthssis.
17. application according to claim 13, wherein the application includes the following steps:
(1) solid phase carrier and reaction reagent are packed into the reaction tube；
(2) reaction tube is then sealed；
(3) by controlling the reaction intraductal atmospheric pressure, the reaction reagent is promoted to carry with the continuous type of flow by the solid phase
Body, and different reagent flow rates is realized in different response procedures, carry out synthesis in solid state.
18. application according to claim 17, wherein required reaction reagent is directly all loaded in the reaction tube
In.
19. application according to claim 17, in which:
When the described in any item air pressure driving continuous flow reactors of application claim 1-8 carry out the solid phase reaction,
After being packed into solid phase carrier and reaction reagent, the reaction tube is sealed by the sealing element, is then given into reaction tube
Giving pressure makes the reaction reagent pass through the solid phase carrier with the continuous type of flow；
When the air pressure of application claim 9 or 10 drives continuous flow reactor to carry out the solid phase reaction, it is being packed into
After solid phase carrier and reaction reagent, described in the mobile realization by the mechanical and horizontally movable machinery moving up and down
Sealing of the sealing element to the reaction tube, pressure is then given into reaction tube keeps the reaction reagent logical with the continuous type of flow
Cross the solid phase carrier；
When the application claim 11 or 12 continuous flowing reaction system of air pressure driving carries out the solid phase reaction, it is being packed into
After solid phase carrier and reaction reagent, the mobile realization by the mechanical and horizontally moveable machinery moving up and down is described close
Sealing of the sealing to the reaction tube, then by the positive pressure gas source and the air valve given into reaction tube pressure make it is described
Reaction reagent passes through the solid phase carrier with the continuous type of flow.
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| CN111983220B (en) * | 2019-05-21 | 2024-03-19 | 北京中科纳泰生物科技有限公司 | Polypeptide magnetic nanoparticle, preparation method and application thereof |
| WO2020252266A1 (en) * | 2019-06-14 | 2020-12-17 | Mytide Therapeutics, Inc. | A manufacturing process for peptide and protein production |
| CN112915956B (en) * | 2021-01-25 | 2022-06-10 | 苏州硒瑞恩生物科技有限公司 | High-precision nucleic acid synthesizer and working method thereof |
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