System and method for producing flavan oligomers

Abstract

To provide a production system and a production method for a flavan oligomer, the system and method being capable of efficiently synthesizing, at high yield, a flavan oligomer in which flavan derivatives are bonded to each other at a desired polymerization level.SOLUTION: A production system 1 for a flavan oligomer comprises: a microreactor 106 in which a first fluid introduced from one inlet and a second fluid introduced from the other inlet are mixed in a flow path; a first container 101 in which the first fluid is prepared; a second container 102 in which the second fluid is prepared; and a recovery container 103 for recovering the generated fluid, wherein the first fluid is a liquid containing a flavan derivative having a flavan skeleton; the second fluid is a liquid containing a Lewis acid; and the generated fluid is recovered into a liquid containing a base. A production method for the flavan oligomer comprises: mixing the first fluid with the second fluid in the microreactor; activating the flavan derivative of the first fluid with the Lewis acid of the second fluid; starting the reaction between the activated flavan derivative and a flavan derivative acting as a nucleophilic body; and stopping the reaction with a base.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] The present invention relates to a system for producing a flavan oligomer in which flavan derivatives having a flavan skeleton are condensed with each other, and a method for producing a flavan oligomer. [Background technology]

[0002] Plants contain many flavonoids as secondary metabolites. Flavonoids are a group of compounds with a flavan skeleton and belong to the polyphenol family. Various flavonoid analogs have been found, differing in the bonding position and number of substituents on the flavan skeleton, modified structures such as sugar chains, and three-dimensional structures. Oligomers formed by the condensation of monomers with a flavan skeleton have also been found in plants.

[0003] Flavonoids are classified into flavanols, flavanones, flavones, isoflavones, anthocyanins, etc. Flavanols include catechin, epicatechin, gallocatechin, epigallocatechin, etc. Flavanones include naringenin, hesperetin, eriodictyol, etc. Flavones include apigenin, luteolin, etc. Isoflavones include genistein, daidzein, etc. Anthocyanins include pelargonidin, cyanidin, delphinidin, etc.

[0004] Flavonoids are known to exhibit various physiological activities, including antibacterial, growth inhibitory, antioxidant, anticarcinogenic, and metabolically stimulating activities. In addition to the activity and dynamics of oligomers, research is also being conducted on flavan derivatives based on the structure of natural flavonoids. Flavan derivatives and their oligomers have great potential as an untapped chemical space, and are expected to serve as lead compounds for new pharmaceuticals.

[0005] Flavanols have a flavan-3-ol skeleton. Flavan oligomers, such as catechin and epicatechin, formed by the condensation of flavan-3-ols, are known as procyanidins. Flavan oligomers are polymers with various degrees of polymerization in plants and exist as mixtures of dimers, trimers, oligomers, etc.

[0006] Currently, the isolation and purification of flavan oligomers from natural products requires significant costs and labor. Furthermore, commercially available flavan oligomers are limited in variety and expensive. Under these circumstances, an efficient synthesis method for flavan oligomers with a predetermined degree of polymerization is desired.

[0007] Patent Document 1 describes a method for synthesizing flavan oligomers using flavan-3-oxo derivatives and flavan-3-ol derivatives as raw materials (see paragraphs 0074-0077). Using flavan-3-oxo derivatives (0.145 mmoL) and flavan-3-ol derivatives (0.435 mmoL) as raw materials, the mixture was refluxed at room temperature for 4 hours in tetrahydrofuran (THF) using silver tetrafluoroborate (AgBF4) (1.1 mmoL) as a reaction catalyst. As a result, the target dimer, a proanthocyanidin adduct, was produced in a 70% yield.

[0008] Patent Document 2 describes a method for synthesizing flavan oligomers using epicatechin as a raw material (see paragraph 0052). An epicatechin derivative (monomer) with a protected hydroxyl group is used as the raw material, and reacted in methylene chloride with zinc triflate (Zn(OTf)2) (0.7 equivalents) as a reaction catalyst at room temperature (20°C) for 1.5 hours. As a result, a dimeric condensation product (dimer) is produced in a yield of approximately 58%.

[0009] Patent Document 3 describes a method for synthesizing flavan oligomers using epigallocatechin as a raw material (see paragraph 0103). An epigallocatechin derivative (monomer) with a protected hydroxyl group is used as the raw material, and the reaction is carried out at room temperature (20°C) for 2 hours using zinc triflate (Zn(OTf)2) (0.8 equivalents) as a reaction catalyst. The resulting dimer condensation product (dimer) is then isolated and purified, and reacted at room temperature (20°C) for 20 hours using ytterbium triflate (Yb(OTf)3) (5 equivalents) as a reaction catalyst. As a result, a tetramer condensation product (tetramer) is produced in a 45% yield.

[0010] Meanwhile, in recent years, the use of microreactors has been increasing in the fields of biotechnology and the manufacturing of pharmaceuticals and chemicals. Microreactors are flow-type reactors with microchannels on the order of μm, and are used for mixing and reacting fluids. Microreactors are fabricated using microfabrication technologies such as molding and lithography.

[0011] A feature of synthesis reactions using microreactors is that molecular diffusion under laminar flow prevails. As the size of the reaction field decreases, molecular diffusion under laminar flow is promoted, allowing fluids to be mixed uniformly and quickly. As the surface area relative to the volume of the fluid increases, the surface effect and heat transfer rate increase, enabling rapid mixing, control of reaction ratios, precise temperature control, and more. Compared to conventional synthesis reactions using batch methods, it is possible to shorten reaction times and improve yields, and this is expected to improve production efficiency. [Prior art documents] [Patent documents]

[0012] [Patent Document 1] Patent No. 5550639 [Patent Document 2] Japanese Patent Application Publication No. 2017-001982 [Patent Document 3] Japanese Patent Application Publication No. 2019-151583 Summary of the Invention [Problem to be solved by the invention]

[0013] Conventionally, flavan oligomers, which are formed by condensation of flavan derivatives having a flavan skeleton, have often been synthesized by a batch process. However, when using a batch process, it is difficult to precisely control the reaction ratio of reactants and the reaction time. In conventional synthesis methods, the polymerization reaction continues, which makes it difficult to synthesize flavan oligomers, in which flavan derivatives are bonded to each other at a desired degree of polymerization, in high yield.

[0014] In conventional synthesis methods, reactants react in unintended ratios or reactants activated by a catalyst react with the product, resulting in the production of mixtures of various degrees of polymerization. In such cases, separation and purification after the reaction is costly and laborious. While methods using excess catalysts can increase yields, using excess catalysts can lead to catalyst loss and increased purification costs.

[0015] In the synthesis method described in Patent Document 1, a flavan-3-oxo derivative is reacted with a flavan-3-ol derivative in a large excess of 3 equivalents. Furthermore, silver tetrafluoroborate (AgBF4) is added in a large excess of 7.5 equivalents. This synthesis method requires costly and laborious separation and purification after the reaction, resulting in poor production efficiency of oligomers with the desired degree of polymerization.

[0016] In the synthesis methods described in Patent Documents 2 and 3, the amount of zinc triflate (Zn(OTf)2) is small, but the reaction requires a long time of 1.5 hours or 2 hours even at room temperature. Furthermore, zinc triflate (Zn(OTf)2) and ytterbium triflate (Yb(OTf)3) may produce solid matter, and when a microreactor with a fine channel is used, there is a risk of the channel being clogged.

[0017] Therefore, an object of the present invention is to provide a system and method for producing flavan oligomers that can efficiently synthesize, in high yield, flavan oligomers in which flavan derivatives are bonded to each other at a desired degree of polymerization.

[0018] In order to solve the above problems, the present invention provides a system for producing a flavan oligomer in which flavan derivatives having a flavan skeleton are bonded to each other, the system comprising at least one microreactor having two inlets for introducing fluids and a flow path for joining the fluids, and mixing a first fluid introduced from one of the inlets with a second fluid introduced from the other inlet in the flow path, a first container in which the first fluid is prepared, a second container in which the second fluid is prepared, and a recovery container for recovering a product fluid produced in the microreactor, the first fluid being a liquid containing a flavan derivative having a flavan skeleton, the second fluid being a liquid containing a Lewis acid, the product fluid comprising an oligomer in which the flavan derivatives are bonded to each other, and being recovered in the recovery container in a liquid containing a base, the flavan derivative having a leaving group activated by the Lewis acid, and a monomer having one flavan skeleton or an oligomer having two or more flavan skeletons. and the degree of polymerization is 17 or less and the oligomer in which the flavan derivatives are bonded to each other is An oligomer in which the flavan derivatives are bonded together in a 1:1 ratio It is characterized in that:

[0019] Furthermore, the method for producing a flavan oligomer according to the present invention is a method for producing a flavan oligomer in which flavan derivatives having a flavan skeleton are bonded to each other, and includes a microreactor system having at least one microreactor having two inlets for introducing fluids and a flow path for joining the fluids, and mixing a first fluid introduced from one of the inlets with a second fluid introduced from the other inlet in the flow path, a first container in which the first fluid is prepared, a second container in which the second fluid is prepared, and a recovery container for recovering a fluid produced in the microreactor, wherein the first fluid is a liquid containing a flavan derivative having a flavan skeleton, and the second fluid is a liquid containing a flavan derivative having a flavan skeleton. A liquid containing a Lewis acid is prepared as a fluid, the first fluid and the second fluid are mixed in the microreactor, a part of the flavan derivative in the first fluid is activated by the Lewis acid in the second fluid, a reaction is initiated between the activated part of the flavan derivative in the first fluid and the remaining part of the flavan derivative in the first fluid acting as a nucleophile, the product fluid during the reaction is recovered in a liquid containing a base, the reaction of the product fluid is stopped with the base, and an oligomer in which the flavan derivatives are bonded to each other is produced, the flavan derivative has a leaving group activated by the Lewis acid and is a monomer having one flavan skeleton or an oligomer having two or more flavan skeletons. and the degree of polymerization is 17 or less and the oligomer in which the flavan derivatives are bonded to each other is An oligomer in which the flavan derivatives are bonded together in a 1:1 ratio It is characterized in that: [Effects of the Invention]

[0020] According to the present invention, a flavan oligomer in which flavan derivatives are bonded to each other at a desired degree of polymerization can be synthesized efficiently in high yield. [Brief explanation of the drawings]

[0021] [Figure 1] FIG. 1 is a schematic diagram of a flavan oligomer production system according to a first embodiment. [Figure 2] FIG. 1 is a diagram illustrating an example of a microreactor. [Figure 3]FIG. 1 is a schematic diagram of a flavan oligomer production system according to a second embodiment. [Figure 4] FIG. 1 is a schematic diagram of a flavan oligomer production system according to a third embodiment. [Figure 5] FIG. 1 is a schematic diagram of a flavan oligomer production system according to a fourth embodiment. [Figure 6] FIG. 1 is a schematic diagram of a flavan oligomer production system according to a fifth embodiment. DETAILED DESCRIPTION OF THE INVENTION

[0022] Hereinafter, a flavan oligomer production system and a flavan oligomer production method according to an embodiment of the present invention will be described with reference to the drawings. Note that common components in the following drawings will be assigned the same reference numerals and redundant explanations will be omitted.

[0023] The flavan oligomer production system according to this embodiment is a system for synthesizing a flavan oligomer in which flavan derivatives having a flavan skeleton are bonded to each other. In this production system, a flavan derivative having a predetermined molecular structure is used as a starting material for the synthesis reaction. A Lewis acid is also used as a reaction catalyst.

[0024] The starting flavan derivative is activated with a Lewis acid to become a cationized electrophile. The activated flavan derivative reacts with an unactivated flavan derivative that acts as a nucleophile, resulting in condensation between the flavan derivatives. This polymerization reaction can produce flavan oligomers in which the flavan derivatives are linked together.

[0025] In the flavan oligomer production system, a microreactor is used for the reaction between a flavan derivative and a Lewis acid, or the reaction between an activated flavan derivative and an inactivated flavan derivative that acts as a nucleophile. In the microreactor, fluids containing the reactants are introduced into a microchannel, which serves as a microreaction field, and the reactants are mixed within the microchannel to initiate the reaction. The Lewis acid is then neutralized with a base to terminate the reaction.

[0026] The use of a microreactor allows precise control of the reaction amounts of reactants, such as flavan derivatives and Lewis acids, as well as the start and end times of the reaction. This allows precise control of the reaction ratio between reactants and the reaction time. Therefore, flavan oligomers, in which flavan derivatives are bonded to each other at a desired degree of polymerization, can be synthesized with high yield.

[0027] The starting flavan derivative may be a monomer of a flavan derivative having one flavan skeleton or an oligomer of a flavan derivative having two or more flavan skeletons. The flavan skeleton is represented by the following formula (a):

[0028] [ka]

[0029] In this specification, the term "oligomer of a flavan derivative" refers to an i-mer (i is an integer of 2 or more) in which multiple flavan derivative monomers are condensed, such as a dimer in which two flavan derivative monomers are condensed, a trimer in which three flavan derivative monomers are condensed, etc. The flavan derivative oligomer also includes so-called polymers in which multiple monomers are condensed.

[0030] The flavan derivative monomers and flavan derivative oligomers may be natural compounds isolated from natural products or chemically synthesized synthetic compounds. The flavan derivative oligomers, which are synthetic compounds, can be synthesized, for example, by using the flavan derivative monomers or the like as starting materials and the flavan oligomer production system according to the present embodiment.

[0031] The flavan derivatives used as starting materials may have protective groups introduced into their substituents, such as hydroxy groups, to prevent unintended reactions. Alternatively, those without protective groups may be used depending on reactivity and other factors. The raw material solution containing the flavan derivative can be prepared by dissolving a predetermined concentration of a flavan derivative monomer or a predetermined concentration of a flavan derivative oligomer in an appropriate solvent that serves as the reaction solvent.

[0032] The protection of the hydroxy group can be carried out, for example, in a polar solvent using a base or a protecting group-introducing compound. Examples of the base include sodium hydride, alkylamide, pyridine, etc. Examples of the protecting group-introducing compound include halogenated hydrocarbons, halogenated acyl compounds, halogenated silyl compounds, etc.

[0033] As the starting flavan derivative, a flavan-3-ol derivative having a hydroxyl-derived substituent at the carbon atom at the 3-position of the C ring is preferred. Furthermore, a derivative having a hydroxyl-derived substituent at the carbon atoms at the 5- and 7-positions of the A ring is more preferred. For example, flavanols such as (+)-catechin, (-)-catechin, (+)-epicatechin, (-)-epicatechin, and derivatives thereof can be preferably used as the starting material.

[0034] Furthermore, as the starting flavan derivative, a derivative having a leaving group at the carbon atom at position 4 of the C ring is more preferable. Also, a derivative having a substituent with an electron donating moiety at the carbon atom at position 3 of the C ring is more preferable. With such a structure, the carbon atom at position 4 of the flavan skeleton can be regioselectively activated by a Lewis acid.

[0035] Furthermore, as the starting flavan derivative, a derivative in which an electron-donating group is bonded to the carbon at the 5th or 7th position of the A ring is more preferable. Also, a derivative in which an electron-donating group is not bonded to the carbon at the 6th position of the A ring is more preferable. With such a structure, the carbon at the 4th position of the flavan skeleton can be activated, and the 4th and 8' positions of the flavan skeleton can be condensed.

[0036] As the monomer of the flavan derivative as the starting material, a compound represented by the following general formula (1) is more preferred.

[0037] [ka]

[0038] [In general formula (1), R 1 ~R 5 are each independently a hydrogen atom, a hydroxy group, an alkoxy group, or OR 9 R represents a substituent represented by the formula: 6 R represents a hydrogen atom, a hydrocarbon group which may have a substituent, an alkoxyalkyl group, an acyl group, a silyl group, or a galloyl group. 7 ~R 8 are each independently a hydrogen atom or R 9 R represents a substituent represented by the formula: 9 represents an optionally substituted hydrocarbon group, an alkoxyalkyl group, an acyl group, or a silyl group. X represents an optionally substituted hydrocarbon group, a halogen atom, or a substituent in which one or more heteroatoms selected from the group consisting of N, O, and S are bonded to a ring-forming atom of the C ring. The wavy line represents a single bond forming an R-configuration or an S-configuration.]

[0039] As the starting material, an oligomer of a flavan derivative, a compound represented by the following general formula (2) is more preferred.

[0040] [ka]

[0041] [In general formula (2), R 1 ~R 5 , R 11 ~R 15 and R 21 ~R 25 are each independently a hydrogen atom, a hydroxy group, an alkoxy group, or OR 9R represents a substituent represented by the formula: 6 , R 16 and R 26 R represents a hydrogen atom, a hydrocarbon group which may have a substituent, an alkoxyalkyl group, an acyl group, a silyl group, or a galloyl group. 7 ~R 8 , R 17 ~R 18 and R 27 ~R 28 are each independently a hydrogen atom or R 9 R represents a substituent represented by the formula: 9 represents a hydrocarbon group, an alkoxyalkyl group, an acyl group, or a silyl group which may have a substituent. X represents a hydrocarbon group, an alkoxyalkyl group, an acyl group, or a silyl group which may have a substituent. X represents a hydrocarbon group, an alkoxyalkyl group, an acyl group, or a silyl group which may have a substituent. X represents a substituent, a halogen atom, or a substituent in which one or more heteroatoms selected from the group consisting of N, O, and S are bonded to a ring-forming atom of the C ring. The wavy line represents a single bond which forms an R-configuration or an S-configuration. n represents an integer of 0 or greater.

[0042] In the general formulas (1) and (2), examples of the alkoxy group include a methoxy group, an ethoxy group, a propoxy group, a butoxy group, a pentyloxy group, etc. As the alkoxy group, a methoxy group is preferred.

[0043] The hydrocarbon group may be either cyclic or acyclic. It may also be either saturated or unsaturated. The hydrocarbon group includes a linear aliphatic hydrocarbon group in which carbon atoms are bonded in a straight chain, a branched aliphatic hydrocarbon group in which carbon atoms are bonded in a branched chain, and an aromatic hydrocarbon group. Examples of the hydrocarbon group include an alkyl group, an alkenyl group, an alkynyl group, a dienyl group, a cycloalkyl group, a cycloalkenyl group, an aryl group, and an arylalkyl group.

[0044] Examples of the alkyl group include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, a hexyl group, etc. The alkyl group preferably has 1 to 10 carbon atoms, more preferably has 1 to 6 carbon atoms, and still more preferably has 1 to 4 carbon atoms.

[0045] Examples of the alkenyl group include a vinyl group, an allyl group, an isopropenyl group, a 1-butenyl group, a 2-butenyl group, a 1-methyl-2-propenyl group, a 2-methyl-1-propenyl group, a 2-methyl-2-propenyl group, a pentenyl group, a hexenyl group, etc. The alkenyl group preferably has 2 to 10 carbon atoms, more preferably has 2 to 6 carbon atoms, and still more preferably has 2 to 4 carbon atoms.

[0046] Examples of the alkynyl group include an ethynyl group, a 1-propynyl group, a 2-propynyl group, a 1-butynyl group, a 2-butynyl group, a 3-butynyl group, a 1-methyl-2-propynyl group, a pentynyl group, a hexynyl group, etc. The alkynyl group preferably has 2 to 10 carbon atoms, more preferably has 2 to 6 carbon atoms, and still more preferably has 2 to 4 carbon atoms.

[0047] Examples of the dienyl group include a 1,3-butadienyl group, a 1,3-pentadienyl group, a 2,4-pentadienyl group, etc. The dienyl group preferably has 4 to 10 carbon atoms, and more preferably has 4 to 6 carbon atoms.

[0048] Examples of the cycloalkyl group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, etc. The cycloalkyl group preferably has 3 to 10 carbon atoms, and more preferably has 4 to 6 carbon atoms.

[0049] Examples of the cycloalkenyl group include a cyclopropenyl group, a cyclobutenyl group, a cyclopentenyl group, a cyclohexenyl group, etc. The cycloalkenyl group preferably has 3 to 10 carbon atoms, and more preferably has 4 to 6 carbon atoms.

[0050] Examples of the aryl group include a phenyl group, a 1-naphthyl group, a 2-naphthyl group, an indenyl group, an o-tolyl group, a m-tolyl group, a p-tolyl group, a 2,3-xylyl group, a 2,4-xylyl group, a 2,5-xylyl group, a 2,6-xylyl group, a 3,4-xylyl group, a 3,5-xylyl group, an o-cumenyl group, a m-cumenyl group, a p-cumenyl group, and a mesityl group. The aryl group preferably has 6 to 10 carbon atoms.

[0051] Examples of the arylalkyl group include a benzyl group, a phenethyl group, a 3-phenylpropyl group, a 4-phenylbutyl group, a triphenylmethyl group, etc. The arylalkyl group preferably has 7 to 10 carbon atoms.

[0052] Examples of the alkoxyalkyl group include a methoxymethyl group, an ethoxymethyl group, a propoxymethyl group, a butoxymethyl group, a methoxyethyl group, an ethoxyethyl group, a propoxyethyl group, a butoxyethyl group, etc. The alkoxyalkyl group preferably has 2 to 6 carbon atoms, and more preferably has 2 to 4 carbon atoms.

[0053] Examples of the acyl group include an acetyl group, a propionyl group, a butyryl group, a benzoyl group, and a naphthoyl group. 6 , R 16 and R 26 As the acyl group, an acetyl group is particularly preferred from the viewpoint of reactivity for activating the flavan derivative.

[0054] Examples of the silyl group include a methylsilyl group, an ethylsilyl group, a dimethylsilyl group, a diethylsilyl group, a trimethylsilyl group, a triethylsilyl group, a triisopropylsilyl group, a tritert-butylsilyl group, a dimethyltert-butylsilyl group, a trimethoxysilyl group, a triethoxysilyl group, a diphenylmethylsilyl group, a diphenylethylsilyl group, a diphenylisopropylsilyl group, a diphenyltert-butylsilyl group, a triphenylsilyl group, a triphenoxysilyl group, a dimethylmethoxysilyl group, a dimethylphenoxysilyl group, and a methylmethoxyphenylsilyl group.

[0055] As a substituent in which one or more heteroatoms selected from the group consisting of N, O, and S are bonded to ring-forming atoms of the C ring, a substituent in which an electron-withdrawing moiety is bonded to the heteroatom bonded to the ring-forming atom of the C ring is preferred. The coordinating ability of the shared electron pair of the heteroatom to the Lewis acid improves the elimination property of the heteroatom.

[0056] Examples of the substituent in which N is bonded to a ring-forming atom of the C ring include an azido group, a nitro group, a carbamoyl group, an alkylamino group, a dialkylamino group, an alkoxyalkylamino group, a dialkoxyalkylamino group, an alkylaminoalkylamino group, a dialkylaminoalkylamino group, an alkylsulfanylalkylamino group, a dialkylsulfanylalkylamino group, an arylamino group, an arylaminoalkylamino group, a nitrogen-containing heterocyclic group, etc. Examples of the nitrogen-containing heterocyclic group include a pyrrolyl group, a pyrazolyl group, an imidazolyl group, a pyridyl group, a pyrazinyl group, a pyrimidinyl group, a pyridazinyl group, an indolyl group, an adenyl group, a thymidyl group, etc.

[0057] As a substituent in which O is bonded to a ring-forming atom of the C ring, ,a Examples of the alkyl group include an alkoxy group, an alkoxyalkoxy group, an alkylaminoalkoxy group, an alkylsulfanylalkoxy group, an aryloxy group, and an aryloxyalkoxy group.

[0058] Examples of the substituent in which S is bonded to a ring-forming atom of ring C include an alkylsulfanyl group, an alkoxysulfanyl group, an alkylaminosulfanyl group, an alkylsulfanylalkylsulfanyl group, an arylsulfanyl group, an alkylsulfonyl group, an alkoxysulfonyl group, an arylsulfonyl group, an aryloxysulfonyl group, an alkylsulfinyl group, an alkoxysulfinyl group, an arylsulfinyl group, and an aryloxysulfinyl group.

[0059] The hydrocarbon group, alkoxyalkyl group, acyl group, silyl group, galloyl group, and substituents in which one or more heteroatoms selected from the group consisting of N, O, and S are bonded to ring-forming atoms of ring C may further have a substituent. The substituents introduced into these substituents may be introduced one or more at substitutable positions. When multiple substituents are introduced, the substituents may be the same or different from each other.

[0060] Examples of the substituent to be introduced into these substituents include the above-mentioned alkyl group, alkenyl group, alkynyl group, dienyl group, cycloalkyl group, cycloalkenyl group, aryl group, arylalkyl group, alkoxy group, alkoxyalkyl group, acyl group, silyl group, hydroxy group, amino group, cyano group, azide group, nitro group, carbamoyl group, halogen atom, etc. Examples of the halogen atom include a chlorine atom, a bromine atom, and an iodine atom.

[0061] In general formulas (1) and (2), R 6 , R 16 and R 26 An acetyl group is particularly preferred as R 7 ~R 8 , R 17 ~R 18 and R 27 ~R 28 A benzyl group is particularly preferred as X. An ethoxyethyl group is particularly preferred as X. n is preferably 0 or more and 15 or less, more preferably 0 or more and 10 or less, and even more preferably 0 or more and 5 or less.

[0062] The flavan derivative as the starting material may be any of the (2R,3R), (2R,3S), (2S,3R), and (2S,3S) forms of the flavan-3-ol skeleton. From the viewpoint of reactivity, the flavan derivative as the starting material may be any of the following: a substituent represented by X and an OR 6 , OR 16 and OR 26 and a substituent represented by the following formula (I) are preferably arranged in syn (cis) configuration.

[0063] The Lewis acid may be a Lewis acid that is highly soluble in the solvent used or a Lewis acid that is liquid at the reaction temperature. The catalyst solution containing the Lewis acid can be prepared by dissolving a Lewis acid at a predetermined concentration in an appropriate solvent that will be the reaction solvent.

[0064] Examples of Lewis acids that can be used include boron trifluoride diethyl etherate (BF3·Et2O), boron trichloride (BCl3), trimethylsilyl trifluoromethanesulfonate (TMSOTf), triethylsilyl trifluoromethanesulfonate (TESOTf), triisopropylsilyl trifluoromethanesulfonate, dimethyl-tert-butylsilyl trifluoromethanesulfonate, triphenylsilyl trifluoromethanesulfonate, and other alkylsilyl perfluoroalkylsulfonates.

[0065] Any suitable base can be used as the base as long as it neutralizes the Lewis acid after the reaction and does not adversely affect the reaction product. The reaction terminating solution containing a base can be prepared by dissolving a base at a predetermined concentration in a suitable solvent.

[0066] Examples of bases that can be used include triethylamine (EtN), N,N-diisopropylethylamine, diazabicycloundecene, diazabicyclononene, diazabicyclooctane, pyridine, 2,6-di-tert-butylpyridine, tetramethylguanidine, etc. Furthermore, when a reaction terminating solution containing a base is not introduced into the microreactor, an aqueous solution containing an inorganic base that is not soluble in organic solvents, such as sodium bicarbonate (NaHCO), sodium carbonate (NaCO), or potassium carbonate (KCO), can also be used.

[0067] Any suitable solvent can be used as long as it dissolves the monomers of the flavan derivative, the oligomers of the flavan derivative, and the Lewis acid, does not inhibit the synthesis reaction, and does not adversely affect the reaction product. From the viewpoint of carrying out an SN1-type nucleophilic substitution-like polymerization reaction, it is preferable to use a polar solvent as the solvent.

[0068] Examples of solvents that can be used include dichloromethane, tetrachloromethane, acetone, acetonitrile, methanol, hexane, benzene, toluene, diethyl ether, diisopropyl ether, dimethyl sulfoxide, dimethylformamide, N-methylpyrrolidone, etc. As the solvent, one of these may be used alone, or a mixed solvent of two or more of these may be used.

[0069] The reaction between the monomers of the flavan derivative represented by the general formula (1) produces a dimer of the flavan derivative represented by the following general formula (3): Depending on the structure and stereoelectronic effect of the monomers used in the reaction, a dimer can be obtained in which the flavan unit bonded to the 4th position of the C ring is in the anti (trans) or syn (cis) configuration relative to the substituent bonded to the 3rd position of the C ring.

[0070] [ka]

[0071] [In general formula (3), R 1 ~R 5 , R 6 , R 7 ~R 9 and X has the same meaning as in general formula (1). The wavy line represents a single bond that forms an R or S configuration.

[0072] Furthermore, the reaction between oligomers of the flavan derivative represented by general formula (2) produces an oligomer of the flavan derivative represented by the following general formula (4). Depending on the structure and stereoelectronic effects of the oligomer used in the reaction, an oligomer can be obtained in which the flavan unit bonded to the 4-position of the C ring is in the anti (trans) or syn (cis) configuration relative to the substituent bonded to the 3-position of the C ring. For example, the reaction between dimers produces a tetramer. The reaction between tetramers produces an octamer.

[0073] [ka]

[0074] [In general formula (4), R 1 ~R 5 , R 11 ~R 15 , R 21 ~R 25 , R 6 , R 16 , R 26 , R 7 ~R 9 , R 17 ~R 18 , R 27 ~R 28 , X, and n are defined as in general formula (2). The wavy line represents a single bond that forms an R or S configuration.]

[0075] The reaction that produces oligomers of flavan derivatives is thought to be based on the following mechanism: Lewis acid acts on the flavan derivative, abstracting the electron pair of the substituent (X) attached to the carbon at the 4th position of the C ring, and also abstracting the electron pair of the substituent (OR 6 ) undergoes neighboring group participation. A cyclic intermediate is formed as a transition state between the 3rd and 4th carbons of the C ring. Then, the substituent (X) is eliminated from the 4th carbon of the C ring, and an activated flavan derivative is produced in which the 4th carbon of the C ring is cationized.

[0076] The activated flavan derivative is attacked by the unactivated flavan derivative, which acts as a nucleophile. Due to electronic effects, the carbon at position 8 of the A ring of the nucleophile becomes the nucleophilic site. The attack of the nucleophile on the activated flavan forms a bond between the carbon at position 4 of the C ring of the activated flavan and the carbon at position 8 of the A ring of the nucleophile. The formation and elimination of the cyclic intermediate are regioselective SN1 reactions, and stereoelectronic effects lead to the formation of regioselective oligomers.

[0077] First Embodiment Next, a system for producing a flavan oligomer and a method for producing a flavan oligomer according to a first embodiment of the present invention will be described with reference to the drawings.

[0078] FIG. 1 is a schematic diagram of a flavan oligomer production system according to the first embodiment. As shown in FIG. 1, the flavan oligomer production system 1 according to the first embodiment includes a raw material liquid container (first container) 101, a catalyst liquid container (second container) 102, a recovery container 103, a first pump 104, a second pump 105, a microreactor 106, a tube 107, a temperature control device 108, a temperature control device 109, and fittings (not shown) that connect the tube 107 to each component.

[0079] Temperature adjustment device 108 and temperature adjustment device 109 are provided to adjust predetermined regions in the system to predetermined temperatures, as indicated by dashed lines in the figure. Microreactor 106 and tube 107 from microreactor 106 to collection container 103 are included in the range adjusted by temperature adjustment device 108. Collection container 103 and tube 107 inside collection container 103 are included in the range adjusted by temperature adjustment device 109.

[0080] The microreactor 106 is a flow-type reactor that has two inlets through which individual fluids are introduced from the outside, a microchannel that merges the introduced fluids, and an outlet through which a product fluid generated by the merger flows out to the outside. The microreactor 106 mixes the fluids introduced from one inlet and the fluid introduced from the other inlet within the microchannel. The mixing of the fluids generates a product fluid that has initiated a predetermined reaction.

[0081] A raw material liquid container 101 and a first pump 104 are connected to one inlet of the microreactor 106 via a tube 107. The raw material liquid container 101 is connected to the suction side of the first pump 104. The discharge side of the first pump 104 is connected to one inlet of the microreactor 106. A raw material liquid containing a flavan derivative as a starting material is prepared in the raw material liquid container 101. The first pump 104 sends the raw material liquid from the raw material liquid container 101 to one inlet of the microreactor 106.

[0082] The other inlet of the microreactor 106 is connected to a catalyst solution container 102 and a second pump 105 via a tube 107. The catalyst solution container 102 is connected to the suction side of the second pump 105. The discharge side of the second pump 105 is connected to the other inlet of the microreactor 106. A catalyst solution containing a Lewis acid is prepared in the catalyst solution container 102. The second pump 105 sends the catalyst solution from the catalyst solution container 102 to the other inlet of the microreactor 106.

[0083] A collection container 103 is connected to the outlet of the microreactor 106 via a tube 107. The collection container 103 is a container for collecting the product fluid generated in the microreactor 106 and the subsequent tube 107. The collection container 103 can store a reaction stop solution containing a base in order to neutralize Lewis acids contained in the product fluid.

[0084] For example, a syringe pump, a tube pump, a plunger pump, a diaphragm pump, a screw pump, manual liquid transfer using a syringe, liquid transfer using a hydraulic head difference, etc. can be used as the first pump 104 or the second pump 105. When a syringe pump is used as the first pump 104 or the second pump 105, a syringe containing the raw material liquid or catalyst liquid can be used as a functional substitute for the raw material liquid container 101 or the catalyst liquid container 102.

[0085] As the material for the microreactor 106, the material for the raw material liquid container 101, the material for the catalyst liquid container 102, the material for the recovery container 103, the material for the tube 107, the material for the tube, syringe, diaphragm, etc. that constitute the liquid-contacting part of the pump, and the material for the fittings, any appropriate material can be used depending on the type of fluid, as long as it does not have an adverse effect on the raw material liquid, catalyst liquid, or product fluid and is unlikely to be deteriorated by these.

[0086] The materials of the microreactor 106, the raw material liquid container 101, the catalyst liquid container 102, the recovery container 103, the tube 107, the material constituting the liquid-contacting part of the pump, and the fittings may be the same or different for each installation location in the system. These materials can be selected appropriately depending on processability, flexibility, etc.

[0087] Examples of materials for the microreactor 106 include stainless steel, gold, glass, Hastelloy, ceramic, PE (polyethylene), PP (polypropylene), TPX (polymethylpentene), PDMS (polydimethylsiloxane), PC (polycarbonate), and fluorine-based resins such as PTFE (polytetrafluoroethylene) and PFA (perfluoroalkoxyalkane).

[0088] The material of the microreactor 106 may be lined with glass or coated with nickel or gold, or may have an oxide film formed by oxidizing silicon, in order to improve corrosion resistance, chemical resistance, and the like.

[0089] Appropriate devices such as a heat exchanger using a heat medium, a constant temperature water bath using a heat medium, a Peltier thermostat, a mantle heater, etc. can be used as the temperature adjustment devices 108 and 109. As the heat medium, water, ethylene glycol, a water / ethylene glycol mixed solvent, a dry ice and water / ethanol mixed solvent, a dry ice and water / methanol mixed solvent, etc. can be used.

[0090] The temperature regulators 108 and 109 may be adjusted to the same temperature range or different temperature ranges. The temperatures adjusted by the temperature regulators 108 and 109 can be adjusted depending on the reaction rate of the synthesis reaction, the stability of the compound, etc. Note that when the synthesis reaction is carried out at room temperature, the temperature regulators 108 and 109 may not be provided.

[0091] FIG. 2 is a diagram showing an example of a microreactor. As shown in FIG. 2, a microreactor 200 capable of mixing fluids at different flow rates can also be used as the microreactor used for synthesizing flavan oligomers.

[0092] The microreactor 200, which can mix fluids at different flow rates, has two inlets (207, 208) through which individual fluids are introduced from the outside, micro-channels (203, 204, 205) through which the introduced fluids join together, and a fluid outlet 209 through which the product fluid generated by the joining at the joining point 206 flows out to the outside.

[0093] The microreactor 200 is formed by an upper plate 201 and a lower plate 202. The upper plate 201 is grooved, and the lower plate 202 is placed on top of it to cover the groove, thereby forming microchannels (203, 204, 205). Such grooves can be formed in either the upper plate 201 or the lower plate 202.

[0094] The lower plate 202 is provided with through-holes (207, 208, 209) at positions overlapping with the respective ends of the microchannels (203, 204, 205). The through-holes (207, 208, 209) include a high flow rate side fluid inlet 207, a low flow rate side fluid inlet 208, and a fluid outlet 209, which penetrate from the microchannels (203, 204, 205) side to the surface of the lower plate 202 opposite to the microchannels (203, 204, 205).

[0095] The through holes (207, 208, 209) may have threads (not shown) formed therein. The tube 107 may be connected to the through holes (207, 208, 209) via a fitting that can be threaded into the threads. Alternatively, the tube 107 may be directly connected to the through holes (207, 208, 209).

[0096] The microchannels (203, 204, 205) are composed of a high flow rate side channel 203 extending from a high flow rate side fluid inlet 207 to a junction 206, a low flow rate side channel 204 extending from a low flow rate side fluid inlet 208 to the junction 206, and a mixing channel 205 extending from the junction 206 to a fluid outlet 209.

[0097] The high flow rate side flow path 203 is used to pass a fluid that has a high mixing ratio and is set to a relatively high flow rate among the fluids mixed in the microreactor 200. On the other hand, the low flow rate side flow path 204 is used to pass a fluid that has a low mixing ratio and is set to a relatively low flow rate among the fluids mixed in the microreactor 200.

[0098] In microreactor 200, a high-flow-rate fluid is introduced from high-flow-rate fluid inlet 207, passes through high-flow-rate channel 203, and reaches confluence 206. A low-flow-rate fluid is introduced from low-flow-rate fluid inlet 208, passes through low-flow-rate channel 204, and reaches confluence 206. The high-flow-rate fluid and the low-flow-rate fluid meet at confluence 206, and begin mixing and reacting. These fluids pass through mixing channel 205 and are discharged to the outside from fluid outlet 209.

[0099] The high flow rate side flow path 203 is provided with a larger total flow path volume than the low flow rate side flow path 204. For example, the flow path length of the high flow rate side flow path 203 is provided longer than the low flow rate side flow path 204, which is provided with the same flow path width and flow path depth. With this structure, even when the mixture ratio is biased toward one fluid and the fluids are controlled to flow rates that are significantly different from each other, it is possible to reduce the difference in timing at which the fluids arrive at the confluence 206.

[0100] The high flow rate side channel 203 branches into two symmetrical branch channels 203a and 203b in the middle, which merge together at a junction 206. The low flow rate side channel 204 connects to the junction 206 between the two branch channels 203a and 203b. At the junction 206, the low flow rate side fluid and the high flow rate side fluid flowing in from the upstream side flow into a mixing channel 205 located downstream. With this structure, the low flow rate side fluid is sandwiched between the high flow rate side fluids and the fluids merge to begin mixing. By sandwiching the low flow rate side fluid between the high flow rate side fluids, the interfacial area between the fluids increases, thereby improving the efficiency of mixing.

[0101] The high flow rate side channel 203, the low flow rate side channel 204, and the mixing channel 205 are preferably provided with a channel diameter, width, or depth of 2 mm or less. Such channels allow the effects of the micro reaction field, such as surface effects and improved heat transfer coefficients, to be fully achieved. In particular, the high flow rate side channel 203 and the low flow rate side channel 204 immediately before the junction 206, the junction 206, and the mixing channel 205 are preferably provided with a channel diameter, width, or depth of 10 μm or more and 1 mm or less. Such channels allow the fluids to be mixed uniformly and quickly by molecular diffusion.

[0102] The microreactor 200 capable of mixing fluids at different flow rates can also be used when the flow rate ratio of the fluids is 1:1. The mixing of the fluids may be in a form in which the fluids are mixed uniformly, or in a form in which the fluids are mixed non-uniformly, for example, in a form in which multiple phases such as an emulsion are formed.

[0103] 2, a microreactor 200 is provided with a high-flow-rate side channel 203 and a low-flow-rate side channel 204 of a predetermined shape. However, the microreactor used for synthesizing flavan oligomers can be provided in any suitable shape as long as it has a microchannel for mixing at least two fluids. For example, the microchannel can be provided in a Y-shape, a T-shape, or a shape that forms a multilayer flow and merges the flow.

[0104] In the microreactor used for synthesizing the flavan oligomer, the flow channel volumes up to the joining of the two fluids may be different from each other or may be the same. The flow channels of the microreactor used for synthesizing the flavan oligomer do not necessarily all need to be minute flow channels. The flow channels of the microreactor can be changed in diameter, width, or depth depending on the type of reaction, etc.

[0105] Next, a method for producing a flavan oligomer using the flavan oligomer production system 1 will be described.

[0106] In the flavan oligomer production system 1, a raw material liquid and a catalyst liquid are mixed in a microreactor 106 to initiate activation of a portion of the flavan derivatives contained in the raw material liquid by the Lewis acid contained in the catalyst liquid. The mixing initiates a reaction between a portion of the flavan derivatives activated by the Lewis acid and the remaining flavan derivatives, which act as nucleophiles, to produce a product fluid. The activated flavan derivatives can be regioselectively condensed with each other through an SN1-type reaction between the activated flavan derivatives and the non-activated flavan derivatives, which act as nucleophiles.

[0107] When producing a flavan oligomer using the production system 1, a raw material solution containing a flavan derivative having a flavan skeleton is prepared in the raw material solution container 101. A catalyst solution containing a Lewis acid is prepared in the catalyst solution container 102. A reaction stop solution containing a base is prepared in the recovery container 103.

[0108] First, a raw material solution containing a flavan derivative prepared in a raw material solution container 101 is sent from the raw material solution container 101 to one inlet of a microreactor 106 by a first pump 104. Also, a catalyst solution containing a Lewis acid prepared in a catalyst solution container 102 is sent from the catalyst solution container 102 to the other inlet of the microreactor 106 by a second pump 105.

[0109] Next, the raw material solution containing the flavan derivatives and the catalyst solution containing a Lewis acid are mixed in the microreactor 106. This mixing initiates activation of some of the flavan derivatives contained in the raw material solution by the Lewis acid contained in the catalyst solution. This then initiates a reaction between some of the activated flavan derivatives and the remaining unactivated flavan derivatives, which act as nucleophiles. The reaction between the flavan derivatives further progresses as the product fluid produced in the microreactor 106 flows downstream through the subsequent tube 107.

[0110] In the microreactor 106 of the production system 1, the flavan derivative as the starting material and the Lewis acid are reacted at a reaction equivalence ratio of flavan derivative:Lewis acid close to 1:0.5. Therefore, to achieve such a reaction equivalence ratio, the flow rate ratio of the raw material solution and the catalyst solution introduced into the microreactor 106, the concentration of the raw material solution prepared in the raw material solution container 101, and the concentration of the catalyst solution prepared in the catalyst solution container 102 are adjusted. The reaction equivalence ratio of the flavan derivative and the Lewis acid may be adjusted by only the flow rate ratio, by only the concentration, or by both the flow rate ratio and the concentration.

[0111] Subsequently, the product fluid discharged from the microreactor 106 and the subsequent tube 107 is collected in a reaction stop solution containing a base in a collection container 103. By collecting the product fluid in the reaction stop solution, the Lewis acid in the product fluid is neutralized with the base, thereby terminating the polymerization reaction. The reaction starts in the microchannel of the microreactor 106, and the product passes through the subsequent tube 107 and is collected in the reaction stop solution containing a base, whereupon the polymerization reaction is terminated, yielding an oligomer in which the flavan derivatives are bonded to each other at the desired degree of polymerization.

[0112] The resulting flavan derivative oligomer can be separated and purified, and then the protecting groups can be deprotected, if necessary. The flavan derivative oligomer can be subjected to a step of introducing a new substituent, a step of introducing a modified structure such as a sugar chain, or other reaction step of converting the three-dimensional structure, skeleton, functional group, etc., before or after deprotection.

[0113] According to the above-described flavan oligomer production system 1 and flavan oligomer production method, the flavan derivatives contained in the raw material solution and the Lewis acid contained in the catalyst solution can react efficiently in the microchannel of the microreactor 106 and in the subsequent tube 107. Therefore, only a portion of the flavan derivatives contained in the raw material solution can be activated by a Lewis acid at a predetermined reaction equivalence ratio. The activated portion of the flavan derivatives can react with the remaining flavan derivatives, which act as nucleophiles, at a predetermined reaction equivalence ratio. The use of a microreactor allows precise control of the flow rate ratio between fluids, the reaction ratio between reactants, and the start and end times of the reaction. Therefore, flavan oligomers in which flavan derivatives are bonded to each other at a desired degree of polymerization can be efficiently synthesized with high yield.

[0114] Furthermore, the flavan oligomer production system 1 and the flavan oligomer production method described above improve the yield of oligomers with a desired degree of polymerization, thereby reducing the cost and effort required for separating and purifying oligomers with a desired degree of polymerization from the synthesized mixture. Furthermore, an excessive amount of catalyst is no longer necessary, reducing catalyst costs and purification costs.

[0115] The reaction equivalent ratio of the flavan derivative and Lewis acid reacted in the microreactor 106 of the production system 1 and the subsequent tube 107 is not particularly limited, as long as the Lewis acid is 0.5 or more equivalents per equivalent of flavan derivative. The reaction equivalent ratio of the flavan derivative and Lewis acid varies depending on the type of flavan derivative and Lewis acid, but from the viewpoint of saving the amounts of flavan derivative and Lewis acid used, a flavan derivative:Lewis acid ratio of 1:0.5 to 1:1 is preferred. The reaction equivalent ratio of the Lewis acid is preferably 1 equivalent or less per equivalent of flavan derivative, preferably 0.5 to 0.9 equivalents, more preferably 0.5 to 0.8 equivalents, even more preferably 0.5 to 0.7 equivalents, and even more preferably 0.5 to 0.6 equivalents.

[0116] At such a reaction equivalence ratio, the ratio of a portion of the flavan derivative activated by the Lewis acid to the remaining flavan derivative acting as a nucleophile approaches 1:1. Because the flavan derivatives can be reacted with each other at a 1:1 ratio, unreacted flavan derivatives (monomers, etc.) can be reduced. Furthermore, by using the microreactor 106 to eliminate variations in reaction conditions, oligomers with a degree of polymerization higher than the desired level can be reduced. In other words, using a flavan derivative monomer or a flavan derivative oligomer as a starting material, a dimer or oligomer with a desired degree of polymerization can be obtained in high yield.

[0117] The reaction equivalent ratio of the Lewis acid and base reacted in the collection container 103 can be any suitable ratio as long as the polymerization reaction of the flavan derivative is terminated. The reaction equivalent ratio of the base is preferably 1 equivalent or more relative to 1 equivalent of Lewis acid reacted in the microreactor 106, and more preferably an excess amount exceeding 1 equivalent. With such an amount, the reaction can be safely terminated even if the Lewis acid does not react properly. The reaction equivalent ratio of the base may be a large excess when the reaction terminating solution is stored in the collection container 103 or when separation and purification are planned.

[0118] Second Embodiment Next, a flavan oligomer production system and a flavan oligomer production method according to a second embodiment of the present invention will be described with reference to the drawings.

[0119] FIG. 3 is a schematic diagram of a flavan oligomer production system according to the second embodiment. As shown in FIG. 3, the flavan oligomer production system 2 according to the second embodiment includes a raw material liquid container (first container) 101, a catalyst liquid container (second container) 102, a recovery container 103, a raw material liquid container (third container) 301, a first pump 104, a second pump 105, a third pump 302, a first microreactor 106, a second microreactor 303, a tube 107, a temperature control device 108, a temperature control device 109, and fittings (not shown) that connect the tube 107 to each component.

[0120] The production system 2 differs from the production system 1 in that it includes multiple stages of microreactors 106, 303 connected in series to each other, and the synthesis reaction of flavan oligomers is carried out in stages.

[0121] In the manufacturing system 2, a second microreactor 303 is connected to the downstream of the first microreactor 106. Furthermore, a raw material liquid container 301 and a third pump 302 are connected to the second microreactor 303.

[0122] Temperature adjustment device 108 and temperature adjustment device 109 are provided to adjust predetermined regions in the system to predetermined temperatures, as indicated by dashed lines in the figure. The first microreactor 106, the tube 107 from the first microreactor 106 to the second microreactor 303, the second microreactor 303, and the tube 107 from the second microreactor 303 to the collection container 103 are included in the range adjusted by temperature adjustment device 108. The collection container 103 and the tube 107 inside the collection container 103 are included in the range adjusted by temperature adjustment device 109.

[0123] The first microreactor 106 and the second microreactor 303 are flow-type reactors each having two inlets through which individual fluids are introduced from the outside, a microchannel through which the introduced fluids join, and an outlet through which a product fluid generated by the joining flows out to the outside. These microreactors 106 and 303 mix the fluids introduced from one inlet with the fluid introduced from the other inlet within the microchannel. The mixing of the fluids generates a product fluid that has initiated a predetermined reaction.

[0124] In the production system 2, a raw material liquid container 101 and a first pump 104 are connected to one inlet of a first microreactor 106 via a tube 107, as in the production system 1. A catalyst liquid container 102 and a second pump 105 are connected to the other inlet of the first microreactor 106 via a tube 107, as in the production system 1.

[0125] An outlet of the first microreactor 106 is connected to one inlet of a second microreactor 303 via a tube 107. A first product fluid produced in the first microreactor 106 and then in the tube 107 is sent to the second microreactor 303.

[0126] A raw material liquid container 301 and a third pump 302 are connected to the other inlet of the second microreactor 303 via a tube 107. The raw material liquid container 301 is connected to the suction side of the third pump 302. The discharge side of the third pump 302 is connected to the other inlet of the second microreactor 303. A raw material liquid containing a flavan derivative as a starting material is prepared in the raw material liquid container 301. The third pump 302 sends the raw material liquid from the raw material liquid container 301 to the other inlet of the second microreactor 303.

[0127] A collection container 103 is connected to the outlet of the second microreactor 303 via a tube 107. The collection container 103 is a container for collecting the second product fluid generated in the second microreactor 303 and the subsequent tube 107. The collection container 103 can store a reaction stop solution containing a base in order to neutralize the Lewis acid contained in the second product fluid.

[0128] As in the manufacturing system 1, an appropriate pump can be used as the first pump 104 or the second pump 105. As in the first pump 104 or the second pump 105, an appropriate pump can be used as the third pump 302. When a syringe pump is used as the first pump 104, the second pump 105, or the third pump 302, a syringe in which the raw material liquid or the catalyst liquid is prepared can be used as a functional substitute for the raw material liquid container 101, the catalyst liquid container 102, or the raw material liquid container 301.

[0129] As with the manufacturing system 1, appropriate materials can be used for the materials of the first microreactor 106, the second microreactor 303, the raw material liquid container 101, the catalyst liquid container 102, the recovery container 103, the raw material liquid container 301, the tube 107, the tubes, syringes, diaphragms, etc. that make up the liquid-contacting parts of the pump, and the fittings.

[0130] The microreactor 200 (see FIG. 2) capable of mixing fluids at different flow rates can be used as the first microreactor 106 or the second microreactor 303. The microreactor 200 capable of mixing fluids at different flow rates may be used only for the first microreactor 106 or only for the second microreactor 303, but is preferably used for both the first microreactor 106 and the second microreactor 303.

[0131] Next, a method for producing a flavan oligomer using the flavan oligomer production system 2 will be described.

[0132] In the flavan oligomer production system 2, a raw material liquid and a catalyst liquid are mixed in a first microreactor 106 to initiate activation of the flavan derivatives contained in the raw material liquid by the Lewis acid contained in the catalyst liquid. The first stage of mixing generates a first product fluid containing the flavan derivatives activated by the Lewis acid. Then, the first product fluid and the raw material liquid are mixed in a second microreactor 303 to initiate a reaction between the flavan derivatives activated by the Lewis acid and the unactivated flavan derivatives acting as nucleophiles. The second stage of mixing generates a second product fluid in which the flavan derivatives have started to react with each other. The flavan derivatives can be regioselectively condensed with each other through an SN1-type reaction between the activated flavan derivatives and the unactivated flavan derivatives acting as nucleophiles.

[0133] When producing a flavan oligomer using the production system 2, a raw material solution containing a flavan derivative having a flavan skeleton is prepared in the raw material solution container 101. A catalyst solution containing a Lewis acid is prepared in the catalyst solution container 102. A raw material solution containing a flavan derivative having a flavan skeleton is prepared in the raw material solution container 301. A reaction stop solution containing a base is prepared in the recovery container 103.

[0134] First, a raw material solution containing a flavan derivative prepared in a raw material solution container 101 is sent from the raw material solution container 101 to one inlet of a first microreactor 106 by a first pump 104. Also, a catalyst solution containing a Lewis acid prepared in a catalyst solution container 102 is sent from the catalyst solution container 102 to the other inlet of the first microreactor 106 by a second pump 105.

[0135] Next, the raw material solution containing the flavan derivative and the catalyst solution containing the Lewis acid are mixed in the first microreactor 106. The mixing initiates activation of the flavan derivative contained in the raw material solution by the Lewis acid contained in the catalyst solution. The activation of the flavan derivative further progresses while the first product fluid produced in the first microreactor 106 flows downstream in the subsequent tube 107. The first product fluid is sent from the first microreactor 106 to one inlet of the second microreactor 303.

[0136] In the first microreactor 106 of the production system 2, the flavan derivative as a starting material and the Lewis acid are reacted at a reaction equivalence ratio of flavan derivative:Lewis acid close to 1:1. Therefore, to achieve such a reaction equivalence ratio, the flow rate ratio of the raw material solution and the catalyst solution introduced into the first microreactor 106, the concentration of the raw material solution prepared in the raw material solution container 101, and the concentration of the catalyst solution prepared in the catalyst solution container 102 are adjusted. The reaction equivalence ratio of the flavan derivative and the Lewis acid may be adjusted by only the flow rate ratio, by only the concentrations, or by both the flow rate ratio and the concentrations.

[0137] Subsequently, the raw material liquid containing the flavan derivative prepared in the raw material liquid container 301 is sent from the raw material liquid container 301 to the other inlet of the second microreactor 303 by the third pump 302 .

[0138] Next, the first product fluid containing the activated flavan derivative and the raw material solution containing the non-activated flavan derivative acting as a nucleophile are mixed in the second microreactor 303. The mixing initiates a reaction between the activated flavan derivative and the non-activated flavan derivative acting as a nucleophile. The reaction between the flavan derivatives further progresses while the second product fluid produced in the second microreactor 303 flows downstream in the subsequent tube 107.

[0139] In the second microreactor 303 of the production system 2, the activated flavan derivative in the first microreactor 106 and the subsequent tube 107 is reacted with the non-activated flavan derivative prepared in the raw material liquid container 301 at a reaction equivalence ratio of activated form:non-activated form close to 1:1. Therefore, to achieve such a reaction equivalence ratio, the flow rate ratio of the first product fluid and the raw material liquid introduced into the second microreactor 303 and the concentration of the raw material liquid prepared in the raw material liquid container 301 are adjusted. The reaction equivalence ratio of the activated flavan derivative and the non-activated flavan derivative may be adjusted by only the flow rate ratio, by only the concentration, or by both the flow rate ratio and the concentration.

[0140] Subsequently, the second product fluid undergoing the reaction, discharged from the second microreactor 303 and the subsequent tube 107, is collected in a reaction stop solution containing a base in the collection container 103. By collecting the second product fluid in the reaction stop solution, the Lewis acid in the second product fluid is neutralized with the base, thereby terminating the polymerization reaction. The polymerization reaction is initiated in the microchannel of the second microreactor 303, and the second product fluid passes through the subsequent tube 107 and is collected in a reaction stop solution containing a base, whereby an oligomer in which flavan derivatives are bonded to each other at a desired degree of polymerization is obtained.

[0141] The resulting flavan derivative oligomer can be separated and purified, and then the protecting groups can be deprotected, if necessary. The flavan derivative oligomer can be subjected to a step of introducing a new substituent, a step of introducing a modified structure such as a sugar chain, or other reaction step of converting the three-dimensional structure, skeleton, functional group, etc., before or after deprotection.

[0142] According to the above-described flavan oligomer production system 2 and flavan oligomer production method, the flavan derivative contained in the raw material solution and the Lewis acid contained in the catalyst solution can react efficiently in the microchannel of the first microreactor 106 and the subsequent tube 107, thereby producing a first product fluid. Furthermore, the activated flavan derivative contained in the first product fluid can react efficiently with the flavan derivative contained in the raw material solution in the microchannel of the second microreactor 303 and the subsequent tube 107. Therefore, the activated flavan derivative can react with the flavan derivative acting as a nucleophile at a predetermined reaction equivalence ratio. The use of a microreactor allows precise control of the flow rate ratio between fluids, the reaction ratio between reactants, and the start and stop times of the reaction. Therefore, flavan oligomers in which flavan derivatives are bonded to each other at a desired degree of polymerization can be efficiently synthesized with high yield.

[0143] Furthermore, the flavan oligomer production system 2 and the flavan oligomer production method described above improve the yield of oligomers with the desired degree of polymerization, thereby reducing the cost and effort required to separate and purify oligomers with the desired degree of polymerization from the synthesized mixture. Furthermore, an excessive amount of catalyst is no longer required, reducing catalyst costs and purification costs. The flavan oligomer production system 2 and the flavan oligomer production method make it easier to control reaction conditions compared to the production system 1.

[0144] The reaction equivalent ratio between the flavan derivative and the Lewis acid reacted in the first microreactor 106 of the production system 2 and in the tube 107 downstream of the first microreactor 106 is not particularly limited, as long as the Lewis acid is 1 or more equivalents per equivalent of flavan derivative. The reaction equivalent ratio between the flavan derivative and the Lewis acid varies depending on the type of flavan derivative and the Lewis acid, but from the viewpoint of saving the amount of Lewis acid used, a flavan derivative:Lewis acid ratio of 1:1 to 1:2 is preferred. The reaction equivalent ratio of the Lewis acid is preferably 2 or less equivalents per equivalent of flavan derivative, preferably 1.0 to 1.8 equivalents, more preferably 1.0 to 1.6 equivalents, even more preferably 1.0 to 1.4 equivalents, and even more preferably 1.0 to 1.2 equivalents.

[0145] The reaction equivalent ratio between the activated flavan derivative and the flavan derivative acting as a nucleophile, which are reacted in the second microreactor 303 of the production system 2 and in the tube 107 downstream of the second microreactor 303, is not particularly limited as long as there is 1 equivalent or more of the flavan derivative acting as a nucleophile for 1 equivalent of the activated flavan derivative. The reaction equivalent ratio between the activated flavan derivative and the flavan derivative acting as a nucleophile varies depending on the types of flavan derivative and Lewis acid, but from the viewpoint of saving the amount of flavan derivative used, it is preferable that the ratio of activated flavan derivative to flavan derivative acting as a nucleophile be 1:1 to 1:2. The reaction equivalent ratio of the flavan derivative acting as a nucleophile to 1 equivalent of the activated flavan derivative is preferably 2 equivalents or less, more preferably 1.0 equivalent to 1.8 equivalents or less, more preferably 1.0 equivalent to 1.6 equivalents or less, even more preferably 1.0 equivalent to 1.4 equivalents or less, and even more preferably 1.0 equivalent to 1.2 equivalents or less.

[0146] When the reaction equivalence ratio is such that the flavan derivative acting as a nucleophile is in excess, the flavan derivative activated with a Lewis acid and the flavan derivative acting as a nucleophile can react reliably, but some unreacted flavan derivative remains. When the reaction equivalence ratio of the activated flavan derivative to the flavan derivative acting as a nucleophile approaches 1:1, the amount of flavan derivative (monomer, etc.) can be reduced. Furthermore, the use of microreactors 106 and 303 eliminates variability in reaction conditions, allowing oligomers with a degree of polymerization higher than the desired level to be reduced. In other words, using a flavan derivative monomer or a flavan derivative oligomer as a starting material, a dimer or oligomer with a desired degree of polymerization can be obtained in high yield.

[0147] The reaction equivalent ratio between the Lewis acid and the base reacted in the collection vessel 103 can be set to the same conditions as those in the production system 1 described above.

[0148] In the manufacturing system 2, the first microreactor 106, the tube 107 from the first microreactor 106 to the second microreactor 303, the second microreactor 303, and the tube 107 from the second microreactor 303 to the collection container 103 are all included in the range of temperature adjustment by the temperature adjustment device 108. With this configuration, the upstream and downstream sides of the second microreactor 303 can be adjusted to approximately the same temperature. This allows for cost reduction and simplification of control.

[0149] However, the first microreactor 106 and the tube 107 from the first microreactor 106 to the second microreactor 303, and the second microreactor 303 and the tube 107 from the second microreactor 303 to the collection container 103 can be controlled by different temperature control devices. More precisely, the upstream and downstream sides of the second microreactor 303 can be controlled to different temperatures. In order to quickly terminate the polymerization reaction, a reaction stop solution containing an excess amount of base can be prepared in the collection container 103, and the temperature control device 109 that controls the temperature of the collection container 103 and the tube 107 in the collection container 103 can be controlled to a higher temperature than these sections.

[0150] <Third embodiment> Next, a flavan oligomer production system and a flavan oligomer production method according to a third embodiment of the present invention will be described with reference to the drawings.

[0151] FIG. 4 is a schematic diagram of a flavan oligomer production system according to the third embodiment. As shown in FIG. 4, the flavan oligomer production system 3 according to the third embodiment includes a raw material liquid container (first container) 101, a catalyst liquid container (second container) 102, a recovery container 103, a reaction stop liquid container (fourth container) 401, a first pump 104, a second pump 105, a third pump 302, a first microreactor 106, a second microreactor 303, a tube 107, a temperature controller 108, a temperature controller 109, and fittings (not shown) that connect the tube 107 to each component.

[0152] The production system 3 differs from the production system 1 in that it includes multiple stages of microreactors 106, 303 connected in series with each other, and the synthesis reaction of flavan oligomers is terminated by mixing a base in the microreactor.

[0153] In the manufacturing system 3, a second microreactor 303 is connected to the downstream of the first microreactor 106. A reaction stop solution container 401 and a third pump 302 are connected to the second microreactor 303.

[0154] Temperature adjustment device 108 and temperature adjustment device 109 are provided to adjust predetermined regions in the system to predetermined temperatures, as indicated by dashed lines in the figure. The first microreactor 106, the tube 107 from the first microreactor 106 to the second microreactor 303, the second microreactor 303, and the tube 107 from the second microreactor 303 to the collection container 103 are included in the range adjusted by temperature adjustment device 108. The collection container 103 and the tube 107 inside the collection container 103 are included in the range adjusted by temperature adjustment device 109.

[0155] In the production system 3, a raw material liquid container 101 and a first pump 104 are connected to one inlet of a first microreactor 106 via a tube 107, as in the production system 1. A catalyst liquid container 102 and a second pump 105 are connected to the other inlet of the first microreactor 106 via a tube 107, as in the production system 1.

[0156] An outlet of the first microreactor 106 is connected to one inlet of a second microreactor 303 via a tube 107. A first product fluid produced in the first microreactor 106 and then in the tube 107 is sent to the second microreactor 303.

[0157] A reaction stop solution container 401 and a third pump 302 are connected to the other inlet of the second microreactor 303 via a tube 107. The reaction stop solution container 401 is connected to the suction side of the third pump 302. The discharge side of the third pump 302 is connected to the other inlet of the second microreactor 303. A reaction stop solution containing a base is prepared in the reaction stop solution container 401. The third pump 302 sends the reaction stop solution from the reaction stop solution container 401 to the other inlet of the second microreactor 303.

[0158] A collection container 103 is connected to the outlet of the second microreactor 303 via a tube 107. The collection container 103 is a container for collecting the second product fluid generated in the second microreactor 303 and the subsequent tube 107. The collection container 103 may or may not store a reaction stop solution containing a base in order to neutralize the Lewis acid contained in the second product fluid.

[0159] As in the production system 1, an appropriate pump can be used as the first pump 104 or the second pump 105. As in the first pump 104 or the second pump 105, an appropriate pump can be used as the third pump 302. When a syringe pump is used as the first pump 104, the second pump 105, or the third pump 302, a syringe containing the raw material liquid, catalyst liquid, or reaction terminating liquid can be used as a functional substitute for the raw material liquid container 101, the catalyst liquid container 102, or the reaction terminating liquid container 401.

[0160] As with the manufacturing system 1, suitable materials can be used for the materials of the first microreactor 106, the second microreactor 303, the raw material liquid container 101, the catalyst liquid container 102, the recovery container 103, the reaction stop liquid container 401, the tube 107, the tubes, syringes, diaphragms, etc. that make up the liquid-contacting parts of the pump, and the fittings.

[0161] The microreactor 200 (see FIG. 2) capable of mixing fluids at different flow rates can be used as the first microreactor 106 or the second microreactor 303. The microreactor 200 capable of mixing fluids at different flow rates may be used only for the first microreactor 106 or only for the second microreactor 303, but is preferably used for both the first microreactor 106 and the second microreactor 303.

[0162] Next, a method for producing a flavan oligomer using the flavan oligomer production system 3 will be described.

[0163] In the flavan oligomer production system 3, a raw material solution and a catalyst solution are mixed in a first microreactor 106 to initiate activation of a portion of the flavan derivatives contained in the raw material solution by the Lewis acid contained in the catalyst solution. The first-stage mixing initiates a reaction between a portion of the flavan derivatives activated by the Lewis acid and the remaining flavan derivatives, which act as nucleophiles, to produce a first product fluid. The first product fluid is then mixed with a reaction stopper solution in a second microreactor 303 to initiate a neutralization reaction between the Lewis acid and a base. The second-stage mixing initiates a second product fluid, which initiates terminating the reaction between the flavan derivatives themselves. The activated flavan derivatives can be regioselectively condensed with each other through an SN1-type reaction between the activated flavan derivatives and the non-activated flavan derivatives, which act as nucleophiles. Subsequently, unintended polymerization reactions can be forcibly terminated by a reaction between the Lewis acid and a base.

[0164] When producing a flavan oligomer using the production system 3, a raw material solution containing a flavan derivative having a flavan skeleton is prepared in the raw material solution container 101. A catalyst solution containing a Lewis acid is prepared in the catalyst solution container 102. A reaction stop solution containing a base is prepared in the reaction stop solution container 401. A reaction stop solution containing a base may or may not be prepared in the recovery container 103.

[0165] First, a raw material solution containing a flavan derivative prepared in a raw material solution container 101 is sent from the raw material solution container 101 to one inlet of a first microreactor 106 by a first pump 104. Also, a catalyst solution containing a Lewis acid prepared in a catalyst solution container 102 is sent from the catalyst solution container 102 to the other inlet of the first microreactor 106 by a second pump 105.

[0166] Next, a raw material solution containing a flavan derivative and a catalyst solution containing a Lewis acid are mixed in the first microreactor 106. This mixing initiates activation of some of the flavan derivatives contained in the raw material solution by the Lewis acid contained in the catalyst solution. Then, a reaction is initiated between some of the activated flavan derivatives and the remaining flavan derivatives, which act as nucleophiles. The reaction between the flavan derivatives further progresses as the first product fluid produced in the first microreactor 106 flows downstream through the subsequent tube 107. The first product fluid is sent from the first microreactor 106 to one inlet of the second microreactor 303.

[0167] In the first microreactor 106 of the production system 3, the flavan derivative as a starting material and the Lewis acid are reacted at a reaction equivalence ratio of flavan derivative:Lewis acid close to 1:0.5. Therefore, to achieve such a reaction equivalence ratio, the flow rate ratio of the raw material solution and the catalyst solution introduced into the first microreactor 106, the concentration of the raw material solution prepared in the raw material solution container 101, and the concentration of the catalyst solution prepared in the catalyst solution container 102 are adjusted. The reaction equivalence ratio of the flavan derivative and the Lewis acid may be adjusted by only the flow rate ratio, by only the concentrations, or by both the flow rate ratio and the concentrations.

[0168] Subsequently, a reaction quenching solution containing a base prepared in a reaction quenching solution container 401 is sent from the reaction quenching solution container 401 to the other inlet of the second microreactor 303 by the third pump 302 .

[0169] Next, the first product fluid undergoing the polymerization reaction and a reaction stop solution containing a base are mixed in the second microreactor 303. This mixing initiates a neutralization reaction between the Lewis acid and the base. The neutralization reaction further progresses while the second product fluid produced in the second microreactor 303 flows downstream through the subsequent tube 107. This neutralization stops the reaction between the unactivated flavan derivative and the Lewis acid, and the reaction between the flavan derivative oligomer produced in the polymerization reaction and the Lewis acid.

[0170] In the second microreactor 303 of the production system 3, the Lewis acid in the first product fluid generated in the first microreactor 106 and the subsequent tube 107 is reacted with the base prepared in the reaction stop liquid container 401 so that 1 equivalent of Lewis acid corresponds to 1 equivalent or more of base. Therefore, to achieve such a reaction equivalence ratio, the flow rate ratio of the first product fluid introduced into the second microreactor 303 to the reaction stop liquid and the concentration of the reaction stop liquid prepared in the reaction stop liquid container 401 are adjusted. The reaction equivalence ratio of the Lewis acid to the base may be adjusted by only the flow rate ratio, by only the concentrations, or by both the flow rate ratio and the concentrations.

[0171] Subsequently, the second product fluid discharged from the second microreactor 303 and the subsequent tube 107 is collected in the collection container 103. A polymerization reaction is initiated in the microchannel of the first microreactor 106, passes through the subsequent tube 107, and is stopped in the microchannel of the second microreactor 303, and is then passed through the subsequent tube 107, whereby an oligomer in which flavan derivatives are bonded to each other at a desired degree of polymerization is obtained.

[0172] The resulting flavan derivative oligomer can be separated and purified, and then the protecting groups can be deprotected, if necessary. The flavan derivative oligomer can be subjected to a step of introducing a new substituent, a step of introducing a modified structure such as a sugar chain, or other reaction step of converting the three-dimensional structure, skeleton, functional group, etc., before or after deprotection.

[0173] According to the flavan oligomer production system 3 and the flavan oligomer production method described above, the flavan derivative contained in the raw material solution and the Lewis acid contained in the catalyst solution react efficiently in the microchannel of the first microreactor 106 and the subsequent tube 107, producing a first product fluid. Furthermore, the Lewis acid contained in the first product fluid reacts efficiently in the microchannel of the second microreactor 303 and the subsequent tube 107. Therefore, after reacting the activated flavan derivative with a flavan derivative acting as a nucleophile at a predetermined reaction equivalence ratio, the Lewis acid can be neutralized to terminate the polymerization reaction of the flavan derivative. The use of a microreactor allows precise control of the flow rate ratio between fluids, the reaction ratio between reactants, and the start and stop times of the reaction. Therefore, flavan oligomers in which flavan derivatives are bonded to each other at a desired degree of polymerization can be efficiently synthesized with high yield.

[0174] Furthermore, the flavan oligomer production system 3 and the flavan oligomer production method described above improve the yield of oligomers with the desired degree of polymerization, thereby reducing the cost and effort required to separate and purify oligomers with the desired degree of polymerization from the synthesis mixture. Furthermore, an excessive amount of catalyst is no longer necessary, reducing catalyst costs and purification costs. The flavan oligomer production system 3 and the flavan oligomer production method allow the reaction to be stopped more quickly and reliably than the production system 1.

[0175] The reaction equivalent ratio between the flavan derivative and the Lewis acid reacted in the first microreactor 106 of the production system 3 and in the tube 107 downstream of the first microreactor 106 can be the same as that in the production system 1. The reaction equivalent ratio between the flavan derivative and the Lewis acid varies depending on the types of flavan derivative and Lewis acid, but is preferably flavan derivative:Lewis acid=1:0.5 to 1:1.

[0176] The reaction equivalence ratio of the Lewis acid and base reacted in the second microreactor 303 and the tube 107 downstream of the second microreactor 303 of the production system 3 can be any suitable reaction equivalence ratio as long as the polymerization reaction of the flavan derivative is terminated. The reaction equivalence ratio of the base is preferably 1 equivalent or more relative to 1 equivalent of Lewis acid reacted in the first microreactor 106, and more preferably an excess amount exceeding 1 equivalent. With such an amount, the reaction can be safely terminated even if the Lewis acid does not react properly. When the reaction terminating solution is stored in the collection container 103, the reaction equivalence ratio of the base can be set in consideration of the amount of the reaction terminating solution in the collection container 103. If separation and purification are planned, a large excess amount may be used.

[0177] In the manufacturing system 3, the first microreactor 106, the tube 107 from the first microreactor 106 to the second microreactor 303, the second microreactor 303, and the tube 107 from the second microreactor 303 to the collection container 103 are all included in the range of temperature adjustment by the temperature adjustment device 108. With this configuration, the upstream and downstream sides of the second microreactor 303 can be adjusted to approximately the same temperature. This allows for cost reduction and simplification of control.

[0178] However, the first microreactor 106 and the tube 107 from the first microreactor 106 to the second microreactor 303, and the second microreactor 303 and the tube 107 from the second microreactor 303 to the collection container 103 can be controlled by different temperature control devices. More precisely, the upstream and downstream sides of the second microreactor 303 can be controlled to different temperatures. In order to reliably terminate the polymerization reaction, a reaction stop solution containing an excess amount of base can be prepared in the collection container 103, and the temperature control device 109 that controls the temperature of the collection container 103 and the tube 107 in the collection container 103 can be controlled to a higher temperature than these sections.

[0179] <Fourth embodiment> Next, a system for producing a flavan oligomer and a method for producing a flavan oligomer according to a fourth embodiment of the present invention will be described with reference to the drawings.

[0180] FIG. 5 is a schematic diagram of a flavan oligomer production system according to the fourth embodiment. As shown in FIG. 5, the flavan oligomer production system 4 according to the fourth embodiment includes a raw material liquid container (first container) 101, a catalyst liquid container (second container) 102, a recovery container 103, a raw material liquid container (third container) 301, a reaction stop liquid container (fourth container) 401, a first pump 104, a second pump 105, a third pump 302, a fourth pump 402, a first microreactor 106, a second microreactor 303, a third microreactor 403, a tube 107, a temperature controller 108, a temperature controller 109, and fittings (not shown) that connect the tube 107 to each component.

[0181] The manufacturing system 4 differs from the manufacturing system 1 in that it includes multiple stages of microreactors 106, 303, and 403 connected in series, in which the synthesis reaction of flavan oligomers is carried out in stages and the synthesis reaction of flavan oligomers is terminated by mixing a base in the microreactor.

[0182] In the manufacturing system 4, a second microreactor 303 is connected downstream of the first microreactor 106. A third microreactor 403 is connected downstream of the second microreactor 303. A raw material liquid container 301 and a third pump 302 are connected to the second microreactor 303. A reaction stop liquid container 401 and a fourth pump 402 are connected to the third microreactor 403.

[0183] The temperature adjustment device 108 and the temperature adjustment device 109 are provided to adjust predetermined regions in the system to predetermined temperatures, as indicated by dashed lines in the figure. The first microreactor 106, the tube 107 from the first microreactor 106 to the second microreactor 303, the second microreactor 303, the tube 107 from the second microreactor 303 to the third microreactor 403, the third microreactor 403, and the tube 107 from the third microreactor 403 to the collection container 103 are included in the range adjusted by the temperature adjustment device 108. The collection container 103 and the tube 107 inside the collection container 103 are included in the range adjusted by the temperature adjustment device 109.

[0184] The first microreactor 106, the second microreactor 303, and the third microreactor 403 are flow-type reactors each having two inlets through which individual fluids are introduced from the outside, a microchannel through which the introduced fluids join, and an outlet through which a product fluid generated by the joining flows out to the outside. These microreactors 106, 303, and 403 mix a fluid introduced from one inlet with a fluid introduced from the other inlet in the microchannel. The mixing of the fluids generates a product fluid that has initiated a predetermined reaction.

[0185] In the production system 4, a raw material liquid container 101 and a first pump 104 are connected to one inlet of a first microreactor 106 via a tube 107, as in the production system 1. A catalyst liquid container 102 and a second pump 105 are connected to the other inlet of the first microreactor 106 via a tube 107, as in the production system 1.

[0186] An outlet of the first microreactor 106 is connected to one inlet of a second microreactor 303 via a tube 107. A first product fluid produced in the first microreactor 106 and then in the tube 107 is sent to the second microreactor 303.

[0187] A raw material liquid container 301 and a third pump 302 are connected to the other inlet of the second microreactor 303 via a tube 107. The raw material liquid container 301 is connected to the suction side of the third pump 302. The discharge side of the third pump 302 is connected to the other inlet of the second microreactor 303. A raw material liquid containing a flavan derivative as a starting material is prepared in the raw material liquid container 301. The third pump 302 sends the raw material liquid from the raw material liquid container 301 to the other inlet of the second microreactor 303.

[0188] An outlet of the second microreactor 303 is connected to one inlet of a third microreactor 403 via a tube 107. A second product fluid produced in the second microreactor 303 and the subsequent tube 107 is sent to the third microreactor 403.

[0189] A reaction stop solution container 401 and a fourth pump 402 are connected to the other inlet of the third microreactor 403 via a tube 107. The reaction stop solution container 401 is connected to the suction side of the fourth pump 402. The discharge side of the fourth pump 402 is connected to the other inlet of the third microreactor 403. A reaction stop solution containing a base is prepared in the reaction stop solution container 401. The fourth pump 402 sends the reaction stop solution from the reaction stop solution container 401 to the other inlet of the third microreactor 403.

[0190] A collection container 103 is connected to the outlet of the third microreactor 403 via a tube 107. The collection container 103 is a container for collecting the third product fluid generated in the third microreactor 403 and the subsequent tube 107. The collection container 103 may or may not store a reaction stop solution containing a base in order to neutralize the Lewis acid contained in the third product fluid.

[0191] As in the production system 1, appropriate pumps can be used as the first pump 104 and the second pump 105. As in the first pump 104 and the second pump 105, appropriate pumps can be used as the third pump 302 and the fourth pump 402. When a syringe pump is used as the first pump 104, the second pump 105, the third pump 302, or the fourth pump 402, a syringe containing the raw material liquid, catalyst liquid, raw material liquid, or reaction stop liquid can be used as a functional substitute for the raw material liquid container 101, the catalyst liquid container 102, the raw material liquid container 301, or the reaction stop liquid container 401.

[0192] As with manufacturing system 1, appropriate materials can be used for the materials of the first microreactor 106, the second microreactor 303, the third microreactor 403, the raw material liquid container 101, the catalyst liquid container 102, the recovery container 103, the raw material liquid container 301, the reaction stop liquid container 401, the tube 107, the tubes, syringes, diaphragms, etc. that make up the liquid-contacting parts of the pump, and the fittings.

[0193] The microreactor 200 (see FIG. 2) capable of mixing fluids at different flow rates can be used as the first microreactor 106, the second microreactor 303, and the third microreactor 403. The microreactor 200 capable of mixing fluids at different flow rates may be used for at least one of the first microreactor 106, the second microreactor 303, and the third microreactor 403, or may be used for two of them, but is preferably used for all of them.

[0194] Next, a method for producing a flavan oligomer using the flavan oligomer production system 4 will be described.

[0195] In the flavan oligomer production system 4, a raw material liquid and a catalyst liquid are mixed in a first microreactor 106 to initiate activation of the flavan derivatives contained in the raw material liquid by the Lewis acid contained in the catalyst liquid. The first-stage mixing generates a first product fluid containing the flavan derivatives activated by the Lewis acid. The first product fluid and the raw material liquid are then mixed in a second microreactor 303 to initiate a reaction between the flavan derivatives activated by the Lewis acid and the unactivated flavan derivatives acting as nucleophiles. The second-stage mixing generates a second product fluid in which the reaction between the flavan derivatives has begun. The second product fluid and a reaction terminating solution are then mixed in a third microreactor 403 to initiate a neutralization reaction between the Lewis acid and the base. The third-stage mixing generates a second product fluid in which the reaction between the flavan derivatives has begun. The SN1 reaction between the activated flavan derivatives and the unactivated flavan derivatives acting as nucleophiles allows the flavan derivatives to be regioselectively condensed. Subsequently, the unintended polymerization reaction can be forcibly terminated by reaction with a Lewis acid and a base.

[0196] When producing a flavan oligomer using the production system 4, a raw material solution containing a flavan derivative having a flavan skeleton is prepared in the raw material solution container 101. A catalyst solution containing a Lewis acid is prepared in the catalyst solution container 102. A raw material solution containing a flavan derivative having a flavan skeleton is prepared in the raw material solution container 301. A reaction stop solution containing a base is prepared in the reaction stop solution container 401. A reaction stop solution containing a base may or may not be prepared in the recovery container 103.

[0197] First, a raw material solution containing a flavan derivative prepared in a raw material solution container 101 is sent from the raw material solution container 101 to one inlet of a first microreactor 106 by a first pump 104. Also, a catalyst solution containing a Lewis acid prepared in a catalyst solution container 102 is sent from the catalyst solution container 102 to the other inlet of the first microreactor 106 by a second pump 105.

[0198] Next, the raw material solution containing the flavan derivative and the catalyst solution containing the Lewis acid are mixed in the first microreactor 106. The mixing initiates activation of the flavan derivative contained in the raw material solution by the Lewis acid contained in the catalyst solution. The activation of the flavan derivative further progresses while the first product fluid produced in the first microreactor 106 flows downstream in the subsequent tube 107. The first product fluid is sent from the first microreactor 106 to one inlet of the second microreactor 303.

[0199] In the first microreactor 106 of the production system 4, the flavan derivative as a starting material and the Lewis acid are reacted at a reaction equivalence ratio of flavan derivative:Lewis acid close to 1:1. Therefore, to achieve such a reaction equivalence ratio, the flow rate ratio of the raw material solution and the catalyst solution introduced into the first microreactor 106, the concentration of the raw material solution prepared in the raw material solution container 101, and the concentration of the catalyst solution prepared in the catalyst solution container 102 are adjusted. The reaction equivalence ratio of the flavan derivative and the Lewis acid may be adjusted by only the flow rate ratio, by only the concentrations, or by both the flow rate ratio and the concentrations.

[0200] Subsequently, the raw material liquid containing the flavan derivative prepared in the raw material liquid container 301 is sent from the raw material liquid container 301 to the other inlet of the second microreactor 303 by the third pump 302 .

[0201] Next, the first product fluid containing the activated flavan derivative and the raw material solution containing the non-activated flavan derivative acting as a nucleophile are mixed in the second microreactor 303. The mixing initiates a reaction between the activated flavan derivative and the non-activated flavan derivative acting as a nucleophile. The reaction between the flavan derivatives further progresses while the second product fluid produced in the second microreactor 303 flows downstream through the subsequent tube 107. The second product fluid is sent from the second microreactor 303 to one inlet of the third microreactor 403.

[0202] In the second microreactor 303 of the production system 4, the activated flavan derivative in the first microreactor 106 and the subsequent tube 107 is reacted with the non-activated flavan derivative prepared in the raw material liquid container 301 at a reaction equivalence ratio of activated form:non-activated form close to 1:1. Therefore, to achieve such a reaction equivalence ratio, the flow rate ratio of the first product fluid and the raw material liquid introduced into the second microreactor 303 and the concentration of the raw material liquid prepared in the raw material liquid container 301 are adjusted. The reaction equivalence ratio of the activated flavan derivative and the non-activated flavan derivative may be adjusted by only the flow rate ratio, by only the concentration, or by both the flow rate ratio and the concentration.

[0203] Subsequently, a reaction quenching solution containing a base prepared in a reaction quenching solution container 401 is sent from the reaction quenching solution container 401 to the other inlet of the third microreactor 403 by a fourth pump 402 .

[0204] Next, the second product fluid undergoing the polymerization reaction and a reaction stop solution containing a base are mixed in the third microreactor 403. This mixing initiates a neutralization reaction between the Lewis acid and the base. The neutralization reaction further progresses as the third product fluid produced in the third microreactor 403 flows downstream through the subsequent tube 107. This neutralization stops the reaction between the unactivated flavan derivative and the Lewis acid, and the reaction between the flavan derivative oligomer produced in the polymerization reaction and the Lewis acid.

[0205] In the third microreactor 403 of the production system 4, the Lewis acid in the second product fluid generated in the second microreactor 303 and the subsequent tube 107 is reacted with the base prepared in the reaction stop liquid container 401 so that 1 equivalent of Lewis acid corresponds to 1 equivalent or more of base. Therefore, to achieve such a reaction equivalence ratio, the flow rate ratio of the second product fluid and the reaction stop liquid introduced into the third microreactor 403 and the concentration of the reaction stop liquid prepared in the reaction stop liquid container 401 are adjusted. The reaction equivalence ratio of the Lewis acid and the base may be adjusted by only the flow rate ratio, by only the concentration, or by both the flow rate ratio and the concentration.

[0206] Subsequently, the third product fluid discharged from the third microreactor 403 and the subsequent tube 107 is collected in the collection container 103. A polymerization reaction is initiated in the microchannel of the second microreactor 303, passes through the subsequent tube 107, and the polymerization reaction is terminated in the microchannel of the third microreactor 403, and passes through the subsequent tube 107, whereby an oligomer in which flavan derivatives are bonded to each other at a desired degree of polymerization is obtained.

[0207] The resulting flavan derivative oligomer can be separated and purified, and then the protecting groups can be deprotected, if necessary. The flavan derivative oligomer can be subjected to a step of introducing a new substituent, a step of introducing a modified structure such as a sugar chain, or other reaction step of converting the three-dimensional structure, skeleton, functional group, etc., before or after deprotection.

[0208] According to the above-described flavan oligomer production system 4 and flavan oligomer production method, the flavan derivative contained in the raw material solution and the Lewis acid contained in the catalyst solution can react efficiently in the microchannel of the first microreactor 106 and the subsequent tube 107 to produce a first product fluid. The activated flavan derivative contained in the first product fluid can react efficiently with the flavan derivative contained in the raw material solution in the microchannel of the second microreactor 303 and the subsequent tube 107 to produce a second product fluid. The Lewis acid contained in the second product fluid can react efficiently with the base contained in the reaction stop solution in the third microreactor 403 and the subsequent tube 107. Therefore, the flavan derivative can be reacted with the Lewis acid at a predetermined reaction equivalence ratio, and the resulting activated flavan derivative can be reacted with a flavan derivative acting as a nucleophile at a predetermined reaction equivalence ratio. The Lewis acid can then be neutralized to terminate the polymerization reaction of the flavan derivative. The use of a microreactor allows precise control of the flow rate ratio between fluids, the reaction ratio between reactants, and the start and stop times of the reaction, allowing for efficient synthesis of flavan oligomers in which flavan derivatives are linked together at a desired degree of polymerization with high yield.

[0209] Furthermore, the flavan oligomer production system 4 and the flavan oligomer production method described above improve the yield of oligomers with the desired degree of polymerization, thereby reducing the cost and effort required to separate and purify oligomers with the desired degree of polymerization from the synthesis mixture. Furthermore, an excess amount of catalyst is no longer necessary, reducing catalyst and purification costs. Compared to the production system 1, the flavan oligomer production system 4 and the flavan oligomer production method allow for easier control of reaction conditions and for the reaction to be stopped quickly and reliably.

[0210] The reaction equivalent ratio between the flavan derivative and the Lewis acid reacted in the first microreactor 106 of the production system 4 and in the tube 107 downstream of the first microreactor 106 can be the same as that of the production system 2. The reaction equivalent ratio between the flavan derivative and the Lewis acid varies depending on the types of flavan derivative and Lewis acid, but from the viewpoint of saving the amount of Lewis acid used, it is preferable that the ratio of flavan derivative:Lewis acid is 1:1 to 1:2.

[0211] The reaction equivalent ratio between the activated flavan derivative and the flavan derivative acting as a nucleophile, which are reacted in the second microreactor 303 of the production system 4 and in the downstream tube 107 of the second microreactor 303, can be the same as that of the production system 2. The reaction equivalent ratio between the activated flavan derivative and the flavan derivative acting as a nucleophile varies depending on the types of flavan derivative and Lewis acid, but from the viewpoint of saving the amount of flavan derivative used, it is preferable that the ratio of activated flavan derivative to flavan derivative acting as a nucleophile is 1:1 to 1:2.

[0212] The reaction equivalent ratio of the Lewis acid and base reacted in the third microreactor 403 of the production system 4 and in the tube 107 downstream of the third microreactor 403 can be the same as that of the production system 3. The reaction equivalent ratio of the base is preferably 1 equivalent or more relative to 1 equivalent of the Lewis acid reacted in the first microreactor 106, and more preferably an excess amount exceeding 1 equivalent.

[0213] Fifth Embodiment Next, a system for producing a flavan oligomer and a method for producing a flavan oligomer according to a fifth embodiment of the present invention will be described with reference to the drawings.

[0214] FIG. 6 is a schematic diagram of a flavan oligomer production system according to the fifth embodiment. As shown in FIG. 6, the flavan oligomer production system 5 according to the fifth embodiment, like the production system 3, includes a raw material liquid container (first container) 101, a catalyst liquid container (second container) 102, a recovery container 103, a reaction stop liquid container (fourth container) 401, a first pump 104, a second pump 105, a third pump 302, a first microreactor 106, a second microreactor 303, a tube 107, a temperature control device 108, a temperature control device 109, and fittings (not shown) that connect the tube 107 to each component.

[0215] The manufacturing system 5 differs from the manufacturing system 3 in that it includes multiple stages of microreactors 106, 303 connected in series with each other, and multiple microreactors 106, 303 are connected in parallel in each stage.

[0216] In the manufacturing system 5, three microreactors are arranged in parallel as the first microreactor 106. Three microreactors are arranged in parallel as the second microreactor 303.

[0217] In the production system 5, a first branch header is connected to one inlet of each of the parallel-arranged first microreactors 106. Similar to the production system 3, a raw material liquid container 101 and a first pump 104 are connected to the first branch header via a tube 107. A second branch header is connected to the other inlet of each of the parallel-arranged first microreactors 106. Similar to the production system 3, a catalyst liquid container 102 and a second pump 105 are connected to the second branch header via a tube 107.

[0218] A first confluence header is connected to the outlet of each of the parallel-arranged first microreactors 106. A third branch header is connected to the first confluence header via a tube 107. The first product fluid produced in the first microreactor 106 and the subsequent tube 107 is confluenced at the first confluence header and sent to the third branch header.

[0219] A third branch header is connected to one inlet of each of the parallel arranged second microreactors 303. A fourth branch header is connected to the other inlet of each of the parallel arranged second microreactors 303. A reaction stop solution container 401 and a third pump 302 are connected to the fourth branch header via a tube 107.

[0220] A second confluence header is connected to the outlet of each of the parallel-arranged second microreactors 303. A collection container 103 is connected to the second confluence header via a tube 107. The collection container 103 is a container for collecting the second product fluid generated in the second microreactor 303 and the subsequent tube 107. The collection container 103 may or may not store a reaction stop solution containing a base to neutralize the Lewis acid contained in the second product fluid.

[0221] In the flavan oligomer production system 5, mixing of the raw material liquid and the catalyst liquid is started in each of the parallel-arranged first microreactors 106, and a first product fluid is produced. Then, mixing of the first product fluid and the reaction stop liquid is started in each of the parallel-arranged second microreactors 303, and a second product fluid is produced.

[0222] It is preferable to control the flow rates of the fluids introduced into the paralleled first microreactors 106 to be equal to each other. It is also preferable to control the flow rates of the fluids introduced into the paralleled second microreactors 303 to be equal to each other. With this control, it is possible to accurately and stably manage the reaction times between the paralleled microreactors.

[0223] It is preferable to control the timing of mixing in the paralleled first microreactors 106 so that they occur at the same time. It is also preferable to control the timing of mixing in the paralleled second microreactors 303 so that they occur at the same time. With this control, it is possible to properly align the reaction times of the paralleled microreactors.

[0224] According to the above-described flavan oligomer production system 5 and flavan oligomer production method, multiple microreactors 106, 303 are arranged in parallel at each stage, thereby enabling the use of a microreaction field for mixing fluids while increasing the overall fluid throughput. Because a large volume of fluids can be mixed overall, it is possible to synthesize a large amount of flavan derivative oligomers with a desired degree of polymerization in high yield, regardless of the concentrations of the raw material solutions, catalyst solutions, reaction stop solutions, etc.

[0225] Although the manufacturing system 5 described above includes three microreactors 106, 303 arranged in parallel, the number of microreactors arranged in parallel can be any number equal to or greater than two. By numbering up the microreactors by parallelizing them, it is possible to easily increase the overall production amount while maintaining the yield of oligomers with a predetermined degree of polymerization.

[0226] The number of parallel microreactors may be the same or different for each stage, and can be changed as appropriate depending on the type of microreactor, the target production amount of an oligomer with a predetermined polymerization degree, etc.

[0227] When the number of parallel microreactors in each stage is the same, the fluid produced in the microreactor in the previous stage can be sent to the microreactor in the next stage without joining or splitting. When the number of parallel microreactors in each stage is the same or different, the fluid produced in the microreactor in the previous stage can be sent to the microreactor in the next stage after being partially joined or split. The joining header or branching header used when joining or splitting may be a combination of multiple joining headers or multiple branching headers.

[0228] Furthermore, in the manufacturing system 5, the microreactors 106 and 303 of the manufacturing system 3 are arranged in parallel, but the microreactors 106 of the manufacturing system 1, the microreactors 106 and 303 of the manufacturing system 2, and the microreactors 106, 303 and 403 of the manufacturing system 4 may also be arranged in parallel.

[0229] Although the embodiments of the present invention have been described above, the present invention is not limited to the above-described embodiments, and various modifications are possible within the scope of the present invention. For example, the present invention is not necessarily limited to those having all of the configurations of the above-described embodiments. It is possible to replace part of the configuration of an embodiment with another configuration, add part of the configuration of an embodiment to another form, or omit part of the configuration of an embodiment.

[0230] For example, the flavan oligomer production system may have a configuration in which four or more stages of microreactors are connected in series. Any of the configurations of the production systems 1 to 5 described above can be repeatedly connected in series for each type of flavan derivative to be polymerized. A k-th stage (k is an integer of 2 or more) microreactor that mixes a mixed fluid produced in a microreactor in a previous stage with a mixed fluid prepared in a container can be connected in series downstream of the first microreactor, and a collection container can be provided in the final stage. With this configuration, a dimer (m is an integer of 1 or more) in which flavan derivatives are bonded to each other at a desired degree of polymerization can be synthesized.

[0231] Furthermore, when the flavan oligomer production system is configured to perform stepwise synthesis reactions (see, for example, FIG. 3), flavan derivatives with different degrees of polymerization may be prepared in respective raw material solution containers and polymerized. For example, a combination of a fully activated flavan derivative monomer and a non-activated flavan derivative dimer, or a combination of a fully activated flavan derivative dimer and a non-activated flavan derivative monomer, may be reacted. This configuration allows synthesis of a 2m+1 mer (m is an integer of 1 or greater) in which flavan derivatives are bonded to each other at a desired degree of polymerization.

[0232] The flavan oligomer production system may also include a fluid detection sensor that detects the arrival of fluids at the microreactor. The use of a fluid detection sensor makes it possible to detect the arrival of fluids at the microreactor through the tube, thereby allowing the fluids to be introduced simultaneously into the confluence of the microreactor. By performing such control, the prepared fluids can be mixed without excess or deficiency, allowing the entire amount of the prepared fluids to react at a predetermined reaction equivalence ratio. This also makes it possible to avoid discarding the reaction mixture that did not react at the desired reaction equivalence ratio. [Example]

[0233] The present invention will be specifically explained below by showing examples, but the technical scope of the present invention is not limited to these examples.

[0234] An oligomer of a flavan derivative was produced using the above-mentioned production system 3 (see FIG. 4). For comparison, an oligomer of a flavan derivative was also produced by a batch method.

[0235] Example 1 Example 1 was carried out using a microreactor in the configuration of manufacturing system 3 (see FIG. 4). As the first microreactor 106, a microreactor 200 (see FIG. 2) capable of mixing fluids at different flow rates was used. The microreactor 200 was made of quartz glass (manufactured by Hitachi Plant Services Co., Ltd.). The channel width and channel depth of the mixing channel 205 of the microreactor 200 were 0.2 mm.

[0236] As the second microreactor 303, a PEEK T-shaped reactor YMC-P-0021 (manufactured by YMC Corporation) was used.

[0237] As the first pump 104, the second pump 105 and the third pump 302, a syringe pump Model 11 Single Syringe Pump 55-1199 (manufactured by Harvard Apparatus) and a syringe Model 11 Single Syringe 70-2208 (manufactured by Harvard Apparatus) were used.

[0238] A PTFE tube (manufactured by GL Science) with an outer diameter of 1 / 16 inch and an inner diameter of 0.5 mm was used as the tube 107. The length of the tube 107 from the first microreactor 106 to the second microreactor 303 was 0.3 m or 0.9 m. The length of the tube 107 from the second microreactor 303 to the collection container 103 was 0.2 m.

[0239] The temperature control device 108 was adjusted to −70° C. using a mixed bath containing dry ice and a water / methanol mixed solvent, and the temperature control device 109 was adjusted to 0° C. using an ice bath.

[0240] As the monomer of the flavan derivative, which is the starting material, a compound represented by the following general formula (5) was used. * indicates a deuterium-labeled benzyl group.

[0241] [ka]

[0242] Trimethylsilyl trifluoromethanesulfonate (TMSOTf) was used as the Lewis acid, triethylamine (EtN) was used as the base, and dichloromethane was used as the solvent.

[0243] A raw material solution containing 0.05 M of a flavan derivative monomer was prepared in raw material solution container 101. A catalyst solution containing 0.05 M of a Lewis acid was prepared in catalyst solution container 102. A reaction stop solution containing 0.3 M of a base was prepared in reaction stop solution container 401.

[0244] A raw material solution containing a flavan derivative monomer and a catalyst solution containing a Lewis acid were mixed in a first microreactor 106, and then a first product fluid in which the flavan derivatives had reacted with each other and a reaction stop solution containing a base were mixed in a second microreactor 303. In the first microreactor 106, the raw material solution containing the flavan derivative monomer was introduced through a high-flow fluid inlet 207, and the catalyst solution containing a Lewis acid was introduced through a low-flow fluid inlet 208. The flow rate of the raw material solution was 1 mL / min. The flow rate of the catalyst solution was 1 mL / min. The flow rate of the reaction stop solution was 1 mL / min. Therefore, the equivalent ratio of the flavan derivative monomer to the Lewis acid was 1:1, and the equivalent ratio of the introduced Lewis acid to the base was 1:6.

[0245] The reaction time of the flavan derivatives was adjusted by the length of the tube 107. When the length of the tube 107 from the first microreactor 106 to the second microreactor 303 was 0.3 m, the reaction time corresponded to 1.77 seconds. When the length of the tube 107 from the first microreactor 106 to the second microreactor 303 was 0.9 m, the reaction time corresponded to 5.30 seconds.

[0246] In order to completely stop the reaction, a reaction stopping solution prepared by dissolving 1 mL of triethylamine (Et3N) in 2 mL of dichloromethane was placed in the collection container 103.

[0247] <Comparative Example 1> Comparative Example 1 was carried out by a batch method. A flavan derivative monomer was placed in a 5 mL two-neck flask. The flask was depressurized, purged with argon gas, and then sealed with a septum cap. A syringe was inserted through the septum to add dichloromethane to the flask, preparing 0.4 mL of a raw material solution containing 0.05 M of the flavan derivative monomer. The two-neck flask was immersed in a mixing bath containing dry ice and a water / methanol mixed solvent at -70°C.

[0248] Then, while stirring at 400-500 rpm, 0.4 mL of a catalyst solution containing 0.05 M Lewis acid was added by running it down the inner wall of the syringe. The reaction time was set to 5 s or 5 min. After the specified reaction time had elapsed, 0.3 mL of a reaction stop solution containing a base was added to stop the reaction.

[0249] The compound represented by the general formula (5) was used as the monomer of the flavan derivative, which was the starting material. Trimethylsilyl trifluoromethanesulfonate (TMSOTf) was used as the Lewis acid. Triethylamine (EtN) was used as the base. Dichloromethane was used as the solvent. The equivalent ratio of the flavan derivative monomer to the Lewis acid was 1:1.

[0250] <Experimental Results> In Example 1 and Comparative Example 1, after the reaction of the flavan derivative monomer, a mixture containing an oligomer of the flavan derivative was obtained. The mixture contained a dimer of the flavan derivative, a higher oligomer of the trimer or higher, and unreacted monomer. The dimer of the flavan derivative is represented by the following general formula (6). In general formula (6), Bn * indicates a deuterium-labeled benzyl group.

[0251] [ka]

[0252] Table 1 shows the reaction time of the synthesis reaction, the yield of the dimer of the flavan derivative, the yield of the trimer of the flavan derivative, the weight yield of the tetramer or higher oligomers of the flavan derivative, and the proportion of unreacted monomer of the flavan derivative. The yield is the percentage of the actual yield, with the maximum yield (theoretical yield) produced from the starting material taken as 100%.

[0253] [Table 1]

[0254] As shown in Table 1, when a microreactor was used, at a reaction time of 1.77 s, the dimer yield was 43%, no trimer was produced, the weight yield of tetramer or higher oligomers was 10 wt%, and the proportion of unreacted monomer was 30%. At a reaction time of 5.30 s, the dimer yield increased to 62%, no trimer was produced, the weight yield of tetramer or higher oligomers decreased to 5 wt%, and the proportion of unreacted monomer decreased to 19%. At both reaction times, the formation of trimer or higher oligomers was suppressed.

[0255] On the other hand, when the batch method was used, the dimer yield was 56%, no trimer was produced, the weight yield of tetramer or higher oligomers was 4 wt%, and the proportion of unreacted monomer was 5% at a reaction time of 5 s. At a reaction time of 5 min, the dimer yield was 20%, the trimer yield was 10%, and the weight yield of tetramer or higher oligomers was 29 wt%. As the reaction time progressed, trimer and higher oligomers of tetramer or higher were rapidly produced, making it difficult to control the degree of polymerization.

[0256] When using the batch method, if the reaction vessel is small, it may be possible to precisely control the reaction time. However, in order to increase the production amount, the reaction vessel must be made larger. If the reaction vessel is large, it becomes difficult to achieve uniform mixing and control the reaction time, resulting in variations in the polymerization reaction. If the reaction time is short, the reaction will not proceed, and if the reaction time is long, the yield of dimer (oligomer with a specified degree of polymerization) will decrease. Therefore, if the reaction vessel is made larger and the production amount is increased, the yield of dimer (oligomer with a specified degree of polymerization) per the same reaction time will decrease.

[0257] In contrast, when a microreactor is used, precise control of the reaction time is possible, which can improve the yield of dimers (oligomers with a predetermined degree of polymerization).When a microreactor is used, it is easy to increase the number of reactions by parallelization, which can increase the production amount while maintaining the yield. [Explanation of symbols]

[0258] 1,2,3,4,5 Flavan oligomer production system 101 Raw material liquid container (first container) 102 Catalyst liquid container (second container) 103 Collection container 104 First Pump 105 Second Pump 106 (1st) Microreactor 107 tubes 108 Temperature control device 109 Temperature control device 200 Microreactors 201 Upper plate 202 Lower Plate 203 High flow rate side channel (micro channel) 204 Low flow rate side channel (micro channel) 205 Mixing channel (microchannel) 206 Confluence 207 High flow rate side fluid inlet (through hole) 208 Low flow rate side fluid inlet (through hole) 209 Fluid outlet (through hole) 301 Raw material liquid container (third container) 302 Third Pump 303 (2nd) Microreactor 401 Reaction stop solution container (4th container) 402 4th Pump 403 (3rd) Microreactor

Claims

1. A system for producing a flavan oligomer in which flavan derivatives having a flavan skeleton are bonded to each other, comprising: The manufacturing system includes: at least one microreactor having two inlets through which fluids are introduced and a flow path through which the fluids join, wherein a first fluid introduced from one of the inlets and a second fluid introduced from the other of the inlets are mixed in the flow path; a first container in which the first fluid is prepared; a second container in which the second fluid is provided; a collection vessel for collecting a product fluid produced in the microreactor; and the first fluid is a liquid containing a flavan derivative having a flavan skeleton, the second fluid is a liquid containing a Lewis acid, the product fluid contains oligomers in which the flavan derivatives are bonded to each other, and is collected in the collection vessel in a liquid containing a base; the flavan derivative has a leaving group that can be activated by the Lewis acid, is a monomer having one flavan skeleton, or an oligomer having two or more flavan skeletons, and has a degree of polymerization of 17 or less; The oligomer in which the flavan derivatives are bonded to each other is an oligomer in which the flavan derivatives are bonded to each other in a 1:1 ratio. A system for producing flavan oligomers, characterized by:

2. A system for producing a flavan oligomer in which flavan derivatives having a flavan skeleton are bonded to each other, comprising: The manufacturing system includes: at least one or more first microreactors each having two inlets through which fluids are introduced and a flow path through which the fluids join together, wherein a first fluid introduced from one of the inlets and a second fluid introduced from the other of the inlets are mixed in the flow path; at least one or more second microreactors each having two inlets through which fluids are introduced and a flow path through which the fluids join together, and which mix a first product fluid produced in the first microreactor and introduced through one of the inlets with a third fluid introduced through the other inlet in the flow path; a first container in which the first fluid is prepared; a second container in which the second fluid is provided; a third container in which the third fluid is provided; a collection vessel for collecting the second product fluid produced in the second microreactor; and the first fluid is a liquid containing a flavan derivative having a flavan skeleton, the second fluid is a liquid containing a Lewis acid, the third fluid is a liquid containing a flavan derivative having a flavan skeleton, the second product fluid contains oligomers in which the flavan derivatives are bonded to each other, and is collected in the collection vessel in a liquid containing a base; the flavan derivative has a leaving group that can be activated by the Lewis acid, is a monomer having one flavan skeleton, or an oligomer having two or more flavan skeletons, and has a degree of polymerization of 17 or less; The oligomer in which the flavan derivatives are bonded to each other is an oligomer in which the flavan derivatives are bonded to each other in a 1:1 ratio. A system for producing flavan oligomers, characterized by:

3. A system for producing a flavan oligomer in which flavan derivatives having a flavan skeleton are bonded to each other, comprising: The manufacturing system includes: at least one or more first microreactors each having two inlets through which fluids are introduced and a flow path through which the fluids join together, wherein a first fluid introduced from one of the inlets and a second fluid introduced from the other of the inlets are mixed in the flow path; at least one or more second microreactors each having two inlets through which fluids are introduced and a flow path through which the fluids join together, and which mix a first product fluid produced in the first microreactor and introduced through one of the inlets with a third fluid introduced through the other inlet in the flow path; a first container in which the first fluid is prepared; a second container in which the second fluid is provided; a third container in which the third fluid is provided; a collection vessel for collecting the second product fluid produced in the second microreactor; and the first fluid is a liquid containing a flavan derivative having a flavan skeleton, the second fluid is a liquid containing a Lewis acid, the third fluid is a liquid containing a base, the second product fluid contains oligomers in which the flavan derivatives are bonded to each other, and is collected in the collection container; the flavan derivative has a leaving group that can be activated by the Lewis acid, is a monomer having one flavan skeleton, or an oligomer having two or more flavan skeletons, and has a degree of polymerization of 17 or less; The oligomer in which the flavan derivatives are bonded to each other is an oligomer in which the flavan derivatives are bonded to each other in a 1:1 ratio. A system for producing flavan oligomers, characterized by:

4. A system for producing a flavan oligomer in which flavan derivatives having a flavan skeleton are bonded to each other, comprising: The manufacturing system includes: at least one or more first microreactors each having two inlets through which fluids are introduced and a flow path through which the fluids join together, wherein a first fluid introduced from one of the inlets and a second fluid introduced from the other of the inlets are mixed in the flow path; at least one or more second microreactors each having two inlets through which fluids are introduced and a flow path through which the fluids join together, and which mix a first product fluid produced in the first microreactor and introduced through one of the inlets with a third fluid introduced through the other inlet in the flow path; at least one or more third microreactors each having two inlets through which fluids are introduced and a flow path through which the fluids are joined, and which mix a second product fluid produced in the second microreactor and introduced from one of the inlets with a fourth fluid introduced from the other inlet in the flow path; a first container in which the first fluid is prepared; a second container in which the second fluid is provided; a third container in which the third fluid is provided; a fourth container in which the fourth fluid is provided; a collection vessel for collecting a third product fluid produced in the third microreactor; and the first fluid is a liquid containing a flavan derivative having a flavan skeleton, the second fluid is a liquid containing a Lewis acid, the third fluid is a liquid containing a flavan derivative having a flavan skeleton, the fourth fluid is a liquid containing a base, the third product fluid contains oligomers in which the flavan derivatives are bonded to each other, and is collected in the collection container; the flavan derivative has a leaving group that can be activated by the Lewis acid, is a monomer having one flavan skeleton, or an oligomer having two or more flavan skeletons, and has a degree of polymerization of 17 or less; The oligomer in which the flavan derivatives are bonded to each other is an oligomer in which the flavan derivatives are bonded to each other in a 1:1 ratio. A system for producing flavan oligomers, characterized by:

5. A system for producing a flavan oligomer according to any one of claims 1 to 4, The flavan derivative is represented by the following general formula (1): 【Chemical 1】 [In general formula (1), R １ ~R ５ are each independently a hydrogen atom, a hydroxy group, an alkoxy group, or OR ９ R represents a substituent represented by the formula: ６ represents a hydrogen atom, a hydrocarbon group which may have a substituent, an alkoxyalkyl group, an acyl group, a silyl group, or a galloyl group. ７ ~R ８ are each independently a hydrogen atom or R ９ R represents a substituent represented by the formula: ９ represents a hydrocarbon group, an alkoxyalkyl group, an acyl group, or a silyl group which may have a substituent. X represents a hydrocarbon group, a halogen atom, or a substituent in which one or more heteroatoms selected from the group consisting of N, O, and S are bonded to a ring-forming atom of ring C. The wavy line represents a single bond forming an R-configuration or an S-configuration.], or a compound represented by the following general formula (2); 【Chemistry 2】 [In general formula (2), R １ ~R ５ , R １１ ~R １５ and R ２１ ~R ２５ are each independently a hydrogen atom, a hydroxy group, an alkoxy group, or OR ９ R represents a substituent represented by the formula: ６ , R １６ and R ２６ represents a hydrogen atom, a hydrocarbon group which may have a substituent, an alkoxyalkyl group, an acyl group, a silyl group, or a galloyl group. ７ ~R ８ , R １７ ~R １８ and R ２７ ~R ２８ are each independently a hydrogen atom or R ９ R represents a substituent represented by the formula: ９ represents a hydrocarbon group, an alkoxyalkyl group, an acyl group, or a silyl group which may have a substituent. X represents a hydrocarbon group, a halogen atom, or a substituent in which one or more heteroatoms selected from the group consisting of N, O, and S are bonded to a ring-forming atom of the C ring. The wavy line represents a single bond forming an R-configuration or an S-configuration. n represents an integer of 0 or more and 15 or less. A system for producing flavan oligomers, characterized by:

6. A method for producing a flavan oligomer in which flavan derivatives having a flavan skeleton are bonded to each other, comprising the steps of: at least one microreactor having two inlets through which fluids are introduced and a flow path through which the fluids join, wherein a first fluid introduced from one of the inlets and a second fluid introduced from the other of the inlets are mixed in the flow path; a first container in which the first fluid is prepared; a second container in which the second fluid is provided; a collection vessel for collecting a product fluid produced in the microreactor; In a microreactor system having As the first fluid, a liquid containing a flavan derivative having a flavan skeleton is prepared; As the second fluid, a liquid containing a Lewis acid is prepared; mixing the first fluid and the second fluid in the microreactor to activate a portion of the flavan derivative in the first fluid with the Lewis acid in the second fluid, and initiating a reaction between the activated portion of the flavan derivative in the first fluid and the remaining portion of the flavan derivative in the first fluid, which acts as a nucleophile; The product fluid during the reaction is recovered in a liquid containing a base, and the reaction of the product fluid is terminated with the base to produce oligomers in which the flavan derivatives are bonded to each other; the flavan derivative has a leaving group that can be activated by the Lewis acid, is a monomer having one flavan skeleton, or an oligomer having two or more flavan skeletons, and has a degree of polymerization of 17 or less; The oligomer in which the flavan derivatives are bonded to each other is an oligomer in which the flavan derivatives are bonded to each other in a 1:1 ratio. A method for producing a flavan oligomer, characterized by:

7. A method for producing a flavan oligomer in which flavan derivatives having a flavan skeleton are bonded to each other, comprising the steps of: at least one or more first microreactors each having two inlets through which fluids are introduced and a flow path through which the fluids join together, wherein a first fluid introduced from one of the inlets and a second fluid introduced from the other of the inlets are mixed in the flow path; at least one or more second microreactors each having two inlets through which fluids are introduced and a flow path through which the fluids join together, and which mix a first product fluid produced in the first microreactor and introduced through one of the inlets with a third fluid introduced through the other inlet in the flow path; a first container in which the first fluid is prepared; a second container in which the second fluid is provided; a third container in which the third fluid is provided; a collection vessel for collecting the second product fluid produced in the second microreactor; In a microreactor system having As the first fluid, a liquid containing a flavan derivative having a flavan skeleton is prepared; As the second fluid, a liquid containing a Lewis acid is prepared; As the third fluid, a liquid containing a flavan derivative having a flavan skeleton is prepared; mixing the first fluid and the second fluid in the first microreactor to activate the flavan derivative in the first fluid with the Lewis acid in the second fluid; mixing the first product fluid and the third fluid in the second microreactor to initiate a reaction between the activated flavan derivative of the first product fluid and the flavan derivative of the third fluid acting as a nucleophile; The second product fluid undergoing the reaction is recovered in a liquid containing a base, and the reaction of the second product fluid is terminated with the base to produce oligomers in which the flavan derivatives are bonded to each other; the flavan derivative has a leaving group that can be activated by the Lewis acid, is a monomer having one flavan skeleton, or an oligomer having two or more flavan skeletons, and has a degree of polymerization of 17 or less; The oligomer in which the flavan derivatives are bonded to each other is an oligomer in which the flavan derivatives are bonded to each other in a 1:1 ratio. A method for producing a flavan oligomer, characterized by:

8. A method for producing a flavan oligomer in which flavan derivatives having a flavan skeleton are bonded to each other, comprising the steps of: at least one or more first microreactors each having two inlets through which fluids are introduced and a flow path through which the fluids join together, wherein a first fluid introduced from one of the inlets and a second fluid introduced from the other of the inlets are mixed in the flow path; at least one or more second microreactors each having two inlets through which fluids are introduced and a flow path through which the fluids join together, and which mix a first product fluid produced in the first microreactor and introduced through one of the inlets with a third fluid introduced through the other inlet in the flow path; a first container in which the first fluid is prepared; a second container in which the second fluid is provided; a third container in which the third fluid is provided; a collection vessel for collecting the second product fluid produced in the second microreactor; In a microreactor system having As the first fluid, a liquid containing a flavan derivative having a flavan skeleton is prepared; As the second fluid, a liquid containing a Lewis acid is prepared; preparing a liquid containing a base as the third fluid; mixing the first fluid and the second fluid in the first microreactor to activate a portion of the flavan derivative in the first fluid with the Lewis acid in the second fluid, and initiating a reaction between the activated portion of the flavan derivative in the first fluid and the remaining portion of the flavan derivative in the first fluid, which acts as a nucleophile; mixing the first product fluid and the third fluid in the second microreactor, and terminating the reaction of the first product fluid with the base to generate oligomers in which the flavan derivatives are bonded to each other; the flavan derivative has a leaving group that can be activated by the Lewis acid, is a monomer having one flavan skeleton, or an oligomer having two or more flavan skeletons, and has a degree of polymerization of 17 or less; The oligomer in which the flavan derivatives are bonded to each other is an oligomer in which the flavan derivatives are bonded to each other in a 1:1 ratio. A method for producing a flavan oligomer, characterized by:

9. A method for producing a flavan oligomer in which flavan derivatives having a flavan skeleton are bonded to each other, comprising the steps of: at least one or more first microreactors each having two inlets through which fluids are introduced and a flow path through which the fluids join together, wherein a first fluid introduced from one of the inlets and a second fluid introduced from the other of the inlets are mixed in the flow path; at least one or more second microreactors each having two inlets through which fluids are introduced and a flow path through which the fluids join together, and which mix a first product fluid produced in the first microreactor and introduced through one of the inlets with a third fluid introduced through the other inlet in the flow path; at least one or more third microreactors each having two inlets through which fluids are introduced and a flow path through which the fluids are joined, and which mix a second product fluid produced in the second microreactor and introduced from one of the inlets with a fourth fluid introduced from the other inlet in the flow path; a first container in which the first fluid is prepared; a second container in which the second fluid is provided; a third container in which the third fluid is provided; a fourth container in which the fourth fluid is provided; a collection vessel for collecting a third product fluid produced in the third microreactor; In a microreactor system having As the first fluid, a liquid containing a flavan derivative having a flavan skeleton is prepared; As the second fluid, a liquid containing a Lewis acid is prepared; As the third fluid, a liquid containing a flavan derivative having a flavan skeleton is prepared; As the fourth fluid, a liquid containing a base is prepared; mixing the first fluid and the second fluid in the first microreactor to activate the flavan derivative in the first fluid with the Lewis acid in the second fluid; mixing the first product fluid and the third fluid in the second microreactor to initiate a reaction between the activated flavan derivative of the first product fluid and the flavan derivative of the third fluid acting as a nucleophile; mixing the second product fluid and the fourth fluid in the third microreactor, and terminating the reaction of the second product fluid with the base to generate oligomers in which the flavan derivatives are bonded to each other; the flavan derivative has a leaving group that can be activated by the Lewis acid, is a monomer having one flavan skeleton, or an oligomer having two or more flavan skeletons, and has a degree of polymerization of 17 or less; The oligomer in which the flavan derivatives are bonded to each other is an oligomer in which the flavan derivatives are bonded to each other in a 1:1 ratio. A method for producing a flavan oligomer, characterized by:

10. A method for producing the flavan oligomer according to any one of claims 6 to 9, comprising: The flavan derivative is represented by the following general formula (1): 【Chemistry 3】 [In general formula (1), R1 to R5 each independently represent a hydrogen atom, a hydroxy group, an alkoxy group, or a substituent represented by OR9. R6 represents a hydrogen atom, a hydrocarbon group which may have a substituent, an alkoxyalkyl group, an acyl group, a silyl group, or a galloyl group. R7 and R8 each independently represent a hydrogen atom or a substituent represented by R9. R9 represents a hydrocarbon group which may have a substituent, an alkoxyalkyl group, an acyl group, or a silyl group. X represents a hydrocarbon group which may have a substituent, a halogen atom, or a substituent in which one or more heteroatoms selected from the group consisting of N, O, and S are bonded to a ring-forming atom of ring C. The wavy line represents a single bond forming an R-configuration or an S-configuration.] or a compound represented by the following general formula (2); 【Chemistry 4】 [In general formula (2), R １ ~R ５ , R １１ ~R １５ and R ２１ ~R ２５ are each independently a hydrogen atom, a hydroxy group, an alkoxy group, or OR ９ R represents a substituent represented by the formula: ６ , R １６ and R ２６ represents a hydrogen atom, a hydrocarbon group which may have a substituent, an alkoxyalkyl group, an acyl group, a silyl group, or a galloyl group. ７ ~R ８ , R １７ ~R １８ and R ２７ ~R ２８ are each independently a hydrogen atom or R ９ R represents a substituent represented by the formula: ９ represents a hydrocarbon group, an alkoxyalkyl group, an acyl group, or a silyl group which may have a substituent. X represents a hydrocarbon group, a halogen atom, or a substituent in which one or more heteroatoms selected from the group consisting of N, O, and S are bonded to a ring-forming atom of the C ring. The wavy line represents a single bond forming an R-configuration or an S-configuration. n represents an integer of 0 or more and 15 or less. A method for producing a flavan oligomer, characterized by:

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