Method for optical resolution of chiral compound and method for producing enantiomer

Abstract

To provide a simple method for optically resolving a chiral compound, which is expected to be industrially applicable.SOLUTION: A method for optical resolution of a chiral compound includes dissolving a mixture of both enantiomers of the chiral compound in a first solvent to prepare a first solution, stirring the prepared first solution, precipitating a first gel in the stirred first solution, and separating the first solution into the first gel and a first supernatant.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] The present invention relates to a method for optical resolution of a chiral compound and a method for producing an enantiomer using the method for optical resolution of a chiral compound. [Background technology]

[0002] Although optical isomers (enantiomers) of chiral compounds have no difference in physical properties such as boiling point and solubility, they may exhibit different physiological activities due to differences in their stereochemistry. For this reason, separation of the enantiomers (optical resolution) is important, and various methods have been proposed. Among these, crystallization is used as a practical method for optical resolution of chiral compounds on an industrial scale (e.g., Non-Patent Documents 1 and 2).

[0003] However, in principle, crystallization requires the separate crystallization of both enantiomers. However, in most cases, the stable crystallization of chiral compounds results in racemic crystals, in which both enantiomers are present in equal amounts in the same crystal. For this reason, only about 5% of chiral compounds can be optically resolved by crystallization. Under these circumstances, there is a need for a simpler method for the optical resolution of chiral compounds that is different from crystallization and that can be applied industrially.

[0004] Under these circumstances, the inventors of the present application discovered that when a gel is precipitated in a solution of a mixture of both enantiomers of a chiral compound (e.g., a racemic mixture), one enantiomer is concentrated in the gel, and based on this finding, they have developed a new method for optical resolution of chiral compounds (Patent Document 1). [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] Cryst EngComm,2010,12,1983-1992 [Non-patent document 2] Cryst. Growth Des. 2011,11,2149-2163 [Patent documents]

[0006] [Patent Document 1] Japanese Patent Application Publication No. 2023-85192 Summary of the Invention [Problem to be solved by the invention]

[0007] The method for optical resolution of chiral compounds using gelation disclosed in Patent Document 1 is a simple method that does not involve complicated steps, and is therefore expected to be industrially applicable. Furthermore, it is possible to optically resolve chiral compounds that form racemic crystals, which have been difficult to resolve using conventional crystallization methods. The present invention provides a method for optically resolving chiral compounds more efficiently using a method for optical resolution of chiral compounds that involves gelation. [Means for solving the problem]

[0008] As a result of extensive research into achieving the above object, the present inventors have found that the above object can be achieved by the following configuration.

[0009] [1] A method for optical resolution of a chiral compound, comprising: dissolving a mixture of both enantiomers of the chiral compound in a first solvent to prepare a first solution; Stirring the prepared first solution; Precipitating a first gel in the stirred first solution; separating the first solution into the first gel and a first supernatant. [2] The method for optical resolution according to [1], wherein the mixture of both enantiomers is a racemic mixture. [3] The method for optical resolution according to [1], wherein the mixture of both enantiomers contains one enantiomer in a larger amount than the other enantiomer. [4] In the first gel, the content of one enantiomer is greater than the content of the other enantiomer; The optical resolution method according to [3], wherein the enantiomeric excess of the one enantiomer in the first gel is greater than the enantiomeric excess of the one enantiomer in the mixture of both enantiomers. [5] The method for optical resolution according to any one of [1] to [4], wherein the chiral compound is an amino acid or an amino acid derivative. [6] The optical resolution method according to [5], wherein the chiral compound is one selected from the group consisting of glutamic acid, aspartic acid, lysine, phenylalanine, tyrosine, tryptophan, histidine, proline, and derivatives thereof. [7] The method for optical resolution according to any one of [1] to [6], wherein the first solvent is a polar solvent. [8] The optical resolution method according to [7], wherein the first solvent is an aprotic polar solvent. [9] The optical resolution method according to [8], wherein the first solvent contains dimethyl sulfoxide.

[10] The optical resolution method according to [7], wherein the first solvent contains water.

[11] The first solvent comprises a good solvent for the chiral compound and a poor solvent for the chiral compound, The preparation of the first solution comprises: dissolving the mixture of both enantiomers in the good solvent to prepare an intermediate solution; The optical resolution method according to any one of [1] to

[10] , further comprising adding the poor solvent to the intermediate solution to obtain the first solution.

[12] A method for optical resolution of a chiral compound, comprising: dissolving a mixture of both enantiomers of the chiral compound in a first solvent to prepare a first solution; Precipitating a first gel in the first solution; separating the first solution into the first gel and a first supernatant; dissolving the first gel separated from the first supernatant in a second solvent to prepare a second solution; Precipitating a second gel in the second solution; separating the second solution into the second gel and a second supernatant; The optical resolution method further comprises stirring at least one selected from the group consisting of the first solution before precipitating the first gel and the second solution before precipitating the second gel.

[13] A method for optical resolution of a chiral compound, comprising: dissolving a mixture of both enantiomers of the chiral compound in a first solvent to prepare a first solution; Precipitating a first gel in the first solution; separating the first solution into the first gel and a first supernatant; Precipitating a third gel in the first supernatant liquid separated from the first gel; separating the first supernatant into the third gel and a third supernatant; The optical resolution method further comprises stirring at least one selected from the group consisting of the first solution before precipitating the first gel and the first supernatant before precipitating the third gel.

[14] The optical resolution method according to any one of [1] to

[13] , wherein the stirring time for at least one stirring step selected from the group consisting of stirring the first solution, stirring the second solution, and stirring the first supernatant is 1 hour to 2 hours.

[15] The optical resolution method according to any one of [1] to

[14] , wherein the stirring speed is 50 rpm to 100 rpm in at least one stirring step selected from the group consisting of stirring the first solution, stirring the second solution, and stirring the first supernatant.

[16] A method for producing one enantiomer and / or the other enantiomer of a chiral compound, comprising: providing a mixture of both enantiomers of said chiral compound; and separating the one enantiomer and / or the other enantiomer from the mixture by the method for optical resolution of a chiral compound according to any one of [1] to

[15] . [Effects of the Invention]

[0010] The present invention provides a simple method for optical resolution of a chiral compound that is expected to be industrially applicable. The present invention also provides a production method for producing one enantiomer or the other enantiomer of a chiral compound using the optical resolution method. [Brief explanation of the drawings]

[0011] [Figure 1] FIG. 1 is a flowchart illustrating the method for optical resolution of a chiral compound according to the first embodiment. [Figure 2] FIG. 2 is a diagram illustrating the optical resolution method of a chiral compound according to the second and third embodiments. [Figure 3] FIG. 3 is a chromatogram of the racemic mixture obtained by chiral HPLC in Experiment 1 of the Example. [Figure 4] FIG. 4 is a graph showing the enantiomeric excess of each sample in Experiment 2 of the Example. DETAILED DESCRIPTION OF THE INVENTION

[0012] Hereinafter, embodiments of the present invention will be described in detail. The following description of the constituent elements may be based on a representative embodiment of the present invention, but the present invention is not limited to such an embodiment. In this specification, a numerical range expressed using "to" means a range that includes the numerical values ​​before and after "to" as the lower and upper limits.

[0013] [First embodiment] As shown in the flowchart of FIG. 1, the optical resolution method of this embodiment includes the following steps.

[0014] Step S1: Dissolving a mixture of both enantiomers of a chiral compound in a solvent (an example of a "first solvent") to prepare a solution (an example of a "first solution"); Step SS: Stir the prepared solution Step S2: Precipitating a gel (an example of a "first gel") in the stirred solution; and Step S3: Separating the solution into a gel and a supernatant.

[0015] As disclosed in Patent Document 1, the inventors of the present application discovered that when a gel is precipitated in a solution of a mixture of both enantiomers of a chiral compound, one enantiomer is concentrated in the gel, and based on this finding, they developed a method for optical resolution of chiral compounds, which includes the above steps S1, S2, and S3. The mechanism behind this is unclear, but it is presumed to be due to the self-accelerating homochiral aggregation of the enantiomers.

[0016] As a result of further intensive research into the method for optical resolution of chiral compounds using gelation, the present inventors discovered a method for more efficient optical resolution of chiral compounds by adding a step (step SS) of stirring the prepared chiral compound solution between steps S1 and S2. By adding step SS, gelation is accelerated compared to when step SS is not added, enabling optical resolution in a shorter time and increasing the concentration of one enantiomer in the gel (i.e., enantiomeric excess). Since a gel is a dispersion that has lost its fluidity and solidified, when considering promoting gelation in a general system, a homogeneous solution should be prepared and then allowed to stand. Therefore, the present inventors' surprising discovery that preparing a homogeneous solution of a chiral compound and then stirring it accelerates gelation (shortens gelation time) and also increases the enantiomeric excess in the gel was surprising. The mechanism behind this is unclear, but is speculated to be as follows.

[0017] In the initial stage of gelation in a chiral compound solution, stochastic fluctuations cause localized gelation favoring one enantiomer. This then gradually spreads throughout the system, resulting in the precipitation of a gel enriched in one enantiomer. For example, in the initial stage of gelation, small homochiral aggregates of one enantiomer first appear locally, then these aggregates connect to form filaments (strings), and these filaments then entangle with each other, resulting in the precipitation of a gel. In conventional methods where stirring is not performed during the initial stage of gelation, even if gelation biased toward one enantiomer proceeds locally, it is difficult for this to spread to the entire system with positive feedback. As a result, the effect of gelation of the other enantiomer proceeding in other parts of the solution cancels out, making it difficult for a significant bias (concentration of one enantiomer into a gel) to occur in the entire system. In contrast, in the present invention, by stirring the chiral compound solution in the early stage of gelation (step SS), it is presumed that the influence of the locally generated enantiomer bias spreads throughout the system, thereby inducing "progression of gelation biased toward one enantiomer" throughout the system. That is, gelation is accelerated (gelation time is shortened), and the enantiomeric excess in the gel increases. Note that the mechanism described above is merely presumed and does not limit the scope of the present invention in any way.

[0018] The optical resolution method of this embodiment will be described in detail below.

[0019] <Step S1 and Step S2> First, a mixture of both enantiomers of a chiral compound is dissolved in a solvent (first solvent) to prepare a solution (first solution) (Step S1).

[0020] The chiral compound is not particularly limited as long as it has an asymmetric carbon and exists as a mirror-image stereoisomer (enantiomer). Examples of chiral compounds include amino acids (e.g., α-amino acids other than glycine) and derivatives thereof. Amino acids and their derivatives can be used as raw materials for various products, such as food additives, pharmaceuticals, and cosmetics, and selectively obtaining only the L-isomer or only the D-isomer is very important. Because this embodiment is a simple method, it can efficiently optically resolve amino acids and their derivatives, contributing to cost reduction of these various products. Examples of amino acids and their derivatives include glutamic acid, aspartic acid, lysine, phenylalanine, tyrosine, tryptophan, histidine, proline, and their derivatives. Of these, phenylalanine, tryptophan, and their derivatives can be more efficiently resolved by the optical resolution method of this embodiment. The chiral compounds used in this embodiment may be commercially available or synthesized.

[0021] The ratio of each enantiomer in the mixture of both enantiomers is not particularly limited. The mixture of both enantiomers may be a racemic mixture in which each enantiomer is present in equal amounts. As will be described in detail later, the enantiomer that accounts for more than half (50% or more) of both enantiomers is concentrated in the gel.

[0022] The solvent is not particularly limited as long as it dissolves the chiral compound. For example, a polar solvent can be used, and an aprotic polar solvent or water is preferred.

[0023] Aprotic polar solvents tend to stabilize the gel that precipitates in the solution, allowing for efficient optical resolution. This is presumably because aprotic polar solvents are less likely to affect the association of chiral compounds that are gelled by hydrogen bonds or other factors. Aprotic polar solvents include acetonitrile, N-methylpyrrolidone, dichloromethane, tetrahydrofuran, ethyl acetate, acetone, dimethylformamide, dimethyl sulfoxide (DMSO), and propylene carbonate. Among these, dimethyl sulfoxide (DMSO), which further stabilizes the gel, is preferred.

[0024] When water is used as the solvent, a water-containing gel is obtained. Water is harmless to the human body and has a low environmental impact, making it important for ensuring the safety and reducing costs of the optical resolution process. The solvent may be an aqueous solvent containing water as the main component, such as physiological saline, boric acid, phosphoric acid, or carbonated buffers.

[0025] The solvent may be a single solvent or a mixture of two or more solvents. When a mixture of two or more solvents is used, the proportion of the aprotic polar solvent such as DMSO or water in the total solvent is preferably 80% by volume or more, or 90% by volume or more.

[0026] The solution of the chiral compound may be composed of only the chiral compound and a solvent, or may contain other compounds such as general-purpose additives (e.g., various electrolytes contained in buffers, etc.) within a range that does not impair the effects of this embodiment.

[0027] The method for preparing a solution of a chiral compound (Step S1) and the method for precipitating a gel (Step S2) are not particularly limited and can be carried out by a general-purpose method. In this embodiment, however, the following method is used to efficiently precipitate a gel. First, a suspension is prepared by suspending a chiral compound in a solvent at a first temperature (e.g., room temperature). Next, the suspension is heated to a second temperature higher than the first temperature. This increases the solubility of the chiral compound in the solvent, and a solution at the second temperature is prepared (Step S1 in FIG. 1). To promote dissolution of the chiral compound in the solvent, the suspension may be stirred, ultrasonically irradiated, or the like before and / or during heating of the suspension.

[0028] Next, the solution at the second temperature is cooled to a third temperature lower than the second temperature, and the solution is allowed to stand at the third temperature for a predetermined time. This causes a gel to precipitate in the solution (step S2 in FIG. 1). In this embodiment, the entire solution does not gel, but only a portion of the solution precipitates as a gel. That is, a gel and a supernatant liquid (an example of a "first supernatant liquid") are produced from the solution.

[0029] The first and third temperatures are not particularly limited as long as they are lower than the second temperature, but from the viewpoint of efficient operation, the first and third temperatures are preferably near room temperature so that the gel precipitates at room temperature. The first and third temperatures are, for example, 15 to 30°C, or 20 to 25°C. The second temperature is also not particularly limited as long as it is equal to or higher than the first and third temperatures, but from the viewpoint of efficient operation, it is, for example, 50 to 100°C, or 60 to 80°C.

[0030] The amount of the chiral compound (a mixture of both enantiomers) in the solution is not particularly limited. For example, it is preferably equal to or greater than the saturated solubility concentration at the third temperature and equal to or less than the saturated solubility at the second temperature so as to promote precipitation of a gel at the third temperature. The amount (concentration) of the chiral compound in the solution is, for example, 2.0 to 50 mM (mol / m 3 ), or 4.0 to 35 mM (mol / m 3 ) is preferred.

[0031] The time for which the solution is allowed to stand at the third temperature can be adjusted as appropriate based on the type and amount of chiral compound, the type of solvent, etc. If the standing time is too short, there is a risk that the gel will not be sufficiently precipitated, while if the standing time is too long, there is a risk that the efficiency of enantiomer resolution will decrease and the gel state will become unstable. The standing time may be, for example, 5 to 48 hours, or 10 to 20 hours.

[0032] <Step SS> In the method for optical resolution of a chiral compound of this embodiment, the solution of the prepared chiral compound is stirred between the above-mentioned steps S1 and S2 (step SS).

[0033] The method (means) for stirring the solution is not particularly limited, and general-purpose stirring equipment such as a magnetic stirrer, a mechanical stirrer, etc. The stirring speed (stirring rotation speed) and stirring time are not particularly limited and may be adjusted appropriately depending on the type and concentration of the chiral compound, the type of solvent, etc. The stirring speed (stirring rotation speed) may be, for example, 50 rpm to 100 rpm, and the stirring time may be, for example, 1 hour to 2 hours.

[0034] Step SS (stirring the solution) is performed after step S1. That is, in this step SS, the homogeneous solution after the chiral compound is completely dissolved in the solvent is stirred. For example, in step S1, the solution may be stirred to promote dissolution of the chiral compound in the solvent, but the stirring in step SS is performed separately from the stirring in step S1. After step SS (stirring the solution), for example, by leaving the solution to stand, a gel precipitates in the stirred solution (step S2).

[0035] The temperature of the solution during stirring is not particularly limited, but from the viewpoint of promoting gelation, it is preferably the same temperature (e.g., room temperature) as that of the subsequent gelation step (step S2) described above. For example, as described above, when a suspension of a chiral compound is prepared at a first temperature (e.g., room temperature), the suspension is heated to prepare a homogeneous solution at a second temperature (step S1), and then the solution is cooled to a third temperature and allowed to stand at the third temperature to precipitate a gel (step S2), stirring of the solution in step SS is preferably stirring the solution cooled to the third temperature.

[0036] <Step S3> After the gel is precipitated in the solution (step S2), the gel is separated from the supernatant (step S3 in FIG. 1). The method for separating the gel from the supernatant is not particularly limited, and general-purpose methods such as decantation, filtration, and centrifugation can be used.

[0037] In this embodiment, one enantiomer is concentrated in the gel, and the other enantiomer is concentrated in the supernatant. This allows optical resolution of a mixture of both enantiomers. Hereinafter, the enantiomer concentrated in the gel will be referred to as enantiomer Ea (an example of "one enantiomer"), and the enantiomer concentrated in the supernatant will be referred to as enantiomer Eb (an example of "the other enantiomer"). Furthermore, the inventors of the present application have discovered that in a mixture of both enantiomers (starting material), the enantiomer that accounts for more than half (50% or more) of the total is concentrated in the gel as enantiomer Ea. For example, when the content of enantiomer Ea is greater than the content of enantiomer Eb (when enantiomer Ea is present in excess of more than 50%) in a mixture of both enantiomers, enantiomer Ea is concentrated in the gel.

[0038] If the starting mixture of both enantiomers is a racemic mixture containing equal amounts of each enantiomer, there is a 50% chance that either enantiomer will be concentrated in the gel as enantiomer Ea, and there is also a 50% chance that either enantiomer will be concentrated in the supernatant as enantiomer Eb.

[0039] In this embodiment, since enantiomer Ea is concentrated in the gel, the content of enantiomer Ea in the gel is greater than the content of enantiomer Eb. That is, the enantiomeric excess of enantiomer Ea in the gel is greater than the enantiomeric excess of enantiomer Ea in the mixture of both enantiomers that is the starting material. For example, when the mixture of both enantiomers is a racemic mixture, i.e., when the enantiomeric excess of enantiomer Ea in the starting material is 0%, the enantiomeric excess of enantiomer Ea in the gel may be, for example, 6 to 22% or 18 to 20%.

[0040] In this embodiment, since enantiomer Ea is concentrated in the gel, the content of enantiomer Ea in the supernatant is reduced. In other words, enantiomer Eb is concentrated in the supernatant. Therefore, for example, when the mixture of both enantiomers is a racemic mixture, the content of enantiomer Eb in the supernatant is greater than the content of enantiomer Ea. The enantiomeric excess of enantiomer Eb in the supernatant is greater than the enantiomeric excess of enantiomer Eb in the mixture of both enantiomers that is the starting material. For example, when the mixture of both enantiomers is a racemic mixture, i.e., when the enantiomeric excess of enantiomer Eb in the starting material is 0%, the enantiomeric excess of enantiomer Eb in the supernatant may be, for example, 2 to 10% or 4 to 8%.

[0041] The optical resolution method of the present embodiment described above is a simple method that does not involve any complicated steps, and is therefore expected to be industrially applicable. Furthermore, the method of the present embodiment can also optically resolve chiral compounds that form racemic crystals, which have been difficult to resolve using conventional crystallization methods.

[0042] <Modification> The optical resolution method of this embodiment is not limited to the method described above. For example, after separation of the gel and the supernatant (step S3 in FIG. 1), the solvent contained in the gel may be removed to extract the enantiomer Ea, or the solvent contained in the gel may be replaced with another solvent, as necessary. In addition, in the embodiment described above, a suspension is prepared at a first temperature, and then the suspension is heated to prepare a solution at a second temperature. However, the present invention is not limited to this. For example, a solution at a second temperature may be prepared by dissolving a chiral compound in a solvent at a second temperature without preparing a suspension at the first temperature. The prepared solution at the second temperature can be cooled to a third temperature or lower and allowed to stand for a predetermined time to precipitate a gel.

[0043] Furthermore, in preparing the solution (step S1 in FIG. 1), a good solvent for the chiral compound and a poor solvent may be used as solvents. For example, first, an intermediate solution may be prepared by dissolving the chiral compound in a good solvent, and then a poor solvent may be added to the intermediate solution to obtain a solution (first solution). According to this method, a gel can be precipitated by preparing the solution and leaving it at room temperature without heating. Since heating is not required, this method can be applied to thermally unstable compounds, improves the efficiency of optical resolution, and reduces costs.

[0044] [Second embodiment] In this embodiment, a method for further increasing the purity (enantiomeric excess) of enantiomer Ea (an example of "one enantiomer") concentrated in the gel by repeating gel precipitation (gelation) multiple times will be described.

[0045] First, as shown in Fig. 2, a solution L (an example of a "first solution") containing a mixture M of both enantiomers of a chiral compound is prepared by the method described in the first embodiment, and a gel G (an example of a "first gel") is precipitated in the solution L, and then the gel G and a supernatant S (an example of a "first supernatant") are separated. The gel G obtained by the first gelation is enriched with enantiomer Ea.

[0046] Next, a solvent (an example of a "second solvent") is added to the gel G, and the gel G is dissolved in the solvent to prepare a solution GL (an example of a "second solution"). Then, a gel GG (an example of a "second gel") is precipitated in the solution GL, and then the gel GG and a supernatant liquid GS (an example of a "second supernatant liquid") are separated.

[0047] In gel G and solution GL prepared using it, the concentration of enantiomer Ea is higher than the concentration of enantiomer Eb (enantiomer Ea is present in excess). As mentioned above, the excess enantiomer is concentrated in the gel. Therefore, the enantiomeric excess of enantiomer Ea in gel GG after the second gelation is greater than the enantiomeric excess of enantiomer Ea in gel G after the first gelation.

[0048] Figure 2 also shows the third gelation of the Gel G series. Solution GG-L was prepared using Gel GG from the second gelation, and Gel GGG was precipitated in Solution GG-L. Gel GGG was then separated from the supernatant GGS. Enantiomer Ea was further concentrated in Gel GGG.

[0049] In the optical resolution method of this embodiment, at least one of solution L (first solution), solution GL (second solution), and solution GG-L is stirred before precipitating the gel. This allows for more efficient optical resolution of chiral compounds. One or two of the liquids may be stirred, or all of the liquids may be stirred. The stirring conditions (rotation speed, stirring time, temperature during stirring, etc.) are the same as those for stirring the solutions described in the first embodiment, and preferred embodiments are also the same.

[0050] As described above, when gelation is repeated multiple times, the purity of enantiomer Ea in the resulting gel can be increased with each gelation. In this embodiment, the enantiomer Ea can be concentrated to a desired enantiomeric excess by a simple method that does not involve any complicated steps.

[0051] The enantiomeric excess of enantiomer Ea in each gel of the Gel G series has the following magnitude relationship. EEa3>EEa2>EEa1>EEa0 EEa0: Enantiomeric excess of enantiomer Ea in mixture M of both enantiomers EEa1: Enantiomeric excess of enantiomer Ea in gel G EEa2: Enantiomeric excess of enantiomer Ea in gel GG EEa3: Enantiomeric excess of enantiomer Ea in gel GGG

[0052] In each gelation, the preparation of the solution, the precipitation of the gel, and the separation of the gel from the supernatant can be carried out in the same manner as described in Embodiment 1. The solvents used to prepare the solutions may be the same or different, but it is preferable that they are the same.

[0053] The number of times gelation is repeated can be appropriately set depending on the required enantiomeric excess, and may be, for example, 1 to 5, or 2 to 3. Even when mixture M is a racemic mixture, i.e., when the enantiomeric excess EEa0 of enantiomer Ea in mixture M is 0%, the enantiomeric excess of enantiomer Ea in the gel can be increased to about 60 to 70% by repeating gelation, for example, three times.

[0054] [Third embodiment] In this embodiment, a method for further increasing the purity of enantiomer Eb (enantiomeric excess) by gelling enantiomer Eb (an example of the "other enantiomer") concentrated in supernatant S shown in FIG. 2 will be described.

[0055] First, a gel SG (an example of a "third gel") is precipitated in a supernatant S (an example of a "first supernatant"). For example, the gel SG can be precipitated in the supernatant S by leaving the supernatant S at a predetermined temperature for a predetermined time. The predetermined temperature can be, for example, 0 to 15°C or 5 to 10°C, and the predetermined time can be, for example, 8 to 48 hours or 12 to 24 hours. Thereafter, the gel SG and the supernatant SS (an example of a "third supernatant") are separated.

[0056] For example, if the starting material mixture M is a racemic mixture, the concentration of enantiomer Eb in the supernatant S is higher than the concentration of enantiomer Ea (enantiomer Eb is present in excess). As described above, the excess enantiomer is concentrated in the gel. Therefore, the enantiomeric excess of enantiomer Eb in the gel SG obtained after the second gelation is greater than the enantiomeric excess of enantiomer Eb in the supernatant S obtained after the first gelation.

[0057] Figure 2 also shows the third gelation of the supernatant S series. Solution SG-L was prepared using gel SG from the second gelation, and gel SGG was precipitated in solution SG-L. Then, gel SGG and supernatant SGS were separated. Enantiomer Eb was further concentrated in gel SGG.

[0058] In the optical resolution method of this embodiment, before precipitating the gel, at least one of solution L (first solution), supernatant S (first supernatant), and solution SG-L is stirred. This allows for more efficient optical resolution of the chiral compound. One or two of the liquids may be stirred, or all of the liquids may be stirred. The stirring conditions (rotation speed, stirring time, temperature during stirring, etc.) are the same as those for stirring the solution described in the first embodiment, and preferred embodiments are also the same.

[0059] In this embodiment, the enantiomer Eb concentrated in the supernatant S can be concentrated in a gel by performing a second gelation. Concentrating the enantiomer Eb in a gel makes it easier to handle the enantiomer Eb thereafter. Furthermore, when gelation is repeated multiple times, the purity of the enantiomer Eb in the resulting gel can be increased with each gelation. In this embodiment, the enantiomer Eb can be concentrated to a desired enantiomeric excess by a simple method that does not involve any complicated steps.

[0060] The enantiomeric excess of enantiomer Eb in each gel of the supernatant S series has the following magnitude relationship. EEb3>EEb2>EEb1>EEb0 EEb0: Enantiomeric excess of enantiomer Eb in mixture M of both enantiomers EEb1: Enantiomeric excess of enantiomer Eb in supernatant S EEb2: Enantiomeric excess of enantiomer Eb in gel SG EEb3: Enantiomeric excess of enantiomer Eb in gel SGG

[0061] In each gelation, the preparation of the solution, the precipitation of the gel, and the separation of the gel from the supernatant can be carried out in the same manner as described in Embodiment 1. The solvents used to prepare the solutions may be the same or different, but it is preferable that they are the same.

[0062] The number of times gelation is repeated can be appropriately set depending on the required enantiomeric excess, and may be, for example, 1 to 5 times, or 2 to 3 times. Even when mixture M is a racemic mixture, i.e., when the enantiomeric excess EEb0 of enantiomer Eb in mixture M is about 0%, the enantiomeric excess of enantiomer Eb in the gel can be increased to, for example, 25 to 35% by repeating gelation, for example, twice.

[0063] [Fourth embodiment] In this embodiment, a production method for producing one enantiomer (enantiomer Ea) and / or the other enantiomer (enantiomer Eb) of a chiral compound using the optical resolution method described in any of the first to third embodiments will be described.

[0064] First, a mixture M of both enantiomers of a chiral compound is prepared. As the mixture M of both enantiomers of a chiral compound, the same mixture as that used in the first to third embodiments can be used.

[0065] Next, the mixture M of both enantiomers is optically resolved using the optical resolution method described in any one of the first to third embodiments, thereby obtaining enantiomer Ea and / or enantiomer Eb.

[0066] Asymmetric synthesis is a method for producing a desired enantiomer, but it is often accompanied by technical difficulties and tends to increase production costs. Alternatively, enantiomer resolution techniques using chiral columns exist, but their use on a large scale is not practical. Therefore, optical resolution methods are suitable for producing a desired enantiomer on an industrial scale. The production method of this embodiment is a simple method, and can produce a desired enantiomer at a lower cost.

[0067] The above-described embodiments may be combined with each other as long as they do not exclude each other. [Example]

[0068] The present invention will be further explained using examples and comparative examples, but the scope of the present invention is not limited by these examples and comparative examples.

[0069] [Experiment 1] (1) Preparation of chiral compound solutions In this example, the commercially available compound (I) (Fmoc-Phe-OH) represented by the following formula (I) was used as the chiral compound. Compound (I) is a phenylalanine derivative.

[0070] [ka]

[0071] 5.15 mL of phosphate buffer (50 mM) was added to 10.3 mg of an equal mixture (racemic mixture) of L- and D-isomers of Compound (I), and a homogeneous solution was prepared by ultrasonic treatment and heating (70°C). 1.5 mL of the prepared solution was divided into two vials, designated as Sample (Solution) IA and Sample (Solution) IB.

[0072] (2) Stirring the solution Sample IA and Sample IB were kept at 20° C. for 1.5 hours. At this time, Sample IA was stirred using a magnetic stirrer (rotation: 80 rpm), while Sample IB was not stirred.

[0073] (3) Gel precipitation and separation of the gel and supernatant Sample IA after stirring and Sample IB without stirring were allowed to stand at 20°C. After stirring, Sample IA was left standing for 17 hours, and a gel precipitated in the solution. Sample IA did not gel entirely, but only part of it gelled, producing a gel and a supernatant liquid. The gel and supernatant liquid of Sample IA were separated by filtration. For sample IB, which was not stirred, no gel precipitated after 17 hours of standing. After 41 hours of standing, a gel precipitated in the solution. Sample IB did not gel entirely, but only partially, producing a gel and a supernatant liquid. The gel and supernatant liquid of sample IB were separated by filtration.

[0074] (4) Evaluation The gels obtained from Samples IA and IB were subjected to chiral high-performance liquid chromatography (HPLC) to measure the ratio of L- to D-isomers of Compound (I). The analytical equipment used was a chiral column (CHIRALPAK® IA-3 (250 x 2.1 mm) manufactured by Daicel Corporation) and a JASCO PU-2080Plus equipped with a variable wavelength UV / Vis detector UV-2070Plus. Measurements were performed using a mixture of hexane / ethanol / trifluoroacetic acid (volume ratio: 90 / 10 / 0.1) as the eluent at a flow rate of 0.2 mL / min and a detection wavelength of 255 nm. The measurement results for Sample IA are shown in Figure 3(a), and the measurement results for Sample IB are shown in Figure 3(b).

[0075] The molar ratio of the D- and L-isomers in the gel of Sample IA was calculated from the area ratio of the peak derived from the L-isomer (Peak L) to the peak derived from the D-isomer (Peak D) in the chromatogram shown in Figure 3(a). The result was a D-to-L ratio of 56:44 (i.e., the enantiomeric excess of the D-isomer: 12%), confirming that the D-isomer was concentrated in the precipitated gel. Thus, in Sample IA, the L- and D-isomers of Compound (I) were partially optically resolved. On the other hand, when the ratio of D- and L-isomers in the gel of sample IB was determined from the chromatogram shown in Figure 3(b) using the same method as for sample IA, the enantiomeric excess of the D-isomer was found to be 2%.

[0076] [Experiment 2] In Experiment 2, a chiral compound different from that in Experiment 1 was used to perform optical resolution of the chiral compound. In addition, in this example, a good solvent (dimethyl sulfoxide (DMSO)) and a poor solvent (phosphate buffer) for the chiral compound were used in preparing a chiral compound solution.

[0077] (1) Preparation of chiral compound solutions In this example, the commercially available compound (II) (Fmoc-Trp-OH) represented by the following formula (II) was used as the chiral compound. Compound (II) is a tryptophan derivative.

[0078] [ka]

[0079] 142.6 mg of an equal mixture (racemic mixture) of L- and D-isomers of Compound (II) was added to 1.26 mL of dimethyl sulfoxide (DMSO) and dissolved, and 11.33 mL of phosphate buffer (50 mM) was added and mixed while heating to 60°C to prepare a homogeneous solution. 1.5 mL of the prepared solution was divided into eight vials and used as sample (solution) Group IIA. In addition, sample (solution) Group IIB, which has a higher concentration of the racemic mixture than Sample Group IIA, was prepared by the following procedure. 169.3 mg of the racemic mixture of Compound (II) was added to 1.28 mL of dimethyl sulfoxide (DMSO) and dissolved, and 11.54 mL of phosphate buffer (50 mM) was added and mixed while heating to 60°C to prepare a homogeneous solution. 1.5 mL of the prepared solution was divided into eight vials to prepare Sample Group IIB.

[0080] (2) Stirring the solution After the temperatures of Sample IIA and Sample IIB were lowered to room temperature (20°C), they were kept at 20°C for 2 hours. At this time, Sample IIA was stirred using a magnetic stirrer (rotation: 100 rpm), while Sample IIB was not stirred.

[0081] (3) Gel precipitation and separation of the gel and supernatant The stirred sample IIA group and the unstirred sample IIB group were left standing at 20°C. As a result, a gel precipitated in the liquid of sample IIA (stirred) after standing for 1 to 4 days (approximately 24 to 96 hours). On the other hand, a gel precipitated in the liquid of sample IIB (unstirred) after standing for 4 to 5 days (approximately 96 to 120 hours). Although the gel precipitation time varied among the samples, the average gel precipitation time was shorter for sample IIA (with stirring) than for sample IIB (without stirring), despite the fact that the solution was lower in concentration. In other words, sample IIA (with stirring) gelled more easily than sample IIB (without stirring).

[0082] In both sample group IIA and sample group IIB, gelation did not occur entirely but only partially, producing a gel and a supernatant. The gel and supernatant for each of sample group IIA and sample group IIB were separated by filtration.

[0083] (4) Evaluation The enantiomeric excess of the gels obtained from Sample Group IIA and Sample Group IIB was determined using the same method (chiral HPLC) as in Experiment 1 above. The results are shown in Figure 4. The vertical axis in Figure 4 represents the enantiomeric excess of the L-isomer. Therefore, the enantiomeric excess of the D-isomer is shown as a negative value in Figure 4.

[0084] As shown in Figure 4, in the sample group IIA, of the eight samples, the L-isomer of compound (II) was enriched in four samples (enantiomeric excess: +10% to +20%), and the D-isomer of compound (II) was enriched in the remaining four samples (enantiomeric excess: -5% to -15%). That is, in the sample group IIA, the L-isomer and D-isomer of compound (II) were partially optically resolved. On the other hand, in the group IIB samples, of the eight samples, the enantiomeric excess of five samples was greater than 0% and less than +1%, and the enantiomeric excess of the remaining three samples was also greater than +1% and less than +3%. [Industrial Applicability]

[0085] According to the method for optical resolution of a chiral compound of the present invention, it is possible to obtain one enantiomer and / or the other enantiomer of various chiral compounds that can be used as raw materials for food additives, pharmaceuticals, cosmetics, etc. Because the present invention is a simple method, it is expected to be industrially applicable and can contribute to reducing the cost of the various products mentioned above.

Claims

1. A method for optical resolution of a chiral compound, comprising: dissolving a mixture of both enantiomers of the chiral compound in a first solvent to prepare a first solution; Stirring the prepared first solution; Precipitating a first gel in the stirred first solution; separating the first solution into the first gel and a first supernatant.

2. 2. The method for optical resolution according to claim 1, wherein the mixture of both enantiomers is a racemic mixture.

3. 2. The method for optical resolution according to claim 1, wherein the content of one enantiomer is greater than the content of the other enantiomer in the mixture of both enantiomers.

4. the first gel contains a greater amount of one enantiomer than the other enantiomer; 4. The method for optical resolution according to claim 3, wherein the enantiomeric excess of the one enantiomer in the first gel is greater than the enantiomeric excess of the one enantiomer in the mixture of both enantiomers.

5. The method for optical resolution according to any one of claims 1 to 4, wherein the chiral compound is an amino acid or an amino acid derivative.

6. 6. The method for optical resolution according to claim 5, wherein the chiral compound is one selected from the group consisting of glutamic acid, aspartic acid, lysine, phenylalanine, tyrosine, tryptophan, histidine, proline, and derivatives thereof.

7. The optical resolution method according to any one of claims 1 to 6, wherein the first solvent is a polar solvent.

8. The method for optical resolution according to claim 7 , wherein the first solvent is an aprotic polar solvent.

9. 9. The method for optical resolution according to claim 8, wherein the first solvent comprises dimethyl sulfoxide.

10. The method for optical resolution according to claim 7 , wherein the first solvent comprises water.

11. the first solvent comprises a good solvent for the chiral compound and a poor solvent for the chiral compound, preparing the first solution dissolving the mixture of both enantiomers in the good solvent to prepare an intermediate solution; The optical resolution method according to any one of claims 1 to 10, comprising adding the poor solvent to the intermediate solution to obtain the first solution.

12. A method for optical resolution of a chiral compound, comprising: dissolving a mixture of both enantiomers of the chiral compound in a first solvent to prepare a first solution; Precipitating a first gel in the first solution; separating the first solution into the first gel and a first supernatant; dissolving the first gel separated from the first supernatant in a second solvent to prepare a second solution; Precipitating a second gel in the second solution; separating the second solution into the second gel and a second supernatant; The optical resolution method further comprises stirring at least one selected from the group consisting of the first solution before precipitating the first gel and the second solution before precipitating the second gel.

13. A method for optical resolution of a chiral compound, comprising: dissolving a mixture of both enantiomers of the chiral compound in a first solvent to prepare a first solution; Precipitating a first gel in the first solution; separating the first solution into the first gel and a first supernatant; Precipitating a third gel in the first supernatant liquid separated from the first gel; separating the first supernatant into the third gel and a third supernatant; The optical resolution method further comprises stirring at least one selected from the group consisting of the first solution before precipitating the first gel and the first supernatant before precipitating the third gel.

14. The optical resolution method according to any one of claims 1 to 13, wherein the stirring time for at least one stirring selected from the group consisting of stirring the first solution, stirring the second solution, and stirring the first supernatant is 1 hour to 2 hours.

15. The optical resolution method according to any one of claims 1 to 14, wherein a stirring rotation speed is set to 50 rpm to 100 rpm in at least one stirring selected from the group consisting of stirring of the first solution, stirring of the second solution, and stirring of the first supernatant.

16. 1. A process for producing one enantiomer and / or the other enantiomer of a chiral compound, comprising the steps of: providing a mixture of both enantiomers of said chiral compound; and separating the one enantiomer and / or the other enantiomer from the mixture by the method for optical resolution of a chiral compound according to any one of claims 1 to 15.

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