KR101465509B1 - Device for continuous reactions and method of using the same for separating amino acid enantiomers - Google Patents

Abstract

Disclosed herein are continuous reaction apparatus and methods capable of continuous separation of amino acid optical isomers. The continuous reaction apparatus of the present invention comprises two continuous reactors, one continuous reactor comprises upper and lower storage vessels, which are connected to the upper or lower reactor of the remaining continuous reactor through a reactor connection tube . When the continuous reaction apparatus of the present invention is used, it is possible to reduce process complexity and waste of time in separating the organic solution layer and the aqueous solution layer in a single reactor, and it is possible to reduce the efficiency of the optically pure amino acid production of the D- or L- .

Description

[0001] The present invention relates to a continuous reaction apparatus and a method for separating amino acid optical isomers using the same,

The present invention relates to a continuous reaction apparatus and a pure amino acid optical isomer separation method using the same, and more particularly, to a continuous reaction reactor for immune extraction reaction and a hydrolysis continuous reactor for extracting amino acids, and an optically pure D- or L- An apparatus for obtaining / separating amino acids, and a method using the same.

Amino acids are basic constituent units of proteins and include amino groups (NH ₂ ) and carboxyl groups (COOH), and their chemical properties are determined by their side chains. An amino acid is an essential substance that constitutes a cell. It is divided into a natural amino acid and a non-natural amino acid according to the artificial synthesis, and is divided into an essential amino acid and a non-essential amino acid depending on whether it is produced in vivo.

There are about 20 kinds of natural amino acids and about 700 kinds of unnatural amino acids. Most natural amino acids are L-form and have low industrial production costs. Most non-natural amino acids are D-type and relatively higher in production cost and industrial added value than L-type.

The separation of amino acids into L-form and D-form is called an optical isomer (enantiomer) or chiral property, and the molecular weight and molecular formula are the same. However, although L-glutamine has a rich taste, D-glutamine has an acidic taste and L-valine is used as a therapeutic agent for hypoallergic disease. However, D-valine has a characteristic of being used as pesticide and insecticide. Optically pure (D-type or L-type single) amino acids composed of only L-type or D-type are used as ligands for asymmetric catalysts or as starting materials or intermediates for synthesizing various drugs and biologically active substances (Helmchen, G .; Pfaltz, A. Acc. Chem. Res. 2000, 33, 336-345).

Amino acids produced by fermentation in a natural state or chemically synthesized are present as L-form or racemic mixtures. Amino acids obtained through fermentation are limited to L-amino acids among natural amino acids. Although optically pure D-amino acids and unnatural amino acids are produced by enzymatic and optical resolution methods, they are expensive to manufacture and have a unit price of 5-10 times higher than that of natural L-amino acids produced by fermentation. (Maruoka, K .; Ooi, T. Chem. Rev. 2003, 103, 3013.).

Until recently, techniques for converting L-form and D-form into L-form and D-form have been continuously developed, that is, chirotechnology (chiral technology) Have developed a method of recognizing the chirality of chiral amino alcohols and amino acids through imine coupling using a chiral selective acceptor, a binaphthol derivative having an aldehyde group, converting L-amino acid into D-amino acid and separating the chiral amino alcohol and amino acid Kim, KM; Lee, A .; Ham, S .; Nam, W .; Chin, JJ Am. Chem. Soc 2007, 129, 1518-1519; Park, H .; Kim, H .; Chin, J .; Nam, W. Org. Lett., 2005, 7, 3525-3527, Korean Registered Patent No. 10-0661280, Korean Patent Publication No. 10-2011-0111007 Korean Patent Publication No. 10-2010-0114483).

The binaphthol derivative having an aldehyde group developed by the present inventor is divided into S-type and R-type, S-type forms an imine bond selectively with D-type amino acid, R-type forms an L- (Kim, KM; Lee, A .; Ham, S .; Nam, W .; Chin, J. J. Am . Chem . Soc . 2007, 129 , 1518) . In this way, chiral compounds having an -OH group adjacent to an aldehyde group in an aromatic ring compound basically produce amino acids and chiral selective imines, and these compounds are collectively referred to as Alanine Racemase Chiral Analogue (ARCA). This is because these compounds are basically chiral derivatives of 5'-phosphate 5pyridoxal (PLP), which plays a key role in the enzymatic activity of Alanine racemase (AR). PLP has an aldehyde group and an adjacent -OH group in an aromatic ring compound, thereby stabilizing amino acid and imine bond, and increasing acidity of alpha hydrogen of amino acid to induce racemization of amino acid. These ARCA compounds form amino acids and imines well and are basically chiral selective for amino acids. The present inventors have made many kinds of ARCA and have filed patent applications so far (Korean Patent Laid-Open No. 10-2010-0106221, No. 10-2010-0114483, Korean Patent No. 1087498, No. 0870227 ).

These ARCA can be used in all organic solvents such as DMSO, CHCl ₃ , CH ₂ Cl ₂ and toluene in the presence of a base such as TEA (Triethanolamine) to convert the L-form of the imine to the D- - convert to a form. The chiral converted amino acid is recovered through hydrolysis by treatment with an acidic aqueous solution such as HCl, and the ARCA is regenerated and reused repeatedly. When an organic solvent such as DMSO mixed with water is used, it is mixed with an aqueous solution during the hydrolysis reaction, resulting in a great cost for regeneration of ARCA and recovery of amino acid. Therefore, it is preferable to use an organic solvent such as toluene, CH ₂ Cl ₂ or the like that does not mix with water to achieve chiral conversion of an amino acid. However, in this case, the chiral conversion reaction usually slows down (at room temperature for 12 hours or more) The HCl salt of TEA together with the amino acid moves to the aqueous solution layer during the hydrolysis, resulting in a cost burden for the purification of the amino acid. Accordingly, the present inventors have developed a process for reacting an organic solvent in which ARCA exists and an aqueous solution in which an amino acid is present, thereby allowing an amino acid in the aqueous solution layer to migrate and selectively migrate to an organic layer (Korean Patent Publication No. 2010-0106221). In this process, excess amino acid is maintained at pH 10-13 in the water layer, and phase transition catalyst such as ARCA and aliquat (Fluka) coexists in the organic layer. Under these conditions, common amino acids migrate to the organic layer in 1-3 hours at room temperature to produce immigrants. Under these conditions, chiral conversion of the imatinic amino acid does not normally occur in the organic layer. After this chiral selective immune extraction reaction, the organic layer is separated from the reactor and subjected to an extraction reaction with an acidic aqueous solution of another reaction vessel. Then, the imine is hydrolyzed and the chiral selected amino acid is transferred to the water layer, and the organic layer is returned to the initial state and can be used repeatedly in the immune extraction reaction. The initial aqueous solution of amino acid used in the immune extraction reaction was maintained in a racemic state using a racemic catalyst such as PLP or salicyl aldehyde, and the chiral selective immobilization extraction reaction and the hydrolysis extraction reaction Repeating both processes results in the conversion of all the first amino acids chiral selectively into L or D forms. Such a chiral selective immune formation extraction reaction, a hydrolysis extraction reaction and a racemization of amino acid based on chiral conversion of amino acid have already been filed by the present inventor (Korean Patent Publication No. 2010-0106221).

In the method disclosed in the above document, when an amino acid chiral conversion is carried out batchwise, it takes time to separate the aqueous solution layer and the organic solution layer from each other in the reactor and transfer the solution to another process, thereby causing a problem that the productivity is lowered.

In the present invention, based on the chiral selective immobilization extraction reaction, the hydrolysis extraction reaction, and the racemization of amino acid, the process for achieving the chiral conversion of the amino acid is carried out through a continuous process rather than a batch type, do.

DISCLOSURE OF THE INVENTION The present invention has been devised to solve the above-mentioned problems, and it is an object of the present invention to provide a device capable of continuously operating a plurality of reaction vessels connected to each other at different heights, The present inventors have succeeded in producing an optically active amino acid efficiently by performing a chiral conversion process of amino acid based on a chiral selective immobilization extraction reaction and a hydrolysis extraction reaction.

In order to solve the above problems, the present inventors divided the optically pure amino acid separation process into a chiral selective immune extraction and an amino acid hydrolysis extraction process based on a hydrolysis extraction reaction, The reaction efficiency can be maximized, and thus the present invention has been accomplished.

The present invention provides a continuous reactor, wherein the continuous reactor is composed of three reaction tanks, the upper, middle and lower reaction tanks being adjacent to each other at different heights, each of the reaction tanks being located between the upper reaction tank and the central reaction tank A first connection pipe and a second connection pipe positioned between the central reaction tank and the lower reaction tank, and each of the reaction tanks is provided with a stirrer, and the upper and lower reaction tanks are respectively provided with input ports , And the lower reaction tank is provided with a pressurizing device.

The present invention also contemplates a continuous reactor of the present invention further comprising an upper storage vessel and a lower storage vessel, wherein the upper storage vessel is connected to the upper reactor through a third connection tube, And is connected to the lower reaction tank.

The present invention also provides a method of extracting an immune from a continuous reactor according to the present invention, comprising continuously introducing an aqueous solution of a racemic amino acid into a bottom reaction tank of the continuous reactor; Continuously injecting a chiral selective receptor solution dissolved in an organic solvent having a specific gravity higher than that of water into the upper reaction tank constituting the continuous reactor; Mixing the aqueous solution of the racemic amino acid and the chiral selective receptor solution in a central reaction tank to form an imine between the amino acid and the chiral selective receptor; The organic solvent containing imine formed in the central reaction tank flows into the lower reaction tank through the second connection pipe, the aqueous amino acid solution flows into the upper reaction tank through the first connection pipe, and the imine formation reaction This happens; And separating the organic solvent containing the imine separately from the lower reaction tank.

The present invention also provides a method of immune extraction using a continuous reactor according to the present invention, comprising continuously introducing an aqueous solution of a racemic amino acid into the upper reactor of the continuous reactor; Continuously injecting a chiral selective receptor solution dissolved in an organic solvent having a specific gravity smaller than that of water into the lower reaction tank constituting the continuous reactor; Mixing the aqueous solution of the racemic amino acid and the chiral selective receptor solution in a central reaction tank to form an imine between the amino acid and the chiral selective receptor; The organic solvent containing imine formed in the central reaction tank flows into the upper reaction tank through the first connection pipe, the aqueous amino acid solution flows into the lower reaction tank through the second connection pipe, and the imine formation reaction This happens; And separately separating the organic solvent containing the imine in the upper reaction tank.

The present invention also provides an optically pure amino acid hydrolysis extraction method using a continuous reactor according to the present invention, the method comprising continuously introducing an acid solution into a bottom reaction tank of the continuous reactor; Continuously injecting into the upper reactor of the continuous reactor a solution containing an imine formed between a chiral selective acceptor and a D- or L-type amino acid dissolved in an organic solvent having a specific gravity greater than that of water; A step of hydrolyzing the acid solution and the organic solvent solution containing the immigration in a central reaction tank and separating the imine into an amino acid and a chiral selective receptor through hydrolysis, the separated amino acid is moved to an acidic aqueous solution layer , The chiral selective receptor is left in the organic solvent, the organic solvent containing the chiral selective receptor is introduced into the lower reaction tank through the second connection pipe, and the acidic aqueous solution containing the separated amino acid passes through the first connection pipe Introducing into the upper reaction tank and performing an imine hydrolysis reaction in the upper and lower reaction vessels, respectively; And separately separating the solution containing the optically pure amino acid contained in the aqueous solution layer in the upper reaction tank.

The present invention also provides an optically pure amino acid hydrolysis extraction method using a continuous reactor according to the present invention, the method comprising continuously introducing an acid solution into the upper reactor of the continuous reactor; Continuously injecting a solution containing an imine formed between a chiral selective acceptor and a D-type or L-type amino acid dissolved in an organic solvent having a specific gravity smaller than that of water in the bottom reaction tank of the continuous reactor; A step of hydrolyzing the acid solution and the organic solvent solution containing the immigration in a central reaction tank and separating the imine into an amino acid and a chiral selective receptor through hydrolysis, the separated amino acid is moved to an acidic aqueous solution layer , The chiral selective receptor is left in an organic solvent, the organic solvent including the chiral selective receptor is introduced into the upper reaction tank through the first connection pipe, and the acidic aqueous solution containing the separated amino acid is passed through the second connection pipe Introducing into the lower reaction tank, and performing an imine hydrolysis reaction in the upper and lower reaction vessels, respectively; And separating the solution containing the optically pure amino acid contained in the aqueous solution layer separately in the lower reaction tank.

The present invention also provides a continuous reaction apparatus comprising two first and second continuous reactors according to the present invention, wherein one of the two continuous reactors comprises an upper and a lower storage vessel, Provides a continuous reaction device connected to the upper or lower reactor of the remaining two of the reactors through a reactor connector.

The present invention also provides a method for separating pure amino acid optical isomers using a continuous reaction apparatus according to the present invention, the method comprising an immersion formation extraction process performed in one of two continuous reactors constituting the continuous reaction apparatus, Wherein the amino acid hydrolysis extraction process comprises the steps of any one of claims 3 or 4, wherein the amino acid hydrolysis extraction process comprises the steps of: Wherein the organic solvent containing the imine produced in the immersion extraction process is a mixture of the first continuous reactor and the second continuous reactor constituting the continuous reaction apparatus, The upper or lower half of the reactor in which the amino acid hydrolysis and extraction reaction is carried out And a step that flows twos.

The present invention can reduce the complexity of the process and waste of time in separating the organic solution layer and the aqueous solution layer in a single reactor and can increase the efficiency of production of optically pure D or L single amino acid using a chiral selective receptor Of course, the cost can be reduced by simplifying the process.

1A and 1B are schematic diagrams of a continuous reactor according to one embodiment of the present invention.
2 is a schematic diagram of a continuous reaction apparatus in which two continuous reactors are connected according to an embodiment of the present invention.

Generally, when a specific material moves between two solution layers that do not mix with each other and the solution is equilibrated in a short period of time, the solution is automatically separated by a countercurrent column method (Thomas A. Verachtert, Wheeling, III. US Patent No. 4491565, Jan. 1, 1985), a mixer-settler method (Giralico, Michael A .; Preston, Michael Joseph, US Patent 7550120, Jul 27, 2006), continuous separation by centrifugal force , David B. US Patent 4284232, Aug. 18, 1981). It is difficult to apply this method to processes for chiral conversion of amino acids based on chiral selective immobilization extraction reaction by ARCA, hydrolysis extraction reaction and racemization of amino acid. The reason for this is that the extraction reaction to form an imine using ARCA and the extraction reaction to hydrolyze the immigrant require about 1-3 hours. For example, when applying the countercurrent column method to an extraction reaction that takes more than one hour, the length of the column must be very long. Applying a general mixer-settler method or centrifugation method, the solution is separated without sufficient reaction in a mixer or a centrifuge.

In order to solve these problems, the present invention achieves a continuous process by connecting multiple reaction vessels to achieve automatic separation of two solutions that do not mix well while assuring sufficient reaction time.

The term chiral selective acceptor used herein refers to chiral compounds having an -OH group adjacent to an aldehyde group in an aromatic ring compound and is referred to as Alanine Racemase Chiral Analogue (ARCA). These compounds are basically chiral derivatives of 5'-phosphate 5pyridoxal (PLP), which plays a key role in the activity of enzymes called alanine racemase (AR). PLP has an aldehyde group and an adjacent -OH group in an aromatic ring compound, thereby stabilizing amino acid and imine bond, and increasing acidity of alpha hydrogen of amino acid to induce racemization of amino acid. They form amino acids and imines well and are basically chiral selective for amino acids. ARCA that may be used herein include, but are not limited to, those described in the following references: Park, H .; Nandhakumar, R .; Hong, J .; Ham, S .; Chin, J .; Kim, KM Chem. Eur. J. 2008, 14, 9935; Tang, L .; Choi, S .; Nandhakumar, R .; Park, H .; Chung, H .; Chin J .; Kim, KM J. Org. Chem . 2008, 73 , 5996; Nandhakumar, R .; Ryu, J .; Park, H .; Tang, L .; Choi, S .; Kim, KM Tetrahedron 2008, 64 , 7704; Tang, L .; Ga, H .; Kim, J .; Choi, S .; Nandhakumar, R., Kim, KM Tetrahedron Lett. 2008, 49 , 6914; Park, H .; Hong, J .; Ham, S .; Nandhakumar, R .; Kim, KM Bull. Kor. Chem. Soc. 2009, 30 , 409; Nandhakumar, R .; Ahn, YS; Hong, S .; Ham, S .; Kim, KM Tetrahedron 2009, 65 , 666; And Korean Patent Laid-Open Publication No. 10-2010-0106221; 10-2010-0114483; Korean Patent Registration No. 1087498; And 0870227.

Hereinafter, a continuous reaction apparatus according to an embodiment of the present invention will be described with reference to the accompanying drawings. Prior to the detailed description of the present invention, terms and words used in the present specification and claims should not be construed as limited to ordinary or dictionary terms. Therefore, the embodiments described in this specification and the configurations shown in the drawings are merely the most preferred embodiments of the present invention and do not represent all the technical ideas of the present invention. Therefore, It is to be understood that equivalents and modifications are possible.

In one aspect, the disclosure is directed to a continuous reactor. The continuous reactor of the present invention is composed of three reaction tanks which are located adjacent to each other at different heights, and each of the reaction tanks includes a first connection pipe located between the upper reaction tank and the central reaction tank, A reaction vessel and a second reaction vessel located between the lower reaction vessel, and each of the reaction vessels is provided with an agitator, each of the upper and lower reaction vessels is provided with an inlet, and the lower reaction vessel is provided with a pressurizing device Respectively.

The continuous reactor of the present invention can be used to carry out an amino acid hydrolysis extraction process based on a chiral selective immersion extraction process and a hydrolysis extraction reaction of an imine.

1 is a schematic diagram of a continuous reactor according to one embodiment of the present application. When the continuous reactor of the present invention is used for chiral selective immersion extraction or amino acid hydrolysis extraction process, each constitution will be described as follows. The continuous reactor comprises three reaction vessels (10, 12 and 14, respectively) consisting of a lower, a middle, and an upper along the height. In the three reaction vessels, the lower reaction vessel 10 and the central reaction vessel 12 are connected to each other via a lower connection pipe or a second connection pipe 11. The central reaction tank 12 and the upper reaction tank 14 are connected to each other via an upper connection pipe or a first connection pipe 13. The position of the upper connection pipe 13 connected to the upper reaction tank 14 in the central reaction tank 12 is higher than the position of the lower connection pipe 11 connected to the lower reaction tank 10 in the central reaction tank 12.

The three reaction vessels 10, 12 and 14 are connected in a stepped manner with different heights, for example. That is, one opening of the lower connection pipe 11 connected to the central reaction tank 12 is connected to the lower reaction tank 10 by the lower connection pipe 11 between the lower reaction tank 10 and the central reaction tank 12 And is positioned higher than the other opening of the connected lower connecting pipe 11 in a horizontal plane. The opening of the upper connection pipe 13 connected to the upper reaction tank 14 is connected to the central reaction tank 12 through the upper connection pipe 13 between the central reaction tank 12 and the upper reaction tank 14, Is positioned higher than the other opening of the connected upper connection pipe (13). On the other hand, the upper reaction tank 14 is the highest and the lower reaction tank 10 is the lowest. An agitator, for example a stirrer 24, is provided at the bottom of the lower reaction tank 10, the central reaction tank 12 and the upper reaction tank 14, respectively. The upper and lower reaction tanks of the present invention are provided with inlet ports 14a and 10a, respectively.

The continuous reactor may further include an upper storage vessel 18 and a lower storage vessel 16. The upper storage vessel 18 is connected to the upper reactor through a third connection pipe and the lower storage vessel 16 is connected to the lower reactor through a fourth connection pipe 17. That is, the lower storage container 16 is connected to one side of the lower reaction tank 10 through the lower storage container connection pipe, that is, the fourth connection pipe 17. The position of the lower connection pipe 11 connected to the central reaction tank 12 from the lower reaction tank 10 is lower than the position of the lower storage container connection pipe 17 connected to the lower storage tank 16 from the lower reaction tank 10, Placed high in plane.

The water layer included in the lower reaction tank 10 can be circulated through the connection pipe 94 connecting the upper storage vessel 18 and the lower reaction vessel 10.

The upper storage vessel 18 is connected to one side of the upper reaction vessel 14 through an upper storage vessel connection pipe or a third connection pipe 15. The position of the upper storage container connecting pipe 15 connected to the upper storage container 18 from the upper reaction tank 14 is lower than the position of the upper connection pipe 13 connected to the middle storage container 12 from the upper reaction tank 14 It is positioned high on the horizontal plane. The upper and lower storage vessels each have valves (22, 24). The lower reaction tank is provided with a pressurizing device so that the aqueous solution of the racemic amino acid introduced into the lower reaction tank 10 can be injected at a constant flow rate against gravity. As a pressurizing device, a general controlled volume pump may be used. The reaction rate can be determined by the feed flow rate through the pressurizer. The chiral selective receptor solution to be injected into the upper reaction tank 14 is supplied with a constant flow rate but does not need to use a separate pressurizing device since gravity is applied.

FIG. 2 is a schematic diagram of an amino acid hydrolysis extraction reactor, which has a configuration corresponding to that described above for the immune extraction reactor, but the configuration used in the amino acid hydrolysis extraction reactor will be separately described and again described. The amino acid hydrolysis extraction reactor comprises at least three hydrolysis extraction chambers (30, 32, 34). One embodiment of the present invention includes a reaction tank for D-type amino acid hydrolysis extraction. In the three amino acid hydrolysis extraction reaction tanks, the lower reaction tank 30 and the central reaction tank 32 are connected to each other through the lower connection pipe 31. The central reaction tank 32 and the upper reaction tank 34 are connected to each other via an upper connection pipe 33. The position of the upper connection pipe 33 connected to the upper reaction tank 34 in the central reaction tank 32 is higher than the position of the lower connection pipe 31 connected to the lower reaction tank 30 in the central reaction tank 32.

The three optically pure (D- or L-type single) amino acid hydrolysis extraction reactors (30, 32, 34) are cascaded. In other words, one opening of the lower connection pipe 31 connected to the central reaction tank 32 is connected to the lower reaction tank 30 by the lower connection pipe 31 between the lower reaction tank 30 and the central reaction tank 32, And is positioned higher than the other opening of the connected lower connecting pipe 31 on a horizontal plane. The opening of one side of the upper connection pipe 33 connected to the upper reaction tank 34 is connected to the central reaction tank 32 by the upper connection pipe 33 between the central reaction tank 32 and the upper reaction tank 34, And is positioned higher than the other opening of the connected upper connection pipe 33 on a horizontal plane. On the other hand, the upper reaction tank 34 is the highest and the lower reaction tank 30 is the lowest. A stirrer, for example a stirrer 44, is installed at the bottom of the lower reaction tank 30, the central reaction tank 32 and the upper reaction tank 34, respectively.

A lower storage container 36 is connected to one side of the lower reaction tank 30 through a lower storage container connection pipe 37. A lower storage container connection pipe 37 connected to the lower storage container 36 from the lower reaction tank 30 The position of the lower connection pipe 31 connected to the central reaction tank 32 in the lower reaction tank 30 is higher than the position of the lower connection pipe 31 in the horizontal plane.

An upper storage vessel 38 is connected to one side of the upper reaction vessel 34 through an upper storage vessel connection pipe 35. The position of the upper storage container connecting pipe 35 connected to the upper storage container 38 from the upper reaction tank 34 is larger than the position of the upper connection pipe 33 connected to the upper storage tank 32 from the upper reaction tank 34 It is positioned high on the horizontal plane.

The continuous reactor of the present invention can be used for a reaction that takes a reaction time of, for example, 30 minutes or more in addition to an amino acid emulsion formation extraction reaction by ARCA, a reaction with an amino acid and an imine forming compound other than ARCA, have.

 Among them, the chiral selective immersion extraction process and the method used in the amino acid hydrolysis extraction process based on the hydrolysis extraction reaction of imine are explained. In this regard, the present invention relates to a method of immune extraction using the continuous reactor of the present invention, and a method of using the immersion extraction reactor according to one embodiment of the present invention will be described as follows.

According to an embodiment of the present invention, an aqueous solution of racemic amino acid (D-, L-amino acid) is injected into the lower reaction tank 10 through the inlet 10a. In the upper reaction tank 14, a chiral selective receptor such as ARCA dissolved in an organic solvent having a specific gravity larger than that of water is injected through the inlet 14a. Examples of the organic solvent having a specific gravity higher than that of water include methylene chloride, chloroform and ethylenedichloride (CH ₂ ClCH ₂ Cl).

A chiral selective receptor solution dissolved in an organic solvent having a specific gravity higher than that of water in the upper reaction tank is mixed in the central reaction tank 12, whereby the reaction between the amino acid and the chiral selective receptor . Then, the organic solvent containing imine formed in the central reaction tank flows into the lower reaction tank through the second connection pipe, the aqueous amino acid solution is introduced into the upper reaction tank through the first connection pipe, The reaction takes place. Then, the organic solvent containing the imine is separately separated from the bottom reaction vessel. Specifically, in the lower storage container 16, a single amino acid of optically pure type D or L forms chiral and selectively forms an imine. For example, when the chiral selective acceptor used is S-form, the D-amino acid selectively forms an imine and is dissolved and stored in the organic solvent used, for example, methylene chloride. The lower storage vessel 16 is provided with a lower storage vessel valve 22 which is capable of separating the immune solution stored therein and, if necessary, for optically pure D- or L-type single amino acid hydrolysis extraction Can be sent to the reactor.

In the upper storage vessel 18, an optically pure aqueous solution of D- or L-type single amino acid is stored. In one embodiment of the present invention, when the chiral selective receptor is S-type, the D- Amino acid aqueous solution. The upper storage container 18 discharges the optically pure D or L single amino acid to the outside as the upper storage container valve 20 is opened. In one embodiment of the present invention, the remaining L- .

The immigration extraction method using the immune extraction reactor according to another embodiment of the present invention is basically the same as the above-described method, except that the monochiral selective receptor is dissolved in an organic solvent having a specific gravity smaller than that of water, Is added to the lower reaction tank 10, not the upper reaction tank, and the aqueous solution of the racemic amino acid is added to the upper reaction tank. Examples of the organic solvent having a specific gravity smaller than that of the water include toluene, ethyl acetate, and methyl isobutyl ketone (MIBK). As a result, in the upper storage vessel 18, an optically pure D- or L-type single amino acid is chirally selectively formed and stored. In one embodiment of the invention, when the chiral selective aqueous solution is S-type, the D-amino acid selectively forms an imine and is dissolved and stored in toluene. The upper storage vessel 18 can open the upper storage vessel valve 20 to separate the immune solution stored therein and, if necessary, send it to the reactor for optically pure D- or L-type single amino acid hydrolysis extraction have.

A lower storage container 16 is connected to one side of the lower reaction tank 10 through a lower storage container connection pipe 17. In the lower storage container 16, an optically pure (D-type or L-type single) aqueous amino acid solution is stored. In one embodiment of the present invention, when the chiral selective aqueous solution is S-type, D- Aqueous solution of the remaining L-amino acid is stored. The lower storage container 16 discharges the optically pure D- or L-type single amino acid to the outside as the lower storage container valve 22 is opened. In one embodiment of the present invention, the remaining L- .

In another aspect, the continuous reactor of the present invention is used in an amino acid hydrolysis extraction process based on a chiral selective immersion extraction process and a hydrolysis extraction process of an immune. Therefore, from this viewpoint, the present invention provides an immersion extraction reaction method The method of using the reactor for hydrolysis and extraction of amino acids according to one embodiment of the present invention will be described as follows.

Acid is continuously supplied to the lower reaction tank 30 through the inlet 30a, and hydrochloric acid is introduced in an embodiment of the present invention. In the upper reaction tank 34, an optically pure D- or L-type single amino acid is chirally injected into the upper reaction tank 34 through an inlet 34a, and an organic solvent solution, which is dissolved in an organic solvent having a specific gravity larger than that of water, In one embodiment of the present invention, the D-amino acid is dissolved in methylene chloride and added. The acid solution and the organic solvent solution containing the imine are mixed in a central reaction tank to separate the imine into an amino acid and a chiral selective receptor through subsequent hydrolysis and the separated amino acid is transferred to an acidic aqueous solution layer, The acceptor remains in the organic solvent. The organic solvent containing the chiral selective receptor is introduced into the lower reaction tank through the second connection pipe and the acidic aqueous solution containing the separated amino acid is introduced into the upper reaction tank through the first connection pipe, Respectively, and an imine hydrolysis reaction occurs.

Separating the solution containing the optically pure amino acid contained in the aqueous solution layer in the upper reaction tank, which may be stored in the upper storage container 38 connected to the upper reaction tank. The upper storage vessel 38 stores an optically pure aqueous solution of D- or L-type single amino acid. The upper storage container 38 can be separated by discharging the aqueous amino acid solution therein as the upper storage container valve 40 is opened.

The chiral selective receptor solution is stored in the lower storage container 36 and the lower storage container 36 discharges the chiral selective receptor solution therein as the lower storage container valve 42 is opened. The chiral selective acceptor stored in the lower storage container 36 is recycled and in one embodiment of the present invention the chiral selective acceptor of the lower storage container 36 is recycled as a chiral selective receptor provided in the immersion extraction reaction tank.

The amino acid hydrolysis and extraction method using the reactor for hydrolysis and extraction of amino acids according to another embodiment of the present invention is basically the same as the above-described method, except that the imine formed between the monosaccharide and the selective acceptor is dissolved in an organic solvent having a smaller specific gravity than water And thus the immersion solution is introduced into the lower reaction tank, not into the upper reaction tank, and the aqueous acid solution is introduced into the upper reaction tank. Examples of the organic solvent having a specific gravity smaller than that of the water include toluene, ethyl acetate, and methyl isobutyl ketone (MIBK). As a result, the solution containing the optically pure amino acid contained in the aqueous solution layer in the lower reaction tank is separately separated and stored in the lower storage container 36, and the lower storage container valve is opened Thereby separating optically pure D- or L-type single amino acids externally. The chiral selective receptor solution is stored in the upper storage container 38 and the upper storage container 38 discharges the chiral selective receptor solution inside as the upper storage container valve 40 is opened. The chiral selective acceptor stored in the upper reservoir 38 is recycled and in one embodiment of the present invention the chiral selective acceptor of the upper reservoir 38 is recycled to a chiral selective acceptor provided in the immersion extraction reactor.

In another aspect, the present invention relates to a continuous reactor comprising two first and second continuous reactors according to the present invention, wherein the upper reactor of the lower storage vessel of the first continuous reactor and the upper reactor of the second continuous reactor comprise a first reactor connection tube Wherein the upper storage vessel of the first continuous reactor and the lower storage vessel of the second continuous reactor are connected through a second reactor connection tube. The relative positions of the first and second continuous reactors are not correlated, but the positions of the vessels in each reactor are arranged as in Fig. The first and second continuous reactors are connected through the lower storage vessel 90 and the upper reactor connection pipe 90 and the upper reactor and lower storage vessel connection pipe 92 as shown in FIG.

The first and second two continuous reactors included in the continuous reaction apparatus of the present invention correspond to a continuous reactor for immersion extraction or a continuous reactor for amino acid hydrolysis extraction, and the respective constitutions are as described above. One reactor is used for immune extraction and in this case comprises upper and lower storage vessels and in a first step the chiral selectable receptors contained in the organic solvent are reacted in a solution of the racemic amino acid (D, L amino acid) D- or L-amino acid) is used to extract an organic solution in which an imine formed with an amino acid is dissolved. The other reactor is used in a two-step process in which an acid is added to an organic solution containing the imine to extract an amino acid, and the reaction apparatus of the present invention is configured to allow the reaction to proceed continuously.

The first process, the immersion extraction process, is as described above. An aqueous solution of racemic amino acid (DL-amino acid) is added to the lower reaction tank 10 of the immersion extraction reaction tank. The upper reaction tank 14 is supplied with a chiral selective receptor dissolved in an organic solvent having a specific gravity higher than that of water, such as methylene chloride, chloroform and ethylene dichloride. In the upper reaction tank 14, a chiral selective receptor dissolved in an organic solvent having a specific gravity larger than that of water is injected through the inlet 14a. In one embodiment, the dilution ratio of the aqueous solution of the racemic amino acid is (water / amino acid = about 3-5 / 1) and the organic solvent dilution ratio of the chiral selective acceptor is (receptor / organic solvent = about 10-15 / 1) have. A pressurizing device (a general metering pump) is used so that the aqueous solution of the racemic amino acid introduced into the lower reaction tank 10 can be injected at a constant flow rate against the gravity. The reaction rate can be determined by the feed flow rate through the pressurizer. The chiral selective receptor solution to be injected into the upper reaction tank 14 is supplied with a constant flow rate but does not use a separate pressurizing device because gravity is applied.

The racemic aqueous solution introduced into the lower reaction tank moves through the lower connection pipe 11 to the central reaction tank 12 and the chiral selective receptor solution introduced into the upper reaction tank also moves to the central reaction tank through the upper connection pipe 13, Is met in the central reaction tank, but the aqueous solution for supplying the amino acid and the organic solution for supplying the chiral selective receptor are not mixed with each other, so that the stirrer 24 is operated to stir the two layers. When the two solutions are mixed, only the type (D-type or L-type) capable of forming a bond with the chiral selective receptor (S-type or R-type) contained in the organic solution of the amino acid in the aqueous solution selectively forms an imine Organic solution. For example, when the chiral selective receptor is S-type, the D-amino acid selectively forms an imine. After the immersion, the organic solution layer having a specific gravity larger than that of water is separated from the aqueous solution layer downward, and the organic solution is moved to the lower reaction vessel 10 through the lower connection pipe 11 by gravity. The aqueous solution layer formed on the upper portion of the central reaction tank moves to the upper reaction tank 14 through the upper connection pipe 13 because the aqueous amino acid solution flows continuously into the central reaction tank in the lower reaction tank at a constant flow rate by the pressurizing device.

Since the organic solution moving from the central reaction tank 12 through the lower connection pipe 11 to the lower reaction tank contains a chiral selective receptor that does not participate in immune formation, the organic solution transferred to the lower reaction tank through the lower connection pipe 11 In the lower connection pipe 11, it forms an immune with the amino acid solution moving from the lower reaction tank to the central reaction tank and the D-amino acid contained in the aqueous solution. In addition, in the lower reaction tank, the D-amino acid and selective immobilization continue to be formed while stirring with the aqueous solution. The stirrer 24 is operated to stir the organic solution layer and the aqueous solution layer which do not mix with each other in the lower reactor. The organic solution layer separated from the aqueous solution layer after the reaction in the lower reaction tank mainly includes immigration and is moved to the lower storage container 16 through the lower storage container connection pipe 17, (22). ≪ / RTI >

The aqueous solution which is separated into the upper layer in the central reaction tank and moves to the upper reaction tank 14 through the upper connection pipe 13 contains the L-amino acid which is left in the form of D-amino acid selectively forming imine when the chiral selective receptor is S- Amino acid which is not involved in immune formation is contained in the upper reaction tube 13. In the process of moving to the upper reaction tank 14 through the upper connection tube 13, The chiral selective receptor solution migrates to the reaction tank 12 to form an imine. In addition, in the upper reaction tank 14, D-amino acid and selective immobilization continue to be formed while stirring with the organic solution. The stirrer 24 is operated to stir the organic solution layer and the aqueous solution layer which do not mix with each other in the upper reactor. The aqueous solution layer separated from the organic solution layer after the reaction in the upper reaction tank mainly contains the L-type amino acid not participating in the reaction and moves to the upper storage vessel 18 through the upper storage vessel connection pipe 15, (18) discharges the aqueous solution through the upper storage container valve (20).

Alternatively, an organic solution containing a chiral selective acceptor such as toluene, EA, MIBK, etc. may be added to the upper reaction tank 14 by injecting an aqueous solution of a racemic amino acid into the lower reaction tank 10, , As described above.

In the case of the amino acid hydrolysis and extraction process, which is the second process, the organic solvent containing the imine generated in the immersion extraction process is mixed with the organic solvent, Is introduced into the upper or lower reaction tank of the reactor in which the amino acid hydrolysis and extraction reaction is carried out. That is, the organic solution containing the imine in the organic solvent having a specific gravity larger than that of water is introduced into the upper reaction tank 34 of the amino acid hydrolysis and extraction reaction tank through the lower storage container valve 22, (E.g., hydrochloric acid) solution at a constant flow rate. For example, the dilution ratio of the acid solution may be (acid concentration: about 1-4 mol / L). A pressurizing device such as a general metering pump is used so that the aqueous acid solution introduced into the lower reaction tank 30 can be injected at a constant flow rate against gravity. The reaction rate can be determined by the feed flow rate through the pressurizer. The organic solution containing imine introduced into the upper reaction tank 34 is supplied with a constant flow rate but does not use a separate pressurizing device because gravity is applied.

The aqueous acid solution introduced into the lower reaction tank moves to the central reaction tank 32 through the lower connection pipe 31 and the organic solution including the imine introduced into the upper reaction tank moves to the central reaction tank through the pipe 35, The aqueous solution supplying the acid and the organic solution supplying the immersion are not mixed with each other, so that the stirrer 44 is operated to stir the two layers. When the two solutions are mixed, the amino acid in the organic solution layer breaks and the amino acid moves to the aqueous solution layer, and the chiral selective receptor remains in the organic solution layer. In one embodiment of the present invention, the D-amino acid selectively forms an imine when the chiral selective receptor is S-type, the D-amino acid moves to the aqueous solution layer while the imine is broken, and the S- Remains. Thereafter, the organic solution layer having a specific gravity larger than that of water is separated from the aqueous solution layer downward, and the organic solution is moved to the lower reaction vessel 30 through the lower connection pipe 31 by gravity. The aqueous solution layer formed on the central portion of the reaction tank moves to the upper reaction tank 34 through the pipe 35 because the acid aqueous solution continuously flows into the central reaction tank in the lower reaction tank 30 at a constant flow rate by the pressurizing device.

Since the organic solution moving from the central reaction tank 32 to the lower reaction tank through the pipe 37 contains immigrants not broken by the acid, (31), the immersion is broken by the acid in the aqueous solution when it comes into contact with the acid aqueous solution which moves from the lower reaction tank to the central reaction tank. Also, in the lower reaction tank, the immersion breakdown contained in the organic solution is continued while stirring with the aqueous acid solution. The stirrer 44 is operated to stir the organic solution layer and the aqueous solution layer which do not mix with each other in the lower reactor. The organic solution layer separated from the aqueous solution layer after the reaction in the lower reaction tank mainly includes a chiral selective receptor and moves to the lower storage container 36 through the pipe 37. The lower storage container 36 is connected to the lower storage container valve 42 ). ≪ / RTI > The chiral selective receptor-containing organic solution is reusable and can be re-introduced into the immune extraction reaction tank in one embodiment of the present invention.

The aqueous solution which is separated into the upper layer in the central reaction tank 32 and moves to the upper reaction tank 34 through the upper connection pipe 33 is an aqueous solution in which the D-amino acid selectively forms an imine when the chiral selective receptor is S- Amino acid aqueous solution and the acid, it is possible to move from the upper reaction tank to the central reaction tank 32 in the upper connection pipe 33 in the process of moving to the upper reaction tank 34 through the upper connection pipe 33 To meet the immune-containing organic solution to continue to break the immigration. In addition, in the upper reaction tank 34, the reaction of breaking the imine by the acid is continued while stirring with the organic solution. The stirrer 44 is operated to stir the organic solution layer and the aqueous solution layer which do not mix with each other in the upper reactor. In one embodiment of the present invention, the aqueous solution layer separated from the organic solution layer after the reaction in the upper reaction tank mainly contains the D-type amino acid separated from the imine and moves to the upper storage vessel 38 through the pipe 35, The upper storage vessel 38 drains the aqueous solution through the upper storage vessel valve 40.

Alternatively, an organic solution containing an imine in an organic solvent (for example, toluene) having a specific gravity smaller than that of water may be introduced into the lower reaction tank 30 and an aqueous acid solution may be added to the upper reaction tank 34. In this regard, As well as

While the present invention has been described in connection with what is presently considered to be practical exemplary embodiments, it is to be understood that the invention is not limited to the disclosed embodiments, but, on the contrary, is intended to cover various modifications and equivalent arrangements included within the spirit and scope of the appended claims. You must see.

For example, the reaction vessels included in the continuous reaction tank for immersion extraction and the continuous reaction tank for hydrolysis and extraction of amino acids may be four, five, or more, and three or more of the continuous reaction vessels may be connected. For example, in a continuous immune extraction reaction tank, a separate continuous reaction tank can be connected for the racemization of amino acids not participating in the reaction (when the D amino acid forms an S-type chiral selective receptor and the imine, L amino acid) It can also be connected to an additional continuous tank to purify the extract.

10, 30: lower reaction tank 12, 32: central reaction tank
14, 34: upper reaction tank 16, 36: lower storage container
18, 38: upper storage container 20, 40: upper storage container valve
22, 42: Lower storage container valve 11, 31: Second (lower) connection pipe
13, 33: first (upper) connection pipe 15, 35: third (upper storage container) connection pipe
17, 37: fourth (lower storage container) connecting pipe 50, 70: upper tank inlet
52, 72: Lower reaction tank inlet 54, 74:
80: first reactor connection pipe 82: second reactor connection pipe
90: Lower storage vessel and upper reactor connection pipe
92: Upper Reactor and Lower Storage Container
94: Upper storage vessel and lower reactor connection pipe

Claims (8)

A continuous reactor, wherein the continuous reactor is composed of an upper reaction tank at the highest position adjacent to each other at different heights, a lower reaction tank at the lowest position, and a middle reaction tank at a position between the upper reaction tank and the lower reaction tank And each of the reaction tanks is connected to a neighboring reaction tank through a first connection pipe located between the upper reaction tank and the central reaction tank and a second connection pipe located between the central reaction tank and the lower reaction tank, Wherein the upper and lower reaction vessels are each provided with an inlet, and the lower reaction vessel is provided with a pressurizing device.
The method according to claim 1,
The continuous reactor further comprises an upper storage vessel and a lower storage vessel, wherein the upper storage vessel is connected to the upper reactor through a third connecting pipe, and the lower storage vessel is connected to the lower reactor through a fourth coupling pipe Connected, continuous reactor.
A process for the extraction of an immune from a continuous reactor according to any one of claims 1 to 3,
Continuously injecting an aqueous solution of racemic amino acid into the lower reaction tank of the continuous reactor;
Continuously injecting a binaphthol derivative having an aldehyde group as a chiral selective receptor solution dissolved in an organic solvent having a specific gravity higher than that of water into the upper reaction tank constituting the continuous reactor;
Mixing the aqueous solution of the racemic amino acid and the chiral selective receptor solution in a central reaction tank to form an imine between the amino acid and the chiral selective receptor;
The organic solvent containing imine formed in the central reaction tank flows into the lower reaction tank through the second connection pipe, the aqueous amino acid solution flows into the upper reaction tank through the first connection pipe, and the imine formation reaction This happens; And
And separating the organic solvent containing the imine separately in the lower reaction tank.
A process for the extraction of an immune from a continuous reactor according to any one of claims 1 to 3,
Continuously injecting an aqueous solution of racemic amino acid into the upper reaction tank of the continuous reactor;
Continuously injecting a binaphthol derivative having an aldehyde group as a chiral selective receptor solution dissolved in an organic solvent having a specific gravity smaller than that of water into the lower reaction tank constituting the continuous reactor;
Mixing the aqueous solution of the racemic amino acid and the chiral selective receptor solution in a central reaction tank to form an imine between the amino acid and the chiral selective receptor;
The organic solvent containing imine formed in the central reaction tank flows into the upper reaction tank through the first connection pipe, the aqueous amino acid solution flows into the lower reaction tank through the second connection pipe, and the imine formation reaction This happens; And
And separating the organic solvent containing the imine separately in the upper reaction tank.
A method for optically pure amino acid hydrolysis and extraction by hydrolyzing an imine formed between an amino acid and a binaphthol derivative having an aldehyde group as a chiral selective receptor solution using the continuous reactor according to claim 1 or 2,
Continuously injecting an acid solution into the lower reaction tank of the continuous reactor;
Continuously injecting into the upper reactor of the continuous reactor a solution containing an imine formed between a chiral selective acceptor and a D- or L-type amino acid dissolved in an organic solvent having a specific gravity greater than that of water;
A step of hydrolyzing the acid solution and the organic solvent solution containing the immigration in a central reaction tank and separating the imine into an amino acid and a chiral selective receptor through hydrolysis, the separated amino acid is moved to an acidic aqueous solution layer , The chiral selective receptor remaining in an organic solvent;
The organic solvent containing the chiral selective receptor is introduced into the lower reaction tank through the second connection pipe and the acidic aqueous solution containing the separated amino acid is introduced into the upper reaction tank through the first connection pipe, A step in which an imine hydrolysis reaction occurs; And
And separating the solution containing the optically pure amino acid contained in the aqueous solution layer in the upper reaction tank separately.
A method for optically pure amino acid hydrolysis and extraction by hydrolyzing an imine formed between an amino acid and a binaphthol derivative having an aldehyde group as a chiral selective receptor solution using the continuous reactor according to claim 1 or 2,
Continuously injecting an acid solution into the upper reactor of the continuous reactor;
Continuously injecting a solution containing an imine formed between a chiral selective acceptor and a D-type or L-type amino acid dissolved in an organic solvent having a specific gravity smaller than that of water in the bottom reaction tank of the continuous reactor;
A step of hydrolyzing the acid solution and the organic solvent solution containing the immigration in a central reaction tank and separating the imine into an amino acid and a chiral selective receptor through hydrolysis, the separated amino acid is moved to an acidic aqueous solution layer , The chiral selective receptor remaining in an organic solvent;
The organic solvent containing the chiral selective receptor is introduced into the upper reaction tank through the first connection pipe and the acidic aqueous solution containing the separated amino acid is introduced into the lower reaction tank through the second connection pipe, A step in which an imine hydrolysis reaction occurs; And
And separating the solution containing the optically pure amino acid contained in the aqueous solution layer in the lower reaction tank separately.
A continuous reaction apparatus comprising a first and a second two continuous reactors according to claim 1 or 2, wherein the upper reservoir of the first continuous reactor and the upper reactor of the second continuous reactor are connected to the first reactor connection pipe Wherein the upper storage vessel of the first continuous reactor and the lower storage vessel of the second continuous reactor are connected through a second reactor connection tube.
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