JP2005194254A - Method for searching optical resolution factor, method for judging possibility of optical resolution and method of resolution - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for searching an optical resolution factors easily from a result of calculation performed by a quantum chemical calculation of differences in physicochemical properties affecting the separation of optical isomers contained in a mixture of optical isomers, performed by a prescribed separating means, a method for judging the possibility of the optical resolution and a method for performing the optical resolution, capable of more surely performing the optical resolution of the optically active compounds by applying the judging method and using an appropriate asymmetric assisting group. <P>SOLUTION: This method for searching the optical resolution factor is provided by obtaining the differences in physicochemical properties affecting the separation of optical isomers contained in the mixture of optical isomers by a prescribed separating means, by the quantum chemical calculation, and from the result of it, searching the physicochemical property of the optical isomer, the most affecting the separation of the optical isomer mixture by the separating means. The method for judging the possibility of the optical resolution is to judge the possibility of the optical resolution of the optical isomer mixture from the result of the search. The method for performing the optical resolution of the optical isomer mixture uses the method for judging the possibility. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  The present invention relates to a method for obtaining a difference in physicochemical properties between optical isomer mixtures that influences separation by a separation means such as chromatography using quantum chemical calculation, and to search for an optical resolution factor from the calculation result. The present invention also relates to a method for determining the possibility of optical resolution utilizing this method, and an optical resolution method for efficiently optically dividing a target optical isomer mixture by applying this determination method.

  In recent organic synthetic chemistry, a technique for efficiently synthesizing an optically active compound of a compound having an asymmetric carbon atom in a molecule such as a natural product is required. However, when synthesizing a compound having an asymmetric carbon atom in the molecule, such a compound is usually obtained as a mixture of optical isomers. In addition, in the structural study of physiologically active substances including natural organic compounds, it is important to determine the absolute configuration of the compound, and it is necessary to efficiently perform the optical resolution of the optical isomer mixture.

  Conventionally, methods for optical resolution of optical isomer mixtures include direct methods of directly splitting optical isomer mixtures (racemate) into optically active forms, and optical splitting agents by reacting optical resolution agents with racemates to lead to optical isomer mixtures. Indirect method of obtaining optically active substances by separating the diastereomers by fractional crystallization or column chromatography using the difference in physicochemical properties between diastereomers, and removing the optical resolving agent part again It has been known. In recent years, the latter indirect method having excellent versatility, particularly a method of optically resolving a mixture of optical isomers by column chromatography has become mainstream.

  As a specific example of this method, a chiral carboxylic acid is used as an optical resolving agent, and this is reacted with a racemic isomer of a secondary alcohol to lead to an ester, and the resulting mixture of optical isomers of the ester is HPLC (High Performance Liquid). Examples thereof include a method of obtaining an optically active alcohol by optical resolution by Chromatography) and hydrolyzing the obtained diastereomer (see Non-Patent Documents 1 and 2 and the prior literatures described in these documents). .

TCI mail. , No. January 17,003, Tokyo Chemical Industry Co., Ltd. CHIRALITY. , 14, 81-84 (2002).

  However, when an optical resolution is performed using, for example, silica gel column chromatography for a racemate of an optically active compound, what factors work and which optical isomer having an absolute configuration or a relative configuration is separated first. It is the current situation that does not understand. In addition, when producing optically active compounds such as pharmaceuticals, the selection or development of an optical resolution agent capable of efficient optical resolution is extremely important at the industrialization level. Based on the experience and past knowledge of organic chemists. Therefore, not all of the optical resolution agents can be selected successfully. The cause is that the agent (hereinafter referred to as “optical resolution factor”) involved in the separation of the optically active substance is unclear.

  The present invention has been made in view of the present situation, and the difference in physicochemical properties affecting the separation of each optical isomer contained in the optical isomer mixture by a predetermined separation means is determined by quantum chemical calculation. An optical resolution factor search method that can easily find an optical resolution factor from the obtained calculation results, an optical resolution possibility determination method using this search method, and an appropriate asymmetry by applying this determination method It is an object of the present invention to provide an optical resolution method capable of performing optical resolution of an optically active compound using an auxiliary group more reliably.

  As a result of intensive studies to solve the above-mentioned problems, the present inventor has obtained (a) all possible conformational isomers by quantum chemical calculation using a computer for optical isomers (diastereomers) to be optically resolved. (B) calculate the charge, orbital energy, molecular volume and molecular surface area on each atom representing the properties of the plurality of conformers, and (c) use the neural network for the results obtained Analysis, and found that the affinity (dipole moment) of silica gel used for optical resolution of the conformational isomer by HPLC can be determined. (D) Among the conformers, configurations having different absolute configurations. Based on the difference in affinity for silica gel between the conformers, we can determine the optical resolution factor group of the optical isomer mixture and judge the possibility of the optical resolution. It was. The present invention has been completed by generalizing these findings.

  Thus, according to the first aspect of the present invention, the difference in physicochemical properties between the optical isomer mixtures affecting the separation of the optical isomer mixture by a predetermined separation means is obtained using quantum chemical calculation, and the calculation result From the above, there is provided an optical resolution factor exploration method characterized by exploring the physicochemical properties of optical isomers that most affect the separation of the optical isomer mixture by the separation means.

  In the exploration method of the present invention, the quantum chemical calculation preferably uses a neural network.

  In the exploration method of the present invention, the quantum chemical calculation uses a computer program that performs a conformational analysis of the molecular structure, and among the conformers of the optical isomer mixture, Calculating (1) an optimal configuration of a plurality of conformers to be calculated, and calculating a physicochemical difference of each conformer of the optical isomer mixture by a neural network ( 2) is preferable.

  Further, in this case, the steps (1) and / or (2) include a Web server that transmits / receives WWW information related to a molecular structure to / from a client via a communication network, and information related to the molecular structure to the Web server. More preferably, a molecular information providing system having a processing server to be provided is used.

  In the exploration method of the present invention, the optical isomer mixture contains an optically active compound (a) that serves as an asymmetric auxiliary group, and an asymmetric carbon atom and a functional group capable of chemically bonding with the compound (a) in the molecule. The optical isomer mixture of the compound (b) having a group is preferably an optical isomer mixture of the compound (c) formed by chemical bonding with the functional group.

  In the probing method of the present invention, the physicochemical property is preferably affinity for a stationary phase used for chromatography of the optical isomer.

  According to a second aspect of the present invention, there is provided a method for determining the possibility of optical resolution by determining whether or not optical resolution of an optical isomer mixture is performed by a predetermined separation means, between the optical isomers contained in the mixture, A difference in physicochemical properties affecting the separation by the separation means is obtained by quantum chemical calculation, and the possibility of optical resolution of the optical isomer mixture is judged from the obtained calculation result. A method for determining the splitability is provided.

  In the determination method of optical resolution according to the present invention, the quantum chemical calculation preferably uses a neural network.

In the determination method for optical resolution according to the present invention, the quantum chemical calculation uses a computer program for performing a conformational analysis of a molecular structure, and among the conformers of the optical isomer mixture, Step (1) for calculating and calculating the optimum configuration of a plurality of conformers to be calculated in the step, and calculating the physicochemical difference of each conformer of the optical isomer mixture with a neural network It is preferable to have the step (2) to be obtained.
Further, in this case, the steps (1) and / or (2) include a Web server that transmits / receives WWW information related to a molecular structure to / from a client via a communication network, and information related to the molecular structure to the Web server More preferably, a molecular information providing system having a processing server to be provided is used.

  In the determination method for optical resolution according to the present invention, the optical isomer mixture contains an optically active compound (a) as an asymmetric auxiliary group, an asymmetric carbon atom and a compound (a) in the molecule, An optical isomer mixture of the compound (c) obtained by chemically bonding the compound (b) having a governmental group capable of bonding with the functional group is preferable.

  In the determination method for optical resolution according to the present invention, the physicochemical property is preferably affinity for a stationary phase used for chromatography of the optical isomer.

  According to the third aspect of the present invention, step (i) of determining the optical resolution of the optical isomer mixture of the compound (c) by the predetermined separation means by the determination method of the present invention, and the separation conditions by the separation means An optical isomer mixture comprising the step (ii) of determining an optically active form of the compound (c) by optically resolving the optical isomer mixture of the compound (c) by the separating means and the step (iii) An optical resolution method is provided.

  In the optical resolution method of the present invention, preferably, the separation means is chromatography, and the step (ii) is a step including selecting a stationary phase and a mobile phase to be used for chromatography.

In the optical resolution method of the present invention, the step (i) is, the different n (n obtained from a different n-number of the optically active compound (a _n) with the compound (b) represents a natural number. ) Of compound (c _n ) is judged by the determination method of the present invention to determine the possibility of optical resolution, and among _n compounds (c _n ), the compound (c _s ) most advantageous for optical resolution is selected. It is preferable that it contains.

  In the optical resolution method of the present invention, the optically active compound (a) having an asymmetric auxiliary group is eliminated from the optically active form of the compound (c) isolated by the above step (iii), and the compound (b) It is preferable to further include a step of isolating the optically active substance.

According to the method for searching for an optical resolution factor of the present invention, the difference in physicochemical properties that affect the separation of each optical isomer contained in the optical isomer mixture by a predetermined separation means is obtained by quantum chemical calculation. The optical resolution factor can be easily found from the obtained calculation result.
According to the determination method of the optical resolution of the present invention, the determination of the optical resolution of the optical isomer mixture can be easily and reliably performed using the result of searching for the optical resolution factor.
Further, according to the optical resolution method of the present invention, the determination method of the present invention can be applied to more reliably perform optical resolution of an optically active compound using an appropriate asymmetric auxiliary group.

  Hereinafter, the present invention will be described in detail by dividing it into 1) an optical resolution factor search method, 2) an optical resolution determination method, and 3) an optical resolution method.

1) Search method for optical resolution factor The optical resolution factor search method of the present invention is based on quantum chemical differences in the physicochemical properties between optical isomer mixtures that affect the separation of optical isomer mixtures by a predetermined separation means. It is obtained by calculation, and the physicochemical properties of the optical isomer that most affect the separation of the optical isomer mixture by the separation means are searched from the calculation result.

(1) Optical isomer mixture The optical isomer mixture targeted by the present invention is an optical isomerism derived from a difference in the absolute configuration of the carbon atom of a compound having at least one asymmetric carbon atom in the molecule. If it is a mixture of bodies, it will not be restrict | limited.
Among them, the optical isomer mixture to be the subject of the present invention is preferably a diastereomeric mixture, and has an optically active compound (a) as an asymmetric auxiliary group and an asymmetric carbon atom in the molecule. The compound (a) and the optical isomer mixture of the compound (b) having a functional group capable of chemical bonding are a diastereomeric mixture of the compound (c) formed by chemical bonding with the functional group. Is more preferable.

  The compound (a) is not particularly limited as long as it is an optically active compound capable of forming a so-called asymmetric auxiliary group by bonding with the compound (b). Examples thereof include optically active carboxylic acids and optically active sulfonamides. Specific examples of these optically active carboxylic acids and optically active sulfonamides are shown in the following (a-1) to (a-5), but are not limited thereto.

The compound (b) is not particularly limited as long as it is an optical isomer mixture having at least one asymmetric carbon atom in the molecule and having a functional group capable of chemically bonding with the compound (a).
Examples of the functional group capable of chemically bonding with the compound (a) include a hydroxyl group and a carboxyl group.
Specific examples of compound (b) include optical isomer mixtures of alcohol compounds and carboxylic acid compounds.

Specific examples of the compound (c) include those obtained by chemically bonding the compound (a) and the compound (b) via the functional group of the compound (b).
As a preferable specific example of the compound (c), the compound (a) is a carboxylic acid compound represented by the formula: A-COOH (wherein A represents an optically active organic group), and the compound (b ) Is an alcohol compound (optical isomer mixture) represented by the formula: B—OH (wherein B represents an organic group having at least one asymmetric carbon atom). An ester compound (optical isomer mixture) represented by C (= O) -OB is exemplified.

  The means for separating the optical isomer mixture is not particularly limited as long as it can be optically resolved using the difference in physicochemical properties between the optical isomers contained in the optical isomer mixture. Known separation means can be used. For example, various chromatography using a difference in affinity for a stationary phase such as column chromatography and thin layer chromatography; fractional crystallization method using a difference in solubility in a solvent; and the like. Among these, the present invention preferably uses column chromatography as a separation means.

Specifically, the optical resolution factor searching method of the present invention can be performed as follows.
Step (1)
First, using a computer program that performs a conformational analysis of the molecular structure, calculate the optimized structure of multiple conformers to be calculated in the next step among the conformers of the optical isomer mixture. (Structural optimization).

  The structure optimization by quantum chemical calculation is, for example, Gaussian Inc., which is a calculation program performed by the molecular orbital method. Manufactured by Gaussian 98 Rev. A. 9 can be performed by using STO-3G of the restricted Heartree-Fock (RHF) method. More specifically, a molecular calculation program using a force field, a semi-empirical molecular orbital method, a molecular orbital method, a density functional method, etc., for example, “CONFLEX 2000” which is a molecular calculation program manufactured by CONFLEX.

Step (2)
Next, for each of the plurality of conformers, a difference in physicochemical properties of each conformer having the optimized structure is calculated using a neural network.

  Specifically, first, charge, orbital energy, molecular volume, and molecular surface area representing the properties relating to each conformer obtained by the structure optimization in the step (1) are calculated, and the result is nonlinear analysis method. And the difference of the physicochemical properties of the compound (c) is calculated and obtained.

  The physicochemical property is not particularly limited as long as it is a factor (also referred to as an optical resolution determining factor) that has a significant influence on optical resolution. Preferable specific examples include affinity (dipole moment) for chromatography stationary phase.

  The calculation of the molecular volume and the molecular surface area of each conformer having the optimized structure is performed using, for example, a calculation program for the molecular volume and the molecular surface area (for example, Chemsoft 3D Pro Ver. 5.0, manufactured by Cambridge Soft). be able to.

  The nonlinear analysis method can be performed using, for example, a hierarchical perceptron type neural network (manufactured by Fujitsu Ltd .: NEUROSIM / L). Using the structure optimization and discrimination ability of the neural network as indices, it is possible to analyze the optical resolution determinants of optically active compounds using asymmetric auxiliary groups.

  A neural network is an information processing program using a computer that imitates the structure of the brain, which is a part of human biological functions, and is broadly divided into a hierarchical type and an interconnected type. Examples of the hierarchical neural network include perceptron and neocognitron.

  Examples of the interconnecting neural network include Associatron, Hopfield network, Boltzmann machine, and the like. The neural network used in the present invention is not particularly limited, and various types can be used. As an embodiment of the present invention, a hierarchical neural network was used, and backpropagation was used as a learning method.

  The steps (1) and / or (2) include a Web server that transmits / receives WWW information related to a molecular structure to / from a client via a communication network, and a processing server that provides information related to the molecular structure to the Web server. It can also be performed using a molecular information providing system having (see Japanese Patent Application Laid-Open No. 2003256668).

Step (3)
Next, the obtained calculation results are compared between conformers having different absolute configurations, and the physicochemical properties (optical resolution factors) of the optical isomers having a significant influence on the optical resolution are obtained. In this case, a plurality of optical resolution factors may exist as an optical resolution factor group.

  According to the optical resolution factor exploration method of the present invention, the difference in physicochemical properties that affect the separation of the optical isomer mixture by the separation means is obtained by quantum chemical calculation, and the obtained calculation result is converted into the optical resolution factor. An optical resolution factor (optical resolution factor group) that influences can be easily and reliably found.

2) Method for determining the optical resolution of an optical isomer mixture The method for determining the optical resolution of an optical isomer mixture according to the present invention is an optical resolution for determining whether or not optical resolution of an optical isomer mixture is performed by a predetermined separation means. A method for determining the possibility, wherein a difference in physicochemical properties affecting the separation by the separation means between the respective optical isomers contained in the mixture is determined by quantum chemical calculation, and the obtained calculation result From the above, the possibility of optical resolution of the optical isomer mixture is judged.

  That is, the determination method of the optical resolution of the optical isomer mixture of the present invention is the difference between the optical resolution factors obtained by the optical resolution factor search method of the present invention for each optical isomer contained in the optical isomer mixture. In comparison, if this difference is greater than or equal to a predetermined value, it is determined that optical division is possible, and if it is less than the predetermined value, it is determined that optical division is impossible or difficult.

  The criterion for determining whether or not the difference in the optical resolution factor is greater than or equal to the optical resolution and determining that the optical resolution is impossible (or difficult) is less than what value Depending on the type of optical isomer and the separation means used. This criterion can be determined semi-empirically depending on the type of optical isomer to be resolved and the separation means used.

  In the determination method for optical resolution according to the present invention, the optical isomer mixture contains an optically active compound (a) as an asymmetric auxiliary group, an asymmetric carbon atom and a compound (a) in the molecule, It is preferably an optical isomer mixture of the compound (c) obtained by chemically bonding the optical isomer mixture of the compound (b) having a functional group capable of bonding with the functional group.

  In the determination method for optical resolution according to the present invention, the physicochemical property is preferably affinity for a stationary phase used for chromatography of the optical isomer.

3) Optical resolution method The optical resolution method of the present invention is a step of determining whether optical resolution of the optical isomer mixture of compound (c) by a predetermined separation means is possible or not by the determination method of the present invention ( i), step (ii) for determining the separation conditions by the separation means, and optical resolution of the optical isomer mixture of compound (c) by the separation means, thereby isolating the optically active form of compound (c) Step (iii). The optical splitting method of the present invention uses the optical splitting possibility determination method of the present invention.

  As a means for separating the diastereomeric mixture of compound (c) into each optically active compound, optical resolution can be performed by utilizing the difference in physicochemical properties between the optical isomers contained in the optical isomer mixture. Any known separation means can be used as long as it can be used. For example, various chromatography using a difference in affinity for a stationary phase such as column chromatography and thin layer chromatography; fractional crystallization method using a difference in solubility in a solvent; and the like. Among these, those using column chromatography as a separation means are preferable.

Step (i)
In step (i), the physicochemical difference obtained for the compound (c) is compared between conformers having different absolute configurations, and when the difference is not less than a predetermined value, optical resolution is performed. Judge that it is possible.
The details of step (i) are as described in the method for searching for an optical resolution determining factor of the present invention.

In the step (i), n different types (n represents a natural number) of compounds (c _n ) obtained from n different types of optically active compounds (a _n ) and compounds (b). The determination method of the present invention preferably determines the possibility of optical resolution, and includes selecting the compound (c _s ) most advantageous for optical resolution among the _n compounds (c _n ). By doing in this way, the optical resolution of the diastereomeric mixture of a compound (c) can be performed more reliably by performing appropriate selection of the optically active compound (a) having an asymmetric auxiliary group.

Step (ii)
Next, conditions for separating the optical isomer mixture of compound (c) by the separation means are determined.
Separation conditions can be appropriately determined semi-empirically depending on the type of compound (c) and separation means. For example, when chromatography is employed as the separation means, a stationary phase and a mobile phase used for chromatography that are most advantageous for separation of a diastereomeric mixture of the selected compound ( _cs ) are selected.

  The stationary phase used in the chromatography is not particularly limited, and conventionally known ones can be used. For example, inorganic polymers such as silica gel and alumina; natural polymers such as cellulose and cellulose derivatives; synthetic polymers such as ion exchange resins; Also, the mobile phase is not particularly limited. For example, a liquid mobile phase such as water, an organic solvent, a mixed solvent of water and an organic solvent, a mixed solvent of two or more organic solvents, or the like; argon, helium, nitrogen, and these two types Gaseous mobile phase such as a mixed gas composed of the above; and the like. In the present invention, it is preferable to use a stationary phase made of an inorganic polymer and a liquid mobile phase from the viewpoints of work efficiency and simplicity.

Step (iii)
Next, the compound (c _n ) is synthesized, and the diastereomeric mixture of the compound (c _n ) is separated using the selected stationary phase and mobile phase used for chromatography.
In this case, as the compound (c _n ), it is preferable to synthesize and separate the optical isomer mixture of the compound (c _s ) that is most advantageous for optical resolution among the _n compounds (c _n ).

  In the optical resolution method of the present invention, the optically active compound (a) moiety having an asymmetric auxiliary group is eliminated from the optical isomer of the compound (c) isolated by the step (iii) to obtain the compound (b It is preferable to further comprise the step of isolating the optically active substance of

  As described above, by applying the determination method of the present invention, an optical resolution of a mixture of optical isomers can be easily and reliably performed by selecting and using an appropriate asymmetric auxiliary group.

  Hereinafter, the present invention will be described in more detail with reference to examples. However, the present invention is not limited to the following examples.

(Example 1)
The conformation was calculated for the ester compound (the following compound (c-1)) obtained by binding the compound represented by the formula (a-2) and 2-hexanol. Conformation generation was performed by searching all conformational spaces using CONFLEX 2000 manufactured by CONFLEX and calculating all the conformations.

  Compound (c-1) has a large number of conformers with an energy rank according to the Boltzmann distribution rule. This is because it has many bonds that can rotate freely. Since each conformer has various physicochemical properties, it is necessary to calculate the conformation.

  Thus, the obtained conformer was manufactured by Gaussian, Gaussian 98 Rev. A. Structural optimization was performed using 9 RHF / STO-3G. In order to optimize the structure of many conformers, the calculation time is enormous and the time cost cannot be ignored. Therefore, RHF / STO-3G, which is the minimum basis function, was selected. As a result of structural optimization by removing the overlapping conformation, 100 R bodies and 101 S bodies were obtained.

  Simultaneously with the structure optimization, the orbital energy, dipole moment and charge of the highest occupied orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO) were also calculated.

  The charges used were Mulliken charge calculations. For each conformation obtained by structure optimization, the molecular surface area, molecular volume and molecular exclusion volume are calculated from the molecular surface area, molecular volume and molecular exclusion volume calculation program (Cambridge Soft: Chem 3D Pro Ver. 5.0). ).

  Next, molecular surface area, molecular volume, molecular exclusion volume, HOMO, LUMO, energy, magnitude of dipole moment in the X-axis direction, magnitude of dipole moment in the Y-axis direction, Z axis Neural network analysis, which is a nonlinear analysis, was performed using the magnitude of the dipole moment in the direction, the total magnitude of the dipole moment, and the charge on each atom.

  Since analysis cannot be performed by directly entering numerical data into the neural network, scaling was performed so that numerical values entered from -1 to 1 as numerical data that the neural network can recognize. At the time of scaling, in order to use the linear part from the characteristics of the sigmoid function used in the neural network, normalization is performed according to the following formula so that it falls within the range of −0.9 to 0.9. Scaling was performed.

Ｎ．Ｖ．：規格化値
Ｘｉ：各項目の変数
Ｘｍｉｎ：各項目での最小値
Ｘｍａｘ：各項目での最大値

N. V. : Normalized value Xi: Variable for each item Xmin: Minimum value for each item Xmax: Maximum value for each item

  Scaling includes molecular surface area of each conformation, molecular volume, molecular exclusion volume, HOMO, LUMO, energy, magnitude of dipole moment in the X axis direction, magnitude of dipole moment in the Y axis direction, dipole in the Z axis direction The magnitude of the child moment and the overall magnitude of the dipole moment were determined for each item.

  Regarding the charge on each atom, since the charge is one of the indexes directly representing the whole characteristics of the molecule, the scaling for each item of the charge is performed without scaling for each item of each atom.

  In neural network analysis, some of the samples need to be learned. The number of samples to be learned is 80% of the total. The remaining 20% was used as an evaluation sample after the neural network learned.

  As the first stage of neural network analysis, the molecular surface area, molecular volume, molecular exclusion volume, HOMO, LUMO, energy, magnitude of dipole moment in the X-axis direction, magnitude of dipole moment in the Y-axis direction as the first stage of neural network analysis All the 60 items of the magnitude of the dipole moment in the Z-axis direction, the overall magnitude of the dipole moment, and the charge on each atom were used. At this stage, since unnecessary structure descriptor parameters are included, the object is to eliminate unnecessary structure descriptor parameters.

  The structure of the neural network used is shown in FIG. The neural network has a three-layer structure in which an input layer (Input Layer) is 60, an intermediate layer (Middle Layer) is 3, and an output layer (Output Layer) is 1. Considering the number of conformation samples obtained, 193 R and S bodies were used for learning, and 18 were used for evaluation after learning. As a result, it was possible to construct a neural network that gave 17 correct answers out of 18.

  In this state, since many unnecessary structure descriptor parameters are included, it is not possible to determine the optical resolution determinant. Therefore, the obtained neural network was changed from −1 to 1 in the input layer, and the sensitivity analysis in the output layer was performed for every 60 input layers.

  As a result, it was found that LUMO and the point charges of C20, C21, C23, H36, H37, H38, H39, H40, H41, H42, H43, H44, H45, H47, and H49 atoms are effective (calculate The numbers of the atoms for determining the coordinates above are shown in the following chemical formulas (c-1-1) and (c-1-2)).

This result suggests two important things.
The first point is that the compound (c-1) has orbital interaction using LUMO. In other words, (SiO ₂ ) _{n in} silica gel chromatography means that HOMO is used. In other words, compound (c-1) is orbitally interacting using LUMO that accepts the lone pair of oxygen atoms of (SiO ₂ ) _n in silica gel chromatography.

The second point is the point of C20, C21, C23, H36, H37, H38, H39, H40, H41, H42, H43, H44, H45, H47, H49 among the atoms of the compound (c-1). It is presumed that the electric charge has an electrostatic interaction with (SiO ₂ ) _n of silica gel chromatography.

  As the second stage of the neural network analysis, LUMO and C20, C21, C23, H36, H37, H38, H39, H40, H41, H42, H43, H44, which are structural descriptor parameters obtained in the previous analysis, The same analysis as in the first stage was performed with 17 parameters including point charges of H45, H47, and H49 atoms and a constant term.

  The structure of the neural network used is shown in FIG. The neural network has a three-layer structure in which an input layer (Input Layer) is 17, an intermediate layer (Middle Layer) is 3, and an output layer (Output Layer) is 1.

  Considering the number of conformation samples obtained, 193 R and S bodies were used for learning, and 18 were used for evaluation after learning. As a result, it was possible to construct a neural network that gave 17 correct answers out of 18.

  From this point onwards, 161 were used for learning, including R and S, and 40 were used for evaluation after learning. However, since the number of intermediate layers in the three-layer structure of the neural network is not appropriately determined, it cannot be said that the neural network structure is optimal.

Therefore, when the number of intermediate layers is 3, the sensitivity analysis in the output layer performed in the first stage is performed. As a result, it was estimated that the point charge of each atom of C20, H37, H38, H39, H40, H42, and H47 had an electrostatic interaction with (SiO ₂ ) _n of silica gel chromatography. At the same time, we found that this neural network contains a constant term and moves in the positive direction from the origin.

  As the third stage of neural network analysis, the point charge of each atom of C20, H37, H38, H39, H40, H42, and H47, which is the structure descriptor parameter obtained in the previous analysis, strongly determines the optical resolution. Therefore, we further optimized the neural network analysis.

  FIG. 3 shows the structure of the used neural network. As structure descriptor parameters, eight parameters including point charges and constant terms of each atom of C20, H37, H38, H39, H40, H42, and H47 were used. Further, the minimum number 3 obtained in the previous step is used as the number of intermediate layers of the neural network.

  However, since the initial value dependency becomes very strong in the learning process of the neural network, it cannot be said that the neural network structure is optimal. Therefore, the dependence on the initial value was examined, and the neural network performed the best learning and determined the minimum initial value that gave the best evaluation result in the evaluation. As a result, the minimum initial value showing 77.5% which is the highest correct answer rate was 7.

Moreover, the sensitivity analysis in the output layer performed in the first step was performed. As a result, it was estimated that the point charge of each atom of H38, H39, H40, and H47 had an electrostatic interaction with (SiO ₂ ) _n of silica gel chromatography. At the same time, it was found that this neural network does not include a constant term.

Furthermore, the structure of the neural network was continuously optimized in the same manner, but the correct answer rate did not exceed 97.5% in learning and evaluation.
Therefore, the optical resolution determinant (physicochemical property affecting optical resolution) of the compound (c-1) is the point charge of each atom of C20, H37, H38, H39, H40, H42, and H47. Become.

  The fact that these seven point charges are the optical resolution determinants of compound (c-1) is what the chemical implications actually have. Therefore, we specifically compared the chemical structure and the results obtained from the neural network.

FIG. 4 shows a structural diagram of the R form (R001) and S form (S058) having the minimum energy of the compound (c-1), and a diagram in which these are superimposed.
From FIG. 4, it can be seen that the following four points are greatly different between both isomers (R-form and S-form) of compound (c-1).

  The first point is that the methyl group at the 1-position of the ester portion of 2-hexanol exists on the naphthyl group in the R form, but does not exist on the naphthyl group in the one S form. From this, a big difference appears clearly in the hydrogen atom bonded to the 1-position methyl group.

  The second point is that the hydrogen atom at the base of the 2-position alcohol of 2-hexanol is in the direction away from the naphthyl group in the R form, but in the direction parallel to the naphthyl group in one S form.

  The third point is that C—H of the 3-position methylene group of 2-hexanol is not in the naphthyl group in the R isomer, but is in a direction perpendicular to the plane to be the naphthyl group. One S-form is on the naphthyl group and is in a direction perpendicular to the plane formed with the naphthyl group.

  The fourth point is that the environment in which this hydrogen atom is placed is greatly different for one hydrogen atom of the methyl group at the 6-position of 2-hexanol. The R-form is in the direction toward the naphthyl group, while the other S-form is in the direction away from the naphthyl group.

The structural differences between the R-form and S-form of the compound (c-1) at the four points described above are consistent with the analysis results of the neural network. Thereby, it is considered that the interaction between (SiO ₂ ) _n and the compound (c-1) in silica gel chromatography is mainly an electrostatic interaction. The large driving force that produces this electrostatic interaction is thought to be due to the difference in environment associated with the conformation of the naphthyl group moiety and the optically active alcohol.

From the above results, it was determined that the compound (c-1) can be separated by silica gel chromatography because the R-form and the S-form differ in the magnitude of the electrostatic interaction with (SiO ₂ ) _n .

  That is, it is presumed that the diastereomeric mixture of compound (c-1) can be optically resolved by silica gel chromatography by selecting an appropriate solvent.

(Example 2)
An ester compound (c) obtained by condensing an optically active carboxylic acid compound (a-4) as an asymmetric auxiliary group shown below and an alcohol compound represented by the formulas (b-1) to (b-3) -2) to (c-4), whether or not optical resolution can be performed by high performance liquid column chromatography (HPLC) was determined as follows.

step 1)
First, in the same manner as the structure optimization method performed in Example 1, the structure optimization of all possible conformations was performed.

<Analysis method>
Conformational occurrence: CONFLEX 2000
Structure optimization: MOPAC 93 Rev. 2 RHF / PM3

Step (2)
About each ester compound, the dipole moment value of each conformation group was computed according to the Boltzmann distribution rule. The results are shown in Table 1 below.

  From Table 1, in the compounds (c-3) and (c-4) obtained by using the compounds (b-2) and (b-3) in which the fluorine atom is substituted at the 3-position and the 4-position, the S-form It can be seen that the dipole moment value of is larger than the R-body dipole moment value. That is, a compound having a large dipole moment value is considered to have a larger interaction with HPLC silica gel. Therefore, when an ester compound is separated by HPLC, an R-form ester compound having a small dipole moment value is first. It is expected to elute.

  From Table 1, in the compound (c-2) in which the fluorine atom is substituted at the 2-position, the difference between the dipole moment values of the R-form and the S-form is very small. That is, regarding the difference in dipole moment value of each diastereomer, the ratio of the two diastereomers to the smaller dipole moment value is 0.7% for compound (c-2) and compound (c-3). ) Is 24.7%, and compound (c-4) is 33.6%. From this, it is expected that the ester compound (c-2) cannot be optically resolved by HPLC. Accordingly, since the difference in dipole moment values is small, it is considered that optical resolution is difficult even if the separation conditions of column chromatography such as the number of theoretical plates and developing solvent are changed.

  An optically active carboxylic acid compound (a-4) and an alcohol compound represented by formulas (b-1) to (b-3) in the presence of dichlorohexylcarbodiimide (DCC) and 4-dimethylaminopyridine (DMAP). The ester compounds (c-2) to (c-4) were synthesized by stirring in dichloromethane. About each obtained ester compound, it isolate | separated by HPLC (a silica gel, 25 (phi) * 400mm column, a solvent: n-hexane / ethyl acetate = 4/1).

  For compound (c-2), R-form and S-form could not be separated. For compound (c-3), R-form and S-form could be separated (yield: R-form 44%, S-form 46%).

Determination method of absolute configuration described in literature: converted to MαNP ester, ¹ H-NMR is measured, and from the result of the difference between the ¹ H-NMR measured values of R and S, the first eluting component is R (Absolute configuration determination method using MαNP).

The R-form and S-form of the obtained ester compound (c-3) are subjected to solvolysis in methanol in the presence of potassium carbonate to give R-form and S-form of optically pure alcohol compound (b-2). I was able to get each body.
In addition, from the ester compound (c-4), optically pure alcohol compound (b-3) R-form and S-form could be obtained in the same manner.
From the above, it was confirmed that the determination result of Example 2 was correct.

Example 3

  An alcohol compound represented by formula (b-4) and an optically active carboxylic acid compound represented by formula (a-3), (a-4), (a-6) and (a-7) are condensed. The obtained ester compounds (c-5), (c-6), (c-7), and (c-8) were examined for the possibility of optical resolution by high performance liquid column chromatography (HPLC) as follows. Judgment was made.

Step (1)
The structure optimization was performed in the same manner as in Example 1.
Step (2)
About each ester compound, the dipole moment value of each conformation group was computed according to the Boltzmann distribution rule. The results are shown in Table 2 below.

  From Table 2, the difference in the dipole moment values of the R-form and S-form of the ester compound (c-6) obtained using the compound (a-4) as an asymmetric auxiliary group is the compound ( It is small compared with the difference of the dipole moment value of the R body and S body of the ester compound (c-5) obtained using a-3). That is, the ratio of the dipole moment value of each diastereomer is such that the ratio of the two diastereomers to the smaller dipole moment value is 12.2% for compound (c-5) and compound (c-6). ) Is 3.5%. From this difference value, it was judged that the ester compound (c-6) was difficult to be optically resolved by HPLC.

  On the other hand, the difference between the dipole moment values of the R-form and the S-form of the ester compounds (c-7) and (c-8) obtained using the compounds (a-6) and (a-7) It was judged that the R-form and S-form can be optically resolved by HPLC more easily than the difference between the dipole moment values of R-form and S-form of -6).

  In the ester compound (c-8), the S isomer has a smaller dipole moment value than the R isomer (the difference in dipole moment values is negative). Therefore, it was expected that the S form had a smaller interaction with the silica gel of HPLC, and the S form was eluted first from the HPLC.

  In the compound (c-7) and the compound (c-8), although the F atom is larger in electronegativity than the Cl atom, the absolute value of the dipole moment difference is larger than that in the compound (c-7). Compound (c-8) is larger. This is because the Cl atom has a larger atomic radius than the F atom, and in the compound (c-8) having a Cl atom, the degree of freedom of the phthalic acid moiety is partially restricted, and the restriction is limited. This is probably because the magnitude of the dipole moment of the whole molecule is consistent with the direction of increasing or decreasing the dipole moment.

Based on the determination of Example 3, optical resolution of the alcohol compound represented by the formula (b-4) was performed using the compound represented by the formula (a-3) as an asymmetric auxiliary group.
The alcohol compound represented by the formula (b-4) is stirred with the compound represented by the formula (a-3) in methylene chloride in the presence of dicyclohexylcarbodiimide (DCC) and 4-dimethylaminopyridine (DMAP). Thus, an ester compound (c-5) was synthesized.

  When the obtained ester compound was optically resolved by HPLC (silica gel, 25φ × 400 mm column, solvent: n-hexane / ethyl acetate = 4/1), it could be separated into R-form and S-form.

Determination method of absolute configuration described in literature: converted to MαNP ester, ¹ H-NMR is measured, and from the result of the difference between the ¹ H-NMR measured values of R and S, the first eluting component is R (Absolute configuration determination method using MαNP).

As for the ester compounds (c-7) and (c-8), when optical resolution was performed in the same manner, the R-form and the S-form could be separated more efficiently. However, the 1st elution component of ester compound (c-7) was R body, and the 1st elution component of ester compound (c-8) was S body (The determination method of the absolute configuration of literature description: M (alpha) NP ester And ¹ H-NMR was measured, and the first elution component was confirmed from the result of the difference between the ¹ H-NMR measurement values of the R and S isomers).

  From this, it is understood that the ester of the desired optically active alcohol can be preferentially eluted by appropriately selecting the asymmetric auxiliary group (compound (a)) to be used.

Each of the obtained optically active ester compounds could be converted into optically pure alcohol compound (b-4) by solvolysis in methanol in the presence of potassium carbonate.
In addition, about the ester compound (c-6), R body and S body were not able to be isolate | separated.
From the above, the determination result of Example 3 was supported.

It is a figure which shows the structure of the neural network (input layer; 60 pieces) used in Example 1. FIG. It is a figure which shows the structure of the neural network (input layer; 17 pieces) used in Example 1. FIG. It is a figure which shows the structure of the neural network (input layer; 8 pieces) used in Example 1. FIG. FIG. 3 is a structural diagram of R-form (R001) and S-form (S058) having the minimum energy of compound (c-1), and a diagram in which both are superimposed.

Claims (16)

  A difference in physicochemical properties between the optical isomer mixtures that affects the separation of the optical isomer mixture by a predetermined separation means is obtained using quantum chemical calculation, and from the calculation result, the optical isomer mixture by the separation means is analyzed. A method for exploring an optical resolution factor, characterized by exploring the physicochemical properties of optical isomers that most affect separation.   The method for searching for an optical resolution factor according to claim 1, wherein the quantum chemical calculation uses a neural network.   The quantum chemical calculation uses a computer program that performs a conformational analysis of the molecular structure, and among the conformers of the optical isomer mixture, a plurality of conformers to be calculated in the next step. A step (1) for calculating and obtaining an optimal configuration and a step (2) for calculating and obtaining a physicochemical difference of each conformer of the optical isomer mixture by a neural network. Or the search method of the optical resolution factor of 2.   The step (1) and / or (2) includes a Web server that transmits / receives WWW information related to a molecular structure to / from a client via a communication network, and a processing server that provides information related to the molecular structure to the Web server. The method for searching for an optical resolution factor according to claim 3, wherein a molecular information providing system is used.   The optical isomer mixture includes an optically active compound (a) that serves as an asymmetric auxiliary group, and a compound (b) having a functional group capable of chemically bonding to the asymmetric carbon atom and the compound (a) in the molecule. The method for searching for an optical resolution factor according to any one of claims 1 to 4, wherein the optical isomer mixture is an optical isomer mixture of the compound (c) formed by chemical bonding with the functional group.   The method for searching for an optical resolution factor according to claim 1, wherein the physicochemical property is affinity for a stationary phase used for chromatography of the optical isomer.   An optical resolution determination method for determining whether or not an optical isomer mixture is optically resolved by a predetermined separation means, which affects the separation by the separation means between optical isomers contained in the mixture. A method for determining the possibility of optical resolution, wherein the difference in physicochemical properties is determined by quantum chemical calculation, and the optical resolution of the optical isomer mixture is determined from the obtained calculation result.   The method for determining the optical resolution possibility according to claim 7, wherein the quantum chemical calculation uses a neural network.   The quantum chemical calculation uses a computer program that performs a conformational analysis of the molecular structure, and among the conformers of the optical isomer mixture, a plurality of conformers to be calculated in the next step. 8. A step (1) for calculating and obtaining an optimum configuration and a step (2) for calculating and obtaining a physicochemical difference of each conformer of the optical isomer mixture by a neural network. Or the determination method of the optical resolution possibility according to 8.   The step (1) and / or (2) includes a Web server that transmits / receives WWW information related to a molecular structure to / from a client via a communication network, and a processing server that provides information related to the molecular structure to the Web server. The method for determining the possibility of optical resolution according to claim 9, wherein a molecular information providing system is used.   The optical isomer mixture includes an optically active compound (a) that serves as an asymmetric auxiliary group, and a compound (b) having a functional group capable of chemically bonding to the asymmetric carbon atom and the compound (a) in the molecule. The method for determining optical resolution according to any one of claims 7 to 10, which is an optical isomer mixture of the compound (c) formed by chemically bonding with an optical isomer mixture through the functional group.   The method for determining optical resolution according to any one of claims 7 to 11, wherein the physicochemical property is affinity for a stationary phase used for chromatography of the optical isomer.   A step (i) of determining the optical resolution of the optical isomer mixture of the compound (c) by a predetermined separation means by the determination method according to any one of claims 7 to 12, and separation conditions by the separation means An optical isomer mixture comprising: (ii) a determining step; and (iii) isolating the optically active form of compound (c) by optically resolving the optical isomer mixture of compound (c) by the separation means. Optical resolution method.   The method for optical resolution of a mixture of optical isomers according to claim 13, wherein the separation means is chromatography, and the step (ii) includes selecting a stationary phase and a mobile phase used for chromatography. In the step (i), n different types (n represents a natural number) of compounds (c _n ) obtained from n different types of optically active compounds (a _n ) and compounds (b), The possibility of optical resolution is determined by the determination method according to claim 7, and the most advantageous compound (c _s ) for optical resolution is selected from _n compounds (c _n ). The method for optical resolution of an optical isomer mixture according to claim 13 or 14.   A step of isolating the optically active form of compound (b) by removing the optically active compound (a) part having an asymmetric auxiliary group from the optically active form of compound (c) isolated in the step (iii). The method for optical resolution of an optical isomer mixture according to claim 13, further comprising:

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