CN109174217B

CN109174217B - Micro-fluidic chip for realizing drying process in synthetic reaction and method thereof

Info

Publication number: CN109174217B
Application number: CN201810892301.8A
Authority: CN
Inventors: 潘建章; 方群; 徐光明; 张宏; 田梅
Original assignee: Zhejiang University ZJU
Current assignee: Zhejiang University ZJU
Priority date: 2018-08-07
Filing date: 2018-08-07
Publication date: 2019-12-31
Anticipated expiration: 2038-08-07
Also published as: CN109174217A

Abstract

The invention discloses a micro-fluidic chip used for a drying process in organic synthesis and a method thereof, belonging to the field of micro-fluidic chip technology and organic synthesis. The micro-fluidic chip is provided with a micro-channel, and both ends of the micro-channel are respectively provided with a channel inlet and a channel outlet; the micro-channel is provided with a plurality of concave cavities along the path, and the concave cavities are formed by the fact that the inner wall of the channel is sunken towards one side away from the center of the channel. The drying micro-fluidic chip has simple structure and easy automation, can realize drying desolventization and solvent phase change of fluid in a chip channel, and can be widely used for micro-fluidic synthesis reaction.

Description

Micro-fluidic chip for realizing drying process in synthetic reaction and method thereof

Technical Field

The invention belongs to the field of microfluidic chip technology and organic synthesis, and particularly relates to a microfluidic chip and a method thereof for a drying process in organic synthesis.

Background

Microfluidic technology has originated from a technology for regulating the flow in microfluidic channels, which has found wide application in biochemical engineering. The appearance of the microfluidic technology promotes the development of related fields such as organic chemistry, material science, biomedicine and the like, opens up a new way for obtaining an ideal product, and provides possibility for deeply researching the mechanism at the molecular level. The chemical reaction is carried out in the microfluidic chip, so that the controllability, safety and selectivity of the reaction are improved, the used reagent amount is small, the reaction is rapid, and the occupied area is small. Among them, two major advantages are: mixing and heat/mass transfer can be performed in short time/space scales; (ii) can be accurately controlled to nm and pL levels. These advantages derive primarily from the size-related transfer of heat and mass. The small volume of the fluid results in a low reynolds number and the fluid is increasingly influenced by viscosity rather than inertia. Furthermore, the large ratio of surface area to volume within the channels ensures thermal uniformity throughout the reactor and rapid heat transfer between the device and the contained fluid.

In chemical synthesis, drying and desolvation processes are often involved, such as fluorination reactions during the synthesis of FDG and indirect labeling of 18F-octreotide. The method is difficult to use in a microfluidic chip, the gas-liquid separation of the currently reported microfluidic chip synthesis mainly uses a gas-permeable membrane PDMS for gas-liquid separation, but the applications of the gas-permeable PDMS material cannot be applied in occasions of strong acid, strong alkali and the like, and the multistep synthesis related to the anhydrous reaction is limited. Therefore, there is a need for a new microfluidic technology to break through this bottleneck state and achieve dry dehydration and solvent exchange of the fluid in the microfluidic chip channel for multi-step synthesis involving anhydrous reaction.

Disclosure of Invention

Aiming at the problems in the prior art, the invention provides the microfluidic chip for realizing the drying process in the synthesis reaction, which has the advantages of simple structure and convenient operation, can realize the drying dehydration and solvent exchange of fluid in a chip channel, and can be used for multi-step synthesis reaction.

The invention adopts the following specific technical scheme:

a micro-fluidic chip for realizing a drying process in a synthetic reaction is provided with a micro-channel, and two ends of the micro-channel are respectively provided with a channel inlet and a channel outlet; the micro-channel is provided with a plurality of concave cavities along the path, and the concave cavities are formed by the fact that the inner wall of the channel is sunken towards one side away from the center of the channel.

In the present invention, the microchannel refers to a fine channel for implementing microfluidic reaction, and the size of the channel is generally 100-2000 μm. The channel center refers to the position of the center line of a channel for flowing reagents or gas in the microchannel, so that the depression of the inner wall of the channel towards the side away from the channel center refers to the depression of the inner wall of the channel from the channel center to the side of the chip substrate, but the depression direction is not necessarily completely vertical to the inner wall of the channel, and can be adjusted as required.

The inlet of the micro-channel can be filled with gas and liquid reagent, and the outlet can be used for discharging gas or liquid or gas-liquid mixture. Since the concave cavity is opened on the inner wall of the channel, the size of the concave cavity is small, and when the liquid reagent flows through the cavity, the reagent is retained in the cavity due to surface tension and cannot be carried out of the microchannel by being pushed by the air flow. And subsequently, keeping gas continuously introduced into the micro-channel, so that the retained reagent in the cavity can be continuously evaporated to realize drying. Compared with the method adopting the PDMS gas-permeable membrane, the micro-fluidic chip can realize the drying and dehydration of the reagent and the solvent exchange by a simple structure, and can also be applied to occasions of strong acid, strong base and the like.

Preferably, the microchannel has a plurality of channel inlets, and all the channel inlets communicate with the front end of the microchannel through the branch channels. The provision of multiple channel inlets may enable different gaseous or liquid reactants to enter the microchannel from different ports without the need for complex valve switching.

Further, the microchannel preferably has two channel inlets, wherein the first channel inlet is used as an inlet for a reagent to be dried, the second channel inlet is used as an inlet for a drying gas, and the two channel inlets are respectively communicated with the front end of the microchannel after being converged by one branch channel. In the present invention, the drying gas refers to a gas introduced into the microchannel for drying the reagent. This setting mode can conveniently realize the dry dehydration to liquid reagent.

Furthermore, the drying gas is inert gas to avoid reaction with effective components in the reagent to be dried.

Preferably, the micro-channels are distributed in a serpentine shape in the microfluidic chip, so that the length of the micro-channels is increased, and the size of the chip is reduced.

Preferably, the concave cavity is horizontally arranged at two sides of the micro-channel, so that the reagent can enter and exit the concave cavity.

Preferably, the concave cavity is smoothly cambered towards the inner surface of the microchannel to avoid dead volume.

Preferably, the microfluidic chip is made of a corrosion-resistant material which does not react with the reagent to be dried, and preferably quartz, silicate glass and borate glass.

Another objective of the present invention is to provide a method for implementing a drying process in a synthesis reaction by using the microfluidic chip according to any of the above schemes, specifically as follows: firstly, injecting a reagent to be dried into the upstream position of a micro-channel through a channel inlet of the micro-channel; then introducing dry gas into the microchannel through the channel inlet to push the reagent to be dried to move to the downstream of the microchannel, and the reagent is continuously retained in the cavity when passing through the concave cavity along the way; keeping the continuous introduction of the dry gas, and continuously evaporating the retained reagent in the concave cavity until the retained reagent is dry.

Preferably, the amount of reagent to be dried injected into the microchannel is not greater than the effective volume of all of the concave cavities in the microchannel. Thus, all injected reagents can be completely retained in the microchannel and cannot be carried out of the microchannel. By the concave cavity, the effective volume is meant the maximum reagent volume that can be accommodated in the cavity when the reagent to be dried is forced to flow through the concave cavity by the drying gas.

The drying micro-fluidic chip has simple structure and easy automation, can realize drying desolventization of fluid in a chip channel to exchange phase with a solvent, and can be widely used for micro-fluidic synthesis reaction.

Drawings

FIG. 1 is a schematic diagram of a microfluidic chip for performing a drying process in a synthesis reaction;

FIG. 2 is another schematic diagram of a microfluidic chip for performing a drying process in a synthesis reaction;

FIG. 3 is a schematic diagram of a first state of use of the microfluidic chip (reagent injection);

FIG. 4 is a schematic diagram of a second usage state of the microfluidic chip (dry gas introduction);

FIG. 5 is a schematic diagram of a third use state of the microfluidic chip (gradual drying of the retained reagent);

fig. 6 is a schematic diagram of a fourth state of use of the microfluidic chip (phase inversion solvent injection);

reference numbers in the figures: a first channel inlet 1, a second channel inlet 2, a channel outlet 3, a microchannel 4, a concave cavity 5, a liquid reagent 6, a dry gas 7, a retentate reagent 8.

Detailed Description

The invention will be further elucidated and described with reference to the drawings and specific embodiments. The technical characteristics in the embodiments of the present invention can be combined correspondingly without mutual conflict.

The micro-fluidic chip can be used for realizing a solvent drying process or a solvent phase-changing process in organic synthesis reaction. The micro-fluidic chip is provided with a micro-channel 4, and two ends of the micro-channel 4 are respectively provided with a channel inlet and a channel outlet for introducing and discharging gas/liquid. The core of the micro-fluidic chip is that a plurality of concave cavities 5 are arranged on the path of a micro-channel 4, and the concave cavities 5 are formed by the concave of the inner wall of the channel to the side away from the center of the channel. The main function of the concave cavities 5 is to be able to be retained in the cavity by surface tension when the liquid reagent to be dried flows through, and to retain all reagents in the concave cavities 5 when the number of the concave cavities 5 is large enough, so that they will not be carried out of the microchannel by the gas. And because the concave cavity 5 is connected with the microchannel, the subsequent gas is continuously introduced into the microchannel, so that the retained reagent in the cavity can be continuously evaporated. The size and shape of the concave cavity 5 are not limited, and the opening direction of the concave cavity on the inner wall of the channel, namely the concave direction, can be adjusted according to the requirement. The depth of the concave cavity 5 can influence the effect of evaporation drying, the increase of the depth is beneficial to containing solution, and the single treatment capacity is increased; decreasing the depth increases the evaporation rate, but decreases the single pass throughput; likewise, the size of the opening of the cavity 5 will also change the evaporation area and thus the evaporation rate. One or more channel inlets and channel outlets may be provided, as determined by the particular requirements of the reaction. When only one channel inlet is provided, different liquid reagents and gases need to be injected into the channel inlet through a valve switching mode, and when the channel inlets are provided with a plurality of inlets, the gases or the liquid reagents injected from each inlet can be introduced into the front end of the microchannel 4 through the branch channels. When there are multiple branch channels, each branch channel can be converged and then connected to the microchannel 4, or can be connected to different positions of the microchannel 4, but it should be noted that the branch channel for introducing the dry gas should be located at the upstream or the same position of the branch channel for introducing the reagent to be dried, as far as possible, since the dry gas needs to push the reagent to be dried on the microchannel 4.

Fig. 1 is a schematic structural diagram of a microfluidic chip for performing a drying process in a synthesis reaction according to an embodiment, and the microfluidic chip is provided with a microchannel 4. The micro-fluidic chip can be made of quartz, silicate glass, borate glass and other corrosion-resistant materials which do not react with the reagent to be dried. One end of the micro-fluidic chip is provided with two channel inlets, wherein a first channel inlet 1 is used as an inlet of a reagent to be dried, a second channel inlet 2 is used as an inlet of a drying gas, the two channel inlets are distributed at the tail ends of two branch ports of a connecting pipeline with a V-shaped structure, the two inlets are communicated with the front end of the micro-channel 4 after being converged by a branch channel respectively, and the reagent to be dried and the drying gas are distributed to be introduced into the micro-channel 4. The end of the microchannel 4 is provided with a channel outlet 3 from which the drying gas or gas-liquid mixture will flow out. The micro-channels 4 are distributed in the chip in a serpentine shape, and a plurality of concave cavities 5 are arranged along the path. The concave cavity 5 in this embodiment is semi-elliptical, and is recessed from the channel cavity to the chip substrate side, and the long axis direction is perpendicular to the inner wall of the micro-channel 4. The inner surface of the cavity 5 facing the microchannel 4 remains as smooth as possible, without dead corners. The concave cavities 5 are mainly continuously arranged in pairs on straight sections of the micro-channel 4, and can be not arranged on the bent sections of the micro-channel 4.

In addition, on the basis of the above embodiment, the opening angle of the concave cavity 5 can be optimized to be horizontal, that is, the concave cavity 5 is horizontally arranged on both sides of the microchannel 4 in the horizontal state of the chip, and the channel walls on both sides are respectively recessed toward one side of the substrate. The lowest position of the cavity 5 is as low as possible below the bottom of the microchannel 4. In a preferred embodiment, the microfluidic chip has dimensions of 100mm × 40mm × 2mm, the cross section of the microchannel 4 is rectangular, the thickness of the microchannel is 1mm, the width of the microchannel is 1.8mm, the effective length of the microchannel is 850mm, and the effective volume of the microchannel is 1530 μ L. The bottom surface of the concave cavity 5 is horizontal and is kept flush with the bottom surface of the micro-channel 4, the thickness of the concave cavity is also kept consistent with that of the micro-channel 4, and the dead volume is reduced as much as possible.

The shape and size of the micro-channels 4 in the micro-fluidic chip and the number of the concave cavities 5 can be adjusted according to the actual situation. For example, in another embodiment, the microfluidic chip may be configured as shown in fig. 2, with two channel inlets distributed at two ends of the branch of a "Y" connecting line, and the microchannel 4 is shorter than that shown in fig. 1, and the number of concave cavities 5 arranged along the path is also smaller, so that the reagent that can be dried at one time is also smaller.

The following will describe a method for performing a drying process using the microfluidic chip shown in fig. 2 as an example in a synthesis reaction. As shown in fig. 3, the liquid reagent 6 to be dried is injected into the upstream position of the microchannel 4 through the first channel inlet 1 of the microchannel 4, the injection process may use a syringe pump or the like, and in order to ensure that the liquid reagent 6 does not remain in the branch channel, the liquid reagent 6 may be pushed downstream of the junction of the "Y" structure by using a part of gas after the injection of the liquid reagent 6.

As shown in fig. 4, a dry gas 7 is then introduced into the microchannel 4 through the second channel inlet 2, the dry gas being selected so as not to react with the reagent, and therefore inert gases such as nitrogen, argon, helium, etc. may be selected. The dry gas 7 pushes the liquid reagent 6 on to move downstream of the microchannel 4 and on its way through each of the concave cavities 5, filling the cavity and being retained in the cavity by surface tension. Thus, as liquid reagent 6 flows along, stagnant reagent 8 fills the concave cavities 5 along the way, and the amount of reagent in microchannel 4 decreases. In the synthesis reaction which needs accurate quantification, all injected reagents to be dried are kept in the micro-channel 4 for drying, but cannot be taken out of the pipeline by the drying gas, so that the amount (by volume) of the reagents to be dried which are injected into the micro-channel 4 at a time is not more than the effective volume of all concave cavities 5 along the micro-channel 4, the loss of substances which need to be kept in a liquid phase is reduced, and the reaction raw materials which need to be accurately metered are ensured to be provided for the subsequent synthesis. Generally, the effective volume of all the concave cavities 5 is preferably larger than the amount of reagent to be dried, so as to improve reliability.

Of course, if the synthesis reaction does not require precise quantification, but only approximately drying of the reagents, which need not be done, part of the liquid reagent 6 may be carried out of the channel outlet 3 with the gas.

After the liquid reagent 6 in the micro-channel 4 is completely filled into the concave cavity 5, or after the excess liquid reagent 6 is pushed by the dry gas 7 to exit the channel outlet 3, the dry gas is continuously kept continuously introduced, and the surface of the retained reagent 8 in the concave cavity 5 continuously evaporates as the dry gas flows through until the reagent is completely dried, or reaches a predetermined drying degree (suitable for a reaction that does not require all reagents to be dried).

As shown in fig. 6, the substance left in each concave cavity 5 after being dried can be dissolved by injecting other solvent into the channel inlet, and then expelled from the channel outlet 3 under the push of gas, and injected into other microfluidic chips to continue the subsequent reaction. Alternatively, another reagent may be injected into the microchannel 4 to directly perform a reaction in the channel.

Of course, in the actual drying process, if the surface material of the microchannel 4 has a certain hydrophilicity, a part of the liquid reagent 6 will spread on the surface of the microchannel to form a liquid film, and this part of the liquid film will be continuously evaporated by the drying gas 7, as well as the retained reagent in the concave cavity 5. If the surface of the microchannel 4 is not hydrophilic, the liquid reagent will be substantially concentrated in the concave cavity. But drying can be achieved in both cases.

In addition, the solution reagent needs to be heated in part of the reaction, so a heater can be arranged at the bottom of the microfluidic chip, and the heater is preferably realized by adopting a microstructure such as a heating chip.

To make the technology in the fieldThe person skilled in the art will better understand the essence of the invention, based on the following¹⁸In F-FDG¹⁸F^-The drying dehydration process and the solvent exchange process of the present invention are described for the use of the chip of the present invention

Application example 1:

by using the chip shown in FIG. 1 or FIG. 2, high-efficiency on-line automatic synthesis can be realized¹⁸In F-FDG¹⁸F^-Drying and dehydrating process. The specific operation process is as follows: by using a precision injection pump¹⁸F^-The eluent is injected into the upstream position of the serpentine microchannel 4 from the inlet 1 of the first channel, after the eluent enters the microchannel 4 of the chip, the temperature of a heater at the bottom of the chip is raised to 80 ℃, and helium is introduced into the serpentine microchannel 4 through the inlet 2 of the second channel. Then, anhydrous acetonitrile CH was added by using a precision syringe pump₃CN is injected into the serpentine micro-channel 4 from the first channel inlet 1 and mixed with the eluent. Acetonitrile can form azeotrope with water, thus reducing the temperature of water when boiling, and can be used as a solvent in a reaction solution without causing interference. The azeotrope formed by acetonitrile and water is pushed by helium to continuously move to the downstream of the micro-channel until reaching the channel outlet 3 of the micro-fluidic chip. In the process of flowing along the way, the azeotrope is continuously filled and retained in the concave cavity 5 along the way, the reagent amount in the micro-channel 4 is continuously reduced until being completely retained in the concave cavity 5, at the moment, helium can directly penetrate through the second channel inlet 2 and is discharged from the channel outlet 3, the helium is continuously introduced, and the retained eluent is continuously evaporated until being dried. And then controlling the heater at the bottom of the chip to stop heating, and stopping introducing helium when the temperature of the microfluidic chip is reduced to room temperature to obtain a dry reactant in the concave cavity 5.

Application example 2:

the chip shown in FIG. 1 or FIG. 2 can also be used for realizing efficient online automatic synthesis¹⁸Solvent exchange process in F-FDG. The specific operation process is as follows: after the fluorination reaction, an acetylated FDG/acetonitrile solution was obtained. The acetylated FDG/acetonitrile solution is injected into the upstream position of the snake-shaped microchannel 4 from the inlet 1 of the first channel by using a precise injection pump, and after the solution enters the chip, the temperature of a heater below the chip is raisedTo 100 ℃ acetonitrile was evaporated. Helium is introduced into the snake-shaped microchannel 4 through the second channel inlet 2, and the solution continuously moves to the downstream of the microchannel until reaching the channel outlet 3 of the microfluidic chip under the pushing and hitting of the helium. Solution is along journey flow in-process, constantly is filled and is detained in along journey concave cavity 5, and the reagent volume in microchannel 4 constantly reduces, until being detained in concave cavity 5 completely, and He gas just can directly run through and discharge from passageway export 3 from second passageway entry 2 at this moment, keeps letting in of helium constantly, and acetonitrile steam will constantly evaporate and be taken out the passageway in the solution that is detained, and other compositions then remain in concave cavity, and acetonitrile constantly evaporates until the evaporation finishes. And after removing the acetonitrile, stopping heating by the heater, and stopping introducing helium when the temperature of the microfluidic chip is reduced to room temperature to obtain a mixture.

The chip is arranged in an online automatic synthesis system, and the processes of automatic reagent drying, solvent exchange and the like can be realized by automatically controlling equipment such as a pump, a valve, a heater and the like. Of course, the chip can also be used for carrying out drying dehydration and solvent exchange of other fluids in the channel, and can be used for multi-step synthesis reaction.

Therefore, the above-mentioned embodiments are only preferred embodiments of the present invention, and should not be construed as limiting the invention. Various changes and modifications may be made by one of ordinary skill in the pertinent art without departing from the spirit and scope of the present invention. All the technical solutions obtained by means of equivalent substitution or equivalent transformation fall within the protection scope of the present invention.

Claims

1. A micro-fluidic chip for realizing a drying process in a synthetic reaction is characterized in that a micro-channel (4) is arranged in the micro-fluidic chip, and a channel inlet and a channel outlet are respectively arranged at two ends of the micro-channel (4); the micro-channel (4) is provided with a plurality of concave cavities (5) along the path, and the concave cavities (5) are formed by the fact that the inner wall of the channel is sunken towards the side departing from the center of the channel; the microchannel (4) is provided with a plurality of channel inlets, including a first channel inlet (1) and a second channel inlet (2), and all the channel inlets are communicated with the front end of the microchannel (4) through branch channels; wherein the first channel inlet (1) serves as an inlet for the reagent to be dried and the second channel inlet (2) serves as an inlet for the drying gas.

2. The microfluidic chip for performing a drying process in a synthesis reaction according to claim 1, wherein the channel inlets of the microchannel (4) have two channel inlets, namely a first channel inlet (1) and a second channel inlet (2), and the two channel inlets are communicated with the front end of the microchannel (4) after being converged by one branch channel.

3. The microfluidic chip for performing a drying process in a synthesis reaction of claim 1, wherein the drying gas is an inert gas.

4. The microfluidic chip for performing a drying process in a synthesis reaction according to claim 1, wherein the microchannels (4) are distributed in a serpentine shape in the microfluidic chip.

5. Microfluidic chip for carrying out drying processes in synthesis reactions according to claim 1, characterised in that the cavity (5) is arranged horizontally on both sides of the microchannel (4).

6. Microfluidic chip for carrying out drying processes in synthesis reactions according to claim 1, characterised in that the internal surface of the cavity (5) facing the microchannel (4) is a smooth arc.

7. The microfluidic chip for performing a drying process in a synthesis reaction according to claim 1, wherein the microfluidic chip is made of a corrosion-resistant material that is non-reactive with a reagent to be dried.

8. The microfluidic chip for performing a drying process in a synthesis reaction of claim 7, wherein the corrosion resistant material is quartz, silicate glass, or borate glass.

9. A method for realizing a drying process in a synthesis reaction by using a microfluidic chip according to claim 1 ~ 8, wherein a reagent to be dried is injected into the upstream position of the microchannel (4) through the channel inlet of the microchannel (4), then a drying gas is introduced into the microchannel (4) through the channel inlet to push the reagent to be dried to move towards the downstream of the microchannel (4) and continuously stay in the cavity while passing through the concave cavity (5), and the drying gas is continuously introduced to continuously evaporate the retained reagent in the concave cavity (5) until the reagent is dried.

10. A method of carrying out a drying process in a synthesis reaction according to claim 9, characterised in that the amount of reagent to be dried injected into the microchannel (4) is not greater than the total effective volume of all the concave cavities (5) along the microchannel (4).