WO2022035228A1 - Amino acid extraction process using t-butyl ketone binaphthol derivative or t-butyl ketone derivative, and continuous reactor for performing same - Google Patents

Abstract

The present application relates to: an amino acid extraction process for simultaneously performing racemization and enantioselective liquid-liquid extraction of amino acids in an aqueous solution by using a t-butyl ketone binaphthol derivative or a t-butyl ketone derivative as a chiral extractant; and a continuous reactor for performing the amino acid extraction process.

Description

Amino acid extraction process using t-butylketone binaphthol derivative or t-butylketone derivative, and continuous reactor for performing the same

The present application provides an amino acid extraction process that simultaneously performs racemization and chiral-selective liquid-liquid extraction of amino acids present in an aqueous solution using t-butylketone binaphthol derivative or t-butylketone derivative as a chiral extractant, and performing the same It relates to a continuous reactor.

Optically pure amino acids are very important industrially because they are used as ligands of asymmetric catalysts or as starting materials or intermediates necessary for synthesizing various pharmaceuticals and physiologically active substances [Helmchen, G.; Pfaltz, A., Acc. Chem. Res. 2000, 33, 336-345].

As an economical method for obtaining amino acids, fermentation methods are widely known. However, amino acids obtainable through fermentation are limited to L-amino acids among natural amino acids. Optically pure D-amino acids and non-natural amino acids are produced through the enzymatic method or optical resolution method, but these methods are expensive to manufacture and thus have a unit price of 5 to 10 times higher than that of natural L-amino acids produced by fermentation. And there are difficulties in mass production. Therefore, efforts to economically mass-produce D-amino acids or non-natural amino acids are actively being made [Maruoka, K.; Ooi, T. Chem. Rev. 2003, 103, 3013].

On the other hand, in the enantioselective liquid-liquid extraction (ELLE) method, the process is simple, scale-up is easy, and low-cost production is possible, so the ELLE method is a pure optical amino acid. Studies to produce Verkuijl, B. J. V.; Minnaard, A. J.; de Vries, J. G.; Heeres, H. J.; Feringa, B. L. Org., Biomol. Chem. 2011, 9, 36-51]. A very important factor in the ELLE of amino acids is the development of a chiral extracting agent with high selectivity.

Numerous amino acid chiral extractors have been developed so far, but the selectivity is generally about 2/1 to 5/1, so the need for the development of a chiral extractant with higher selectivity for amino acid ELLE is very high [(a) Amato, M. E.; Ballistreri, F. P.; D'Agata, S.; Pappalardo, A.; Tomaselli, G. A.; Toscano, R. M.; Sfrazzetto, G. T. Eur. J., Org. Chem. 2011, 28, 5674-5680; (b) Colera, M.; Costero, A. M.; Gavina, P.; Gil, S., Tetrahedron: Asymmetry 2005, 16, 2673-2679].

In the Republic of Korea Patent No. 10-1185603 (method for obtaining optically pure amino acids), pyridoxal-5'- in order to racemize the amino acids in the aqueous solution layer by using a binaphthol derivative, which is an amino acid chiral converting agent, as a chiral extracting agent for amino acid ELLE. A method of heating at 50°C to 100°C using phosphate (PLP; pyridoxal-5'-phosphate) or a salicyl derivative as 5% equivalent of an amino acid is presented. The binaphthol derivative extracts the amino acids of the aqueous solution layer into the organic layer through imine formation, and the chiral selectivity is about 5/1 to 20/1 depending on the type of amino acid, showing very high selectivity compared to the previously developed chiral extracting agent. However, this method has disadvantages in that expensive PLP is used in a large amount and the risk of generating impurities increases as amino acids and PLP are destroyed as the temperature is heated. Since the binaphthol derivatives in the organic layer may be decomposed or the binaphthol ring may lose optical activity due to rotation, racemization at high temperature has a disadvantage that ELLE extraction and racemization cannot be performed at the same time. Korean Patent No. 10-1561828 discloses a method for racemizing amino acids. See also Bulletin of the Chemical Society of Japan, Vol. 51, No. 8, pp. 2366-2368 (1978) and Inorganic Chemistry. Vol. 9, No. 9, pp. 2104-2112 (1970) also discloses a method for racemizing amino acids. The fastest method for racemization of amino acids is to use 1 mol% equivalent of pyridoxal-5'-phosphate (hereinafter PLP) and 0.5 mol% equivalent of Cu ²⁺ ions of the amino acid in an aqueous solution at pH 11 to 12 at room temperature. to be stirred in Using the above method, the racemization of common amino acids is completed in about 2 hours at room temperature. In the ELLE experiment of amino acids using a binaphthol derivative as a chiral extracting agent, racemization of the aqueous layer was attempted using Cu ²⁺ /PLP catalyst, but Cu ²⁺ ions of the aqueous layer used as a catalyst for racemization were converted to the organic layer. As it passed, the organic layer was contaminated, and the racemization of the aqueous layer was stopped and did not proceed any further. Therefore, efforts to racemize the amino acids in the aqueous solution layer and extract one chiral amino acid to the organic layer in a chiral-selective way are limited. For this reason, EECR in which amino acids are racemized in an aqueous solution layer and at the same time, chiral-selectively extracted into an organic layer has not been reported in the existing literature.

Korean Patent No. 10-1558949 and U.S. Patent No. 9,845,288 disclose a t-butylketone binaphthol derivative, which is a chiral extracting agent having significantly higher chiral selectivity than a binaphthol derivative. The binaphthol derivatives including the t-butyl ketone derivative can be used as a chiral extracting agent for the liquid-liquid extraction method, that is, the ELLE method, for the amino acid of the aqueous layer, and for the amino acid of the aqueous layer rather than other known chiral extracting agents. It shows a very high selectivity. In addition, binaphthol chiral extractors having an aldehyde or ketone group have great advantages over other chiral extractors because they extract the amino acid itself (underivatized amino acid).

On the other hand, the ELLE has many advantages as mentioned above, but has the disadvantage of selectively bringing an amino acid having one chirality among the amino acids in the aqueous solution layer while leaving the amino acid having the other chirality in the aqueous solution layer. there is. That is, the ELLE method has no choice but to expect a theoretical yield of up to 50%. If the amino acids in the aqueous solution layer can be racemized, the efficiency of ELLE can be further increased because amino acids having the desired chirality can be further extracted from the aqueous layer after ELLE.

The present application provides an amino acid extraction process that simultaneously performs racemization and chiral-selective liquid-liquid extraction of amino acids present in an aqueous solution using t-butylketone binaphthol derivative or t-butylketone derivative as a chiral extractant, and performing the same It relates to a continuous reactor.

However, the problems to be solved by the present application are not limited to the problems mentioned above, and other problems not mentioned will be clearly understood by those skilled in the art from the following description.

The first aspect of the present application includes using a t-butylketone binaphthol derivative represented by the following formula (1) or a t-butylketone derivative represented by the following formula (2) as a chiral extractant, and racemization of amino acids in an aqueous solution and An amino acid extraction process is provided, wherein chiralselective liquid-liquid extraction is performed simultaneously:

[Formula 1]

;

[Formula 2]

;

In Formula 1 or Formula 2,

Wherein X is, each independently, hydrogen; halogen group; amino group; nitro group; cyano group; formyl group; carboxyl group; C _1-10 alkylcarbonyl group; C _6-10 aryl group; C _1-10 alkoxy group; and a C _1-10 alkyl group unsubstituted or substituted with one or more substituents selected from the group consisting of a halogen group, a hydroxyl group, an amino group, a cyano group, a nitro group, and a C _6-10 aryl group;

Y is, each independently, hydrogen; halogen group; amino group; nitro group; cyano group; formyl group; carboxyl group; C _1-10 alkylcarbonyl group; C _6-10 aryl group; C _1-10 alkoxy group; and a C _1-10 alkyl group unsubstituted or substituted with one or more substituents selected from the group consisting of a halogen group, a hydroxyl group, an amino group, a cyano group, a nitro group, and a C _6-10 aryl group;

wherein n and m are each independently an integer of 0 to 4;

Wherein R ₁ is a divalent functional group, substituted or unsubstituted by a C _1-5 straight-chain or branched alkyl group (alkyl group), C _1-5 straight-chain or branched alkylene group (alkylenyl group), C _{2 -5} of a straight or branched chain alkenylene group (alkenylenyl group), C _2-5 of a straight or branched chain alkynylene group (alkynylenyl group), C _3-10 of a cyclic alkylene group (cyclicalkylenyl group), C _5-10 is an arylene group of

wherein R ₂ is a halogen group or a C _1-5 linear or branched alkyl group substituted or unsubstituted with OH; C _3-10 cyclic alkyl group unsubstituted or substituted with a halogen group or OH; a C _2-5 linear or branched alkenyl group unsubstituted or substituted with a halogen group or OH; a C _2-5 linear or branched alkynyl group unsubstituted or substituted with a halogen group or OH; Or an aryl group unsubstituted or substituted with a halogen group or OH.

A second aspect of the present application is a continuous reactor for performing the amino acid extraction process according to the first aspect, wherein the continuous reactor consists of three parts: an amino acid extraction process part, a hydrolysis process part, and a neutralization process part, The extraction process part and the hydrolysis process part are to have at least one reaction tank, and provide a continuous reactor for obtaining optically pure amino acids by cyclically performing an amino acid extraction process, a hydrolysis process, and a neutralization process.

According to the embodiments of the present application, copper ions and/or pyridoxal-5'-phosphate may be used as a racemization catalyst during the amino acid extraction process, and the racemization catalyst may be used until the extraction process is completed. Pyridoxal-5'-phosphate may not be degraded.

According to the embodiments of the present application, the copper ions and/or the pyridoxal-5'-phosphate do not move to the organic layer, so that chiral selective extraction and amino acid racemization can occur at the same time. It is possible to improve the yield of chiral transformation.

According to the embodiments of the present application, amino acids in aqueous solution can be extracted with very high chiral selectivity by simultaneously performing chiral-selective liquid-liquid extraction and racemization through a continuous reactor.

According to the embodiments of the present application, by reacting in a continuous process through a continuous reactor, all amino acids in the aqueous solution layer are converted to L-amino acids or all DL-amino acids to D-amino acids, or all D-amino acids or DL-amino acids to L- A pure amino acid can be obtained by optical conversion into an amino acid.

1A is a photograph of enantioselective liquid-liquid extraction performed using a conventional binaphthol aldehyde derivative compound as an amino acid chiral extracting agent in an embodiment of the present application.

Figure 1b is a photograph of performing a liquid-liquid chiral extraction method using Compound 1, which is a t-butylketone derivative, as a chiral extracting agent in an embodiment of the present application.

Figure 2 shows the structural difference between the imine bond between the conventional binaphthol derivative-phenylalanine and the compound 1-phenylalanine that does not contain t-butylketone in one embodiment of the present application.

3A is a diagram schematically illustrating a limitation of a conventional ELLE method according to an embodiment of the present application.

FIG. 3B schematically illustrates an enantioselective extraction coupled with racemization (EECR) process coupled with racemization according to an embodiment of the present application.

4 shows the crystal structure of compound 1-phenylalanine obtained by recrystallizing an organic layer obtained through chiral-selective extraction of phenylalanine according to an embodiment of the present application.

Figure 5a, in one embodiment of the present application, shows a schematic diagram of a continuous reaction system (CRS; continuous reaction system) for continuously performing all processes by continuously connecting the EECR process, the hydrolysis process, and the neutralization process.

Figure 5b, in an embodiment of the present application, shows that the EECR / hydrolysis continuous process experiment of phenylalanine was performed using the experimental apparatus according to the drawing of the continuous reactor.

Hereinafter, embodiments and implementations of the present invention will be described in detail with reference to the accompanying drawings so that those skilled in the art to which the present invention pertains can easily carry out. However, the present application may be embodied in several different forms and is not limited to the embodiments and examples described herein. And in order to clearly explain the present invention in the drawings, parts irrelevant to the description are omitted, and similar reference numerals are attached to similar parts throughout the specification.

Throughout this specification, when a part is "connected" with another part, this includes not only the case where it is "directly connected" but also the case where it is "electrically connected" with another element interposed therebetween. do.

Throughout this specification, when a member is said to be located “on” another member, this includes not only a case in which a member is in contact with another member but also a case in which another member is present between the two members.

Throughout this specification, when a part "includes" a certain element, it means that other elements may be further included, rather than excluding other elements, unless otherwise stated.

As used herein, the terms "about," "substantially," and the like are used in a sense at or close to the numerical value when the manufacturing and material tolerances inherent in the stated meaning are presented, and to aid in the understanding of the present application. It is used to prevent an unconscionable infringer from using the mentioned disclosure in an unreasonable way.

The term “step to” or “step of” to the extent used throughout this specification does not mean “step for”.

Throughout this specification, the term "alkyl (group)" may include linear or branched C _1-20 alkyl (group), respectively, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosanyl, or all possible isomers thereof. However, it may not be limited thereto.

Throughout this specification, the term "alkylene (group), respectively, refers to a divalent hydrocarbon group in the form of a linear or branched C _1-20 alkylene (group), for example, methylene, ethylene , propylene, butylene, pentylene, hexylene, heptylene, octylene, nonylene, decylene, undecylene, dodecylene, tridecylene, tetradecylene, pentadecylene, hexadecylene, heptadecylene, It may include, but may not be limited to, octadecylene, nonadexylene, eicosanylene, or all possible isomers thereof.

Throughout this specification, the term "alkenyl (group)" refers to a monovalent hydrocarbon group in which at least one carbon-carbon double bond is included in an alkyl (group) having 2 or more carbon atoms among the alkyl (group) defined above. As one, it may be one containing a linear or branched, C _2-20 alkenyl (group), but may not be limited thereto.

Throughout the present specification, the term “alkenylene (group)” may mean a divalent hydrocarbon group including the alkenyl (group) defined above, but may not be limited thereto.

Throughout this specification, the term "alkynyl (group)" refers to a monovalent hydrocarbon group in which at least one carbon-carbon triple bond is included in an alkyl (group) having 2 or more carbon atoms among the alkyl (group) defined above. As one, linear or branched, C _2-20 alkynyl (group) may be included, but may not be limited thereto.

Throughout the present specification, the term "alkynylene (group)" may mean a divalent hydrocarbon group in a form including an alkynyl (group) as defined above, but may not be limited thereto.

Throughout this specification, the term “aryl(group)” refers to a monovalent functional group formed by the removal of a hydrogen atom present in one or more rings of arenes, such as phenyl, biphenyl, terphenyl (terphenyl), naphthyl (naphthyl), anthryl (anthryl), phenanthryl (phenanthryl), pyrenyl (pyrenyl), or may include all possible isomers thereof, but may not be limited thereto. The arene is a hydrocarbon group having an aromatic ring, and may include a monocyclic or polycyclic hydrocarbon group, and the polycyclic hydrocarbon group may include one or more aromatic rings and may include an aromatic ring or a non-aromatic ring as an additional ring. , which may not be limited thereto.

Throughout this specification, the term "arylene (group)" may mean a divalent hydrocarbon in a form including the aryl (group) as defined above, but may not be limited thereto.

Throughout this specification, the term "cycloalkyl (group)" is a form of a monovalent functional group having a saturated hydrocarbon ring, and may include C _3-8 cycloalkyl (group), for example, cyclopropyl, cyclo It may include, but may not be limited to, butyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, or all possible isomers thereof.

Throughout the present specification, the term "cycloalkylene (group)" may mean a divalent hydrocarbon in a form including a cycloalkyl (group) as defined above, but may not be limited thereto.

Throughout this specification, the term "alkoxy (group)" is a form in which an alkyl group as defined above is combined with an oxygen atom, and may include C _1-20 alkoxy (group), for example, methoxy, ethoxy, Propoxy, butoxy, pentoxy, hexyloxy, hepyloxy, octyloxy, nonyloxy, decyloxy, undecyloxy, dodecyloxy, tridecyloxy, tetradecyloxy, pentadecyloxy, It may include, but may not be limited to, hexadecyloxy, heptadecyloxy, octadecyloxy, nonadecyloxy, eicosanyloxy, or all possible isomers thereof.

Throughout this specification, the term "halogen group" means that a halogen element belonging to Group 17 of the periodic table is included in the compound in the form of a functional group, and the halogen element is, for example, F, Cl, Br, or I may be, but may not be limited thereto.

Throughout this specification, the term “alkali metal” refers to a metal belonging to Group 1 of the periodic table, and may be Li, Na, K, Rb, Cs, or Fr, but may not be limited thereto.

Throughout this specification, the term "combination(s) of these" included in the expression of the Markush form means one or more mixtures or combinations selected from the group consisting of the components described in the expression of the Markush form, It means to include one or more selected from the group consisting of the above components.

Throughout this specification, reference to “A and/or B” means “A or B, or A and B”.

Hereinafter, embodiments of the present application have been described in detail, but the present application may not be limited thereto.

The first aspect of the present application includes using a t-butylketone binaphthol derivative represented by the following formula (1) or a t-butylketone derivative represented by the following formula (2) as a chiral extractant, and racemization of amino acids in an aqueous solution and An amino acid extraction process is provided, wherein chiralselective liquid-liquid extraction is performed simultaneously:

[Formula 1]

;

[Formula 2]

;

In Formula 1 or Formula 2,

Wherein X is, each independently, hydrogen; halogen group; amino group; nitro group; cyano group; formyl group; carboxyl group; C _1-10 alkylcarbonyl group; C _6-10 aryl group; C _1-10 alkoxy group; and a C _1-10 alkyl group unsubstituted or substituted with one or more substituents selected from the group consisting of a halogen group, a hydroxyl group, an amino group, a cyano group, a nitro group, and a C _6-10 aryl group;

Y is, each independently, hydrogen; halogen group; amino group; nitro group; cyano group; formyl group; carboxyl group; C _1-10 alkylcarbonyl group; C _6-10 aryl group; C _1-10 alkoxy group; and a C _1-10 alkyl group unsubstituted or substituted with one or more substituents selected from the group consisting of a halogen group, a hydroxyl group, an amino group, a cyano group, a nitro group, and a C _6-10 aryl group;

wherein n and m are each independently an integer of 0 to 4;

Wherein R ₁ is a divalent functional group, substituted or unsubstituted by a C _1-5 straight-chain or branched alkyl group (alkyl group), C _1-5 straight-chain or branched alkylene group (alkylenyl group), C _{2 -5} of a straight or branched chain alkenylene group (alkenylenyl group), C _2-5 of a straight or branched chain alkynylene group (alkynylenyl group), C _3-10 of a cyclic alkylene group (cyclicalkylenyl group), C _5-10 is an arylene group of

wherein R ₂ is a halogen group or a C _1-5 linear or branched alkyl group substituted or unsubstituted with OH; C _3-10 cyclic alkyl group unsubstituted or substituted with a halogen group or OH; a C _2-5 linear or branched alkenyl group unsubstituted or substituted with a halogen group or OH; a C _2-5 linear or branched alkynyl group unsubstituted or substituted with a halogen group or OH; Or an aryl group unsubstituted or substituted with a halogen group or OH.

According to one embodiment of the present application, the method for preparing the compound according to Formula 1 or 2 is according to a previously known method.

The present inventors have developed a method for recognizing the chirality of amino alcohols and amino acids through imine bonds and converting L-amino acids into D-amino acids using a binaphthol derivative having a carbonyl group as follows [(a)Park , H.; Kim, K. M.; Lee, A.; Ham, S.; Nam, W.; Chin, J., and J. Am. Chem. Soc. 2007, 129, 1518-1519; (b) Kim, K. M.; Park, H.; Kim, H.; Chin, J.; Nam, W., Org. Lett. 2005, 7, 3525-3527]:

[Conventional binaphthol derivative compound]

.

Therefore, in the present art, by using a new process of racemization and enantioselective extraction (EECR) coupled with racemization that rapidly racemizes amino acids in aqueous solution and extracts them into an organic layer with very high chiral selectivity, the largest It overcomes the limitations of the general enantioselective liquid-liquid extraction (ELLE), which extracts only 50% of the organic layer, and optically converts all amino acids in the aqueous layer into L-type or D-type to have pure optical chirality. A method for preparing an amino acid is provided.

According to one embodiment of the present application, the t-butyl ketone binaphthol derivative or the t-butyl ketone derivative may be used in an optically pure form.

According to one embodiment of the present application, racemization and enantioselective liquid-liquid extraction (ELLE) of the amino acid in the aqueous solution are performed simultaneously with enantioselective extraction (EECR) coupled with racemization. It is called coupled with racemization) process technology.

According to one embodiment of the present application, the chiral extractant may be used for L/D optical conversion of amino acids, but is not limited thereto.

According to one embodiment of the present application, the chiral extractant may have a chiral selectivity of about 95% or more, but is not limited thereto. For example, the chiral extractant may be about 95% or more, about 96% or more, about 97% or more, about 98% or more, or about 99% or more.

According to one embodiment of the present application, the t-butyl ketone binaphthol derivative or the t-butyl ketone derivative may include an (S)-type or (R)-type optical isomer, but is not limited thereto.

According to one embodiment of the present application, the t-butyl ketone binaphthol derivative or the t-butyl ketone derivative may include the following compound 1 or the following compound 2, but is not limited thereto:

[Compound 1]

,

[Compound 2]

.

According to one embodiment of the present application, the compound 1 and the compound 2 may be used in (S) form or (R) form which is an enantiomer thereof.

According to one embodiment of the present application, the t-butyl ketone binaphthol derivative and the t-butyl ketone derivative may each include a carbonyl group (C=O) that binds to an amino acid to form an imine, but is limited thereto. not.

According to one embodiment of the present application, the principle of optical resolution is due to the difference in stability of the imine compound, and a representative example of an alpha amino acid that can be optically resolved can be represented by the compound of Formula 3 below, and L by an absent carbon in the molecule -form or D-form enantiomers may exist:

[Formula 3]

NH ₂ CHR ₃ COOH

According to one embodiment of the present application, in the above formula, R ₃ is a monovalent organic group or halogen group other than hydrogen, preferably a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or It may be an unsubstituted cyclic alkyl group, or a substituted or unsubstituted aryl group.

According to one embodiment of the present application, in the case of the S-type optical isomer of the t-butylketone binaphthol derivative represented by Formula 1 of the present application, the D-type amino acid is selectively extracted, and the t-butylketone binaphthol In the case of the R-type optical isomer of the derivative, the L-type amino acid can be selectively extracted.

According to one embodiment of the present application, copper ions and/or pyridoxal-5'-phosphate, which are the racemization catalysts, may be present in the aqueous solution layer during the amino acid extraction process, but is limited thereto it is not

Conventional chiral-selective liquid-liquid extraction has a limitation in that the theoretical yield is only 50% by extracting only one of the racemic mixtures, and when the amino acids remaining in the aqueous solution are racemized, metal ions, which are the racemization catalysts, move to the organic layer. As a result, the organic layer is contaminated with metal ions and racemization of the amino acids in the aqueous layer does not proceed any further, so there is a difficulty in not being able to use the amino acids remaining in the aqueous layer.

According to one embodiment of the present application, the metal ion catalyst may be used as a racemization catalyst.

According to one embodiment of the present application, copper ions and/or pyridoxal-5'-phosphate may be used as a racemization catalyst during the amino acid extraction process, and the racemization catalyst until the extraction process is complete. Pyridoxal-5'-phosphate may not be degraded.

According to one embodiment of the present application, the copper ion and/or the pyridoxal-5'-phosphate do not move, so that chiral selective extraction and amino acid racemization can occur at the same time, so that chiral transformation Yield can be improved.

According to one embodiment of the present application, the chiral extracting agent prevents the metal ion catalyst of the aqueous solution layer from moving to the organic layer and contaminating it, thereby providing a principle that enables chiral selective extraction and amino acid racemization to occur at the same time. The theoretical chiral conversion yield of amino acids can be greatly improved from 50% to 100%.

According to one embodiment of the present application, the pyridoxal-5'-phosphate may be about 4 mol%, but is not limited thereto. For example, the pyridoxal-5'-phosphate can be about 4 mole%, about 3.5 mole%, about 3 mole%, about 2.5 mole%, about 2 mole%, about 1.5 mole%, or about 1 mole% However, the present invention is not limited thereto. According to one embodiment of the present application, the pyridoxal-5'-phosphate may be about 1 mol%. According to one embodiment of the present application, when the pyridoxal-5'-phosphate is about 5 mol% or more, the rate of racemization increases, but the cost increases, and the amount of copper ions must also be increased. There is a disadvantage that precipitation may occur.

According to one embodiment of the present application, the copper ion may be about 2.5 mol%, but is not limited thereto. For example, the copper ion may be about 2,5 mol%, about 2 mol%, about 1.5 mol%, about 1 mol%, or about 0.5 mol%, but is not limited thereto. According to one embodiment of the present application, the copper ion may be about 0.5 mol%.

A second aspect of the present application is a continuous reactor for performing the amino acid extraction process according to the first aspect, wherein the continuous reactor consists of three parts: an amino acid extraction process part, a hydrolysis process part, and a neutralization process part, The extraction process part and the hydrolysis process part are to have at least one reaction tank, and provide a continuous reactor for obtaining optically pure amino acids by cyclically performing an amino acid extraction process, a hydrolysis process, and a neutralization process.

According to one embodiment of the present application, a first connector (U1) positioned between the amino acid extraction process unit and the hydrolysis process part, and a second connector positioned between the hydrolysis process part and the neutralization process part (U2), and the neutralization process unit may include a third connector (U3), but is not limited thereto.

According to one embodiment of the present application, an aqueous solution of racemic amino acids (L-amino acid, D-amino acid, or DL-amino acid) is continuously added through the inlet to the amino acid extraction process unit, and the specific gravity is greater than that of the racemic amino acid aqueous solution A chiral selective receptor solution dissolved in an organic solvent is continuously added.

According to one embodiment of the present application, the amino acid aqueous solution and the organic solvent are mixed in the amino acid extraction step to form imine, and the organic solvent including imine is introduced into the hydrolysis step through P1 (pump 1) and , the amino acid aqueous solution not containing the imine is returned to the amino acid extraction step again through P5 (pump 5).

According to one embodiment of the present application, the organic solvent containing the imine moves to the hydrolysis step, and is divided into an aqueous layer containing the organic solvent and enantiomerically pure amino acids. The organic layer moving in the second connector U2 moves to the third connector U3 for neutralization, and the neutralization process is performed in U3.

According to one embodiment of the present application, the chiral selective extraction process, the hydrolysis process, and the neutralization process may be recycled in the continuous reactor, but is not limited thereto.

According to the embodiments of the present application, chiral-selective liquid-liquid extraction and racemization are simultaneously performed through a continuous reactor to extract amino acids in aqueous solution with very high chiral selectivity to the organic layer.

According to the embodiments of the present application, by reacting in a continuous process through a continuous reactor, all amino acids in the aqueous solution layer are converted to L-amino acids or all DL-amino acids to D-amino acids, or all D-amino acids or DL-amino acids to L- A pure amino acid can be obtained by optical conversion into an amino acid.

Hereinafter, the present application will be described in more detail with reference to Examples, but the present application is not limited thereto.

<Example 1: Repeat process of EECR and hydrolysis 5 times for phenylalanine>

Preparation of organic layer and aqueous layer: D-phenylalanine (0.66 g, 4.0 mmol), NaOH (0.164 g, 4.08 mmol), pyridoxal-5'-phosphate (PLP; pyridoxal-5'-phosphate) (0.011 g, 0.04 mmol) ), CuSO ₄ 5H ₂ O (0.01 g, 0.04 mmol) was dissolved in water (2 ml) to prepare an aqueous layer, (R)-Compound 1 (0.60 g, 1.0 mmol), Aliquat-336 (0.43 g, 1.05) mmol) was dissolved in CDCl ₃ (1.0 mL) to prepare an organic layer.

1A is a photograph of enantioselective liquid-liquid extraction performed using the following conventional binaphthol aldehyde derivative compound as an amino acid chiral extracting agent, and Cu ²⁺ to racemize phenylalanine in an aqueous solution layer; FIG. This indicates that when enantioselective liquid-liquid extraction is attempted by adding a /PLP catalyst, Cu ²⁺ ions migrate to the organic layer and contaminate it. This makes it impossible to try liquid-liquid chiral extraction methods any longer.

[Conventional binaphthol derivative compound]

.

1b is a photograph of a liquid-liquid chiral extraction method using Compound 1, which is a t-butylketone derivative, as a chiral extracting agent. In order to racemize phenylalanine in an aqueous solution layer, Cu ²⁺ /PLP catalyst is added to the liquid- Shows the results of trying the liquid chiral extraction method. Although the experiment of extracting phenylalanine after extraction and hydrolysis was repeated 5 times, it can be seen that Cu ²⁺ ions of the aqueous solution layer remain in the aqueous solution layer as they are. As a result of analyzing the chirality of the amino acids in the aqueous solution layer by HPLC, it can be seen that the racemization state is continuously maintained.

2 shows the structural difference between the imine bond between the binaphthol derivative not containing t-butylketone-phenylalanine and compound 1-phenylalanine and when compound 1 is used as an extractant, the Cu ²⁺ ions in the aqueous solution move to the organic layer. It explains why not.

EECR process: After mixing the aqueous layer and the organic layer in a vial container, the organic layer was separated by stirring at room temperature for 6 hours. As a result of ¹ H NMR of the organic layer, about 99% or more of phenylalanine obtained as imine was L-form and showed very high chiral selectivity.

By reacting in a continuous process through a continuous reactor, all amino acids in the aqueous layer are optically converted to L-amino acids or all DL-amino acids to D-amino acids, or all D-amino acids or DL-amino acids to L-amino acids to obtain pure amino acids can be obtained.

3A schematically illustrates the limitations of the conventional ELLE method. The ELLE method has a disadvantage in that up to 50% of the amino acids in the aqueous solution layer can be extracted into the organic layer.

Figure 3b schematically illustrates the EECR process. The EECR can be extracted into the organic layer so that all of the amino acids of the aqueous solution layer have one chirality (maximum 100%).

4 shows the crystal structure of Compound 1-phenylalanine obtained by recrystallizing an organic layer obtained through chiral selective extraction of phenylalanine.

Hydrolysis process: The organic layer from which amino acids were extracted by the enantioselective extraction coupled with racemization (EECR) process was mixed with an aqueous hydrochloric acid solution (1.0 N, 2 mL) and stirred at room temperature for 2 hours. All amino acids of the organic layer moved to the aqueous layer, and it was confirmed through ¹ H NMR that the organic layer returned to the state before the start of the EECR process.

5 repetitions of EECR and hydrolysis process: After the hydrolysis process, the recovered organic layer is neutralized by injecting an aqueous Na ₂ CO ₃ solution, and 1 equivalent of amino acid is added to the aqueous solution layer used in the EECR process, mixed together and stirred. The EECR process was performed, and the organic layer was subjected to a hydrolysis process. In this way, the EECR/hydrolysis process was repeated 5 times.

Recovery of optically pure phenylalanine: The EECR/hydrolysis process was repeated 5 times and the optical purity of each aqueous phenylalanine solution obtained in the hydrolysis process was measured by HPLC. As a result, the average L-type phenylalanine was 98.7%. NaOH 2.0 N aqueous solution was added to the aqueous solution to adjust the pH to 6.0, and 0.55 g of phenylalanine produced by precipitation was obtained as a solid (yield 343% based on compound 1). At this time, the imine formation rate of phenylalanine was maintained at 90% to 95% for 5 times.

[Compound 1-(S) Form]

.

<Example 2: EECR and hydrolysis process for alanine repeated 5 times>

For alanine, the EECR/hydrolysis process was repeated 5 times in the same manner as in Example 1 above. In the case of alanine, the imine formation rate of the organic layer was about 60%, and the aqueous alanine solution obtained through hydrolysis was adjusted to pH 6.0 and an ethanol solvent was added to obtain 0.13 g of a solid alanine compound having an optical purity of 96.3%. Yield: 146% (based on compound 1).

<Example 3: EECR/hydrolysis process for leucine 5 replicates>

For leucine, the EECR/hydrolysis process was repeated 5 times in the same manner as in Example 1. By adjusting the pH of the aqueous leucine solution obtained through hydrolysis to 6.0, 0.52 g of a solid leucine compound having an optical purity of 98.3% was obtained. At this time, the imine formation rate of leucine was maintained at 70% to 80% for 5 times. Yield: 397% (based on compound 1).

<Example 4: EECR/hydrolysis process for isoleucine 5 times repeated experiment>

For isoleucine, the EECR/hydrolysis process was repeated 5 times in the same manner as in Example 1. In the case of isoleucine, since racemization at room temperature is very slow, the temperature of the aqueous solution layer was maintained at 40° C. to 60° C. for 4 hours for racemization after the EECR process. By adjusting the pH of the aqueous solution of isoleucine obtained through hydrolysis to 6.0, 0.50 g of an isoleucine solid compound having an optical purity of 98.3% was obtained. At this time, the imine formation rate of isoleucine was maintained at about 80% for 5 times. Yield: 382% (based on compound 1).

<Example 5: EECR/hydrolysis process for valine 5 replicates>

For valine, the same EECR/hydrolysis process as in Example 1 was repeated 5 times. In the case of valine, since racemization at room temperature is very slow, the temperature of the aqueous solution layer was maintained at 70° C. for 4 hours for racemization after the EECR process. By adjusting the pH of the aqueous valine solution obtained through hydrolysis to 6.0, 0.60 g of L-valine having an optical purity of 98.5% was obtained. At this time, the imine formation rate of valine was maintained at 70% to 80% for 5 times. Yield: 513% (based on compound 1).

<Example 6: EECR/hydrolysis process for tryptophan repeated 5 times>

For tryptophan, the EECR/hydrolysis process was repeated 5 times in the same manner as in Example 1. Racemization was performed at room temperature. By adjusting the pH of the aqueous tryptophan solution obtained through hydrolysis to 6.0, 0.63 g of L-tryptophan having an optical purity of 98.7% was obtained. At this time, the imine formation rate of tryptophan was maintained at about 80% for 5 times. Yield: 308% (based on compound 1).

<Example 7: EECR/hydrolysis process for methionine repeated 5 times>

For methionine, the EECR/hydrolysis process was repeated 5 times in the same manner as in Example 1. Racemization was performed at room temperature. By adjusting the pH of the aqueous solution of methionine obtained through hydrolysis to 6.0, 0.55 g of L-methionine having an optical purity of 98.8% was obtained. Yield: 369% (based on compound 1).

<Example 8: EECR/hydrolysis continuous process experiment of phenylalanine using a continuous reactor>

Figure 5a shows a schematic diagram of a continuous reaction system (CRS) for continuously performing all processes by continuously connecting the EECR process, the hydrolysis process, and the neutralization process.

FIG. 5b is a view of performing an EECR/hydrolysis continuous process experiment of phenylalanine using the experimental apparatus according to the continuous reactor diagram of FIG. 5a.

The continuous reactor according to FIG. 5a consists of three steps of performing an amino acid extraction process, a hydrolysis process, and a neutralization process, respectively. The amino acid extraction process is carried out in continuously stirred reactors R1 to R3, which flow into a first connector (U1) allowing separation of the reaction mixture into an organic layer and an aqueous layer. A peristaltic pump P1 moves the separated organic layer to the continuously stirred reactor chambers R4 to R6 of the hydrolysis process which carries the hydrolysis of the imine in U1. Subsequent separation of the layers in the second connector (U2) provides an organic layer and said aqueous layer containing enantiomerically pure amino acids as their HCl salts. The acidic organic layer flowing from U2 goes to a third conduit (U3) for neutralization before being recycled to R1, where a new EECR cycle begins. During this process, additional starting L-AA (or DL-AA) is also fed into the reactor R1 to compensate for the depletion of L-AA (or DL-AA). This system is an extended variant of the well-known connector U-tube design for performing continuous transfer of material from one side to another.

The EECR process is performed in the amino acid extraction process part, and the aqueous solution of the amino acid extraction process part is L-AA, L-phenylalanine (6.0 g, 32 mmol), PLP (0.03 g, 0.12 mmol), CuSO ₄ 5H ₂ O (0.015 g, 0.06 mmol) was added and dissolved in water (20 mL), and then NaOH was added to adjust the pH to 12.0. An organic layer was prepared by dissolving S-t-butylketone binaphthol derivative (Compound 1) (4.5 g, 7.6 mmol) and Aliquat 336 (4.3 g, 8.5 mmol) in a methylenechloride solvent (40 mL):

After filling the amino acid extraction process part with the aqueous solution first and flowing the organic layer to allow the EECR process to proceed sufficiently, move the organic layer of U1 toward the hydrolysis part filled with hydrochloric acid aqueous solution (2.0 N, 20 mL) P1 (Pump 1) The organic layer separated from U2 was moved through P3 to U3, the neutralization reaction section filled with Na ₂ CO ₃ aqueous solution (1.0 N, 5 mL), so that hydrolysis was sufficiently performed. The organic layer that has passed through the neutralization process is returned to R1, which is the first reactor, through P4. If the reaction proceeds with careful attention to the first amino acid extraction process, hydrolysis process, and neutralization process manually, the reaction proceeds automatically from the second amino acid extraction process, hydrolysis process, and neutralization process. When the amount of phenylalanine in the aqueous solution layer of the amino acid extraction process part decreased by about 1 equivalent with respect to Compound 1, 1 equivalent (1.5 g) of phenylalanine corresponding thereto was manually added together with NaOH in a solid state. In this way, the continuous process equipment was operated for 48 hours.

In addition to the initially used 6.0 g of phenylalanine, the amount of additional phenylalanine was all 7.5 g. After the operation of the continuous process equipment was completed, the aqueous layer of the hydrolysis part was separated, and the pH was adjusted to 6.0 to obtain 6.0 g (32 mmol, optical purity 98.7%) of solid phenylalanine. This corresponds to a yield of 421% based on compound 1, and corresponds to a yield of 44% based on 13.5 g of phenylalanine used (about 4 g of phenylalanine in the aqueous solution of the amino acid extraction process part) remaining, so the actual yield is well in excess of 50%).

<Example 9: Crystal structure of compound 1 and imine of phenylalanine>

Crystals were obtained from a methylene chloride solution of the imine compound prepared by reacting Compound 1 with phenylalanine. The structure of this crystal was confirmed using an X-ray diffractometer, and Table 1 below shows the X-ray analysis data.

wavelength	0.71073 Å
decision system	triclinic
space group	P1
unit cell dimension	a = 10.4978(2) Å α= 114.6704(10)° b = 13.0490(2) Å β= 100.7775(11)° c = 13.8968(3) A γ = 101.0028(11)°
volume	1620.45(5) Å 3
Z	One
Density (calculated)	1.160 Mg/m 3
absorption coefficient	0.095 mm -1
F(000)	598
crystal size	0.200 x 0.200 x 0.100 mm 3
Theta range for data collection	1.690° to 24.152°
index range	-12≤h≤12, -15≤k≤15, -15≤l≤15
collected reflections	43005
independent reflection	10296 [R(int) = 0.0386]
Theta completeness = 25.422°	87.9%
Absorption correction	multi-scan
Purification method	Full matrix least squares for F 2
Data/Limits/Parameters	10296 / 113 / 816
Goodness of fit to F2	1.046
final R index [I>2 sigma (I)]	R1 = 0.0601, wR2 = 0.1703
R index (all data)	R1 = 0.0723, wR2 = 0.1845
Absolute structural parameters	0.03(3)
the biggest difference. peak and hall	0.827 and -0.206 e.Å -3

The above description of the present application is for illustration, and those of ordinary skill in the art to which the present application pertains will understand that it can be easily modified into other specific forms without changing the technical spirit or essential features of the present application. Therefore, it should be understood that the embodiments described above are illustrative in all respects and not restrictive. For example, each component described as a single type may be implemented in a dispersed form, and likewise components described as distributed may also be implemented in a combined form.

The scope of the present application is indicated by the following claims rather than the above detailed description, and all changes or modifications derived from the meaning and scope of the claims, and their equivalents should be construed as being included in the scope of the present application. .

Claims (10)

1. It includes using a t-butylketone binaphthol derivative represented by the following formula (1) or a t-butylketone derivative represented by the following formula (2) as a chiral extractant,

   An amino acid extraction process, in which racemization of amino acids in aqueous solution and chiral-selective liquid-liquid extraction are performed simultaneously:

   [Formula 1]

   

   ;

   [Formula 2]

   

   ;

   In Formula 1 or Formula 2,

   Wherein X is, each independently, hydrogen; halogen group; amino group; nitro group; cyano group; formyl group; carboxyl group; C _1-10 alkylcarbonyl group; C _6-10 aryl group; C _1-10 alkoxy group; and a C _1-10 alkyl group unsubstituted or substituted with one or more substituents selected from the group consisting of a halogen group, a hydroxyl group, an amino group, a cyano group, a nitro group, and a C _6-10 aryl group;

   Y is, each independently, hydrogen; halogen group; amino group; nitro group; cyano group; formyl group; carboxyl group; C _1-10 alkylcarbonyl group; C _6-10 aryl group; C _1-10 alkoxy group; and a C _1-10 alkyl group unsubstituted or substituted with one or more substituents selected from the group consisting of a halogen group, a hydroxyl group, an amino group, a cyano group, a nitro group, and a C _6-10 aryl group;

   wherein n and m are each independently an integer of 0 to 4;

   Wherein R ₁ is a divalent functional group, substituted or unsubstituted by a C _1-5 straight-chain or branched alkyl group (alkyl group), C _1-5 straight-chain or branched alkylene group (alkylenyl group), C _{2 -5} of a straight or branched chain alkenylene group (alkenylenyl group), C _2-5 of a straight or branched chain alkynylene group (alkynylenyl group), C _3-10 of a cyclic alkylene group (cyclicalkylenyl group), C _5-10 is an arylene group of

   wherein R ₂ is a halogen group or a C _1-5 linear or branched alkyl group substituted or unsubstituted with OH; C _3-10 cyclic alkyl group unsubstituted or substituted with a halogen group or OH; a C _2-5 linear or branched alkenyl group unsubstituted or substituted with a halogen group or OH; a C _2-5 linear or branched alkynyl group unsubstituted or substituted with a halogen group or OH; Or an aryl group unsubstituted or substituted with a halogen group or OH.
2. The method of claim 1,

   The chiral extractant will be used for the purpose of L / D optical conversion of amino acids, amino acid extraction process.
3. The method of claim 1,

   The chiral extractant will have a chiral selectivity of 95% or more, amino acid extraction process.
4. The method of claim 1,

   The amino acid extraction process, wherein the t-butyl ketone binaphthol derivative or the t-butyl ketone derivative includes an optical isomer of (S) type or (R) type.
5. The method of claim 1,

   The t-butylketone binaphthol derivative or the t-butylketone derivative includes the following compound 1 or the following compound 2, amino acid extraction process:

   [Compound 1]

   

   ;

   [Compound 2]

   

   .
6. The method of claim 1,

   The t-butylketone binaphthol derivative and the t-butylketone derivative each contain a carbonyl group (C=O) that combines with an amino acid to form an imine, an amino acid extraction process.
7. The method of claim 1,

   An amino acid extraction process, wherein copper ions and/or pyridoxal-5'-phosphate, which are racemization catalysts, are present in the aqueous solution layer during the amino acid extraction process.
8. A continuous reactor for performing the amino acid extraction process according to any one of claims 1 to 7, comprising:

   The continuous reactor consists of three parts: an amino acid extraction process part, a hydrolysis process part, and a neutralization process part,

   The amino acid extraction process part and the hydrolysis process part are to have at least one reaction tank,

   Obtaining an optically pure amino acid by cyclically performing an amino acid extraction process, a hydrolysis process and a neutralization process,

   continuous reactor.
9. 9. The method of claim 8,

   A first connector (U1) located between the amino acid extraction process part and the hydrolysis process part, and

   A second connection pipe (U2) positioned between the hydrolysis process part and the neutralization process part,

   The neutralization process unit will include a third connecting pipe (U3), the continuous reactor.
10. 9. The method of claim 8,

    wherein the chiral selective extraction process, the hydrolysis process and the neutralization process are recycled within the continuous reactor.

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