Abstract:
An organic synthesis microreactor mixes fluids in a very narrow space and causes the fluids to react in multiple stages. The reactor consists of an introduction portion and a reaction portion disconnectably connected. The introduction portion introduces reagents from channels and, if necessary, mixes and reacts the reagents. The reaction portion accepts a reagent or reaction liquid from the introduction portion and mixes and reacts the reagent or reaction liquid with other reagent.

Description:
BACKGROUND OF THE INVENTION  
       [0001]     1. Field of the Invention  
         [0002]     The present invention relates to an apparatus for organic synthesis and reactions and, more particularly, to an apparatus which is used for organic synthesis and reactions and permits analysis of reaction mechanisms and reaction intermediate structures.  
         [0003]     2. Description of Related Art  
         [0004]     A technique for causing plural substances to mix and react with each other in a quite small space is known as microchip technology or microreactor technology and expected to be put into practical use to provide increased chemical reaction rates and improved efficiencies.  
         [0005]     Microchip reactors for chemical synthesis are often made of glass because of their excellent chemical resistance. Since it is difficult to directly connect a tube, which is used to introduce a synthesis reagent, with a microchannel in a microchip made of glass, it is customary to connect the tube with a holder via a connector after the microchip reactor is held with the holder.  
         [0006]     At tube joints, O-rings are often used to prevent liquid leakage. Therefore, eluates from rubber members and dead volume often present problems. In one available method, a tube is adhesively fixed to the surface of a glass reactor. However, depending on the used solvent, there is the possibility that the adhesive dissolves out. Furthermore, it is possible to machine a threaded structure into a glass material, the structure being used for connection of tubes of liquid chromatographs. Nonetheless, a high level of technique is required to machine the structure, and high cost is necessary.  
         [0007]     Furthermore, a reagent solution having high viscosity may be used depending on the kind of synthesis reaction. The reagent may clog up the channel after introduction of the reagent. Especially, the channel tends to be clogged up near tube joints.  
         [0008]     Microreactor products used for chemical synthesis have already been sold from some manufacturers. The microreactors are chiefly made of glass. A digital representation of a commercially available microreactor for mixing of two reagents is shown in  FIG. 7 . The glass microreactor is composed of two plates. A microchannel is formed in one of the plates. A fluid inlet hole and a fluid exit hole are formed in the other. The two plates are bonded together by thermocompression.  
         [0009]     This microreactor is held to a holder. Tubes for introduction of reagents are connected with the microreactor using connectors. The tubes are connected with syringe pumps. Reagent solutions are introduced into the microreactor by the syringe pumps. The introduced reagents are made to meet at the Y-shaped portion of the channel and mixed. The reagents are made to react with each other in the downstream channel, thus producing reaction products.  
         [0010]     A well-known on-line method of detecting reaction products is a thermal lens microscope technique. Where a measurement is performed using a mass spectrometer (MS) or nuclear magnetic resonance spectrometer (NMR) to make structural analysis of reaction products, it is required that the reaction products be collected at the exit of the microreactor and that the sample be introduced into the MS or NMR off-line.  
         [0011]     Vigorous research is now underway to connect a microchip reactor or microreactor having various functions with an MS or NMR having high qualitative analysis capabilities in an on-line manner to perform analyses. See Japanese Utility Model No. S57-75558 and Published Technical Report No. 2004-502547 of the Japan Institute of Invention and Innovation. There are the following research reports:  
         [0012]     (1) Microchip-NMR  
         [0013]     A monograph has been published describing research in which a circular liquid reservoir is formed in a channel within a microchip reactor as shown in  FIG. 8 , a microcoil is brought close to the reservoir, and a trace amount of sample is investigated. J. H. Walton et al., Analytical Chemistry, Vol. 75, pp. 5030-5036 (2003). Microcoils or probes dedicated for microchip reactors are at a research stage. There are almost no applications to chemical synthesis.  
         [0014]     (2) Flow NMR  
         [0015]     Reaction reagents are mixed and reacted with each other using a static mixer. The reaction liquid is guided into a probe for flow NMR via a line, and an NMR measurement is performed. This research is at a practical level. The experiment needs a flow NMR probe. Furthermore, there is a drawback that the distance from the reaction portion to the position in the NMR magnet irradiated with an RF magnetic field is long.  
         [0016]     (3) Microchip-MS  
         [0017]     As shown in  FIG. 9 , when a microchip reactor is fabricated, a nanoelectrospray nozzle is integrated with the microchip reactor. J. Kameoka et al., Analytical Chemistry, Vol. 74, pp. 5897-5901 (2002). Mass analysis is enabled by applying a high voltage to the nozzle. There are more applications in the biological field than in synthetic chemistry.  
         [0018]     Microchip reactors and microreactors for chemical analysis have the following problems.  
         [0019]     (1) Since the microreactor is of the integrated construction, parts cannot be replaced. Therefore, if the channel or a tube joint is clogged up, the whole microreactor must be replaced. If the microreactor is made of glass, the running cost is high.  
         [0020]     (2) Eluates from the material of the connector and dead volume present problems.  
         [0021]     (3) When reaction products are detected on-line, usable detectors are limited to those using absorption of light.  
         [0022]     (4) When structural analysis of reaction products is performed using an analytical instrument, it is normally necessary to introduce a sample in an off-line manner.  
         [0023]     Where on-line detection using a combination of a microchip reactor and an analytical instrument consisting of an NMR is performed, there are the following problems:  
         [0024]     (1) It is necessary to design and develop a dedicated NMR probe. This needs an exorbitant amount of initial investment.  
         [0025]     (2) Since the design of the microchip reactor is dedicated for NMR, it is difficult to connect the reactor directly with other detectors.  
         [0026]     Where on-line detection using a combination of a microchip reactor and an analytical instrument consisting of a flow NMR spectrometer is performed, there are the following problems.  
         [0027]     (1) It is necessary to design and develop a dedicated flow probe. This necessitates a huge amount of initial investment.  
         [0028]     (2) It is difficult to place the reaction portion into the probe. Normally, the reaction portion is placed outside the magnet. Consequently, there is a time lag from reaction to detection.  
         [0029]     Where on-line detection using a combination of a microchip reactor and an analytical instrument consisting of an MS is performed, there are the following problems:  
         [0030]     (1) There are only few examples of application to chemical synthesis.  
         [0031]     (2) The design of the microchip reactor is dedicated for MS. It is difficult to connect the microchip reactor directly with other detectors.  
       SUMMARY OF THE INVENTION  
       [0032]     The present invention has been made in view of the foregoing problems. It is an object of the present invention to provide a microchip reactor which is for use in organic synthesis and which can be used in combination with many analytical instruments.  
         [0033]     This object is achieved in accordance with the teachings of the present invention by an organic synthesis reactor in which fluids are mixed in a very narrow space and reacted in multiple stages. The reactor has an introduction portion for introducing plural reagents from plural channels and a reaction portion disconnectably connected with the introduction portion. Where needed, the introduction portion mixes the introduced reagents and causes them to react with each other. In the reaction portion, a reagent or reaction liquid introduced from the introduction portion is mixed and reacted with other reagents. The introduction portion has an inlet channel for introducing a reagent, introduced from the outside, into the reaction portion and a first discharge channel for discharging the reaction liquid, discharged from the reaction portion, to the outside. The reaction portion has a reaction channel in communication with the inlet channel and a second discharge channel. The reaction channel causes plural reagents sent in from the inlet channel to mix and react. The second discharge channel places the reaction channel into communication with the first discharge channel to return the reaction liquid produced in the reaction channel to the introduction portion.  
         [0034]     In one feature of the present invention, the introduction portion is a microchip having a substrate made of a resin having chemical resistance. The substrate is provided with a microchannel. The reaction portion is a microchip having a substrate made of glass or quartz, the substrate being provided with a microchannel.  
         [0035]     In another feature of the present invention, the introduction portion has an inlet hole for introducing a reagent and a discharge hole for discharging the reaction liquid. The inlet hole and the discharge hole are flush with each other.  
         [0036]     In a further feature of the present invention, the microchannels are formed on both surfaces of the substrate made of glass or quartz by wet etching or drilling. Then, the substrate having the microchannels is sandwiched between two plates of glass or quartz. The substrate and the plates are bonded together by thermocompression, thus completing the reactor.  
         [0037]     In yet another feature of the present invention, the substrate has a thickness of 1 to 5 mm.  
         [0038]     In an additional feature of the present invention, the reaction portion has been finished in a cylindrical or prismatic form having a length of 50 to 300 mm and a maximum width of 2 to 10 mm.  
         [0039]     In still another feature of the present invention, the microchannels have a width and a depth of 50 to 500 μm.  
         [0040]     In yet an additional feature of the present invention, the reaction portion has a detection portion used in combination with an analytical instrument for analyzing the reaction liquid.  
         [0041]     In still a further feature of the present invention, the analytical instrument is at least one of NMR, ESR, and thermal lens microscope.  
         [0042]     In an additional feature of the present invention, an electrospray nozzle for use in combination with a mass spectrometer (MS) for analyzing the reaction liquid is mounted in the discharge hole in the introduction portion for discharging the reaction liquid.  
         [0043]     Because the organic synthesis reactor according to an embodiment of the present invention is designed as described above, the reactor can be fabricated in a microchip form capable of being used in combination with many analytical instruments.  
         [0044]     Other objects and features of the invention will appear in the course of the description thereof, which follows. 
     
    
     BRIEF DESCRIPTION OF THE DRAWINGS  
       [0045]      FIGS. 1A, 1B  and  1 C schematically show an organic synthesis reactor according to one embodiment of the present invention;  
         [0046]      FIGS. 2A, 2B  and  2 C schematically show an organic synthesis reactor according to another embodiment of the present invention;  
         [0047]      FIGS. 3A and 3B  schematically show an organic synthesis reactor according to a further embodiment of the present invention;  
         [0048]      FIG. 4  is a cross-sectional view of a thermal lens microscope that embodies an organic synthesis reactor according to an embodiment of the present invention;  
         [0049]      FIG. 5  is a cross-sectional view of an NMR spectrometer that embodies an organic synthesis reactor according to an embodiment of the present invention;  
         [0050]      FIG. 6  is a cross-sectional view of a mass spectrometer that embodies an organic synthesis reactor according to an embodiment of the present invention;  
         [0051]      FIG. 7  shows a commercially available microchip;  
         [0052]      FIG. 8  shows a related-art technique in which a microchip is applied to an NMR spectrometer; and  
         [0053]      FIG. 9  shows another related-art technique in which a microchip is applied to a mass spectrometer.  
     
    
     DESCRIPTION OF THE PREFERRED EMBODIMENTS  
       [0054]     Embodiments of the present invention are hereinafter described with reference to the accompanying drawings.  
       FIRST EMBODIMENT  
       [0055]     Referring to  FIGS. 1A, 1B  and  1 C, there is shown an organic synthesis reactor according to one embodiment of the present invention. The reactor has a reagent introduction-and-reaction portion  2  that is connected at a contact portion  4  with an extensional reaction portion  1  via a connector jig  3 .  
         [0056]     The extensional reaction portion  1  is made of a glass substrate having a thickness of 1 to 5 mm. Microchannels are formed on both surfaces of the glass substrate by wet etching or drilling. The glass substrate  1   a  is provided with a through-hole  12  to permit a reagent solution to flow from the channel in the front surface to the channel in the rear surface.  
         [0057]     The width and depth of the channels are 50 to 500 μm. The design of the channels and machining method can be modified according to the purpose of use.  
         [0058]     The glass substrate having the microchannels are then held between two glass plates. The glass substrate  1   a  and glass plates  1   b ,  1   c  are bonded together by thermocompression. The whole assembly is finished in a cylindrical or prismatic form by a cutting technique. Alternatively, a glass stock may be machined into a semicylindrical form, and microchannels may be formed in this semicylindrical form. Preferably, the length of the extensional reaction portion  1  is 50 to 300 mm. The diameter of the cylindrical form or the maximum width of the prismatic form is 2 to 10 mm.  
         [0059]     Screw holes are formed in the reagent introduction-and-reaction portion  2  to permit connection of tubes. Also, channels are formed in this portion  2 . When the extensional reaction portion  1  and the reagent introduction-and-reaction portion  2  have been connected, their channels are aligned. Consequently, a reagent solution can be passed through the channels.  
         [0060]     The connector jig  3  has guide portions to facilitate aligning the extensional reaction portion  1  and reagent introduction-and-reaction portion  2 . The contact portion  4  is surface-treated or used in combination with a sealant to prevent liquid leakage.  
         [0061]     Three reagent inlet holes  5  are formed in the reagent introduction-and-reaction portion  2 . Two of the three inlet holes  5  meet each other and are combined into one conduit immediately ahead of a first reaction portion  7  formed within the reagent introduction-and-reaction portion  2 . The conduit passes through the first reaction portion  7  of the bent (e.g., serpentine) channel, where a first reaction between reagents is produced. The conduit is in communication with a first reaction liquid channel  8  formed in the extensional reaction portion  1 .  
         [0062]     A reagent inlet channel  6  extends from the remaining one of the reagent inlet holes  5  and meets the first reaction liquid channel  8  in a second reaction-and-mixture portion  9  formed in the extensional reaction portion  1 , thus forming one conduit. This conduit is in communication with a second reaction portion  10  of the bent (e.g., serpentine) channel, where a second reaction between the reagents is induced.  
         [0063]     The second reaction portion  10  is in communication with a detection channel  11  of the bent (e.g., serpentine) channel. The second reaction portion  10  passes through a through-hole  12  and reaches the rear side of the extensional reaction portion  1 , the through-hole  12  being formed in the vertical direction. The second reaction portion  10  then passes into the reaction liquid discharge hole  14  through a reaction liquid discharge channel  13 . The three reagent inlet holes  5  and reaction liquid discharge hole  14  are formed in the same side surface of the reagent introduction-and-reaction portion  2 .  
         [0064]     In this way, in the present embodiment, the microchannels in the microchip are formed in both top surface side and bottom surface side of the reagent introduction-and-reaction portion  2  and extensional reaction portion  1 . That is, the present embodiment is characterized in that there are two layers of channels.  
         [0065]     Preferably, the material of the organic synthesis reactor is so selected that the reactor can be used in a temperature range from −70° C. to +200° C. To permit mass production using a molding technique, the reagent introduction-and-reaction portion  2  is preferably made of a chemical-resistant resin, such as PEEK (polyetheretherketone), Teflon™, or Diflon. Preferably, the extensional reaction portion  1  is made of glass or quartz.  
         [0066]     Where viscous reagents are used, the channels inside the reagent introduction-and-reaction portion  2  tend to be clogged up especially easily. Consequently, it can be anticipated that the running cost of the reactor in operation will be reduced by designing this portion tending to be clogged up as a replaceable external part attached to the extensional reaction portion  1 .  
       SECOND EMBODIMENT  
       [0067]      FIGS. 2A, 2B  and  2 C show an organic synthesis reactor according to another embodiment of the present invention. The reactor has a reagent inlet portion  22  that is connected at a contact portion  24  with a reagent reaction portion  21  via a connector jig  23 .  
         [0068]     The reagent reaction portion  21  is made of a glass substrate having a thickness of 1 to 5 mm. Microchannels are formed on both surfaces of the glass substrate by wet etching or drilling. The glass substrate is provided with a through-hole  33  to permit a reagent solution to flow from the channel in the front surface to the channel in the rear surface.  
         [0069]     The width and depth of the channels are 50 to 500 μm. The design of the channels and machining method can be modified according to the purpose of use.  
         [0070]     The glass substrate having the microchannels is then held between two glass plates. The glass substrate and glass plates are bonded together by thermocompression. The whole assembly is finished in a cylindrical or prismatic form by a cutting technique. Alternatively, a glass stock may be machined into a semicylindrical form, and microchannels may be formed in this semicylindrical form. Preferably, the length of the reagent reaction portion  21  is 50 to 300 mm. The diameter of the cylindrical form or the maximum width of the prismatic form is 2 to 10 mm.  
         [0071]     Screw holes are formed in the reagent inlet portion  22  to permit connection of tubes. Also, channels are formed in the inlet portion  22 . When the reagent reaction portion  21  and the reagent inlet portion  22  have been connected, their channels are aligned. Consequently, a reagent solution can be passed through the channels.  
         [0072]     The connector jig  23  has guide portions to facilitate aligning the reagent reaction portion  21  and reagent inlet portion  22 . The contact portion  24  is surface-treated or used in combination with a sealant to prevent liquid leakage.  
         [0073]     Three reagent inlet holes  25  are formed in the reagent inlet portion  22  and are in communication with three reaction liquid channels  27 , respectively, formed in the reagent reaction portion  21 .  
         [0074]     Two of the three inlet holes  25  meet each other and are combined into one conduit in the first reaction-and-mixture portion  28 . The conduit is in communication with the first reaction portion  29  of the bent (e.g., serpentine) channel, where a first reaction between reagents is produced. The conduit then meets another reaction liquid channel  27  in the second reaction-and-mixture portion  30  to form one conduit which is in communication with the second reaction portion  31  of the bent (e.g., serpentine) channel, where a second reaction between the reagents is induced.  
         [0075]     The second reaction portion  31  is in communication with a detection channel  32  of the bent (e.g., serpentine) channel. The detection channel  32  passes through a through-hole  33  and reaches the rear side of the reagent reaction portion  21 , the through-hole  33  being formed in the vertical direction. The second reaction liquid then passes into the reaction liquid discharge hole  35  through a reaction liquid discharge channel  34 . The three reagent inlet holes  25  and reaction liquid discharge hole  35  are formed in the same side surface of the reagent inlet portion  22 .  
         [0076]     In this way, in the present embodiment, the microchannels in the microchip are formed in both top surface side and bottom surface side of the reagent inlet portion  22  and reagent reaction portion  21 . That is, the present embodiment is characterized in that there are two layers of channels.  
         [0077]     Preferably, the material of the organic synthesis reactor is so selected that the reactor can be used in a temperature range from −70° C. to +200° C. To permit mass production using a molding technique, the reagent inlet portion  22  is preferably made of a chemical-resistant resin, such as PEEK (polyetheretherketone), Teflon™, or Diflon. Preferably, the reagent reaction portion  21  is made of glass or quartz.  
         [0078]     Where viscous reagents are used, the channels inside the reagent inlet portion  22  tend to be clogged up especially easily. Consequently, it can be anticipated that the running cost of the reactor in operation will be reduced by designing this portion tending to be clogged up as a replaceable external part attached to the reagent reaction portion  21 .  
       THIRD EMBODIMENT  
       [0079]      FIGS. 3A and 3B  show an organic synthesis reactor according to a further embodiment of the present invention. The reactor has a reagent inlet portion  52  that is connected at a contact portion  54  with a reagent reaction portion  51  via a connector jig  53  and using screws  55 .  
         [0080]     The reagent reaction portion  51  is made of a glass substrate having a thickness of 1 to 5 mm. Microchannels are formed on both surfaces of the glass substrate by wet etching or drilling. The glass substrate is provided with a through-hole  64  to permit a reagent solution to flow from the channel in the front surface to the channel in the rear surface.  
         [0081]     The width and depth of the channels are 50 to 500 μm. The design of the channels and machining method can be modified according to the purpose of use.  
         [0082]     The glass substrate having the microchannels is then held between two glass plates. These glass substrate and glass plates are bonded together by thermocompression. One end portion of the assembly is cut into an elongated T-shaped form. The end portion of the reagent reaction portion  51  is shaped like the letter T to press and join the reagent inlet portion  52  by the connector jig  53 . The T-shaped end portion of the reagent reaction portion  51  is made asymmetrical right and left to prevent the senses of the reagent reaction portion  51  and reagent inlet portion  52  from being confused when they are connected. The connector jig  53  has a structure for recognizing the asymmetrical portion or an asymmetrical fitting portion.  
         [0083]     Screw holes are formed in the reagent inlet portion  52  to permit connection of tubes. Also, channels are formed in the inlet portion  52 . When the reagent reaction portion  51  and the reagent inlet portion  52  have been connected, their channels are aligned. Consequently, a reagent solution can be passed through the channels. The contact portion  54  is surface-treated or used in combination with a sealant to prevent liquid leakage.  
         [0084]     Three reagent inlet holes  56  are formed in the reagent inlet portion  52  and are in communication via three reagent inlet channels  57 , respectively, with three reaction liquid channels  58 , respectively, formed in the reagent reaction portion  51 .  
         [0085]     Two of the three inlet holes  56  meet each other and are combined into one conduit in the first reaction-and-mixture portion  59 . The conduit is in communication with the first reaction portion  60  of the bent (e.g., serpentine) channel, where a first reaction between reagents is produced. The conduit then meets another reaction liquid channel in the second reaction-and-mixture portion  61  to form one conduit which is in communication with the second reaction portion  62  of the bent channel, where a second reaction between the reagents is induced.  
         [0086]     The second reaction portion  62  is in communication with a detection channel  63  of the bent channel. The second reaction liquid passes through a through-hole  64  and reaches the rear side of the second reagent reaction portion  62 , the through-hole  64  being formed in the vertical direction. The second reaction liquid then passes into the reaction liquid discharge hole  66  through a reaction liquid discharge channel  65 . The three reagent inlet holes  56  and reaction liquid discharge hole  66  are formed in the same side surface of the reagent inlet portion  52 .  
         [0087]     In this way, in the present embodiment, the microchannels in the microchip are formed in both top surface side and bottom surface side of the reagent inlet portion  52  and reagent reaction portion  51 . That is, the present embodiment is characterized in that there are two layers of channels.  
         [0088]     Preferably, the material of the organic synthesis reactor is so selected that the reactor can be used in a temperature range from −70° C. to +200° C. To permit mass production using a molding technique, the reagent inlet portion  52  is preferably made of a chemical-resistant resin, such as PEEK (polyetheretherketone), Teflon™, or Diflon. Preferably, the reagent reaction portion  51  is made of glass or quartz.  
         [0089]     Where viscous reagents are used, the channels inside the reagent inlet portion  52  tend to be clogged up especially easily. Consequently, it can be anticipated that the running cost of the reactor in operation will be reduced by designing this portion tending to be clogged up as a replaceable external part attached to the reagent reaction portion  51 .  
       FOURTH EMBODIMENT  
       [0090]      FIG. 4  shows one embodiment of the present invention in which such an organic synthesis reactor is mounted in various analytical instruments. Liquid delivery modules  36 ,  37 , and  38 , such as syringe pumps, are connected with the organic synthesis reactor by tubes, such as capillaries.  
         [0091]     Reagent solutions sent out from the liquid delivery modules  36  and  37  are mixed by a mixing portion  28  where channels intersect. The solutions are reacted in a first reaction portion  29 . The reagent solutions reacted in the first reaction portion are mixed with a reagent introduced from the liquid delivery module  38  in a mixing portion  30  located immediately behind the first reaction portion  29 . Thus, a second stage of reaction is induced in a second reaction portion  31 . Instead of the reagent, a reaction inhibitor or diluting solvent may be introduced from the liquid delivery module  38 . The reaction liquid obtained in the second reaction portion  31  is introduced into a detection channel  32 , where the reaction products are detected by a thermal lens microscope  39 . Then, the reaction liquid is discharged out of the organic synthesis reactor from a reaction liquid discharge hole  35  through a through-hole  33  and through a reaction liquid discharge channel  34  in the rear surface. The liquid is then recovered.  
       FIFTH EMBODIMENT  
       [0092]      FIG. 5  shows an embodiment of the present invention in which the organic synthesis reactor is mounted in an NMR spectrometer. The organic synthesis reactor can be directly attached to the NMR spectrometer 40 of normal construction. The reactor and liquid delivery modules are connected by tubes, such as capillaries. The reactor is mounted to an NMR sample tube holder having a diameter of 5 mm and to a rotor and inserted into an NMR probe having a diameter of 5 mm (finding the widest use). Under this condition, the reactor is used instead of an NMR sample tube. The organic synthesis reactor may also be combined with an electron spin resonance (ESR) spectrometer by a similar method.  
       SIXTH EMBODIMENT  
       [0093]      FIG. 6  shows an embodiment of the present invention in which the organic synthesis reactor is mounted in a mass spectrometer (MS). With the organic synthesis reactor, MS detection can be easily performed simply by connecting a nano-electrospray nozzle  41  to a reaction liquid discharge hole  35 . The operation regarding introduction of reagents is the same as in the third and fourth embodiments. In this embodiment, the reaction liquid is discharged from the nano-electrospray nozzle  41 . Mass spectra of the reaction products within the reaction liquid can be measured by electrospray ionization caused by application of a high voltage.  
         [0094]     The present invention can find wide application in research into organic synthesis and reactions.  
         [0095]     Having thus described our invention with the detail and particularity required by the Patent Laws, what is desired protected by Letters Patent is set forth in the following claims.